Human Hypothalamus - Basic and Clinical Aspects, Part 2

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CHAPTER TITLE
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Acknowledgements
I would like to express my gratitude for the continuous help and critical remarks of all those who made this work
possible, especially Peter Bakker Afra van den Berg, Ronald Bleys, George Bruyn, Ruud Buijs, Liesbeth Dubelaar,
Frank van Eerdenburg, Tini Eikelboom, Bart Fisser, Eric Fliers, Bas Gabrels, Tony Goldstone, Louis Gooren, Valeri
Goncharuk, Joop van Heerikhuize, Michel Hofman, Witte Hoogendijk, Inge Huitinga, Tatjana Ishunina, Marina
Kahlmann, Dries Kalsbeek, Wouter Kamphorst, Michiel Kooreman, Berry Kremer, Frank Kruijver, Jenneke Kruisbrink,
Gert Jan Lammers, Fred van Leeuwen, Rong-Yu Liu, Paul Lucassen, Gerben van der Meulen, Gerben Meynen, Jan
van de Nes, Elly de Nijs, Willeke van Ockenburg, Sebastiaan Overeem, Maria Panayotacopoulou, Joris van der Post,
Chris Pool, Rivka Ravid, Erik Scherder, Eus van Someren, Henk Stoffels, Elly Tjoa, Suzanne Trottier, Unga Unmehopa,
Paul van der Valk, Wilma Verweij, Ronald Verwer, Jos Wouda, Jiang-Ning Zhou, all other participants of the
Netherlands Brain Bank team, and all staff members, students, and guest workers of the Netherlands Institute for
Brain Research. The persons who kept me from working on this book are too numerous too mention.
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CONTENTS
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List of abbreviations
A
AADC
AC
AD
ACTH
ADHD
AGRP
AIDS
AIP
ALD
ALS
AM
AMPA
AMDLX
ANP
APOE
AT
ATD
AVP
BDNF
BMI
BST
BSTdspm/
BNSTdspm
BSTc
BSTm
CAG
CAH
CART
CCK
CDC
CG
ChAT
CM
CMV
CNS
CRH
CSF
CT
DII
amygdala
aromatic L-amino acid decarboxylase
anterior commissure
Alzheimers disease
corticotropin
attention deficit hyperactivity disorder
agouti-related peptide
acquired immune deficiency syndrome
acute intermittent porphyria
adrenoleukodystrophy
amyotrophic lateral sclerosis
anteromedial subnucleus of the basal nucleus
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
adhesion molecule-like X
atrial natriuretic peptide
apolipoprotein E
angiotensin
1,4,6-androstratriene-3,17-dione (aromatase
inhibitor)
arginine vasopressin
brain-derived neurotropic factor
body mass index
bed nucleus of the stria terminalis
darkly staining posteromedial
component of the bed nucleus of the stria
terminalis
central nucleus of the bed nucleus of the
stria terminalis
medial nucleus of the bed nucleus of the
stria terminalis
DNA sequence that codes for glutamine
repeats. An expanded sequence is found
in Huntingtons disease
congenital adrenal hyperplasia
cocaine- and amphetamine-regulated
transcript
cholecystokinin
center for disease control and prevention
chiasmal gray
choline acetyltransferase
corpora mamillaria
cytomegalovirus
central nervous system
corticotropin-releasing hormone
cerebrospinal fluid
computer tomography
deiodinase type II
DAX-1
DA
DB/DBB
DDAVP
DES
DHEA
DHEAS
DM/DMN/
DMH
DMI
DMV
DNA
DSM-III R/IV
DYN
EAE
ECT
EEG
EM
ER-/
ERT
FAI
FO/Fx
FSH
GA
GABA
GAD
GAP
GFAP
GHRH
GnRH
HCG
Hcrt1-2
HD
H&E
HMPG
5-HIAA
HIOMT
HITF
HIV
HLA
HNS
HPA-axis
dosage-sensitive sex-reversal, adrenal

hypoplasia, congenital, X-chromosome-1
dopamine
diagonal band of Broca
1-desamine-8-D-arginine vasopressin
(= desmopressin)
diethylstilbestrol
dehydroepiandrosterone
dehydroepiandrosterone sulfate
dorsomedial nucleus of the hypothalamus
desmethylimipramine
dorsal motor nucleus of the nervus vagus
deoxyribonucleic acid
diagnostic and statistical manual mental
disorders (American Psychiatric
Association), third revised edition/fourth
edition
dynorphin
experimental allergic encephalomyelitis
electroconvulsive therapy
electroencephalogram
electron microscope
estrogen receptor-/
estrogen replacement therapy
free androgen index
fornix
follicle-stimulating hormone
Golgi apparatus
gamma-aminobutyric acid
glutamic acid decarboxylase
gonadotropin hormone-releasing hormoneassociated peptide
glial fibrillary acidic protein
growth hormone-releasing hormone
gonadotropin-releasing hormone (= LHRH)
human chorionic gonadotropin
hypocretin (orexin) 1-2
Huntingtons disease
hematoxylineosin staining
3-methoxy-4-hydroxyphenylglycol
5-hydroxyindoleacetic acid
hydroxyindole-O-methyltransferase
human intestinal trefoil factor
human immunodeficiency virus
human leukocyte antigen
hypothalamoneurohypophysial system
hypothalamopituitaryadrenal axis
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HVA
5-HT
I
III
ICC
icv
IF
IFN
IGF
IHA
IL-1
INAH1-4
INSP4
KALIG-1
LC
LCA
LH
LHA
LHRH
LPH
LV
LVP
MAO
MAP(A/B)
MCH
MCR1-4
MDMA
ME
MEN
MELAS
MHPG
MHC
MPN
MRI
MS
()MSH
(m)RNA
NA
NADPH
NAPH
NAT
NBB
NBM
N-CAM
NEI
NFT
NGF
NKB
NMDA
NOS
NP
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LIST OF ABBREVIATIONS
homovanillic acid
(= serotonin (5-hydroxytryptamine)
infundibulum
third ventricle
immunocytochemistry
intracerebroventricularly
infundibular nucleus
interferon
insulin-like growth factor
intermediate hypothalamic area
interleukin-1
interstitial nucleus of the anterior
hypothalamus 1-4
inositol-(1,3,4,5)-tetrakisphosphate
Kallmans syndrome interval gene-1
locus ceruleus
leukocyte common antigen
luteinizing hormone
lateral hypothalamic area
luteinizing hormone-releasing hormone
(= gonadotropin-releasing hormone,
GnRH)
lipotropic hormone
lateral ventricle
lysine vasopressin
monoamine oxidase
microtubule-associated protein (A/B)
melanin-concentrating hormone
melanocortin1-4 receptor
3,4-methylenedioxymethamphetamine
(= ecstasy)
median eminence
multiple endocrine neoplasia
mitochondrial encephalopathy, lactic
acidosis and stroke-like episode syndrome
3-methoxy-4-hydroxyphenylglycol
major histocompatibility complex
medial preoptic nucleus
magnetic resonance imaging (fMRI =
functional MRI)
multiple sclerosis
-melanotropin
(messenger) ribonucleic acid
norepinephrine
nicotinamide adenine dinucleotide
nicotinamide adenine dinucleotide, reduced
form
N-acetyl-transferase
Netherlands Brain Bank
nucleus basalis of Meynert
neural cell adhesion molecule
neuropeptide glutamic acid isoleucine
neurofibrillary tangles
nerve growth factor
neurokinin B
N-methyl-D-aspartate
nitric oxide synthase
neuritic plaque
NPAF
NPY-IR
NSM
NST/NTS
NT
NT-3, 4/5
NTI
NTL
OC
ORL1
OT
OVLT
OXT
P
p75
PACAP
PAP
PBN
PC
PCR
PD
PDD
PDYN
PENK
PET
PHM
PNS
POAH
POMC
PSP
PVA
PVN
PWS
REM
RHT
RIA
RT-PCR
SAD
SCN
SDN(-POA)
SHBG
SIADH
SIDS
SN
SNP
SNRPN
SON
SOREMPS
SPECT
SRY
SSRI
SWS
neuropeptide AF
neuropeptide-Y-like immunoreactivity
nucleus septalis medialis
nucleus of the solitary tract
neurotensin
neurotrophin-3, 4/5
nonthyroidal illness
lateral tuberal nucleus/nucleus tuberalis
lateralis
optic chiasm
opioid receptor-like receptor
optic tract
organum vasculosum lamina terminalis
oxytocin
perikarya
low-affinity neurotrophin receptor
pituitary adenylcyclase-activating
polypeptide
peroxidase-anti-peroxidase
parabrachial nucleus
prohormone convertase
polymerase chain reaction
Parkinsons disease
pregna-4,20-diene-3,6-dione
prodynorphin
proenkephalin
positron emission tomography
peptide methionine amine
peripheral nervous system
preoptic anterior hypothalamic area
pro-opiomelanocortin
progressive supranuclear palsy
periventricular area
paraventricular nucleus
PraderWilli syndrome
rapid eye movement
retinohypothalamic tract
radioimmunoassay
real-time polymerase chain reaction
seasonal affective disorder
suprachiasmatic nucleus
sexually dimorphic nucleus (of the preoptic
area) = INAH-1
sex hormone-binding globulin
syndrome of inappropriate secretion
antidiuretic hormone
sudden infant death syndrome
substantia nigra
single nucleotide polymorphism
small nuclear riboprotein-associated
polypeptide
supraoptic nucleus
REM sleep onset periods
single-photon emission computed
tomography
sex-determining region Y
selective serotonin reuptake inhibitor
slow-wave sleep
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LIST OF ABBREVIATIONS
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T3
T4
TBS
TENS
TG
TH
THA
TH-IR
TMN
TR
TRH
triiodothyronine
thyroxine
Tris-buffered saline
transcutaneous electrical nerve stimulation
tuberal gray
tyrosine hydroxylase
tetrahydroaminoacrine
tyrosine hydroxylase-immunoreactive
tuberomamillary nucleus
thyroid hormone receptor
thyrotropin-releasing hormone
Trk A, B, C
TSH
VR1,2,3
VEP
VIP
VLPO
VMN/VMH
VP
tyrosine kinase neurotrophin receptor A,

B or C
thyrotropin
vasopressin receptor 1, 2 or 3
visual evoked potential
vasoactive intestinal polypeptide
ventrolateral preoptic region of the
hypothalamus
ventromedial nucleus
vasopressin
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Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)

The Human Hypothalamus: Basic and Clinical Aspects, Part II
D.F. Swaab, author
2004 Elsevier B.V. All rights reserved
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CHAPTER 17
Vascular supply and vascular disorders
. . . the vital spirit in the blood from the heart is changed

into animal spirit in the rete mirabile . . . (Anderson and
Haymaker, 1974)
from the internal carotid artery, the fetal configuration.

In the majority of cases, the P2 segment obtains its blood
primarily from the basilar artery, the adult configuration.
Multiple anomalies are found in 13% of the circles. The
incidence of all varieties of anomalous vessels is higher
in brains with infarcts than in control cases (Alpers
et al., 1959; Riggs and Rupp, 1963; Battacharji et al.,
1967), indicating that they are a risk factor for
pathological changes. The hypothalamic vessels the
anterior, middle and posterior groups receive their
blood supply both from perforating branches (Figs. 17.1,
17.3, 24.1, 24.2) derived from the circle of Willis and
from stems of cerebral arteries (see Chapter 17.1g; Table
17.1).
The preoptic and anterior parts of the hypothalamus
and the septal area are supplied mainly by the anterior
cerebral and anterior communicating artery. The tuberal
region and the posterior region extending backward to
the rostral part of the mamillary body, together with the
thalamus in its lower anterior quarter, are mainly supplied
by the posterior communicating artery. The posterior
portion of the hypothalamus is supplied with blood by
branches arising from the bifurcation of the basilar, posterior, cerebral and neighboring parts of the posterior
communicating artery. These vessels reach the hypothalamus mainly by way of the posterior perforated
substance and supply mamillary bodies, posterior and
lateral hypothalamic nuclei, and the subthalamus (Figs.
17.1, 17.3).
Venous drainage of the human hypothalamus takes
place via the anterior cerebral vein, the basal vein of
Rosenthal (Fig. 17.1) and the internal cerebral vein
(Fig. 17.3). These channels lead into the great cerebral
vein of Galen (for details, see Haymaker et al., 1969,
Chapter 5).
. . . the central nervous system regulates the activity of the

adenohypophysis by means of a humoral relay through
the hypophysial portal vessels (Green and Harris, 1947)
17.1. Blood supply to the hypothalamus and

pituitary
Arterial blood supply to the human hypothalamus is
derived from terminal branches of the internal carotid and
basilar arteries and from the anastomoses between them,
which form the arterial circle of Willis or circulus arteriosis ceribri (Fig. 17.1). Willis never claimed to be the
first to describe the circle, but he is still honored every
year on St. Martins day, the day he died in 1675
(Wolpert, 1997). In addition, the anastomotic arterial
circuminfundibular plexus and a prechiasmal anastomotic
arteriocapillary plexus can be considered as a source of
spare blood supply to the hypothalamus, should any of
the branches be occluded. There are many variations in
the pattern of the circle of Willis (Fig. 17.2). A normal
configuration of the circle of Willis occurs in less than
50% of subjects. The most frequent anomaly is a filiform
caliber of one of the component vessels in 27% of the
circles, most frequently localized in the posterior communicating arteries. A duplication of vessels is observed in
19%, the anterior communicating artery being the favorite
site for such accessory vessels. In 8% of the circles, a
midline, persistent corpus callosum branch is present. In
15% of cases, the supply to the postcommunicating part
(P2 segment) of the posterior cerebral artery is mainly
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Fig. 17.1. Hypothalamic and related vessels as viewed from the basal aspect of the brain: the circle of Willis. (From Haymaker et al., 1969,
Fig. 5.1 with permission.)
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VASCULAR SUPPLY AND VASCULAR DISORDERS
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Fig. 17.2. Anatomical variations in the circle of Willis. (From Alpers et al., 1959, Figs. 19 with permission.)
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D.F. SWAAB
Fig. 17.3. Arteries (red) of the hypothalamus and adjacent structures as viewed medially. Veins (blue) draining the superior and rostral parts of
the hypothalamus are illustrated. (From Haymaker et al., 1969, Fig. 5.2 with permission.)
(a) Stalk/median eminence region

After describing the origin of the portal vessels in the
median eminence in 1933, Popa and Fielding erroneously
deduced that blood in the portal vessels flowed upwards,
from the pituitary to the hypothalamus. On the basis of
histological observations Wislocki and King, in 1936,

proposed that the blood flow in the portal vessels (see
Chapter 17.1c) was downwards. In 1947 and 1949, using
a combination of india ink perfusion techniques and direct
microscopic observations in the living rat, Green and
Harris subsequently demonstrated that this was indeed
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TABLE 17.1
Arterial supply of the hypothalamus.
Anterior group of arteries
(from internal carotid,
anterior cerebral and
posterior communicating)
Intermediate group of arteries

(from posterior communicating
Posterior group of arteries

(from posterior communicating,
posterior cerebral and basilar)
Periventricular system
Suprachiasmatic nucleus
Medial preoptic area
Anterior area
Supraoptic nucleus
Paraventricular nucleus
Lateral hypothalamic area
Infundibular nucleus
Ventromedial nucleus
Dorsomedial nucleus
Nuclei tuberis laterales
Posterior nucleus
Lateral mamillary nucleus
Medial mamillary nucleus
Supramamillary area
Lateral hypothalamic area
Posterior nucleus
Lateral mamillary nucleus
Medial mamillary nucleus
Supramamillary area
From Haymaker, 1969, table 51, with permission.
rodents. One can, however, distinguish an upper

infundibular stem, located in the suprasellar region, which
contains the portal system, and a lower infundibular stem,
which contains the fibers running to the infundibular
process or neurohypophysis. The pars tuberalis of the
pituitary forms the most rostral boundary of the median
eminence (McKinley and Oldfield, 1990). The median
eminence gets its blood supply from the superior
hypophysial arteries that spring from the internal carotid
artery (Fig. 17.6; Daniel and Prichard, 1975). The portal
system is described in Chapter 17.1).
the case (for historical references, see Meites, 1992;

Raisman, 1997).
The median eminence is separated from the neighboring tuber by the sulcus infundibularis (Fig. 17.4) and
it is continued by the infundibular stem/stalk toward the
neural lobe. Thus the median eminence is made up of
the proximal segment of the neurohypophysis, attached
to the tuber, and this constitutes the walls of the
hypophysial recess (Duvernoy, 1972). The median
eminence is the site of neurosecretion of a number of
releasing and inhibiting hormones that are synthesized in
the hypothalamus and act on the adenohypophysis (see,
e.g. Chapter 11 for the infundibular nucleus and Chapter
8.5 for CRH and vasopressin from the paraventricular
nucleus). The neuropeptides are transported to the anterior pituitary gland by the portal system. On the other
hand, peptides produced by the supraoptic nuclei (SON)
and paraventricular nuclei (PVN), such as vasopressin
and oxytocin, are for the largest part transported to the
most distal part of the neurohypophysis, the infundibular
process, which is also known as the pars nervosa or the
posterior pituitary. At the outer surface of the human
hypothalamus, the median eminence is no longer evident,
since it is incorporated into the upper part of the
infundibular stem. There is also no strict delineation
between an internal and external zone as observed in, e.g.
(b) Pituitary
The pituitary derives its blood supply, directly or indirectly, from two main sources, one above and the other
below the level of the diaphragm sellae, i.e. the superior
and inferior hypophysial arteries, respectively (for review,
see Daniel and Prichard, 1975; Figs. 17.5 and 17.6).
Radiographic microvascular injections showed that the
inferior hypophysial artery is, in most cases, the dominant supply to both the neurohypophysis and the portal
system (Gebarski, 1993). The superior and inferior
hypophysial arteries are both paired vessels and spring
from the internal carotid artery on each side, the inferior
artery arising from the cavernous segment of the internal
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D.F. SWAAB
Fig. 17.4. Floor of the diencephalon in man. 1 = optic chiasm,

2 = posterior side of the median eminence and of the stalk crossed by
the portal vessels. The arrows indicate the sulcus infundibularis. 3 = postinfundibular eminence or posterior tuber, 4 = mamillary bodies, 5 =
optic tracts. (From Duvernoy, 1972, Fig. 24 with permission.)
carotid, and the superior artery having its origin shortly

after the carotid has emerged from the cavernous sinus
and passed through the dura mater, the supraclinoid part.
Both the superior and inferior hypophysial arteries anastomose with their contralateral counterparts. There is also
a substantial anastomotic channel which runs through the
pituitary gland and connects a branch of the superior
hypophysial artery with a branch of the inferior one, i.e.
the artery of the trabecula (Figs. 17.5, 17.6; Daniel and
Prichard, 1975).
(c) Portal system
The primary plexus of the portal system is made up of
two vascular systems that are intricately linked: the
surface network (the rete mirabile of Galenus) and the
deep network. The surface network (or mantel plexus)
covers the surface of the median eminence. From this
network stem numerous short capillary loops that penetrate into the median eminence, where neurosecretory
substances are released into them (Duvernoy, 1972). Cajal
has already described hypothalamic nerve fibers that
terminate on the capillaries of the median eminence, while
Fig. 17.5. Blood supply of the human pituitary gland and hypothalamus
(sagittal sections). The sinusoids of the pars distalis are supplied by
two types of portal vessels: (i) long portal vessels (LPV) draining capillary loops (C) in the upper infundibular stem (i.e. neural tissue of the
stalk); and (ii) short portal vessels (SPV) draining capillary loops in
the lower infundibular stem. Cap, capillary bed; H, hypothalamic
neurons; IHA, inferior hypophysia artery; P, primary capillary bed;
SHA, superior hypophysial artery. For other details see legend to Fig.
17.6. (From Daniel and Prichard, 1975, Fig. 36 with permission.)
Harris and Campbell (1966) have shown that these capillaries are of the specialized fenestrated type also found
in other secretory and absorptive organs. Here, the
bloodbrain barrier is permeable to larger molecules.
The deep network is divided into a long capillary loop
and a huge subependymal capillary network connected
to the rest of the primary portal plexus (Duvernoy,
1972). The deep network is made up of voluminous
twisted capillaries. These capillaries are often situated
transversally under the ependyma, which lines the pars
caudalis tuberis (Fig. 17.7). Those situated near the posterior insertion of the median eminence are drained
exclusively into the portal system. However, most of the
posterior capillary formations are drained both toward
the portal system and towards the lateral hypothalamic
veins (Fig. 17.8). The capillaries near the mamillary
bodies have a blood supply and drainage that are
exclusively in the direction of the hypothalamus and independent of the portal system (Duvernoy, 1972). The main
feature of the deep network is the large number of coiled
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Fig. 17.6ad. Neoprene latex-injected preparations of the human pituitary gland which show some of the main features of the vascular arrangements. (a) The pituitary gland and neighboring structures are viewed from the front. The superior hypophysial artery (SH) is seen springing from
the internal carotid artery (IC) on each side, anastomosing in front of the pituitary stalk (S), and giving off branches to supply a primary capillary bed (not visible here) within the stalk. The long portal vessels which drain this bed and run down the stalk into the pars distalis are better
seen in (b). The artery of the trabecula (AT), seen also in (b), although plunging into the pars distalis, does not deliver blood directly to this lobe,
which has a purely portal venous blood supply. O, ophthalmic artery; OC, optic chiasma. (b) A similar preparation, partially macerated to show
the long portal vessels (LPV) running down the stalk (S) and breaking up into the sinusoids (Si) of the pars distalis. AT, artery of the trabecula.
(c) Sagittal section of a stalk (anterior surface on right) in which the blood vessels have been displayed by a red cell staining method (benzidine).
Note the convoluted capillary loops (C), which are typical of the primary capillary bed in the stalk, draining into a long portal vessel (LPV). One
of these capillary complexes is elongated into a spike (Sp) such as the one seen in (d). (d) Neoprene cast of a long spike of convoluted capillaries (C) taken from an injected stalk (all tissue has been macerated). The afferent artery (A) to this capillary complex, and the long portal vessel
(LPV) into which it drains, are both seen. (From Daniel and Prichard, 1975, Fig. 18 with permission.)
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Fig. 17.7. Vascularization of the floor of the diencephalon in human. cho, optic chiasm; bo, optic tracts; pc, section of the mesencephalon; cm,
mamillary bodies; t, hypophysial stalk; si, sulcus infundibularis. A dotted line surrounds the place occupied by the postinfundibular eminence (PIE).
Only the deep network is shown in this drawing. 1 and 19, arterioles which supply the PIE; 2, deep network exclusively drained by tuberal veins
(39); 4 and 49, deep capillary network with mixed drainage via lateral tuberal veins and via long posterior portal vessels (5); 59, branch of a
portal vessel draining the surface network; this network is not shown in this drawing; 6, deep network exclusively drained toward the hypophysis
by portal vessels (5); 7, branch of the superior hypophysial arteries which bend over and reach the deep network of the median emincence
(8); this network is drained by deep portal vessels (9). (From Duvernoy, 1972, Fig. 25 with permission.)
capillary loops of characteristic form and varying degree

of complexity which are seen in the neural tissue of the
upper infundibular stem (Fig. 17.8). Fed by terminal
branches of the superior hypophysial artery, these capillary loops form a 12 mm long and 50100 m wide
corkscrew of capillaries, called gomitoli by Fumagalli
(1942; for reference, see Daniel and Prichard, 1975), and
they form part of a first capillary bed in a portal system
of circulation.
Apart from a few vessels near the junction of the stalk
with the hypothalamus, the loops drain through long,
straight vessels of the venous type, which run down the
stalk into the anterior pituitary and empty there into a

second capillary bed. These straight efferent channels are
the long portal vessels of the hypophysial portal system,
which provide the pars distalis with by far the greater part
of its exclusively portal blood supply, serving its anterior
and lateral regions. The majority of the long portal vessels
are found on the anterior and lateral aspects of the stalk
within the superficial sheath of the pars tuberalis, but some
lie at a deeper level and others on the posterior surface
of the stalk, even where there are no epithelial cells of
the pars tuberalis. At the upper extremity of the stalk, a
few of the capillary loops drain upwards into veins in the
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Fig. 17.8a, b. A median sagittal section of the floor of the third ventricle. The following elements are shown (from left to right): OCH, optic
chiasm; ME, median eminence; IR, infundibular recess; S, stalk; PIE, postinfundibular eminence (posterior tuber) separated from the median
eminence by the sulcus infundibularis (SI); MB, mamillary body; 3eV, third ventricle. Vascular tuberohypophysial connections: (a) Anterolateral
connections. 1, capillary tufts which belong to the deep network of the primary plexus and which are supplied by the tuberal arterioles (downward-pointing arrow). These tufts have some veinules which join the tuberal veins (upward-pointing arrow); 2, portal vessels; 3, surface network
and its drainage. (b) Posterior connections. 4, superficial network lining the PIE. It continues toward the superficial network of the primary plexus
(5); 6, portal vessel; 7, drainage of the surface network by a tuberal vein; 8, deep network which is exclusively drained by tuberal veins (arrows);
9, deep network with a mixed drainage toward the hypophysis (arrow). (From Duvernoy, 1972, Fig. 23 with permission.)
tuber cinereum, but apart from this there is no outflow of

blood from the capillary bed of the stalk into the systemic
venous circulation (Daniel and Prichard, 1975).
In the lower infundibular stem, i.e. where the hypothalamo-neurohypophysial tract runs down the stalk and
bends sharply backwards to approach the infundibular
process, the vascular pattern is also characteristic (Fig.
17.8). There are many short, parallel vessels running into
the tissue from below and in front, and ending in coiled
capillary loops similar to those of the pituitary stalk. These

capillary loops can receive their blood supply from either
the inferior or the superior hypophysial arteries, as their
afferent vessels spring from an artery deep within the
gland which is continuous at one end with a branch of
the inferior or the superior hypophysial artery and at the
other with a branch of the superior hypophysial artery,
the artery of the trabecula. The efferent limbs of small
groups of these capillary loops join together to form short
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portal vessels that open into the sinusoids of the adjacent

part of the pars distalis. Apart from their smaller size,
these short portal vessels are similar to the long portal
vessels. There is no drainage from the lower infundibular
stem into systemic veins.
There are also connections between the vessels of the
portal plexus and those of the posterior tuber (Figs.
17.417.8). In the posterior tuber there is a vascular
formation whose pattern differs from that of the other
hypothalamic vessels. The meshes of the surface network
in this area are generally smaller than those of the more
rostral mantel plexus. From this network stem numerous
short capillary loops that penetrate the hypothalamus near
the infundibular nuclei. In this respect the conspicuous
neurofibrillary pathology, characterized by terminal-like
processes contacting the neurohemal vasculature of the
infundibular nucleus, is of interest (Chapter 11g). This
neurofibrillary degeneration is largely restricted to males
over the age of 60 years and seems to be located in the
terminals of neurosecretory neurons, whose chemical
nature still has to be established (Schultz et al., 1996,
1997a, b, c; see also Chapters 11 and 28.1).
(d) Infundibular process
The infundibular process or posterior pituitary has the
conventional arteryvein pattern of circulation. Its abundant network of capillaries, which are much smaller in
calibre than the sinusoids of the pars distalis, is fed by
offshoots from branches of the inferior hypophysial artery
which encircle the lobe. The drainage of this capillary
bed is through veins which empty into one of the
surrounding venous sinuses (Daniel and Prichard, 1975).
The neurovascular zone behind the tuber cinereum
extends almost to the mamillary bodies and it often
contains islands of pars tuberalis glandular cells, but this
is by no means a constant finding. The zone mainly
consists of blood vessels surrounded by connective tissue
sheets in which smooth muscle cells, collagen and reticular fibers may be recognized, and by perivascular
plexuses of nerve fibers. The contralateral connections
between the tuberal vessels and the primary portal plexus
are even more numerous in humans than in other
mammals. The descending connections, by far the more
numerous, are formed of tuberal arterioles that supply the
capillary tufts of the deep network. The very rare small
veins that form the ascending connections merge into
superficial retrochiasmatic veins (Fig. 17.8) (Duvernoy,
1972).
(e) Artery of the trabecula

A macroscopic view of the pituitary gland would suggest
that the artery of the trabecula (the loral artery), a branch
of the superior hypophysial artery that plunges into the
pars distalis from above (Fig. 17.6), carries arterial blood
to this lobe. However, dissection of injected tissues has
shown that the artery of the trabecula does not break up
into sinusoids; it merely passes through the pars distalis.
In a core of fibrous tissue, the trabecula, on its way to
supply capillary loops in the lower infundibular stem,
anastomoses with a substantial branch of the inferior
hypophysial artery that comes up to join it from below
(Fig. 17.6). Usually the artery of the trabecula gives off
one branch which runs toward the stalk near the upper
surface of the pars distalis to supply some of the capillary loops in the lower part of the stalk. The blood
circulating through the sinusoids of the pars distalis
thus seems to be solely portal venous blood. However,
in some instances a very short arterial twig, either from
the artery of the trabecula or from the dura mater
surrounding the gland, may penetrate among the immediately adjacent epithelial cells. The blood supplied
by these twigs is confined to very small areas and only
reaches the sinusoids immediately surrounding them
(Daniel and Prichard, 1975).
(f) Vascular bed of the pars distalis
The vascular bed of the pars distalis consists of a dense
network of freely anastomosing vessels, interspersed
amongst the parenchymal cells. These sinusoids, which
are larger than capillaries, receive no arterial blood, but
are fed solely by the long or the short portal vessels which
bring to them blood which has already passed through a
primary capillary bed in the infundibular stem, where the
hypothalamic releasing and inhibiting hormones are transmitted into the blood stream (Daniel and Prichard, 1975).
Indeed, magnetic resonance imaging (MRI) studies have
shown contrast material flowing from the median
eminence to the adenohypophysis in vivo in humans
(Gebarski, 1993). In contrast, in vivo collection of blood
from the pituitary stalk using transphenoidal microsurgery
again suggested the possibility of retrograde blood flow
from the pituitary to the hypothalamus. Using microsuction and hormone assays of LH, FSH, prolactin, growth
hormone, TSH and ACTH immediately after pituitary
tumor removal showed 50600 times higher levels in
pituitary stalk blood than in peripheral blood. Apart from
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retrograde blood flow from the pituitary, the authors

think that a hypothalamic secretion of these hormones
may cause these high levels. It should be noted, though,
that the aspiration technique used in that study might
have interfered with the normal direction of the
blood flow, and that aspiration took place after tumor
resection, which might also have disturbed the normal
flow.
The studies of Daniel and Prichard (1975) have shown
that the two groups of portal vessels, long and short,
each have their own territories of distribution in the
pars distalis; the long portal vessels supply the bulk of
the lobe, the short portal vessels supplying only the
region adjacent to the lower infundibular stem and
the infundibular process. This observation was originally
derived from a study of injected preparations but was
subsequently confirmed by the distribution of necrotic
and living areas found in patients subjected to pituitary
stalk section, an operation in which the long portal vessels
are severed, but the short portal vessels, together with
their afferent supply, remain intact. Having passed
through the sinusoids of the pars distalis, the blood is
collected by small venules at the periphery of the lobe
and finally empties into one of the venous sinuses that
surround the pituitary gland (Daniel and Prichard, 1975).
13
1960). The precommunicating part of the anterior cerebral

artery supplies the nucleus basalis of Meynert. It was
hypothesized that the decrease in perivascular nerve
density in this segment in Alzheimers disease may be
related to the decreased neuronal metabolic activity in
this region (Bleys and Cowen, 2001). Isolated hypothalamic infarction is an uncommon event, due to the rich
vascular supply of this region. Anteromedial arteries arise
from the anterior cerebral artery and supply the anterior
hypothalamus. Posteromedial hypothalamic perforating
arteries arise from the proximal portion of the posterior
cerebral artery at the bifurcation of the basilar artery and
supply the posterior hypothalamus. Short hypothalamic
arteries branch off from the posterior communicating
artery. In the case of fetal configuration of the posterior
bifurcation of the posterior communicating artery, which
occurs in 15% to 30% of all individuals, the blood supply
to the hypothalamus can arise solely from the carotid
system and may thus be more liable to embolic infarction
(Crompton, 1963; Rudelli and Deck, 1979; Austin and
Lessell, 1991).
(h) Optic chiasm
The arterial supply of the human optic chiasm comes
from a superior and inferior group of branches of the
circle of Willis. The superior group of vessels is derived
from the two anterior cerebral arteries and occasionally
from the anterior communicating artery above the optic
pathways. The inferior group is derived from the basilar,
the posterior communicating, the posterior cerebral and
the internal carotid arteries (Figs. 17.1, 17.9). The superior group of arteries supplies all optic nerves and tracts,
but only the lateral portions of the optic chiasm. The
decussating fibers in the central chiasm receive their arterial supply solely from the inferior group. In addition,
the inferior group supplies the optic nerves and tracts.
During pituitary tumor surgery, the inferior vessels were
often distorted, suggesting that the bitemporal hemianopsia caused by pituitary tumors can be the result of
ischemia by vascular compression rather than neural
compression (Dawson, 1958).
(g) Hypothalamus
The vascular supply of the anterior hypothalamus takes
place by means of fine arterial branches that arise from
the internal carotid artery, the anterior and posterior
communicating arteries, and the proximal portion of the
anterior cerebral artery (Table 17.1). One to three perforating arteries arise from the anterior communicating
artery and penetrate the floor of the third ventricle through
the optic tracts and anterior perforated substance (Figs.
17.1, 17.3; Crompton, 1963; De Divitiis et al., 2002).
Injection of the anterior cerebral artery has been
performed up to the point of the anterior communicating
artery, which includes the recurrent artery of Heubner
that arises just proximal to the anterior communicating
artery, courses backwards and enters the brain in the
region of the anterior perforated area. The anterior
hypothalamic nuclei, including the preoptic areas, the
paraventricular and supraoptic areas up to the region of
the infundibulum, the ventromedial and, to a lesser extent,
the dorsomedial areas, were constantly injected. The hypothalamic region thus appeared to be irrigated by a few
branches from the artery of Heubner (Ostrowski et al.,
(i) Lamina terminalis

The lamina terminalis (see Chapter 30.5b for details on
its vascularization), which covers the suprachiasmal
extension of the third ventricle, separates the lateral
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Fig. 17.9. The visual pathways and their arterial supply. It is apparent that the visual pathways pass through the circle of Willis, and the arterical
supply can be divided into a superior and an inferior group. The superior group of vessels is derived from the anterior cerebral arteries (ACA)
and spares the central chiasm. The inferior group of vessels is derived from the internal carotid artery (ICA), the posterior cerebral artery (PCA)
and the posterior communicating artery. The central chiasm containing the decussating fibers derives an arterial blood supply only from the
inferior group of vessels. (Fig. 2 from Bergland and Bronson, 1969 with permission.)
groups of arteries that descend from the anterior cerebral

arteries to the lateral portion of the chiasm. Indeed,
the lamina terminalis and underlying recess preclude
the superior group of vessels from directly contribut-
ing to the arterial supply of the central portion of

the chiasm. A surgical approach fenestrating the
lamina terminalis can be virtually bloodless (Katayama
et al., 1994; Chapter 17.2d) and is frequently
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used for lesions that occur within the anterior third

ventricle or invade or compress the walls of the chamber
(De Divitiis et al., 2002).
15
crucial role in the development of intracranial arterial

spasm that is most marked in the anterior part of the
circle of Willis is supported by a number of observations. If vasospasm develops, such an autonomic effect
may occur preferentially after the rupture of aneurysms
in locations adjacent to the hypothalamus that involve
vessels that supply the hypothalamus. There is also postmortem and postoperative evidence for such a mechanism.
The ischemic lesions may be not only ipsilateral to the
lesion, but also bilateral. Autonomic dysfunction or a
hypothalamic basis are also apparent from ECG changes
following the rupture of an aneurysm. Various pathogenetic mechanisms that cause the hypothalamic injury
and subsequently intracranial arterial spasm have been
proposed (Wilkins, 1975). There is a marked preponderance of microhemorrhages in the SON, and they are also
more severe than the microhemorrhages that occur in the
PVN. This may be due to the location of the SON close
to the pia. The highly vascularized nature of the SON
and PVN seems to make them more prone to microhemorrhages than the other nuclei of the hypothalamus.
Hypothalamic lesions generally occur together with
lesions in the cortex and basal ganglia (Crompton, 1963;
Neil-Dwyer et al., 1994).
17.2. Vascular lesions of the hypothalamus

(a) Subarachnoidal aneurysm
The hypothalamus is occasionally damaged by ruptured
subarachnoidal aneurysms of the circle of Willis (for
review, see Crompton, 1963). A number of aneurysms,
such as those arising from the bifurcation of the internal
carotid artery, may become buried in the anterior hypothalamus. Others, such as those arising from the anterior
or posterior communicating artery, may bleed directly on
the fine arterial branches that arise from the circle of
Willis and in this way supply the hypothalamus.
Crompton (1963) has reported on a consecutive series of
106 autopsies on patients dying after the rupture of berry
aneurysms, 61% of whom were found to have hypothalamic lesions. He confined his studies mainly to the
anterior part of the hypothalamus, where the majority of
lesions were found. The highest incidence of hypothalamic lesions was found in the case of aneurysms at the
anterior or posterior communicating arteries. Although
basilar artery aneurysms characteristically damage the
mamillary bodies, they may produce lesions much further
toward the front of the hypothalamus. Saccular aneurysms
may act like pituitary adenomas and cause irreversible
hypopituitarism. Such aneurysms have been described as
complications of yttrium-90 implantation for pituitary
adenomas (Horvath et al., 1997).
The hypothalamic lesions caused by ruptured
aneurysms were usually ipsilateral to the ruptured
aneurysm, or bilateral, especially with aneurysms situated
in the midline. The majority of cases involved ischemic
lesions. Microhemorrhages were not as common, and
massive hemorrhages involved the hypothalamus in only
a small number of instances. Microhemorrhages depend
to a large degree on the close proximity of the bleeding
aneurysm, whereas ischemic lesions may, in addition,
depend on vascular hypotension and arterial vasoconstriction or spasm, which may occur contralateral to the
aneurysm (Crompton, 1963). Acquired ischemic deficits
account for about 30% of the early complications of a
subarachnoidal hemorrhage (Neil-Dwyer et al., 1994).
The hypothesis that hypothalamic injury due to subarachnoidal hemorrhage or craniocerebral trauma plays a
(b) Infarction and hemorrhage

The most common lesion in the infundibulum is an infarction, taking the form of small areas of necrosis, usually
in the midline of the tuber cinereum or upper infundibular
stem. These infarcts are characterized by a pooling of
neurosecretory material around their periphery and by the
presence of adjacent axonal swellings. Occlusion of the
proximal part of the anterior cerebral artery due to occlusive arteriosclerosis may cause emotional changes,
including weakness, anxiety and poor cognitive skills and
personality disorders (Ostrowski et al., 1960; Webster et
al., 1960). Ischemic lesions may be at least part of the
basis of the neuronal damage found in the nucleus basalis
of Meynert and the reduced choline acetyltransferase
activity in the cerebral cortex observed after fatal head
injury (Murdoch et al., 2002).
Horners syndrome has been reported due to an ipsilateral posterior hypothalamic infarction that occurred in
the absence of other signs of hypothalamic dysfunction.
Symptoms of extension of the infarct into the posterior
limb of the internal capsule (i.e. contralateral faciobrachial
weakness and dysarthria) were present. Occlusion of a
hypothalamic branch of the posterior communicating
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artery was the likeliest cause of the infarction. Horners

syndrome can result from an interruption, at any point,
of the sympathetic pathway from the hypothalamus to the
orbit. Hypothalamic Horners syndromes are most often
caused by diencephalic tumors and hemorrhages, and least
often by infarction (Austin and Lessell, 1991).
In addition, a case of a highly selective anterior
hypothalamic infarction has been described as a result of
avulsion of part of the optic chiasm, together with the
anterior perforating arteries passing through it. Following
the assault, symptoms such as altered thermoregulation,
alternating diabetes insipidus and inappropriate antidiuretic hormone secretion, altered patterns of sleep and
arousal, and changing cardiac arrhythmias were found
(Rudelli and Deck, 1979). In a child in which perinatal
hypoxia was followed by hypothalamic hemorrhage, West
syndrome with gelastic seizures was found (Kito et al.,
2001; Chapter 26.2). In the pituitary stalk, linear and
petechial hemorrhages or later scarring may be seen.
Hemorrhages may also occur in the ventromedial nuclei
and corpora mamillaria (Treip, 1970b). Trauma may cause
posterior lobe hemorrhage, ischemia in the anterior
hypothalamus and destruction or avulsion of the pituitary
stalk, followed by hypopituitarism. Posttraumatic diabetes
insipidus is generally transient (Horvath et al., 1997).
Subcortical infarctions may also impact the blood
supply of the hypothalamus and interrupt the function of
the suprachiasmatic nucleus, as indicated by the greater
daytime sleepiness of these stroke patients (Bliwise et al.,
2002).
Subependymal hemorrhages around the third ventricle
are a common occurrence and may also impinge upon
the PVN. In 90% of the cases, subarachnoid hemorrhage
is accompanied by ischemic lesions of the hypothalamus:
small perivascular hemorrhages and edema of the
surrounding tissue were found in the periventricular
region, including the PVN and SON. It is hypothesized
that prolonged sympathetic activity in these patients
would cause vasoconstriction, and thus lesions in the
hypothalamus and myocard (Doshi and Neil-Dwyer,
1977). Vasopressin plasma levels have been reported to
be increased in patients with subarachnoid hemorrhage
(Mather et al., 1981), but these findings were not
confirmed by others (Franceschini et al., 2001). For
hemorrhages in the neurohypophysis, see Chapter 22.1.
Hemorrhagic lesions in the subthalamic nucleus may
cause hemiballismus, usually at the contralateral side of
the body, characterized by violent, involuntary, wild
flinging movements (Parent and Hazrati, 1995).
Multiple endocrine abnormalities have been reported

in stroke patients, namely: absence of a sleep-related
increase in growth hormone plasma levels, elevated
prolactin nocturnal release, and blunted serotonin-mediated prolactin release, low basal thyroid-stimulating
hormone levels, impaired thyrotropin-releasing hormonestimulated secretion of thyroid-stimulating hormone, and
increase in beta-endorphin cerebrospinal fluid levels.
Abnormalities of the pituitary-gonadal axis, in particular
high LH serum levels and low serum testosterone levels,
have also been reported. Furthermore, disruption of some
biological rhythms, namely of beta-endorphin and melatonin, have been described. In the past few years, attention
has also been devoted to the clinical significance of these
endocrine abnormalities, particularly with regard to the
possibility that they may worsen the extension of the
ischemic area and outcome of stroke.
In unprecedented ischemic cerebral infarction patients,
mean 24-hour plasma vasopressin levels were higher than
in control subjects, and correlated with the severity score
of the neurological deficit and with the mean size of the
lesion. The increase occurred independently of osmotic
and/or baroreceptorial mechanisms, which are known to
be the major stimuli for vasopressin secretion. Various
mechanisms may account for increased vasopressin secretion during stroke. The heightened intracranial pressure
may contort the pituitary stalk and interfere with the regulation of vasopressin release from the posterior pituitary.
Alternatively, a release of neuromodulators from the periinfarct lesion into the third ventricle and affecting the
cells within the magnocellular nuclei may be suggested.
It may also be so that in the course of cerebral ischemia
an increased serotoninergic and/or a decreased dopaminergic tone may induce an enhanced vasopressin release
from the hypothalamus (Franceschini et al., 2001).
(c) Systemic atherosclerosis
Whether or not accompanied by arterial hypertension,
systemic atherosclerosis is accompanied by degenerative
and chronic ischemic neural alterations, which are most
marked in the ventromedial nucleus. Ischemic-atrophic
lesions, sometimes with nuclear cytoplasmatic vacuolation, and neuronal hyperchromasia with or without glial
satellitosis were observed. The SON and PVN tended to
show degeneration as well as an intense accumulation of
lipofuscin in the cytoplasm. In addition, hyperplastic
astrocytes, denoting glial reaction, were found around
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small vessels, as an expression of chronic tissular anoxia.

The reactive protoplasmic astrocytes appeared more in
the subependymal paraventricular region. In all cases of
atherosclerosis, vascular alterations occurred, i.e. thickening of the intima, and hyalinosis and sclerosis of the
small vessels (Kelemen and Becus, 1977). The deep
perivascular nerves of the basal arteries of the circle of
Willis show changes with aging and Alzheimers disease.
The precommunicating part of the anterior cerebral artery
is involved in the vascular supply of the substantia innominata (Bleys et al., 1996) and suggests a relationship
between vascular changes and the decreased neuronal
activity in the nucleus basalis of Meynert (Salehi et al.,
1994, 1998).
17
(e) Radiation therapy

Radiation therapy may lead to delayed vascular complications such as obliteratur vasculopathy. Radiationinduced microscopic vascular anomalies or telangiectasia
may cause hemorrhages. In addition, intracranial fusiform
aneurysms may be formed. In chronic occlusive large
vessel disease of arteries of the circle of Willis that occurs
as a result of radiation therapy, an abnormal network
(moyamoya) may develop at the base of the brain
(Sinsawaiwong and Phanthumchinda, 1997). Moyamoya
disease may also develop following a basal meningitis
(Vrs et al., 1997), but the etiology of this vessel abnormality is unknown in most cases. The peak incidence
occurs in the first decade and there is a female predominance. In children, moyamoya disease presents most
commonly with transient ischemic attacks, and these
children may have seizures. It begins with stenosis of the
carotid fork and progresses to complete occlusion of the
middle and anterior cerebral arteries with the formation
of a vascular network of collaterals. The children may
present with decreased growth velocity, growth hormone
deficiency and hypothyroidism (Mootha et al., 1999).
Moyamoya vessels may also have a prenatally determined
origin, and some data point to a genetic basis of
moyamoya disease (Vrs et al., 1997). Rupture of the
overgrown perforating arteries that function as collaterals
may be the main cause of single or repeated cerebral
hemorrhage in moyamoya disease. The formation of a
collateral network is accompanied by aneurysms, arteriovenous malformations and ectasia or fenestration of the
cerebral arteries.
(d) Cavernous malformation

Cavernous malformation can occur at any location in the
central nervous system, including the pineal, chiasmatic
and optic nerve regions. Cavernous malformations
involving the third ventricle are rare, but several cases
have been reported. The clinical manifestations may
be visual field defects, endocrine function deficits and
hydrocephalus in those with malformation of the foramen
of Monro region, and deficits of short-term memory in
those with malformations of the lateral wall or floor of
the third ventricle. Malformations of the third ventricle,
unlike malformations in other brain regions, frequently
show rapid growth and mass effects. Cavernous malformations are known to increase in size during pregnancy
and to decrease after delivery. Rapid growth of cavernous
malformations is attributable to repeated intralesional
hemorrhages, but extra lesional hemorrhages are also not
uncommon. The treatment of this particular group of
malformations will thus have to consist of a more
aggressive approach. The risk of regrowth and extralesional hemorrhage appear to be reduced by complete
excision by means of the translamina-terminalis approach
for the suprachiasmatic region, the transventricular
or transcallosal interfornical approach for the foramen
of Monro region and the transvelum interpositum
approach for the lateral wall of the third ventricle
(Katayama et al., 1994). Later a successful zygomatic
approach using a Neuro-navigator was reported for the
treatment of a deep-seated cavernous angioma.
(Kurokawa et al., 2001). For a case of cerebrovascular
cavernous malformation in the mamillary bodies, see
Chapter 16.d.
17.3. Choroid plexus of the third ventricle

Choroid plexus tissue is found in the roof of the third
ventricle. It is made up of elements from the
leptomeninges and the ependyma. Highly vascularized
tela choroidea evaginates and acquires an epithelium to
form the choroid plexus. The choroid plexus is involved
in the production of cerebrospinal fluid (CSF), largely
due to the secretion of hypertonic saline, which is then
brought to isotonicity by diffusion of water through the
ependymal cells. The water channels aquaporin-1 and -4
are expressed in the choroid plexus, where they may play
a role in CSF formation (Venero et al., 2001). Moreover,
microvilli of the choroid plexus may be involved in readsorption. The choroid plexus is a finely regulated selective
interface for the delivery of nutrients, hormones and
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trophic factors, as well as for the transduction of peripheral signals, an enzymatic protective barrier, a clearance
site for deleterious compounds and catabolites, and an
immunologically active interface (for review, see
Strazielle et al., 2000). The capillaries of this tissue have
larger diameters (1020 m) than regular capillaries and
have been designated sinusoids. The vascular endothelium is fenestrated (McKinley and Oldfield, 1990). The
CSF-generating choroid plexus has many V1 binding sites
for vasopressin. Vasopressin decreases the CSF formation rate and elicits structural changes in the rat choroid
plexus (Johanson et al., 1999). In the choroid plexus of
the lateral ventricle of Alzheimer patients, we found an
increase in vasopressin-binding sites (Korting et al.,
1996). The functional meaning of this alteration is not
clear at present. The choroid plexus of the third ventricle
has not yet been studied.
(a) Colloid cysts
Colloid cysts of the third ventricle (Fig. 17.10) are slowgrowing, benign tumors that typically have an onset
between 20 and 55 years of age. The incidence is approximately 1:1000, which makes it the most common tumor
of the third ventricle. Occasionally colloid cysts can be
identified at autopsy, as was the case with Harvey Cushing
himself (Akins et al., 1996). Colloid cysts of the third
ventricle are sometimes more conspicuous on CT than
on MRI. There is a controversy about the origin of these
cysts. It has been suggested to be a remnant of the paraphysis, which is situated at the rostral end of the
diencephalic roof and which disappears completely prior
to birth. However, this theory was challenged by Arins
Kappers (1955). In his opinion, paraphyseal cystic tumors
developing from the choroidal fold between the foramina
of Monro in the third ventricle in the adult human brain
are, for the most part, not of paraphyseal origin but arise
from detached and degenerated embryonic diencephalic
vesicular recesses included in the choroidal fold. An endodermal nature of the cysts has also been proposed.
Another possible origin could be from the diencephalic
ependymal pouches or choroid plexus. However,
immunocytochemical and ultrastructural evidence argues
against a simple choroid plexus or ependymal origin
(Akins et al., 1996). Colloid cysts usually range from a
few millimeters to 9 cm in size. They are composed of
fibrous connective tissue wall lined by squamous,
columnar epithelial cells enclosing a homogenous gelatinous material of cellular debris and eosinophilic
substance. By a narrow pedicle or broad base, the cysts

are attached to the choroid plexus at the superior anterior roof of the third ventricle, immediately posterior to
the foramina of Monro (Gkalp et al., 1996; Hwang et
al., 1996; Fig. 17.10). The cyst wall may occasionally be
calcified (Yceer et al., 1996). The symptoms are generally attributed to acute hydrocephalus. Head positional
changes can usually alleviate the symptoms, but a case
has been described of colloid cyst rupture while disco
dancing (Akins et al., 1996). The classic symptoms
consist of intermittent paroxysmal headaches with nausea,
papilledema and vomiting. Transient diplopia, blurry
vision, dizziness, weakness and paresthesia of the extremities, gait disturbances, fever, drop attacks, loss of
consciousness, dementia, cognitive state changes and
unexpected sudden death have also been reported. The
colloid cyst may apply direct pressure on the autonomic
centers of the hypothalamus. In the absence of hydrocephalus, patients with colloid cysts may manifest
disturbances of memory, emotion and personality and
even psychosis, possibly due to compression of the
hypothalamus. Colloid cysts have been approached neurosurgically by different routes. The morbidity and mortality
rates, however, are considerable. Ventricular shunting has
been proposed, but this does not eliminate the cyst. In
addition, CT-guided stereotaxic aspiration has been used
successfully in some patients. Recurrent cysts following
previous aspiration procedures have been reported
(Lobosky et al., 1984; Nitta and Symon, 1985; Mathiesen
et al., 1993; 1997; Lewis et al., 1994; Cabbell and Ross,
1996; Filkins et al., 1996; Gkalp et al., 1996; Hwang et
al., 1996; Carson et al., 1997; Ferrera et al., 1997; Young
and Silberstein, 1997). A few cases of familial colloid
cysts of the third ventricle have been described. These
rare cases suggest that genetic factors may play a role
in the pathogenesis of these cysts. Consistent with the
idea that colloid cysts are developmental abnormalities
is the fact that they are sometimes associated with
a variety of congenital defects (Akins et al., 1996;
Vandertop, 1996).
(b) Xanthogranuloma
Xanthogranuloma of the third ventricle is considered to
be a degenerated colloid cyst (for a xanthogranulomatous
change of a craniopharyngioma, see Chapter 19.5c).
The xanthogranulamatous changes occur following
hemorrhage and macrophagic reaction. The wall shows
aggregations of pale foaming cells, hemosiderin-laden
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Fig. 17.10. Colloid cyst of the third ventricle. Sagittal T-weighted (TR 500 ms; TE 15 ms, flip angle 90) (a) and coronal T1-weighted (TR 600
ms; TE 15 ms) (b) images show that the lesion is diffusely hyperintense. (From Gkalp et al., 1996, Fig. 1 with permission.)
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macrophages, lymphoplasmatic chronic inflammatory

infiltrate, cholesterol clefts and foreign body-type giant
cells (Kudesia et al., 1996). A case has been reported of
xanthogranuloma with massive hematoma in the third
ventricle. The 35-year-old woman had a history of 1
month of progressively deteriorating consciousness. The
mass in the third ventricle that produced obstructive
hydrocephalus was successfully removed (Tomita et al.,
1996).
(c) Choroid plexus papilloma
Choroid plexus papillomas are more common in children
than in adults, and the children usually present with signs
and symptoms of increased cranial pressure due to
obstructive hydrocephalus. Macrocranium and sunset eyes
are found, while vomiting or developmental delay are
especially seen in children over 2 years of age. A shunting
procedure is frequently required. Choroid plexus papilloma is generally a histologically benign and slowly
growing tumor, although rapid growth has been described.
They often extend into the lateral ventricle through the

foramen of Monro. In a 2-year-old boy, episodic rightward anterolateral head tilt and large-amplitude positional
anteroposterior head-bobbing reminiscent of the bobblehead doo syndrome has been described, which was due
to a cystic choroid plexus papilloma that had arisen within
the left lateral ventricle but slipped into the third ventricle
through the foramen of Monro. Other clinical features
that have been described with the third ventricle papillomas include autonomic diencephalic seizures of
Penfields type, endocrine disturbances and menstrual
irregularities, obesity, precocious puberty, diabetes
insipidus, behavioral problems and psychosis (see Chapter
27.1). In one case the choroid plexus papilloma was not
attached to the choroid plexus but to the brain parenchyma
at the surface of the posterior commissure (Fortuna et al.,
1979; Jooma and Grant, 1983; Schijman et al., 1990;
Pollack et al., 1995; Shuto et al., 1995; Carson et al.,
1997; Costa et al., 1997a; Nakano et al., 1997). For third
ventricle chordoid glioma, see Chapter 19.10.
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CHAPTER 18
Disorders of development and growth
syndrome (Christensen et al., 2000), with amphalocele,

diaphragmic hernia and kidney anomalies (Mazzitelli et
al., 2002).
By means of a model of four separate initiation sites
for neural tube fusion, based on observations in the mouse,
neural tube defects have been explained by failure of
fusion of one of the closures or their contiguous neuropores. According to this model, anencephaly results from
failure of closure 2 for meroacranium and closures 2 and
4 for holoacranium. Spina bifida cystica is the result of
the failure of the rostral and/or caudal closure 1 fusion.
Craniorachischisis results from failure of closures 2, 4 and
1 (Van Allen et al., 1993). Closure 3 nonfusion is rare,
presenting as a midfacial cleft extending from the upper
lip area (stomodeum) through the face (facioschisis)
and frontal bones, with resulting anencephaly (faciocranioschisis) (Van Allen et al., 1993; Urioste and Rosa,
1998). Frontal and parietal cephaloceles occur at the
sites of the junctions of cranial closures 32 and 24 (the
prosencephalic and mesencephalic neuropores). Occipital
cephaloceles result from incomplete membrane fusion of
closure 4. In humans, the most caudal neural tube was
presumed to have a 5th closure site involving L2S2.
Closure below S2 is by secondary neurulation (Van Allen
et al., 1993). Closure sites were presumed to be controlled
by separate genes expressed during embryogenesis, and
variations in rate and location of closures would make
embryos more susceptible to environmental and other
factors. Genetic variations of neural tube closure sites
occur in mice and are also evident in humans (Van Allen
et al., 1993; Zlotogora, 1995), e.g. familial neural tube
defects with Sikh heritage (proposed deficit closure 4
and rostral 1), MeckelGruber syndrome (closure 4) and
WalkerWarburg syndrome (24 neuropore, closure 4).
Environmental and teratogenic exposures frequently
18.1. Anencephaly
Optimum non nasci
(a) Failures of fusion and the factors involved

Anencephaly (Fig. 18.1) is the most severe form of neural
tube defects and is due, according to some authors, to a
failure in the closure of the rostral neuropore between 16
and 26 days after conception. Others are of the opinion
that this happens a little later, i.e. in the 4th postfertilization week (ORahilly and Mller, 1999). The incidence
of anencephaly generally ranges from 110 per 10,000
births. It is etiologically heterogeneous and has genetic
and environmental components such as maternal nutrition and exposure to teratogens. Numerous agents can
cause anencephaly in laboratory animals (De Sesso et al.,
1999; Mazzitelli et al., 2002). Anencephaly is twice more
prevalent in females than in males (Lary and Panlozzi,
2001). When genetically determined, the most obvious
form is X-linked. For prenatally detected neural tube
defects, the estimated aneuploidy rate is estimated from
2% of the isolated neural tube defects to 24% of the
multiple congenital malformation cases (Chen et al.,
2001). Genetic defects in the gene for 5,10-methylenentetrahydrofolate reductase are associated with a 3.57-fold
increased risk for neural tube defects (De Sesso et al.,
1999). One anencephalic fetus with a mosaic 45,X/146,X,
r(X)(p11.22q12) karyotype (Nowaczyk et al., 1998)
and a number of anencephalic fetuses with a ring
chromosome 13 or a deletion of chromosome 13
(Chen et al., 2001) have been reported. Anencephaly
occurs most frequently as an isolated defect, but
it has also been described in association with a partially
duplicated head (diprosopus), with the acrocallosal
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Fig. 18.1. Anencephaly.
affect specific closure sites, e.g. folate deficiency (closures 2, 4 and caudal 1) and valproic acid (closure 5 and
canalization) (Van Allen et al., 1993). Closure 3 was seen
following maternal exposure to ergot derivates (Urioste
and Rosa, 1998). However, recent careful research by precise graphic reconstructions indicates that the model of
multiple sites of fusion of the neural folds may not be
valid in humans. In human embryos, two de novo sites
of fusion of the neural folds appear in succession: in
the rhombencephalic region and in the procencephalic
region, adjacent to the chiasmatic plate (Fig. 18.2). Fusion
from site proceeds bidirectionally (rostral and caudal),
whereas that from is unidirectional (caudal only). The
fusions terminate in neuropores, of which there are 2: one
rostral and one caudal. Human neural tube defects can
thus be classified on the basis of these 3 sites of fusion
and 2 neuropores in the human embryo (ORahilly and
Mller, 2002). Anencephaly is proposed to originate as

an abnormality of mesenchymal structures, while the brain
is secondarily lost to injury in utero because of its exposed
position (Kashani et al., 2001).
(b) Brain pituitary remnants
The anencephalic child usually has no definable brain
structures rostral of the brainstem (Nakano, 1973). The
neural tissue in the more rostral areas, including the hypothalamus, is an amorphous mass of blood vessels and
primitive nerve cells (Fig. 18.3). Anencephalic fetuses
thus provide a model for pituitary development in
the absence of the hypothalamus and for revealing the
possible functions of the fetal hypothalamus in intrauterine development and birth. In anencephalics and
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Fig. 18.2. The neural tube at the middle of stage 12, showing the two regions of fusion of the neural folds. Arrows indicate the direction of fusion,
and black dots show the position of the two neuropores. The fusion of the neural folds begins first at site and then at site . At it spreads
in both directions, ending rostrally as the dorsal lip of the rostral neuropore, which meets the terminal lip from . The first four somites are occipital and are stippled, as is also the mesencephalon. The outlines of somites 10, 15, 20 and 25 are included. (From ORahilly and Mller, 2002,
Fig. 1 with permission.)
the pituitary in any of the seven anencephalics of 3048

weeks gestation (Visser and Swaab, 1979). Anencephalic
children do have a pars distalis of the pituitary (Nakano,
1973). In our group of anencephalics, a neurohypophysis
was present only in one case, but it did not contain
vasopressin or oxytocin (Visser and Swaab, 1979). The
normal, very high, umbilical cord levels of vasopressin
as found in controls during spontaneous labor do not
occur in anencephalics either (Oosterbaan and Swaab,
1987). However, the levels of oxytocin in amniotic fluid
and in the umbilical circulation of anencephalic children
fetuses with holoprosencephaly (cyclopsia and median

cleft), adenohypophysial tissue was found not only in the
sella turcica, but also in the open craniopharyngeal canal
and in the pharyngeal connective tissue at the external
side of the cranial base. Hormone production in the
pharyngeal pituitary was evident from immunocytochemistry (Kjaer and Fischer-Hansen, 1995; Hori et al.,
1999). On morphological grounds the pars intermedia
and neurohypophysis were reported to be absent in 75%
of the anencephalics. We did not find -melanotropin
(MSH) staining as a marker of the intermediate lobe of
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are similar in anencephalics without hydramnios and in

controls. Oxytocin is therefore probably not derived from
hypothalamic neurons but from fetal sources other than
the fetal brain (Oosterbaan and Swaab, 1987). Oxytocin
mRNA has indeed been found in human amnion, chorion
and decidua (Chibbar et al., 1993; Chapter 8e). The
adrenotropic deficiency of the pars distalis of the pituitary in anencephalic children is apparent from the fact
that the adrenal glands are invariably hypoplastic
(Nakano, 1973; Visser and Swaab, 1979; Mazzitelli et
al., 2002), while the fetal adrenal of anencephalic children can be stimulated in utero by corticotropin (ACTH)
(Honnebier et al., 1974). The low level of corticosteroids
in anencephalics also seems to be responsible for the
increased size of the thymus (Mazzitelli et al., 2002).
Fetal adrenal insufficiency goes together with low estriol
excretion by the pregnant mother (Macafee et al., 1973).
At 1718 weeks of gestation, the number and size of
ACTH cells in the pituitary of anencephalics is normal,
but after 32 weeks their number and size are reduced
(Pilavdzic et al., 1997). Bgeot et al. (1978) reported that
- and -endorphins and -lipotrophin staining were
present in the pituitary of anencephalic children, but that
the cells were smaller and less numerous than in normal
fetuses. Both growth hormone and prolactin are under
hypothalamic control during fetal development. In eight
anencephalic fetuses of 1926 weeks of gestation, blood
was sampled by cordocentesis. Both growth-hormone and
insulin-like growth factor-1 (IGF-1) levels were lower,
and prolactin levels higher, than in matched control
fetuses, indicating a disorder of hypothalamic function.
The reduction of IGF-1 is probably due to decreased
secretion of growth hormone (Arosio et al., 1995). At 32
weeks, gonadotropes are almost entirely absent in the
anencephalic pituitary (Pilavdzic et al., 1997). On the
other hand, it was found that the absence of the hypothalamus in anencephalics does not compromise the
maturation of the pituitary-thyroid function between 17
and 26 weeks of gestation (Beck-Peccoz et al., 1992) and
the morphology of lactotropes in the anencephalic pituitary is normal (Pilavdzic et al., 1997). After the age of
40 weeks, the amounts of growth hormone and
thyrotropin (TSH) in anencephalics were low, while
prolactin amounts were within the normal range (Hayek
et al., 1973).
When there is no more food for the young in the egg and
it has nothing on which to live it makes violent movements,
searches for food and breaks the membranes. In just the
same way, when the child has grown big and the mother
cannot continue to provide him with enough nourishment,
he becomes agitated, breaks through the membranes and
incontinently passes out into the external world, free from
any bounds (Hippocrates, cited from Kloosterman, 1968).
(c) Intrauterine growth and birth

Data on intrauterine growth of anencephalic children
suggest that the human fetal brain stimulates the growth
of the fetus as well as of the placenta. The intrauterine
growth rate of the anencephalic fetus is much lower than
that of the controls but shows a steady increase that
continues beyond term (Fig. 18.4; Honnebier and Swaab,
1973; Mazzitelli et al., 2002). The lowest body weights
are found in the cases of associated anencephaly. It is
interesting that, at term, the birthweight of anencephalic
boys is some 150 g higher than that of girls (Honnebier
and Swaab, 1973), showing that the presence of the fetal
hypothalamus is not required for the sex difference in
birthweight. The placenta of anencephalics also weighs
less, which suggests that the fetal brain may normally
stimulate the growth of this organ. Indeed, various pituitary hormones were found to stimulate placental growth
in a rat model for anencephaly (Swaab and Honnebier,
1974) and, surprisingly, -MSH was found to stimulate
fetal growth in rat (Swaab and Honnebier, 1974). It should
be mentioned here that the major -MSH-like substance
in the human fetal pituitary might not be -MSH itself,
but desacetyl -MSH (Tilders et al., 1981), which is
presumed to play a role in fetal development. These findings should be followed up.
The concept of the fetal brain playing a crucial role
in the start of labor originates from observations in cows
and sheep. Gestational length was increased in Guernsey
cattle with fetal pituitary aplasia (Kennedy et al., 1957)
and in cyclop fetuses, due to the poisonous plant veratrum
californicum, which caused pituitary aplasia or pituitary
dystopia (Binns et al., 1964). These observations were
followed by the classic experiments in sheep in which
fetal adrenalectomy, fetal hypophysectomy, infusion
of ACTH, and glucocorticoids showed that the fetal
hypothalamopituitary adrenal axis starts labor in this
species (Liggins et al., 1967; Drost and Holm, 1968;
Liggins and Kennedy, 1968; Liggins, 1969; Liggins,
2000). Later, a critical experiment was carried out by
McDonald and Nathanielsz (1991). They showed that
stereotactic destruction of the fetal paraventricular nucleus
in sheep was followed by prolonged pregnancy length.
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Fig. 18.3. The neural tissue left in anencephaly is an amorphous mass of bloodvessels and primitive nerve cells. (From C.U. Arins-Kappers
collection, Netherlands Institute for Brain Research.)
Observations on human anencephalics suggest that the

human fetal brain, too, is important for the timing of
the correct, at term, moment of birth. As a group,
however, anencephalics have a shorter gestational length,
since anencephalics with hydramnios are born prematurely (Fig. 18.5; Swaab et al., 1977). Mean gestation
length is normal in spontaneously born anencephalics
from pregnancies without hydramnios, in contrast to the
sheep model. However, a high percentage of prematurely
and postmaturely born anencephalic children is found,
indicating that a function of the human fetal brain in
the timing of birth (Honnebier and Swaab, 1973; Fig.
18.5). It is presumed that fetal corticotropin-releasing
hormone (CRH) from the paraventricular nucleus plays
a key role in the timing mechanism for the initiation of
human birth (see Chapter 8.5).
In addition, the course of labor is protracted in

anencephalic children. In particular the expulsion stage
and birth of the placenta take too long. This suggests that
the fetal brain releases compounds such as oxytocin that
may speed up delivery (Swaab et al., 1977; see Chapter
8.1). The fact that about 50% of the anencephalics die
during the course of labor (Honnebier and Swaab, 1973)
points to the importance of intact fetal brain systems for
dealing with the stress of birth. The extremely strong
release of fetal vasopressin that normally occurs in spontaneous labor and that is absent in anencephalics
(Oosterbaan and Swaab, 1987) may play a role, since
fetal vasopressin is involved in redistribution of the fetal
circulation to those organs that are of vital importance
(Chapter 8.1).
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Fig. 18.4. Birthweight (grams) by gestation length. The curves are the smoothed centile lines of the control group (Kloosterman, 1970). The
dots represent the birth weights of 122 anencephalic fetuses. (From Honnebier and Swaab, 1973, Fig.1 with permission.)
(d) Anencephaly, the diagnosis of death and

transplantation
An interest has arisen for the organs of anencephalics for
transplantation purposes. However, only a minority of
anencephalics may serve this purpose. Generally some
60% of the fetuses with anencephaly die before or during
birth (Honnebier and Swaab, 1973). Eighty percent of
liveborns die within 3 days. When death occurs, the
organs are usually so deteriorated that they are no longer
suitable for transplantation. However, on the parents
request, a German anencephalic newborn was reanimated
in 1987 immediately after birth and kept warm and fed
to maintain organ viability, after which the heart was
transplanted into another baby, with excellent results
(Abbatista et al., 1997).
While the organs of anencephalics can be kept viable
by means of improved intensive care techniques, it has
become increasingly difficult to determine when death
has occurred. The legislations of Western cultures unanimously accept the idea that brain death means the
irreversible loss of all those functions that identify a
person, the functions that give him a personality and
cognitive skills. Cerebral trunk deaths make these functions impossible and is thus equivalent to death. Human
life can be defined by the presence of cerebral activity
or by potential cerebral activity. In anencephalic children
cerebral trunk activity is not finalized and other cerebral
structures cannot recover in such children. In fact, brain
death occurs in anencephalics without cerebral trunk death
(Abbattista et al., 1997). In the Uniform Determination
of Death Act of the USA, two criteria for determining
death are described: irreversible cessation of circulatory
and respiratory function, and irreversible cessation of all
functions of the entire brain, including the brainstem.
Because anencephalic neonates may maintain both a
heartbeat and respiration without medical assistance, their
situation does not meet the first criterion. Moreover, they
may have an active brainstem, which means the second
criterion is not met either. Because of the definition of
brain death there is thus no practical possibility of using
anencephalic infants as organ donors under the dead
donor rule (see also Chapter 32.4). One of the possible
solutions to this problem is to change the present standard for whole brain death to make permanent loss of
consciousness the critical brain function that defines life
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Fig. 18.5. Frequency distribution of gestation length: (A) for a control group of 49,996 pregnant women; (B) for mothers of all anencephalic
fetuses (n = 147); (C) for mothers of anencephalic fetuses (n = 29) without hydramnios, omitting those who had stillborn fetuses with third-degree
maceration, fetuses given intrauterine injections or twins, and those in whom labour was induced. (From Swaab et al., 1977, Fig. 3 with permission.)
or death. These children are considered to have a lack of

consciousness from birth and an inability to ever gain
consciousness or awareness. The same arguments go
for prenatally acquired hydrocephaly. In this condition
a developmental or encephaloclastic process, often of
infectious, toxic or genetic origin, affects the major

vessels of the anterior circulation, resulting in an extensive
reduction in brain matter that is replaced with cerebrospinal fluid (McAbee et al., 2000). However, the possible
use of organs of such children raises the specter of a
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misdiagnosis, resulting in wrongful death. At present,

Germany is the only country where live-born anencephalic infants are considered to be legally dead. Another
fear is that aggressive life support for anencephalic infants
who will serve only as organ banks will erode public
confidence in transplantation (Lafreniere and McGrath,
1998).
18.2. Transsphenoidal encephalocele and empty sella
syndrome
Transsphenoidal encephaloceles are rare anomalies (Chong
and Newton, 1993; Morioka et al., 1995). They are
sporadic, with some evidence of autosomal recessive
inheritance. They are often associated with other midline
anomalies such as agenesis of the corpus callosum, cleft
palate, hypertelorism and coloboma, a v- or tongue-shaped
retinochoroidal depigmentation (Chong and Newton,
1993; Brodsky et al., 1995). Clinically, transsphenoidal
encephalocele children present with craniofacial deformities, cerebrospinal fluid (CSF) rhinorrhea, meningitis and
often panhypopituitarism (Chong and Newton, 1993;
Brodsky et al., 1995). Progressive hypothalamic-pituitary
dysfunction, diabetes insipidus and chiasmatic syndromes
result from herniation of the pituitary gland, third ventricle
and optic chiasm in a meningeal pouch that protrudes
ventrally through a large round defect in the sphenoid
bone into the nasopharynx (Chong and Newton, 1993;
Brodsky et al., 1995; Morioka et al., 1995; Fig. 18.6).
Hyperprolactinemia was found in four patients who
were considered to have had hypothalamic dysfunction
(Morioka et al., 1995). Cerebrospinal fluid rhinorrhea may
be treated surgically (Willner et al., 1994; Clyde et al.,
1995). It is presumed that the transsphenoidal encephalocele results from an early teratogenic event, occurring
between the 4th and 6th week of gestation (Brodsky et al.,
1995).
Herniation of the third ventricle/arachnoid into the
sellar fossa may be caused by surgery or radiation of
pituitary adenoma, pituitary apoplexia, bromocryptine
treatment of pituitary adenoma or postpartum pituitary
necrosis. Increased CSF pressure is presumed to be
responsible for primary empty sella syndrome. Visual
impairment is frequently associated with intrasellar herniation (Kobayashi et al., 1996). Primary empty sella
syndrome is frequently accompanied by growth hormone
deficiency and hypogonadotropic hypogonadism, but only
rarely by central hypothyroidism (Cannavo et al., 2002;
Fig. 18.6. Sagittal sections of MR image of a child with encephaloceles. (A) 0.22-T MR image (TR/TE 500/40) at 8 years of age.
Sphenoethmoidal (arrow) and transsphenoidal (arrowhead) encephaloceles are seen. A part of the transsphenoidal encephalocele protrudes
from the roof of the epipharynx (double arrows). (B) 0.5-T MR image
(TR/TE 500/30) at 11 years of age. The appearance of the basal
encephaloceles remains unchanged compared with 3 years earlier. The
stretched pituitary stalk (white arrow) extends into the encephalocele
(egg-shaped cavity with low-intensity image). A thin structure, thought
to be the pituitary gland, is seen at the posterior inferior wall of the
encephalocele (arrowhead). (C) the structure is slightly enhanced by
Gd-DTPA. (From Morioka et al., 1995, Fig. 2.)
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Chapters 18.6b, 24.1a). A combination of empty sella,

diabetes insipidus and polydipsia with Aspergers
syndrome has been published (Raja et al., 1998).
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Fisher-Hansen, 1995). Endocrine deficiencies, caused by

hypothalamic and/or pituitary dysfunction, can be the only
clinical problem in milder forms of holoprosencephaly.
Holoprosencephaly has also been found in a Klinefelter
fetus (Armbruster-Moraes et al., 1999; Michaud, 2001).
Holoprosencephaly arises during the first 4 weeks of
embryonic development due to failure of ventral forebrain
induction by axial mesendoderm. During the blastogenesis there is failure or incomplete division of the prosencephalon into cerebral hemispheres. The most severe form
of prosencephaly, cyclopia, is predicted by the requirement of the axial mesendoderm for eye separation.
Because of the importance of midline signaling in hypothalamic development, it is not surprising that the hypothalamus is either missing or lacking in structures in
holoprosencephalic brains. Multiple genetic causes have
been identified, especially in SHH, SIX3, 2IC2 and TGIF,
and chromosomal abnormalities, notably trisomies 13 and
18, have been found (Sarnat and Flores-Sarnat, 2001;
Patterson, 2002).
Aspergers syndrome has also proposed to be a mild
form of midline defect (Tantam et al., 1990). Primary and
secondary dysraphia have been reported in fetuses whose
mothers used alcohol during pregnancy (Konovalov et al.,
1997).
18.3. Congenital midline defects: optic nerve

hypoplasia and septo-optic dysplasia (De Morsiers
syndrome)
Congenital midline defects include a wide spectrum of
impaired midline clearage defects of the embryonic forebrain, including the various forms and grades of severity
of holoprosencephaly, that is seen in 80% of trisomy 13
patients (Battaglia, 2003), schizencephaly (Chapter 18.8),
septo-optic dysplasia (Chapter 18.3b) and dystopia of the
neurohypophysis (Chapter 18.4). The septum pellucidum
is generally absent (Chapter 18.8). Holoprosencephaly is
the most common brain malformation in humans, with a
prevalence rate of 1 in 250 in early embryogenesis, and
1.26 in 10,000 in a prospective birth cohort study
(Patterson, 2002). Alobar, semilobar and lobar forms
of holoprosencephaly are the different grades of severity.
In alobar holoprosencephaly, the prosencephalon fails to
cleave sagittally into cerebral hemispheres, transversely
into telencephalon and diencephalon, and horizontally
into olfactory tracts and bulbs. Minimal manifestations
discussed here include absent olfactory tracts and bulbs
(arhinencephaly), agenesis of the corpus callosum and
hypopituitarism. Feeding difficulties, neurodevelopmental
disability, visual impairment and seizures due to hypoglycemia or hyponatremia are common occurrences in
congenital midline defects (Takahashi et al., 2001). There
is always some degree of noncleavage of the hypothalamus, and the hypothalamus is one of the most severely
affected structures. As many as 67% of children with
holoprosencephaly exhibit diabetes insipidus. Other endocrinopathies involving pituitary function are less common
(Sarnat and Flores-Sarnat, 2001). Most of the patients have
multiple pituitary hormone deficiencies, and the severity
of endocrine abnormalities correlates with the degree of
hypothalamic nonseparation (Plawner et al., 2002). A few
patients with midline defects and persistent hyponatremia
due to a reset osmostat have been described, including
one with a chromosome 13 abnormality. The osmosensitive hypothalamic neurons are presumed to be dysfunctional as a result of the chromosome abnormality
and/or the anatomic midline defect (Gupta et al., 2000).
An open craniopharyngeal canal with adenohypophysial
tissue can be present in holoprosencephaly (Kjaer and
(a) Optic nerve hypoplasia

Optic nerve hypoplasia is a congenital abnormality of one
or both optic nerves associated with a diminished number
of axons. After completion of the optic nerves, insults
result in atrophy. The abnormality can be associated with
several endocrine and central nervous system disorders.
The most common is septo-optic dysplasia (see below).
Zeki et al. (1992) found that optic nerve hypoplasia can
be associated with partial or complete absence of the
septum pellucidum (52%), hydrocephaly (38%), parencephaly (24%), dilatation of the suprasella and chiasmatic
cisterns (19%), partial or complete absence of the corpus
callosum (14%), or an intracranial cyst. Incomplete forms
of septo-optic dysplasia have also been reported by others
(Furujo and Ichiba, 1998). Behavioral problems in optic
nerve hypoplasia were reported to range from attentiondeficit disorders to autistic, aggressive and violent
behavior. In literature, optic nerve atrophy has, moreover,
been associated with anencephaly, schizencephaly, cerebral atrophy, cerebral infarcts, encephalocoeles,
colpocephaly, and congenital suprasellar tumors (Zeki et
al., 1992).
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(b) Septo-optic dysplasia

Septo-optic dysplasia (De Morsiers syndrome, MIM
182230) is a developmental anomaly of midline structures
characterized by uni- or bilateral hypoplasia of the optic
nerves, tracts and chiasm, and by absence of the septum
pellucidum, that was first noted by Reeves, in 1941, and
first described by De Morsier, in 1956. In 88% of the
patients the visual system is bilaterally affected (Fig.
18.7). Children with optic nerve hypoplasia in this
syndrome are blind in 2050% of the cases, or severely
visually impaired in another 40%. A specific ocular
fundus appearance with marked small optic disc and
isolated tortuosity of the retinal veins is present. In addition to optic disc dysplasia, morning glory sign has been
found as well (Hellstrm et al., 2000). De Morsier considered the entity to be a part of median cranioencephalic
dysrhaphias, while others thought it to be a mild form
of holoprosencephaly (Ellenberger et al., 1970) or part
of a spectrum of complex midline cranio-facial malformations overlapping with optic nerve hypoplasia, the
syndrome of an absent septum pellucidum (see Chapter
18.7), and procencephaly (Hellstrm et al., 2000). Septooptic dysplasia has also been described as part of
schizencephaly, a structural disorder of cerebral cortical
development. In addition, septo-optic dysplasia may be
associated with cortical developmental malformations, the
septo-optic dysplasia-plus spectrum (Miller et al.,
2000). The scar-like lesions in the walls of the third
ventricle and the fusion of the ventricular walls are consistent with a destructive or disruptive lesion, whose nature,
however, is not clear (Roessmann et al., 1987). Viral
infections, gestational diabetes, and ingestion of large
amounts of quinidine in early pregnancy have all been
suggested as etiological factors for the sporadic form
(Acers, 1981; Costin and Murphree, 1985). In addition,
the possibility of a vascular disruption (Miller et al.,
2000), drug toxicity, and an association between fetal
alcohol effects and a complex cerebral anomaly with
features of septo-optic dysplasia and incomplete holoprosencephaly have been reported (Coulter et al., 1993;
Hellstrm et al., 2000). The insult that causes septo-optic
dysplasia occurs presumably before 10 weeks and at about
46 weeks of gestation, when the ganglion cells of the
retina are developing (Patel et al., 1975; Hellstrm et al.,
2000). The homeobox gene HESX1 is implicated in a
familial form of septo-optic dysplasia. HESX1 expression
begins in prospective forebrain tissue at the anterior
extreme of the rostral neural folds and eventually ends
Fig. 18.7. (a) Sagittal image of septo-optic dysplasia: severe hypoplasia

of the pituitary gland, the stalk and the chiasma (arrowhead). Partial
ectopy of the cerebellar tonsils in the foramen magnum (arrow). (b)
Coronal image of septo-optic dysplasia: absence of the septum pellucidum evidenced by the cross. (c) Sagittal image of posterior pituitary
ectopia (arrowhead), hypoplastic anterior pituitary, ectopia of the cerebellar tonsils (arrow) and the arachnoid cyst, posterior to the cerebellar
hemispheres (cross). (From Zucchini et al., 1995, Figs. 24 with
permission.)
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in the ventral diencephalon. However, later in development it becomes restricted to Rathkes pouch. Two
siblings with septo-optic dysplasia were homozygous for
a missense mutation within the HESX1 homeobox. In
addition, heterozygous mutations in HESX1 have been
found that are associated with milder pituitary phenotypes
(Dattani et al., 1999; 2000; Dattani and Robinson, 2000;
Thomas et al., 2001). A four-generation family with septooptic dysplasia has been reported to be associated with
Waardenburg syndrome type 1. In addition, a proband
exhibited septo-optic dysplasia; a G to C transversion was
identified in PAX3 exon 7 (Carey et al., 1998). One 25year-old patient with septo-optic dysplasia and retinitis
pigmentosa had an isolated mitochondrial complex III
deficiency and a heteroplastic mutation in the cytochrome
b gene (Schuelke et al., 2002).
Hypopituitarism is also an important component of this
syndrome (Hoyt et al., 1970), and the term septo-opticpituitary dysplasia has been in use since this study of
Hoyet et al. Hypopituitarism has been considered to be
secondary to hypothalamic damage rather than to be due
to intrinsic pituitary defects. Indeed, one child responded
to the administration of growth hormone-releasing
hormone (GHRH) with accelerated growth (Leaf et al.,
1989). On the other hand, not only a hypoplastic pituitary, but also an empty sella, with or without an ectopic
pituitary, may be found (Willnow et al., 1996). The
endocrine deficiencies may vary from isolated growthhormone deficiency to panhypopituitarism (Leaf et al.,
1989; Willnow et al., 1996). If the endocrinopathies
remain unnoticed, the children might suffer from hypoglycemia, adrenal crisis and sudden death (Hellstrm et
al., 2000). Moreover, sexual precocity, delayed puberty,
central hypogonadism, adrenal insufficiency, hypothyroidism and vasopressin-responsive diabetes insipidus
have been described (Arslanian et al., 1984; Willnow et
al., 1996; Antonini et al., 2002). In a series of 23 patients
with optic-nerve hypoplasia, hypopituitarism was found
in 15 of these patients. Stimulated prolactin levels were
higher than in controls (Costin and Murphree, 1985).
Smaller studies also showed growth hormone deficiency,
hypothyroidism, elevated prolactin, ACTH deficiency and
diabetes insipidus (Izenberg et al., 1984). One patient has
been described who grew normally despite growth
hormone and IGF-1 deficiency. IGF II or insulin levels
could not explain this finding either (Bereket et al., 1998).
Interestingly, patients have been described without CRH
or thyrotropin-releasing hormone (TRH) secretion but
with retained gonadotropin secretion. This may be
31
explained by the fact that luteinizing hormone-releasing

hormone (LHRH) neurons develop outside the hypothalamus, in the nasal placode, and migrate to the
hypothalamus after the development of the midline hypothalamic defect, i.e. after the 5th8th week of pregnancy
(see Chapter 24.2). Moreover, the abnormal hypothalamic
anatomy may alter the normal suppression of LHRH
neuron function, resulting in precocious puberty (Nanduri
and Stanhope, 1999).
The syndrome is not rare (Roessmann et al., 1987) and
is highly variable (Morishima and Aranoff, 1986). In
some series of patients with septo-optic dysplasia,
60100% of them had clinical optic nerve hypoplasia with
varying degrees of nystagmus and visual impairment.
Only 5060% lacked the septum pellucidum (Fig. 18.8;
Arslanian et al., 1984; Stanhope et al., 1984). During
pregnancy adrenal hypoplasia may result in a subnormal
maternal urinary oestriol excretion (Macafee et al., 1973).
Neurological abnormalities such as epileptic seizures,
cerebral palsy, microcephaly and mental retardation do
occur (Acers, 1981; Costin and Murphree, 1985; Antonini
et al., 2002). With the advent of brain imaging, a number
of additional cerebral hemispheric malformations have
been reported (Willnow et al., 1996). Patients with septooptic dysplasia are at risk of unexpected death at all ages,
although most deaths occur in very early childhood
(Gilbert et al., 2001).
Neuropathological study of a limited number of cases
revealed that the optic nerves were attenuated and
contained only a few myelinated fibers (Roessmann et
al., 1987). This agrees with the small optic disc that was
seen in all patients (Costin and Murphree, 1985). The
optic chiasm is also severely atrophic and the lateral
geniculate nuclei are small. In the anterior part of the
hypothalamus, the tissue may be distorted. The supraoptic
and paraventricular nuclei are sometimes absent, or the
cells may be abnormally small or few when they are identified by neurophysin staining (Fig. 18.9; Roessmann et
al., 1987). This explains the varying degrees of diabetes
insipidus and suggests that the term hypothalamic
should indeed be added to the designations (septo-opticpituitary dysplasia) mentioned above. The changes in the
hypothalamus in fact seem to be the most consistent ones.
The olfactory bulbs and tracts may also be absent (Patel
et al., 1975; Roessmann et al., 1987). The frequent perinatal problems found in this syndrome (Willnow et al.,
1996) may be related to the damaged fetal hypothalamopituitary adrenal system that is involved in the timing
mechanism of birth (Chapters 8.5, 18.1) and the fetal
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Fig. 18.8. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (A) The paraventricular nucleus (PVN)
is absent in hematoxylineosin staining (* = sulcus hypothalamicus, III = third ventricle). Bar represents 0.5 mm. (B) Only a few small PVN neurons
were present that stained for the vasopressin precursor by means of an anti-glycopeptide antibody (Boris Y-2). Bar represents 100 m.
hypothalamoneurohypophysial system that normally

stimulates the course of labor and protects the fetus
against the stress of labor (Chapter 8.1). There may be
a narrowing and a fusion of the third ventricular walls
anteriorly, with pronounced subependymal glia proliferation; the ependyma of the third ventricle may be
distorted; ependymal scars may be found and
leptomeningeal astrocytic heterotopics seen at the base of
the brain (Roessmann et al., 1987; Fig. 18.10). Aplasia
of the fornix may also be found (Willnow et al., 1996).
In two patients a hamartomatous mass was found in the
region of the cerebral trigone. The posterior pituitary may
be absent or hypoplastic. Posterior pituitary ectopia and

infundibular hypoplasia are seen as variable components
of septo-optic dysplasia (Brodsky and Glasier, 1993; see
Chapter 18.4). Enlargement of the pituitary stalk has also
been demonstrated in patients with septo-optic dysplasia
and diabetes insipidus (Zeki et al., 1992).
In collaboration with A. Dean (London, UK), we
examined a case of septo-optic dysplasia with panhypopituitarism and diabetes insipidus for which the patient
had received replacement therapy (NHB 96-179). It
concerned a girl of 4 years and 5 months who died of
bronchopneumonia. Her brain weight was 773 g, which
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Fig. 18.9. Septo-optic dysplasia (De Morsier syndrome) in a girl of 4 years and 5 months (NHB 96-179). (a) An area of necrosis in the hypothalamus
(see asterisks) lateral of the PVN. Bar represents 500 m. (b) Calcifications in the lateral part of the hypothalamus. Bar represents 100 m.
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is below the 1st percentile. Her body weight and height

were well below the 3rd centile line for age. Growth
retardation was detected from 20 weeks of gestation
onwards. Labor was induced at 41 weeks of gestation but
was diverted into an emergency Caesarian section due to
the occurrence of a maternal grand mal seizure and fetal
distress. She was born at 41 weeks with a birthweight of
2820 g. There was no evidence of antiepileptic medication
during pregnancy. The girl was found to have visual
problems and pale hypoplastic optic discs at the age of
3 months. MRI showed a hypoplastic pituitary gland with
absent or very small stalk. Neuropathology showed that
the thyroid and adrenal were about half the expected
weight and that the adrenal cortex was thin. Leptomeningeal and white-matter heterotopias and posterior
fossa crowding were found. Concerning the olfactory
pathway, the sulcus lateral to the left gyrus rectus
contained a discrete island of glioneuronal tissue that
blended with the leptomeninges and possessed a small
number of myelinated axons. The equivalent sulcus on
the right contained a small myelinated tract. The anterior
pituitary gland appeared to be normal for the most part,
but the neurohypophysis was relatively thin. The pars
intermedia was represented by a conspicuous epitheliumlined cleft. Throughout the hypothalamus there were
well-circumscribed fields of astrocytosis, with strong glial
fibrillary acidic protein (GFAP) staining. In addition, a
very strong band of GFAP positivity was present along
the lateral and third ventricle. The optic nerve, chiasm
and tracts were thin, gray and degenerated. The degenerated part of the optic nerve contained only remnants of
myelin. In the region of the optic nerve, the leptomeninga
contained GFAP-positive heterotopias. The wall of the
third ventricle was not scarred. A lesion was present in
the hypothalamus at the level of the sulcus hypothalamicus, in a position that was lateral to the normal location
of the paraventricular nuclei (PVN). The PVN and
supraoptic nuclei (SON) were, however, virtually absent
in this patient (Figs. 18.8, 18.9), but a few small PVN
neurons were stained with anti-glycopeptide along the
third ventricle above the level of the sulcus hypothalamicus and some thick-beaded fibers were found close to
the foramen of Monro. No staining was found with antiglycopeptide in the suprachiasmatic nucleus. The absence
of the SCN was also apparent from the type of arrhythmicity in a child with septo-optic dysplasia, who reacted
with normal sleepwake cyclicity to melatonin administration. In the case we studied, the hypothalamus was
strongly distorted and calcifications were present in
various areas (Fig. 18.10). However, a number of structures was distinguished, i.e. island of Calleja, diagonal
band of Broca, basal nucleus of Meynert, commissura
anterior, fornix, nucleus tuberalis lateralis and corpora
mamillaria. The arcuate nucleus could not be identified.
Anti-vasopressin (Truus, 29-01-86) or anti-oxytocin (O2-T) did not stain cells in the PVN or SON. No staining
was found in the infundibular region with anti-vasopressin, anti-oxytocin or anti-glycopeptide (Boris-Y-2).
The stalk could not be identified.
A case with both septo-optic dysplasia and Cornelia
de Lange syndrome (Chapter 32.2) has been described
(Hayashi et al., 1996) and the condition of a 16-year-old
boy with hypothalamic endocrine disorders, a hypoplastic
pituitary gland, decreased posterior pituitary lobe intensity, absence of the left eye, mental retardation and a
hypoplastic left optic nerve was also considered to be
within the spectrum of septo-optic dysplasia (Miyako et
al., 2002).
18.4. Dystopia of the neurohypophysis
(a) True ectopia
When it occurs as an isolated defect, ectopia of the neurohypophysis is considered to be due to an abnormality in
the descent of the neurohypophysis. This congenital
abnormality may be part of midline brain anomalies,
including septo-optic dysplasia (Zucchini et al., 1995).
Posterior pituitary ectopia and infundibular hypoplasia are
in fact considered to be variable components of septooptic dysplasia (Kaufman et al., 1989; Brodsky and
Glasier, 1993; see Chapter 18.3b) and may be based on
a HESX1 mutation (Mitchell et al., 2002). A developmental theory suggests that genetic, teratologic or
traumatic factors interfere with the normal development
around 6 weeks of gestation. In cases of dystopia of the
neurohypophysis, the pituitary fossa contains only adenohypophysial tissue and no endocrine abnormalities. No
instance of isolated diabetes insipidus due to dystopia of
the neurohypophysis has been reported. Dystopia of the
neurohypophysis has been described as an extremely rare
accidental finding at autopsy (Fig. 18.10). It may be
discovered by MRI as a round structure with a high-intensity signal on T1-weighted MRI images of the region of
the median eminence. In general, true dystopia of the
neurohypophysis is not associated with perinatal problems or clinical symptoms (Aydan and Ghatak, 1994).
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Fig. 18.10. (a) Inferior view of brain showing a dystopic neurohypophysis posterior to chiasma and anterior to mamillary bodies. (From Aydin
and Ghatak, 1994; Fig. 1 with permission.) (b) Dystopic neurohypophysis surrounded by a meningeal capsule. Arrowheads indicate the rim of
adenohypophyseal tissue (H&E, magnification 16). (From Aydin and Ghatak, 1994, Fig. 2 with permission.)
On MRI, dystopia of the neurohypophysis may closely

simulate tumors such as granular cell myoblastomas,
astrocytomas, neuronal hamartomas or meningiomas in
the hypothalamic area. The absence of symptoms related
to the adeno- and neurohypophysis argues in favor of true
dystopia of the neurohypophysis and the consideration of
this condition in the differential diagnosis of hypothalamic lesions may prevent unnecessary biopsies or
neurosurgical procedures (Aydan and Ghatak, 1994).
in patients with anterior pituitary abnormalities such as

pituitary dwarfism (isolated growth hormone deficiency)
or multiple pituitary hormone deficiencies, including
central diabetes insipidus, or diabetes mellitus. In addition,
periventricular heterotopias may be present (Fujisawa
et al., 1987a; Kelly et al., 1988; Maghnie et al., 1991;
Appignani et al., 1993; Mszros et al., 2000; Den Ouden
et al., 2002; Mitchell et al., 2002). In such cases the
adenohypophysis can be hypoplastic, the infundibulum
absent and the posterior lobe ectopic at the bottom of
the median eminence (Mszros et al., 2000). A 43-yearold man with eunuchoid habitus and open epilepsies
had an agenesis of the pituitary stalk, a small anterior
pituitary remnant and an ectopic neurohypophysis. He
(b) Dystopia with anterior pituitary abnormalities

Dystopia of the neurohypophysis in individuals without
clinical symptoms has to be distinguished from dystopia
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had untreated panhypopituitarism. He had always been

short for his age but continued to grow and finally reached
a length of 193 cm (Den Ouden et al., 2002). In cases of
growth hormone deficiency associated with an ectopic
posterior pituitary on MRI after gadolinium injection,
patients without a pituitary stalk present a more severe
form of the disease, with multiple anterior pituitary
hormone deficiencies (Chen et al., 1999b). Twin boys
with hypopituitarism, hypoplasia of the anterior pituitary
gland, ectopic posterior pituitary tissue and paracentric
inversions of the short arm of chromosome 1 have been
described. This syndrome is probably due to impaired
down migration of the posterior pituitary (Siegel et al.,
1995). Acquired dystopia of the neurohypophysis has
often been considered to be the result of perinatal injury
causing stalk transsection and subsequent regeneration of
the hypothalamoneurohypophysial tract fibers as a newly
formed ectopic posterior lobe at the proximal stump
(Fujisawa et al., 1987a). A large majority of the patients
with anterior pituitary abnormalities indeed have a history
of perinatal problems in the form of difficult presentation
and perinatal anoxia. However, since only 50% of the
patients with multiple pituitary deficiencies and evident
MRI damage of the sellar area have such a positive history
for adverse perinatal events (Cacciari et al., 1990), doubts
have risen about the direct association between neonatal
insult and pituitary damage. An alternative explanation
from the interruption during birth hypothesis, and a
much more likely one, is that an early prenatal congenital
disconnection defect occurs that leads to hypothalamopituitary and other brain anomalies. Because of the active
role of the fetus in the initiation and course of labor, such
congenital defects may contribute first to labor problems
and later to, e.g. growth hormone deficiency (Maghnie et
al., 1991; Argyropoulou et al., 1992; Triulzi et al., 1994;
see Chapter 18.6; for a discussion of the question whether
a difficult delivery is cause or effect, see Chapter 8.1).
18.5. The optic chiasm
The optic chiasm (4 mm thick, 12 mm wide and 8 mm
long) lies about 1 cm above the pituitary fossa). About
53% of the fibers decussate and there are about 2 million
axons for each nerve. The most frequent complaints of
patients with chiasmal compression (Fig. 19.26) from
pituitary tumors are progressive loss of central acuity and
dimming of the visual field, especially its temporal portion.
Interestingly, it has been hypothesized that that could
have been what defeated the Philistine giant Goliath, as
described in the Bible book of Samuel; the fact that he

was a slow-moving and ponderous acromegalic giant with
a pituitary tumor that caused bitemporal hemianopsia
(Berginer, 2000). For field defects in chiasmal lesions, see
Anders et al. (1999). Chiasmal compression and hypopituitarism have been found a few times in cases of
intrasellar chordomas, tumors derived from notochordal
rests (Thodou et al., 2000). Optic atrophy is a late sign of
chiasmal compression by a pituitary tumor. T2-weighted
reversed MR images depicting the optic pathway are
useful in selecting the appropriate surgical approach
(Eda et al., 2002). Chiasmal apoplexy or hemorrhage into
the optic chiasm is generally caused by intrachiasmal
cavernous or arteriovenous vascular malformation, but has
also been found due to a pituitary macroadenoma hemorrhaging into the optic chiasm (Pakzaban et al., 2000).
(a) Misrouting in albinism
Retinofugal axons are misrouted in the optic chiasm so
that some of the axons from the temporal retina those
that stay on their own side in normal brains cross in
albinos. The abnormality is present in any animal and
human individual that lacks pigment in the retinal pigment
epithelium, no matter what genetic mechanisms are
responsible for the lack of pigment. Abnormalities in
the lateral geniculate nucleus of a human albino have
been described (Guillery et al., 1975). The abnormal
decussation of temporal retinogeniculostriate projections
associated with albinism is reflected in the potential distribution of the visual evoked potentials (VEP). Following
monocular stimulation, misrouted optic projections
produce VEP asymmetry across the occipital left and right
hemispheres in 100% of the albinos and not in normal
controls (Apkarian et al., 1983). Several reports have
suggested that some patients with PraderWilli syndrome
(see Chapter 23.1) also demonstrate the presence of
misrouted optic pathway projections (Creel et al., 1986,
1987). In PraderWilli syndrome, hypopigmentation of
hair, skin and eye have indeed been described and
proposed to be of neural crest origin. However, Apkarian
et al. (1989) did not find the characteristic contralateral
hemispheric asymmetry of VEPs as seen in albinism. On
the other hand, their VEP profiles were found to be atypical and difficult to interpret. Moreover, an 8-month-old
boy has been described with Angelmans syndrome, with
crossed asymmetry in monocular flash VEP scalp distribution, previously considered to be pathognomonic of
albinism. He had skin and hair hypopigmentation, but
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Fig. 18.11. Achiasmatic child (111.12). Coronal axial MRI slices demonstrate an abnormality of the chiasmal region. T1-weighted MRI coronal
sections with 4-mm-image slice thickness failed to show a normal chiasmal plate but rather two separate tracts adjoining the inferior region of
the third ventricle. Midsagittal sections also failed to identify a chiasmal structure or normal supraoptic recesses. Beginning anteriorly: (A) Coronal
T1-weighted section shows normal intracranial optic nerves (arrows) lying beneath the frontal lobes and above the pituitary gland; (B) as the
coronal sections advance 4 mm posterior to the preceding section, a downward-bulging third ventricle is visualized along with adjacent optic
structures on the left and right. However, no chiasmal structure is imaged. (From Apkarian et al., 1993, Fig. 3 with permission.)
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normal ocular pigment and normal maculae. Cytogenetic

studies demonstrated a microdeletion of the maternal
chromosome 15q11-13 (Thompson et al., 1999).
(b) Non-decussating retinal-fugal fiber syndrome
In two unrelated children, a visual pathway malformation was found in which nasal retinal-cortical projections
were unable to decussate due to an inborn absence of the
optic chiasm (Fig. 18.11). These fibers erroneously route
ipsilaterally to visual projection targets. Both children had
reduced distance visual acuity for their age, alternating
esotropia, torticellis, head tremor and ocular motor instability in the form of early-onset nystagmus. When tested
for VEPs, using full field monocular stimulation, instead
of showing contralateral asymmetry as found in albinism,
the VEP profiles of both children revealed misrouted ipsilateral asymmetry (Apkarian et al., 1994).
(c) Other optic chiasm pathology
For arterial supply of the optic chiasm, see Chapter 17.1h.
A case of avulsion of the optic chiasm is described in
Chapter 17.2b. In a case of primary bilateral anophthalmia, the supraoptic nucleus was described as lying flat,
parallel to the meningeal surface and in one mass, but
otherwise normal (Recordon and Griffiths, 1938). A rare,
lethal X-linked syndrome with microcephaly, dysmorphic
features and normal eyes is accompanied by bilateral optic
pathway aplasia. Necrosis of the optic pathways, hypothalamus and brainstem following irradiation of a pituitary
tumor has been described. Gliomas in the optic pathway,
which tend to occur in young children, may cause vision
loss and optic atrophy. For a chiasmatic glioma, see Fig.
19.10. Optic pathway gliomas may be associated with
neurofibromatosis type I as described in Chapter 19.4b.
Chiasmatic and chiasmatic/hypothalamic gliomas are different entitities. For the chiasmatic/hypothalamic tumors,
there was more morbidity and no prolongation of time to
progression when radical resections were compared with
more limited resections. A less radical resection and radiotherapy for preventing a subsequent progression is, therefore, recommended (Steinbock et al., 2002). The most
common site for optic pathway gliomas with neurofibromatosis is the orbital nerve, followed by the optic chiasm,
while the most common localization of involvement for
the optic pathway gliomas without neurofibromatosis is
the optic chiasm (Kornreich et al., 2001).
Neurofibramatosis type 1 is an autosomal dominant

genetic disorder, but about half of the cases are spontaneous mutations. Patients with this disorder run an
increased risk of developing both benign and malignant
tumors. Gliomas, astrocytomas and ependymomas have
frequently been reported. A patient with a neurofibromatosis type 1 had a mass in the hypothalamus and
anterior optic pathway that disappeared over a 9-month
period, suggesting dysplastic changes rather than a
neoplasm (Zuccoli et al., 2000). Gangliomas and
ganglioneuromas of the optic chiasm have also been
described (Shuangshoti et al., 2000). Neurohypophysial
germinomas may not only cause diabetes insipidus and
anterior pituitary dysfunction but also compression of the
optic chiasm (Saeki et al., 2000; Iwaki, 2001).
In septo-optic dysplasia the optic nerves and optic
chiasm are affected (see Chapter 18.3). The optic chiasm
is often affected in neurosarcoidosis (Westlake et al.,
1995; Chapter 21.1; Fig. 21.1), in multiple sclerosis
(Chapter 21.2; Fig. 21.5) and Wolframs syndrome
(Chapter 22.7). In addition, Langerhans cell histiocytosis
(Chapter 21.3) may affect the optic pathway. The histiocytes are characterized by CD1a- and S-100-positive
cells, and ultrastructurally by the presence of membranous cytoplasmic structures of 200400 nm in width and
shaped like tennis rackets, which are known as Birbeck
granulas. In Wolframs syndrome (Dean et al., unpubl.
observations) the optic nerves and optic chiasm are atrophied. Although rare, visual loss may result from primary
central nervous system lymphoma in AIDS (Lee et al.,
2001b). According to some studies, there is optic nerve
degeneration in Alzheimers disease (Hinton et al., 1986;
Chapter 4.3).
Slight demyelization of the optic tracts and chiasm has
been reported in LaurenceMoon/BardetBiedl syndrome
(Chapter 23.3) and in acute intermittent porphyria
(Perlroth et al., 1966; Chapter 28.3).
18.6. The growth hormone axis in development and
aging
Growth hormone synthesis and release are regulated by a
number of hypothalamic factors that are delivered to the
pituitary gland by the pituitary portal system. GHRH forms
out of 4044 amino acids (Schally et al., 2001) and stimulates growth hormone production, while somatostatin
(Chapter 8.7b) inhibits its secretion. The endogenous
growth hormone pulses are most likely due to episodic
release of GHRH and not influenced by somatostatin
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(Dimaraki et al., 2001). Growth hormone-releasing

peptide (GHRP), Ghrelin, is an endogenous ligand for the
growth hormone secretagogue receptor (Tolle et al., 2003)
and stimulates GHRH release (Wren et al., 2002). This
growth-hormone secretagogue of 28 amino acids is also
an orexigenic peptide, acting through activation of
the neuropeptide-Y (NPY) pathway (Kojima et al.,
2001; Chapter 23c) and induces a release of CRH and
vasopressin (Wren et al., 2002). Ghrelin secretion is
sexually dimorphic with women in the late follicular
phase having higher levels than men and is suppressed
by somatostatin (Barkan et al., 2003). In addition to the
growth hormone-releasing and -inhibiting factors, growth
hormone secretion is controlled by autofeedback connections (Farhy et al., 2001). In their turn, GHRH and
somatostatin synthesis and release are modulated by NPY,
pro-opiomelanocortin, galanin, thyroid hormones, gonadal
hormones and adrenal corticosteroids. In addition, growth
hormone secretion is regulated by acetylcholine that
topically inhibits somatostatin in the hypothalamus. In
obesity a chronic state of hypersecretion of somatostatin
results in inhibition of growth hormone release. Also
the noradrenergic system is involved in growth hormone
regulation. GHRH is a member of a gene family that also
includes genes for vasoactive intestinal polypeptide (VIP;
Chapter 4a), pituitary adenylcyclase-activating polypeptide (PACAP), secretin, gastric inhibitory peptide (GIP)
and glucagon. The gene consists of 6 exons. Exon 2-4
encodes a GHRH precursor that is cleaved into GHRH and
a carboxy-terminal peptide. GHRH is widely expressed
in the nervous system, but the most prominent activity
is located in the median eminence and infundibular
nucleus. GHRH neurons are activated in this nucleus
during prolonged illness (Goldstone et al., 2003). GHRH
affects growth hormone production, thus stimulating the
proliferation of the pituitary somatotrophs by enhancing
growth hormone synthesis at the transcriptional level.
Growth hormone secretion is also stimulated. In plasma,
GHRH is rapidly inactivated by a dipeptidylaminopeptidase to GHRH3-44 with a half life of approximately
7 min (Cordido et al., 1989; Bluet-Pajot et al., 1995; 1998;
Baumann and Maheshwari, 1999; Ghigo et al., 2000;
Veldhuis et al., 2001).
Immediately postnatally, GHRH causes a growth hormone hyperresponsiveness which in all likelihood is due
to a reduced pituitary sensitivity to somatostatin. After a
period of stable plasma levels, growth hormone responses
to GHRH decline after the third to fourth decade in men
and after the menopause in women (Mller et al., 1993).
39
Sexual dimorphism is present in the regulatory mechanisms involved in growth hormone and IGF secretion
(Jaffe et al., 1998). Newborns secrete high levels of
growth hormone, but low levels of IGF-I. Estradiol stimulates the IGF-I production in puberty (Ghigo et al.,
2000). The brain is also a target for growth hormone.
Growth hormone receptor mRNA is expressed in the
human brain and growth hormone participates in laboratory animals in the modulation of feeding behavior, sleep
and breathing control, and learning and memory. Growth
hormone mRNA has so far not been found in human
brain samples (Castro et al., 2000).
Eutopic and ectopic GHRH hypersecretion by certain
tumors may be associated with pituitary growth hormone
cell hyperplasia or adenoma and growth hormone hypersecretion. Hamartomas (Chapter 19.3) or gliomas
(Chapter 19.4) may secrete high levels of GHRH.
Hypersecretion of GHRH occurs in fewer than 1% of the
cases of acromegaly. In the large majority of these cases,
patients have carcinoid tumors in the bronchus, gastrointestinal tract or pancreas, which secrete high levels of
GHRH (Schally et al., 2001).
(a) Noonan syndrome
In 1963 Noonan and Ehmke first described several children with a typical facial appearance, i.e. hypertelorism,
down-slanting palpebral fistures, ptosis and low-set
posteriorly rotated ears. The incidence of Noonan
syndrome is suggested to be between 1 in 1000 and 1 in
2000. Apparently, there are familial and sporadic cases
of this syndrome (Collins and Turner, 1973). Growth
reduction is the same for height and weight, while
head circumference has a normal distribution. There are
additional characteristic features in Noonan syndrome.
Polyhydramnios complicates 33% of the affected pregnancies and there is a high incidence of cardiac anomalies.
Major milestone delay is a common feature, puberty is
often delayed, and there is hypotonia and hyperextensibility in the younger child. Significant feeding difficulties
are present in 76% of the children. However, developmental outcome in the older child does not seem to confirm
earlier reports of frequent mental retardation. Speech delay
may be related to loss of hearing in Noonan syndrome. In
fact, abnormal hearing is present in 40% and abnormal
vision in 94% of the children with Noonan syndrome
(Sharland et al., 1992). Growth hormone secretion, which
has been reported to be characterized in Noonan syndrome
by low-amplitude and few spontaneous bursts, is held
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responsible for the short stature and low growth velocity.

The levels of plasma IGF-I, the main mediator of growth
hormone actions, would be low or low normal, but these
data are controversial (Spiliotis et al., 1984; Ahmed et al.,
1991; Tanaka et al., 1992). The evidence for a defect in
the growth hormone/IGF-I axis in Noonans syndrome
has led to growth hormone therapy (Ahmed et al.,
1991; Thomas and Stanhope, 1993). The average age
at diagnosis of Noonan syndrome is 9 years (Sharland
et al., 1992). The differential diagnosis includes Turners
syndrome, various other chromosomal abnormalities (see
below), teratogens such as alcohol and primidone.
We have seen the hypothalamus of a 6-year-old girl
with Noonans syndrome (A253/94) referred to us by Dr.
A. Dean (London, UK). She died following a liver graft
given because of a liver failure that was probably due
to a reaction to repeated exposure to halothane. The
hypothalamus revealed normal microscopic anatomy.
Following long-microwave treatment of the sections,
GHRH-containing neurons became visible in apparently
normal amounts in the arcuate nucleus (Fig. 18.12).
Quantification was not performed.
(b) Multiple pituitary deficiencies, isolated growth
hormone deficiency
Patients with multiple pituitary deficiencies, including
growth hormone deficiencies, generally have an MRI
pathology that indicates suprasellar damage that usually
also appears from neuroendocrine tests (Cacciari et al.,
1990; Den Ouden et al., 2002). The occurrence of acquired
severe growth hormone deficiency is extremely common
in adult patients bearing non-functional tumor masses in
the hypothalamo-pituitary area and increases following
neurosurgery or radiation (Corneli et al., 2003; Chapter
25.3). Also in isolated growth hormone-deficient children,
the anterior lobe of the pituitary may be hypoplastic, the
infundibulum absent and the posterior pituitary ectopic at
the bottom of the median eminence (Mszros et al.,
2000). In addition, pediatric patients with mitochondrial
myopathy, encephalopathy, lactic acidosis and stroke-like
episodes were diagnosed with growth-hormone deficiency,
most probably based upon a defect in the GHRH neurons
(Matsuzaki et al., 2002). Children with organic causes for
growth hormone deficiency, i.e. congenital malformation,
tumor, radiation, chemotherapy or infiltrating disorders,
have elevated responses of the hypothalamo-pituitary
adrenal axis, possibly by disruption of central control
pathways (Finkelstein et al., 2001; Chapter 25.3).
Interruption of the pituitary stalk by a perinatal insult

and regeneration of the posterior pituitary from the proximal stump have been presumed to be the cause of growth
hormone defects in children (see Chapter 18.4; Zucchini
et al., 1995; Yoo, 1998). However, the absence of perinatal insults and the presence of other brain anomalies,
such as microcephaly, facial or sella abnormalities,
ectopic or absent neurohypophysis, periventricular heterotopias, thin or absent pituitary stalk, anterior visual
pathway anomalies such as optic nerve hypoplasia, and
a HESX1 mutation suggest the presence of a congenital
developmental defect in some patients (Maghnie et al.,
1991; Argyropoulou et al., 1992; Triulzi et al., 1994;
Mszros et al., 2000; Mitchell et al., 2002). An undescended pituitary stalk would be part of such defects.
There are patients in this group whose somatotrophs function but whose hypothalamic GHRH release is impaired.
In patients with an invisible or thin pituitary stalk on MRI
and prenatal or perinatal onset of hypothalamic pituitarism, growth hormone deficiency and ACTH deficiency
gradually develop during the first decades of life
(Miyamoto et al., 2001). Growth hormone deficiency is
also found in septo-optic dysplasia (Chapter 18.3).
Prolonged labor and breech delivery have been documented in only 5060% of the children with growth
hormone deficiencies, and one may question, therefore,
the idea that disturbed labor is the cause of growth
hormone deficiencies. An alternative explanation for
the combination of labor problems and pituitary stalk
abnormalities is that early prenatal congenital hypothalamic-pituitary abnormalities could contribute to labor
problems because of the participatory role of the fetus in
the induction and course of labor. Breech delivery and
prolonged labor may thus be part of a complex clinical
picture, including congenital brain anomalies (Maghnie
et al., 1991; Argyropoulou et al., 1992; Zucchini et al.,
1995; Chapter 8.1). Abnormal embryonic development,
e.g. due to alcohol abuse during pregnancy, could serve
as an explanation. It is presumed that growth hormone is
the pituitary hormone most likely to be affected by lesions
in the hypothalamic region, since it has only a limited
reserve capacity for GHRH (Hellstrm et al., 1998). It is
of interest in this respect that isolated growth hormone
deficiency may go together with pituitary stalk interruption and ectopic neurohypophysis (Vanelli et al., 1997).
In the case of growth hormone deficiency associated
with a posterior pituitary hyperintense MRI signal,
patients without a pituitary stalk on MRI after gadolinium
injection present a more severe form of the disease in
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Fig. 18.12. The immunoreactivity of growth hormone-releasing hormone with antibody 747 in the arcuate nucleus of Noonans syndrome, Wolframs
syndrome and control cases. (a) A Noonans syndrome case stained with antibody 747; no. A253/94. (b) The same case as (a), shown at lower
magnification. (c) A 6-year-old control; no. 87-305. (d) The same case as (c), shown at lower magnification. Note that there is no clear difference
between the Noonans syndrome and control cases. Bar = 50 m. (Preparation by A. Salehi.)
41
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childhood, when associated with multiple anterior pituitary hormone deficiency (Chen et al., 1999b). The idea
that growth hormone deficiency is often a result of hypothalamic rather than pituitary dysfunction is supported by
the observation that synthetic GHRH analogues can
promote accelerated linear growth in such cases (Thorner
et al., 1985; Zucchini et al., 1995).
Drastic effects of growth hormone deficiency on intelligence have not been found (Meyer-Bahlburg et al.,
1978) and children with growth hormone deficiency
referred for growth hormone therapy are generally of
normal intelligence. However, they do have more learning
problems and are also at risk for behavioral problems.
Characteristically such children are shy, withdrawn
and socially isolated and have problems with mood and
attention. Anxiety, depression, somatic complaints and
attention deficits have been identified. The frequency of
these symptoms declines over a period of 3 years, beginning shortly after the start of the growth hormone
replacement therapy, which suggests that growth hormone
therapy might have central effects as well (Stabler et al.,
1996; Nyberg, 2000). Growth hormone also acts directly
on the brain, since growth hormone receptors are present
in the brain (Nyberg, 2000). Indeed, growth hormone
therapy early in development leads to a rapid catch-up
of cranial growth, whereas in isolated growth hormone
deficiency head circumference is reduced (Laron et al.,
1979). Moreover, hypopituitary women had significantly
lower scores in 4 out of 7 neuropsychological tests,
although they had received suitable replacement therapy
for TSH and ACTH insufficiency. This group of patients
had a higher incidence of mental disorders and increased
symptoms of mental distress. Although the cause of
impairment was most probably multifactorial, growth
hormone deficiency probably contributed to the results
(Blow et al., 2002). It thus seems that the central effects
of growth hormone should get more attention in the future.
Multiple pituitary deficiencies go together more
frequently with empty sella (34%) than isolated growth
hormone deficiency (less than 10%), in which few abnormalities of the sellar region are found. Empty sella is
generally considered to be of congenital origin, possibly
a malformation due to an incomplete or deficient sellar
diaphragm (Cacciari et al., 1990, 1994). However, empty
sella is commonly seen in patients with benign intracranial hypertension and may also be the sequel to
pituitary apoplexy. About 50% of the adult patients with
primary empty sella have antipituitary antibodies that
indicate previous autoimmune hypophysitis (Anderson
et al., 1999). Primary empty sella syndrome is frequently

accompanied by growth hormone deficiency and hypogonadotropic hypogonadism, but not by central
hypothyroidism (Cannavo et al., 2002). In addition, empty
sella accompanied by growth hormone deficiency is
observed in Gitelmans syndrome (Bettinelli et al., 1999).
Growth hormone deficiency in combination with empty
sella syndrome has also been described in BardetBiedl
syndrome (Chapter 23.3). Long-term survivors of childhood malignancies who received cranial and craniospinal
radiation may result in decreased final height. Substitution
of growth hormone after diagnosis of growth hormone
deficiency should be considered for these patients at a
young age (Mller et al., 1998a; Chapter 25.3). Partial
empty sellar syndrome with an atrophied pituitary gland
is seen in primary neuroendocrinopathies and in patients
with elevations in intracranial pressure and has once been
reported in a top body builder with a long history of
exogenous abuse of growth hormone, testosterone and
thyroid hormone. Whether this was due to negative
hormone feedback or frequent elevation of intracranial
pressure by weight lifting is not known (Dickerman and
Jaikumar, 2001).
Moyamoya disease is a rare vascular disease that results
in narrowing of the blood vessels of the circle of Willis
and the formation of a network of collateral vessels at the
base of the brain for compensatory perfusion (see Chapter
17.2). Moyamoya disease may be accompanied by growth
hormone deficiency and hypothyroidism (Mootha et al.,
1999).
In the acute phase of a severe head injury, an augmented
tone of both GHRH and somatostatin may be present. The
increased IGF-1 levels suggest that these alterations could
be advantageous for rapid recovery (De Marinis et al.,
1999). Growth hormone deficiency is also a very frequent
occurrence after neurosurgery for hypothalamus-pituitary
masses.
In narcolepsy patients, 50% of the growth hormone
secretion takes place in daytime, whereas controls secrete
only 25% during the day. Hypocretin deficiency (Chapter
28.4) is thus accompanied by a disruption of circadian
GHRH release (Overeem et al., 2003).
(c) Genetic forms of GHRH deficiency
An autosomal recessive form of hypothalamic GHRH
deficiency has been described. This is a genetically heterogeneous group of disorders that are generally inherited
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as an autosomal recessive trait. Autopsy of a 78-year-old

dwarf with this syndrome revealed a normal pituitary and
hypothalamus (Rimoin and Schechter, 1973). However,
no immunocytochemistry or quantification of hypothalamic nuclei was performed. In addition, two siblings
have been described with partial trisomy 1 (q31.1-q32.1)
due to a familial insertion. Short stature was found with
growth hormone deficiency and an ectopic pituitary
growth velocity responded well to treatment with growth
hormone. Intelligence was normal (Schorry et al., 1998).
Humans with GHRH resistance due to an inactivating
mutation in the GHRH-receptor gene have been described
that resemble in many aspects the little mouse model
that has a single base change (A G) in the gene for
the GHRH receptor. The human families became known
by the occurrence of a Karachi newspaper article on The
dwarfs of Sindh. The mode of transmission is autosomalrecessive with a high degree of penetrance. Several
families with mutations of the GHRH receptor have
now been described. The clinical picture of homozygous
individuals with the inactivating GHRH-receptor mutation largely resembles that of severe, isolated growth
hormone deficiency. The affected individuals have normal
proportions and look like miniature versions of normal
people. Although intelligence seems to be normal,
the skull is considerably smaller (some 4 SD below the
normal mean) than what has been described in classic
growth hormone deficiency, where head circumferences
are near normal to about 2 SD below normal. This is
in agreement with the microcephalus described in the
little mouse. The endocrine profile corresponds to that
of isolated growth hormone deficiency (Baumann and
Maheshwari, 1999).
In hereditary Gitelman disease, growth hormone
deficiency is associated with a partial vasopressin
deficiency, empty sella and a renal tubular disorder. It is
caused by mutations in the gene encoding the thiazidesensitive sodium chloride transporter (TSC; SLC12A3) of
the distal convoluted tubes (Bettinelli et al., 1999). In
addition, a possible familial syndrome of retinitis pigmentosa, growth hormone deficiency and acromegalic skeletal
dysplasia has been described (Hedera and Gorski, 2001).
In Downs syndrome the neuronal control of GHRH
secretion is impaired, while the pituitary growth hormone
pool is fully preserved. It is thought that the precociously
impaired tuberoinfundibular cholinergic pathways may
lead to somatostatinergic hyperactivity and low growthhormone responsiveness to GHRH (Beccaria et al., 1998;
Chapter 26.5).
43
(d) Adult growth hormone deficiency

After cessation of longitudinal growth, growth hormone
continues to serve an important role in the regulation of
body metabolism to optimize body composition and function. In all species examined, peripheral growth hormone
levels decline with age (Bartke, 1998), probably reflecting age-related neurotransmitter control leading to GHRH
hypoactivity (Ghigo et al., 2000). Adults, especially those
with a history of hypothalamic or pituitary disease, or
those that underwent growth hormone treatment in childhood, may be deficient for growth hormone, which causes
adiposity, reduced lean body mass and reduced physical
fitness. Although some patients may be asymptomatic,
others have specific complaints of fatigue, low energy
levels, and impairment of memory and concentration.
Patients with growth hormone deficiency can be diagnosed by a provocative test such as an insulin-tolerance
test (Newman and Kleinberg, 1998). It has been suggested
that the age-related changes in growth hormone secretion
in humans may be due to an increased somatostatin tone.
Endocrine studies are, however, also compatible with the
view that the GHRH neurons may be involved in declining growth hormone secretion during aging (Russell-Aulet
et al., 1999). The contribution of GHRH to the maintenance of growth hormone secretion appears to be
sexually dimorphic and more important in men than in
women (Orrego et al., 2001). The concept that the
somatopause is primarily hypothalamically driven is supported by the observation that long-acting derivatives of
the hypothalamic peptide GHRH given subcutaneously to
healthy 70-year-old men increase growth hormone and
IGF-I levels to those encountered in 35-year-olds
(Lamberts et al., 1997b). Changes in GHRH neurons
during aging have so far not been studied in the human
hypothalamus.
In many adults who were growth hormone-deficient
as children, a high incidence of social phobia and depression has been found. Growth hormone-deficient adults
put on growth hormone therapy report improvements
in their psychological well-being and health, mental
alertness, motivation and working capacity, indicating
the presence of central effects of growth hormone in
adulthood. This possibility is reinforced by the observation that adult patients with either multiple pituitary
hormone deficiencies or isolated growth hormone deficiencies may show subnormal memory performance
that may be reversible with growth hormone treatment.
Growth hormone receptors are indeed present in the brain
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(Deijen et al., 1996; Nyberg, 2000). Growth hormone

may prevent the auto-cannibalistic effects of acute
diseases on muscle mass. Lamberts et al. (1997) have,
moreover, shown that, in a randomized placebo-controlled
trial of 6 weeks, growth hormone administration in
elderly individuals with an acute hip fracture causes a
statistically significant earlier return to independent
living after the fracture. Growth hormone replacement in
elderly people may also have positive effects on body
composition, exercise tolerance and lipids. Multicenter,
double-blind placebo-controlled long-term follow-up
studies are needed to study the long-term central effects
and side-effects of such a therapy (Whitehead et al., 1992;
Bartke, 1998; Newman and Kleinberg, 1998; Barkan
et al., 2000). Probably only a subgroup of elderly people
may benefit from growth hormone substitution (Marcus,
1996). Guidelines for the diagnosis and treatment of adults
with growth hormone deficiency have been formulated
(Invited report of a workshop, 1998). In a report of the
Australian multicenter trial of growth hormone treatment
in growth hormone-deficient adults, excessive IGF-1
levels were found, together with modest decreases in total
and low-density lipoprotein cholesterol, substantial reductions in fat mass and modest improvements in perceived
quality of life (Cuneo et al., 1998). Long-term follow-up
studies are needed even more now that overexpression of
growth hormone above the physiological range in transgenic mice and in patients with acromegaly is known to
be associated with reduced life expectancy. In contrast,
Ames dwarf mice with hereditary growth hormone,
prolactin and thyrotropin deficiency live much longer than
normal animals from the same strain (Bartke, 1998).
Acute critical illness or injury initially results in an
elevation of circulating levels of growth hormone. The
number of growth hormone bursts is increased, and
the peak growth hormone levels as well as interpulse
concentrations are high (Van den Berghe, 1999).
The catabolic state of prolonged critical illness is considered to be a natural defense mechanism in case of serious insults, providing the metabolic substrates and host
defense required for survival and for the delay of anabolism.
This condition of protein wasting is not prevented or
reversed by food. The endocrine response to prolonged illness consists of an inactivation of anabolic pathways, i.e. a
decreased activity of the thyrotropic axis as found in nonthyroidal illness (Chapter 8.6c), reduced pulsatile secretion
of ACTH, TSH, luteinizing hormone (LH) and prolactin,
and a low activity of the somatotropic axis, as indicated by
reduced pulsatile growth hormone levels and IGF-1 levels.
The pathogenesis apparently has a hypothalamic component, since both axes are readily activated by coinfusion of
TRH and growth hormone secretagogues (Van den Berghe
et al., 1998). In fact, infusion of growth hormone secretagogues appears to be a novel endocrine strategy to reverse
the catabolic state of critical illness (Van den Berghe et al.,
1997a, Van den Berghe, 2000).
18.7. Hydrocephalus
(a) Hydrocephalus and the subcommissural organ
The subcommissural organ lies below the rostral part of
the posterior commissure and develops in the second
month of intrauterine life, concurrently with the pineal
gland, to reach its maximum development during fetal
life. It regresses around the time of puberty. In the adult
only isolated relics remain. This organ is highly permeable but does not have fenestrated capillaries. Therefore,
it formally fails to qualify as a circumventricular organ.
There is some evidence that it may be involved in the
hypertension produced by aldosterone acting on the brain.
The subcommissural organ also contains an appreciable
number of prolactin receptors that may be involved in
the regulation of water metabolism. Moreover, the subcommissural organ is a secretory organ and the site of
origin of Reissners fiber, a mucopolysaccharide strand
that passes down the center of the brainstem and spinal
cord to the filum terminale (Ganong, 2000). In human
fetuses of 180230 mm crown-to-heel length, a subcommissural organ is found that has glandular properties.
The posterior lobe of the pineal organ is built up from
this specialized ependyma. A Reissners fiber, however,
has not been formed at that moment (Olsson, 1961). Two
main components of the subcommissural organ are
distinguished: the ependymal part, forming the secretory
cells, and the hypendema, which consists of glia, vascular
and parenchymal-like cells. In experimental animals
spontaneously showing hydrocephalus, and in induced
postnatal hydrocephalus, complete absence or a progressive reduction of the subcommissural organ has been
found. In two hydrocephalic brains from spontaneous
abortions of 20 and 21 gestational weeks that showed a
significant dilation of the lateral and third ventricles, the
subcommissural organ was also severely altered. The
rostrocaudal length was only 50% of its normal value,
and the global volumes were much smaller. The pseudostratified ependymal cells, normally high, were arranged
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Fig. 18.13. Frontal views of the subcommissural organ (SCO) and subjacent ependyma. A, B: SCO of the normal case 3H. D, E: SCO of the
hydrocephalic case 1H. C, F: border between SCO and subjacent ependyma of the fetal brain (C, normal; F, hydrocephalus; PC, posterior
commissure). Bars: A, D 60 m; B, C, E, F 35 m. (From Castaeyra-Perdomo et al., 1994; Fig. 2 with permission.)
in a narrow layer (Fig.18.13; Castaeyra-Perdomo et al.,

1994). These alterations might be interpreted as a consequence of hydrocephalus (Weller and Schulman, 1972),
since atrophy of the ependymal lining as well as of the
paraventricular nuclei has been reported in cases of

slightly increased pressure of the cerebrospinal fluid
(Bauer, 1959). Castaeyra-Perdomo et al. (1994), on the
other hand, interpret the presence of a possibly functional
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but considerably reduced subcommissural organ in one of

their subjects as a precocious involution of the organ, possibly causing pathological changes in the regulation of
fetal cerebrospinal fluid, and ultimately leading to hydrocephalus. At present, cause and effect of the dysplastic
subcommissural organ changes in the fetus with hydrocephalus are not clear.
(b) Hypothalamic symptoms of hydrocephalus
In some 38% of hydrocephaly cases, optic nerve hypoplasia
is involved (Zeki et al., 1992; Chapter 18.3). A 4-year-old
child with optic chiasm glioma, nonobstructive hydrocephalus, optic nerve hypoplasia and hypernatremia
without polyuria or polydipsia, possibly due to hypothalamic osmoreceptor dysfunction, has been described.
She had postventriculoperitoneal shunting ascites that
improved with chemotherapy. The high protein content
was presumed to alter CSF adsorption (Shuper et al.,
1997). Permanent visual loss is a well-established major
sequela of idiopathic intracranial hypertension. One case
has been reported of a woman who had visual loss, an
empty sella turcica and polycystic ovary syndrome (Au
Eong et al., 1997). Hydrocephaly of the child may go
together with low estriol excretion by the pregnant mother
(Macafee et al., 1973), illustrating the importance of an
intact fetal hypothalamicpituitaryadrenal axis for the
production of this maternal hormone. Increased CSF levels
of vasopressin have also been recorded in hydrocephalus
(Srensen et al., 1985; Srensen, 1986).
In children, akinetic mutism has been described as an
extremely rare complication of obstructive hydrocephalus,
possibly due to damage of the ascending dopaminergic
projections that run periventricularly. The gradually
increasing size of the third ventricle will probably damage
the median forebrain bundles that contain the dopaminergic projections coming from the brainstem (Lin et al.,
1997). Indeed, parkinsonism has been found to be associated with akinetic mutism in a case of obstructive
hydrocephalus that was treated with a shunt. Other
patients with akinetic mutism after surgical removal of a
tumor from the anterior hypothalamus, or patients with
obstructive hydrocephalus, responded to dopamine
receptor agonists, but not to presynaptic dopamine
mimetics, supporting the idea that the symptoms were
due to a loss of dopaminergic input (Ross and Stewart,
1981; Anderson, 1992).
Hydrocephalus may also be accompanied by behavioral
disorders: a 9-year-old child has been described with a
psychosis due to a third ventricular choroid plexus papilloma and mild to moderate hydrocephalus (Carson et al.,
1997; see Chapter 17.3).
High serum levels of growth hormone, IGF-I and
diabetes mellitus have been reported in a case of obstructive hydrocephalus caused by a diverticulum of the third
ventricle. IGF-I is a mediator of growth hormone. The
endocrine abnormalities improved after the placement of
a ventriculoperitoneal shunt. The diverticulum of the third
ventricle might have compressed the aquaduct through
the dorsal and ventral aspects of the mesencephalon. It
is not clear whether the increased growth hormone levels
were due to hypersecretion of GHRH or hyposecretion
of somatostatin from the hypothalamus (Okada et al.,
1998).
Autonomic dysfunction is often associated with hydrocephalus (Thorley et al., 2001) and the cardiovascular
failure that may suddenly lead to unexpected death may
be due to pressure on the hypothalamus and other brain
structures (Rickert et al., 2001).
(c) Causes of hydrocephalus
Chronic hydrocephalus in later life may result from
aquaduct stenosis. Compression of the surrounding
parenchyma may result in dysfunction of the hypothalamopituitary axes, leading to precocious puberty,
amenorrhea, hyperinsulinemia, impaired growth hormone
responses, abnormalities of temperature control, obesity,
diabetes insipidus, abnormalities of autonomic regulation,
visual symptoms, and disorders of temperature and other
biological rhythms. The hypothalamus may ultimately be
transformed into a thin membrane with a loss of nuclear
architecture and gliosis (Page et al., 1973; Suzuki et al.,
1990; Horvath et al., 1997). A cyst of the septum pellucidum is rarely so large that it leads to hydrocephalus,
but a number of such cases have been described (Sarwar,
1989; Silbert et al., 1993; Lancon et al., 1996; Chapter
18.8). However, a colloid cyst of the third ventricle may
more frequently cause hydrocephalus (Chapter 17.3a;
Hwang et al., 1996). Hydrocephaly, in addition, may be
caused by cavernous malformations of the third ventricle
when these are situated in the region of the foramen of
Monro (Katayama et al., 1994; Chapter 17.2a).
Diencephalic syndrome may go together with hydrocephalus (Chapter 19.4) and craniopharyngiomas of early
childhood can produce hydrocephalus and symptoms of
increased intracranial pressure (Costin, 1979; Chapter
19.5a). Also arachnoid cysts may cause hydrocephalus
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(Todd et al., 2000; Chapter 19.10). In addition, hydrocephaly is a symptom of Biemond syndrome type
II and related disorders (Verloes et al., 1998; Chapter
23.3b).
Endoscopic third ventriculostomy has become a wellestablished procedure for the treatment of various forms
of noncommunicating hydrocephalus. Although it is
generally considered to be an easy and safe procedure, a
case in which the patient suffered a fatal subarachnoidal
hemorrhage has been reported in the literature. In order
to avoid vascular injury, perforation of the floor of the
third ventricle should be performed in the midline,
halfway between the infundibular recess and the mamillary bodies, just behind the dorsum sellae. If it is done
this way, diabetes insipidus, oculomotor palsy and
vascular injury are claimed to be unlikely to occur
(Chapter 17.1i).
47
months. Moreover, the cavum septum pellucidum is seen

in 1220% of the adult autopsies but in much lower
frequencies in neuroimaging studies (i.e. some 2.2%).
This discrepancy is probably due to the CSF that is
drained from the ventricles at autopsies and the limited
resolution of imaging techniques (Bruyn, 1977; Sarwar,
1989). In addition, the prevalence of the cavum septum
pellucidum, determined by patient seclection since
Pauling et al. (1998) found that the incidence was 1.1%
in healthy children vs. 6.9% as the outcome of a clinical
pediatric sample. This possibility is supported by the work
of Nopoulos (1990). A cyst of the septum pellucidum is
arbitrarily defined as a space with a diameter of more
than 10 mm. Symptomatic cysts are rare (Sarwar, 1989),
but an expanding cyst of the septum pellucidum may
cause obstruction of the interventricular foramina and
produce headaches, papilledema, emesis and loss of
consciousness. Behavioral, autonomic, sensorimotor,
neuro-ophthalmic symptoms and hydrocephalus may
occur (Lancon et al., 1996).
The cavum Vergae (Verga, 1851) is the posterior extension of the cavum septum pellucidum and develops in
the 5th month of pregnancy. It is connected to the cavum
septum pellucidum by an aquaduct (Fig. 18.14).
Embryologically they are a single cavity. The cavum
Vergae does not extend further than the recessus suprapinealis of the third ventricle and according to autopsy
studies it is present in 100% of the fetuses but only in
30% of the full-term neonates. Anteriorly its boundaries
are the anterior limbs of the fornix, superiorly the
boundary is the body of the corpus callosum, posteriorly
it is the splenium and inferiorly the psalterium and
hippocampal commissure (Bruyn, 1977; Sarwar, 1989).
A cavum Vergae alone does not identify individuals at
risk for cognitive delays, in contrast to a cavum septum
pellucidum that may serve as a significant marker of
neurodevelopmental abnormalities (Bodensteiner et al.,
1998). A cyst of the cavum Vergae causing definite symptoms is a rare occurrence (Leslie, 1940).
Although there is a great deal of controversial literature about this subject it seems that there is no statistically
significant relationship between the prevalence of a cavum
septum pellucidum and cavum Vergae, either on their
own or concurrently, and neurological or psychiatric
deficits (Bruyn, 1977; Sarwar, 1989; Schaefer et al., 1994;
Kwon et al., 1998). Nevertheless, a wide cavum septum
pellucidum in which the leaves of the cavum are separated by more than 1 cm is frequently associated with
abnormalities of neurological function. Variations in the
18.8. Septum pellucidum abnormalities

The septum pellucidum, called septum telencephali by
Stephan and Andy (1962), is a thin translucent plate of
two laminae and extends from the anterior part of the
corpus callosum to the superior surface of the fornix, and
from the organum vasculosum lamina terminalis to the
splenium of the corpus callosum. The septum pellucidum
is continuous with the septum verum (Chapter 7.3). The
septum pellucidum is only present in higher primates. It
forms at 67 weeks of gestation (Groenveld et al., 1994)
and contains glia cells, fibers, some scattered neurons and
veins that connect with the choroid plexus. It is lined
with ependyma on the ventricular side. The septum pellucidum is an important relay station between the
hippocampus and hypothalamus (Bruyn, 1977; Sarwar,
1989), but a functional deficit in their ability to navigate
was not found in children without a septum pellucidum
(Groenveld et al., 1994).
The cavum septum pellucidum, first described by the
Leyden professor Francois Dubois de la Bo or Silvius
in 1671 (Bruyn, 1977), is a space between the mesial
blades of the septum pellucidum (Fig. 18.14). The cavum
septum pellucidum is thus not part of the ventricular
system and should not be considered as the fifth
ventricle. The one-cell-thick lining of the cavum is not
epidymal. It is bordered superiorly by the corpus callosum
and anterior commissure and its floor is formed by the
fornix. It is macroscopically present as a 1-mm-wide
space in 100% of the fetuses, in 85% of the subjects at
1 month postnatally, 45% at 2 months and 15% at 36
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Fig. 18.14. ac. Schematic representation of the cerebral ventricular

system. (a) Lateral view; hatched area represents the cavum septi pellucidi (1), the aquaductus septi (2) and the cavum Vergae (3). (b, c)
Anteroposterior view, showing cavum septi pellucidi (b) and both cava
(c) (dotted areas). (From Bruyn, 1977, Fig. 8, p. 303.)
septum pellucidum might represent anomalous development of midline structures and might therefore be one of
the markers associated with clinical abnormalities such
as mental retardation (Schaefer et al., 1994). Indeed, a
number of cases of neurological and psychiatric disorders have been described that are associated with the
presence of a cavum septum pellucidum. An increased
prevalence of cavum septum pellucidum may be related
to boxing injuries, described as dementia pugilistica or
punch-drunk syndrome. A cavum septum pellucidum is
present in 18% of boxers and in 5% of the general population. The main width of the cavum is 5.2 mm, compared
with only 3% of the control subjects, and it is not
uncommon for the fornix to become totally severed
(Corsellis et al., 1973; Casson et al., 1984; Silbert et al.,
1993). Although there is no question that there is a
positive association between professional boxing and the
presence of a cavum septum pellucidum, it has been
hypothesized that this abnormality may be one of the
alterations in the limbic system, resulting in a behavior
that makes pugalism a more attractive career choice in

this subgroup of people (Bodensteiner and Schaefer,
1997). This possibility can be studied by prospectively
scanning those who want a license to fight professionally. Patients with large cysts of the septum pellucidum
and cavum Vergae have been reported who suffered from
persistent or intermittent obstructive hydrocephalus, intermittent headache and postural loss of consciousness. The
symptoms are directly related to pressure effects from the
cavum septum pellucidum, since stereotactic puncture of
the cyst or shunting produces a sustained remission from
further headaches (Silbert et al., 1993). Cases with
akinetic mutism have been reported that are related with
pathology in the septal area or hypothalamus. Akinetic
mutism resulting from obstructive hydrocephalus, e.g.
following shunt failure, is thought to be due to damage
to the periventricular area, where ascending dopaminergic
projections pass. Two of such cases (9 years and 13 years
of age) were reported to have a prominent cavum septum
pellucidum (Lin et al., 1997). It is, however, not clear
what the exact role is of the observed wide cavum septum
pellucidum in the pathogenesis of akinetic mutism in these
children. Midline cerebral malformations, e.g. cavum
Vergae and cavum septum pellucidum, are also more
frequently found in schizophrenia (Scott et al., 1993;
Kwon et al., 1998; Nopoulos et al., 1998; Rajarethinam
et al., 2001). The enlargement of a cavum septum pellucidum may even be more severe in patients with childhood
schizophrenia. Moreover, patients with a complete nonfusion of the septal leaflets were observed in this category,
lending further support to the probability of a developmental disorder as arising of this disease (Nopoulos et
al., 1998; Chapter 27.1). The presence of a cavum septum
pellucidum in schizophrenia may be associated with a
poor prognosis (Fukuzako and Kodama, 1998). Cavum
septum pellucidum not only has increased prevalence in
schizophrenia and neurodevelopmental disorders, but also
perhaps in other psychotic disorders (Kirkpatrick et al.,
1997; Kwon et al., 1998). Indeed, after a comprehensive
review, Bruyn (1977) concluded that one-third to onehalf of the patients with cavum septum pellucidum had
seizures and 15% often suffered from psychosis, dementia
and/or personality changes. This conclusion has been
supported by the study of Kwon et al. (1998), who
observed an increased prevalence of cavum septum pellucidum, not only in schizophrenia patients but also in
patients with affective disorder or schizotypical personality disorder. The combination of cavum septum
pellucidum and schizophrenia has been associated with
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part of a spectrum of complex midline craniofacial malformations. Moreover, a case of septo-optic dysplasia in
Cornelia de Lange syndrome has been described (Hayashi
et al., 1996; Chapter 32.2). Overlap occurs between septooptic dysplasia, optic nerve hypoplasia and the syndrome
of an absent septum pellucidum with proencephaly. The
septum pellucidum is also absent in holoprocephaly, in
Aperts syndrome (acrocephalosyndactyly), sometimes
following neonatal leptomeningitis, or neonatal brain
trauma, and can be present in Chiari type II malformations (Bruyn, 1977; Sarwar, 1989; Groenveld et al., 1994).
Tumors that originate from the septum pellucidum are
extremely rare, but gliomas, astrocytomas and oligodendrogliomas from the corpus callosum may extend into
the septum pellucidum. Midline lipomas, sometimes calcified, are usually developmental malformations of the
corpus callosum, but a lipoma confined to the septum
pellucidum has been described (Sarwar, 1989). Tumors
in the septal region may be associated with aggression
(Albert et al., 1993). Slowly growing tumors of the anterior midline structures affecting the septum pellucidum
and adjacent structures such as the fornix may in addition cause emotional instability and memory problems,
while, in fast-growing tumors, increasing stupor is seen
(Zeman and King, 1959).
hemizygous deletion of 22q11 chromosome (Catch 22

syndrome), and to partial trisomy of chromosome 5
(Vataja and Elomaa, 1998). In mental retardation or developmental delay, the frequency of septum pellucidum is
increased, but a cavum Vergae has been observed with
the same frequency as in normal and retarded populations (Bodensteiner et al., 1998). A rare case of an abscess
that formed in the cavum septum pellucidum after the
elimination of a bacterial meningitis by antibiotics has
been reported. The abscess disappeared during continuation of the antibiotics (Kihara and Miyata, 2002).
The absence of the septum pellucidum almost always
signifies substantial neurological disease, since it is hardly
ever an isolated finding. However, isolated absence of
the septum pellucidum does exist (Supprian et al., 1999),
and the rare absence of the septum pellucidum alone does
not predict significant intellectual, neurological or behavioral dysfunction (Groenveld et al., 1994). A few patients
present with schizophrenic psychosis (Supprian et al.,
1999). Agenesis of the septum pellucidum can be part of
a developmental brain disorder such as schizencephaly
(Denis et al., 2000) as part of a continuum of the spectrum of proencephaly or the absence can be acquired in
case of a long-standing, substantial hydrocephalus. In the
developmental category, septo-optic dysplasia should be
mentioned (see Chapter 18.3), which is considered to be
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CHAPTER 19
Tumors
19.1. Symptoms due to hypothalamic tumors
(67%), hypothalamic hamartomas (100%) and subarachnoid cysts or arachnoidocele (100%). With the exception
of one patient with pineal germinoma, all lesions were
localized in the suprasellar area. The data suggested that
in glial cell tumors (Chapter 19.4), hamartomas (Chapter
19.3), gangliogliomas of the tuber (Chapter 19.3c) and
subarachnoid cysts an unknown factor, probably secreted
by the tumors, accelerates luteinizing hormone-releasing
hormone (LHRH) maturation (Rivarola et al., 2001). A
cranial MRI is thus indicated for children with central
precocious puberty (Ng et al., 2003). Tumors of the
tuberal and preoptic region of the hypothalamus are often
found in hypogonadism (Bauer, 1954). This is the case,
e.g. for craniopharyngioma (Chapter 19.5a), infundibuloma (Chapter 19.4c), pineal region tumors (Chapter
19.7), peritheloid sarcomas and angiomas. Other symptoms of hypothalamic tumors are hyperphagia and obesity
(Fig. 19.13), subcutaneous fat depletion (Connors and
Sheikholislam, 1977), fits of rage (Albert et al., 1993;
Chapter 26.3 for ventromedial hypothalamus syndrome),
amnesia, and attacks of laughter or crying (Bauer, 1954;
Haugh and Markesbery, 1983; Kahane et al., 1994;
Chapters 19.2, 19.3, 19.5). Cachexia (diencephalic
syndrome; Chapter 19.4a) and markedly elevated leptin
plasma levels, with increasing body mass index (Bmi),
are found in patients with hypothalamopituitary damage,
which suggests unrestrained leptin secretion. Leptin insensitivity is presumed in these patients (Patel et al., 2002).
In a patient with a probable hypothalamic germ cell
tumor, hypoadrenalism, hypogonadism, diabetes insipidus
and hypercalcenia have been found (Hotta et al., 1998).
Cushing described patients with hypothalamic tumors
associated with a duodenal ulcer and proposed the
existence of a parasympathetic center in the hypothalamus, which would send fiber tracts to the vagal center
Primary tumors and metastasis may be the causes of

nonspecific symptoms such as headaches, nausea,
vomiting, papilledema or seizures, or of more specific
hypothalamic symptoms, depending on the size of the
tumor and its location. But also in nonspecific symptoms
the hypothalamus may be involved. For instance, plasma
and cerebrospinal fluid (CSF) levels of vasopressin are
increased in brain tumors with brain edema (Tenedieva
et al., 1994), and intracranial tumors may accompany
increased levels of CSF vasopressin (Srensen et al.,
1985; Srensen, 1986; Tenedieva et al., 1994).
(a) Endocrine and autonomic disturbances
Bauer (1954) reviewed 60 cases with various hypothalamic lesions that were collected from the literature and
that consisted largely of different kinds of hypothalamic
tumors, which are dealt with in Chapters 19.119.9. This
group of tumors contained low-grade optic gliomas as
found in pediatric patients with neurofibromatosis type I
(Robben et al., 1995; Chapter 19.4b), an astrocytic hamartoma (Chapter 19.3a), an infundibuloma (Chapter 19.4c),
astrocytoma (Chapter 19.4b), ependymoma or germinoma
(see Chapter 19.2).
Bauer (1954) listed a number of tumors, such as
hamartomas, that affect the posterior region of the hypothalamus, in particular the corpora mamillaria, and that
may cause precocious puberty (Chapters 19.3, 24.1).
Ganglioglioma were found to produce precocious puberty
in babies, three times more often in boys than in girls
(Sheehan and Kovacs, 1982; Chapter 19.4c). In a more
recent study, precocious puberty was found to be associated with glial cell tumors (19%), germ cell tumors
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(Carmel, 1985; Dolenc, 1999; Buijs and Kalsbeek, 2001;

Chapter 30). Autonomic seizures, paroxism of hypertension, tachycardia and sweating have been found in the
diencephalic syndrome (Chapter 19.4a; Connors and
Sheikholislam, 1977). When tumors cause ventricular
obstruction with a rise in intracranial pressure and/or
hydrocephalus, a loss of circadian temperature fluctuations may be found (Page et al., 1973), due to a disorder
of the circadian system (Chapter 4).
Other hypothalamic symptoms found in cases
with tumors are retarded growth, diabetes insipidus,
amenorrhea, panhypopituitarism, dysthermia, bulimia,
hydrocephalus (Coffey, 1989; see also Chapters
19.219.5, 19.7), prolonged fever and hyponatremia
(Spiegel et al., 2002; Chapters 22.6, 30.2). Tumors in the

region of the optic pathway or infundibulum may cause
optic atrophy, visual deficits (see Chapters 19.219.5)
or visual hallucinations (Baruk, 1936; Haugh and
Markesbery, 1983). Hypothalamic hamartomas (Chapter
19.3) may cause gelastic seizures, but this may also occur
after tumors (Chapter 26.2). Following a hypothalamic
glioma, a patients sexual orientation changed from
heterosexual to pedophile with impotence (Miller et al.,
1986; Fig. 19.1; Chapter 24.5e).
Hypothalamic lesions due to craniopharyngioma or
pilocytic astrocytoma may be accompanied by decreased
nocturnal melatonin levels and increased daytime sleepiness (Mller et al., 2002a).
Fig. 19.1. An infiltrating hypothalamic glioma in a patient with a change in sexual orientation from heterosexuality to pedophilia. (From Miller
et al., 1986, Fig. 3 with permission.)
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astrocytoma (Sorensen et al., 1995). Akinetic mutism was

observed following surgical removal of an epidermoid
cyst from the anterior hypothalamus that had probably
destroyed the median forebrain bundles that contain the
dopaminergic projections (Ross and Stewart, 1981;
Chapter 18.8). A similar condition has been described in
the literature in a case of chronic encephalitis that led to
destruction of the posterior hypothalamic nuclei and the
mamillary bodies. On the basis of akinetic mutism due
to an epidermoid cyst of the third ventricle (Cairns et al.,
1941), it was hypothesized nearly 40 years ago that
consciousness depends on the synthesis of impressions
from the outside world with those from inside the body,
and that hypothalamicthalamic connections, such as the
bundle of Vicq dAzyr and the connection between the
posterior hypothalamic nucleus and the medial nucleus
of the thalamus, would play a crucial role in this process.
From the data that are available now it seems that
lesioning of the dopaminergic projections from the brainstem is responsible for the symptoms of akinetic mutism
(Chapter 18.8). Removal of a hypothalamic tumor resulted
in an overwhelming urge to sleep during daytime. This
was hypothesized to be due to destruction of the suprachiasmatic nucleus (Chapter 4) or to an incomplete lesion
of the hypocretin/orexin system (Arii et al., 2001; Chapter
14, 28.4). Tumors, especially of the posterior part of the
(b) Cognitive and behavioral disorders

Psychiatric symptoms due to the tumors localized in the
hypothalamus included psychiatric disturbances, diagnosed, for example, as schizophrenia, psychoneurosis and
manic excitement (Malamud, 1967; Chapter 27.1; Fig.
19.2). Another example is a 9-year-old boy with a choroid
plexus papilloma of the third ventricle (Chapter 17.3c)
who developed a psychosis (Carson et al., 1997; Chapter
19.5a). A patient with craniopharyngioma (Chapter 19.5)
or prolactinoma may present with a significant behavioral
disturbance accompanied by deteriorated work performance, intermittent explosive disorder, hypersexual
behavior, confusional syndromes and hallucinations
(Carroll and Neal, 1997).
Patients with tumors of the region of the third ventricle
may exhibit the symptoms of Korsakoffs syndrome:
some impoverishment of intellect, changes of personality
(usually euphoria or apathy), disorientation, confabulation and memory impairment. The memory defects
concern both imprinting and retrieval (Williams and
Pennybacker, 1954). Tumors causing bilateral destruction
of the fornix may cause memory problems (Chapter 16),
but there are exceptions (Woolsey and Nelson, 1975).
Periods of transient global amnesia have been reported
after spontaneous hemorrhage in a hypothalamic pilocytic
Fig. 19.2. Left, periventricular location of tumor in floor, walls, and roof (including fornix) of third ventricle. Right, Histologic appearance of a
glioblastoma multiforme with characteristic pleomorphism, giant cells and focal necrosis (hematoxylin Van Gieson; slightly reduced from 75).
The clinical diagnosis was schizophrenic reaction and epilepsia of unknown origin. (From Malamud, 1967, Fig. 4 with permission.)
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hypothalamus, may cause somnolence or altered levels

of consciousness (Davison and Demuth, 1946; Coffey,
1989). Coma with hyperthermia is a prominent symptom
after acute injury of the hypothalamus, seen, e.g. after
removal of craniopharyngial tumors from the floor of the
third ventricle (Cairns, 1952).
Near total destruction of the anterior and middle part
of the hypothalamus and a partial preservation of the more
caudal part following total removal of a craniopharyngioma in a child has been described. The child survived
for a period of 6 years. The following symptoms were
found: diabetes insipidus due to destruction of the
supraoptic and paraventricular nucleus (SON and PVN;
see Chapter 22.2), chronic hypernatremia, which persisted
in spite of vasopressin substitution, absence of thirst
(characteristic of a lesion of the anterior hypothalamus;
Chapter 22.2), hyperphagia (based upon lesion of the
PVN and ventromedial nucleus (VMN)); (Chapters 23.1,
26.3), hypothyroidism and hypoadrenalism due to a
lesion of the PVN; Chapters 8.5, 8.6), impairment of
temperature regulation (damage of, e.g. the laterocaudal
hypothalamus, preoptic area and PVN; Chapter 3030.2),
abnormality of sleep pattern and reversal of diurnalnocturnal sleep rhythms, probably due to a lesion of
the suprachiasmatic nucleus (SCN) and posterior
hypothalamus; Chapter 4), episodic savage behavior
(lesion of the VMN; Chapter 26.3, 26.9) and diabetes
mellitus due to hyperphagia (Killeffer and Stern, 1970;
Chapter 26.3).
Hypothalamic syndromes may also be caused by a large
number of different pathological processes that arise in
the pituitary or the parasellar region, e.g. due to pituitary masses that undergo silent infarction, cysts, pituitary
adenomas, acute or chronic infection with abscess formation, metastasis or aneurysms (Melmed, 1995).
The syndrome of idiopathic hypothalamic dysfunction
of childhood may accompany permanently dilated pupils,
obesity, central hypoventilation, hypersomnia, hyperphagia, personality changes, abnormal temperature
regulation, decreased sensitivity to pain, adipsic hypernatremia, hyperprolactinemia, seizures amd precocious
puberty (North et al., 1994; Sirvent et al., 2003; Chapter
32.1). It is thought to be a nonmetastatic paraneoplastic
syndrome, secondary to a neuronal crest tumor, e.g. to
a ganglioneuroma or ganglioneuroblastoma. There can
be extensive lymphocytic/histocytic infiltrates in the
hypothalamus and other brain areas, associated with
some neuronal loss and reactive gliosis. The neoplasm
may produce antineuronal antibodies, such as anti-Hu
(Ouvrier et al., 1995), as has also been observed in limbic

encephalitis (Alamowitch et al., 1997; Chapter 32.1).
Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory
loss and sometimes dementia, due to antineuronal antibodies. Patients with anti-Ta (also called anto-Ma2)
antibodies are young men with testicular tumors. They
frequently show hypothalamic involvement through
symptoms such as diabetes insipidus, loss of libido,
hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism, and a poor neurological outcome. Sometimes
the outcome is favorably influenced by treatment of the
tumor (Gultekin et al., 2000).
19.2. Germinoma and teratoma
One-third of all brain tumors in the pineal region (see
Chapter 19.7) consist of parenchymal tumors (pineocytomas, pineoblastomas), one-third of glia tumors
(astrocytomas, ganglion gliomas) and one-third of germ
cell tumors, of which less than one-third are germinomas
(Styne, 1993; Fig. 19.19). Germinomas and teratomas are
tumors of germ cell origin and make up 0.49.4% of all
childhood brain tumors. Germinomas are the least differentiated of the germ cell group, whereas teratomas
differentiate along all three germ cell layers (Fig. 19.3;
Chong and Newton, 1993). Germ cell tumors may contain
one cell type (pure) or more than one cell type
(mixed) (Schut et al., 1996). Twenty to thirty-five
percent of the germinomas are present in the sellar and
suprasellar region.The age of the patients is limited to
the first three decades. Germinomas were previously
known as pinealomas, ectopic pinealomas, atypical
teratomas or dysgerminomas (Coffey, 1989; Fujisawa
et al., 1991; Styne, 1993; see Chapter 19.7). They tend
to be located in the midline area, such as in the pineal
region (Chapter 19.7), and in the suprasellar and third
ventricular regions. Germinomas of the hypothalamoneurohypophysial axis seem to originate from the
neurohypophysis (Saeki et al., 2000). A 5-year-old girl
that presented with diabetes insipidus and a loss of the
hyperintense MRI signal of the neurohypophysis was
found to have an immature hypothalamic teratoma 7
months later (Lee et al., 1996). A 16-year-old boy had
polyuriapolydipsia and diplopia. MRI was suggestive of
an optic nerve glioma, but the high human chorionic
gonadotropin (HCG) levels led to the right diagnosis, i.e.
germinoma (Carella et al., 1999). Neurohypophysial
germinomas may cause not only diabetes insipidus and
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Fig. 19.3. Suprasellar teratoma. A. Parasagittal MR scan shows an area of hyperintensity in the interpeduncular cistern, representing the fatty
component of the tumor. B. Midsagittal section shows the more solid portion of the tumor with irregular areas of hyperintensity and isointensity.
C. Midsagittal postcontrast-enhanced MRI scan shows enhancement of the solid portion of the tumor. (From Chong and Newton, 1993, Fig. 27
with permission.)
et al., 1997). The initial endocrine symptoms are generally diabetes insipidus or pituitary insufficiency, but also
hyperprolactinemia, hydrocephalus, visual field defects
and optic atrophy (Coffey, 1989; Fujisawa et al., 1991;
Rutka et al., 1992; Chong and Newton, 1993; Nishio et
al., 1993a; Mootha et al., 1997; Saeki et al., 2000; Iwaki,
2001). In addition, polydipsia and adipsia have been
reported (Zazgornik et al., 1974). In a woman with a
hypothalamic germinoma, profound anterograde amnesia
and hyperphagia were reported (Coffey, 1989).
Interestingly, the fine structure of the suprasellar germinoma which can be revealed by transphenoidal biopsy
when the lesion progresses or if tumor markers (see
below) are positive (Mootha et al., 1997) is identical
to that of the classic testicular seminoma, consisting of
primordial germ cells with large pleomorphic nuclei with
prominent bar-like nucleoli and vacuolated cytoplasm
containing alkaline phosphatase (Schut et al., 1996), infiltrated with lymphocytes.
In men, germinomas may cause precocious puberty
because they may secrete chorionic gonadotropins
(HCG), which stimulate the secretion of testosterone.
Some germinomas such as endothelial sinus tumors
multiple anterior pituitary deficiencies, but also compression of the optic chiasm and of the hypothalamus (Saeki
et al., 2000). What we know of the pineal germinomas
also applies to those of the suprasellar region (Schut
et al., 1996); they have even been seen synchronously in
a few patients (Ellenbogen and Moores, 1997; Saeki
et al., 1999; Fig. 19.4), suggesting a common origin.
Germinomas are malignant but also highly radiosensitive,
which makes early diagnosis of vital importance
(Fujisawa et al., 1991; Mootha et al., 1997; Leger et
al., 1999). Endoscopic management of a pineal and
suprasellar germinoma has been reported (Ellenbogen
and Moores, 1997). A combination of radiotherapy and
chemotherapy is advocated in order to improve the
outcome. However, pituitary dysfunctions often persist
after treatment (Saeki et al., 2000).
In contrast to craniopharyngiomas, germinomas tend
to be homogeneous and rarely have cystic components.
The first abnormal, contrast-enhanced MRI finding is
generally isolated pituitary stalk thickening (Mootha et
al., 1997; Czernichow et al., 2000). The normally hyperdense MRI signal of the posterior pituitary is often absent
(Rutka et al., 1992; Chong and Newton, 1993; Mootha
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Fig. 19.4. Pineal and suprasellar germinoma. Precontrast (A) and postcontrast-enhanced (B) midsagittal MR imaging scans. A suprasellar-enhancing
mass has caused distortion of the anterior third ventricle. Note also the downward displacement of the supratentorial portion of the aqueduct and
the anterior displacement of the posterior third ventricle caused by the pineal-region mass (arrows). (From Chong and Newton, 1993, Fig. 26 with
permission.)
secrete -fetoprotein or placental alkaline phosphatase,

which may also be used as tumor markers (Styne, 1993;
Mootha et al., 1997; Carella et al., 1999; Rivarola et al.,
2001; Fig. 19.18). Increased serum levels of lactate-dehydrogenase have been proposed as another marker for a
germinoma (Carella et al., 1999). HCG is strongly
elevated in chorion carcinomas (Schut et al., 1996). With
the exception of the benign teratoma, all intracranial germ
cell tumors are malignant, capable of CSF dissemination
and of forming systemic metastases. Tumors in the
suprasellar region may be metastatic when it concerns
germinomas involving the pineal gland. Pineal region
germinomas (Fig. 19.4) are more common in males, while
there is a distinct predilection for females to harbor these
tumors in the suprasellar region. Subependymal spread
along the lining of the third ventricle is a common feature
(Rutka et al., 1992; Chong and Newton, 1993; Iwaki,
2001). In a 25-year-old man, a neurohypophysial tumor
that presented with visual disturbance and hyperprolactinemia appeared to be a rare mixture of a germinoma
and prolactinoma (Sugiyama et al., 1999). One case of a
suprasellar germinoma in a patient with Cornelia de Lange
syndrome has been reported, suggesting a causal relationship between teratogenesis and oncogenesis (Sugita
et al., 1986).
Teratomas may be mature (benign) or immature (malignant). Teratomas differentiate along all three germ cell
layers. Fat and calcifications are often present in teratomas
(Chong and Newton, 1993; Fig. 19.3). In one case of
primary bilateral anophthalmia, a teratoma of 5 2 mm
size containing cysts, glandular structures, intestinal
epithelium, fibrous tissues with nerve cells and fibers and
cartilage, was found in the region of the mamillary body
(Recordon and Griffiths, 1938). Yolk sac or endodermal
sinus tumor, choriocarcinoma and embryonal cell tumor
represent the less-common nongerminoma germ cell
tumors. The endodermal sinus tumor is also found in
the ovaries, testes, cervix and vagina of children. A
few of such tumors have been identified in the pineal
gland region (Chapter 19.7). The tumor has a typical
honeycomb pattern and is believed to be derived from
antecedents of the yolk sac (yolk sac carcinoma).
It is a highly vascular tumor capable of producing fetoprotein, while the HCG levels are usually negative.
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the tissue. They do contain neurons large and small

that are similar to those of the tuber and adjacent
structures (Driggs and Spatz, 1939; Clarren et al.,
1980; Albright and Lee, 1992; Fig. 19.8). Cystic changes
have occasionally been observed in huge hypothalamic
hamartomas due to intratumoral hemorrhage and liquefactive necrosis (Prasad et al., 2000). Hamartomas were
shown to contain neuron-specific enolase, synaptophysin
and neurofilaments, and some of them have corticotropinreleasing hormone (CRH), LHRH, metenkephalin
(Valdueza et al., 1994a) or growth hormone-releasing
hormone (GHRH) (Scheithauer et al., 1983)-containing
neurons. Generally, hamartomas are associated with an
MRI that is isointense, relative to gray matter. However,
a 1.5-year-old patient with a pedunculated hypothalamic
hamartoma was described whose T1-weighted MRI
images were hyperintense and thus suggestive of adipose
tissue. Microscopically an admixture of neuroectodermal
elements, namely glial cells, neurons and nerve bundles,
was found, along with mesenchymal elements in the form
of fibroadipose tissue (Sharma et al., 1998).
It metastasizes early to various regions of the brain,

including the hypothalamus (Yen, 1993; Schut et al.,
1996) and it has been proposed that these germ cell tumors
are derived from errant germ cells origin-ating in the yolk
sac endoderm (Chong and Newton, 1993).
19.3. Hamartoma
(a) Hypothalamic hamartoma
Hypothalamic neuronal hamartomas are rare malformations that may arise from the mamillary bodies or the
tuber cinereum and that occur at the ventral aspect of
the posterior hypothalamus (Chong and Newton, 1993;
Figs. 19.5, 19.6). In rare cases they may have a prechiasmatic location (Valdueza et al., 1994a). They
may be pedunculated or sessile, i.e. with a broad and
unconstricted interface with the hypothalamus (Albright
and Lee, 1992; Valdueza et al., 1994a; Arita et al., 1999;
Fig. 19.7). Arita et al. (1999) distinguished a parahypothalamic (= pedunculated) and an intrahypothalamic
(= sessile) type. Hamartomas are made up of mature but
disorganized neural tissue that shares similarities with
the tissue observed in the normal hypothalamus and are
therefore considered to be malformations rather than
neoplasms. They usually do not grow and do not invade
Symptoms of hamartomas
Gelastic seizures, characterized by attacks of laughter,
have been noted in 48% of the hamartomas. In addition,
attacks of crying have been described (see Chapter 26.2).
The epileptic syndrome is characterized by gelastic
Fig. 19.5. Hamartoma of the tuber cinereum. Midsagittal (A) and coronal (B) T1-weighted MR scans. A pedunculated mass (arrows) is noted in
the region of the tuber cinereum. The lesion is isointense to the adjacent brain. (From Chong and Newton, 1993, Fig. 24 with permission.)
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Fig. 19.6. Asymptomatic hypothalamic hamartoma (NHB 84186; 29 years of age) in the median eminence/pituitary stalk region stained for its
strong vasopressin innervation. The tumor was less densely innervated by oxytocin fibers and did not stain for luteinizing hormone-releasing
hormone. Bar = 1 mm.
seizures beginning in early childhood, often in the

neonatal period. One child was diagnosed at 3 months of
age with spells characterized by hyperpnea, followed by
cooing respirations, and giggling and smiling at 1520
min intervals. Single photon-emission computed tomography (SPECT) demonstrated dramatic ictal uptake in the
area of the 2.8-cm-diameter tumor, with normalization
during the interictal phase (DiFazio et al., 2000). Usually
there is a later development of focal seizures and a pattern
of symptomatic generalized epilepsy with tonic, atonic
and other seizure types in association with low spikeand-wave discharge and cognitive deterioration (Berkovic
et al., 1997). In a patient with refractory localizationrelated epilepsy associated with a hypothalamic
hamartoma, it was found that the frontal and temporal
cortex contributed to slowing of the heart rate, while the
lesion per se in the hypothalamus was not involved in
that phenomenon (Kahane et al., 1999). SPECT showed
ictal hyperperfusion in the hamartomas, the hypothalamic

regions and thalamus only. Depth electrodes implanted
in the hamartoma demonstrated focal seizures and electrical stimulation reproduced the typical gelastic events.
Stereotactic radio frequency lesioning of the hamartoma
resulted in seizure remission. These observations indicate
that the gelastic seizures originate from the hypothalamic
hamartoma and adjacent structures (Berkovic et al., 1997;
Kuzniecky et al., 1997; Freeman et al., 2003). However,
the interictal spike-wave does not arise from the hamartoma itself since it did not disappear following hamartoma
resection (Freeman et al., 2003). Tasch et al. (1998) could
not find any neuronal damage in the temporal lobes of
patients with hypothalamic hamartomas and gelastic
epilepsy using proton magnetic resonance spectroscopy
imaging, which is further evidence that gelastic seizures
do not originate in the temporal lobe but in the hamartomas themselves.
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A study of interictal spike electroencephalographic

(EEG) source analysis in hypothalamic hamartoma
epilepsy also demonstrated that the source of the spike
activity was located in the neighborhood of the
hamartoma and not in the cortex (Leal et al., 2002). In
addition, visual disturbances, precocious puberty (in 74%
or more of the cases; Styne, 1997; Rivarola et al., 2001),
acromegaly, diabetes insipidus or other endocrinopathies
have been reported. A child has been described with
precocious puberty due to a hypothalamic hamartoma on
the basis of neurofibromatosis type 1 (Biswas et al., 2000).
Children with gelastic seizures and hypothalamic hamartoma display a great number of psychiatric disorders,
including oppositional defiant disorders (83%), attentiondeficit-hyperactivity disorder (75%), conduct disorder
(33%) speech retardation and learning impairment (33%),
and anxiety and mood disorders (17%). In 3058%,
significant rates of aggression were noted (Weissenberger
et al., 2001). The behavioral and cognitive defects
illustrate the role of the hypothalamus in these processes.
Hamartomas may be associated with seizure disorders
that become drug-resistant (Munari et al., 1995).
Moreover, there may be behavioral disorders; the children are restless, violent, emotionally unstable, antisocial
and intellectually impaired. All children with gelastic
seizures and hypothalamic hamartoma display cognitive
deficits ranging from mild to severe (Frattali et al., 2001).
The mental decline is often progressive. The behavioral
disorders are probably mediated by disruption of the
connections between the mamillary bodies and other brain
structures.
Hamartomas are clinically evidenced in infants ranging
between 1 and 7 years of age and may range from 2 to
30 mm in size. The manifestation in a neonate has
also been described (Guibaud et al., 1995). The clinical
symptoms of hamartomas depend on their size and local-
ization (Valdueza et al., 1994a; Fig. 19.7 and Table 19.1).

Precocious puberty usually occurs in small, autonomous
LHRH-producing pedunculated hamartomas (types 1a and
1b, according to Valdueza et al., 1994a, Fig. 19.10;
Debeneix et al., 2001; Table 19.I), or the parahypothalamic type, according to Arita et al., 1999; Nishio et al.,
2001). Precocious puberty may be accompanied by rapid
statural growth, persisted breast swelling and pigmented
areolae as a sign of the exposure to high levels of oestrogens (Arisaka et al., 2001). Precocious puberty in a case
of hypothalamic hamartoma has also been described in
association with agenesis of the corpus callosum
(Alikchanov et al., 1998). For a differential diagnosis of
sexual precocity, see Albright and Lee (1992) and Chapter
24.1. Gelastic epilepsy and associated seizures are
observed only in large, sessile type IIa and IIb hamartomas (Fig. 19.7), characterized by a broad attachment to
the mamillary bodies (Valdueza et al., 1994a; Debeneix
et al., 2001). A displacement of the floor of the third
ventricle and/or an intrahypothalamic location (type IIb;
Fig. 19.7) may cause behavioral abnormalities (Valdueza
et al., 1994a). Hyperphagia, obesity, rage and dementia
have been described in a 20-year-old woman who had
a hamartoma that destroyed the ventromedial hypothalamus. She experienced hallucinations, had hypofunction
of the adrenals, gonads, thyroid, diabetes insipidus
and diabetes mellitus, and unexplained fever, probably
also due to the fact that autonomic regulatory functions were affected (Reeves and Plum, 1969; see VMN
syndrome, Chapter 26.3.). However, hamartomas are not
always accompanied by symptoms. The lesion can also
be found incidentally on postmortem examination
(Mahachoklertwattana et al., 1993; Kahane et al., 1994;
Valdueza et al., 1994a; Munari et al., 1995). We observed
a strong vasopressin innervation and some oxytocin innervations, but no LHRH or CRH in a hamartoma that was
TABLE 19.1.
Classification of hypothalamic hamartoma.
Type
1a
1b
11a
11b
Size
Attachment
Origin
Hypothalamic displacement
Common features
Smallmedium
Pedunculated
Tub cin
No
PP (or asymptomatic)
Smallmedium
Pedunculated
Mam bod
No
PP (or asymptomatic)
Mediumlarge
Sessile
Tub cin/mam bod
Slight
Gel, gen
Mediumlarge
Sessile
Tub cin/mam bod
Marked
Gel, gen, beh
Tub cin, tuber cinereum; Mam bod, mamillary body(ies); Gel, gelastic epilepsy; Gen, generalized and/or other epileptic types; Beh, behavioral
disorder; PP, precocious puberty. (From Valdueza et al., 1994a.)
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Fig. 19.7. Schematic drawing of different types of hypothalamic hamartomas on sagittal images. (From Valdueza et al., 1994a, Fig. 8 with
permission.)
found by accident at autopsy and that was situated in the

stalk/median eminence region (Fig. 19.6).
Pathogenesis. There are a number of theories on the
pathogenesis of endocrinopathies in relation to hamartomas:
ii(i) Neurons within a hamartoma would stimulate
hypothalamic neuroendocrine systems by direct
connections;
i(ii) The tumor might have a mechanical effect on the
hypothalamus. As an example, a case has been
reported of a 1.9-year-old girl with precocious
puberty and gelastic seizures due to a hypothalamic
hamartoma that was situated dorsally of the SCN.
She had melatonin levels that were low for her
chronological age but appropriate for the pubertal
status, suggesting a causal relationship between
lowered melatonin levels and puberty, due to
interruption of the connections between the SCN
and the pineal gland (Commentz and Helmke,
1995). However, the alternative, i.e. that decreased
melatonin levels are found following induction of

puberty by whatever mechanism and without interruption of the connections between the SCN and
pineal, seems at least as probable (Chapter 4.5d).
(iii) Neurons of the hamartoma would actively secrete
a hormone that activates the pituitary (Wolman
and Balmforth, 1963; Scheithauer et al., 1983;
Mahachoklertwattana et al., 1993). Judge et al.
(1977) demonstrated that a hamartoma in a
19-month-old boy with precocious puberty showed
all the characteristics of an independent neuroendocrine unit, supporting the latter of the three
hypotheses. It contained neurons that resembled
those of the hypothalamus, containing 100 nm of
neurosecretory granules and blood vessels, with
fenestrated endothelium and double basement
membranes, characteristics of vessels of the median
eminence that would permit release of neurosecretory products into the bloodstream. Each vessel
was almost totally surrounded by axons. In addition,
immunocytochemically the neurons appeared to
contain LHRH. The negative feedback between
gonads and brain was intact but partially resistant to
steroid suppression. These observations indicate that
the hamartoma may have caused precocious puberty
by autonomous production and release of LHRH.
Also the demonstration of neurosecretory cells and
their fibers that end on the portal vessels in a
girl with precocious puberty and a hypothalamic
hamartoma (Wolman and Balmforth, 1963) supports
this concept. In a review on long-term data
concerning 10 children with an LHRH-producing
hamartoma and their effective treatment with LHRH
agonists (see below), Mahachoklertwattana et al.
(1993) conclude also that the congenital malformation functions as an ectopic LHRH pulse generator.
Scheithauer et al. (1983) described a patient
who had a hypothalamic neuronal hamartoma that
had been present for 31 years and was associated
with hypopituitarism, a growth-hormone-producing
pituitary adenoma and acromegaly. Microscopically
the hamartoma was composed of ill-defined aggregates of small and large neurons and neuritic
processes. The neurons contained an abundance of
75- to 125-nm electron-lucent granules. GHRH
(somatoliberin) was demonstrated in these neurons.
The pituitary contained a predominantly growth
hormone-containing adenoma that was presumed to
be secondary to the neuronal abnormality, and a
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minute nodule of prolactin adenoma. So this case,

too, supported the third possible pathogenetic mechanism, i.e. hormone secretion by the neurons in the
hamartoma.
(iv) Hypothalamic hamartomas may induce precocious
puberty by the production of trophic factors that are
able to activate the normal LHRH network in the
patients hypothalamus. One of such factors is transforming growth factor-, which facilitates the gliato-neuron signaling process controlling the onset of
female puberty in rodents and nonhuman primates.
This factor (and not LHRH) has been found in girls
with hamartomas that induced precocious puberty
(Jung et al., 1999; Rivarola et al., 2001; Jung and
Ojeda, 2002).
61
However, some patients did report episodes of emotional

lability (Feuillan et al., 2000).
A number of papers advise against surgery as the initial
management of precocious puberty in case of hypothalamic hamartomas, because of the delicate site where the
tumor is located, and advised LHRH agonists (Stewart et
al., 1998). Surgical resection may, however, be an alternative treatment to LHRH only in the rare instance of
mass enlargement or compression of adjacent tissues that
is causing progressive neurological deficits or hydrocephalus (see also Albright and Lee, 1992; Valdueza
et al., 1994a), or when the seizures are refractory to
antiepileptic medication. Successful, complete or nearly
complete resection of hypothalamic hamartomas has been
achieved by a subtemporal approach (Nguyen et al.,
2003), the transcallosal approach (Rosenfeld et al., 2001;
Freeman et al., 2003) and by the lamina terminalis
approach (Kramer et al., 2001; Chapter 30.5). Resection
of hypothalamic hamartomas can alleviate both the
seizures and the behavioral and cognitive abnormalities,
but complications are frequent (Palmini et al., 2002).
However, examinations of a small series of children with
precocious puberty who underwent microsurgical treatment, suggested that this treatment was a good decision
(Luo et al., 2002). A case has been presented with gelastic
seizures associated with a hypothalamic hamartoma.
Partial resection failed to reduce the seizures, but subsequent stereotactic radiofrequency ablation resulted in
progressive improvement (Parrent, 1999). The new development of noninvasive focal radiation performed with a
gamma knife was successful in a number of patients with
intractable epilepsy, abnormal behavior and precocious
puberty due to an inaccessible hypothalamic hamartoma.
MRI performed 12 months later demonstrated complete
disappearance of the lesion (Arita et al., 1998; Regis
et al., 2000; Dunayer et al., 2002), but no change in the
size of the lesion was observed in other cases (Unger
et al., 2000, 2002). Gamma knife surgery may be especially useful for small sessile lesions, failed partial
resections and patients not appropriate for open surgery
(Nguyen et al., 2003). In patients with refractory epilepsy
secondary to hypothalamic hamartomas, seizures were
also controlled by intermittent stimulation of the left vagal
nerve (Murphy et al., 2000).
Related disorders. Hypothalamic hamartomas may also
be found as part of the orofacialdigital syndrome (MIM
165590; Fujiwara et al., 1999), which is a heterogeneous
syndrome and includes at least 11 types. They include
hypothalamic hamartomas, developmental delay, multiple
Therapy. The response to antiepileptic drug therapy has

invariably been disappointing (Wakai et al., 2002). It
should be noted that hamartomas are developmental
abnormalities that may well be found with other widespread abnormalities in the brain, which may provide a
structural basis for the poor response of seizures to
removal of the hamartomas or the presence of other apparently focal epileptogenic zones (Sisodya et al., 1997). An
example is a boy who had gelastic epilepsy, hypothalamic hamartoma, precocious puberty and agenesis of the
corpus callosum. The child had a dramatically impaired
mental function and a split brain pattern of the interictal EEG, indicating a developmental anomaly of the
commissural structures of the brain (Alikchanov et al.,
1998).
Mahachoklertwattana et al. (1993) treated nine patients
with an LHRH agonist. The basis of this therapy is that
interruption of the obligatory pulsatile release of LHRH
downregulates the release of follicle-stimulating hormone
(FSH) and LH. The response to this therapy was excellent. Later also young children, for example a 1-year-old
girl and an 8-year-old boy with precocious puberty, were
successfully treated with a super long-acting LHRH analogues that indeed induced regression of the hypothalamic
hamartoma (Nishio et al., 2001). Long-term follow-up
studies of children treated with LHRH analogues have
started only relatively recently (Feuillan et al., 1999). One
year after stopping the LHRH therapy, the LHRH-stimulated LH and FSH and testosterone returned to the normal
range. By 4 years after therapy, all patients had pubic hair.
The dimensions of the patients hamartomas did not
change with therapy, and no new neurological symptoms
or signs after discontinuation of therapy occurred.
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gingival granula, hamartomatous nodules on the tongue,

low-set ears, micrognathia and polysyndactyly of the
hands and feet. Orofacialdigital syndrome type VI
(Vradi syndrome) is an autosomal recessive trait of
orofacial anomalies, cerebellar dysgenesis and polysyndactyly. Cerebellar hypoplasia and variants of the
Dandy-Walker complex are the most common CNS
malformations reported in patients with this syndrome. A
boy with Vradi syndrome had hypothalamic hamartoma
and precocious puberty (Stephan et al., 1994). In addition, a boy was reported with hypothalamic hamartoma
and precocious puberty associated with agenesis of the
corpus callosum, Dandy-Walker complex and heterotopic
gray matter (Gulati et al., 2002).
(b) Hamartomatous nodules
In a thorough study of 239 consecutive autopsies, Sherwin
et al. (1962) found small hamartomatous nodules of the
posterior hypothalamus in 21% of the patients, suggesting
that such lesions are far from rare. Endocrinological
abnormalities and systematic neoplastic processes were
significantly associated with the presence of such malformations. An intimate relationship between the nodules and
perforating vessels existed. The nodules were located adjacent to or 1 mm lateral to the mamillary body, and 1 mm
rostral to the corresponding cerebral peduncle. In all cases
a branch of the posterior communicating artery penetrated
the center of the nodule. By carefully following the path
of this artery, the nodule was often found surrounding its
site of entry into the brain (Fig. 19.8). Microscopically,
the nodules were composed of an outer layer of compact
glial tissue and a central, loose glial tissue containing nerve
cells. These harmatomatous nodules should be distinguished from the true hamartomous nodules that arise
almost invariably from the central portion of the tuber
cinereum caudal from the pituitary stalk.
(c) Intrasellar gangliocytoma
A tumor related to a hamartoma is an intrasellar neuronal
choristoma or intrasellar gangliocytoma with neurons
of hypothalamic type, often within growth hormonecontaining pituitary adenomas resulting generally in
acromegaly and sometimes in Cushings syndrome,
galactorrhea and amenorrhea. Sometimes these are
endocrinologically nonfunctioning masses (Scheithauer et
al., 1983; Asa et al., 1984; Morikawa et al., 1997; Geddes
et al., 2000; Chapter 19.10). In a pituitary corticotroph
adenoma, neurons that stained for corticotropin (ACTH)

were described (Vidal et al., 2002). The term choristoma is preferable to the term hamartoma when
abnormal neoplastic cells are displaced from the normal
anatomical site (Rhodes et al., 1982). However, the term
choristoma is confusing, since it is also used for the
unrelated pituicyte-derived granular cells of the neurohypophysis (Chapters 19.4c, 22.1; Figs. 19.14, 21.1).
Rhodes et al. (1982) call these pituitary tumors ganglionneuromas. In addition, the terms gangliomas and
gangliocytoma are used for this group of tumors
(Morikawa et al., 1997). A case report mentioned the
presence of a gangliocytoma masquerading as a
prolactinoma with suprasellar and temporal lobe extension. The 36-year-old man presented with bitemporal
hemianopsia and a high serum prolactin concentration.
Later the tumor appeared to consist of dysplastic neurons
that were strongly immunoreactive for the neuronal
markers synaptophysin and neurofilament, and for
prolactin. This appeared to be a prolactin-secreting
gangliocytoma (McCowen et al., 1999). Such tumors in
acromegalic patients are closely associated with pituitary
adenomas and are often growth hormone and prolactin
positive (Geddes et al., 2000). It seems as if ganglion
cells have differentiated within the adenoma. For the
pathogenesis of this type of tumor, the alternative, i.e.
that it is primarily a tumor of neurons producing a GHRH
inducing secondary adenomas and acromegaly has also
been considered by some authors and discounted by others
(Geddes et al., 2000). It has also been suggested that a
progenitor cell might give rise to both adenohypophysial
cells and neurons producing, e.g. GHRH (Asa et al.,
1984). The tumors contain ganglion cells, fascicles of
unmyelinated neuronal processes, collagen and some glial
cells. If they contain neoplastic astrocytes they are termed
gangliogliomas. Rhodes et al. (1982) described a
ganglion-neuroma with epithelial cysts, the cells of which
resembled ependymal cells of the floor of the third
ventricle. Some of these cells were glial fibrillary acidic
protein (GFAP)-positive. It is supposed to be a tumor of
embryonic rests from the ventral neural ridge, displaced
early in development (Asa et al., 1980; Rhodes et al.,
1982; Morikawa et al., 1997). A ganglioglioma of the
tuber is a congenital tumor that at first glance appears to
be microscopically similar to an ordinary glioma, but it
produces a specific clinical picture: it is characterized by
precocious puberty in babies. In addition to astrocytes, it
contains nerve cells, sometimes scattered diffusely and
sometimes arranged in groups. It is three times as common
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Fig. 19.8. Hamartomatous nodules. A. In the right posterolateral tuber cinereum a conical nodule is shown (arrow). A small artery, arising from
the midpoint of the posterior communicating artery, enters its base. Two veins emerge from the nodule. BF. Representative serial sections are
demonstrated through the same nodule, beginning with the mamillary body level and extending to the extreme lateral tuberal area. In B, the band
of tissue between the vessels with a reversed 7 shape is the subpial white matter of the nodule. In C, D, and E the perforating artery appears
to have pulled down a wedge of tissue from the hypothalamic floor. In F the protuberant nodule exhibits ganglion cells, nerve fibers, and
whorled subpial fibers on the right. (From Sherwin et al., 1962, Fig. 13 with permission.)
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in men as in women. The patients usually die before the

age of 8 (Sheehan and Kovacs, 1982). Cases without
endocrinopathies may represent incomplete expression of
the hypothalamic neuronal choristoma-pituitary adenoma
complex (Scheithauser et al., 1983). For gangliocytoma
of the neurohypophysis, see Chapter 19.10.
(d) Hamartoblastomas (PallisterHall syndrome)
PallisterHall syndrome is a developmental disorder
consisting of hypothalamic hamartoma, pituitary dysfunction, polydactyly and visceral malformations. This
syndrome was first reported in infants. It consists of
hamartoblastomas of the hypothalamus with primitive,
undifferentiated neurons. For this reason the term hypothalamic hamartoblastoma was assigned initially to these
tumors. However, when children with this condition
survive, the neurons look more or less mature and are
admixed with astrocytes and minimal white matter, and
they are now thought to be hamartomas (Sills et al., 1993;
Kuo et al., 1999). On MR images the classic hypothalamic hamartoma/hamartomablastoma is noncalcified and
nonenhancing, homogeneously isointense to gray matter
(Kuo et al., 1999). A multilobulated mass arising from
the base of the brain that was shown to be a subhypothalamic heterotopia on the basis of a hamartoblastoma
has been described by Splitt et al. (1994). This patient
also had short or absent olfactory tracts.
The disorder is inherited as an autosomal dominant
trait with incomplete penetration, variable expressivity or
gonadal or somatic mosaicism (Biesecker et al., 1994;
Penman Splitt et al., 1994) and has been mapped to chromosome 7p13, colocalizing the PNS locus and the GL13
gene encoding a zinc finger transcription factor (Kang et
al., 1997). An unbalanced chromosomal translocation
between 7p and 3q has been reported in one patient
(Squires et al., 1995). Most cases are sporadic, but one
familial case has been reported (Sills et al., 1993; Kuo
et al., 1999). Hamartoblastomas arise probably in the 5th
week of pregnancy and seem to be part of a complex
pleiotrophic congenital syndrome that includes absence
of the pituitary, craniofacial abnormalities, cleft palate,
malformations of the epiglottis or larynx, congenital heart
defects, hypopituitarism, short-limb dwarfism with postaxial polydactyly, anorectal atresia, renal anomalies and
abnormal lung lobulation and hypogenitalism. For
syndromes that overlap with PallisterHall syndrome, see
Sills et al. (1993) and Kuo et al. (1999).
Endocrine evaluation showed hypopituitarism, i.e. low

serum cortisol, T4, growth hormone and insulin-like
growth factor (IGF-1) (Feuillan et al., 2001). One case
was treated with growth hormone until final height
was reached (Galasso et al., 2001). It was suggested
that hypothalamic deficiency would contribute to hypopituitarism in this syndrome. In addition, short olfactory
tracts suggest a relation with the arrhinencephaly defects.
The neurohypophysis is sometimes absent. The condition
was thought to be fatal in the neonatal period, but has
also been described in a patient older than 12 years
(Clarren et al., 1980; Chong and Newton, 1993; Sills et
al., 1993; Squires et al., 1995). The main cause of death
in the first cases to be described was acute adrenal insufficiency associated with panhypopituitarism (Kuo et al.,
1999).
19.4. Glioma
The majority of the gliomas affecting the hypothalamus
are diffusely infiltrative fibrillary or pilocytic (hair cell)
astrocytomas. Depending on their location, hypothalamic
gliomas may manifest themselves in the form of, e.g.
eating disorders, disturbances of temperature regulation,
precocious puberty, somnolence, rage, visual impairment
or hydrocephalus (Dolenc, 1999; Rivarola et al., 2001).
Pilocytic astrocytoma causing hypothalamic lesions may
be associated with decreased nocturnal melatonin levels
and increased daytime sleepiness (Mller et al., 2002a).
A rare case of a hypothalamic low-grade astrocytoma
causing gelastic seizures has been reported (Coppola et
al., 2002; Chapter 26.2). Most pilocytic astrocytomas arise
within the visual system. Optic pathway gliomas tend to
occur in young children and comprise 5% of the pediatric intracranial tumors (Janss et al., 1995). They may
(1) be confined to the optic nerve and cause opthalmological symptoms, including visual hallucinations (Haugh
and Markesbery, 1983) or (2) involve the optic chiasm
and hypothalamus and cause neuroendocrine symptoms
and symptoms of raised intracranial pressure. Chiasmatic/
hypothalamic tumors and tumors involving the chiasm
should only be distinguished because they are different
entities with a different prognosis and different treatments
(Steinbock et al., 2002). In addition, they may give rise
to diencephalic syndrome (Russells syndrome), spasmus
nutans or moyamoya disease. Very rarely does a hypothalamic glioma bleed within the subarachnoid space,
into the cerebrum or into the ventricles (Devi et al.,
2001). The diencephalic syndrome is seen in infants with
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children (Kornreich et al., 2001). They may give rise to

diencephalic syndrome of emaciation in infancy and
childhood, which was originally described by Russell in
1951. It is typified by severe weight loss, despite normal
linear growth, optic atrophy and signs of hypothalamic
dysfunction. In 90% of cases, it is due to a hypothalamooptic glioma (Pelc, 1972; Figs. 19.919.13), such as a
fibrillary or pilocytic astrocytoma, craniopharyngioma or
germ cell tumor. Pure optic gliomas are rare. Of the
32 cases of the diencephalic syndrome in which the
cellular type of the tumor was established, 25 had an
astrocytoma, 4 a polar spongioblastoma (now called
juvenile pilocytic astrocytoma), 1 an oligodendroglioma,
1 an astro-oligodendroglioma and 1 an ependymoma (Pelc,
1972). Burr et al. (1976) found a germinoma in one case.
The presence of Rosenthal fibers or intracytoplasmatic
masses of electron-dense material is characteristic (Styne,
1993). Possible embryological elements were present in
tumors of five other patients. It has become apparent that
in some 9% of the cases, nondiencephalic tumors appeared
posterior chiasmatic-hypothalamic tumors and is the only

neoplastic disorder of the central nervous system associated with infantile failure to thrive. Spasmus nutans is
characterized by head bobbing, head tilt and monocular
nystagmus in infants and is caused by gliomas that
are confined to the optic nerve. Moyamoya disease is
an occlusive disorder of the large cerebral arteries of
the circle of Willis, causing an abnormal capillary
network of moyamoya vessels to develop at the base of
the brain. It may occur as a consequence of irradiation
of optic pathway gliomas and may lead to massive cerebral hemorrhage (Chapters 17.2e, 25.3; Oka et al., 1981;
Chamberlain, 1995; Sinsawaiwong and Phanthumchinda,
1997).
(a) Diencephalic syndrome: hypothalamo-optic
glioma/optic pathway glioma
This low grade astrocytoma accounts for 5% of all brain
tumors and for 1015% of supratentorial tumors in
Fig. 19.9. A. Diencephalic syndrome. Note the severe emaciation of the whole body and the characteristic pseudohydrocephalic appearance. B.
MRI of the brain. T1-weighted sagittal images (repetition time/echo time: 570/15) after gadolinium enhancement demonstrate the presence of a
large tumor involving the hypothalamic region, distorting the chiasm and brainstem, and extending into the third ventricle. Neuropathologically,
the tumor proved to be a hypothalamic astrocytoma with pilomyxoid features. (From Zafeiriou et al., 2001, Figs. A, B, with permission.)
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Fig. 19.10. Chiasmatic glioma. Sagittal (A) and parasagittal and coronal (B) MR scans. The tumor has enlarged the left side of the chiasm and
the left optic nerve (arrows). (From Chong and Newton, 1993, Fig. 25 with permission.)
to be present with similar clinical features (Burr et al.,

1976). The majority of pilocytic astrocytomas are nonaggressive and have a low proliferation index. However, a
subpopulation has a propensity for aggressive behavior.
Diffuse astrocytomas show a high proliferation index
(Cummings et al., 2000). Although most optic gliomas
are histologically low-grade astrocytomas, they tend to
infiltrate along the optic pathways. In 70% of cases with
hypothalamic glioma, involvement of the optic nerves or
the whole optic pathway is also present. Some chiasmatic
tumors remain quiescent for several years, others grow
slowly (Pelc, 1972; Rutka et al., 1992; Perilongo et al.,
1997). However, the whole spectrum from pilocytic (WHO
grade I) to glioblastoma (WHO grade IV) may be present
(Cummings et al., 2000). Gliomas of the optic nerve
include highly infiltrative tumors that behave in a malignant manner (anaplastic astrocytomas, WHO grade III;
glioblastomas, WHO grade IV) (Cummings et al., 2000).
The age of onset ranges from the newborn period to
4 years, with the peak incidence between 2 and 7 months
of age (Pelc, 1972). In 63% of cases, death occurs before
the 2nd year (Pelc, 1972).
Although extremely rare, diencephalic syndrome of

emaciation can occur in an adult harboring a tumor, e.g.
a craniopharyngioma, in the anterior hypothalamus
(Miyoshi et al., 2003). The main clinical features of the
diencephalic syndrome include a failure to thrive, extreme
cachexia with normal height, hyperkinesis, alert appearance, vomiting, surprisingly happy affect or euphoria,
pallor without anemia, hypothermia, excessive sweating,
nystagmus and decreased visual acuity. Nystagmic eye
jerking is found in 70% of the cases (Pelc, 1972).
Precocious puberty has also been described (Robben et al.,
1995) and is probably related to tumor location (CollettSolberg et al., 1997). In addition, disturbances of temperature regulation or appetite, autonomic seizures, paroxisms
of hypertension, tachycardia, diabetes insipidus or a
syndrome of inappropriate vasopressin secretion are found
(Chong and Newton, 1993; Connors and Sheikholislam,
1977; Chapter 22.6). Despite a normal caloric intake, these
children lose weight, according to some authors possibly
due to their disproportionately high energy output (Braun
et al., 1959; Greenes and Woods, 1996). Other factors in
emaciation may be the anterior pituitary defect (Russell,
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Fig. 19.11. Inferior surface of brain. The large multiloculated cystic tumor can be seen anterior to the brain stem in the region of the
hypothalamus. (From Braun et al., 1959, Fig. 2 with permission.)
gigantism with growth hormone excess (Manski et al.,

1994). A 4-year-old child with optic chiasm glioma had
nonobstructive hydrocephalus. He had a ventriculoperitoneal shunt following which marked ascites developed.
The ascitic fluid was rich in protein, most probably
explaining the hydrocephalus he had previously. The
CSF protein level and the amount of ascites fluid were
influenced by chemotherapy. Very unusual hypernatremia
develops in those cases, presumably by osmoreceptor
dysfunction (Shuper et al., 1997).
Surgery, chemotherapy and radiation therapy have
been advocated as therapies for chiasmatic-hypothalamic
gliomas (Nishio et al., 1993b; Konovalov et al., 1994;
Valdueza et al., 1994b; Chamberlain, 1995; Janss et al.,
1951), elevated growth hormone levels or other endocrine

defects (Greenes and Woods, 1996), or subcutaneous fat
depletion due to autonomic alterations (Connors and
Sheikholislam, 1977). Hydrocephalus is sometimes also
present, as are large hands, feet and genitalia. Tumor cells
and/or increased concentration of CSF protein is present
in most patients. Dissemination via the CSF has also been
reported. There may be an inappropriate, even paradoxical,
plasma growth hormone response to hyperglycemia and
hypoglycemia, and lack of diurnal variation in plasma
cortisol (Burr et al., 1976; Costin, 1979Greenes and
Woods, 1996). In a 16-month-old boy, an extensive
optic pathway glioma probably infiltrating into somatostatinergic pathways was observed, accompanied by
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Fig. 19.12. Midsagittal section of brain. The cyst is seen to invaginate the wall of the third ventricle. The cyst is ovoid and contains a
gelatinous, slightly granular matter. (From Braun et al., 1959, Fig. 3 with permission.)
1995; Greenes and Woods, 1996Silva et al., 2000; Kageji

et al., 2003; Khafaga et al., 2003). Decisions about the
institution of chemotherapy depend on many factors, such
as the age of the patient, whether the child has a neurofibromatose type of tumor (see below), tumor grade and
tumor size, tumor location, and the potential sequelae of
radiotherapy and chemotherapy (Packer, 2000). A high
response rate to cisplatin/etoposide was found in childhood low-grade glioma (Massimino et al., 2002).
According to some authors, postoperative radiation
therapy is effective and can prevent loss of vision
(Grabenbauer et al., 2000). Others start more conservatively with CSF shunting, treating a rapidly expanding
tumor with mass surgery and giving chemotherapy. Only
when chemotherapy is found to be ineffective do they

advise radiation therapy (Alshail et al., 1997). Treatment
of the diencephalic syndrome with carboplatin and
vincristine regimen results in demonstrable weight gain,
may cause tissue shrinkage and in some cases significantly delays the need for other therapies. Dolenc
(1999) points to the recently radically changed treatment
which has made atraumatic microsurgical resection
the method of choice for hypothalamic gliomas. Gammaknife radiosurgery is effective in low-grade astrocytomas. Complete cure was observed in some cases (Kida
et al., 2000). Spontaneous involutions of pilocytic
astrocytoma has been reported in some children
(Balkhoyor and Bernstein, 2000). It should be noted
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Fig. 19.13. Magnetic resonance images: (a) Coronal brain section showing the normal human hypothalamus at the level of the optic chiasm; and
(b) line drawing of the principal structures. (c) Sagittal section through normal pituitary gland and hypothalamus; and (d) line drawing of the principal structures. (e) Coronal section demonstrating suprasellar mass lesion (glioma) with invasion of the mediobasal hypothalamus and distortion
of the third ventricle, leading to obesity, and (f) line drawing of the principal structures. (g) Sagittal image showing upward expansion of glioma
into medial hypothalamus; and (h) line drawing of the principal structures. (From Pinkney et al., 2002 Fig. 1 with permission.)
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that major causes of endocrine abnormalities in hypothalamic chiasmatic gliomas were field irradiation and
tumor surgery (Collett-Solberg et al., 1997).
(b) Gliomas of the optic pathways
Associated with neurofibromatosis, gliomas of the optic
pathway are considered to be separate entities and account
for 1070% of this group of tumors (Kornreich et al.,
2001). The diencephalic syndrome, diffuse EEG changes,
delayed development and seizures are also found in
patients with neurofibromatosis type I (Venes et al., 1984;
Chong and Newton, 1993; Robben et al., 1995; Cummings
et al., 2000). This is an autosomal, dominant disorder with
a prevalence of 1 in 3000 to 4000 and is caused by a
mutant gene on the long arm of chromosome 17 (q11.2)
(Styne, 1997). Approximately half of the cases are
spontaneous mutations (Zuccoli et al., 2000). The neurofibromatose gene encodes a tumor-suppressor factor
which interacts with the ras oncogene p21 (Gottschalk
et al., 1999). The data provided on the association between
glioma of the optic pathway are variable. Ten to seventy
percent of the patients with visual-pathway gliomas have
neurofibromatosis and 515% of patients with neurofibromatosis have a tumor of the optic pathway (Styne,
1993; Valdueza et al., 1999b; Janss et al., 1995). Optic
pathway glioma is the most common brain tumor
associated with Von Recklinghausens disease. In patients
with neurofibromatosis, the most common site of
involvement is the orbital nerve; the tumor is smaller,
the original shape of the optic pathway is preserved and
optic components are uncommon (Kornreich et al., 2001).
Neurofibromatous type I patients may follow a more
aggressive course of the disease (Valdueza et al., 1994b).
One of these cases with emaciation, marked increase in
serum growth hormone levels, and anaplastic astrocytoma
of the optic chiasmahypothalamic region has been
described in an adult (Tanabe et al., 1994). In a 5-yearold boy with neurofibromatosis type I, a chiasmatic glioma
caused a rapid visual acuity loss, which improved significantly after radiation (Adams et al., 1997). However,
generally there is only minimal tumor enlargement, while
in most cases the optic glioma patients without neurofibromatose show a clear propensity (Kornreich et al.,
2002). Hydrocephalus as complication (Gottschalk et al.,
1999) is extremely rare in neurofibromatosis cases
(Kornreich et al., 2001). Endocrine dysfunction occurs
less often in neurofibromatosis patients who are treated
conservatively (Collett-Solberg et al., 1997). Differential
diagnosis includes germinoma, craniopharyngioma,

meningeoma, lymphoma, histiocytosis and inflammatory
conditions. Traditionally the treatment has included
radiation, surgical resection and, in some special cases,
chemotherapy (Gottschalk et al., 1999). The observation
of postoperative regression of a biopsy-proven opticochiasmatic glioma strengthens the argument for conservative therapy in young children with neurofibromatosis
(Venes et al., 1984). In some patients, mainly children,
with neurofibromatosis I as revealed on serial MRI, spontaneous partial or even total remission of the neoplasm in
the hypothalamic region was found, implying also that a
cautious approach to therapeutic management should be
taken in asymptomatic cases (Gottschalk et al., 1999;
Zuccoli et al., 2000).
(c) Other gliomas
Intrinsic astrocytomas of the posterior pituitary (pituicytomas) or stalk (infundibulomas) are rare (Scothorne,
1955). Infundibuloma (or astrocytoma of the third
ventricle or glioma of the tuber) occur mainly in childhood or adolescence and often cause death at that stage,
although there are long survivors. Histologically it is a
fibrillary astrocytoma. In children the capillaries tend to
be arranged in plexuses remarkably reminiscent of the
gomitoli in the upper part of the pituitary stalk (Chapter
17.1c), suggesting that the tumor is derived from the
neurohypophysial tissue of the infundibulum (Sheehan
and Kovacs, 1982). In contrast to the granular cell tumors,
the cells contain no pigment (Massie, 1979). Only a few
pilocytic pituitary astrocytomas or pituicytomas have been
described. MRI shows extension of the tumor into the
stalk. There may be panhypopituitarism as an early manifestation, whereas diabetes insipidus may be absent,
probably by vasopressin release above the level of the
tumor (Nishizawa et al., 1997). The astrocytic nature of
such a tumor can be confirmed by the presence of GFAP
staining. Such tumors closely resemble pilocytic astrocytomas in other parts of the central nervous system
(Schothorne, 1955). A 40-year-old man has been
described with such a tumor, visual failure and hyperprolactinemia (Rossi et al., 1987). Another case of a
pituicytoma presented in a 26-year-old woman with dizziness and visual obscuration. MRI revealed a pituitary
mass with suprasellar extension. Immunocytochemistry
was positive for GFAP, S-100 and vimentin. This pituicytoma was not a pilocytic variant (Hurley et al., 1994).
One case of a pituicytoma causing hypopituitarism and
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Fig. 19.14. Granular cell tumor. NHB 98-010, female, 75 years of age. Hematoxylineosin. Bar = 2 mm.
visual impairments or headache (Jenevein, 1964; Symon

et al., 1971; Massie, 1979; Horvath et al., 1997; see also
Chapter 22.1).
Gliomatosis cerebri is an uncommon tumoral pathology,
but its incidence may be grossly underestimated. It is a
neuroepithelial neoplasm of unknown origin. Less than
200 cases have been reported in the literature. The tumoral
proliferation consists of astrocytes, oligodendrocytes or
both, with different degrees of maturation. When infiltrating myelinated tracts, the cells often form parallel rows
among nerve fibers. In these cases myelin sheaths may be
destroyed, but axons survive. Immunocytochemistry may
or may not show GFAP expression. Areas of high mitotic
activity and microvascular proliferation may be observed,
but there is no necrosis. The hypothalamus may be affected,
in some cases resulting in a hypothalamic syndrome.
However, the most frequent clinical manifestations are
mental deterioration and personality changes. In addition,
signs of increased cranial pressure, including empty sella,
have been reported (Peretti-Viton et al., 2002).
visual disturbances was not only positive for GFAP,

vimentin and epithelial membrane antigen, but had aggregates of intermediate filaments in a concentric pathway
(fibrous body) and secretory granules. It might also have
arisen from the stromal folliculostellate cells of the adenohypophysis (Cenacchi et al., 2001).
A special form of gliomas are the granular cell tumors
or choristomas that are composed of large cells with
granular, lightly eosinophilic, cytoplasm. They are
thought to derive from pituicytes, i.e. modified astrocytes
in the neurohypophysis. Occasional tumor cells may
contain brown pigment similar to that found in pituicytes.
The granules in this pigment stain with Sudan black,
characterizing it as a lipopigment. Minute nodules of granular cells are commonly found in the posterior pituitary
and stalk. They occur in some 5% of the pituitaries, are
called tumorlets, granular cell myoblastoma or choristoma, and are generally asymptomatic (Fig. 19.14, 22.1;
Horvath et al., 1997). Symptomatic granular cell tumors
are rare and may be associated with diabetes insipidus,
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For third ventricle chordoid glioma (Pomper et al.,

2001), see Chapter 17.3; and, for septum pellucidum
tumors, see Chapter 18.8. The subependymal giant cell
astrocytoma in tuberous sclerosis is described in Chapter
19.8.
19.5. Craniopharyngioma, Rathkes cleft cysts and
xanthogranuloma
(a) Craniopharyngioma
A low-grade developmental neoplasm, craniopharyngioma is thought to be derived from Rathkes pouch, the
pituitary anlage and can arise anywhere along the
craniopharyngeal canal. This canal is usually obliterated
during the 12th week of gestation. Rathkes pouch occurs
in embryos of 812 mm (2nd6th week) and is obliterated
between 6 and 8 weeks (Rottenberg et al., 1994). Rare

cases have indeed been described with a persistent craniopharyngeal canal and an intimate relationship that showed
up on MRI between the canal and the infrasellar part
of a craniopharyngioma (Chen, 2001), or with a nasopharyngeal extension of a normally functioning pituitary
gland extending into the nasopharynx (Ekinci et al., 2002).
It is the commonest intracranial tumor of nonglial origin
and accounts for 713% of all intracranial tumors under
14 years of age. The peak age is at 7 years (Costin, 1979),
but there is also a second, smaller peak in the sixth decade
(Harwood-Nash, 1994; Miller, 1994). A craniopharyngioma arising de novo in middle age has also been
reported (Arginteanu et al., 1997). A subset of craniopharyngiomas consists of monoclonal tumors arising from
activation of oncogenes located at specific chromosomal
loci.
Fig. 19.15. Craniopharyngioma in infundibulum. An incidental autopsy finding. NHB 96.077, male, 63 years of age. Hemotoxylineosin. Bar =
200 m.
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but frequently extends into the third ventricle (Tada et

al., 1992) and stretches the optic chiasm (Fig. 19.16).
Craniopharyngiomas of the third ventricle occur twice
more often in men than in women (Tada et al., 1992).
Craniopharyngioma is best visualized by MRI (HarwoodNash, 1994; Hald et al., 1995; Fig. 19.16), while white
calcifications are best visualized by computed tomography
(CT) (Hald et al., 1995). On T1-weighed MRI images,
not only peritumoral edema but also edema spreading
along the optic tracts can be observed. Patients with large
pituitary adenomas or with tuberculous sellae meningiomas have such edema along the visual pathway. Edema
along the optic tract is thus a useful MRI finding with
which to distinguish craniopharyngiomas from other
common parasellar tumors (Nagahata et al., 1998).
Neuroradiologically, a third ventricle craniopharyngioma
may mimic a choroid plexus papilloma (Tada et al.,
1992). Tumors present in early childhood frequently
produce hydrocephalus (Chapter 18.7) and symptoms
of intracranial pressure (see Chapter 19.1; headache,
vomiting, memory loss, seizures, hemiparesis or abnormal
behavior), which may obscure the multiple endocrine
abnormalities (for review, see Costin, 1979).
Craniopharyngioma are present in two distinctive histological patterns: one resembling tooth-forming tissues,
i.e. the adamantinomatous craniopharyngiomas, and the
Craniopharyngiomas grow slowly, are usually well

encapsulated, and may be solid and contain calcium or
may be cystic (Costin, 1979). Pediatric craniopharyngiomas were found to be cystic in 99% and to contain
calcifications in 93% (Zhang et al., 2002). The cysts
contain machinery oil fluid consisting of cholesterol,
keratin, proteinaceous fluid, hemorrhage and necrotic
debris (Chong and Newton, 1993). Cystic craniopharyngiomas contain moderate to high immunoreactivity
for vascular endothelial growth/permeability factor, in
contrast to the more solid form of this tumor (Vaquero
et al., 1999). Craniopharyngioma are considered to arise
from squamous cell nests, thought to be vestigial remnants
of Rathkes pouch and frequently found in the
hypophysial stalk. Both the epithelial portions of craniopharyngiomas and the squamous cell nests in the pars
tuberalis of the pituitary stalk express keratin (Asa et al.,
1981; Fig. 19.15). Craniopharyngiomas do not express
cytokeratins 8 and 20 (Xin et al., 2002). Malignant transformation of craniopharyngioma is rare. It was proposed
that leukemia inhibitory factor (LIF), which is expressed
in the epithelial cells of adamantinomatous craniopharyngiomas, may play a role in the development and
progression of craniopharyngiomas (Tran et al., 1999).
In the majority of cases, the craniopharyngioma does
not remain confined to the sella, causing hypopituitarism,
Fig. 19.16. Suprasellar craniopharyngioma. Precontrast (A) and postcontrast (B) sagittal T1-weighted images. A heterogeneous mass is noted in
the suprasellar region, causing marked distortion of the anterior third ventricle. The anterior portion appears to be cystic, with rim-like enhancement after contrast administration. The posterior portion of the tumor, showing low signal intensity on T1-weighted images and heterogeneous
enhancement on the post-contrast-enhanced scans, represents the solid portion of the tumor containing calcifications. A pineal cyst is noted
incidentally. (From Chong and Newton, 1993, Fig. 18 with permission.)
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less common squamous papillary craniopharyngiomas.

These two types of craniopharyngiomas can be distinguished radiologically. The adamantinomatous type has
typically large, nonenhancing hyperintense cysts on
T1-weighed images, while the squamous-papillary type
appears as a hypointense cyst on noncontrast T1-weighed
image. The adamantinomatous type simulates adamantogenic tumors. This type of craniopharyngioma may
originate from migrated dental progenitor cells which are
presumed to accompany the upward extension of Rathkes
cleft in an early embryonal stage (Oka et al., 1997).
A few adamantinomatous craniopharyngeomas were
found to contain melanin pigment, which attests to the
similarities with odontogenic tumors of the jaw (Harris
et al., 1999). Transitional or mixed examples of the
two types of craniopharyngioma also occur. Previous
suggestions that the squamous papillary type is found
only in adults, never calcifies, does not invade the
brain and is associated with a better outcome (no recurrences, better clinical status) are only partially correct
(Miller, 1994; Crotty et al., 1995). The cases studied
by Davies et al. (1997) were evenly divided between
the adamantinomatous and the papillary types. Although
the benign tumor with an aggressive course is believed
to develop from the epithelial cell remnants of the
hypophysial-pharyngeal duct or Rathkes pouch, it is
difficult to account for squamous papillary tumors
on the basis of this hypothesis, since they do not resemble tumors of the tooth-forming epithelium. Also,
Rathkes pouch remnants do not usually have a stratified epithelium (Miller, 1994). Estrogen and progesterone
receptors have been demonstrated in both types of
craniopharyngiomas, raising the possibility that
these tumors can be influenced by steroids (Thaper et al.,
1994).
Craniopharyngiomas of the third ventricle may originate in ectopic epithelial nests of the infundibulum (Fig.
19.15), or a more distant site of an epithelial nest in the
brain around the third ventricle (Tada et al., 1992). They
are wholly within the third ventricle and can be distinguished from suprasellar lesions by the presence of an
intact floor of the third ventricle. Headache and visual
disturbances are the most common presenting features,
while, unlike the suprasellar craniopharyngiomas, endocrine disturbances are not a common finding. Subtotal
removal followed by radiotherapy has been proposed as
the treatment of choice (Davies et al., 1997), but in
children younger than 5 years it may be reasonable to
follow subtotal resection and to delay radiation until
recurrence, in order to diminish neurocognitive sequelae

(Khataga et al., 1998).
The signs and symptoms of a craniopharyngioma are
characteristically: headache, nausea and vomiting (BinAbbas et al., 2001; Rutka et al., 1992), growth failure,
increased intracranial pressure, and visual loss. However,
the clinical features depend on the size of the tumor and
its location, as well as the age of the patient (Costin,
1979). Presenting endocrine complaints are infrequent but
hypothalamic symptoms may include diabetes insipidus,
inappropriate antidiuretic hormone secretion, hyperprolactinemia, deficiencies of LH, FSH, ACTH, TSH, cortisol
or panhypopituitarism (Miller, 1994; Sklar, 1994; Paja et
al., 1995; Gonzales-Portillo et al., 1998; Bin-Abbas et al.,
2001), including hypogonadism (Bauer, 1954). Which of
these symptoms are due to hypothalamic lesions, to pressure on the hypothalamic pituitary vessels or on the
pituitary itself remains debatable, since many of the
lesions extend into the third ventricle (Crotty et al., 1995).
Growth hormone deficiency is generally present in children with craniopharyngioma. The growth rate of these
children may, however, stay normal, since craniopharyngeomas induce an increase in insulin secretion that keeps
IGF-1 normal (Pinto et al., 2000). In addition, patients
with a craniopharyngiomas often suffer from severe
obesity. Significantly, higher leptin levels were found in
patients with a suprasellar craniopharyngioma. It has been
suggested that these patients develop obesity because their
hypothalamic structures become insensitive to leptin,
resulting in a disturbed feedback from the hypothalamus
to adipose tissue. Severe hypoglycemia and reduction
of insulin requirement have been found in a girl with
insulin-dependent diabetes mellitus as a first sign of a
craniopharyngioma (Lebl et al., 1999). Increased daytime
sleepiness and decreased night-time melatonin levels
have been found in craniopharyngiomas, probably
due to hypothalamic lesions (Mller et al., 2002a).
Craniopharyngiomas may also cause psychiatric symptoms, e.g. hypersexual behavior, confusional syndromes,
hallucinations, or marked deterioration in occupational
performance (Carroll and Neal, 1997). Two cases of
patients have been published who meet the DSM-III-R
criteria for intermittent explosive disorder. Episodes
of rage develop before and/or after surgery for removal
of the craniopharyngioma. MRI revealed hypothalamichypophysial involvement. It was suggested that
hypothalamic lesions played a major role in the development of aggressive behavior in both cases (Tonkonogy
and Geller, 1992). Moreover, Killefer and Stern (1970)
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reported a case in which episodic savage behavior and

rage spells developed several weeks after total removal
of a craniopharyngioma. Malamud (1967) presented three
cases with craniopharyngiomas, respectively diagnosed as
schizophrenia, manic excitement and psychoneurosis. A
rare case of an adult with a craniopharyngioma presenting
with a diencephalic syndrome of emaciation was reported
(Miyoshi et al., 2003).
Total surgical tumor removal while avoiding hazardous
intraoperative manipulation provides favorable early
results and a low risk of recurrence of the craniopharyngioma (Fahlbusch et al., 1999; Duff et al., 2000).
The frontobasal interhemispheric approach, even made
through a small craniotomy window, is a valid choice for
the removal of craniopharyngiomas extending outside the
sellarsuprasellar region. Tumors can be removed via
this approach with preservation of the pituitary stalk,
hypothalamic structures and perforating vessels (Shirane
et al., 2002). The trans-lamina terminalis hypothalami
approach seems to be a valid choice for the removal of
purely intraventricular craniopharyngeomas (Maira et al.,
2000). Subtotal resection is associated with increased
risk of tumor recurrence and is usually followed by
radiotherapy. Long-term disease control is excellent after
subtotal resection and postoperative radiotherapy,
while a high risk of recurrence is found in the subtotal
resection without radiation. In that case, approximately
one-third of the patients exhibited morbid obesity (Duff
et al., 2000; Eisenstat, 2001). Following radiotherapy
the periods of tumor shrinkage are often long (mean
29 months). Temporary enlargement of the solid component usually occurs during radiotherapy and does not
represent tumor progression. Sometimes cystic enlargement also occurs comparatively early after radiotherapy,
and enlarged cysts often shrink spontaneously. After
shrinkage, small solid or cystic nodules enhanced with
contrast medium often remain. MRI allows assessment
of the extent of hypothalamic damage after surgery for
craniopharyngioma and thereby prediction of the patients
most at risk for severe postoperative weight gain (De Vile
et al., 1996). Multiple pituitary hormonal deficiencies
are quite frequent following radical surgery (Bin-Abbas
et al., 2001). It is worth preserving the pituitary stalk
and gland at surgery because of the definite chance that
intact anterior pituitary functions may be maintained.
Postoperative diabetes insipidus must be accepted as a
common complication of complete removal of a craniopharyngioma (Honegger et al., 1999), but judicious use
of desmopressin (DDAVP) and stress doses of gluco-
75
corticoids are advised to guide the patient through the

postoperative period (Eisenstatt, 2001). In addition,
gamma-knife radiosurgery, external beam irradiation,
fractionated stereotactic radiotherapy and intracavitary
irradiation give encouraging results (Eisenstatt, 2001;
Isaac et al., 2001; Barajas et al., 2002; Schulz-Ertner et
al., 2002; lfarsson et al., 2002; Varlotto et al., 2002).
A phase II study showed that interferon--2a is active
against some childhood craniopharyngiomas and may
provide an alternative treatment strategy (Jakacki et al.,
2000).
A small number of craniopharyngiomas with ciliated
epithelia has been described. In these tumors, craniopharyngiomatous tissue and Rathkes cleft epithelium are
intermingled, which seems to imply an intimate relationship between these two lesions (Oka et al., 1997).
(b) Rathkes cleft cysts
Cysts known as Rathkes cleft cycsts are relatively
common incidental microscopic findings, i.e. in some
1233% of the normal pituitaries at autopsy (Matsudo et
al., 2001), and are found during life, with increasing
frequency, by CT or MRI scans (Ward et al., 2001).
Occasionally the cysts become larger and symptomatic
by compression of surrounding structures, i.e. the hypothalamus, pituitary and visual pathways (Concha et al.,
1975; Eisenberg et al., 1976). Most of them occur in
the zona intermedia of the pituitary and may derive
from remnants of Rathkes pouch, thus sharing a similar
origin with craniopharyngioma (Ward et al., 2001).
Concomittant pituitary adenoma and Rathkes cleft cysts
are found. The frequency of the combination is some 4%
of the pituitary adenomas and 11% of the Rathkes cleft
cysts (Sumida et al., 2001). Patients may develop symptoms such as headache, hyperprolactinemia, galactorrhea,
decreased libido, impotence, visual field deficits, diabetes
insipidus, inappropriate secretion of vasopressin, amenorrhea or hypopituitarism such as adrenal insufficiency if
the cyst is large enough to push against adjacent structures. Repeated aseptic meningitis and spontaneous
resolution of Ratkes cleft cyst are also noted (Matsuno
et al., 2001; Ward et al., 2001).
The cyst wall is composed of a single layer of
columnar, cuboidal or squamous epithelium, which
may be ciliated and contain goblet cells. The cyst
may contain mucoid yellow and grumous material,
serous or CSF-like contents, or cellular debris (Chong
and Newton, 1993; Eguchi et al., 1994; Iwai et al.,
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2000; Ward et al., 2001). In addition, a case with amyloid

deposition (Concha et al., 1975) and one with ossification (Nakasu et al., 1999) has been described. These cysts
are usually confined to the sella (in older literature the
disorder is termed intrasellar craniopharyngioma) and
usually do not calcify (Harwood-Nash, 1994). The cysts
are seldom located entirely in the suprasellar region,
which then often leads to the mistaken diagnosis
of a craniopharyngioma (Rottenberg et al., 1994).
Histologically one may distinguish Rathkes cleft cysts
from craniopharyngiomas, e.g. in biopsies, by staining for
cytokeratins. Rathkes cleft cysts and pars intermedia of
the pituitary express cytokeratins 8 and 20, whereas craniopharyngiomas do not express these cytokeratins (Xin
et al., 2002). Moreover, Rathkes cleft cysts do not grow
they lack calcification and machine oil-like fluid content
which distinguishes them from craniopharyngiomas
(Chong and Newton, 1993). The unique MRI finding of
Rathkes cleft cysts high intensity on T1-weighted
images and low signal intensity on T2-weighted images
seems to depend on the protein and not on
the cholesterol concentration (Hayashi et al., 1999).
Symptoms of Rathkes cleft cysts may include generalized pituitary hypofunction, hyperprolactinemia, multiple
endocrinopathies, headaches and visual disturbances
(Rutka et al., 1992; Horvath et al., 1997). A few cases
have been described with symptomatic pituitary hemorrhage into a Rathkes cleft cyst with sudden, severe
retro-orbital headache, nausea and visual loss (Nishioka
et al., 1999). A case has been described of a Rathkes
cleft cyst, surrounded by areas of noncaseous granulomatous tissue with scattered multinucleated giant cells of
foreign body type, similar to a sarcoid lesion. Two years
later the patient reported a sudden visual impairment due
to sarcoidosis of the optic nerve. Remission of neurological symptoms followed corticosteroid therapy. The
diagnosis sarcoidosis was firmly confirmed when the
patient underwent surgery for new lesions on the acoustic
and facial nerves. The pituitary lesions were probably due
to secondary granulomatous infiltration of the pituitary
gland, where a small congenital asymptomatic Rathkes
cyst was already present (Cannav et al., 1997). Rathkes
cleft cyst was also found in a mosaic Klinefelter
46,XY/47,XXY patient with hypothalamic panhypopituitarism, partial diabetes insipidus and other endocrine
disorders (Gotoh et al., 2002).
Overexpression of LIF in mice that are transgenic for
LIF was found to lead to invagination of the anterior wall
of Rathkes pouch and the formation of cysts lined by
LIF-immunoreactive epithelial cells. Strong LIF immunoreactivity was also found in human Rathkes cleft cysts
(Tran et al., 1999), suggesting failed differentiation of
Rathkes epithelium to hormone-secreting cells (Akita et
al.,1997). Treatment consists of excision of the lesion,
and the transnasal transphenoidal approach has been
advocated (Ward et al., 2001).
(c) Xanthogranuloma
Xanthogranulomas (cholesterol granulomas) are considered to be a xanthogranulomatous change of craniopharyngioma (for a xanthogranulomatous degeneration
of a colloid cyst, see Chapter 17.3b). They consist of
cholesterol clefts, macrophages, chronic inflammatory
infiltrates, necrotic debris and hemosiderin deposits. They
lack the additional features of adenomatous craniopharyngiomas and some 35% contain squamous or
ciliated cuboidal cells. They preferentially occur in
adolescents and young adults (mean age 27 years), have
a predominant intrasellar localization, smaller tumor size,
more severe endocrinological deficits, longer preoperative history, lower frequency of calcification and visual
disturbances, better resectability and a more favorable
outcome than craniopharyngiomas. They are therefore
proposed to be clinically and pathologically distinct from
the classic adenomatous craniopharyngiomas (Paulus
et al., 1999).
19.6. Dermoid and epidermoid tumors
Dermoid and epidermoid cysts may compress the hypothalamus and pituitary and cause hypopituitarism, diabetes
insipidus or cranial nerve deficits. Both of these tumors
are benign and slow growing. They tend to wriggle around
adjacent neural structures, depending on the spaces they
occupy. The cyst walls of these tumors contain stratified
squamous epithelium and an outer layer of connective
tissue. Dermoid tumors occur in children but also in
adults. They are most commonly located in the fourth
ventricle or the vermis and are less commonly seen in
juxtasellar position. The cyst walls of these tumors contain
dermal appendages, hair follicles, sebaceous glands and
sweat glands, and stratified squamous epithelium. The
yellow contents of the cyst consist of a waxy material
containing desquamated keratin products, hair and cholesterol crystals. Epidermoid tumors occur in the fourth to
fifth decades of life. They are found in the basal cisterns,
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often in a lateral location, and produce remarkably few

pressure effects. The cyst walls of these tumors contain
a simple stratified squamous epithelium resting on an
acute layer of connective tissue. No skin appendages such
as sweat glands or hair follicles are found. The cyst
contains a waxy material with desquamated keratin products and cholesterol crystals. The cholesterol in the lumen
shines through, giving a silvery appearance, so that they
are sometimes called pearly tumors (Sheehan and
Kovacs, 1982; Chong and Newton, 1993). In the case of
an epidermoid (Rathkes pouch) cyst of the third ventricle,
a state of akinetic or trance-like mutism has been
described in the older literature. A 14-year-old girl slept
more hours than normal, but was easily aroused. Her eyes
followed moving objects but there were no other voluntary movements. She was quite mute or answered in
whispered monosyllables. She suffered loss of emotional
expression and painful stimuli caused reflex withdrawal.
Repeated commands were carried out occasionally, albeit
feebly, slowly and incompletely. She had to be fed, but
swallowed readily. There was total incontinence. This
syndrome was treated three times by aspiration of the
cyst. Each time there was a rapid, almost immediately
disappearance of the symptoms. Ten minutes after
the cyst was emptied, the child sat up in bed and said
Where am I?, as if waking from a sleep. The state of
akinetic mutism was not due to a general rise of intracranial pressure. Most functions that were affected are
considered to be cortical functions, i.e. voluntary movement, including speech, spontaneous activity of all
kinds, emotional expression, perception and memory. The
state of akinetic mutism was therefore interpreted as
an interruption of pathways between hypothalamus and
thalamus alongside the third ventricle by local pressure,
leading to an interruption of the hypothalamic input to
the cortex. The two connections speculated to be involved
are the bundle of Vicq dAzyr and the connection between
the posterior hypothalamic nucleus (Chapter 13.3), which
is considered to be a controlling center for the sympathetic system and the medial nucleus of the thalamus.
The latter fibers run along the third ventricle (Cairns
et al., 1941).
77
(pineocytoma and pineoblastoma), (iii) glial neoplasms,

and (iv) cysts (Fetell and Stein, 1986; Fig. 19.18;
Smirniotopoulos et al., 1992). Most pineal region masses
are malignant germ cell tumors that occur in young male
patients. The most common one is a germinoma (Fig.
19.17). Malignant, aggressive tumors (germinomas,
pinealoblastomas, immature teratoma and lymphoma)
invade the pineal parenchyma, generally leading to a
complete abolishment of melatonin secretion. On the other
hand, less aggressive benign tumors (pineocytomas, pilocytic astrocytomas and meningeoma) generally allow
normal secretion and circadian rhythm of melatonin
(Grimoldi et al., 1998). A child with a germ cell tumor
involving the pineal region markedly suppressing melatonin secretion suffered from severe insomnia. Exogenous
melatonin restored sleep continuity, thus providing
evidence for the essential role of melatonin in normal
sleep (Etzioni et al., 1996; see Chapter 4.5). The differential diagnosis of pineal region masses is extensive and
includes tumors, vascular lesions and even a case of histiocytosis (Gizewski and Forsting, 2001).
(a) Germ cell tumors
Primordial germ cells develop from embryonic cells of
the yolk sac wall, near the allantois. Between 5 and 8
weeks of gestation, they move into the genital ridges.
Misguided germ cells that move into the hypothalamicpineal region are supposed to give rise to extragonadal
germ cell tumors. Germ cell tumors occur primarily in
children and young adults in midline structures throughout
the body, including the pineal and suprasellar region
(Smirniotopoulos et al., 1992; Fig. 19.19). For suprasellar
and sellar localization, see Chapter 19.2. Pineal region
germ cell tumors occur almost exclusively in male
patients, while suprasellar germ cell tumors do not have
a sex preference.
Germ cell tumors are classified according to Teilums
scheme (Fig. 19.18; Fetell and Stein, 1986). In Fig. 19.18
the presence of the tumor markers HCG and -fetoprotein
are also indicated. Such markers can also be used to
monitor therapeutic interventions (Massie et al., 1993;
Tarng and Huang, 1995). CSF levels of these markers
may be more sensitive and precede elevations in serum.
Germinomas are generally negative for -fetoprotein,
while HCG is usually absent or only slightly elevated. HCG is markedly elevated and -fetoprotein is
usually normal with choriocarcinomas (Schut et al.,
1996). Germinomas do not have a pineal origin and thus
19.7. Pineal region tumors

According to the pathological classification of Russell
and Rubinstein, the following types of tumors have to be
distinguished in the pineal region: (i) teratomas (including
all germ cell-derived tumors); (ii) pineal cell tumors
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Fig. 19.17. Intrachiasmal craniopharyngioma. Sagittal (A) and coronal (B) T1-weighted MR scans. The tumor has a slightly heterogeneous
appearance and has caused marked expansion of the chiasm (arrows). (From Chong and Newton, 1993, Fig. 20 with permission.)
Fig. 19.18. Teilums proposed scheme of differentiation of germ cell tumors. HCG = human chorionic gonadotropin, AFP = -fetoprotein.
(Modified by Fetell and Stein, 1986, Fig. 4.)
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generally do not produce melatonin. Only a few rare

cases of germinomas have been described that produce
melatonin. The melatonin-synthetizing enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) were present in this case, while the
high blood levels of melatonin became undetectable
postoperatively (Grimoldi et al., 1998).
A germinoma is the most typical pineal region mass. It
was formerly called atypical teratoma and is histologically identical to ovarian dysgerminoma and testicular
seminoma. Male patients are 217 times more affected
than female patients. The peak age of presentation is in
the second decade. A germinoma is a malignant tumor
composed of large, multipotential, primitive germ cells
and infiltrating lymphocytes, epithelioid cells (probably
derived from macrophages) and macrophages. Often the
lymphocytes penetrate deeply into the cytoplasm, even
into the nucleus of the tumor cell. The infiltrating cells
may be directly cytotoxic to the tumor cells (Wei et al.,
1992; Grimoldi et al., 1998). Histologically germinomas
of the pineal region are identical to those in the suprasellar region (Chapter 19.2; Schut et al., 1996). A germinoma
may invade the adjacent brain structure and also spread
through the CSF (Fig. 19.19) in 3237% of cases (Schut
et al., 1996). Pure germinomas are associated with low or
undetectable HCG levels in serum and CSF (Sklar, 2002).
A primitive germ cell that may lead to a malignancy
is called an embryonal carcinoma. It may give rise to a
differentiated teratoma that is a benign and slow-growing
tumor but may also be locally invasive or metastasize.
Teratoma also have a male prevalence of a factor 2.8.
Teratoma are neoplasms that recapitulate normal organogenesis, usually producing tissues representing a mixture
of two or more of the embryonic layers of ecto-, mesoand endoderm. It might produce tissue that mimics the
skin and has to be differentiated from a dermoid cyst
(Chapter 19.6) by the presence of components of diverse
tissues. They contain lipid areas and may have calcifications (Fig. 19.20). Usually -fetoprotein and HCG are
elevated or slightly above normal (Schut et al., 1996).
Some embryonal carcinomas contain elements of teratoma
and are termed teratocarcinomas. An embryonal carcinoma cell is believed to be a precursor malignancy that
can also differentiate into a tumor of extraembryonic
tissue. These tumors give both elevated -fetoprotein and
HCG levels (Schut et al., 1996). If the resulting tumor
contains trophoblastic tissue it is called a choriocarcinoma (which usually produces markedly elevated HCG
levels) (Schut et al., 1996), if it contains yolk sac elements
Fig. 19.19. Germinoma with seeding. (a) Sagittal T1-weighted MR

image of a 22-year-old man demonstrates two lesions (dots) that are
homogeneous and are equal in signal intensity to that of gray matter.
There is a dominant mass in the pineal region and a second, smaller
mass in the suprasellar cistern. (b) Coronal T1-weighted MR image of
the same patient after administration of gadopentetate dimeglumine
demonstrates abnormal enhancement of the enlarged pituitary
infundibulum, which represents seeding from the pineal germinoma. (c)
Sagittal gross specimen obtained at autopsy of a different patient also
demonstrates two prominent masses. The original germinoma is the
large mass in the pineal region. The second mass, in the suprasellar
cistern, represents CSF dissemination. Together, these two masses
compress and distort the brain stem. The pineal mass extends well
below the tentorium and encroaches on the roof of the fourth ventricle.
It also spreads anteriorly, to the foramen of Monro, through the cistern
of the velum interpositum (*). (From Smirniotopoulos et al., 1992, Fig.
4 with permission.)
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Fig. 19.20. Teratoma. (a) CT scan of a 4-year-old boy demonstrates a heterogeneous mass in the pineal region extending anteriorly into the cistern
of the velum interpositum. The mass contains several large chunks of calcification and a darker, cystic-appearing area (arrowhead). Heterogeneity
like this, especially when there is lipid material and calcification, is a hallmark of a mature teratoma. (b) After contrast material is administered,
there is relatively homogeneous enhancement of the noncalcified solid portions of the tumor. The cystic region does not appear enhanced. (c) T1weighted MR image of the same patient demonstrates a mildly heterogeneous mass largely isointense relative to gray matter. However, there are
focal areas of T1-weighted shortening (arrowhead) from lipid material (e.g. sebaceous). The cystic region (*) has higher signal intensity than that
of CSF because of proteinaceous material. (d) Sagittal T1-weighted MR image of an 8-year-old boy demonstrates a grossly heterogeneous mass
with large amounts of hyperintense lipid material. It extends anteriorly toward the cistern of the velum interpositum and posterior third ventricle.
Note the cystic region (*). The signal intensity void of the internal cerebral veins (arrowhead) is superior to the mass, but, in addition, there is a
thin rim of hypointensity encircling the mass, suggesting a tumor capsule. (Courtesy of L. Baker, MD, University of California, San Francisco).
(e) Sagittal gross specimen of a mature pineal teratoma from a different patient shows a grossly heterogeneous mass that is well encapsulated
(arrowhead). The varied contents of this partially cystic mass include a superior portion with a cheesy consistency for sebaceous material. In
the sagittal plane, it is clear that much of this mass is below the tentorium. (From the L. Rubinstein collection, AFIP.) (From Smirniotopoulos,
1992, Fig. 5 with permission.)
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Fig. 19.21. Yolk sac tumor in a 9-year-old boy. (a) Axial CT scan obtained without the use of contrast material demonstrates a round, relatively
homogeneous, low attenuation mass, engulfing the calcifications within the central pineal gland. Germinomas are usually high-attenuation masses;
thus, other diagnoses should be considered. However, the appearance is neither specific for nor suggestive of yolk sac tumor. There is an incidental dural osteoma (arrow). (b) Axial CT scan obtained after contrast material is administered shows homogeneous enhancement, which is also
non-specific. (c) Axial T2-weighted MR image demonstrates nonspecific homogeneous hyperintensity (higher than the signal intensity of gray
matter) of the mass. (d) Sagittal MR image obtained without the use of contrast material demonstrates minimal heterogeneity in the mass, which
is slightly hypointense relative to gray matter. (e) Sagittal MR image obtained after administration of gadopentetate dimeglumine shows prominent
but slightly heterogeneous enhancement. (Smirniotopoulos, 1992, Fig. 9 with permission.)
it is called an endodermal sinus tumor or yolk sac tumor

(which usually produces high levels of -fetoprotein
(Schut et al., 1996) (Fig. 19.21). Both are highly malignant
(Fetell and Stein, 1986; Smirniotopoulos et al., 1992).
Adjuvant therapy consisting of preoperative chemotherapy with cisplatin and ectoposide and concomitant
radiotherapy, followed by radical surgical removal of the
tumor, is proposed as a highly effective treatment of
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Fig. 19.22. Pineocytoma. (a) Plain CT scan shows a large and relatively homogeneous mass in the pineal region, with peripheral displacement of
pineal calcification (arrows). The mass has extended anteriorly along the velum interpositum. This is the exploded pineal appearance that suggests
an intrinsic pineal parenchymal neoplasm. (b) Contrast-enhanced CT scan shows homogeneous enhancement in the mass, which assumes a triangular shape as it conforms to the contours of the pulvinar of the thalami and velum interpositum. (c) Axial proton-density-weighted MR image
shows the mass is homogeneously hyperintense; it is diamond shaped because it fills the two opposing triangles of the velum interpositum (anterior) and quadrigeminal plate cistern (posterior). (d) Sagittal T2-weighted image shows the mass is under the internal cerebral veins (arrow) and
extends anteriorly along the velum interpositum. The mass also extends interiorly, separating the cerebellum from the brain stem, and encroaches
on the superior medullary velum (the roof of the fourth ventricle). (From Smirniotopoulos et al., 1992, Fig. 11.)
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pediatric patients with primary intracranial yolk sac tumor,

embryonal carcinoma or mixed germ cell tumors containing yolk sac tumor components (Ushio et al., 1999).
(b) Pineal parenchymal tumors
A pineocytoma (Fig. 19.22) is composed of cells that
resemble mature pineocytes (Coca et al., 1992) and are
arranged in a glandular pattern. However, it may behave
like pineoblastoma, seeding via the CSF. In contrast, a
pineoblastoma is histologically identical to a medulloblastoma. It may invade adjacent brain structures spread
by the CSF and is considered a primitive neuroectodermal
tumor of the pineal region. These tumors have no sexual
predilection. Both tumors are malignant and may contain
intrinsic calcifications. In addition, pineal parenchymal
tumors might have ganglionic and astrocytic differentiation. Neither melatonin nor HIOMT are considered to be
useful markers for parenchymal tumors and also HCG
and -fetoprotein are usually negative. Tumoral pineal
cells differentiate either toward a neurosensory pathway
characterized by the presence of sensory elements
(vesicle-crowned rodlets or synaptic ribbons and fibrous
elements), or toward a neuroendocrine pathway with the

occurrence of many dense-core vesicles (Fetell and Stein,
1986; Smirniotopoulos et al., 1992; Jouvet et al., 1994;
Schut et al., 1996). Pineocytomas and a peneoblastoma
showed a decrease in the somatostatin receptor subtype
sst 2 and a complete loss of sst 5 expression (Champier
et al., 2003).
(c) Glial neoplasms
Glial neoplasms make up about one-third of the pineal
tumors. One-third of these tumors are benign; however,
astrocytomas may infiltrate the white matter along long
tracts. True glioblastomas rapidly become lethal (Fetell
and Stein, 1986; Smirniotopoulos et al., 1992).
(d) Cysts, tumors of supporting elements and
miscellaneous
The epiphysis often contains pineal cysts
1994), most of which are of glial origin.
they have an ependymal lining and there
cavities from the third ventricle (Duvernoy
(Fain et al.,
Occasionally
are vestigial
et al., 2000).
Fig. 19.23. Lipoma. (a) Axial CT scan shows a fatty attenuating mass in the pineal region that does not enhance. With its homogeneity and lack
of enhancement, the mass is most likely not a teratoma. It occupies most of the quadrigeminal plate cistern. (b) Sagittal T1-weighted MR image
shows a mass in the quadrigeminal plate cistern with homogeneous high signal intensity, similar to the signal intensity from the subcutaneous fat
and clival marrow. As with many other pineal region masses, it extends inferiorly (below the tentorium) and pushes the cerebellum away from
the brain stem. (From Smirniotopoulos, 1992, Fig. 14 with permission.)
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Moreover, malignant rhabdoid tumor (Muller et al, 1995)

and malignant melanoma are found. Melanoblasts are
present in most parts of the pia and may give rise to
tumors (Rubino et al., 1993). In addition, primary
myeloblastoma (Voessing et al., 1992), lipoma (Fig.
19.23), meningeomas, spindle cell carcinomas, choroid
plexus papilloma, hemangioblastoma, progonoma (a
melanocytic neuroectodermal tumor), chemodectomas
that presumably arise from sympathetic fibers that innervate the gland, and metastatic neoplasms should be
mentioned (Fetell and Stein, 1986; Smiriniotopoulos et
al., 1992).
(e) Clinical symptoms of pineal region tumors
Most patients with pineal region tumors have nonspecific symptoms of increased intracranial pressure,
i.e. headaches, nausea, vomiting, visual abnormalities,
papilledema and seizures. In addition, short stature,
obstructive hydrocephalus causing hypothalamic compression and anterior pituitary deficiency (growth
hormone deficiency, hypothyroidism, low cortisol),
diabetes insipidus, hypogonadism, high prolactin, and
precocious or delayed puberty are found. Precocious
puberty due to pineal tumor may be explained by: (i)
destruction of the pineal gland by the tumor, interfering
with its normal antigonadotropic effect; (ii) destruction
of hypothalamic sexual inhibitory centers; and (iii) ectopic
secretion of gonadotropins such as -HCG, which acts
like LH (Fetell and Stein, 1986; Rivarola et al., 1992,
2001; Smirniotopoulos et al., 1992).
There is indeed quite some evidence that hamartomas
have cells with the capacity of LHRH pulse generators
(see Chapter 19.3). In some cases either a lack of the
maximum night melatonin plasma value or higher-thannormal nocturnal melatonin concentrations could indicate
a pineal region tumor (Mandera et al., 1999).
A patient with histiocytosis that was present as a mass
in the pineal gland presented with incomplete ocular palsy
(Gizewski and Forsting, 2001).
19.8. Tuberous sclerosis (BournevillePringle
syndrome) and tumors of the hypothalamus
Tuberous sclerosis is an autosomal dominant hereditary
disease, although most cases probably arise sporadically.
Its presentation varies, showing lesions in brain and skin,
facial angiofibromas, retinal hamartomas, epileptic
seizures, mental retardation, autism and attention-deficit
hyperactivity disorder. Among the various epileptic

syndromes, Wests syndrome is the most typical (Crino
and Henske, 1999; Mizuguchi and Takashima, 2001;
Andres, 2003). Embryologically both the brain and the
skin are derived from ectoderm; tuberous sclerosis therefore belongs to the neurocutaneous syndromes (Morse,
1998) or phakomatosis with multisystem involvement
(Inoue et al., 1998b). Brain lesions in tuberous sclerosis
consist of cortical tubers, white matter abnormalities and
subependymal nodules that may also occur in the third
ventricular wall and that show calcification with
increasing age. The cortical tubers and subcortical heterotopic nodules are static, while the uncontrolled growth of
subependymal giant cell astrocytomas may lead to hydrocephalus and death (Crino and Henske, 1999; Mizuguchi
and Takashima, 2001). The prevalence of tuberous sclerosis is at least 1 in 10,000 (Inoue et al., 1998b; Crino
and Henske, 1999). The tumor-like growth may include
cells of more than one type, such as glioblasts and neuroblasts. Tuberous sclerosis is caused by mutations in the
tumor-suppressor gene TSC1 on chromosome 9q34 or in
TSC2 on 16p13.3 (Inoue et al., 1998b; Mizuguchi and
Takashima, 2001). TSC1 and TSC2 genes encode distinct
proteins, hamartin and tuberin, respectively. TSC2 mutations are more prevalent in sporadic cases (Crino and
Henske, 1999). Benign brain tumors are frequently seen
in tuberous sclerosis, which may also affect the hypothalamus. Giant cell astrocytomas occur in about 10% of
the children with tuberous sclerosis (Gunatilake and
Harendra De Silva, 1995). Subependymal giant cell
tumors have the tendency to enlarge and occur in 1015%
of tuberous sclerosis patients. Why such tumors occur
only in the area of the foramen of Monro is not clear
(Inoue et al., 1998b). A few tuberous sclerosis patients
have been described with a giant cell astrocytoma filling
the third ventricle (Turgut et al., 1996).
In his series of 60 autopsy cases with pathological
lesions of the hypothalamus, Bauer (1954) described one
patient with tuberous sclerosis whose corpora mamillaria were involved, and in whom precocious puberty,
convulsions and disturbed water balance were found.
Moreover, tuberous sclerosis of the hypothalamus has
caused obesity (Bastrup-Madsen and Greisen, 1963) and
has been associated in one case with a cavum septum
pellucidum (Bruyn, 1977). More recently, a case report
was published on a boy who developed precocious
puberty at 13 months and who had a hypothalamic
hamartoma and periventricular calcified lesions. The
manifestations of precocious puberty were based upon
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tuberous sclerosis and were effectively reduced by LHRH

(De Cornulier et al., 1993; cf. Chapter 19.3). In addition,
a child has been described who suffered from tuberous
sclerosis and laughing seizures due to a neoplasm rising
from the floor of the left lateral ventricle and extending
downwards into the hypothalamus. Ventricular dilatation
was noted on the left side as a result of the tumor causing
an obstruction of the foramen of Monro (Gunatilake and
Harendra De Silva, 1995). It is not known whether children with tuberous sclerosis so often suffer from sleep
disturbances because their hypothalamic systems are
affected. However, melatonin improves the total sleep
time in these patients (OCallaghan et al., 1999; Hoban,
2000).
Only a few cases have been reported of neuroendocrine
disturbances on the basis of tuberous sclerosis.
Bloomgarden et al. (1981) described hyperprolactinemia,
amenorrhea and galactorrhea in a female patient with
tuberous sclerosis. The hyperprolactinaemia was unresponsive to protirelin, chlorpromazine, levedopa,
bromocriptine mesylate or estrogen. It is not clear whether
the hyperprolactinemia was derived from the pituitary or
a hamartoma. Tinguy du Pouet et al. (1985) published a
case of tuberous sclerosis with diabetes insipidus, hyperprolactinaemia, growth hormone deficiency and delayed
puberty, based upon a hypothalamic periventricular
hamartoma. Microscopic examination revealed bizarre
giant cell clusters to be the main feature of the tubers.
These giant cells have both astrocytic and neuronal
features, suggesting that they are the product of a dysgenetic event in early development. In the white matter the
giant cells align in rows that appear to follow the path
of neuronal migration. Probably those cells that migrate
to the cortex form the tubers, and those that show incomplete migration give the white matter lesions. Some may
not migrate and produce subependymal nodules (Inoue
et al., 1998b).
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frequently involving the pituitary stalk and hypothalamus.

These tumors may show rapid growth, differentiating the
lesion from a benign pituitary adenoma (Chong and
Newton, 1993). Also, brain tumors may give rise to hypothalamic metastases. For instance, Bauer (1954) reported
metastases to the third ventricle, infundibulum and
corpora mamillaria of a frontal lobe tumor. Metastasis
of the hypothalamic-pituitary region may also be an
atypical postmortem finding in systemic cancer. In symptomatic cases, diabetes insipidus due to a tumor in the
infundibulum or neurohypophysis is the usual clinical
manifestation, especially seen in the terminal stages
(Kimmel and ONeill, 1983; Schubiger and Haller, 1992;
Ten Bokkel Huinink et al., 2000). Serious loss of neurons
and gliosis may occur in the supraoptic and paraventricular nucleus when the stalk and neurohypophysis are
destroyed by metastases (Duchen, 1966). In addition,
circadian rhythm disturbances have been described in case
of localization of a metastasis of an adenocarcinoma of
the rectum in the suprachiasmatic region (Fig. 4.2).
Diabetes insipidus is a rare complication of acute
myeloid leukemia and acute lymphoblastleukemia. In
most cases a local leukemic infiltrate was found, most
often of the posterior lobe, but also in the hypothalamus
(Fig. 19.24). In some patients, however, overt leukemic
infiltrates were missing and scant thrombosis of small
vessels in the hypothalamus and posterior lobe of the
pituitary were seen. Moreover, some patients have been
described with diabetes insipidus established in the
preleukemic phase of acute myeloid leukemia. In one of
the patients, diabetes insipidus was a result of a hypothalamic lesion as judged from endocrine studies
(Puolakka et al., 1984). When one considers that the
posterior lobe, and not the anterior lobe, of the pituitary
is directly supplied by arterial blood from the systemic
circulation, the predilection for metastasis in this structure is understandable. The anterior lobe is supplied by
the portal system. When this system is obstructed by a
tumor, it is almost invariably by direct extension of the
tumor from the posterior lobe (Duchen, 1966), and
microinfarcts of the pituitary are the result (Kimmel and
ONeill, 1983).
Other clinical manifestations of metastases in this
region are anterior pituitary failure, and visual disturbances due to chiasmatic and optic nerve involvement
(Kimmel and ONeill, 1983). In fact, patients with tumors
who develop diabetes insipidus or hypopituitarism most
probably harbor pituitary metastases and not an adenoma
(Schubiger and Haller, 1992). Once a case with metastatic
19.9. Metastases
Brain metastases are common and often occur in patients
whose systemic cancer is quiescent. The most common
sources of metastatic tumors in the pituitary-hypothalamic region are carcinomas of the lungs or breasts,
and leukemia/lymphoma (Schubiger and Haller, 1992;
Chong and Newton, 1993). Metastatic carcinoma
originating from the gastrointestinal tract have also
been described. In cases of metastases, MR images
may show an enhancing lesion in the pituitary gland,
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Fig. 19.24. Female, 79 years of age, with chronic myeloide leukemia (NHB 88-093). Leukemic infiltration is present in the hypothalamus, just
above the supraoptic nucleus (SON). Bar represents 100 m.
spread of a small oat-cell carcinoma of the lung was

reported, involving both the posterior pituitary and the
pineal (Suganuma et al., 1994). It was proposed by way
of explanation that in both structures the bloodbrain
barrier is absent. In addition, violent hunger and obesity
have been reported as clinical evidence of hypothalamic
involvement in children with acute leukemia. Massive
diffuse leukemic infiltration was present in such cases at
the level of the ventromedial nuclei of the hypothalamus
(Heaney et al., 1954; Bastrup-Madsen and Greisen, 1963).
19.10. Other tumors
In the chiasmal and sellar region, approximately 10%
of the neoplasms are meningiomas. They may originate
from the superior leaf of the diaphragma sellae anterior
or posterior of the pituitary stalk or from the inferior
leaf of the diaphragma sellae (Beems et al., 1999).
Meningiomas of the inferior leaf of the sellar diaphragm

may produce primarily bitemporal hemianopsia and
hypopituitarism. Sometimes they grow around cranial
nerves. Sellar region meningiomas may produce hyperprolactinemia by mechanical effects on the pituitary stalk,
and may thus mimic prolactinomas. Meningiomas may
also cause diabetes insipidus or hypogonadism (Sheehan
and Kovacs, 1982; Horvath et al., 1997). Meningiomas
without dural attachment are rare (Beems et al., 1999),
but meningioma in contact with the pituitary stalk have
been described. As the pituitary stalk has no dura mater,
the tumor may have originated from the arachnoid
membrane of the pituitary stalk. The histological diagnosis was meningotheliomatous meningioma in one case
and meningioma in another (Hayashi et al., 1997).
Moreover, cases of meningioma of the third ventricle
have been described. Posterior third ventricular meningiomas usually originate from the falxtentorial junction
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or the connective tissue stroma of the pituitary gland.

Meningiomas in the anterior part of the third ventricle
usually result from the mesenchymal cell populations
belonging to the velum interpositum, the tela choroida
and the plexus choroidus. The patients have signs and
symptoms of increased intracranial pressures, diabetes
insipidus, motor disturbances, cranial nerve dysfunction
and, sometimes, short-term memory deficit (Pau et al.,
1996). Several data indicate that sex hormones may be
involved in the pathogenesis of meningiomas. The
majority of these tumors start to grow during the period
of maximum gonadal activity. These are the only common
intracranial tumors with a significantly higher incidence
in women, the female-to-male ratio being 2.5:1. In some
cases of meningiomas a relapsing course in relation to
pregnancy was found. In most cases these tumors were
located near the optic or oculomotor nerves. In addition,
there is an association between meningiomas and breast
cancer. Moreover, meningiomas have steroid hormonebinding sites for estrogens, progesterone, glucocorticoids,
mineralocorticoids and androgens (Poisson, 1984).
Juxtasellar or suprasellar subarachnoid cysts or arachnoidocele are benign. The subarachnoid space is formed
by an expansion of the intercellular space when the
cellular components of the meninx primitiva are removed.
The increase in the intercellular and primitive subarachnoid space are first observed at about 14 weeks of
gestation. Any abnormal event during this process may
result in the formation of an arachnoid cyst (Nishio et
al., 2001). The cysts may be asymptomatic and patients
may present with headache, optic-nerve compression,
disorders of growth, puberty, amenorrhea, obesity,
disturbed hypothalamopituitary function or hydrocephalus
(Adan et al., 2000; Todd et al., 2000). Rivarola et al.
(2001) and Starzyj et al. (2003) reported precocious
puberty in four children with a subarachnoid cyst.
Arachnoid cysts may also be found in autism (Tantam
et al., 1990). Fifteen percent of all arachnoid cysts are
parasellarly located. They can be congenital in origin,
develop from adhesions in the subarachnoid space or be
associated with another abnormality, such as a hamartoma. As they continue to expand slowly, they may push
against adjacent brain structures, cause hydrocephalus and
even remodel the adjacent skull. The differential diagnosis includes an epidymal cyst, a parasitic cyst or a
Rathkes cleft cyst (Chong and Newton, 1993; Nishio et
al., 2001). The minimally invasive treatment using stereotactic intracavitary irradiation of arachnoid cysts using
chromic colloidal phosphorus-32 proved to be safe and
87
Fig. 19.25. Coronal section of brain at midthalamus level with a chordoid

tumor obliterating the cavity of the third ventricle (arrow). Note
attachments of the mass to the roof of the ventricle and right thalamus,
and its downward extension to involve the hypothalamus. (From Vajtai
effective (Todd et al., 2000). Others have inserted a

cystperitoneal shunt (Nishio et al., 2001; Starzyj et al.,
2003).
Hypothalamic chordoma were reported in a few
patients. Chordoma are malignant neoplasms thought to
derive from fetal notochordal rests. Chordomas and chondromas are usually situated in the basis sphenoid behind
the posterior clinoid plate (Commins et al., 1994).
Third ventricle chordoid glioma arise from the hypothalamic (suprasellar) third ventricle region (Fig. 19.25).
The histology is reminiscent of chordoma or choroid
meningeoma. The tumor is composed of cords and clusters of epithelioid cells in a mucoid matrix and a
low-grade infiltrate of mature lymphocytes and plasma
cells. Russell bodies are present in the latter. Adjacent
brain tissue shows gliosis and numerous Rosenthal fibers.
The low-grade tumor arises preferentially in middle-aged
women. The symptoms may include forgetfulness,
headache, lethargy, homonymous hemianopsia, hypothalamic dysfunction and obstructing hydrocephalus.
Immunocytochemically, markers such as GFAP and
vimentin indicate that they are glia by nature. In imaging
studies, the tumor appears as a large, well-circumscribed
third ventricular mass, sometimes with a cystic component. The way the epithelioid cells are arranged in clusters
suggests a choroid plexus, or a meningothelial or notochordal derivation, but it may also be derived from the
subependymal tissue. The current treatment of choice is
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surgical resection (Brat et al., 1998; Vajtai et al., 1999;

Pomper et al., 2001; Kurian et al., 2002). Sometimes a
chordoma can mimic a pituitary adenoma and cause
bitemporal hemianopsia due to chiasmal compression and
hypopituitarism (Thodou et al., 2000).
Occasionally lipomas of 13 cm in diameter are found.
They might form a polyp hanging by a pedicle from the
undersurface of the tuber into the cisterna, or on the
ventral side of the mamillary bodies. Lipoma are usually
symptomless, located in the midline and found by accident. Macroscopically a lipoma might resemble a
hamartoma. Other lipoma might grow as a large mass
into the hypothalamus, replacing the entire tuberal region
and mamillary bodies. Histologically it is basically a
lipoma, but usually there are a few plaques of bone
embedded in the fat. Although the tumors are only
reported in adults, they are presumably congenital
(Sheehan and Kovacs, 1982; Kurt et al., 2002).
Malignant lymphoma is a condition of middle age and

affects both sexes equally. This is a type of tumor that
occurs more frequently in other parts of the brain than
in the hypothalamus and used to be called reticular
cell sarcoma. This tumor forms a pinkish solid mass in
the infundibulum and neighboring hypothalamus and
sometimes extends down the stalk to replace the posterior pituitary. Histologically it is diffuse and nonfollicular
in 6090% of the patients and consists of round or
polygonal cells with lobulated nuclei. In 98% of these
tumors the cells are derived from B lymphocytes.
Clinically the tumor is usually characterized by diabetes
insipidus and hypogonadism, sometimes also by
obesity, somnolence or psychiatric symptoms (Sheehan
and Kovacs, 1982). A case of primary hypothalamic
lymphoma was found to mimic neurosarcoidosis by
pleocytosis, increased spinal fluid protein, diabetes
insipidus, anterior lobe dysfunction, hepatic granuloma,
Fig. 19.26. A 24-year-old woman with a large adenoma of the pituitary (A) Mid-sagittal section. The optic chiasm (arrow) and anterior commissure (AC) are located on and above the adenoma, respectively. Anterior communicating artery complex (ACAC) is located closely in front of
optic chiasm and on the adenoma. (B) Coronal section. Optic chiasm (arrow) is flattened and displaced superiorly. (C) Axial section. Optic nerves
(arrows) are visible. (D) Axial section 3.5 mm above C. Optic tracts (arrow) and mamillary bodies (MB) are visible. (From Eda et al., 2002
Fig. 3.)
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to radiation therapy (Hasegawa et al., 1995). An endodermal cyst of the third ventricle has histological
similarities to the gastrointestinal epithelium and is
considered to be derived from the embryonic endodermal
layer, i.e. from the most cranial portion of the primitive
intestine (Bttner et al., 1997). A central neurocytoma
confined to the third ventricle presented clinically as
subarachnoid hemorrhage. It was a well-differentiated
neoplasm of neuronal origin, with a cystic component
and intratumoral hemorrhage. Synaptophysin, neuronspecific enolase, ultrastructurally identified synapses,
neurosecretory granules or neuritic processes demonstrated the neuronal lineage of these tumor cells.
Neurocytomas of the lateral ventricle may also spread
into the third ventricle. A gangliocytoma of the neurohypophysis is a very rare tumor (Chapters 19.3c, 22.1,
22.6). It may produce vasopressin and lead to inappropriate antidiuretic hormone secretion (Fehn et al., 1998;
Chapter 22.6). One patient with Cushings syndrome
appeared to have a gangliocytoma of the neurohypophysis containing ACTH-producing cells. The neurons
themselves did not express ACTH or CRH (Geddes
et al., 2000). In addition, ganglioglioma of the optic
chiasm were found most frequently as mixed glioneuronal tumors and more commonly in children
(Shuangshoti et al., 2000). Gliomatosis cerebri is
described in Chapter 19.4c.
hypercalcemia, elevated angiotensin-converting enzyme

(a carboxy-peptidase that hydrolyzes angiotensin I to
angiotensin II; produced, e.g. by epitheloid cells of the
sarcoid granuloma). The lack of response to prednisone
was, however, atypical for sarcoidosis, and emergency
transplenoidal resection disclosed a large B-cell
lymphoma, a disease that is usually also steroid-responsive (Bayrakdar et al., 1997).
A Large adenoma of the pituitary may push upwards
and produce pressure on the front of the chiasm,
or between the optic nerves (Fig. 19.26). The first
symptom is usually bitemporal hemianoptia, and there
is optic atrophy. Less often the tumor may impinge
on the back of the chiasma. Pressure on the hypothalamus may lead to fatigue and sleepiness, excessive eating
or anorexia, hypothermia, diabetes insipidus, hydrocephalus and hypopituitarism. The patient may also feel
cold due to hypothyroidism, perform less well and have
headaches (Sheehan and Kovacs, 1982; Harris et al.,
2002).
Gait disturbances and behavioral changes in a 51-yearold woman appeared to be due to a small, blackberry-like
subependymal tumor, i.e. a cavernoma behind the
interthalamic adhesion in the third ventricle. A huge,
mixed cavernous angioma and astrocytoma in the hypothalamus manifested by headache, visual field defect, gait
disturbance and convulsions, responded remarkably well
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CHAPTER 20
Hypothalamic infections
20.1. Inflammatory conditions affecting the

hypothalamus
region. The granulomatous lesion was composed of

small cavities filled with necrotic material. The abscess
cavity was encircled by layers of collagen and florid
granulomatous tissue with giant cells (Fig. 20.1). There
was no evidence of systemic tuberculosis (Indira et al.,
1996). In the case of a hypophysial tuberculoma, a
thickened pituitary stalk in contrast MRI scans may be
useful for the differentiation from pituitary adenomas
(Sinha et al., 2000; Pramo et al., 2002). However, in
some developing countries, but also in the USA, patients
have been described with a hypothalamic tuberculoma,
causing the signs and symptoms of panhypopituitarism
(Flannery et al., 1993). Intracranial calcifications develop
in approximately one-third of the children who recovered
from tuberculous meningitis. The calcified lesions may
destroy hypothalamic or pituitary tissue and result, e.g.
in somatotropic or gonadotropic deficiencies or diabetes
insipidus (Asherson et al., 1965; Haslam et al., 1969).
Patients with tubercular meningitis may die suddenly,
probably due to hypothalamic apoplexia. Hypothalamic
damage secondary to infarction has been reported repeatedly. Other patients may develop panhypopituitarism due
to chronic scarring and calcification of the hypothalamus
(Indira et al., 1996).
In cholera cases, the hypothalamus showed a decrease
in Gomori-stained neurosecretory material. The paraventricular nucleus (PVN) was sometimes vacuolated
(Choudhury, 1969).
(a) Bacterial infections

One hundred years ago, tuberculosis was one of the
diagnoses most frequently made in the Western countries.
In 1893, Starr reported that 50% of all brain tumors
were due to tuberculosis, and, in the early years of
the last century, Cushing said that about 30% of all
space-occupying lesions within the cranium were attributable to tuberculosis (Scully et al., 1983). Tuberculous
meningitis may cause, e.g. epilepsy, hemiplegia, paraplegia, optic atrophy and blindness, deafness, mental
retardation, hydrocephalus and hypothalamopituitary
disorders such as diabetes insipidus, obesity, hypogonadism, and, when the periventricular portion of the
hypothalamus is involved, precocious sexual development
(Bauer, 1954; Lorber, 1958; Asherson et al., 1965). In
areas where tuberculosis is endemic, hypothalamic tuberculoma can still form an important radiologically
differential diagnosis to be distinguished, e.g. from astrocytoma, craniopharyngioma, hamartoma and germinoma.
A case report on a 10-year-old boy may serve as an
example. For 6 months this boy had had hypothalamic
symptoms, i.e. progressive loss of vision, headaches and
vomiting, and it was noticed that he gained weight
and ate and slept excessively for 4 months. There was
compression of the third ventricle with hydrocephalus.
He underwent placement of a ventriculoperitoneal shunt
prior to exploration. A biopsy of the suprasellar mass
revealed tuberculoma. Postoperatively the patient developed polyuria and hypothermia. The patient died on
the 7th postoperative day. At autopsy the suprasellar
mass was found to be occupying the entire hypothalamic
(b) Acute viral meningoencephalitis

Hypothalamopituitary symptoms such as hypopituitarism,
including hypogonadism, hyperprolactinemia and the
syndrome of inappropriate secretion of vasopressin may
be caused by acute viral meningoencephalitis (Bauer,
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Fig. 20.1. Tuberculosis of the hypothalamus (A). A histological preparation shows an abscess cavity field with caseous material bordered by poorly
formed granulomas with giant-cell reaction and fibrosis. (B) Higher magnification of the abscess wall shows epitheloid cells and Langerhans-type
giant cells. (From Indira et al., 1996, Fig. 3 with permission.)
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1954; Kupari et al., 1980; Lichtenstein et al., 1982;

Ishikawa et al., 2001b). According to Bauer (1954), the
periventricular portion of the hypothalamus can be
involved in various types of encephalitis and encephalomeningitis, including tuberculosis, which may result
in precocious puberty and diabetes insipidus. Acute
virus encephalitis frequently goes together with lesions
in the hypothalamus. A 12-year-old girl was diagnosed
as having acute disseminated encephalomyelitis. She
manifested hypersomnia and intense lesions in the
hypothalamus. The low hypocretin levels in the cerebrospinal fluid (CSF) of this patient explained the
hypersomnia (Kubota and Kabayashi, 2002; Chapter
28.4). Hypothalamic lesions have been reported, e.g.
following varicella-zoster, smallpox, measles, coxsackie
virus B, poliovirus and inoculation for rabies in patients
who died during the acute stage of encephalitis (Ishikawa
et al., 2001b).
A recent study using MRI confirmed the presence of
hypothalamopituitary abnormalities and dysfunctions in
rabies (Ishikawa et al., 2001b). Indeed, rabies is virtually
always fatal, once symptoms are evident (Pleasure and
Fischbein, 2000). Sexual manifestations of rabies, such
as priapism, penile hyperexcitability with erection, ejaculation on the slightest touch of the penis, and excessive
libido have been reported (Dutta et al., 1996). It has been
proposed that rabies may have played a key role in the
belief in vampires in the 18th century. Vampires allegedly
were dead people who left their graves and killed people
and animals (Gmez-Alonso, 1998). Rabies is a zoonosis
transmitted by a bite, scratch or inhalation of the virus.
Bat-borne rabies can be spread without traumatic exposure. Once inoculated, the virus spreads centripetally via
peripheral axons to the central nervous system (CNS),
where it is capable of transsynaptic spread. The intimate
relationship between the hypothalamus and the autonomous system (Buijs and Kalsbeek, 2002) may thus be
the explanation for the frequent involvement of the
hypothalamus. The untreated patient with furious (i.e.
encephalitic) rabies following dog bite frequently manifests a tendency to wander, to be restless, to show signs
of autonomic dysfunction, a hypersensitivity to stimuli,
a feeling of terror, persistent insomnia, an increasing
agitation, hydrophobia and muscular spasms. Paralytic
symptoms (dumb form) and coma may appear before
the patient dies. Rabies shows similarities to vampirism.
The muscle spasms may cause hoarse sounds, saliva
cannot be swallowed and vomiting of bloody fluid occurs.
Bat rabies is reported to give a high incidence of focal
93
brainstem signs and myoclonus, sometimes hemiparesis

or hemisensory deficits, ataxia, chorea or Horner
syndrome. The rabid patient may rush at those who
approach him, biting and tearing at them as if he were a
wild animal. Hypersexuality and violent rape attempts
may be striking manifestations of furious rabies. In some
men penile erection can last for several days. The literature reports cases of rabid patients who had intercourse
up to 30 times a day (Gmez-Alonso, 1998; Pleasure and
Fischbein, 2000).
Hypothalamopituitary insufficiency has been observed
following influenza A and herpes simplex encephalitis
(Kupari et al., 1980; Ishakawa et al., 2001). Following
herpes simplex encephalitis, MR images showed involvement of the substantia innominata and of the corpora
mamillaria in patients who were left with memory difficulties (Kapur et al., 1994). Hypothalamic encephalitis
has also caused a marked sinus bradycardia so severe
(with a heart rate of less than 30 beats per minute), that
a temporary pacemaker had to be implanted (Ishikawa et
al., 2001b).
(c) Post- and parainfectious encephalomyelitis
Hypothalamic lesions are a much less frequent occurrence
in the post- and parainfectious encephalomyelitis than in
the acute stages of encephalitis. A combination of hyperthermia, hyperphagia and secondary hypothyroidism has
been described in a boy after 1 year of high fever due to
a varicella infection. Diurnal fluctuations in temperature
and water excretion were abnormal, but diurnal fluctuations in serum corticosteroid levels were present.
Temperature regulation did not respond to the ordinary
regulatory stimuli. At autopsy, focal areas of gliosis and
lymphocytic infiltration were only found in the hypothalamus, particularly in the region of the supraoptic
nucleus (SON) and tuber cinereum (Lipsett et al., 1962).
A case of hypothalamic encephalitis with influenza
A/Netherlands/110/72, which was preceded by infectious
mononucleosis, showed a severe chronic inflammatory
reaction. There were round-cell accumulations in the
perivascular spaces, astroglial proliferation, foci of histiocytes, macrophages and edema; nerve cells were affected
(Ongerboer de Visser et al., 1976). In bulbar poliomyelitis,
diffuse inflammatory hypothalamic changes have been
observed in 85% of the cases. The SON is most severely
affected, whereas the tuberal and mamillary nuclei are
usually spared (Baker et al., 1952). In cases of bulbar
poliomyelitis where a prolonged hyperthermia is manifest,
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cell damage is the most severe in the rostral portion of the

hypothalamus. Because the PVN involvement alone is
reported to be exclusively associated with temperature elevations, the PVN has been proposed to be an essential
structure as far as lowering body temperature is concerned.
In cases of hypothermia, lateral and medial hypothalamic
nuclei are involved (Brown et al., 1953). A 3-year-old boy
developed obesity and had a fever for half a year. He died
of an allergic reaction to penicillin. Autopsy revealed a
severe bilateral drop of neurons in the ventromedial hypothalamic nuclei, with diffuse hyperplasia of astrocytes
(Wang and Huang, 1991; for ventromedial hypothalamus
syndrome, see Chapter 26.3).
(d) Fungal infections
Persistent fever of unknown origin may be due to a fungal
infection such as Candida albicans, aspergillus or mucor
species, or other fungi acting on the hypothalamus
(Barwick et al., 1994). Patients immunocompromised
by acquired immunodeficiency syndrome (AIDS), by
immunosuppressive drugs or treated by prolonged antibiotic therapy for gram-negative organisms are also
susceptible to central mycotic abscesses (see Chapter
20.3). Associated infections include, e.g. cryptococcosis.
Candida albicans causes meningitis, hydrocephalus,
cortical microscopic abscesses, cerebritis, granulomas and
vasculitis.
(e) Other hypothalamic infections
The hypothalamus is rather infrequently involved in bacterial infections such as -hemolytic streptococcus, pneumococcus and in the neonate Listeria monocytogenes.
Posterior lobe microabscesses are a common preterminal
incidental finding at autopsy (Horvath et al., 1997).
Hypothalamic pituitary deficiency has been described in
a case of Weils disease, which is due to leptospirosis.
Panhypopituitarism was found, but hypothalamic participation could not be demonstrated (Panidis et al., 1994).
Neurocysticercosis is a CNS infection caused by Taenia
larvae. In patients with such inflammatory lesions in the
anterior hypothalamus, obesity and hyperphagia were
observed (Lino et al., 2000). Lymes disease is a multisystem disorder caused by infection with the Borrelia
burgdorferi spirochete. Neuro-ophthalmic and ocular manifestations of Lymes disease, including papilledema,
increased intracranial pressure and optic atrophy, have frequently been reported (Balcer et al., 1997). Post-Lyme
syndrome is characterized by severe fatigue, malaise and
cognitive complaints. The latter component is more pronounced in Lymes disease than in chronic fatigue syndrome (Chapter 26.8a).
Whipples disease is a rare disease characterized by a
widespread, chronic granulomatous infiltration of the
gastrointestinal, cardiac, pulmonary and nervous systems.
There is a 6:1 male predominance. It is caused by the
rod-shaped baccillus Tropheryma whippelii, with a
delayed hypersensitivity as the underlying mechanism.
CNS involvement occurs in 1020% of cases. Lesions
consist of a gliovascular inflammatory reaction with a
predilection for hypothalamus, cingulate gyrus, basal
ganglia, insular cortex and cerebellum. Large numbers of
swollen, gemistocytic astrocytes and smaller collections
of the classic foamy macrophages are found. Perivascular
cuffs of mononuclear cells and lymphocytes are frequently
encountered also. Stuffed microglia frequently surround
nerve cells, a process accompanied by a definite loss
of neurons. CNS involvement may remain clinically
silent. Hypothalamopituitary involvement may include
symptoms of insomnia or hypersomnia, weight gain
and polydipsia, in combination with ophthalmoplegia.
Transient, almost complete sleep loss caused by cerebral
manifestation of this disease has been described.
Endocrine tests revealed flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin,
indicating that the suprachiasmatic nucleus was affected.
Whipples disease can be treated with antibiotics that
effectively cross the bloodbrain barrier, such as penicillin, TMP-SMZ or chloramphenicol (Mendel et al.,
1999; Voderholzer et al., 2002).
20.2. Encephalitis lethargica (Von Economos
encephalitis)
Encephalitis lethargica was first described by Constantin
von Economo in Vienna in 1917. Among the wounded
soldiers of World War I, he noted patients with peculiar
symptoms, including a remarkable sleepiness for which
the syndrome was named. The cause of the epidemic,
which affected 5 million victims, was never determined.
The histopathology of the acute cases included inflammated cells, congested blood vessels, hemorrhages, cellular necrosis, chromatolysis, neuronophagia and gliosis.
The mesencephalic and basal ganglia were the most
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frequent sites of the lesions, but the hypothalamus, too,

appeared to be one of the predilection sites, which might
relate to some of the neuropsychiatric symptoms, e.g.
sleep and circadian disturbances (see Chapter 4), disturbances of sexual behavior (Chapter 24.5), mood (Chapter
26.4), obsessive and compulsive behavior (Chapter 26.6)
and aggression (Chapter 26.9). The lethargy resembled
abnormally profound sleep. Often the patient could be
roused, would answer a question intelligently and then
relapse into a stupor. Insomnia and marked disturbances
of the diurnal pattern were also reported.
Von Economo broadly divided encephalitis lethargica
into the somnolence-ophthaloplegia type with lesions in
the posterior wall of the third ventricle near the oculomotor nucleus and the choreatic-insomniac type, due
to an anterior lesion in the lateral wall of the third
ventricle near the corpus striatum. In postencephalitis
parkinsonism, oculogyric crises were found. They were
linked to obsessive and compulsive behavior. Some
patients had compulsive sexual or violent thoughts along
with oculogyric deviation. Mood disorders were striking,
including recurrent mania, episodic depression and bipolar
mood disorders (Cheyette and Cummings, 1995). Among
the neurological disorders that developed months to years
after the acute infection, a 10% incidence of morbid
obesity was found. Whether these patients indeed had
lesions in the mediobasal hypothalamus was not established (Nagashima et al., 1992). Children tended to
manifest somewhat different symptoms in cases of
encephalitis lethargica than adults. They were more likely
to display an inversion of the sleep rhythm: they often
had insomnia at night and slept during the day. Many
children displayed behavioral disturbances, including
sexual precocity, exhibitionist tendencies and sexual
aggression. Although a number of the behavioral symptoms indicate hypothalamic involvement, no relationship
has developed between particular hypothalamic lesions
and behavioral disturbances in encephalitis lethargica
(Cheyette and Cummings, 1995).
More recently two patients were described with
acute encephalitis, the features of which including
parkinsonism, fever, lethargy, fluctuations of consciousness, pupillary abnormalities, oculogyric crises, delusions,
loss of temperature regulation, profuse sweating, disturbances of the sleep cycle and severe dyskineas suggested
encephalitis lethargica. Both patients responded rapidly
and dramatically to intravenous methylprednisolone,
although some hypothalamic symptoms remained in one
patient. The cause is not known (Blunt et al., 1997).
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20.3. Acquired immunodeficiency syndrome (AIDS)

Hypothalamic disturbances, such as endocrine or autonomic dysfunction, hyper- or hypothermia and vegetative
symptoms, have frequently been reported in patients with
AIDS. These include adrenal insufficiency, hyperprolactinemia, central diabetes insipidus and changes in the
hypothalamopituitary gonadal axis (Croxson et al., 1989;
Dluhy, 1990; Merenich et al., 1990; Sullivan et al., 1992;
Moses et al., 2003) as well as weight loss, fever, and
fatigue (Hellerstein et al., 1990). Frank hypopituitarism
due to destruction or infiltration of the hypothalamic
region is rare in patients with AIDS: only a few cases of
hypopituitarism have been described in AIDS patients.
More subtle defects, due to the human immunodeficiency
virus (HIV), or other HIV-mediated factors of hypothalamopituitary function, occur frequently, although in a
routine H&E staining generally no obvious signs of local
inflammation are observed in the region of the PVN.
In some patients periventricular cuffs are present in the
hypothalamus (Fig. 20.2). In addition, no obvious difference was seen for leukocyte-common antigen (LCA) or
GFAP staining between hypothalamic sections of groups
of controls and AIDS patients (Purba et al., 1993). When
AIDS causes endocrine problems, the focus in literature
is generally on the endocrine end-organs, i.e. the thyroid,
adrenal glands, gonads and kidneys, and not on the
possible causes on the level of the pituitary, and certainly
not on the level of the hypothalamus (Merenich, 1994).
However, cytokines such as interleukin-1 (IL-1), IL-6
and tumor necrosis factor (TNF), which are produced by
immune cells, may affect hypothalamic corticotropinreleasing hormone (CRH) neurons (Freda and Bilezikian,
1999). Cytomegalovirus (CMV) involvement has sometimes been found in the adenohypophysis, neurohypophysis and hypothalamus (Sullivan et al., 1992; Purba
et al., 1993; Merenich, 1994). In the neurohypophysis,
Cryptococcus sp., Aspergillus sp., Toxoplasma sp. and
Pneumocystes carinii were observed in AIDS patients
(Figs. 20.3). In addition to endocrine and autonomic dysfunctions, also visual loss may occur in AIDS. An AIDS
patient has been described with a chiasmatic mass due to
a primary central nervous system lymphoma (Lee et al.,
2001).
Vasopressin
Central diabetes insipidus has been found in a patient
with AIDS due to cytomegalovirus infection of the
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Fig. 20.2. Perivascular cuff in the hypothalamus in a case of AIDS ( 42 years). Bar = 200m.
hypothalamus. The patient did not have polyuria because

of the accompanying glucocorticoid deficiency. In addition, low testosterone, follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) were found (Moses et al.,
2003). Central diabetes insipidus has also been reported
in a few AIDS patients in whom anterior pituitary function was preserved. Desmopressin resulted in complete
resolution of this symptom (Merenich, 1994). The number
of vasopressin-expressing neurons in the PVN in a group
of AIDS patients was, however, not significantly lower
than in controls (Purba et al., 1993), indicating that, due
to destruction of the SON and PVN, hypothalamic
diabetes insipidus must be a rare phenomenon. In
addition, several AIDS patients with the syndrome of
inappropriate antidiuretic hormone secretion have been
reported (Merenich, 1994). Hyponatremia occurs in
3050% of AIDS patients (Sellmeyer and Grunfeld,
1996).
Oxytocin
We observed a 40% drop in the number of oxytocinexpressing neurons in the PVN in AIDS patients (Purba
et al., 1994). However, no decrease in oxytocin-messenger
RNA (mRNA) of the PVN was measured by quantitative in situ hybridization in AIDS patients (Guldenaar
and Swaab, 1995), suggesting differences in oxytocin
precursor processing in AIDS. If this is indeed the case,
it may be of importance for those autonomic functions
that are regulated by oxytocin fibers projecting from the
PVN to the brainstem (Chapter 30).
Oxytocin receptors are present in AIDS-related
Kaposis sarcoma, an intensely angioproliferative disease,
possibly of vascular origin. Oxytocin treatment of Kaposi
cells led to a significant increase in cell proliferation and
could therefore be considered a possible relevant growth
factor involved in Kaposis sarcoma progression (Cassoni
et al., 2002).
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Fig. 20.3. Toxoplasmosis infection in the hypothalamus in a case of AIDS. Bar = 200 m.
hyperactivity (see above) to subclinical disturbances to

frank adrenal insufficiency (Freda and Bilezikian, 1999).
Data concerning ACTH secretion are conflicting, which
may at least be partly due to the stage of infection
(Lortholary et al., 1996). In a group of HIV-positive
homosexual men in relatively good health, no difference
in cortisol levels was found (Kertzner et al., 1993). This
negative finding was presumed to be due to the relatively
early stage of the disease (Rotterdam and Dembitzer,
1993), but an attenuated ACTH and cortisol response to
a cold stressor challenge was observed in asymptomatic
HIV-1 positive persons (Kumar et al., 2002). The HPA
axis can show abnormalities in different directions. On
the one hand, the adrenal gland is known to be a common
site of opportunistic infections (Rotterdam and Dembitzer,
1993). On the other hand, there are studies that report
that cortisol is elevated at all stages of infection and
particularly in AIDS patients (Christeff et al., 1997).
Hypothalamopituitaryadrenal (HPA) axis

Increased serum cortisol levels are the most common
finding as AIDS progresses (Grinspoon et al., 1994;
Merenich, 1994; Savastano et al., 1994; Lortholary et al.,
1996; Sellmeyer and Grunfeld, 1996, Christeff et al.,
1997; Freda and Bilezikian, 1999). There has even been
a report of a case of Cushings syndrome associated with
AIDS (Savastano et al., 1994). It has been proposed that
the HIV virus may stimulate CRH or corticotropin
(ACTH) either directly or indirectly via stimulation of
cytokines. In addition, HIV is a major life stressor. HIV
viral load is also immediately high in the hippocampus,
which inhibits CRH. Moreover, the POMC promotor is
100% homologous to a region of the HIV-1 genome, and
HIV viral protein R can interact with corticosteroid receptors. Which of these putative mechanisms is of clinical
importance has to be investigated (Kumar et al., 2002).
Abnormalities of the HPA axis in AIDS may range from
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Adrenal insufficiency also results in low cortisol levels,

and a blunted cortisol response to ACTH stimulation has
been observed in AIDS patients, accounting, at least
partly, for weight loss, general weakness, anorexia
(Savastano et al., 1994), and hypotension or hyponatremia, which are all Addison symptoms, in spite of
elevated cortisol levels. In fact, 12% of the AIDS patients
are glucocorticoid-resistant (Grinspoon et al., 1994;
Merenich, 1994; Norbiato et al., 1997). Although histological modification of the adrenal glands has often been
described during the late stages of HIV infection, reports
of adrenal insufficiency are rare (Lortholary et al., 1996).
Suppressed circadian secretion of ACTH in association
with increased basal cortisol levels has also been observed
in a small number of patients with AIDS. On the other
hand, normal and elevated ACTH and cortisol levels have
been found in others with preserved adrenal function.
Moreover, the development of cortisol resistance has been
presumed (Grinspoon et al., 1994; Merenich, 1994). So
far, however, there are no direct observations available
on activity changes of the CRH neurons in the PVN of
AIDS patients. In contrast to cortisol, the serum dehydroepiandrosterone (DHEA) levels generally decreased in
each later stage of HIV infection. The increased cortisol
levels and the decreased levels of DHEA, an antiglucocorticoid compound, may, at least partly, provoke a drop
in CD4+ cells and a shift from type 1 to type 2 cytokine
production (Christeff et al., 1997; Clerici et al., 1997). A
fall in DHEA levels predicts progression to AIDS, independent of CD4 cell counts (Sellmeyer and Grunfeld,
1996). Antiglucocorticoid drugs may be helpful in HIV
disease, as they antagonize the immunosuppression
induced by increased levels of cortisol (Norbiato et al.,
1997). Whether DHEA administration may influence the
disease process favorably has not been studied.
Circulating levels of alpha-melanotropin (MSH are
elevated in HIV-infected patients (Catania et al., 2000).
Hypothalamopituitarythyroid axis
Thyroid function is normal in most patients with HIV
infection (Grinspoon et al., 1994). Opportunistic infections of the thyroid have been found, but most of the
patients did not present with thyroid dysfunction
(Sellmeyer and Greenfeld, 1996). Hypothyroidism has
been seen in AIDS patients but is considered to be due
to altered peripheral metabolism of thyroid hormone and
not to changes on the level of the pituitary or hypothalamus. In the terminal phases of AIDS, thyroid hormone
axis changes are similar to those observed in other serious
conditions, i.e. those of the euthyroid sick syndrome

(Merenich et al., 1990; Merenich, 1994; Sellmeyer and
Grunfeld, 1996; Fliers et al., 1997; Chapter 8.6).
Hypothalamopituitarygonadal axis
In the early stages of AIDS, total and free testosterone
are elevated and the LH response to LHRH is exaggerated (Merenich et al., 1990). This may be explained
by a direct stimulatory effect of the HIV virus on the
pituitary or hypothalamic level. However, as AIDS
progresses, one-third of the men develop hypogonadism,
with lower testosterone levels and higher LH and FSH
levels. These changes may affect cognition, mood, libido
and energy levels (Croxson et al., 1989; Ng et al., 1994).
Testicular atrophy is a common finding in AIDS (Rogers
and Klatt, 1988). Some of the medications used may also
affect gonadal function (Sellmeyer and Grunfeld, 1996).
Prolactin levels are normal or mildly elevated (Croxson
et al., 1989; Merenich et al., 1990). The gonadal axis has
not been studied adequately in women with AIDS, but
menstrual irregularities, decreased libido and hair loss
have been reported (Merenich, 1994).
Growth hormone
Two cases of growth hormone deficiency in AIDS have
been reported that were coupled to sex steroid deficiency.
One of the cases was associated with gonadotropic failure.
The patients had evidence of dysfunction at the hypothalamic, pituitary and end-organ level (Ng et al., 1994).
In HIV-infected men who did not show signs of wasting,
normal growth-hormone secretion, insulin-like growth
factor-1 (IGF-I) and IGF-binding protein-3 concentrations
were found (Heijligenberg et al., 1996).
Circadian changes
When HIV-infected males are compared with controls,
significantly higher levels are found for cortisol, and lower
ones for DHEA, DHEA-S and ACTH. Plasma testosterone
levels decreased in a later stage of HIV infection (Villette
et al., 1990). Analysis of the circadian rhythm of plasma
hormone levels clearly indicated an altered adrenal
hormonal state in HIV-infected male patients, even during
the asymptomatic period of the infection. For instance,
plasma cortisol at 04.30 h was more than twice as high
in HIV-infected patients than in time-matched controls
(Villette et al., 1990). Abnormal ACTH and cortisol
circadian rhythms have also been reported in stage IVc
AIDS patients (Lortholary et al., 1996). Although such
data might point to early changes in the suprachiasmatic
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nucleus, these authors did not take into consideration that

comparisons were made between HIV-infected men, some
of whom were homosexual, whereas sexual orientation of
the controls was not specified (Villette et al., 1990). The
difference in the suprachiasmatic nucleus in homosexual
men as compared to heterosexual men (Swaab and
Hofman, 1990) may thus have biased these observations.
Circadian growth hormone secretion in asymptomatic HIV
infection and AIDS without wasting is not different from
that in healthy subjects.
99
The external envelope of the HIV virus contains a glycoprotein (gp 120) that has been shown to be neurotoxic and
to cause learning deficits in rats. Vasoactive-intestinal
polypeptide (VIP) was found to block the gp 120-induced
neurotoxicity in culture, and a VIP receptor antagonist
displayed toxic properties to neurons in culture. Possible
repercussions of these observations for the VIP cells in the
suprachiasmatic nucleus (SCN) (Chapter 4c, d) of the
hypothalamus in HIV-infected patients have never been
studied.
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CHAPTER 21
Neuroimmunological disorders
21.1. Neurosarcoidosis of the hypothalamus
led to the diagnosis of schizophrenia, schizoaffective

disorder and dementia. Also, mental status associated with
delirium, euphoria, depression, aggression, apathy and
cognitive deficits have been described. If neurosarcoidosis
occurs, it has a striking predilection for the hypothalamus
and pituitary, i.e. in 1026% of cases (Robert, 1962;
Turkington and Macindoe, 1972; Stern et al., 1985;
Vanhoof et al., 1992; Oksanen, 1994; Guoth et al., 1998;
Schielke et al., 2001). Central diabetes insipidus occurs
in about 25% of patients with neurosarcoidosis (Bullmann
et al., 2000) and can be the first manifestation of the
disease (Konrad et al., 2000). Hyperprolactinaemia may
be present (Molina et al., 2002). Other manifestations
of hypopituitarism are hypoglycemia, dwarfism, panhypopituitarism, hypogonadism, obesity, and weight gain or
weight loss (Bell, 1991; Murialdo and Tamagno, 2002;
Randeva et al., 2002). Symptoms also attributed to
hypothalamic involvement in sarcoidosis are somnolence,
insomnia, hypothermia, extreme variations in body
temperature, intolerance to cold, anorexia, hyperphagia,
and progressive obesity and personality changes (Robert,
1962; Branch et al., 1971; Bell, 1991; Sommer et al.,
1991; Vanhoof et al., 1992). In addition, a patient
with hypothalamic sarcoidosis was described who
had polyuria, inappropriate vasopressin (VP) release
and excessive thirst. The patients fitted the criteria of
SchwartzBartter (Chapter 22.6a) and the neurosarcoidosis was confirmed by autopsy (Kirkland et al., 1983).
Up to 20% of neurosarcoidosis patients have psychiatric manifestations. These can range from mild apathy
to severe mental deterioration (Vanhoof et al., 1992;
OBrien et al., 1994). In addition, memory loss associated
with confusion has been described (Sharma, 1997).
A 67-year old woman who had neurosarcoidosis,
which damaged the anteromedial hypothalamus with an
The etiology of sarcoidosis is unknown. Environmental

factors, infectious agents or hereditary factors may be
involved. The seasonal clustering reported for various
types of sarcoidosis (Wilsher, 1998) suggests that circannual fluctuations in the immune system or in infections
may be important. Melatonin may mediate circannual
immunological fluctuations (Nelson and Demas, 1997).
Since a patient developed neurosarcoidosis 22 years after
augmentation mammoplasty through the injection of
silicone gel (Yoshida et al., 1996), it has been suggested
that immunomodulations by foreign bodies such as
silicone may also be a pathogenic risk factor in
sarcoidosis.
(a) Clinical presentation
Neurological involvement is rather rare; it occurs in about
5% of the sarcoidosis patients and leads to death in
1218% of all cases (Vanhoof et al., 1992; OBrien
et al., 1994; Sharma, 1997). Criteria for the diagnosis of
possible, probable and definitive neurosarcoidosis have
been proposed (Zajicek et al., 1999). Neurosarcoidosis
may be confused clinically with multiple sclerosis,
Lyme disease, Bechets disease, histiocytosis-X,
Wegeners granulomatosis, Whipples disease, lymphomatosis, meningeal carcinomatosis and a variety of
infections, including cryptococcal meningitis, tuberculosis, syphilis, toxoplasmosis, and fungal infections. The
diagnosis of isolated neurosarcoidosis, can only be established by biopsy (Graham and James, 1988; Sommer
et al., 1991; Zajicek et al., 1999; Randeva et al., 2002;
Chapters 20.1, 21.3). In addition, neurosarcoidosis has
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extension into the mamillary bodies, did not only have

hyperphagia and hyperdipsia, but also had severe memory
failure, characterized by spontaneous confabulations,
disorientation and severely impaired free recall with
preserved recognition. The authors argued that damage
of the anterior hypothalamus rather than of the mamillary bodies was responsible for the confabulary amnesia
(Ptak et al., 2001). The exact role of hypothalamic and
other lesions in the psychiatric symptoms (see Chapter
26) has to be better defined. The optic nerve is, after the
facial nerve, the second most commonly involved cranial
nerve in neurosarcoidosis. MR images may show optic
nerve enhancement. The characteristic picture is that of
an atypical optic neuritis often subacute in onset, which
might recover following steroids or cause permanent
visual impairment (Zajicek et al., 1999). The optic nerve
is affected in some 5% of the patients with sarcoidosis
(Sharma and Anders, 1985; Stern et al., 1985; Graham
and James, 1988; Westlake et al., 1995; Fig. 21.1). The
optic chiasm is also frequently affected (Walker et al.,
1990). Space-occupying sarcoid lesions may lead to
papilledema and optic nerve atrophy (Sharma and Anders,
1985; Katz et al., 2003). Most of the cases in which
sarcoidosis is manifested as an optic nerve tumor were
mistaken for optic nerve meningioma (Macafee et al.,
1999). Diplopia has also been reported (Molina et al.,
2002). One case has been described that presented in a
very unusual manner, with anosmia and visual changes.
Noncaseating granulomata were subsequently found in
the respiratory epithelium and submucosal (Kieff et al.,
1997). Once an association was described between a
Rathkes cleft cyst and sarcoidosis lesions scattered
around it, causing an intra- and extracellular mass and
hypopituitarism without diabetes insipidus (Cannav et
al., 1997).
Sudden death resulting from hypothalamic sarcoidosis
has been reported a few times. In one case, autopsy
revealed neurosarcoidosis with secondary hydrocephalus.
The other case was a 23-year-old woman who had experienced 6 months of amenorrhea and a 50-pound weight
gain. She had an extensive infiltration of the hypothalamus, including the pituitary stalk, the median
eminence/infundibular nucleus, the right optic nerve,
mamillary bodies, the supraoptic nucleus and the walls
of the third ventricle, including the paraventricular
nucleus (PVN). The PVN showed a marked cell loss.
Death was proposed to be due to the loss of PVN neurons
that innervate autonomic centers, leading to cardiopulmonary arrest (Gleckman et al., 2002).
(b) Pathology
Neurosarcoidosis is due to noncaseating granulomas infiltrating the hypothalamus (Graham and James, 1988; Bell,
1991). The granulomas are initially made up of loosely
organized epithelioid cells derived from macrophages
that are surrounded by a ring of T-lymphocytes. In older
granulomas large numbers of epithelioid and giant cells
are surrounded by a small number of lymphocytes (Bell,
1991). Around the granulomas nerve cells may disappear,
demyelination and gemistocytic reactive astrocytes are
found (Robert, 1962). In addition, space-occupying
sarcoid lesions can be found at the base of the brain
and in the floor of the third ventricle. They may also
manifest themselves as a pituitary pseudotumor (Robert,
1962; Timsit et al., 1993) or, e.g. Rathkes cleft cyst
(Cannav et al., 1997). Whereas earlier postmortem findings pointed mainly to partial or total destruction of the
pituitary by granulomas, later examination of both the
pituitary and the hypothalamus showed extensive and
preferential infiltration of the hypothalamus by granulomatous inflammation or granulomas, and little, if any,
involvement of the pituitary itself (Bell, 1991; Fig. 21.2).
Autopsy was only performed on a few patients with
neurosarcoidosis and showed granulomata diffusely scattered in the median eminence and bilaterally throughout
the hypothalamus (Selenkow et al., 1959; Turkington and
MacIndoe, 1972). In addition, late stages of hyalinized
granulomata have been reported throughout the hypothalamus. They consisted of multiple discrete, round to
oval masses of 100300 m (Branch et al., 1971). One
patient has been reported presenting with diabetes
insipidus. He had a posterior pituitary mass but no other
abnormalities in the pituitary, infundibulum and hypothalamus. The mass showed complete repression after
corticosteroid treatment, but diabetes insipidus persisted
(Loh et al., 1997).
The most common MRI abnormality in cases of
neurosarcoidosis is the presence of multiple white-matter
lesions (Zajicek et al., 1999). MRI may demonstrate hypothalamic periventricular and meningeal lesions (Bell,
1991) and thickening of the pituitary stalk that extends
toward the optic chiasm (Walker, 1990). Only rarely does
neurosarcoidosis present itself as an intracranial mass
lesion. An example is the case described by Grand et al.
(1996; Fig. 21.3) with a lesion resembling a bunch
of grapes on MR images, extending from the right
frontotemporal area toward the midline, involving the
hypothalamus. The arachnoid covering the optic chiasm,
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Fig. 21.1. Sarcoidosis involving the optic nerve and hypothalamus. Top: T1-weighted coronal magnetic resonance imaging scan showing asymmetrical thickening of the chiasm (solid arrow). Center: Following gadolinium enhancement, an increased signal can be seen in the hypothalamus,
third ventricle (open arrow) and meninges (solid arrow), due to sarcoidosis. Bottom: Sagittal cut showing enhancement in the hypothalamus and
pituitary stalk (open arrow), with enlargement of the pituitary gland (solid arrow). (From Westlake et al., 1995, Fig. 1 with permission.)
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Fig. 21.2. Sarcoidosis nodules scattered through the hypothalamus (H&E). (From Sheehan et al., 1982, Fig. 3.45 with permission.)
pituitary stalk and floor of the third ventricle may be

opaque, thickened and sprinkled with many miliary
nodules (Robert, 1962; Vanhoof et al., 1992). Periventricular enhancement indicates active inflammation (Bell,
1991) and involvement of the ependymal lining often
leads to complete obliteration of the third ventricle and
to hydrocephalus (Robert, 1962; Scott, 1993).
(c) Endocrine changes
The prevalence of neuroendocrine disturbances due to
neurosarcoidosis has a peak around 3039 years of age.
Hypogonadotropic hypogonadism, polyuria and polydipsia are the most frequently occurring symptoms in
patients with sarcoidosis of the hypothalamus and pitu-
itary (Murialdo and Tamagno, 2002). Whereas the symptoms of diabetes insipidus were initially attributed to
diabetes insipidus caused by vasopressin deficiency
(Selenkow et al., 1959; Robert, 1962; Branch et al., 1971;
Stern et al., 1985), later studies indicated that they more
often result from primary polydipsia and possibly from
destruction of the osmoreceptors, without vasopressin
deficiency (Bell, 1991). The displacement of the pituitary
bright spot to the upper infundibulum in neurosarcoidosis
(Walker et al., 1996) correlates with the presence of
diabetes insipidus. A patient has been described
with diabetes insipidus and a large posterior pituitary
mass that was most probably due to sarcoidosis. A
complete regression of the posterior pituitary mass was
found after corticosteroid therapy, but the diabetes
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Fig. 21.3. (a, b) Sagittal and (c) coronal T1 images after i.v. gadolinium: sarcoidosis of the hypothalamus. Multiple nodular enhancement resembling a bunch of grapes in the right temporal lobe; extension toward the hypothalamohypophyseal region. (d) Axial T2 image: lesions of the
intermediate intensity signal surrounded by extensive edema. (From Grand et al., 1996, Fig. 2 with permission.)
insipidus persisted and the patient continued to need his

intranasal vasopressin therapy during the 12-month
follow-up (Loh et al., 1997). Inappropriate secretion of
vasopressin has also been described in neurosarcoidosis
(Stern et al., 1985).
Deficiency of anterior pituitary hormones most often
occurs on the basis of hypothalamic dysfunction, although
the pituitary might sometimes be primarily involved as
well (Selenkow et al., 1959; Robert, 1962; Stern et al.,
1985; Graham and James, 1988; Bell, 1991). Patients
may have hypothyroidism, hypogonadism, changes in
pubic hair and body hair, loss of libido, secondary amenorrhea, hypoadrenalism, panhypopituitaris, increased
serum prolactin and, less often, galactorrhea (Robert,
1962; Turkington and MacIndoe, 1972; Stern et al., 1985;
Graham and James, 1988; Verhage et al., 1990; Bell,

1991; Lipnick et al., 1993, Westlake et al., 1995; Molina
et al., 2002; Murialdo and Tamagno, 2002; Randeva et
al., 2002). However, it should be noted that Munt et al.
(1975) were unable to confirm by radioimmunoassay the
high incidence of hyperprolactinemia in patients with
neurosarcoidosis involving the hypothalamus.
Normally, hypoglycemia stimulates rapid increase
of hormones such as catecholamines, glucagon, cortisol
and growth hormone to act in concert to increase
plasma glucose concentration. This action is regulated
by the ventromedial region of the hypothalamus. A
patient has been described who had complete loss of the
counterregulatory response to hypoglycaemia due to a
hypothalamic sarcoid infiltration (Fry et al., 1999).
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(d) Therapy
Administration of oral corticosteroids, 4080 mg/day,
is the usual first line of therapy for neurosarcoidosis,
and often corticosteroids are given long-term, despite the
absence of controlled studies of their efficacy and
the high frequency of serious side effects (Murialdo
and Tamagno, 2002; Randeva et al., 2002).
Methylprednisolone pulse therapy has also been applied
(Molina et al., 2002). In general, neurosarcoidosis is more
resistant to therapy than the pulmonary variety and longterm, high-dose corticosteroid therapy is generally not
very well tolerated and not very effective. Methotrexate,
cyclosporine-A and cyclophosphamide seem to be more
effective (Murialdo and Tamagno, 2002). Recently, the
TNF- antagonist infliximab has been tried with some
success in the treatment of systemic sarcoidosis and
in optic disc swelling in sarcoidosis (Katz et al., 2003).
However, in over half of the neurosarcoidosis patients
the disease progresses despite corticosteroid or other
immunosuppressive therapies (Zajicek et al., 1999).
21.2. Multiple sclerosis (MS) and the hypothalamus

MS is an inflammatory demyelinating disease of the
central nervous system. It is generally a disease of young
adulthood with a peak age of onset between 25 and 30
years of age. The initial course of MS is often characterized by spontaneous relapses and remissions, but it can
also run a primary progressive course. Although the exact
etiology of the disorder is unknown, there is clinical and
laboratory evidence suggesting that it is a multicausal
disease with genetic, autoimmune and environmental
components (Duquette and Girard, 1993). The premenstrual period triggers exacerbations. In fact, 45% of all
exacerbations seem to start in this period (Zorgdrager and
De Keyser, 2002). There is a decreasing NorthSouth
gradient in risk and there are race and sex differences
in predisposition (Limburg, 1950; Kurtzke et al., 1979;
Sadovnik and Ebers, 1993). Seasonal fluctuations in peak
exacerbation rate depend on the region. Exacerbations
of optic neuritis and MS have the highest frequencies
in spring and the lowest in winter. The seasonal fluctuations are presumed to be related to a dysregulation of
interferon- and viral infections (Balashov et al., 1998;
Jin et al., 2000). In addition, stressful life experiences
are considered to be risk factors (Goodin et al., 1999;
Martinelli, 2000). However, an Israeli paper shows that,
contrary to expectation, the number of relapses during a

war and the following months may even be significantly
lower (Nisipeanu and Korczyn, 1993). Several genetic
factors seem to be involved in the risk of developing
MS and in the course of the disease. HLA-DRB1*1501
alleles and estrogen receptor polymorphisms are of importance in this connection and may also be the basis of
the sex differences in the prevalence of MS (Kikuchi
et al., 2002). In addition, single-nucleotide polymorphism
(SNP) in interleukin-1 (IL-1), - and in the IL-1
receptor antagonist influence long-term prognosis in MS
(Mann et al., 2002). Apolipoprotein E (ApoE) is involved
in the transport of lipids necessary for membrane repair,
and is encoded by a gene on chromosome 19q13. MS
patients with an ApoE 3/4 genotype have a more severe
disease course, according to some studies (Fazekas et al.,
2000, 2001), while later onset of chronic progressive MS
was observed in patients carrying the ApoE2 allele
(Ballerini et al., 2000). However, other studies did not
find an association between ApoE4 and adverse outcome
in MS (Masterman et al., 2002). An SNP haplotype near
ApoE is associated with MS susceptibility (Schmidt
et al., 2002). Several other polymorphisms have also been
implicated in the susceptibility and course of MS (Cocco
and Marrosu, 2000).
(a) Autonomic, behavioral and neuroendocrine
symptoms
A number of autonomic and neuroendocrine functions
that are often found to be disturbed in MS point to hypothalamic involvement in this disease. Such autonomic
functions include disturbed functions of the bowel and
bladder, and of sexual behavior (Matthews, 1991; Hulter
and Lundberg, 1995; Mattson et al., 1995), as well as
sweating, and respiratory and cardiovascular regulation
(Anema et al., 1991; Fowler et al., 1992; Howard et al.,
1992), disturbed temperature regulation (Lammens et al.,
1989; Tsui et al., 2002), such as acute and chronic
hypothermia (Sullivan et al., 1987, White et al., 1996)
and poikilothermy (Kurz et al., 1998) and sleep disturbances (Campbell et al., 1982; Clark et al., 1992;
Ferini-Strambi et al., 1994; Tachibana et al., 1994; Tsui
et al., 2002). One patient had asymmetric sweating of the
right forehead and shoulder, due to MS lesions in the
left hypothalamus (Ueno et al., 2000). An MS patient
was described with a new plaque in the hypothalamus
who developed acute hypersomnia and undetectable
CSF hypocretin levels (Iseki et al., 2002). A significant
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reduction in tremor has been reported among MS patients

after subthalamic ventral intermediate nucleus brain stimulation (see Chapter 15.1). However, patient satisfaction
with this procedure was variable (Berk et al., 2002).
Sexual dysfunction in patients with MS is typically
characterized by diminished libido, erectile and ejaculating dysfunction in men, and poor lubrication and
anorgasmy in women. Hypersexual behavior and paraphilias are distinctly uncommon in this group of patients,
but have been described associated with focal brain
lesions in the hypothalamic and septal regions (Frohman
et al., 2002).
Some endocrine disturbances in MS are also related to
hypothalamic alterations. They include: abnormal testosterone levels (Grinsted et al., 1989; Markianos and Sfagos,
1989), which may lead to hypothalamic hypogonadism,
decreased libido and impotence, and may be treated with
testosterone (Bourdette et al., 1988); hyperprolactinemia,
in five of nine cases accompanied by hypothalamic lesions
(Kira et al., 1991; Tsui et al., 2002); altered growth
hormone and TSH levels (Klapps et al., 1992); and
inappropriate antidiuretic hormone secretion (Apple
et al., 1978; Tsui et al., 2002). Alpha-melanotropin
(MSH) levels are increased in patients with a greater
inability score (Catania et al., 2000). A failure of suppression of cortisol levels was observed following
dexamethasone treatment (Reder et al., 1987; Grasser
et al., 1996; Fassbender et al., 1998; Kmpfel et al., 1999;
Then Bergh et al., 1999), indicating a hyperactive
hypothalamopituitaryadrenal (HPA) axis. Cortisol levels
in postmortem CSF of MS patients are elevated by some
80% in comparison with controls, which is another
indication of an increased HPA activity (Erkut et al.,
2002). A severe impairment of the ACTH and metapirone
test was reported by some authors (Brambilla et al., 1974),
while others did not find a difference in the plasma cortisol
response to corticotropin (ACTH) in MS patients (Wei
and Lightman, 1997; Kmpfel et al., 1999). The latter
group also reported lower dehydroepiandrosterone sulfate
(DHEAS) secretion in MS patients. It should be noted
that the pathophysiology of hypercortisolism in MS seems
to be different (see below) from that in depression. MS
is presumed to be associated with increased prominence
of hypothalamic VP secretion (Michelson et al., 1994;
Michaelson and Gold, 1998; cf. Chapter 26.4). Indeed,
the entire increase in corticotropin-releasing hormone
(CRH)-expressing neurons in MS appeared to be due to
an increase in those CRH neurons that colocalize VP
(Erkut et al., 1995; Fig. 21.4). Not only do the CRH
107
neurons play an essential role in cortisol regulation, they

also influence mood (Chapters 21.2b, 26.4), and it is therefore of particular interest that treating relapsing-remitting
MS patients with a combination of corticosteroids and
the antidepressant moclobemide favors normalization of
the HPA axis (Then Bergh et al., 2001). It has been
proposed that the pineal gland may be implicated in the
relapsing-remitting nature of the disease. Melatonin was
even claimed to be able to cause acute exacerbation of
symptoms. Abnormal plasma melatonin levels were found
in half of the MS patients during exacerbations. Most of
them had nocturnal levels that were below the daytime
values. There was also a significant relation between
melatonin levels, age of onset of symptoms and the
duration of illness. Pineal calcification was found in nearly
all the MS patients. These observations were hypothesized to be related to the occurrence of seasonal variations
in MS, the influence of climatic variables, and the low
incidence of MS in African and American black populations (Sandyk and Awerbuch, 1992). Exactly how the
pineal function is related to the MS disease process should
be investigated further. Since fatigue and sleep disturbances are frequent and disabling symptoms inMS,
and because of the presumed disturbed pineal function,
we investigated whether these symptoms might be
due to disrupted circadian sleep/wake regulation.
However, no evidence was found for a generalized
circadian disturbance in MS patients, which indicates
that the suprachiasmatic nucleus will generally not be
seriously affected in this disease (Taphoorn et al., 1993).
Vasopressin levels in CSF, but not in plasma, were found
to be decreased in MS (Olsson et al., 1987). It is not
clear what exactly the source of this diminished amount
of CSF vasopressin is, since we did not find an indication
for an activity change in the vasopressin neurons of the
PVN in MS (Purba et al., 1995). In addition, Michelson
and Gold (1998) presume that MS is associated with
increased hypothalamic vasopressin secretion and Erkut
et al. (1995) showed that the entire increase in the number
of CRH-expressing neurons in MS was due to those
CRH neurons that coexpress vasopressin. Desmopressin
(DDAVP, nasal spray) is a vasopressin agonist that is
effective both in the treatment of nocturnal enuresis and
in the treatment of increased daytime urinary frequency,
which often seriously disrupts work and social activities
in MS patients. A side effect of this therapy might be
the development of hyponatremia. Although the patient
should be warned about the symptoms of side effects due
to hyponatremia, i.e. malaise, headache and nausea
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(Hoverd and Fowler, 1998), long-term use of DDAVP

has been shown to be safe and effective by others (Tubridy
et al., 1999).
Lower levels of CSF somatostatin have been found in
MS patients during relapse, and a strong relationship has
been found between cognitive decline and decrease in
CSF somatostatin levels (Roca et al., 1999). It is not
known which brain area is responsible for the changes
in somatostatin levels.
(b) Mood changes
Although euphoria was mentioned as the dominant
emotional change in MS in an old paper (Cottrell and
Wilson, 1926), a fact that is generally known in clinics,
more recent literature has repeatedly shown that depression is the major mood change in these patients (Rao
Fig. 21.4. Increased numbers of corticotropin-releasing hormone (CRH)

and vasopressin (VP) in multiple sclerosis (MS). Numbers of CRH
neurons that do not localize VP (CRH-only) or that colocalize VP (CRH
+ VP) in the PVN of 8 MS patients and 8 controls. Tissue was obtained
from the Netherlands Brain Bank (Amsterdam, the Netherlands).
Clinicopathological data (mean SEM), age, 51.0 3.8 years (MS), 52.6
5.0 years (controls); postmortem delay 12.9 5.6 h (MS), 13.9 3.9
h (controls); fixation time 49 14 h (MS), 36.7 4.3 h (controls);
duration of MS, 23 years; primary progressive MS 2/8 and secondary
progressive MS, 6/8. Neurons are counted in the PVN after immunocytochemical double-staining of VP and CRH as described (Erkut
et al., 1995). The difference in numbers of CRH/VP neurons between
the MS and the control group is significant (p = 0.046). (Based upon
Erkut et al., 1995, Fig. 3). Note that the increase in CRH-expressing neurons in MS is solely due to an increase in CRH cells coexpressing VP.
et al., 1992). MS patients are frequently depressed,

irritable and short-tempered (Dalos et al., 1983; Schubert
and Foliart, 1993; Fassbender et al., 1998). There is a
significant interaction between the level of neurological
impairment and depression in patients with MS (Mohr et
al., 1997b). However, comparison of MS patients with a
group of traumatic paraplegics as disease controls also
showed a significantly higher incidence of emotional
disturbances in the MS patients, especially during periods
of relapse (Dalos et al., 1983), and a boost of depression
in MS may even occur shortly before neurological symptoms develop (Whitlock et al., 1980; Joffe et al., 1987;
Minden and Schiffer, 1990; Millefiorini et al., 1992). so
that the mood changes do not only seem to be due to the
presence of a neurological disability alone. In agreement
with this idea, Fassbender et al. (1998) found that both
affective and neuroendocrine disorders in MS were related
to the inflammatory disease and not to disability. A relationship is presumed between the hyperactive HPA axis
(see previous section) and depression in MS and, indeed,
a combined treatment with corticosteroids and the antidepressant moclobemide normalizes HPA axis function
in relapsing-remitting MS patients (Then Bergh et al.,
2001). A relationship has also been observed between
MS lesions in the left arcuate fasciculus, i.e. in the
suprainsular white matter and depression in MS (Pujol et
al., 1997), while major depression is known also to result
from left cortical lesions. The higher levels of depression
in MS are associated with sleep complaints (Campbell et
al., 1992). The very high rate of depression among MS
patients does not have a genetic basis (Sadovnick et al.,
1996). Although interferon--1B reduces the frequency
and severity of exacerbations of MS in patients with the
relapsing-remitting form, it also causes flu-like symptoms
and increases depression within the first 6 months after
starting this therapy. Subsequent treatment of depression
improves the adherence to interferon therapy (Mohr et
al., 1997a; Walther and Hohfeld, 1999).
(c) The HPA axis in relation to susceptibility and
recovery
As shown by animal models, the HPA axis, which is a
central system in the regulation of immune responses
(Rivest, 2001), may influence susceptibility to and
recovery from MS. Studies on experimental allergic
encephalomyelitis (EAE), the most extensively studied
animal model of MS (Polman et al., 1986; Pender, 1987;
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Sobel et al., 1988; McDonald, 1994; Rodriguez and

Scheithover, 1994), have indicated that the activity of the
HPA axis may be crucial in these processes. In certain
rat strains, such as the Lewis rat, low corticosteroid levels
are accompanied by a high susceptibility to EAE,
whereas, once the disease has been established, elevation
of corticosteroid levels is required for spontaneous
recovery (MacPhee et al., 1989; Sternberg et al., 1989;
Mason et al., 1990; Villas et al., 1991; Kuroda et al.,
1994). In line with these findings, glucocorticoids, CRH
and urocortin are capable of suppressing EAE in Lewis
rats (Bolton and Flower, 1989; Poliak et al., 1997).
In relation to the possibility that low corticosteroid
levels may lead to increased susceptibility to MS, it is
of interest to note that, from the fourth decade of life
onwards, CRH neurons become gradually more activated
(Chapter 8.5b; Figs. 8.26, 8.27). This is also the age
at which MS prevalence starts to decline in the population. Both markers for activity of these neurons,
the total number of paraventricular nucleus cells and the
proportion of VP-expressing CRH neurons show an
age-dependent increase (Raadsheer et al., 1994a, b).
No data are available as yet on age-related changes in
CRH mRNA in the human PVN. As animal experiments
have shown that an increased HPA axis activity may
lead to decreased susceptibility to EAE, the age-related
increase in CRH activity suggests that this may be an
important factor leading to decreasing prevalence of MS
with age. Data on CRH neuron activity before the age
that MS prevalence increases are at present not available.
It has been observed that from 12 to 20 years of age the
saliva cortisol level gradually increases (Walker et al.,
2001), but the peak age of onset occurs one decade later.
Of course it is not known whether those young subjects
who have lower HPA axis activity are indeed at risk to
contract MS. However, the observation that in EAE
the HPA axis is six-fold increased in activity and in MS
only 2.5 times (Wei and Lightman, 1997) was proposed
to point to a relative deficiency of the HPA axis in
MS patients. It is questionable, though, whether these
observations in two different species with a different
time course in the disease process can indeed be compared
so easily. However, this possibility agrees with the observation that the insulin-induced cortisol increase in
MS patients was lower than in healthy controls (Teasdale
et al., 1967).
CRH neurons are clearly activated in MS patients, as
appears from the 2.4-fold increase in the number
of neurons expressing CRH (Purba et al., 1995) and
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the 4.5-fold increase in neurons coexpressing CRH and

VP (Erkut et al., 1995; Fig. 21.4). In fact, the latter study
showed that the entire increase in CRH cell numbers in
MS was due to an increase in those CRH neurons that
colocalized VP, which is different from the situation in
depression (see Chapter 26.4). VP potentiates both the
peripheral and central effects of CRH (see Chapter
8.5). Our data agree with the increase in plasma levels
of corticosteroids reported in MS (Millac et al., 1969;
Reder et al., 1987; Michelson et al., 1994) and the
presence of an enlarged adrenal gland in this condition
(Reder et al., 1987, 1994). Moreover, postmortem CSF
cortisol level in MS is elevated by 80%. Cortisol levels
in CSF appeared to reflect postmortem serum cortisol,
since these levels were highly correlated (Erkut et al.,
2002). The dexamethasoneCRH-suppression tests indicated hyperactivity of the HPA axis only in primary and
secondary progressive MS, while relapsing-remitting
patients had response patterns similar to controls (Heesen
et al., 2002).
The increased HPA axis activity may be seen as an
effort to suppress the disease process. Indeed, exogenous
corticosteroids improve the rate of recovery from acute
exacerbations of MS and attacks of monosymptomatic
optic neuritis. However, there is at present no convincing
evidence that glucocorticoid therapy reduces the
frequency of MS exacerbations or delays the progression
of neurological disability (Milligan et al., 1987; Miller
et al., 1992; Frequin et al., 1994; Wenning et al., 1994;
Andersson et al., 1998). The strong increase in CRHneuron activity thus seems compatible with the idea that
the brain defends itself against the disease process
(MacPhee et al., 1989), although it is not entirely
successful in this. Indeed, an endocrine paper concluded
that the HPA axis activation in MS is a reaction to the
disease process, since it correlates with a marker for
the acute phase response, white blood cell counts and with
gadolinium enhancement in MRI (Wei and Lightman,
1997; Fassbender et al., 1998). The enhanced response
in the dexamethasone-suppression test in MS correlated
with disease activity and with the clinical subtype of MS
in such a way that increased HPA axis activity relates
to an increased disease activity or severity (Wei and
Lightman, 1997; Then Bergh et al., 1999). In agreement
with this idea, Millac et al. (1969) and Grasser et al.
(1996) found increased cortisol levels in MS only during
exacerbations and a heterogeneity of the HPA system
function, possibly at the corticosteroid receptor level.
Although the presence of a partial glucocorticoid receptor
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deficiency in some MS patients can, at present, not be

excluded as the reason for a different course of HPA
axis activation, there does not seem to be any gross
disorder of the HPA axis in MS (Millac et al., 1969).
In line with this conclusion is the observation that,
after cessation of the corticosteroid therapy for relapses,
HPA axis function is normal and corticosteroid replacement therapy seems unnecessary (Mir et al., 1990).
In addition, it has been observed that cortisol release
induced by the dexamethasoneCRH test, is negatively
associated with the presence and number of gadoliniumenhancing lesions and positively associated with
ventricular size. This suggests a protective effect of
the HPA axis drive on acute lesion inflammation in
MS. These observations can, however, also be explained
in a different way. The observation that prolonged treatment with prednisolone significantly decreases brain
volume (Hoogervorst et al., 2002) is another reason to
have reservations about long-term corticosteroid therapy
in MS.
CRH itself may also be directly involved in the defense
against the disease process, because it has a neuroprotective effect (Fox et al., 1993) and immunomodulating
actions (Webster et al., 1998). Moreover, CRH has
analgesic properties (Lariviere and Melzach, 2000).
It is remarkable that the condition of most women
with MS stabilizes or improves during pregnancy, but
after delivery they run an increased risk of suffering a
relapse. It is estimated that the risk that the condition
takes a turn for the worse is between 20% and 75%.
However, it is not clear what factors determine susceptibility changes during pregnancy and postpartum (Birk
et al., 1990), although steroid hormones are presumed
to be implicated. Hormonal changes preceding the
menstruation may worsen symptoms in a subgroup of
women with relapsing-remitting MS (Zorgdrager and De
Keyser, 1997).
(d) Inflammation, demyelination and hypothalamic
structures
MS is an immune-mediated disease characterized by
inflammatory demyelinating perivascular lesions in the
white matter, disseminated in time and space (Raine,
1994). In addition, brain weight is decreased (Jelliffe and
White, 1935; Erkut et al., 1995). Although ample literature
covers the neuropathology of MS, little reference has
been made to the hypothalamus. Hypothalamic lesions as
mentioned by Brownell and Hughes (1962) are said to

make up only 1% of the total lesions, which does not
agree with our observations, which showed a large number
of demyelinated plaques to be present in hypothalamic
and adjacent structures in a high proportion of MS
patients (Huitinga et al., 2001). Moreover, acute unilateral
optic neuritis is generally not included in hypothalamic
involvement, while, within 5 years, in some 30% of
patients, it was followed by clinically definite MS.
Corticosteroids did not influence this risk, nor the degree
of neurological disability in a 5-year follow-up study
(Optic Neuritis Study Group, 1997). Unilateral optic neuritis occurs often as an initial manifestation of MS. Acute
bilateral optic neuritis is less common. Swelling and
demyelinating lesions in myelinated bundles can be shown
by MRI, also following gadolinium enhancement (Fig.
21.5), and pathology has confirmed the inflammatory
nature and demyelination. The optic radiations are almost
always involved (Newman et al., 1991; McDonald and
Barnes, 1992). MS lesions are mentioned by Bignani
(1961) and Peters-Bonn (1958) to be present not only
around the walls of the lateral ventricles, but also around
those of the third ventricle. Early periventricular lesions
are situated around subependymal veins, causing focal
perivenous demyelination. The lesions subsequently
coalesce with neighboring lesions (Adams et al., 1987).
A limited number of other papers mentions the involvement of the hypothalamus in MS: Zimmerman and Netzky
(1950) found that the paraventricular nucleus of the
hypothalamus is sometimes involved in MS; Bignani
et al. (1961) described fresh plaques throughout the whole
hypothalamus in a patient with a depression, profuse
sweating and hyperthermia. An MS patient has been
described with acute relapses associated with drowsiness
and hypothermia. Although MRI, endocrine and autonomic
studies failed to localize a lesion in the hypothalamus,
subsequent necropsy showed plaques of demyelination
throughout the hypothalamus, including the area of the
posterior hypothalamic nucleus (White et al., 1996). In
addition, a woman with MS who had presented with
hypothermia, dysphagia, lethargy, dysrhythmicity and
bronchopneumonia, showed a large, mature, gray, translucent gliotic plaque involving the hypothalamus at the
postmortem. At the microscopic level, there was evidence
of current activity in a proportion of that plaque. In
addition to gliosis, lymphocytic cuffing of vessels and
occasional macrophages containing lipid debris were seen
(Edwards et al., 1996a). Kamalian et al. (1975) reported
a malignant case of MS in which the disease began with
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in body temperature, depression and an activated HPA

axis (see above) we investigated the possible presence of
MS lesions in 16 MS patients using myelin Klver
hematoxylin staining, CR3/43 (anti-HLA-DR, -DP, -DQ)
as a marker for activated microglial cells (Graeber et al.,
1994), glial fibrillary acidic protein (GFAP, marker for
astrocytes), KP1 (recognizes macrophages and microglial
cells) and amyloid precursor protein (APP, detects axonal
damage; Ferguson et al., 1997). The myelinated bundles
in and around the hypothalamus analyzed were the optic
system (optic nerves, optic chiasm and optic tract), the
fornix, internal capsule and anterior commissure. We
distinguished between active demyelinating lesions
containing foamy macrophages and microglial cells and
chronic, inactive hypocellular gliotic lesions (De Groot
et al., 2001; Huitinga et al., 2001; Figs. 21.621.10). The
hypothalamus of 16 of 17 MS patients contained demyelinated lesions (Fig. 21.6). The incidence of active lesions
was high (60%) and outnumbered chronic inactive gliotic
lesions in the internal capsule. In 4 out of 17 MS patients,
axonal damage was observed and in 3 of 17 MS patients
gray matter lesions were apparent. Duration of MS was
inversely related to the active hypothalamic MS lesion
score. Since comparison of hypothalamic lesions with MS
rapid weight loss and terminated after 17 months with

generalized muscle wasting and cachexia. Demyelinating
lesions were found in the lateral hypothalamus and a
relationship was proposed between the clinical symptoms
and the localization of the lesions, because lesions in the
lateral hypothalamus may cause aphagia and anorexia (see
Chapter 23). The optic nerves and chiasm were almost
completely demyelinated and there was intense reactive
astrogliosis. The fornix showed a patchy loss of myelin.
A plaque-like sclerotic lesion was located in the left lateral
hypothalamus. The plaque showed almost complete loss
of myelin, a moderate, diffuse astrogliosis and occasional
small lymphocytic infiltrates. The right lateral hypothalamus showed slight myelin loss. The dorsomedial and
ventromedial nuclei appeared to be unaltered. An old
plaque with its pronounced fibrillary astrogliosis continued into the left mamillary body and fornix, surrounded
by more cellularly active lesions. There were also
subacute lesions with perivascular infiltrates along the
third ventricle. In MS patients with hyperprolactinemia,
hypothalamic lesions were present in 5 of 9 patients (Kira
et al., 1991; Tsui et al., 2002).
Because MS patients show hypothalamic signs and
symptoms such as fatigue, sleep disturbances, changes
Fig. 21.5. Multiple sclerosis patient with optic chiasmal neuritis. MR. T1-weighted images after gadolinium enhancement. Coronal (A) and axial
(B) views demonstrating a thickened optic chiasm with focal enhancement (arrows). (From Newman et al., 1991, Fig. 2 with
permission.)
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Fig. 21.6. Multiple sclerosis (MS) lesions in the human hypothalamus. A and B: Kluver staining of the hypothalamus of a control subject (82016, (A) and a MS patient (93-051, (B). Myelin is stained blue. Note that, in the control subject the myelinated bundles (IC: internal capsule, FX:
fornix, OS: optic system) can easily be distinguished, whereas, in the MS patient, myelin bundles contain large white spots or are even barely
visible (i.e. the OS in MS patient 93-051) because of demyelinating MS lesions (*). In the control subject, the anterior commissure (AC) is not
present at this level. The left FX in the MS patient is partly demyelinated. IF: infundibulum, P: PVN. Magnification: 4.5 . C and D: Human
leukocyte antigen (HLA-DR, -DP, -DQ) staining of an active MS lesion in the internal capsule in MS patient 95-065 (C) and a (p)reactive lesion
also in the internal capsule of MS patient 96-026 (D). Note the foamy character of the HLA-positive macrophages in the active lesion in (C),
indicative of myelin phagocytosis, and the ramified character of the HLA-positive macrophages in the (p)reactive lesion in (D), indicative of
activated microglial cells. Arrow points at perivascular leukocyte cuffing. Magnification: 400 . bv = blood vessel. Tissue was obtained from the
Netherlands Brain Bank. (From preparation by I. Huitinga.)
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disease severity in MS (Schrijver et al., 1999) and because

priming with IL-1 suppresses EAE in the Lewis rat
(Huitinga et al., 2000b).
Since demyelinating lesions in fiber bundles in and
adjacent to the hypothalamus (i.e. the fornix, anterior
commissure, internal capsule and optic system) may
be the basis for autonomic and endocrine alterations
in multiple sclerosis (MS) patients, we investigated the
relationship between the presence of hypothalamic lesions
and the state of activation of CRH neurons in MS patients
(n = 15). The state of activation of CRH neurons was
determined by quantifying the number of CRH neurons
that did or did not contain vasopressin, as well as the
amount of CRH mRNA expressed in the paraventricular
nucleus. The state of activation of CRH neurons in the
MS group was compared with that in controls (n = 14).
Hypothalamic MS lesions were determined as described
above. As found previously (Erkut et al., 1995; Purba
et al., 1995), numbers of CRH neurons that colocalize
vasopressin are significantly increased in MS. In line with
these findings we also found increased levels of CRH
mRNA in MS. Interestingly, there was a strong, significant negative relationship between the numbers of
CRH neurons that colocalize vasopressin (the population
of CRH neurons that is increased in MS) and active MS
lesions in the hypothalamus. There was no relation
between CRH single positive neurons and the active
lesion score. The effect was thus neuron-specific. The
chronic inactive lesion score did not correlate with the
numbers of CRH that colocalize VP in MS; the effect
thus concerns only the immunologically active lesions.
The same negative relationship was seen between the
amount of CRH mRNA expression and the active lesion
score in MS. This relationship, too, concerned only
immunologically active lesions and not the chronic
inactive gliotic lesions. Interestingly, controls also showed
a negative relationship between HLA score (activated
microglial cells) and the amount of CRH mRNA expression, indicating that the relationship between activated
microglial cells and the decreased activation of CRH
neurons is not MS specific. Thus, whereas as a group MS
patients have activated CRH neurons, the presence of
active lesions and activated macrophages and microglial
cells in or around the hypothalamus of MS patients
induces a significant decrease in the activation of CRH
neurons. Apparently, MS patients with many active
lesions in the hypothalamus have a diminished activity
of the HPA system (Huitinga et al., 2002). The clinical
consequences of such an impaired activity of the HPA
Fig. 21.7. Active and chronic inactive lesion scores (bars) and the incidence of active and chronic inactive lesions per fiber bundle (numbers
on top of the bars) in the hypothalamus of multiple sclerosis patients:
the internal capsule (IC), anterior commissure (AC), fornix (FX) and
optic system (including optic nerve and optic chiasm, OS). Note that
the AC and the FX were not present in the sections studied in all
patients. The active lesion score includes (p)reactive and active lesions
and the chronic inactive lesion score includes only chronic inactive
hypocellular gliotic lesions. Bar represents the mean SEM. (From
Huitinga et al., 2001, Fig. 2 with permission.)
lesions in other areas of the brain in the same patients

(n = 7) showed a great similarity as both stage and appearance were concerned, this negative relation in all
likelihood reflects the clinical consequences of high
disease activity throughout the whole brain. In controls
no demyelinating lesions were seen, but, in 11 control
cases, HLA expression was observed that was lower than
in MS patients. Thus, systematic pathological investigation of the hypothalamus in MS patients reveals an
unexpectedly high incidence of active lesions.
Preactive lesions were also found in the neurosecretory
supraoptic nucleus (SON) (Fig. 21.11). In the oxytocin
neurons of the PVN and accessory nuclei, IL-1 was
found (Fig. 21.12). In MS patients fewer neurons in the
PVN were found to be positive for this cytokine (Huitinga
et al., 2000a; Fig. 21.13). This finding may be of particular
interest in relation to MS, since a specific combination
of IL-1 and IL-1 receptor antagonist is associated with
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Fig. 21.8. Microphotographs of multiple sclerosis (MS) lesions. A: CD68-positive foamy macrophages in an active lesion in the internal capsule
(IC) of MS patient 95-065. B: Klver staining of an active lesion in the OS of MS patient 95-065. Arrows point at two foamy macrophages at
the edge of the lesion. Arrowheads point at luxol fast blue-positive particles in the macrophages. C: Gliosis in a chronic active lesion in the IC
of patient 95-065. Arrows point at glial fibrillary acidic protein (GFAP)-positive hypertrophic astrocytes. D: human leukocyte antigen (HLA-DR,
-DP, -DQ)-positive microglial cells (arrow) and HLA-positive leukocytes (arrowhead) in the VirchowRobin space around a blood vessel (Bv),
indicative of a (p)reactive MS lesion in the IC of MS patient 96-026. E: A chronic inactive lesion in the OS of patient 93-051. Arrows point at
HLA-DR, -DP, -DQ-positive microglial-like cells and arrowheads point at isomorphic gliosis and widened extracellular spaces typical for gliotic
tissue. F: Perivascular accumulation of CD3-positive T cells near an active lesion in the IC of patient 95-065. Bar = 15 m. (From Huitinga et
al., 2001, Fig. 3 with permission.)
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Fig. 21.9. Microphotograph of axonal damage and HLA expression in the supraoptic nucleus (SON) and the median eminence. A: Bodian staining
of the optic system (OS) of MS patient 93-051. Note the reduced density of axons as compared to the axonal density in Fig. B. B: Bodian staining
of the OS of MS patient 96-026. There is no sign of axonal damage in the OS of this MS patient. C: amyloid precursor protein (APP)-immunoreactive axons in the IC of MS patient 91-070. Note the large-diameter (57 m) of the APP-immunoreactive axons. Adjacent to this area is an
active MS lesion (not shown). D: HLA-DP, -DQ, -DR-positive microglial cells in the SON of MS patient 96-026. Arrow points at an HLA-positive microglial-like cell that seems to be in close contact with an SON neuron. E: HLA-DR, -DP, -DQ-immunoreactive microglial-like cells in the
median eminence of control 93-085. Arrows point at HLA-reactive microglial-like cells in close vicinity of blood vessels (Bv). F: HLA-DR, -DP,
-DQ-immunoreactive cells in the median eminence of MS patient 95-095. Arrow points at a small lesion of HLA-positive cells. Bar = 15 m.
(From Huitinga et al., 2001, Fig. 4 with permission.)
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Fig. 21.10. The relationships between the duration (in years) of multiple sclerosis (MS) and the active lesion score (left panel, p = 0.001, r =
0.719) and chronic inactive lesion score (right panel, p = 0.102, r = 0.410) in the hypothalamus. Note that there is a significant inverse correlation between the active lesion score and the duration of MS, i.e. leading to death, but not between the chronic inactive lesions score and the
duration of MS. (From Huitinga et al., 2001, Fig. 5 with permission.)
system in a subgroup of MS patients should be studied

further.
(e) Differential diagnosis of optic neuritis
Acute optic neuritis in MS should be differentiated from
Lebers hereditary optic neuropathy. In children, optic
neuritis is often bilateral. It usually follows infections
such as measles, chicken pox and infectious mononucleosis in nearly half of cases, and there is a seasonal
fluctuation, with the greatest number presenting in April.
While the risk of MS after childhood optic neuritis is low
(some 15%), the risk factor for adults is 75% (McDonald
and Barnes, 1992).
The diagnosis of MS has often been applied to patients
with a syndrome that has recently been renamed recurrent
optic neuromyelitis with endocrinopathies. It has been
described in Antillean women from Martinique and
Guadeloupe. Myelopathic symptoms and visual problems
recurred. Spinal cord involvement consisted of a band-like
sensory loss and MRI shows caviation-like images. The
endocrinopathies consisted of amenorrhea, galactorrhea,
diabetes insipidus, hypothyroidism or hyperphagia. In

the spinal cord, demyelinizing lesions with diffuse
spongiosis are found with thickened blood vessel walls
without evidence of inflammation. Autonomic abnormalities are present in half of cases. Demyelination of the optic
tracts is observed; the optic neuromyelitis is probably
of postinfectious origin. In three cases MRI revealed
lesions in the pituitary and inferior hypothalamus (Vernant
et al., 1997).
21.3. Langerhans cell histiocytosis
(HandSchllerChristian disease; histiocytosis-X)
HandSchllerChristian disease, with its granuloma
that are preferentially located in the hypothalamus and
pituitary (Gagel, 1941; Treip, 1992; Fig. 21.14) is also
known as Langerhans histiocytosis or histiocytosis-X
(Kepes and Kepes, 1969; Schneider and Gthert, 1975).
The terms Gagels granuloma, eosinophilic granuloma,
Ayalas granuloma, LettererSiwe disease and hypothalamic granuloma have all been used (Horvath et al., 1997;
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Fig. 21.11. Microphotograph of a (p)reactive lesion in the optic nerve (on) and in the supraoptic nucleus (son) in multiple sclerosis (MS) patient
96-307. A: HLA-DP, -DQ, -DR-positive cells in the ON and SON (arrowheads point at HLA-DP, -DQ, -DR-negative SON neurons) in section
601. B: Interleukin-1(IL-1)-staining of section 599. The same area as in A, containing the son and a rim of the on. Arrowheads point at IL1-negative and the arrow points at an IL-1-positive neuron in son. In the on, arrowheads point at IL--ir glial cells. C: Magnification of HLA-DP,
-DQ, -DR-positive cells in the on; D: magnification of interleukin-1 (IL-1)-ir cells in the on. Note: in the gray matter in the son, as well as in
white matter in the on, HLA-DP, -DQ, -DR-ir glial cells are present that are indicative of a (p)reactive MS lesion in both areas, whereas
IL-1-ir cells are only present in the on and not in the son. Bar: 45 m in A, B; 15 m in C, D. (From Huitinga et al., 2000a, Fig. 4 with
permission.)
Rosenzweig et al., 1997). The disease may represent an

uncontrolled immunological reaction to an unknown
antigen (DAvella et al., 1997; Schmitz and Favara, 1998).
In a very small number of families, recurrence of the
disease has been reported (Arico and Egeler, 1998). There
is a unifocal benign form of the disease in which the
hypothalamus and pituitary are spared. It is characterized
by a solitary lytic bone lesion. The multifocal form is
more aggressive and, in childhood, presents with the
clinical triad diabetes insipidus, exophthalmus and lytic

bone disease secondary to granulomas in the hypothalamus and pituitary gland. On MR images the pituitary
stalk is thickened symmetrically. However, after a few
years there is a complete reversal of the pituitary stalk
enlargement in a large percentage of the patients. The
normal high MRI signal density in the posterior lobe is
frequently absent. Associated involvement of the temporal
bone supports the diagnosis (Chong and Newton,
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Fig. 21.12. Microphotograph of interleukin-1 (IL-1)-ir neurons in the paraventricular nucleus (PVN) in two control cases and two multiple sclerosis (MS) patients illustrative of IL-1 staining intensity in the control versus the MS group. Per patient the rank number in estimated numbers
of IL-1-ir PVN neurons in the group (see Fig. 21.13) are given in parentheses: A: control 96-163 (3rd), B: MS 90-246 (1st), C: control 96-019
(9th), D: MS 96-352 (9th). Arrows point at IL-1-positive neurons containing a nucleolus and arrowheads point at IL-1-negative neurons containing
a nucleolus. Bar = 15 m. (From Huitinga et al., 2000a, Fig. 6 with permission.)
1993; Fig. 21.15; Rami et al., 1998; Leger et al., 1999;

Czernichow et al., 2000).
The classic triad of diabetes insipidus, exophthalamus
and lytic bone disease is present in only 25% of the cases.
Visual disturbances and endocrine dysfunctions such as
delayed or precocious puberty, hypogonadism, growth
retardation, growth hormone deficiency in the insulin
hypoglycemic tolerance test, hypothyroidism, hypoadrenalism, panhypopituitarism, diabetes insipidus, morbid
obesity and modest hyperprolactinemia may also be present (Ober et al., 1989; Chong and Newton, 1993; Lin et
al., 1998; Rami et al., 1998; Modan-Moses, 2001; Beswick

et al., 2002; Harris et al., 2002). A few cases with polyneuropathy have been described. One such an atypical
case is a patient with Langerhans cell histiocytosis and
polyneuropathy, diagnosed 12 years after the development
of diabetes insipidus following head trauma (Malko et
al., 2000). A girl with Langerhans cell histiocytosis developed diabetes insipidus and central precocious puberty at
7.5 years of age (Municchi et al., 2002).
In a late stage of the disease, vegetative disorders,
short-term memory deficits, psychic disturbances, disor-
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since then agreement has been reached about the role of

the Langerhans cell, a cell with features similar to the
Langerhans cell of the epidermis, which is now considered to be the principal proliferating cell in the disease
(Ober et al., 1989; Schmitz and Favara, 1998). The normal
epidermal Langerhans cell is a dendritic, antigenpresenting cell characterized by the intracytoplasmic,
tennis racket-shaped Birbeck granule of 200400 nm
in width and by expression of CD1a and S-100.
Tissue damage is caused by excessive production of
cytokines and prostaglandins (Rosenzweig et al., 1997).
Lymphocytes and plasma cells, eosinophils, giant cells
and microglia are also found. In one case an adult male
with Langerhans cell histiocytosis diabetes insipidus
occurred 5 years before the skin lesions and the hypothalamic mass became evident (Catalina et al., 1995;
Horvath et al., 1997). By using positron-emission tomography (PET), both increased and decreased glucose
metabolism was found in cases of Langerhans cell
histiocytosis. The increased activity probably represents
an active, ongoing disease process, and areas of decreased
activity either represent a burnt-out brain lesion caused
by the disease or a decreased brain metabolism of other
origin (Calming et al., 2002).
An unusual case of isolated histiocytosis presented as
a solitary mass in the pineal gland with incomplete ocular
palsy (Gizewski and Forsting, 2001). Spreading may occur
through portal vessels or via the systemic circulation
(Wilke, 1956). A primary phase of histiocyte proliferation is followed by brain atrophy or demyelination and
gliosis of unknown origin (Barthez et al., 2000).
Apart from corticosteroids (Harris et al., 2002),
chemotherapy and low-dose radiotherapy have been
reported to be successful treatments for Langerhans
cell histiocytosis masses in the hypothalamus (Catalina
et al., 1995). At least in those patients with shortterm polyuria or polydipsia, and with an abnormality in
water-deprivation tests, rapid treatment with hypothalamopituitary radiation therapy seems justified. However,
there seems to be no rationale for treating patients with
full diabetes insipidus, as there is no evidence that patients
in later stages of the disease will respond to this therapy
(Rosenzweig et al., 1997). Although chemotherapy may
cause a regression of the Langerhans cell histiocytosislesion, even in some cases with good therapeutic results,
hormone deficiencies are usually irreversible (Rami et al.,
1998).
In the case of a solitary hypothalamic granuloma, where
Langerhans cell histiocytosis was found with diabetes
Fig. 21.13. Total numbers of interleukin-1-immunoreactive (IL-1-ir)

neurons in the paraventricular nucleus (PVN). Bars indicate the median.
Triangles indicate individual cell counts. Note the high interindividual
variation. The total number of IL-1-ir neurons in the PVN was significantly decreased in the multiple sclerosis (MS) group as compared to
the control group (p < 0.05). In addition to the reduction in numbers of
IL-1-ir neurons in the PVN, also the IL-1 staining intensity was
strongly reduced in most MS patients. (From Huitinga et al., 2000a,
ders of temperature regulation and hypersomnolence have

been described (Schneider and Gthert, 1975; Yen, 1993;
Kaltsas et al., 2000). The disorder may have a waxing
and waning course. About 50% of the patients with
hypothalamic diabetes insipidus due to histiocytosis-X
had antibodies against VP neurons. In a patient who
became pregnant, diabetes insipidus remitted at about
the 28th week of gestation and recurred after delivery.
Improvement of the disease during pregnancy supports
the notion of an autoimmune pathogenesis (Scherbaum,
1992).
The disease is neuropathologically characterized by
infiltration of the hypothalamus and pituitary, including
the pars distalis by lipid-laden histiocytes or foam cells
that appear to be involved in the autoimmune process
(Scherbaum et al., 1986). Autoimmunity to hypothalamic
vasopressin cells may be present in a large percentage of
patients with central diabetes insipidus and Langhanss
cell histiocytosis (Pivonello et al., 2003). The X in the
term histiocytosis-X indicated an unknown cell, but
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Fig. 21.14. Gagel granuloma (Langerhans histiocytosis). Sagittal section of the pituitary gland, showing enlargement of the stalk and posterior
lobe (on the right) by granulomatous infiltration. Hematoxylin & eosin. 5.5. (From Treib et al., 1992, Fig. 16.11 with permission.)
insipidus and panhypopituitarism, complete microsurgical

excision was performed (DAvella et al., 1997). Some
clinicians advocate the combination of surgical excision
with postoperative radiation (olak, 1998). However,
surgical resection and chemotherapy with prednisolone
and vinblastine have also been effective (Lin et al., 1998).
Dynamic evaluation of pituitary function was not a useful
predictor of late endocrine sequelae, with the possible
exception of the progressively decreasing thyrotropin
(TSH) response to thyrotropin-releasing hormone (TRH)
(Lin et al., 1998; Maghnie et al., 1998b).
ErdheimChester disease, first described in 1930 as
lipoid granulomatosis, is a rare condition, predominantly
of middle-aged males. The pathological hallmark of this

disease consists of xanthogranulomatous infiltrations of a
wide variety of tissues by cells of macrophage or histiocyte lineage. Symmetrical predominantly sclerotic bone
lesions sparing the epiphysis and the predominance of
lipid-laden histiocytes or foam cells in the patients
retroperitoneal tissues was considered as a diagnostic of
ErdheimChester disease. This entity is distinct from
histiocytosis-X, but the two diseases may represent a
disease spectrum. Patients have been described with multiorgan involvement, thrombocytopenia, central diabetes
insipidus, panhypopituitarism, hyperprolactinemia, gonadotropin insufficiency, decreased insulin-like growth factor
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Fig. 21.15. Histiocytosis. Sagittal (A) and coronal (B) precontrast and postcontrast-enhanced MR scans. The pituitary stalk (arrows) is markedly
enlarged. Prominent contrast enhancement of the stalk is noted. (From Chong and Newton, 1993, Fig. 23 with permission.)
I levels and bilateral adrenal enlargement, suggesting

hypothalamic-pituitary dysfunction. The high-intensity
signal of the posterior pituitary on T1-weighted images
may be absent on MR images, the pituitary stalk and dura
may be thickened and a hypothalamic mass has been
described. The diagnosis of the rare cranial localizations
is usually made on the basis of a biopsy (Tritos et al.,
1998a; Oweity et al., 2002; Perras et al., 2002).
21.4. Other neuroimmunological hypothalamic

disorders and lesions
The idiopathic hypothalamic dysfunction syndrome of
childhood (Chapter 32.1) may be based upon a nonmetastatic paraneoplastic syndrome related to the presence
of an occult neural-crest tumor. The tumor probably
produces antineuronal antibodies that lead to extensive
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Fig. 21.16. Granular ependymitis of the third ventricle in a case of sudden death (NHB 96-077, 68). Bar = 400 m.
lymphocytic/histocytic infiltrates in the hypothalamus

and other brain areas. Lymphocytic hypophysitis and
autoimmune diabetes insipidus are discussed in Chapter
22.2.
Granular ependymitis are periventricular lesions characterized by raised pyramidal granulations with focal
gliosis in the subependymal region. The overlying
ependyma is trophic, eroded or absent (Fig. 21.16). Some
of the cases with ependymitis or subependymal gliosis
are active, in the sense that they contain lymphocytic
infiltrates. Granular ependymitis is generally associated

with ventricular dilatation or meningitis. Although granular ependymitis is more frequently seen in MS, it is
certainly not specific for this disease and also found in,
e.g. Parkinsons disease, vascular disease and senile
atrophy. In addition, it is found in, e.g. meningococcal
or pneumococcal meningitis. In MS, granular ependymitis
may provide a possible route for the exchange of inflammatory agents between the brain and the CSF (Adams
et al., 1987).
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infections such as viral encephalitis, i.e. following infections with the Epstein-Barr or the Varizella zoster virus
(Merriam 1986; Fenzi et al., 1993; Salter and White,
1993; Mller et al., 1998b). Perivascular inflammatory
infiltrates and microglial proliferation of nodular type
were observed in the hypothalamus (Fig. 28.1), in particular the floor of the third ventricle and in the
periaqueductal gray. In two previous cases, inflammatory
changes were present in the hypothalamus and in the
temporal lobe or they were confined to the thalamus.
Prevalence of T-lymphocytes in the affected area was
suggestive of an unknown viral antigen responsible
for the immuneresponse and is consistent with the
observation that in 35% of the KleineLevin cases
the onset is preceded by respiratory disease or vaccination
(Fenzi et al., 1993). In addition, the increased (HLA)DQB1*0201 allele frequency was significantly increased
in KleineLevin syndrome. This, together with the young
age of onset, the recurrence of symptoms and the frequent
infectious precipitating factors suggests an autoimmune
etiology for KleineLevin syndrome (Dauvilliers et al.,
2002).
In GuillainBarr syndrome, inappropriate vasopressin

secretion (Chapter 22.6a) and undetectable CSF levels of
hypocretin (Ripley et al., 2001; Kanbayashi et al., 2002;
Chapter 28.4) have been described, pointing to hypothalamic involvement.
Paraneoplastic encephalitis is characterized by personality changes, irritability, depression, seizures, memory
loss and sometimes dementia. It is due to antineuronal
antibodies. Patients with anti-Ta (anti-Ma2) antibodies
frequently have hypothalamic involvement, as appears,
e.g. from diabetes insipidus, loss of libido, hypothyroidism, hypersomnia, hyperthermia and panhypopituitarism.
The tumor should be treated (Gultekin et al., 2000; Chapter
19.1b, 32.1).
For the possible autoimmune destruction of the
orexin/hypocretin system in the lateral hypothalamus in
case of narcolepsy, see Chapter 28.4.
In anorexia and bulimia nervosa patients, autoantibodies against -MSH, ACTH and luteinizing hormonereleasing hormone (LHRH) have been found (Fetissov
et al., 2002; Chapters 22.2b, 23.2), but their function has
not yet been elucidated.
KleineLevin syndrome (periodic somnolence and
morbid hunger, see Chapter 28.1) may follow viral
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CHAPTER 22
Drinking disorders
As to the function of the posterior lobe, the experimental

evidence is unequivocal. Its removal causes no symptoms.
Moreover, its structure is nonglandular. Camus and Roussy
were quite justified in speaking of it as an atrophied nervous
lobe . . . We have, therefore, no evidence that pituitrin is
anything more than a pharmacologically very interesting
extract (Bailey and Bremer, 1921; from Anderson and
Haymaker, 1974).
stretch receptors, which send inhibitory signals to the

hypothalamus via an as yet unidentified neuronal pathway.
The osmotic threshold for thirst is similar to that for
vasopressin release. That a rapid fall in thirst takes place
before any significant change in plasma osmolality occurs
can be considered as a defense mechanism which protects
against overhydration (McKenna and Thompson, 1998).
Histamine, produced in the tuberomamillary nucleus
(TMN), elicits drinking, increases the release of vasopressin and decreases urine output via H1 and H2
receptors (Brown et al., 2001). Animal experiments have
revealed a number of peptides that regulate drinking
behavior, such as angiotensin II (Chapter 30.5) and
orexin-A, which is also involved in eating (Chapter 23).
The kidney concentrates or dilutes urine under the
influence of vasopressin. The segmental permeabilities
in the nephron correlate with the expression of different
members of the aquaporin family, seven members of
which have been identified in the kidney. Vasopressindependent expression of aquaporin-2 is found in the apical
membrane of the principal cells of the collecting duct
(King and Yasui, 2002).
Osmoregulation and thirst. Plasma osmolality is precisely

maintained within a remarkably narrow range of 282298
mosmol/kg, which is achieved by the close integration of
the antidiuretic action of vasopressin and the sensation
of thirst. Plasma osmolality is the most important physiological determinant of vasopressin secretion (Robertson,
2001; Chapter 8.e). Changes in osmolality were always
thought to be detected in the circumventricular organs
that are said to send information to the vasopressinproducing neurons (see Chapter 8), but the identification
of water channels, or aquaporins, in the supraoptic and
paraventricular nucleui (SON and PVN) has challenged
this traditional theory. The presence of messenger RNA
(mRNA) for aquaporins in the SON and PVN may indicate that these nuclei have osmoreceptors that are
independent of the osmoreceptors in the circumventricular organs, such as the subfornical organ and the
organum vasculosum laminae terminalis (see Chapter
30.5). Data from a patient with defective osmoregulation
of thirst with preservation of osmoregulation of vasopressin release (Hammond et al., 1986) provides
corroborative evidence of separate osmoreceptors of thirst
and vasopressin release.
The osmotic threshold at which secretion of vasopressin
begins is 284.3 mosmol/kg. During drinking there is an
almost instantaneous suppression of vasopressin secretion, probably due to the activation of oropharyngeal
22.1. Pathology of the neurohypophysis

The neurohypophysis consists of: (1) the pars nervosa
(neural or posterior lobe); (2) the infundibular process
(pituitary stalk), which contains the nerve tracts from the
supraoptic and paraventricular nucleus (SON and PVN),
a thin tongue of anterior pituitary tissue (pars tuberalis,
containing predominantly gonadotrophs, while somatotropic, mammotropic, corticotropic and thyrotropic cells
are rare) (Baker, 1977; Osamura and Watanabe, 1978)
and the vessels of the portal system (see Chapter 17.1);
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and (3) the pars infundibularis (infundibulum). The neurohypophysis is characterized by its rich vascularity, nerve
endings, Herring bodies and pituicytes, which are specialized astrocytes that are, at least in part, glial fibrillary
acidic protein (GFAP)-positive (Velasco et al., 1982). The
capillaries have fenestrated endothelial cells and extensive perivascular spaces.
Clinically, pathology of the neurohypophysis may
lead to diabetes insipidus (see Chapter 22.2) or to
inappropriate secretion of vasopressin (SchwartzBartter
syndrome; see Chapter 22.6). Apart from disturbances of
water metabolism, abnormalities in the posterior pituitary,
particularly space-occupying lesions, may cause symptoms such as headache and visual disturbances. In
addition, the intracranial pressure may increase, producing
anterior-pituitary compression. Damage to the pituitary
stalk may interrupt the portal circulation and lead to
infarction of the anterior lobe and thus to endocrine
impairments.
Congenital malformations in the neurohypophysis have
also been described, such as agenesis of the posterior
lobe of the pituitary in a fetus in the progeny of a mother
who used alcohol during pregnancy (Konovalov et al.,
1997), and persistence of the infundibular recess by which
the third ventricle is protruding into the neurohypophysis.
The infundibular recess in the neurohypophysis normally
disappears in human embryos by the 45-mm stage
(Cabanes, 1978). Moreover, duplication of the pituitary,
of the adenohypophysis as well as the neurohypophysis,
have been reported (Hori, 1983). The pituitary stalk is
rarely duplicated in holoprosencephaly (Sarnat and
Flores-Sarnat, 2001). Loss of the infundibulum or pituitary stalk due to traumatic damage has been reported
(Grossman and Sanfield, 1994). Dystopia of the neurohypophysis may either be asymptomatic or accompany
anterior pituitary anomalies (Aydan and Ghatak, 1994;
Chapters 18.4, 18.6). Twin boys, born at 35 weeks
of gestation, with hypopituitarism, hypoplasia of the
anterior pituitary gland, an ectopically localized posterior
pituitary at the base of the median eminence, had a
paracentric inversion of the short arm of chromosome 1.
The smooth appearance at the base of the median
eminence and the absence of the pituitary stalk in these
boys implied a developmental alteration. However, the
causal relationship to the chromosome 1 anomaly remains
to be determined (Siegel et al., 1995). Dystopia of the
neurohypophysis is frequently accompanied by growth
hormone and other pituitary deficiencies and is now
generally considered to be a developmental disorder or
disconnection rather than an interruption of the stalk

due to complications at birth (Mszros et al., 2000; see
also Chapters 18.4, 18.6). In the empty-sella syndrome,
the intrasellar CSF does not seem to influence posterior
lobe function (Zucchini et al., 1995), while hypogonadotropic hypogonadism and growth hormone deficiency
frequently occur (Cannav et al., 2002).
The following histological and histopathological
phenomena may be found in the neurohypophysis (for
some reviews, see also Kovacs, 1984; Treip, 1992;
Horvath et al., 1997, 2000). Basophilic corticotropin
(ACTH) and beta-melanotropin (MSH)-containing cell
invasion (Osamura and Watanabe, 1978; Horvath et al.,
2000) is generally not present before the age of 20 years
and does not occur before puberty. This phenomenon is
frequently (in 30%) seen in older subjects, especially in
aging men. ACTH and -endorphin (or pro-opiomelanocortin) cell hyperplasia occurs in 29% of men and
14% of women. Eighty percent of the male and 77% of
the female subjects with this hyperplasia were over 50
years of age (Horvath et al., 1999). These cells are generally not related to any endocrine abnormality (Sheehan
and Kovacs, 1982; Sano et al., 1993; Horvath et al., 1999).
Although some authors consider these cells to be one of
the possible origins of basophil pituitary adenomas, in
the literature only two cases of basophil adenomas in the
posterior lobe have indeed been recorded (Kuebber et al.,
1990). In addition, a gangliocytoma (Chapter 19.3c)
containing ACTH-producing cells and inducing Cushings
syndrome has been found in the neurohypophysis (Geddes
et al., 2000).
Glandular structures (Rasmussen, 1933), i.e. ectopic
salivary gland tissue resembling serous acinar and duct
cells (Schochet et al., 1974; Osamura and Watanabe,
1978; Horvath et al., 1997) and lymphocytic foci are
common incidental findings in the posterior lobe or stalk
without clinical consequences, but they are sometimes
found in septicemia.
The commonest finding in the infundibular stem and
process is acute hemorrhage, often petechial, but sometimes large enough to cause appreciable damage to the
infundibular process. Necrosis within the infundibular
process itself is very rare. Hemorrhages and necroses may
be associated with postpartum necrosis of the anterior
pituitary, increased cranial pressure, shock, disseminated
intravascular coagulation, septicemia and various hematological disorders. Traumatic brain injuries such as a
gunshot wound may damage the pituitary stalk,
infundibulum, and/or hypothalamus, and cause diabetes
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insipidus (Alaca et al., 2002). Accumulation of neurosecretory material and retraction bulbs are evidence of
ruptured axons. In case of thrombotic thrombocytopenic
purpura, vessels in the neural lobe may contain hyaline
thrombi. Agonal thrombi may also be seen in the vessels
of the infundibular stem. Chronic changes following
lesions are atrophy and loss of pituicytes. Hemosiderin
deposition may be found in longstanding cases and can
appear within 8 days of injury (Chapter 25.4).
Chronic inflammation with infiltration of lymphocytes,
predominantly of the T-cell and CD4+ type, and plasma
cells are found in cases of lymphocytic infundibuloneurohypophysitis and may cause diabetes insipidus.
This disorder mainly occurs in women and most often
in the later stages of pregnancy. It is characterized by
thickening of the pituitary stalk, enlargement of the neurohypophysis, absence of the hyperintense MRI signal of
the posterior pituitary, diabetes insipidus, visual
disturbances and anterior pituitary deficiencies, while
sometimes a large mass may involve the hypothalamus,
infundibulum, optic nerves, chiasm and tracts (Kamel
et al., 1998; Maghnie et al., 1998b; Tubridy et al., 2001;
Ouma and Farrell, 2002; see Chapter 22.2b).
An autoimmune-mediated process is presumed and
the disorder may respond to corticosteroids (Ouma
and Farrell, 2002). Panhypopituitarism and diplopia,
secondary to fourth nerve palsy, have been described.
Fibrosis following infections may also be found in the
neurohypophysis.
Cystic changes in the infundibular process have been
described, as well as squamous keratin positive cell nests
(Asa et al., 1981), which are frequently found in the
pituitary stalk.
Hypovolemic shock of the mother at the time of
delivery may not only cause pituitary necrosis, but
also affect the tuber cinereum, pituitary stalk, SON and
PVN. Hypopituitarism of pregnancy may be accompanied by diabetes insipidus of sudden onset following
severe postpartum hemorrhage. However, true diabetes
insipidus is rare in Sheehans syndrome, and lesions may
be present in the posterior lobe without corresponding
clinical symptoms. In fact, 50% of the Sheehans
syndrome patients did not get diabetes insipidus for more
than 30 years after the causative event (Otsuka et al.,
1998). Probably the amount of damage to the SON and
PVN will determine whether or not diabetes insipidus
will occur in Sheehansyndrome, but other factors are
certainly not excluded (Sheehan and Kovacs, 1982).
Indeed, in some cases of postpartem hypopituitarism,
127
considerable degeneration in the SON and PVN has

been reported. The estimated numbers of remaining
SON neurons was often only some 2025%. The
accessory SON may also disappear. The PVN is sometimes as strongly affected as the SON, but sometimes
retains its normal neuronal values. In addition, nearly all
cases had petechial hemorrhages in the hypothalamus,
apparently related to the terminal coma (Whitehead,
1963).
Granulomas may be present on the basis of tuberculosis
(see Chapter 20.1), neurosarcoidosis (Loh et al., 1997;
see Chapter 21.1), syphylis, a small-vessel vasculitis such
as Wegeners granulomatosis (Woywodt et al., 2000;
Chapter 22.2) or granulomatous hypophysitis, histologically characterized by infiltration of multinucleated giant
cells, plasma cells and lymphocytes (Fujiwara et al.,
2001). The neurohypophysis is also frequently involved
in histiocytosis. Diabetes insipidus may be an early sign
of this disease (Catalina et al., 1995). On MR images a
thickened stalk may be seen as expression of preclinical
histiocytosis (Zucchini et al., 1995; see Chapter 21.3).
Numerous eosinophilic leukocytes and lipid-laden foamy
macrophages may be present or fibrosis may prevail.
ErdheimChester disease is probably a distinct form of
histiocytosis (Tritos et al., 1998a).
Granular cell tumors (termed choristomas by
Sternberg in 1921, and granular cell myoblastomas or
tumorettes by Shanklin in 1947) are the most common
primary neurohypophysial tumors. The term choristoma
is confusing, as it is also used for the unrelated neuronal
choristomas or gangliocytomas or ectopic ganglion cells
(see Chapter 19.3c). They occur in some 517% of
pituitaries (Sano et al., 1993; Fig. 19.16). Granular cell
tumors are a special form of glioma (Chapter 19.4c) that
are found after the second decade in some 6% of the
pituitary glands (Luse and Kernohan, 1955). They consist
of large cells with granular, lightly eosinophylic cytoplasm (Fig. 22.1). They are mostly small, 12 mm
or even smaller, and are not evident from a glancing
inspection. They grow slowly, are histologically benign,
well demarcated, but unencapsulated. The majority
remain asymptomatic. In those rare cases where granule cell tumors are symptomatic, they may cause
diabetes insipidus, hypopituitarism, visual impairment or
headache (Symon et al., 1971; Massie, 1979; Barrande
et al., 1995; Ji et al., 1995) (see Chapter 19.4c). A
case has been described of a granular cell tumor of the
neurohypophysis that most probably causes acromegaly.
The presumed growth hormone-releasing hormone-like
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compound has, however, not been identified in the tumor

(Losa et al., 2000). Histologically, granular cell tumors
are composed of large, spherical, oval or polygonal cells
with eccentrically located nuclei and abundant acidophilic
cytoplasm, containing PAS positive neuramic acid and
carbohydrate-containing granula that appear to be lysosomes under the electron microscope (EM). The brown
cytoplasmatic granules (Fig. 22.1) may be sufficiently
numerous to import a brown pigmented appearance to
the tumor (Massie, 1979). The cells are presumed to originate from pituicytes (Luse and Kernohan, 1955; Jenevein,
1964; Massie, 1979; Mller et al., 1980; Horvath et al.,
1997). Granular cell tumors label with lectin, S-100, and
not with neuron-specific enolase, myelin basic protein,
vimentin, keratin or desmin, but mostly not with GFAP.
Some showed reactivity, however, for -1-antitrypsin, 1-antichymotrypsin and cathepsin B. The latter marker
suggests a lysosomal disorder. The fact that GFAP does
not usually label the tumors does not support the pituicyte as a progenitor of granular cell tumors, but it does
not exclude this possibility either (Nishioka et al., 1991;
Losa et al., 2000). Indeed, Barrande et al. (1995) and
Lafitte et al. (1994) have both reported a granular cell
tumor to be positive for GFAP.
Metastatic carcinomas in the posterior pituitary
constitute the most important neoplasms. They may be
derived from, e.g. carcinomas of the bronchus, breast,
colon or prostate, or from malignant melanoma, sarcomas,
lymphoma, Hodgkins disease or leukemia, and may
give rise to diabetes insipidus (Schubiger and Haller,
1992; Ten Bokkel Huinink et al., 2000) (see Chapter
19.9).
Only seldom are other neoplasms found in the
neurohypophysis, i.e. gliomas, pituitary astrocytomas
or pituicytomas, which may be derived from pituicytes.
Immunocytochemically they may be positive for GFAP,
vementin and epithelial membrane antigen. The presence
of intermediate filaments in a concentric way (fibrous
body), and secretory granules in one case, suggested
the possibility that the tumor might also arise from
folliculostellate cells of the adenohypophysis (Cenacchi
et al., 2001). MRI scans show extension of the tumor
into the pituitary stalk. Panhypopituitarism may be an
early manifestation of this tumor, while diabetes insipidus
may be absent, suggesting vasopressin release to take
place above the level of the tumor (Nishizawa et al.,
1997). In addition, gangliogliomas, hamartomas (Chapter
19.3; Fig. 19.9), epidermoids, suprasellar germinomas
(Chapter 19.2), craniopharyngiomas (Chapter 19.5) and
lipomas have been reported (Hurley et al., 1994).

Gangliocytoma or ectopic ganglion cells of the neurohypophysis have been described that produce vasopressin
(Fehn et al., 1998; Horvath et al., 2000; Chapter 22.6),
ACTH (Geddes et al., 2000) or -endorphin (Horvath et
al., 2000). It is not clear whether they should be considered the result of abnormal migration during embryonic
life, differentiation/maturation of neuroblasts, or transdifferentiation from proliferating pars intermedia cells
(Horvath et al., 2000). Germinomas of the neurohypophysis and median eminence may cause diabetes
insipidus, multiple deficiencies of the anterior pituitary
compression of the optic chiasm and hypothalamus. This
tumor can develop simultaneously with a similar tumor
in the pineal region (Saeki et al., 1999). The first abnormal
MRI sign in cases of germinoma in children and adolescents is pituitary stalk thickening (Mootha et al., 1997).
Two cases of a meningioma of the pituitary stalk has
been described that must have originated from the arachnoid membrane, since it had no dura attachment (Hayashi
et al., 1997; Beems et al., 1999). Neoplasms of the
infundibulum are described under various names, i.e.
infundibuloma, hamartoma, glioma or astrocytoma (see
Chapter 19.4). Extremely rare is a pituitary adenoma
located entirely outside the sella turcica arising from the
pars tuberalis, causing visual disturbance (Hamada et al.,
1990).
An early stage of cytoskeletal alterations as revealed
by antibodies against abnormally phosphorylated tau (e.g.
AT8, PHF-1 or Alz-50) are found in fibers and Herring
body-like swellings in some aged patients, even if the
brain is devoid of Alzheimer changes. Such changes are
hardly detectable with sensitive silver methods. The relationship of these early Alzheimer changes in the
neurohypophysis, and those in the SON, PVN and the
rest of the brain, should be further investigated. In addition, the functional implications of these cytoskeletal
changes are not yet clear (Schultz et al., 1997).
For stalk sectioning lesions, see Chapters 18.4, 18.6
and 25.4. The pituitary stalk may also be absent, because
it was never formed in development (e.g. Den Ouden et
al., 2002; Chapters 18.4, 18.6). A thin or invisible pituitary stalk on MR images may be found in children with
prenatal or perinatal-onset hypothalamic hypopituitarism
who gradually develop growth hormone and ACTH deficiency (Miyamoto et al., 2001). A very thin stalk ending
in a neurohypophysis without the normal MRI hypertensisity (see below) was found in a child with a persistent
large craniopharyngeal canal and an enlarged empty sella
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Fig. 22.1. Cells of a granular cell tumor in the neurohypophysis. Note the brown-pigmented cytoplasmic granules (NHB 92-001).
Bar = 100 m.
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turcica filled with CSF (Ekinci et al., 2003). A thickened

pituitary stalk on MR images may indicate the presence
of Langerhans histiocytosis (Czernichow et al., 2000;
Chapter 21.3), lymphocytic hypophysitis (Iglesias and
Dez, 2000; Chapter 22.2b), lymphocytic infundibuloneurohypophysitis (Takahashi et al., 1999; Chapter
22.2b), a germinoma (Leger et al., 1999; Czernichow et
al., 2000; Chapter 19.2) or a hypophyseal tuberculoma
(Sinha et al., 2000; Pramo et al., 2002).
Pathological states of the neurohypophysis may be
reflected in a disappearance of the MRI high-intensity
signal of the posterior pituitary that is normally present
in 90% of subjects (Brooks et al., 1989; Tien et al., 1991).
This MRI signal was first thought to be caused by fat
within the sella turcica. The source of the hyperintense
MRI signal is now presumed to be the neurosecretory
granules containing vasopressin (Fujisawa et al., 1989),
but no attention has been paid so far to the contribution
of oxytocin-containing granules. It should also be noted
that, in the case of persistent elevation of vasopressin
plasma levels as found in diabetes mellitus and hemodialysis, the hyperintense MRI signal in the neurohypophysis
may be decreased, possibly due to depletion of vasopressin storage. When treating for hyperglycemia, plasma
levels of vasopressin promptly decrease and the hyperintense MRI signal reappears within 12 months (Sato et
al., 1995; Fujisawa et al., 1996; Chapter 22.5; Fig. 22.1).
The high intensity MRI signal is frequently absent in case
of macroadenoma of the anterior pituitary, craniopharyngioma, traumatic stalk transsection, patients with
empty sella syndrome and diabetes insipidus. In both
primary central diabetes insipidus (Chapter 22.2a) and
secondary diabetes insipidus due to, e.g. germinoma,
teratoma (Mootha et al., 1997; Chapter 19.2), Wolframs
syndrome (see Chapter 22.7) or histiocytosis-x, the
normal high-intensity MRI signal was not detected. In
some patients with macroadenomas, a small, high signal
intensity region was seen above the pituitary gland
without any high intensity from within the gland itself
(Colombo et al., 1987; Fujisawa et al., 1987b), suggesting
the presence of a newly formed miniature-posterior lobe
above the level of the neurohypophysis. The presence of
a high-intensity MRI signal on the pituitary adenoma
surface in the case of a supradiaphragmatic extension
is supposed to be due to blockage of the hypothalamoneurohypophysial fibers, with an accumulation of
neurosecretory granules. It generally predicts functional
integrity after removal of the large pituitary adenoma
(Salehi et al., 2002).
22.2. Diabetes insipidus

The brain secretes thoughts as the kidney secretes urine
(Jakob Moleschott,18221893)
Diabetes insipidus was distinguished from diabetes

mellitus in 1674 by the English physician Thomas Willis
(for references see Sawin, 2000). Diabetes insipidus is
characterized clinically by polyuria (defined as the
passage of amounts of diluted urine in excess of 2 l/m2
per 24 h or approximately 40 ml/kg per 24 h) in older
children or adults) and polydipsia, and biochemically by
inappropriately diluted urine in the face of rising plasma
osmolality. Diabetes insipidus may be due to vasopressin
deficiency in familial central diabetes insipidus, to a defect
in the mechanism of kidney receptors for vasopressin, or
to mutations in the vasopressin-regulated water channel
of the renal collecting duct aquaporin-2 (Deen et al., 2000,
Chapter in nephrogenic diabetes insipidus; Fig. 1.14) or
to primary polydipsia (Chapter 22.3). Approximately 3%
of the aquaporin-2 in collecting ducts is excreted into
urine, and the urinary excretion of this water channel
protein correlates positively with plasma vasopressin
levels (Ishikawa, 2000). The simultaneous measurement
of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the
differential diagnosis of diabetes insipidus and primary
polydipsia (Diederich et al., 2001). Thirst is the most
prominent symptom of hypothalamic diabetes insipidus
and is the necessary stimulus to replace urinary losses.
The mechanism of regulation of thirst is normal in the
vast majority of patients with central diabetes insipidus.
On the other hand, the combination of diabetes insipidus
and hypodipsia has also been described in association
with surgery to the anterior communicating artery
aneurysms, head injury, tumors, sarcoidosis, hydrocephalus and toluene exposure. Since patients with adipsia
and vasopressin deficiency in response to osmotic stimuli
may have entirely normal vasopressin responses to nonosmotic stimuli, such as hypotension and apomorphine, the
site of the lesion in these patients seems to be the osmoreceptor (Bayliss and Cheethan, 1998; McKenna and
Thompson, 1998). Central diabetes insipidus with thickened pituitary stalk on MR images may indicate the
presence of Langerhans histiocytosis (Chapter 21.3)
or germinoma (Leger et al., 1999; Chapter 19.2). The
old treatment, pitressin in oil, given intramuscularly,
was effective for 24 h, but the injection was often painful. Desmopressin (1-desamino-8-arginine vasopressin,
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DDAVP), however, does not have the pressor effect

as seen with pitressin and lysine vasopressin (LVP)
treatment and is effective when given as a nasal
spray twice daily. DDAVP is now also available in
tablet form. Patients with central diabetes insipidus
have an increased heart rate, left ventricular contractility
and impaired diastolic function. These alterations, which
can be reversed by DDAVP, are probably due to
stimulation of the sympathetic nervous activity induced
by hypovolemia. In children with diabetes insipidus, the
incidence of complications of DDAVP treatment is
high, especially in those that are cortisol-deficient or
treated with carbamazepine also. Children may develop
water intoxication with seizures, as well as asymptomatic
hyponatremia, and may even die (Rizzo et al., 2001).
The normal high MRI signal of the posterior lobe is
generally not detected in familial diabetes insipidus
and secondary diabetes insipidus, e.g. due to germinomas,
teratomas, Langerhans cell histiocytosis, or Wolframs
syndrome (Fujisawa et al., 1987b; Tien et al., 1991;
Rutishauser et al. 1996; Maghnie et al., 2000; Flck
et al., 2001; see Chapter 21.3, 22.1, 22.7), although
there seem to be exceptions to this rule (Miyamoto,
1991; Maghnie et al., 1992; Hansen et al., 1997). Increased
release due to persistent elevation of plasma vasopressin
levels, as found in diabetes mellitus (Chapter 22.5), may
also accompany a decreased MRI signal intensity of the
neurohypophysis (Fujisawa et al., 1996). The source of
the hyperintense MRI signal of the posterior pituitary is
most probably the neurosecretory granules that contain
vasopressin (Fujisawa et al., 1989), although the contribution of oxytocin and its precursor to the bright spot is
not known. The presence of a bright spot in diabetes
insipidus seems to depend on the type of mutation, the
turnover of neuropeptides in the neurohypophysis and
possibly also the amount of oxytocin that is present.
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substitution therapy with exogenous vasopressin or

analogues. Urine production may amount to some 20
l/day. The urinary excretion of the renal collecting duct
water channel aquaporin-2 in central diabetes insipidus
is one-eighth of that of controls (Ishikawa et al., 2000).
Most mutations are presumed to impair the folding and
intracellular trafficking of the preprohormone for vasopressin. In the long run, the mutant precursor seems to
be toxic for the neuroendocrine neurons. As an example
of the autosomal dominant form of familial diabetes
insipidus, members of a Dutch family may be mentioned,
who appeared to have a point mutation in one allele of
the affected gene, based upon a G to T transversion
at position 17 of the neurophysin encoding exon B on
chromosome 20p13 (Bahnsen et al. 1992; Fig. 22.2b).
Some 40 different mutations have now been found in
kindreds with familial hypothalamic diabetes insipidus
(Fig. 22.3), including six mutations in the part that
encodes the signal peptide, and the rest, in different loci
in the neurophysin II moiety, i.e. in exon 1 or 2, including
two in vasopressin itself, five nonsense mutations (premature stopcodons) in exon 2 or 3, and one trinucleotide
deletion in exon 2 (Ito et al., 1991; Miller, 1993; Yuasa
et al., 1993; Nagasaki et al., 1995; Rittig et al., 1996;
2002; Hansen et al., 1997; Grant et al., 1998; Heppner
et al., 1998; Calvo et al., 1999; Rutishauser et al., 1999;
Siggaard et al., 1999; Abbes et al., 2000; Fuji et al., 2000;
Skordis et al., 2000; Flck et al., 2001; Nijenhuis et al.,
2001; Boson et al., 2003). All the dominant mutations
contrast with the recessive mutation in vasopressin itself.
The mutated form of vasopressin is a weak agonist
with approximately 30-fold reduced binding to the vasopressin receptor (V2) (Willants et al., 1999). A familial
autosomal dominant form of neurohypophysial diabetes
was also described that is based upon a missense mutation encoding the vasopressin moiety, leading to a
substitution of histidine for tyrosine at position 2 in vasopressin. The pituitary bright spot on MR images was
absent. The polyuria and polydipsia started between the
ages of 6 months and 3 years in this family (Rittig et al.,
2002).
The few available postmortem histological observations in families with hereditary hypothalamic diabetes
insipidus point to severe neuronal death in the SON and
PVN, associated with a loss of nerve fibers in the posterior pituitary (Hanhart, 1940; Braverman et al. 1965;
Green et al., 1967; for the mutation of this kind, see
Bergeron et al. 1991; Mahoney et al., 2002; Fig. 22.4),
suggesting that the mutated product might be toxic to the
(a) Familial central diabetes insipidus

Familial hypothalamic diabetes insipidus is transmitted
as an autosomal dominant or X-linked recessive disorder
(Fig. 22.2a). The gene responsible for the X-linked form
of diabetes insipidus has not yet been cloned (Hansen
et al., 1997).
Familial central diabetes insipidus is a rare disease that
accounts for about 5% of all cases of diabetes insipidus
(Bayliss and Cheetham, 1998). Affected individuals have
low or undetectable levels of circulating vasopressin and
suffer from polydipsia and polyuria, and they respond to
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Fig. 22.2. (a) Pedigree of a Dutch family with hereditary hypothalamic diabetes insipidus, comprising five generations. Black symbols denote
affected individuals, women are indicated by circles and men by squares. Samples were available from individuals marked by arrows. (From
Bahnsen et al., 1992, Fig. 1 with permission.) (b) DNA sequencing gel, demonstrating the difference in exon B between the normal and the mutated
vasopressin-neurophysin gene allele of the individual IV-3. The missense mutation G-T is indicated by arrows. Numbering of the deduced amino
acid sequence corresponds to human neurophysin. (From Bahnsen et al., 1992, Fig. 2 with permission.)
neurosecretory cell. Slowly acting toxicity would also

explain the variable age at onset of the disease (Schmale
et al., 1993); we observed that diabetes insipidus may not
strike until an individual reaches the age of approximately
89 years (Bahnsen et al., 1992). Other observations, too,
indicate that vasopressin secretion is normal for the first
few years of life, or even up to school age, and that
diabetes insipidus then develops rapidly, after which it
may continue to aggravate slowly for a decade or more
(McLeod et al., 1993; Hansen et al., 1997; Grant et al.,
1998; Siggaard et al., 1999; Mahoney et al., 2002). Family
members with a mutation in vasopressin replacing Pro7
of mature vasopressin with Leu were asymptomatic

for at least the first year of life, although no normal
vasopressin was produced. Leu-vasopressin had apparently sufficient in vivo activity to delay the symptoms.
As for the claim of Mahoney et al. (2002), that in
autosomal dominant central diabetes insipidus the magnocellular vasopressin neurons are lost, but the parvocellular
neurons that supply vasopressin and corticotropinreleasing hormone (CRH) to the median eminence
are preserved, no direct postmortem evidence is available
with double staining. Also, Bergeron et al. (1991)
presumes that the smaller vasopressin neurons that are
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Fig. 22.3. Schematic diagram of the coding regions of the arginine vasopressinneurophysin II (AVP-NPII) gene and the primary structure of the
preprohormone, showing the location and type of mutations identified in familial hypothalamic diabetes insipidus. (From Rittig et al., 1996, Fig.
1 with permission.)
neurosecretory cells in the various types of familial

diabetes insipidus.
When the mutant of the Dutch kindred was stably
expressed in a mouse pituitary cell line, the mutant
precursor was synthesized, but processing and secretion
were dramatically reduced and the protein did not seem
to reach the trans-Golgi network (Olias et al., 1996).
Studies in which various other human mutant vasopressin
precursors were expressed in cell lines also showed an
accumulation of the mutated vasopressin precursor in the
endoplasmic reticulum, a reduced viability of the cells
(Ito et al., 1997; Nijenhuis et al., 2001) and a reduced
vasopressin expression (Iwasaki et al., 2000). Mutant
vasopressin precursors do not fold correctly and probably
cannot be processed and routed normally so that they do
not move from the endoplasmic reticulum to the Golgi
apparatus and neurosecretory granules. By mis-sorting,
the mutations interfere with the expression of the normal
allele, explaining the dominant nature of the disease. It
has been shown in cell culture that the mutant precursor
accumulates in the endoplasmic reticulum. Homo- and
preserved may project to nonpituitary targets. However,

these smaller neurons may well be degenerating neurons,
and there is no proof that these neurons do or do not
project to the neurohypophysis.
The onset of the symptoms and the severity of the
polyuria vary considerably within the families. One
missense mutation in neurophysin (1665T>G) is associated with early-onset diabetes insipidus. One index case
developed the symptoms at 1 month of age (DiMeglio et
al., 2001). On the other hand, in a postmortem case of a
44-year-old man with hereditary diabetes insipidus, no
clear cell death was found in the SON and PVN, but
immunocytochemically the neurons hardly stained for
vasopressin in the PVN (Nagai et al., 1984), which indicated very late degeneration of the vasopressin neurons.
One can perhaps consider this as an early phase of degeneration, although the history and several hormonal
functions were atypical in these patients (Hansen et al.,
1997). More systematic data from age-related studies and
postmortem observations using quantitative methods are
needed in order to establish the natural history of the
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Fig. 22.4. Supraoptic nucleus (SON), medial portion. Severe loss of vasopressin-expressing (VP) neurons in hereditary diabetes insipidus (b, d) as
compared to age-matched control (a, c), with only rare immunoreactive cells (arrows). Slight gliosis and attenuation of the capillary network is
also evident (d). VP immunostain; a, b 80, c, d 250. (From Bergeron et al., 1991, Fig. 2 with permission.)
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heterodimer formation between wild-type and mutant

precursor formation occurs and impairs intracellular
trafficking of wild-type precursor from the endoplasmic
reticulum to the Golgi apparatus, and may interfere with
the production of other proteins that are essential for
survival of the neurons. The mutant proteins accumulate
in the endoplasmic reticulum and aggregates will form
that also contain the wild-type molecules, resulting in the
activation of a general degradation system, autophagy,
resulting in vasopressin deficiency (Sinha et al., 2000).
The swollen autophagic vesicles contain cathepsin D (a
lysosomal protease), endolin (a marker for late endosomes) and lysosomal-associated membrane protein-1,
suggesting that they may be degradative autolysosomes,
as shown in transgenic rats that express a Japanese mutant
vasopressin gene (Davies and Murphy, 2002). The facts
that most mutations do not affect the vasopressin moiety
itself and the slow development of the misfolding neurotoxicity is the mechanism (Eubanks et al., 2001;
Nijenhuis et al., 2001) that causes the neurosecretory
neurons in hereditary hypothalamic diabetes insipidus to
degenerate seem to explain why children do not develop
diabetes insipidus until later, and why in adulthood degeneration of vasopressin neurons is found. However, the
premature 87STOP mutation may have a different pathogenetic mechanism (Eubanks et al., 2001).
Central diabetes insipidus is associated with increased
baseline ACTH and cortisol secretion, and increased
responsiveness of these two hormones to CRH administration. Replacement with DDAVP completely normalizes
the ACTH and cortisol response to CRH, but not the
baseline secretion of ACTH and cortisol (Pivonello et al.,
2002).
135
the vasopressin cell bodies (Scherbaum, 1992), but ultimately their presence seems to go together with partial
or complete diabetes insipidus (De Bellis et al., 1994,
2002). A longitudinal study of patients with endocrine
autoiommune diseases but without overt diabetes
insipidus showed that the clinical phase can be preceded
by a long subclinical period characterized by antibodies
against vasopressin cells without impairing the posterior
lobe function. However, the presence of such antibodies
indicates a high risk of developing overt diabetes
insipidus. The hyperintense MRI signal of the posterior
pituitary can persist even in the early phase of the development of diabetes insipidus and only disappear later.
Consequently, this is not a useful tool for the prediction
of the progression of autoimmune diabetes insipidus
(De Bellis et al., 1999, 2002). The pituitary stalk is
often thickened on MR images (Maghnie et al., 2000; De
Bellis et al., 2002; Pivonello et al., 2003). Interestingly,
DDAVP treatment of patients with partial central diabetes
insipidus for 1 year showed recovery of posterior lobe
function and disappearance of the antibodies against
vasopressin cells. These results are in line with the
isohormonal therapy given in preclinical stages in some
other endocrine autoimmune diseases (De Bellis et al.,
1999). Infundibulohypophysitis usually presents with
diabetes insipidus and is often associated with disturbances of vision (Tubridy et al., 2001; Ouma and Farrell,
2002). The infiltrate is predominantly composed of
lymphocytes and plasma cells and may involve the hypothalamus, infundibulum, optic nerves, chiasm and tracts.
A dramatic improvement may take place following
administration of corticosteroids (Ouma and Farrell,
2002). Patients with lymphocytic infundibuloneurohypophysitis presenting as diabetes insipidus may have
autoantibodies to vasopressin and on MR images show a
normal pituitary with a focal nodular thickening of the
infundibulum, stalk thickening, and lack of hyperintense
signal of the normal neurohypophysis (De Bellis et al.,
2002). In fact, most patients with idiopathic central
diabetes insipidus have lymphocytic neurohypophysitis
(Pivonello et al., 2003).
Apart from diabetes insipidus, loss of hyperintense
posterior lobe signal and thickened pituitary stalk,
lymphocytic hypophysitis can also manifest itself with
anterior pituitary disorders. Some 90% of cases with
lymphocytic hypophysitis are female and at least 65%
are associated with pregnancy. Sixty percent of cases have
symptoms such as headache and visual defect, and 40%
have hyperprolactinemia with functional involvement of
(b) Autoimmune diabetes insipidus

Idiopathic diabetes insipidus is associated with autoimmunity in one third of the cases. Indeed, autoantibodies
against the vasopressin-cell surfaces have been found
(Fig. 22.5). Autoimmune central diabetes insipidus is very
likely in young patients with a clinical history of autoimmune diseases and radiological evidence of pituitary stalk
thickening (Scherbaum, 1992; De Bellis et al., 1999,
2002; Pivonello et al., 2003). Conversely, the low titer
autoantibodies in patients with non-idiopathic central
diabetes insipidus probably represents an epiphenomenon.
Autoantibodies are never found in familial central
diabetes insipidus (Pivonello et al., 2003). It has not yet
been established whether the autoantibodies observed in
diabetes insipidus are indeed cytotoxic and might destroy
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Fig. 22.5. (a) Autoantibodies to hypothalamic vasopressin cells. An unfixed 7-m cryostat section of human hypothalamus at the level of the
supraoptic nucleus (SON) was incubated with native serum from a patient with idiopathic hypothalamic diabetes insipidus and stained with FITClabeled anti-human IgG. Note that the cytoplasm of large cells is stained. It is shown by the four-layer, double-fluorochrome immunofluorescence
test with antivasopressin in the second sandwich that vasopressin cells were stained ( 250). (b) The same area of the SON as in (a) incubated
with normal human serum and FITC-labeled polyvalent anti-human immunoglobulin. Note that the background is brighter than the dark neurosecretory cell bodies ( 400). (c) The same area of the SON as in (a) incubated with the serum of a patient with systemic lupus erythematosus
containing the rare anti-ribosomal antibodies visualized by FITC-labeled anti-human IgG, which may, in very rare cases disturb the detection of
vasopressin-cell antibodies. Note the coarsely granulated cytoplasmic staining of the two large cell bodies ( 400). (d) Cryostat section (7 m) of
human hypothalamus at the level of the SON. The specimen was obtained from a donor aged 50 years. The section was incubated with normal
human serum and FITC-labeled polyvalent anti-human immunoglobulin. The autofluorescent lipofuscin deposits in the cell bodies of large
neurosecretory cells hamper the evaluation of test results ( 250). (From Scherbaum, 1992, Fig. 1 with permission.)
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the anterior pituitary (Iglesias and Dez, 2000; Tubridy

et al., 2001).
Stereotactic biopsies of the neurohypophysis or pituitary stalk revealed chronic inflammation with infiltration
lymphocytes predominantly of the CD4+ subpopulation
and plasma cells. The natural course of the lymphocytic
infundibuloneurohypophysitis generally seems to be selflimited, but glucocorticoid therapy has been given to
reduce intracranial hypertension. This therapy is presumed
to contribute to the reduction of the mass, although proof
of such an effect is lacking (Imura et al., 1993; Koshiyama
et al., 1994; Paja et al., 1994; Chico et al., 1998; Kamel
et al., 1998; Maghnie et al., 1998a).
Specific subtypes of the major histocompatibility
complex (MHC), the human leukocyte antigens (HLA),
can be correlated with this disease and other autoimmune
endocrine disorders. The differential diagnosis of a
thickened pituitary infundibulum includes sarcoidosis,
tuberculosis, germinoma, infiltrations from pituitary
adenoma, hypothalamic glioma or teratoma, and mass
lesions such as craniopharyngioma, Rathkes pouch cyst,
tumor of the pituitary infundibulum, metastases, and
Langerhans cell histiocytosis (Kamel et al., 1998). In
fact, autoimmunity to vasopressin-producing cells may be
present in a large percentage of patients with central
diabetes insipidus associated with Langerhans cell histiocytosis (Pivonello et al., 2003). An 8-year-old child who
presented with acute-onset diabetes insipidus followed by
an acquired growth hormone deficiency had an enlarged
pituitary stalk and absence of posterior pituitary hyperintensity as shown by MRI. At the age of 15 years,
a large hypothalamic mass and panhypopituitarism
ere found. The perivascular inflammatory lymphocytic
infiltrates suggested the presence of a lymphocytic
infundibuloneurohypophysitis that reacted favorably to
glucocorticoids (Maghnie et al., 1998a). Transient
diabetes insipidus associated with lymphocytic infundibuloneurohypophysitis and a thickened pituitary stalk shown
on MR images has also been described in a 77-year-old
woman (Takahashi et al., 1999). A case of diabetes
insipidus caused by nonspecific chronic inflammation of
the hypothalamus was reported that had acute multifocal
placoid pigment epitheliopathy with an immunogenic
predisposition as well as HLA class I antigen A2 and
class II antigen DR4, which might also be a case of
autoimmune reaction (Watanabe et al., 1994).
Cases with necrotizing infundibulohypophysitis and a
combination of diabetes insipidus and hypopituitarism
have been described. It is possible that this disorder, as
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described by Ahmed et al. (1993), represents an end stage

of lymphocytic infundibulitis, but alternatively it may be
a unique syndrome. Wegeners granulomatosis is a
systematic necrotisizing vasculitis with neurological
symptoms in some 50% of cases. Antineutrophil cytoplasmic antibodies are present. A few cases have been
described in which the disease remained confined to the
anterior and posterior pituitary, causing hypopituitarism
and diabetes insipidus. The patients did not respond to
immunosuppressive therapy with cyclophosphamide, but
in some patients corticosteroids gave a clinical remission
(Rosete et al., 1991; Roberts et al., 1995; Berthier et al.,
2000; Woywodt et al., 2000). Transient diabetes insipidus
has also been described in GuillainBarr syndrome
(Pessin, 1972). It should also be mentioned that iatrogenic antibodies may be raised by treatment with
vasopressin, making the patients refractory to treatment
with vasopressin and causing diabetes insipidus (Bisset
et al., 1976).
On the basis of the limited literature on autoimmune
diabetes insipidus, it seems certainly worthwhile to
look for autoimmune processes that may be directed
toward other hypothalamic neurons and might be an
explanation for hypothalamic symptoms in other neurological, psychiatric or neuroendocrine diseases (see, e.g.
idiopathic hypothalamic dysfunction syndrome of childhood (Chapter 19.1; 32.1), adipsia (Chapter 22.3),
anorexia and bulimia nervosa (Fetissov et al., 2002;
Chapter 23.2), obsessive-compulsive disorder (Chapter
26.6), KleineLevin syndrome (Chapter 28.1) and
narcolepsy (Chapter 28.4).
(c) Pregnancy-induced diabetes insipidus
During pregnancy a transient form of diabetes insipidus
sometimes occurs. The central form may respond to
DDAVP but not to vasopressin, because the vasopressin
analogue is much less susceptible to degradation to placental vasopressinase (Hansen et al., 1997). Vasopressinase
during pregnancy is the same enzyme as cystine-aminopeptidase or oxytocinase. It may, at least partly, be
responsible for the fact that the metabolic clearance of
vasopressin during pregnancy increases fourfold. The
enzyme decreases to undetectable levels in several days
postpartum. Cases have been described with a transient diabetes insipidus during pregnancy due to extraordinarily
high plasma vasopressinase activity. However, a more
likely cause of polydipsia and polyuria during pregnancy
is the unmasking of subclinical forms of either central
or nephrogenic diabetes insipidus (see Chapter 22.2e).
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Apart from the presence of vasopressinase, a decreased

threshold for thirst contributes to the aggravation of diabetes insipidus. When, during pregnancy, thirst increases,
more water is consumed and the urine volume becomes
unacceptable. The lowering of the thirst threshold is accompanied by a similar lowering of the osmotic threshold for
the release of vasopressin. The result is that pregnant
women drink more water, which may subsequently be
retained. The exact mechanism for the altered osmoregulation in pregnancy is obscure, but the combination of
changes in water homeostasis and vasopressin metabolism
that occurs in normal pregnancy seems to provide an explanation for the transient expression of diabetes insipidus in
pregnant women, especially in the case of latent forms of
neurogenic or nephrogenic diabetes insipidus (Durr et al.,
1987; Iwasaki et al., 1991; Robinson and Amico, 1991;
Treip, 1992; Williams et al., 1993; Van der Post et al.,
1994; Lindheimer and Davison, 1995; Naruki et al., 1996).
On the other hand, a partial central diabetes insipidus, e.g.
due to an asymptomatic craniopharyngioma, should also
be considered in cases of pregnancy-induced diabetes
insipidus (Fluteau-Nadler et al., 1998). The safety of
DDAVP treatment for the child during pregnancy still
has to be established (cf. Linder et al., 1986). In case
of pregnancy-induced diabetes insipidus, the oxytocin
levels may be normal, depending on the exact cause of this
disorder (Sende et al, 1976; Shangold et al., 1983).
(d) Other causes of central diabetes insipidus
Diabetes insipidus has also been observed as part of a
midline developmental anomaly, e.g. in septo-optic
dysplasia (see Chapter 18.3), holoprosencephalic syndromes in which the development of the SON and
PVN is disturbed (Sztriha et al.,1998; Robertson, 2001;
Sarnat and Flores-Sarnat, 2001) and in dystopia of the
neurohypophysis (Chapter 18.4). Structural lesions of
the hypothalamus in children may accompany weight
gain, diabetes insipidus, osmoreceptor dysfunction
(hypernatremia with absent thirst), pituitary deficiencies
and hyperprolactinemia (Cianfarani et al., 1993). Partial
central diabetes insipidus with an elevated threshold of
thirst and enhanced renal water handling to maintain body
water was found in a woman who, as a 4-year-old child,
had had meningitis, followed by a ventriculoperitoneal
shunt operation because of normal-pressure hydrocephalus (Fukagawa et al., 2001). In addition, diabetes
insipidus can be present in hypothalamic Langerhans
cell histiocytosis (Czernichow et al., 2000; Modan-Moses
et al., 2001; Municchi et al., 2002; Chapter 21.3),
ErdheimChester disease (a distinct form of histiocytosis)

(Tritos et al., 1998a), Wolframs syndrome (Chapter
22.7) and in association with LaurenceMoon/Bardet
Beidl syndrome (Chapter 23.3), hypoxic/ischemic brain
damage, hemorrhage, infarcts, Sheehans syndrome (see
Chapter 17.2), inflammation and abscess formation
(see Chapter 20) and tumors of the hypothalamus,
including metastases (see Chapter 19), or of the pituitary.
In cases of pituitary adenomas with supradiaphragmatic
extension that lead to permanent diabetes insipidus, no
high-intensity MRI signal is observed (Saeki et al., 2002).
Following craniotomy for a pituitary tumor, a patient
developed central diabetes insipidus, with absence of
the posterior pituitary bright spot. She survived the severe
hyponatremia, but developed permanent (6 months)
disorientation to time and place, even after DDAVP
administration (Gomez-Daspet et al., 2002). Diabetes
insipidus may also be found following traumatic injuries
(Chapter 25.1) or be due to toxins (snake venom,
tetrodotoxin; Robertson, 2001) and result from surgical
manipulations affecting either the SON and PVN or,
more frequently, following sectioning of the hypothalamoneurohypophysial tract (see Chapter 25.4) and in
GuillainBarr syndrome (Treip, 1970b; Pessin, 1972;
Rudelli and Deck, 1979; Stern et al., 1985; Fujisawa et
al., 1987b; Bell, 1991; Laing et al., 1991; Arisaka et al.,
1992; Catalina et al., 1995; Bayliss and Cheetham, 1998).
Diabetes insipidus may also occur in neurosarcoidosis
(see Chapter 21.1), in idiopathic giant cell granulomatous hypophysitis, which is histologically characterized
by infiltration of multinucleated giant cells, plasma cells
and lymphocytes (Fujiwara et al., 2001), and in paraneoplastic limbic encephalitis, due, for instance, to anti-Ta
(= anti-Ma2) antibodies (Gultekin et al., 2000). Lesions
of the neurohypophysis alone may not result in diabetes
insipidus when the neurosecretory nuclei remain intact.
A syndrome of partial diabetes insipidus has been reported
in anorexia nervosa, where vasopressin seems to be
secreted erratically, independent of plasma sodium levels
(Gold et al., 1983). Although uncommon, central diabetes
insipidus may develop following spinal trauma and/or
surgery; it is thought that the sympathetic tone is then
disturbed and vascular dilation may cause a drop in blood
flow in the neurohypophysis and median eminence
(Kuzeyli et al., 2001).
(e) Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus can be inherited or
acquired. It is characterized by an inability to concentrate
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urine despite normal or elevated plasma vasopressin levels

(Barberis et al., 1998). About 9095% of patients with
nephrogenic diabetes insipidus are males with the Xlinked recessive form of the disease (OM1M 304800),
who have mutations in the vasopressin receptor-2 gene,
located on Xq28 (Van den Ouweland et al., 1992;
Birnbaumer, 2000; Morello and Bichet, 2001; Fig. 22.6).
Severe disease of this X-linked form is expressed in
hemizygous boys, whereas heterozygous girls may have
moderate expression to no symptoms at all. Sporadic cases
are frequent and they usually represent X-linked recessive nephrogenic diabetes insipidus rather than the
autosomal form (Bichet et al., 1988; Holtzman et al.,
1993; Ala et al., 1998; Deen and Knoers, 1998; Wildin
et al., 1998; Rocha et al., 1999; Wildin and Cogdell,
1999). Over 155 mutations within the vasopressin receptor
(V2) gene may cause inherited nephrogenic diabetes
insipidus (Morello et al., 2001; Chen et al., 2002). The
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loss-of-function vasopressin receptor mutation R137H,

which is associated with familial nephrogenic diabetes
insipidus, induces constitutive arrestin-mediated desensitization. The binding of arrestins to phosphorylated
receptors mediates the agonist-dependent desensitization
and internalization of G-protein-coupled receptors. The
affinity of arrestin for the phosphorylated G-proteincoupled receptor regulates the ability of the internalized
receptor to be dephosphorylated and recycled back to the
plasma membrane. Unregulated desensitization can thus
induce nephrogenic diabetes insipidus (Barak et al., 2001).
Other vasopressin receptor mutants cause nephrogenic
diabetes insipidus by other mechanisms, e.g. by a lack
of vasopressin binding or signaling, by retention in the
endoplasmic reticulum or by a lack of binding of the
mutated receptor with the molecular chaperone calnexin
(Morello et al., 2001). A large number of vasopressin V2
receptor mutants have been identified (Arthus et al.,
Fig. 22.6. Schematic representation of the V2 receptor and identification of 155 putative disease-causing AVPR2 mutations. A solid circle indicates the location of (or the closest codon to) a mutation; a number indicates more than one mutation in the same codon. There are 78 missense
mutations, 42 frameshift mutations, 6 in-frame deletions or insertions and 3 splice site mutations. Eight large deletions and one complex mutation
are not shown. (From Morello and Bichet, 2001, Fig. 7 with permission.)
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2000), causing defects in its intracellular trafficking, its

membrane localization, ligand-binding affinity and selectivity (Albertazzi et al., 2000; Pasel et al., 2000; Postina
et al., 2000).
In less than 10% of families, nephrogenic diabetes
insipidus has an autosomal-recessive or autosomal dominant (OM1M 222000 and 125800, respectively) mode of
inheritance, caused by mutations on chromosome 12q13
in the gene of the water channel protein aquaporin-2
(Deen and Knoers, 1998; Rocha et al., 1999; Wildin and
Cogdell, 1999; Morello and Bichet, 2001; Fig. 22.7). One
mutant protein leading to the autosomal dominant form
was able to form heterotetramers with the wild-type
aquaporin-2, in contrast to the mutants found in the recessive form (Kamsteeg et al., 2000). Normally, after binding
of vasopressin to the V2 receptor, the receptor activates
the G-protein Gs that stimulate a phosphorylation
cascade, which promotes translocation of presynthesized
aquaporin-2 water channels, which are then inserted into
the apical membrane of the renal collecting duct cells
and make them permeable for water. Mutations in
the aquaporin-2 water channel makes the collecting
duct impermeable for water, as do mutations in the

V2 receptor, resulting in nephrogenic diabetes insipidus
(Fig. 8.6; Deen and Knoers, 1998; Birnbaumer, 1999;
Deen et al., 2000). With the aquaporin-2 mutants, all
cases of nephrogenic diabetes insipidus were identified,
a unique feature for a genetic disease (Birnbaumer, 2000;
Lin et al., 2002a). One mutant was studied in more
detail. The mutant protein was mainly retained in the
Golgi apparatus (Kamsteeg et al., 2000). Another mutant
in a family with dominant nephrogenic diabetes insipidus
revealed a single-nucleotide deletion in one aquaporin-2
allele. The mutated protein appeared to be localized in
the basolateral membrane and late endosomes/lysosomes,
whereas the wild-type protein was expressed in the
apical membrane. Upon coexpression, the wild-type and
mutated protein complex mistargeted to late endosomes/
lysosomes, resulting in an absence of the wild-type protein
in the apical membrane. Misrouting after heteroligomerization, rather than a lack of function, thus seems to
be the cause of nephrogenic diabetes insipidus in this
family with a deletion in the aquaporin-2 gene (Marr
et al., 2002).
Fig. 22.7. A. Schematic representation of the aquaporin-2 (AQP-2) protein and identification of 26 putative disease-causing AQP2 mutations. A
monomer with six transmembrane helices is represented. The location of the protein kinase A phosphorylation site (Pa) is indicated. This site is
possibly involved in the arginine vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis. Solid circles indicate the locations of the mutations. B. Representation of the six-helix barrel of the AQP1 protein
viewed parallel to the bilayer. (From Morello and Bichet, 2001.)
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Nephrogenic diabetes insipidus generally manifests a

few days after birth. It will usually result in profound
polyuria and consequent dehydration, vomiting, constipation, fever, irritability and a failure to thrive in infancy.
Episodes of dehydration can cause brain damage, permanent mental retardation and even death. There may be a
history of hydramnios (Bayliss and Cheetham, 1998; Jonat
et al., 1999; Van Lieburg et al., 1999; Wildin and Cogdell,
1999). Nephrogenic diabetes insipidus is characterized by
normal or elevated concentrations of vasopressin and an
insensitivity to exogenously administered vasopressin
analogues. It may be partially controlled by thiazide
diuretics, amiloride or indomethacin (Hansen et al., 1997).
Polyuria in nephrogenic diabetes insipidus may be
completely concealed by concomittant adrenal failure.
Polyuria starts immediately after corticosteroid replacement, probably because of an intrarenal mechanism.
Cortisol seems to be required for an optimal excretion of
water (Iwasaki et al., 1997; Bayliss and Cheetham, 1998).
On the other hand, we observed strongly decreased vasopressin staining in the SON and PVN following
corticosteroid treatment (Erkut et al., 1998), indicating a
lack of free vasopressin that may also contribute to
unmasking nephrogenic diabetes insipidus. Selective
nonpeptide V2-renal vasopressin receptor antagonist
rescued the function of V2-renal receptor mutants by
promoting their proper folding and maturation. Such
compounds may thus have potentially therapeutic effects
(Paranjape and Thibonnier, 2001).
In addition, nephrogenic diabetes insipidus may be
based on osmotic diuresis (diabetes mellitus; see Chapter
22.5), hypercalcemia, and hypocalcemia (both of which
impair the action of vasopressin on the distal nephron),
chronic renal disease, drugs such as lithium and demeclocycline, postobstructive uropathy, solute washout from
the renal medulla and primary polydipsia (Bayliss and
Cheetham, 1998; Chapter 22.3).
In rare cases of Gitelmans syndrome, growth hormone
deficiency or multiple pituitary hormone deficiencies are
associated with empty sella and diabetes insipidus. The
disease is caused by mutations in the gene encoding TSC
(SLC12A3) of the distal convoluted tubule (Bettinelli et
al., 1999).
Cases of transient vasopressin (DDAVP)-resistant
diabetes that developed during gestation have been
reported. A pathogenetic factor, such as increased production of prostoglandin E2, may cause resistance to
DDAVP. The hyperprostoglandin E-syndrome is a variant
of Bartters syndrome and may be induced by lithium or
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hydronephrosis (Jin-No et al., 1998). Indomethacin and

hydrochlorothiazide normalize prostoglandin E levels
and decrease urine volumes. A T1-weighed MR image
of the posterior pituitary may reveal decreased intensity
due to increased vasopressin release. The syndrome
remitted in the puerperium (Barron et al., 1984; Ford and
Lumpkin, 1986; Jin-No et al., 1998). These thus appear
to be cases of nephrogenic diabetes that were unmasked
by pregnancy.
Defective urine-concentrating ability due to a complete
deficiency of aquaporin-1 was described in a few
unrelated subjects. Aquaporin-1 is the archetypal waterchannel protein that is abundantly present in the renal
proximal tubular epithelium, the thin descending limb of
the loop of Henle and the descending vasa recta of the
kidney. The gene for aquaporin-1 is localized on chromosome 7. The two subjects with a complete deficiency
of aquaporin-1 did not have polyuria, but both had an
impaired ability to concentrate their urine maximally
when deprived of water. People with a complete deficiency of aquaporin-1 have thus unidentified mechanisms
of fluid readsorption in the proximal tubules that compensate for the deficiency of aquaporin-1 (King et al., 2001).
22.3. Primary polydipsia and adipsia
(a) Primary polydipsia
Primary polydipsia is characterized by thirst, excessive
fluid intake and hypotonic polyuria, despite preservation
of the ability to secrete appropriate amounts of vasopressin in response to osmotic stimuli. A physiological
inhibition of vasopressin is present due to excessive
drinking. This condition was reported for the first time
by Nothnagel in 1881. He described a man who was
kicked by a horse, causing him to fall backward onto the
back of his head. Within half an hour he developed a
fierce thirst, drank 3 l of water and beer within half an
hour and only then did he start to urinate. The thirst
persisted for 4 days (Anderson and Haymaker, 1974). The
simultaneous measurement of plasma vasopressin and
plasma osmolality in a dehydration test is the best
diagnostic tool in the differential diagnosis of primary
polydipsia and diabetes insipidus (Diederich et al., 2001).
In addition to psychiatric disorders, primary polydipsia
may be associated with neurosarcoidosis or with congenital absence of the corpus callosum. In the case of tumors
in the pineal or suprasellar region, a transient polydipsia
can precede a state of adipsia (Zazgornik et al., 1974).
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In a patient who suffered from polydipsia secondary to

sarcoidosis, a normal reaction to vasopressin was found.
Following treatment with vasopressin, abrupt cessation of
thirst occurred when serum osmolality had been lowered
to 275 mosmol/kg (normally below 290 mosmol/kg). This
patient thus had an abnormal sensation of thirst (Mellinger
and Zafar, 1983). Polydipsia, polyuria and an increased
thirst sensation can also be present during untreated thyrotoxicosis (Harvey et al., 1991).
Primary polydipsia is an isolated clinical abnormality
characterized by abnormal thirst. Compulsive waterdrinking is sometimes also called dipsogenic diabetes
insipidus. However, the term dipsogenic polydipsia is
generally used for somatic patients. The disorder is
known to occur in association with damage to the hypothalamus, such as closed head trauma, neurosarcoidosis,
infections, multiple sclerosis or medicines such as lithium,
or carbamazepine (Robertson, 2001). The vasopressin
levels of compulsive water-drinking psychiatric patients
are higher, at any given level of osmolality, but vasopressin secretion can only account for hyponatremia
not for polydipsia, the primary problem. Angiotensin II,
a known dipsinogen in animals, has also been proposed
as a possible etiological factor. Neuroleptics increase
angiotensin II, induce thirst in animals and release vasopressin (Verghese et al., 1993), but there are no reports
on changes in this peptide with respect to primary polydipsia in patients. The syndrome is characterized by
excessive water drinking, explained by the patient as
having severe, persistent and unquenchable thirst, and
which leads to the production of hypotonic polyuria. A
hyperintense T1-weighted MRI signal is clearly present
in the neurohypophysis of patients with this syndrome.
Three distinct abnormalities of the control of thirst appreciation have been identified in clinical studies. First, the
osmotic threshold for thirst appreciation is lowered to
such an extent that patients are thirsty even at plasma
osmolalities so low that they are associated with a
complete lack of vasopressin secretion. The second abnormality is that patients drink more than healthy controls
in response to a given rise in plasma osmolality. Finally,
their thirst is not suppressed even while they are drinking;
they continue to feel thirsty even when imbibing large
quantities of water. It has been suggested that primary
polydipsia is caused by abnormal function of the osmoreceptors that govern thirst, but the failure of the action
of drinking to suppress thirst indicates that nonosmotic
control of thirst is also abnormal. It therefore seems likely
that there is a second abnormality in the integration of
osmotic and nonosmotic control of thirst in primary polydipsia (Thompson et al., 1991; McKenna and Thompson,
1998).
(b) Psychogenic polydipsia
Primary polydipsia may be associated with psychiatric
disorders and is then generally termed psychogenic polydipsia (Thompson et al., 1991). The criterion used for
polydipsia is 2.5 l of urine per day, and a urine specific
gravity of less than 1008. In one patient with psychogenic diabetes insipidus a normal posterior pituitary
MRI bright spot was detected (Chiumello et al., 1989),
indicating storage of vasopressin. Aquaporin-2 excretion
in the urine is not changed in these conditions (Ishikawa,
2000). Associated disorders such as sporadic convulsive
seizures, comatose states, hydronephrosis, enuresis,
urinary incontinence, projectile-type vomiting and malnutrition may be present (Blum et al., 1983). Polydipsia and
water intoxication cause considerable morbidity and
mortality in chronic psychiatric patients. Polydipsia in
psychiatric patients has been described prior to the use
of neuroleptics. Many names are being used in literature
for this disorder, which include psychogenic polydipsia
or compulsive water drinking, intermittent hyponatremia,
polydipsia syndrome and self-induced water intoxication.
Water intoxication occurs in 50% of the polydipsic
patients, due to cerebral edema caused by hyponatremia.
The symptoms include headache, blurred vision, anorexia,
nausea, vomiting and diarrhea, muscle cramps, restlessness, confusion, exacerbation of psychosis, convulsion,
coma and death. Polydipsia and water intoxication
are strongly associated with chronicity of the illness;
80% of the patients suffer from schizophrenia, others
from affective disorders, alcohol abuse, mental retardation, organic brain disorders and personality disorders
(Chiumello et al., 1989). For unknown reasons, patients
with psychogenic polydipsia and intermittent hyponatremia have larger ventricle to brain ratios. Since this
ratio and the lateral ventricle volume decrease during
water loading, water loading does not account for the
diminished brain volume observed in these patients
(Leadbetter et al., 1999).
(c) Adipsinogenic disorders
Inappropriate lack of thirst, with consequent failure to
drink in order to correct hyperosmolality, is characteristic of adipsinogenic disorders (Robertson, 2001). The
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patient denies thirst or does not drink spontaneously.

Plasma osmolality and plasma sodium are elevated and
blood volume is contracted with a raised blood urea. Poor
cerebration and drowsiness are common symptoms and
the condition can progress to somnolence, fits, hemiplegia,
coma, rhabdomyolysis and acute renal failure. Four
main patterns of abnormal osmoregulatory function have
been described. Type A is characterized by an upward
resetting of the osmotic thresholds for both thirst and
vasopressin release. This rare condition is sometimes
referred to as essential hypernatremia. Patients will
usually respond to advice to drink approximately 2 l of
fluid daily. Type B is characterized by subnormal thirst
and vasopressin release to osmotic stimuli. They are able
to secrete some vasopressin and the disorder may be due
to partial destruction of the osmoreceptors. Type B adipsia
has been described in association with microcephaly and
dysplasia of the corpus callosum, early puberty and
aggressive behavior, and increased renal sensitivity to
vasopressin. Complete destruction of the osmoreceptor is
classified as type C osmoreceptor dysfunction. Surgery
for ruptured aneurysms associated with clipping of the
anterior communicating artery of the circle of Willis, ablation of tumors, granulomata, toluene exposure and head
injury may cause this condition. As these patients secrete
normal amounts of vasopressin in response to nonosmotic
stimuli, the site of the lesion is the osmoreceptor, rather
than the SON or PVN. Because thirst and vasopressin
deficiencies are complete, the patients are at great risk of
life-threatening hyponatremia. In particular some patients
who develop adipsic diabetes insipidus following surgery
to aneurysms of the anterior communicating artery show
significant defects of cognitive function, including shortterm memory loss. They are also unable to manage their
fluid intake without assistance (McKenna and Thompson,
1998; Smith et al., 2002).
The adipsogenic disorders are supposed to be based
upon an osmoreceptor dysfunction and often associated
with a defective osmoregulated vasopressin secretion and
diabetes insipidus. Patients are at risk for de- and overhydration (Verdin et al., 1985; Ball et al., 1997). The
patients usually have structural hypothalamic abnormalities such as germinoma or other tumors such as gliomas
(Zazognik et al., 1974; Hammond et al., 1986). In addition, vascular abnormalities, granulomatous diseases,
trauma, hydrocephalus, congenital malformations, histiocytosis, microcephaly and ventricular cysts have been
found. Surgery or irradiation may also cause this disorder
(Hammond et al., 1986; Ball et al., 1997). In one case a
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pseudotumor cerebri and an empty sella turcica were

found. Pseudotumor cerebri was diagnosed on the basis
of a high intracranial pressure, normal CSF composition,
signs of intracranial hypertension and normal radiographic
studies. Deficiency of vasopressin secretion was presumed
to result from neurohypophysial suppression (Verdin
et al., 1985).
A number of children with a number of hypothalamic
dysfunctions, including hypodipsia, are described in
Chapter 32.1. The case of a 9-year-old boy may serve as
a first example. In him, the onset of obesity was accompanied by decreased activity, episodes of lethargy,
increased perspiration, mood changes, wide temperature
oscillations, hypernatremic crises, high prolactin levels,
an inability to excrete a water load and hypothyroidism.
A follow-up study after 4 years could not identify any
demonstrable hypothalamic structural lesion. The patient
had a loss of thirst, there was no diabetes insipidus, and
no explanation for the strong hypothalamic abnormalities
could be offered (Hayek and Peake, 1982). In one case
of a 2-year-old child who lacked thirst perception and
suffered from polyphagia, obesity and inadequate temperature regulation, autopsy was performed and revealed
inflammation of the hypothalamic nuclei (Travis et al.,
1967). The possibility that inflammatory or autoimmune
processes in the hypothalamus are the cause of this condition should thus be further investigated. In two unrelated
boys of 13 and 18 years of age, a hypothalamic syndrome
has been described consisting of early puberty dysfunction associated with aggressive behavior (Dunger et al.,
1985). The pathogenetic mechanism of this syndrome has
not yet been clarified. An absence of thirst has also been
reported in Kallmann syndrome (see Chapter 24.3),
together with hypernatremia and an elevated osmotic
threshold for vasopressin release. The fact that some
patients with Kallmann syndrome have osmoreceptor
dysfunction and abnormal thirst regulation indicates
that there is more extensive hypothalamic involvement in
this disorder than previously appreciated (Hochberg
et al., 1982). In various reported cases of hypodipsic
hypernatremia, associated defects in antidiuretic function
occurred. In several patients a deficiency of vasopressin
was demonstrated with osmotic but not with nonosmotic
stimuli, indicating that the osmoreceptors for thirst and
vasopressin occupy overlapping areas in the anterior
hypothalamus (Hammond et al., 1986). In addition, a
unique patient has been described who had hypernatremia
and hypodipsia without any defect in the osmoregulation
of vasopressin secretion. This indicates that the neuronal
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pathways that mediate osmoregulation of thirst and vasopressin secretion in humans are so discrete that they can
be affected separately. Development was delayed in this
child and optic atrophy and intracerebral calcifications
were found, as, e.g. in the case of a congenital cytomegalovirus infection (Hammond et al., 1986). In one
patient with defective hypothalamic osmoreceptors a
normal posterior pituitary bright spot was seen on MR
images (Chiumello et al., 1989), which also indicates
different locations for the two functions.
Treatment consists of attempting to prevent chronic
fluid deficit, e.g. by adopting a regime of regular water
intake based on changes in body weight (Hammond et
al., 1986). The hypertonic saline test with measurements
of plasma osmolality and vasopressin is useful for distinguishing partial diabetes insipidus from psychogenic
polydipsia and for the diagnosis of complex disorders of
osmoreceptor and posterior pituitary function (Mohn et
al., 1998).
22.4. Nocturnal diuresis
Children with nocturnal enuresis, defined by persistent
bed-wetting for at least 3 nights a week after the 5th year
of age (Mller et al., 2002b), fail to wake in response to
the need to void. Nocturnal diuresis or nightly bed-wetting
in children older than 7 years affects about 10%. From
this age onward there is a spontaneous cure rate of about
15%/year, which means that few children remain affected
after the age of 16 years. The problem may lie in the
arousal mechanism and/or in the amount of urine
produced at night. Vasopressin is involved in both antidiuresis and arousal. Different subgroups of nocturnal
enuresis with probably different etiologies are distinguished (Lckgren et al., 1999). For a long time now,
DDAVP has been advertised as a treatment for nocturnal
diuresis (Klauber, 1989; Janknegt and Smans, 1990;
Nevus et al., 2002). The vasopressin analogue was
claimed to lead to total or almost total dryness in approximately two-thirds of the enuretics (Hunsballe et al.,
1998). DDAVP has no major effects on sleep in enuretic
children as such, but does delay bladder emptying
(Nevus et al., 2002). The possibility of permanent effects
of peptides on brain development (Swaab et al., 1988)
has, however, never been considered in these young children, although central effects of this compound are very
probable (Mller et al., 2002b). In spite of the fact that
DDAVP is generally used, the scientific basis for the use
of DDAVP in children with nocturnal diuresis is considered by some to be rather narrow (De Jong and Van der
Heyden, 1991) and, when the recommended dose of
DDAVP is exceeded, coupled with high fluid intake, it
is even liable to cause hyponatremia and seizures (Davis
et al., 1992). Hyponatremia resulting in delirium, seizures
and/or coma may occur in children and occasionally in
adults who are given DDAVP for nocturnal diuresis
(Chan, 1997; Donoghue et al., 1998; Chapter 22.6). In
addition to DDAVP, alarms are used and behavioral
therapy is given (Lckgren et al., 1999). Interestingly,
some cases of primary nocturnal enuresis and nephrogenic diabetes insipidus have been found to be caused
by mutations in the aquaporin-2 gene which cause this
protein to be inactive. Although one would expect
DDAVP to be inactive, treatment with DDAVP resolves
primary nocturnal enuresis completely. DDAVP consequently does not act exclusively through alteration of the
renal concentrating ability but also seems to act by central
targets. There are families with primary nocturnal diuresis
that have a disease locus at chromosome 12q13-21 around
the aquaporin-2 gene locus (Radetti et al., 2001).
However, since no mutation in the aquaporin-2 coding
sequence has been found, this gene is excluded as a candidate for autosomal dominant nocturnal enuresis in these
families.
In a significant proportion of patients with nocturnal
enuresis, the normal diurnal rhythm in plasma vasopressin
and urine output is reported to be absent (Nrgaard et
al., 1985; Rittig et al., 1989). However, a later study has
shown that such an abolished circadian rhythm is only
present in the subgroup of DDAVP-responding diuretics
with considerable polyuria and poorly concentrated urine
at night (Hunsballe et al., 1998). There is a subgroup
of children who respond to high (but not to normal)
doses of DDAVP (Nevus et al., 1999a). Various relevant
differences between DDAVP responders and nonresponders have been reported. Nonresponders have a smaller
spontaneous bladder capacity, and responders produce
less-concentrated urine (Nevus et al., 1999a).
Enuretic children responding to DDAVP treatment
have more rapid eye movement sleep than therapy-resistant children (Nevus et al., 2002). The favorable response
of nonresponders to anticholinergic medication supports
the hypothesis that these children had nocturnal bladder
instability (Nevus et al., 1999b). In addition, responders
have a lower nocturnal aquaporin-2 excretion than nonresponders, while plasma vasopressin levels and osmolality
were similar. DDAVP treatment is proposed to increase
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aquaporin-2 secretion in the responders, thus reducing

nocturnal water loss (Radetti et al., 2001).
With the lack of normal, diurnal vasopressin rhythms
in some cases of nocturnal enuresis and the presence
of a normal melatonin rhythm (Kirchlechner et al.,
2001), one may wonder whether immaturity of the
retinohypothalamic tract innervating the SON, or of
the suprachiasmatic nucleus (SCN) efferents close to the
SON and possibly innervating its dendrites (Dai et al.,
1998a; see Chapter 4), may contribute to a subgroup of
patients with this disorder. The other possibility, i.e. that
the SCN itself is a relatively late-maturing structure
(Swaab et al., 1991, 1994), is less likely, because in children with nocturnal enuresis the melatonin rhythm as
measured by 6-hydroxy-melatonin sulfate excretion in the
urine is normal (Kirchlechner et al., 2001). Alternatively,
Hunsballe et al. (1998) and Jonat et al. (1999) propose
that nocturnal pituitary vasopressin failure is not the sole
mechanism of nocturnal polyuria in enuretics persisting
into adulthood, although they also mention that this group
of older enuretics, even in adulthood, fail to establish
normal rhythms in urine output. A normal day-to-night
variation in urine output may account for the poor efficacy of DDAVP in the nonresponders according to these
authors.
However, another study has shown that enuretic children needed plasma vasopressin levels that are 23 times
higher in order to maintain osmolality. These data point
to a defect at the level of the vasopressin receptor or at
the level of the signal transduction pathway (Eggert et
al., 1999). Devitt et al. (1999) have shown that enuretic
children that have either very low or very high plasma
vasopressin levels are unresponsive to DDAVP. The children with very high plasma vasopressin levels are
probably children with a nephrogenic diabetes insipidus
based on an aquaporin-2 defect, since there is linkage to
chromosome 12q. This diagnosis has been questioned
since it was discovered that nocturnal enuresis responds
to DDAVP. However, a case report has been published
on a boy with a nephrogenic diabetes insipidus based
upon a molecular-genetically confirmed mutation of the
vasopressin V2 receptor gene on chromosome q28. This
boy has nocturnal enuresis and DDAVP does not affect
urine osmolality. Although the daily intranasal application of DDAVP does not further reduce urine output, it
dramatically decreases the frequency of bed-wetting. It
has therefore been hypothesized that the target for this
DDAVP effect may be the vasopressin V1b receptor,
influencing the central regulation of bladder control.
145
In a 67-year-old patient with ShyDrager syndrome

(multisystem atrophy), nocturnal polyuria was observed,
associated with an abnormal circadian rhythm of vasopressin. The patients plasma vasopressin levels were
higher during the day than during the night (Ozawa et
al., 1993), indicating that a disorder of the SCN was later
indeed confirmed in this disease (Ozawa et al., 1998). In
order to determine whether the nocturnal decrease in vasopressin secretion into plasma found in this patient with
multisystem atrophy was a usual finding in this disorder,
Ozawa et al. (1999) determined plasma vasopressin levels
in 13 of such patients. The vasopressin levels showed
considerable variations, but were indeed lowest during
the night.
DDAVP can be effective (Mathias et al., 1986). In
patients with other causes of autonomic failure nocturnal
polyuria and overnight weight loss may also be found.
The possible mechanism for diuresis and natriuresis
induced by recumbency is not known, but may include
resistance to mineralocorticoids, inappropriate secretion
of vasopressin, increased renal perfusion from a rise in
blood pressure, and release of atrial natriuretic peptide.
DDAVP reduces nocturnal polyuria, diminishes overnight
weight loss and raises supine blood pressure (Mathias et
al., 1986). In geriatric patients the diurnal rhythm of
water excretion disappears or is reversed (Minamisawa,
1980; Chapter 4.3), and nocturia is frequent in the elderly
(Kallas et al., 1999). After a complete examination has
ruled out the most common organic and behavioral causes
of nocturia in the elderly, DDAVP may be given and
decrease night-time diuresis. Elderly patients who are
treated with DDAVP should be monitored periodically
for the development of hyponatremia and fluid overload
(Kallas et al., 1999; Weiss and Blaivas, 2000). It should
be noted that familial hypothalamic diabetes may be
mistaken for enuresis nocturna (Hansen et al., 1997).
22.5. Vasopressin hypersecretion in diabetes mellitus
Diabetes mellitus is associated with polyuria and polydipsia. In patients with diabetic ketoacidosis, plasma
osmolality and vasopressin levels are increased, circulating volume is decreased and urinary excretion of the
aquaporin-2 water channel is increased (Kusaka et al.,
2002). Polyuria persists despite markedly elevated levels
of vasopressin, due to the osmotic effect of hyperglycemia
and altered osmoregulation of vasopressin secretion and
thirst. Polyuria is classically said to be due to the osmotic
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diuresis caused by glucosuria. However, when hyperglycemia is improved by i.v. infusion of insulin and fluid,
plasma vasopressin levels decrease promptly, within 6 h,
although plasma osmolality is still high. This indicates
that both osmotic and nonosmotic stimuli are involved in
the hypersecretion of vasopressin. The nonosmotic control
of vasopressin may contribute to circulating homeostasis,
protecting against severe blood volume depletion in
diabetic patients suffering from hyperglycemia and dehydration, and in patients with diabetic coma (Walsh et al.,
1979; Ishikawa et al., 1990; Fujisawa et al., 1996). On
the other hand, vasopressin may play a critical role in
diabetic hyperfiltration and albuminuria induced by
diabetes mellitus. Vasopressin elevation is considered to
be an additional risk factor for diabetic nephropathy
(Bardoux et al., 1999). Attenuated thirst and drinking
response may be important factors in the development of
the hypernatremic dehydration, which is characteristic
of this condition (McKenna and Thompson, 1998).
Subnormal osmoregulated thirst sensation and fluid intake
could contribute to the development of hypernatremia
characteristic of hyperosmolar coma. These patients
respond to water deprivation with exaggerated secretion
of vasopressin, blunted thirst sensation and attenuated
drinking during rehydration. Reduced thirst and drinking
in association with exaggerated vasopressin release has
also been reported in aging. Therefore a premature
aging of the osmoreceptor has been proposed to exist
in those subjects who are at risk of hyperosmolar coma
(McKenna et al., 1998). The MRI signal intensity of the
posterior lobe in patients with uncontrolled non-insulindependent diabetes mellitus is lower than in healthy
controls. This is thought to be due to a decreased vasopressin content of the posterior lobe, due to persistent
hypersecretion, which accompanies the elevation of
plasma vasopressin levels. The normal hyperintense signal
reappears after diabetic control within 12 months
(Fujisawa et al., 1996; Fig. 22.8). Plasma vasopressin and
urinary excretion of aquaporin-2 are decreased to normal
levels promptly in days (Kusaka et al., 2002). During the
acute phase of ketoacidosis, cerebral complications may
develop. A lethal outcome has been reported in 6070%
of the cases and 15% survive with severe neurological
disorders. Neuroendocrine consequences are rare but
have been described. A 5-year-old child survived an
intracerebral crisis following ketoacidosis with visual
impairment due to a vascular occipital lesion. Two to
four months after the initial episode, a hypothalamopituitary disorder developed, consisting of growth hormone,
Fig. 22.8. A. The hyperintense signal in the posterior lobe is absent at

the first MRI examination of a patient with uncontrolled diabetes
mellitus. The signal-intensity ratio of the posterior lobe to the pons is
1.07. B. The hyperintense signal appears after diabetic control (arrow).
The signal intensity ratio of the posterior lobe to the pons is 1.54. (From
Fujisawa et al., 1996, Fig. 2 with permission.)
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ACTH, TSH deficiencies and central precocious puberty.

MR images showed no visible lesion in the hypothalamopituitary region (Tubiana-Rufi et al., 1992).
Both vasopressin and oxytocin are released from the
neurohypophysis in hypoglycemia. Serotonergic 5-HT3
receptors at least partly mediate the vasopressin response,
but not the oxytocin release to hypoglycemia (Volpi
et al., 1998).
It has been hypothesized that type 2 diabetes mellitus
is due to damage of the ventromedial nucleus or to a
defect of insulin or insulin receptors in the brain (Das,
2002), but evidence for this idea is lacking at present.
147
and adrenal function are normal. Plasma osmolality is

below the osmotic threshold for thirst, and drinking
is minimal. In fact, the threshold for thirst seems to be
reset to protect the lower plasma osmolality. In contrast
to the situation in nephrogenic diabetes insipidus (Chapter
22.2) total and apical membrane expression of aquaporin2 is increased (Deen et al., 2000; Ishikawa, 2000) and
this water channel is excreted in higher amounts in the
urine in cases of inappropriate secretion of vasopressin
with hyponatremia, also after acute water load (Saito
et al., 1998; 2000a; Deen et al., 2000; Ishikawa, 2000).
In this syndrome the hydro-osmotic action of vasopressin
is exaggerated more than expected from the plasma
vasopressin levels, with nonsuppressible but normal vasopressin levels, in spite of the hypo-osmotic condition
(Saito et al., 2001).
The syndrome was first described following exogenously administered pitressin (Goldstein et al., 1983;
McKenna and Thompson, 1998) and may also be due to
excessive vasopressin release from the posterior pituitary,
despite hypo-osmolality (Ishikawa et al., 1996). It should
be noted here that, in cases of nonosmotic baroreceptormediated stimulation of vasopressin release, as in the
case of pulmonary hypertension or liver cirrhosis, there
is a decrease in effective blood volume or arterial
underfilling. Therefore the enhanced vasopressin release
(Panayotacopoulou et al., 2002), lower plasma sodium
and osmolity, e.g. in congestive heart failure (Szatalowicz
et al., 1981; Rondeau et al., 1982), cannot be considered
to be inappropriate but rather as an appropriate reaction to a hemodynamic stimulus. The same holds true
for the increased excretion of aquaporin-2, indicating
increased vasopressin release in cardiac failure and liver
cirrhosis (Cadnapaphornchai and Schrier, 2000; Schrier
et al., 2001). It is thus better to exclude the diagnosis of
inappropriate secretion of antidiuretic hormone in these
conditions (Kovacs and Robertson, 1992). Also the
release of vasopressin in children with severe head injury
appeared to be appropriate in response to hypovolemia
and/or sodium administration (Simma et al., 2001).
The inappropriate vasopressin syndrome may be due
to ectopic production of vasopressin by extrahypophysial
neoplasms, e.g. by a bronchus carcinoma (Table 22.1).
Such paraneoplastic symptoms are found, in particular,
in head and neck malignancies. Most tumors of this kind
are squamous carcinomas with lower numbers of olfactory
neuroblastomas or esthesioneuroblastoma, small cell
neuroendocrine carcinomas, adenoid cystic carcinomas
and undifferentiated carcinomas (Ferlito et al., 1997;
22.6. Inappropriate secretion of vasopressin

(a) Syndrome of inappropriate secretion of antidiuretic
hormone (SchwartzBartter syndrome)
The syndrome of inappropriate secretion of antidiuretic
hormone (SchwartzBartter syndrome) is characterized
by high vasopressin levels that are nonsuppressible by
acute water load, renal sodium loss (high urine sodium
concentrations of more than 40 mmol/l), hypotonic hyponatremia (serum sodium level less than 134 mmol/l),
and by urine that is relatively or absolutely hyperosmolar
to serum. The clinical features may include confusion,
muscle cramps, seizures, fatigue, loss of appetite, nausea,
vomiting, some clouding of consciousness and coma
(Kovacs and Robertson, 1992; Saito, 2001; Milionis et al.,
2002). Electrophysiological evidence indicates that
hypoosmolality promotes epileptiform activity by
strengthening both the excitatory synaptic communication
in the neocortex and the field effects among the entire cortical population (Andrew, 1991). In 61% of patients with
central pontine myelinolysis on which autopsy was performed, hyponatremia was found (Brisman and Chutorian,
1970; Burcar et al., 1977; Apple et al., 1978; Hirshberg
and Ben-Yehuda, 1997). Indeed, rapid correction of
hyponatremia may lead to central pontine and extrapontine myelinolysis, for which alcoholism and malnutrition
are risk factors (Chan, 1997). The pathogenetic mechanism involved in this relation-ship is unknown. When
postoperative hyponatremic encephalopathy develops,
menstruant women are 25 times more likely to die or have
permanent brain damage than men or postmenopausal
women (Ayus et al., 1992).
In inappropriate vasopressin secretion, urine osmolality
is usually greater than 300 mosmol/kg, edema-forming
states or volume depletion are absent, while renal function
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TABLE 22.1.
Etiology of the syndrome of inappropriate secretion of vasopressin. In most patients the defect in urinary dilution is caused by ectopic
production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of vasopressin.
Congenital
Eutopic
Malformations
Acquired
Ectopic
Neoplasm
Drugs
Eutopic
Neoplasm
Drugs
Head trauma
Infections
Pulmonary
Neurologic
Metabolic
Agenesis corpus callosum, cleft lip and palate, other midline effects
Carcinoma of bronchus, duodenum, pancreas, prostate, ovary, bladder; thymoma, mesothelioma, sarcoma
Vasopressin, pitressin or DDAVP, oxytocin
Carcinoma of bronchus
Vincristine, carbamazepine, nicotine, phenothiazine, cyclophosphamide, tricyclic antidepressants, monoamine oxidase
inhibitors, serotonin reuptake inhibitors
Closed, penetrating
Bacterial or viral pneumonia, abscess of lung or brain, tuberculosis of lung or brain, aspergilloma, encephalitis, bacterial
or viral meningitis
Asthma, pneumothorax, positive-pressure respirator
GuillainBarr, multiple sclerosis, delirium tremens, psychosis, amyotrophic lateral sclerosis, hydrocephalus,
cerebrovascular occlusion or hemorrhage, cavernous sinus thrombosis
Acute porphyria
From Robertson, 2001, p. 688.
Mller et al., 2000b). Such tumors may also be the reason

for the high (830%) incidence of this syndrome
following neck dissection (Zacay et al., 2002). Other
neoplasmas that may produce ectopic vasopressin are, e.g.
oat cell or adenocarcinomas of the lung, lymphomas,
leukemia, Hodgkins disease, mesotheliomas, Ewing
sarcomas and esthesioneuroblastomas (Kovacs and
Robertson, 1992; Horvath et al., 1997). Moreover, brain
tumors, both primary brain tumors and metastases
(Kovacs, 1984), including a case of craniopharyngioma,
a hypothalamic glioma (Brisman and Chutorian, 1970)
and a ganglioma of the neurohypophysis, which produced
vasopressin and caused inappropriate vasopressin secretion (Fehn et al., 1998), have been described. A case of
Ratkes cleft cyst was accompanied by this syndrome
(Iwai et al., 2000).
Other diseases which may be accompanied by increased
vasopressin release include head injuries in which IL-6
may be the mediator through which the vasopressin secretion is stimulated (Gionis et al., 2003). The syndrome
is also associated with fractures in the frontotemperal
region extending to the base of the skull (Twijnstra
and Minderhoud, 1980), pneumonia, exacerbations of
multiple sclerosis, brain infarction, hematoma, traumata,
subarachnoid hemorrhage, subdural hematoma, stroke,
polyneuritis, asthma, hepatorenal syndrome (Mather
et al., 1981; Kovacs and Robertson, 1992; Pasqualetti

et al., 1998) and a case of Wernickes encephalopathy
(Haak et al., 1990; Gonzalez-Portillo et al., 1998). In
addition, a case of anterior hypothalamic infarction that
had alternating inappropriate vasopressin secretion and
diabetes insipidus has been described (Rudelli and Deck,
1979). Moreover, inappropriate antidiuretic hormone
excretion has been described in a few patients with
Whipples disease, caused by the gram-positive bacterium
Tropheryma whippelii. Evidence of hypothalamic involvement, including contrast enhancement in the mamillary
bodies, was found by CT and MRI. The patient experienced changes in sleep pattern, memory loss and other
neurological symptoms (Marinella an Chey, 1997). In
addition, this syndrome was found to accompany central
nervous system infections such as meningitis (tuberculosus, or a fungal infection such as coccidioidomycosis),
encephalitis, brain abscess and malaria (Haak et al.,
1990; Webb et al., 2002). Since interleukin-6 was found
to cause a strong elevation of plasma vasopressin levels
(Mastorakos et al., 1994), this cytokine may be one of
the mediators causing the syndrome of inappropriate vasopressin secretion during active infections or inflammatory
diseases. Hypothyroidism may lead to inappropriate vasopressin secretion according to some authors (Hanna and
Scanlon, 1977), but may be due to a direct action of
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thyroid hormones on the kidney (Sahun et al., 2001) and

should be excluded from this diagnosis by others. The
same goes for renal and adrenal insufficiency (Kovacs and
Robertson, 1992).
Inappropriate vasopressin secretion has also been
described in hydrocephalus, cerebellar and cerebral
atrophy, delirium tremens, GuillainBarr syndrome,
myocardial infarction and after medicines, e.g. following
administration of vasopressin, or of oxytocin when given
in large quantities for the induction or augmentation of
labor or following excessive self-administration via a
nasal spray by nursing mothers. The syndrome of inappropriate vasopressin secretion has been found in patients
using psychotropic drugs (Spigset and Hedenmalm, 1995)
such as chlorpropamide, carbamazepine, antipsychotics,
antidepressants, nonsteroidal antiinflammatory drugs,
acetylcholine esterase inhibitors, vincristine, vinblastine,
dopaminergic drugs, chlorothiazide, nicotine, phenothiazides, cyclophosphamide, morphine or barbiturates
(Pessin, 1972; Hamilton, 1978; Spigset and Hedenmalm,
1995; Chan, 1997; Horvath et al., 1997; Goldman, 1999),
after taking ecstacy (Henry et al., 1998) and in a case
of Wernickes encephalopathy (Haak et al., 1990).
The syndrome is also found in schizophrenic patients
(Goldman et al., 1997). In fact, polydypsia would be
present in some 20% of the chronic psychiatric inpatients
and hyponatremia in more than 10% (DeLeon, 2003). In
some of these cases, but certainly not in all, this may be
due to antipsychotic drugs (Hirshberg and Ben-Yehuda,
1997; see Chapter 27.1). In one patient with schizophrenia, hyponatremia disappeared after recovery from
psychosis by electroconvulsive therapy (Suzuki et al.,
1992), indicating that SchwartzBartter syndrome may be
due to the disease process.
The treatment of inappropriate vasopressin secretion
consists of fluid restriction, urea, furosemide, or a mineral
corticoid (Ishikawa et al., 1996; Decaux, 2001; Wong et
al., 2003). In addition, effective treatment has been
described with demeclocycline, a nonpeptide V2 vasopressin receptor antagonist or diphenylhydantoin (Kamoi
et al., 1999; Decaux, 2001; Paranjape and Thibonnier,
2001). No evidence has been found to support fluidrestriction therapy in patients with the syndrome of
inappropriate secretion of vasopressin in meningitis
(Mller et al., 2001).
A subset of psychiatric patients have a version of
altered antidiuretic hormone activity known as reset
osmostat, in which urine osmolality and sodium excretion can be suppressed, and hence appear normal, if
149
plasma osmolality is sufficiently diminished. This holds

true for enhanced vasopressin action on the kidney by
neuroleptics, but to a similar degree also for all schizophrenics or acute psychosis that enhances vasopressin
secretion as in a subset of polydipsic schizophrenic
patients who become water-intoxicated. To exclude this
variant the patient should be given an oral waterload.
Although urine osmolality and sodium concentration in
these patients are low, it is typical for reset osmostat to
be considerably higher than what one would be likely
to see with normal antidiuretic function (Goldman,
1999). Reset osmostat has also been described in a
number of patients with central nervous system midline
defects, including one with a chromosome 13 anomaly
(Gupta et al., 2000). The inappropriate vasopressin
secretion reported in acute intermittent porphyria is
thought to be due to damage to the SON and PVN
(Chapter 28.3). An unusual case of inappropriate antidiuresis in the absence of excess vasopressin due to a
nonfunctional pituitary macroadenoma has been reported
(Hung et al., 2000).
(b) Cerebral/central salt wasting
Inappropriate secretion of vasopressin is differentiated
from cerebral/central salt wasting caused by excessive
renal sodium loss which leads to a decrease in extracellular fluid volume (Kamoi et al., 1999). Also in this
syndrome, vasopressin levels are increased, despite hypoosmolality. It has been proposed that inappropriate
natriuresis is caused by natriuretic hormones such as atrial
natriuretic peptide (ANP) or by an alteration of the neural
input to the kidney (Ishikawa et al., 1996). Since mineralocorticoids might improve hyponatremia dramatically,
a disorder of the reninaldosterone system may be
involved. Hyponatremia accompanied by renal sodium
loss and volume depletion has been reported in patients
with primary cerebral tumors, carcinomatous meningitis,
subarachnoidal hemorrhage, head trauma and after
intracranial surgery or pituitary surgery. The volume
condition, which is different from the inappropriate vasopressin secretion syndrome has to be determined by
physical investigation and hematocrit (Ishikawa et al.,
1996). The treatment consists of sodium and water
replacement and a mineralocorticoid (Ishikawa et al.,
1996). It has been proposed that damage to the lamina
terminalis (Chapter 30.5) important for the interaction
between osmoreceptors and the SON and PVN may be
the cause of this disorder (Kamoi et al., 1999).
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(c) Other causes of hyponatremia

There may be various causes of hyponatremia (Robertson,
2001). Idiopathic inappropriate secretion of vasopressin
is frequently found among elderly hospitalized patients
(Goldstein et al., 1983; Chan, 1997; Miller, 1997). In
elderly people with the syndrome of inappropriate antidiuretic hormone secretion, 42% were found to be
stuporous and 10% had seizures. Sensory impairment was
mainly found in patients with sodium levels below 110
mmol/l The majority, i.e. 60% of cases, was idiopathic,
while the main causes identified were pneumonia and
medication (Hirshberg and Ben-Yehuda, 1997). It should
be mentioned that the reduced renal concentrating ability
also contributes to enhanced vasopressin secretion in
elderly people (see Chapter 8.3).
Severe hyponatremia may also occur in some patients
with Addisons disease or untreated hypopituitarism
with hypocortisolism and hypothyroidism. They have
inappropriately high vasopressin levels in relation to the
low plasma osmolality. In addition, hyponatremia not
infrequently occurs in elderly patients with secondary
adrenal insufficiency. The hyponatremia in patients with
adrenal insufficiency can be cured by corticosteroids or
corticosteroids combined with mineralocorticoids. These
hormones suppress vasopressin secretion and normalize
the elevated aquaporin-2 excretion (Ahmed et al., 1967;
Salomez-Granier et al., 1983; Oelkers, 1989; Hanna and
Scanlon, 1997; Iwasaki et al., 1997, 2001; Yatagai et al.,
2003). The synthesis of vasopressin seems thus under the
inhibitory control of adrenal corticosteroids (Ahmed et
al., 1967). And indeed, in the hypothalamus of patients
who had received corticosteroid treatment we not only
found a decreased number of CRH-expressing neurons in
the paraventricular nucleus, but also a lower vasopressin
staining in the supraoptic and paraventricular nucleus
(Erkut et al., 1998).
Hyponatremia is well recognized in primary hypothyroidism. Some 75% of the hypothyroid patients have
raised plasma vasopressin levels, which do not suppress
normally after water ingestion. The high plasma vasopressin levels in hypothyroid patients may be due to a
nonosmotic stimulus, presumably hypovolemia, resulting
in urine concentration, even when plasma osmolality is
high. Thyroid replacement will restore sodium concentrations to normal in most patients. However, in refractory or symptomatic cases, moderate fluid restriction may
enhance recovery (Hanna and Scanlon, 1997).
Hyponatremia is also found in gastrointestinal bleeding,

leading to hypovolemia with nonosmotic stimulation of
vasopressin and renal failure, partly because of the
decreased clearance of vasopressin (Cadnapaphornchai
and Schrier, 2000).
22.7. Wolframs syndrome
(a) Clinical symptoms
Wolframs syndrome (DIDMOAD: Diabetes Insipidus,
Diabetes Mellitus, Optic Atrophy and Deafness; OMIM
222300) was first described by Wolfram and Wagener
in 1938, although the association between optic atrophy
and diabetes mellitus was already known in 1858 by
the work of Albrecht von Graefe, a German ophthalmologist (Khardori et al., 1983). It is a disorder involving
the presence of vasopressin-sensitive diabetes insipidus,
juvenile-onset, insulin-dependent diabetes mellitus, slowly
progressive atrophy of the optic nerve and perceptive
hearing loss due to degeneration of the cochlear nuclei
(Khardori et al., 1983; Mtanda et al., 1986; Rando et al.,
1992); but only in 13% of cases are all four components
present (Gunn et al., 1976). Juvenile diabetes mellitus
and atrophy of the optic nerves, chiasm and tracts are the
symptoms that occur most frequently in Wolframs
syndrome (Scolding, 1996). Diabetes mellitus manifests
at a median age of 6 years, followed by optic atrophy
at 11 years. Diabetes insipidus occurs in 73% of cases,
but Gunn et al. (1976) gives much lower figures, while
nephrogenic diabetes insipidus was excluded, (Thompson
et al., 1989); deafness occurs in 62% of cases within the
second decade and renal tract abnormalities in 58% of
cases within the third decade, followed by neurological
complications in 62% of cases in the fourth decade
(Barrett et al., 1995; Barrett and Bundey, 1997; Dean
et al., 2000; Fuqua, 2000). Apart from these features, the
clinical picture is highly variable and may include
anosmia, degeneration and gliosis of olfactory bulbs and
tracts, ataxia, vertigo, dysarthria, dysphagia, nystagmus,
mental retardation, diffuse cortical atrophy, psychiatric
disorders and seizures (Marquardt and Loriaux. 1974;
Carson et al., 1977; Cremers et al., 1977; Shannon et al.,
1999; Dean et al., 2002, unpubl. res.). In addition, a focus
of MRI signal change in the right substantia nigra was
observed in a 12-year old Wolfram patient (Galluzzi
et al., 1999).
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Endocrine abnormalities may include growth retardation,

hypothyroidism, hypogonadism, amenorrhea, gynecomastia and testicular atrophy (Marquardt and Loriaux,
1974; Rando et al., 1992; Kinsley et al., 1995; Collier et
al., 1996; Barrett and Bundey, 1997). Sexual maturation
appears to be delayed in some cases. Frequent mention was
made of menstrual disorders, sometimes leading to amenorrhea. Defective fertility may occur in patients of both
sexes (Editorial, 1986; Thompson et al., 1989; Barrett et
al., 1995; Kinsley et al., 1995). According to Khardori et
al. (1983) there would be no adrenal atrophy in Wolframs
syndrome, but Marquardt and Loriaux (1974) found a
blunted cortisol response to pyrogen infusion, although
they responded normally to metyrapone and ACTH. The
hypothalamopituitary adrenal axis in Wolframs syndrome
thus needs further investigation. The course and management of the diabetes mellitus is different from that of
patients with classic type I diabetes (Kinsley et al., 1995).
Optic atrophy is probably not secondary to retinal
pathology, but part of a generalized process of neurodegeneration (Mtanda et al., 1986). Dilatation of the
efferent urinary tract, i.e. hydronephrosis, hydroureter and
atonic bladder, may also be present in Wolframs
syndrome (Cremers et al., 1977). The urinary tract abnormalities were presumed to be secondary to polyuria (Wit
et al., 1986), but degeneration of the nerves innervating
the bladder is a more likely explanation (Thompson
et al., 1989). Sixty percent of the Wolfram syndrome
patients die at age 35 (Kinsley et al., 1995) from neurological disorders and urinary tract infections.
151
mutations were found in a cohort of 19 Wolfram patients

by Hardy et al. (1999). The patients described by Rtig
et al. (1993) had pigmented retinopathy and thus probably KearsSayre syndrome (Dean et al., 2002, unpubl.
res.). The patient with mitochondrial mutations described
by Pilz et al. (1994) probably suffered from Lebers hereditary optic neuropathy (Dean et al., 2002, unpubl. res.).
The later finding that WFS1 protein (see below) is not
located on mitochondria also argues against the idea that
Wolframs syndrome would be a mitochondria-mediated
disorder (Takeda et al., 2001). Mitochondrial abnormality
may, however, be present in a minority of the Wolfram
patients (Barrett et al., 1995; Scolding et al., 1996; Rigoli
et al., 1998), be a polymorphism rather than a pathogenic
point mutation (Jackson et al., 1994), and thus a risk
factor for the disease (Hofmann et al., 1997). Barrientos
(1996a, b) suggested an opposite relationship, i.e. that
the chromosomal defect on chromosome 4p16.1 might
predispose to mitochondrial DNA deletions. This possibility remains an interesting point for future research, the
more so since a Wolfram patient has been described
with mitochondria that was morphologically abnormal
and showed a deficient glutamate metabolism (Bundey
et al., 1992).
A novel gene (WFS1) encoding a putative transmembrane protein was found on chromosome 4p16.1 (Inoue
et al., 1998). In the same year another group found the
same gene on chromosome 4p, which they called
wolframin. Wolframin codes for an 890-amino acids transmembrane protein and carries various loss-of-function
mutations in 90% of Wolfram patients (Strom et al., 1998;
Khanim et al., 2001). Mutation screening in Wolfram
families showed a series of different mutations including
stop, frameshift, deletion, nonsense and missense mutations, multiple polymorphisms and insertion mutations,
most of them located in exon 8. At present little is known
about the intracellular location of the protein or its
physiological functions (Gerbitz, 1999; Khanim et al.,
2001; Dean et al., 2002; Domnech et al., 2002). The
intracellular localization of the WFS1 protein is primarily
in the endoplasmic reticulum, suggesting a role in, e.g.
membrane trafficking or protein processing. It was
suggested that the WFS1 protein was important for the
survival of islet -cells. Indeed, missense mutations have
been found in the WFS1 gene in type 1 diabetes,
suggesting that this gene may play a role in
the development of this type of diabetes (Awata et al.,
2000). Noninactivating mutations in WFS1 do not lead
(b) Molecular genetics, differential diagnosis and

psychiatric symptoms
Wolframs syndrome is an autosomal-recessive, neurodegenerative disease, generally located on chromosome
4p16.1 (Cremers et al., 1977; Polymeropoulos et al., 1994;
Kinsley et al., 1995; Barrientos et al., 1996a, b; Hofmann
et al., 1997). However, some Wolfram patients have
linkage to chromosome 4q22-24 (El-Shanti et al., 2000).
In addition, mutations and multiple deletions of mitochondrial deoxyribonucleic acid (DNA) have been
claimed to be present in Wolfram syndrome patients,
leading to a respiratory chain defect (Rtig et al., 1993;
Hofmann et al., 1997). However, Seyrantepe et al.
(1996) found no deletion in mitochondrial DNA of nine
Wolfram patients, and neither did we in our patients (Dean
et al., 2002, unpubl. res.). No pathogenetic mitochondrial
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to Wolframs syndrome, but to low-frequency, sensorineural hearing impairment (Cryns et al., 2002; Lesperance
et al., 2003).
A new phenotypic variant has been described with
absent diabetes insipidus, presence of peptic ulcer disease
and bleeding tendency secondary to a platelet aggregation
defect. It also turned out to be a genotypic variant with
linkage to a second Wolfram syndrome locus (WFS2) on
chromosome 4q22-24 (Ajlouni et al., 2002).
The exact prevalence of Wolframs syndrome is
unknown, but probably between 1 in 100,000 (Rando et
al., 1992) and 1 in 770.000 (Barrett et al., 1995). A large
proportion of the individuals who are homozygous for
the condition suffer severe psychiatric symptoms that lead
to suicide attempts or psychiatric hospitalization (Swift
et al., 1991; Barrett et al., 1995). Of the homozygous
Wolfram syndrome patients, 60% experienced episodes
of severe depression, psychosis or organic brain
syndrome, as well as impulsive verbal and physical
aggression, and 25% had a severe mental illness (Swift
et al., 1991). Heterozygous carrier frequency is between
1 in 100 (Polymeropoulos et al., 1994) and 1 in 354
(Barrett et al., 1995). It is therefore of great interest that

there is some evidence that the heterozygous carriers of
the gene for Wolframs syndrome may have a predisposition for significant psychiatric illness that is some 26
times larger than that of noncarriers. Wolframs syndrome
was claimed to account for about 8% of all psychiatric
hospitalizations or suicides in the USA. The most prominent psychiatric manifestations are supposed to be
depression, violent or aggressive behavior, and organic
brain syndrome (Swift et al., 1990; Owen, 1998; Swift
et al., 1998). A subsequent study did not, however,
confirm those high frequencies of psychiatric illness in
heterozygous carriers (Barrett et al., 1995). A number of
linkage studies have provided evidence for the existence
of a bipolar susceptibility gene on chromosome 4p16.
However, so far no evidence has been found that polymorphisms in the Wolfram gene play an important role
in determining the susceptibility to affective illness or
schizophrenia (Evans et al., 2000b; Middle et al., 2000;
Khanim et al., 2001; Torres et al., 2001). Preliminary
evidence suggests a role for the WFS1 gene in the pathophysiology of impulsive suicide (Sequeira et al., 2003).
Fig. 22.9. Paraffin sections through the paraventricular nucleus of a Wolframs syndrome patient 94-133. (A) With the antibody III-D-7 that recognizes processed vasopressin, no immunoreactivity is found. (B) No immunoreactivity is present either with the antibody PS41 predominantly
recognizing the processed form of neurophysin (NP), but (C) many positive cells are stained with the antibody Boris Y-2, recognizing the
glycopeptide part of the VP precursor. These data indicate a processing disorder. Bar: 25 m. (From Gabrels et al., 1998a, Fig. 1 with permission.)
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not to involve an osmoreceptor defect (Thompson et al.,

1989). Older publications reported no abnormalities in
the hypothalamus of Wolfram patients (Cremers et al.,
1977; Khardori et al., 1983; Mtanda et al., 1986). While
Karp et al. (1978) had already pointed to loss of neurons
and accumulation of iron and calcium in hypothalamic
nuclei, the phenomena were not reported by others. The
SON and PVN are affected (see below), there is not only
atrophy of the optic nerve, optic chiasm and optic tracts,
but also demyelination and degeneration of the brainstem
and cerebellum (Carson et al., 1977; Scolding et al.,
1996). Degeneration has also been reported of the
olfactory bulbs and tracts, as well as loss of neurons in
the lateral geniculate nucleus, atrophy of the superior
colliculus, pons, medullary reticular activating system,
loss of fibers of the cochlear nerve, loss of neurons in
the cochlear nuclei and inferior colliculus, substantia
nigra, superior and inferior olives and cerebellum.
Swollen and dystrophic axons were found in the pons,
fornix, hippocampus and the deep cerebral white matter.
The prediction that 25% of all patients hospitalized for

depression are Wolfram heterozygotes (Swift and Swift,
2000) can now be tested by mutation screening.
(c) The hypothalamoneurohypophysial system
The differential diagnosis includes olivopontocerebellar
atrophy, multisystem atrophy, congenital rubella syndrome, Lebers hereditary optic atrophy, KearnsSayre
syndrome, and thiamine-responsive anemia with diabetes
mellitus and deafness. The association of diabetes mellitus
with optic atrophy also occurs in Friedreichs ataxia,
Refsums disease, Alstrms syndrome and Lawrence
Moon/BardetBiedl syndrome (Chapter 23.3; Dean et al.,
2002, unpubl. res.). Deafness and diabetes also occur in
the 3243 mitochondrial DNA mutation (Barrett and
Bundey, 1997).
The use of three dynamic stimuli, i.e. an osmotic stimulus, hypoglycemia and a baroregulator stimulus, showed
the diabetes insipidus to be of hypothalamic origin and
Fig. 22.10. Quantification of the total number of vasopressinergic neurons as stained by the anti-glycopeptide antibody Boris-Y-2 and compared
with antivasopressin of controls as stained by Truus 18-9-85 (see Swaab et al., 1995a) showed a normal total number of vasopressin neurons
in the PVN of the Wolframs syndrome patient 94-133, and a modest decrease in the number of neurons staining for oxytocin (OXT). (From
J.S. Purba and D.F. Swaab, unpubl. observations.)
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Fig. 22.11. (a) A control case, (95-33, with very long postmortem delay of 6 days stained with antibody 748 (anti-growth hormone releasing
hormone (GHRH)) in the infundibular nucleus. (b) The same case as (a), shown at lower magnification. (c) A Wolfram case, 94-133, with a postmortem delay of 6 days. (d) The same case as (a), shown at lower magnification. Note the lower number of neurons expressing GHRH in this
case of Wolframs syndrome. In another case of Wolframs syndrome (95-68), no GHRH staining at all was found in the infundibular nucleus.
Scale bar = 50 m. (From A. Salehi and D.F. Swaab, unpublished results.)
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The latter changes were sufficient to cause a changed

MRI signal intensity on MR images of the area around
the ventricles (Shannon et al., 1999). MRI can also show
atrophy of the optic nerves, hypothalamus, including the
unusually wide third ventricle, brainstem, cerebellum and
cerebellar hemispheres (Scolding et al., 1996; Gens et
al., 1997; Dean et al., 2003, in prep.). The posterior lobe
of the pituitary is largely absent (Carson et al., 1977).
The absence of a high-intensity MRI signal in the region
of the posterior pituitary that normally gives rise to a
posterior lobe bright spot is in agreement with the degeneration of the hypothalamoneurohypophysial system, but
has also been described with various other causes of
hypothalamic diabetes insipidus (Rando et al., 1992; Dean
et al., 2002, unpubl. res.; see Chapter 22.2). We performed
immunocytochemistry in three cases of Wolframs
syndrome (Dean et al., unpubl. res.). In the two Wolfram
patients with diabetes insipidus (94-133 and 96-46) we
found that the SON contained hardly any neurosecretory
neurons, using thionine staining, and no neurons that
stained processed vasopressin. There was, moreover, a
strong gliosis present in the SON as stained by GFAP.
The PVN did not contain processed vasopressin or neurophysin-expressing neurons either (Fig. 22.9). However,
using a potent antibody against the vasopressin precursor
(antiglycopeptide 22-39 Boris Y-2; Friedmann et al.,
1994), a normal number of vasopressinergic neurons was
present in the PVN (Figs. 22.9, 22.10), although the cells
were clearly too small (Fig. 22.9). No vasopressinergic
neurons were found in the SON with Boris Y-2. Only a
partial loss of oxytocin neurons was found in the PVN.
In one Wolfram patient, who had a mild form of diabetes
insipidus (95-68), there was only a partial absence of
processed vasopressin, while no gliosis was present in
the SON of this patient. It seems thus that in these patients
with diabetes insipidus, there is no global loss of vasopressin neurons in the PVN as has been presumed
155
(Thompson et al., 1989), while neuronal loss seems to

take place in the SON. Degeneration was thus more severe
in the SON than in the PVN, in contrast with the report
by Carson et al. (1977). On the other hand, Shannon et
al. (1999) found severe loss of the magnocellular neurons
in the SON and PVN and no immunoreactivity for vasopressin in a female Wolfram patient of 38 years of age.
The conclusion of our own observations on three cases
was that the vasopressin neurons were present in the PVN
in these Wolframs syndrome cases, but did not produce
processed vasopressin, possibly due to a deficiency in
processing of the precursor with later superadded neuronal
loss. In the two Wolfram patients who did not have vasopressin staining, there was indeed also an absence of
protein convertase (PC)-2 and the molecular chaperone
7B2, strongly suggesting the presence of a processing
disturbance of the vasopressin precursor (Gabrels et al.,
1998a; Dean et al., unpubl. res.). The anterior commissure showed gliosis, loss of axons and scattered mineral
concretions.
In addition, in two Wolfram cases (94-133 and 95-68),
no or only a few growth-hormone-releasing hormone
(GHRH)-expressing neurons were observed in the
infundibular nucleus (A. Salehi, unpublished results; Fig.
22.11). Indeed, one case of a Wolframs syndrome patient
has been described with a disturbance in the growth
hormone axis (Hofmann, 1997). Growth hormone
responded normally to AVP and insulin but also failed
to respond to an infusion of pseudomonas polysaccharide
complex (Marquardt and Loriaux, 1974). This neuroendocrine axis should thus be studied further in Wolframs
syndrome. The determinations of 1-44 GHRH in venous
plasma of Wolfram patients as an indicator of hypothalamic GHRH release may be an interesting procedure for
estimating the central disturbance of this neuroendocrine
axis (Kimber et al., 1997).
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CHAPTER 23
Eating disorders (Fig. 23A)
Oh Lord, make my words sweet and appetizing. Tomorrow

I may have to eat them (Prof. Head, 1959, cited by G.W.
Bruyn, 1997).
Obesity is one of the most pressing health problems in

the Western world. It is, among other things, responsible
for 6575% of essential hypertension, diabetes mellitus
and cardiovascular problems (Hall et al., 2001). This
epidemic is in need of therapeutics, but only limited
progress has been made as far as the pharmacotherapy
of this condition is concerned (Van der Ploeg, 2000;
Clapham et al., 2001). The etiologies of eating disorders
such as anorexia nervosa, bulimia nervosa (Chapter 23.2)
and obesity are poorly understood. Inherited vulnerabilities, cultural pressures and adverse individual and family
experiences are presumed to have a part in the pathogenetic mechanisms (Walsh and Devlin, 1998; Polivy and
Herman, 2002), while biological factors have only
recently become the subject of studies (Fig. 23.1).
Some clinical observations illustrate the importance
of hypothalamic mechanisms for governing satiety and
hunger (Lustig et al., 1999). Lesions in the ventromedial
hypothalamic area cause increased appetite (Chapter
26.3) and obesity (Fig. 19.13), whereas lesions in the
lateral hypothalamic area (LHA) may cause anorexia
(Chapter 14).
Uncommon, intractable hypothalamic obesity syndrome
occurs after cranial insults. It is often coupled with other
hypothalamopituitary disturbances that may exacerbate
the obesity, such as growth hormone deficiency or
hypothyroidism, but the obesity remains after hormone
replacement. Neurocystiscerosis in the anterior hypothalamus, an infection caused by the presence of Taenia larvae, was accompanied by obesitas and hyperphagia (Lino
et al., 2000). Satiation produces significant decreases in
bloodflow in the hypothalamus of obese women (Gautier
et al., 2001). Using a new temporal clustering technique
for focal MRI (fMRI), Liu et al. (2000) observed two
eating-related peaks in neural activity at two different
Fig. 23A. Museo del Prado, Madrid. JuanCarro de Miranda, Eugenia

Martinez Vallejo, La Monstrua Desnuda, 1680 (Catalogue no. 2800)
Sanz Vega 3079.
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Fig. 23.1. Central and peripheral pathways involved in the regulation of food intake and energy stores. Leptin is secreted by adipose tissue and
circulates to the brain, where it crosses the bloodbrain barrier to reach the arcuate nucleus (ARC) within the hypothalamus. Here, a cascade is
initiated that ultimately regulates feeding behavior, various endocrine systems and other functions. Leptin directly affects neurons (so-called firstorder neurons), in which either the anorexigenic peptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)
or the orexigenic peptides neuropeptide-Y (NPY) and agouti-related protein (AGRP) are colocalized. The POMCCART- and NPYAGRPcontaining neurons, which are regulated in an opposing manner by leptin, project further to other brain centers. These include the ventro- and
dorsomedial hypothalamus (VMH, DMH), which also express NPY, the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA),
which express the neuropeptides orexin (ORX) and melanin-concentrating hormone (MCH). The LHA and other brain areas communicate with
the cerebral cortex, where feeding behavior is finally coordinated. During and after a meal, various signals are generated in the periphery, which
include taste signals from the oral cavity, gastric distention and humoral signals (e.g. cholecystokinin) from secretory cells of the gastrointestinal
tract. These afferent signals are transmitted mainly by the vagus nerve, but also by the sympathetic nervous system to the hindbrain, particularly
the nucleus of the solitary tract (NTS). This brain region communicates with higher brain areas such as the hypothalamus and the cerebral cortex.
(From Chiesi et al., 2001, Fig. 1 with permission.)
times with distinct localization, i.e. in the upper-anterior

and medial region of the hypothalamus. However, these
areas cannot be linked at present to the microscopic or
chemical anatomy of the hypothalamus, although there
was a dynamic interaction between these fMRI responses

and plasma insulin levels.
Eating disorders may accompany many diseases.
Progressive wasting is a common occurrence in many
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types of cancer, acquired-immunodeficiency syndrome

(AIDS) and other infectious diseases, cardiovascular
disease and rheumatoid arthritis. The cachexia-anorexia
syndrome is one of the main factors that lead to death
and is thought to be due to cytokine stimulation of anorexigenic neuropeptides in the hypothalamus (Inui, 1999;
Plata-Salamn, 2000). Some 50% of the patients with
hypothalamic amenorrhea (Chapter 24.1a) have an eating
disorder (Perkins et al., 2001). Eating disorders, either
leading to obesity or to underweight, are associated with
a number of genetic and epigenetic factors (Chapter 23d,
e) and frequently occur in adults with an intellectual
disability (Gravestock, 2000; Chapters 26.5, 23.1, 23.3).
In addition, cultural influences are considered by some
authors to be of crucial importance, as illustrated by
historical and cultural differences (Bemporad, 1997).
Although a large number of brain areas other than the
hypothalamus form a complex network reacting to hunger
and satiety (Del Parigi et al., 2002), these areas will not
be systematically dealt with in this monograph. Indeed,
hunger in normal volunteers is associated with an
increased cerebral blood flow not only in the hypothalamus, but also in the insular cortex, orbitofrontal cortex,
cingulate cortex and parahippocampal and hippocampal
formation, thalamus, caudate, precuneus, putamen and
cerebellum. In addition, satiation was associated with
changes in blood flow in the ventromedial prefrontal
cortex, dorsolateral prefrontal cortex, thalamus, amygdala,
cingulate cortex, insular cortex, parahippocampal gyrus,
temporal cortex, cerebellum and inferior parietal lobule
(Rolls, 1984; Tataranni et al., 1999; Gautier et al., 2001).
The larger number of brain structures involved in eating
disorders in adolescence may be associated with an
elevated risk of developing a broad range of physical
and mental health problems. Adolescents with eating
disorders run a substantially elevated risk of anxiety disorders, cardiovascular symptoms, chronic fatigue, chronic
pain, depressive disorders, limitations in activities due to
poor health, infectious diseases, insomnia, neurological
symptoms and suicide attempts (Johnson et al., 2002).
An interesting example of a nonhypothalamic eating
disorder is the Gourmand syndrome, characterized by
a preoccupation with food and a preference for fine eating,
generally due to lesions involving the right anterior
cerebral hemisphere (Regard and Landis, 1997).
It should be noted that central neural mechanisms and
autonomic system function occur in parallel. Sympathetic
nervous system activation has a general inhibitory effect
on gastrointestinal function, reducing intestinal motility
159
and gastric emptying. It also plays a major role in the

control of lipolysis in adipose tissue, both directly and
due to effects on pancreatic hormone secretion (Snitker
et al., 2000). Animal experiments using immunocytochemistry denervations and retrograde transsynaptic
tracers have demonstrated parasympathetic and sympathetic control of, e.g. the pancreas by the paraventricular
nucleus (PVN) and other hypothalamic centers involved
in the regulation of food intake (Buijs et al., 2001). Diet
is a potent regulator of adaptive thermogenesis. Starvation
can decrease resting metabolic rate by 40%, while feeding
acutely increases metabolic rate. Activation of the satiety
systems decrease food intake and increase sympathetic
nervous system outflow, leading to catabolic effects,
whereas activation of the hunger systems increases food
intake and parasympathetic nervous outflow, leading to
anabolic effects (Nonogaki, 1999). Depression of the
sympathetic and parasympathetic system is associated
with increasing percentages of body fat (Peterson et al.,
1988). Recent animal experimental work has revealed that
the autonomic innervations of fat tissue consist not only
of the sympathetic system, known for its catabolic effect,
but also of a parasympathetic anabolic input. In addition,
the observed somatotopic organization of the subcutaneous versus intraabdominal fat has provided an excellent
explanation for the dissociation in distribution of these
two fat compartments, e.g. in the metabolic syndrome, in
Cushings syndrome and in AIDS lipodystrophy (Kreier
et al., 2002).
An important matter is eating, because it brings together
those that are apart.
Talmoed Bawli
(a) Hypothalamic nuclei involved

Classically, lesions in the ventromedial nucleus (VMN;
Chapter 26.3) are thought to cause avaricious appetite
(Haugh and Markesbery, 1983), whereas lesions in the
LHA (Chapter 14) are thought to cause anorexia (Chapter
14). However, lesions that are precisely restricted to the
rat VMN do not cause hypothalamic obesity, and it has
been proposed that the observed obesity is largely due to
damage of the nearby aminergic medial forebrain bundle,
rather than to a particular nucleus such as the VMN itself
(Gold 1973; Chapter 9). On the other hand, for the
feeding-suppressing action of histamine, the VMN
appears to be the most important site of action (Brown
et al., 2001). Moreover, the presence of hypocretin
(orexin) neurons in the lateral hypothalamus, and in
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particular in the perifornical region, has brought this structure back into focus with regard to eating regulation
(Sakurai et al., 1998; Chapter 14). Recent neurobiological research has revealed a great number of different
hypothalamic neuronal systems, such as neuropeptide-Y
(NPY), and fibers innervating the hypothalamus such as
the aminergic systems, which are involved in the physiology and pathology of food intake. This points to
extensive circuits and networks involved in eating
behavior, rather than one particular nucleus, such as the
VMN or LHA, as the responsible center (Flynn et al.,
1988; Kalra et al., 1999; Chapter 26.3; Fig. 23.1).
One of the most potent stimulants of food intake, NPY,
a 36-amino acid member of the pancreatic polypeptide
family, is produced in the infundibular nucleus (= arcuate
nucleus in rodents; see Chapter 11). The letter Y refers
to two tyrosine residues, which occur at both ends of the
molecule (Tomaszuk et al., 1996). In the human hypothalamus, moderate amounts of NPY messenger RNA
(mRNA) were found not only in the infundibular nucleus
but also in the PVN (Jacques et al., 1996). Injections of
NPY directly into the PVN elicit a dose-dependent
increase in feeding (Stanley et al., 1984). Animal experimental evidence clearly shows that upregulation
of NPY and increased receptor availability underlie hyperphagia (Kalra et al., 1999). It is proposed that there
is altered processing of NPY in mice with the recessive
anorexia mutation (anx), which causes decreased
food intake and starvation, which lead to death at 22 days
after birth (Broberger et al., 1997). For other feeding
regulating peptides in the infundibular nucleus, see
Chapter 23c.
The highest concentration of NPY in the human hypothalamus is found in the infundibular nucleus and in the
VMN (Corder et al., 1990). NPY specifically enables the
ingestion of carbohydrates and would have little or no
impact on the consumption of fat or protein (Leibowitz,
1992). NPY neurons project to the rat PVN on galanin
neurons (Horvath et al., 1996) and corticotropin-releasing
hormone (CRH) neurons (Li et al., 2000), which are both
involved in the regulation of ingestive behavior. In addition, NPY fibers innervate thyrotropin-releasing hormone
(TRH) neurons (Mihaly et al., 2000). In the monkey PVN,
NPY-containing terminals are found on cocaine- and
amphetamine-regulated transcript (CART)-producing
neurons (see below) (Dall Vechia et al., 2000).
The PVN is a major appetite-regulating center in which
oxytocin, CRH and galanin neurons, and NPY, noradrenaline, dopamine and serotonin terminals meet. It is,
moreover, presumed that NPY serves as a messenger

between the neuronal processes that regulate reproduction and those that maintain energy homeostasis, and may
thus be a key molecule in the nutritional infertility seen
in anorexia (Kalra and Kalra, 1996; see Chapter 23.2).
In addition, NPY is one of the strongest genetic factors
identified that affect serum cholesterol levels (Uusitupa
et al., 1998). Not only the PVN but also the perifornical
area is a major focus of NPY effects on feeding behavior
(Stanley et al., 1993). The activity of NPY and its receptors fluctuate over the course of the day (Leibowitz, 1992).
It has been hypothesized that a defective inhibition of the
NPY neuron that colocalizes agouti-related protein
(AGRP) (see below) would result in reduced energy
expenditure, disturbances of glucose and lipid metabolism, and obesity (Morton and Schwartz, 2001). Our
research showed the opposite. The infundibular NPY
content is decreased in PraderWilli patients and nonsyndromal obesity (Goldstone et al., 2002; Fig. 23.8).
Surprisingly, the absence of NPY in mice fails to alter
their feeding pattern or body weight. Because a deficiency
of even a single component of the pathway that limits
food intake (such as leptin or the melanocortin (MC)-4
receptor; see above) can result in obesity, it has been
suggested that anorexigenic signals are more redundant
than those limiting food intake, and that NPY is not the
only factor responsible for normal feeding and leptin
response (Woods and Stock, 1996; Shimada et al., 1998;
see below). NPY effects are mediated by a family of
receptor subtypes Y1-5 and there is strong evidence
for the occurrence of additional receptor subtypes.
Inactivation of the Y2 receptor in mice caused increased
body weight, food intake, fat deposition and an attenuated response to leptin (Naveilhan et al., 1999). The Y4
and Y5 receptors have been cloned and expressed. The
Y5 receptor has been suggested to be the Y1-like receptor
in feeding (Gerald et al., 1996; Balasubramaniam, 1997).
However, Y5 receptor knock-out mice developed only
mild late-onset obesity, so it does not seem to be the
most critical feeding receptor in mice (Marsh et al., 1998).
The Y5 receptor has also been designated as Y2b, and
the confusion increased with the concurrent publication
of a different Y receptor that was also called Y5. Y5
mRNA levels are high in the human hypothalamus, while
conventional radio ligand techniques do not detect Y5like binding sites (Statnick et al., 1998). Following the
International Union of Pharmacology (IUPHAR) recommendations, the Y receptor that has been referred to as
both Y5 and Y2b has been designated Y6. The message
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for Y6 is present in the human brain and absent in rat

tissue. However, the human Y6 gene appears to contain
a frame-shift mutation followed by a stop codon, truncating the receptor at the sixth transmembrane domain,
probably rendering the receptor inactive in all primates
tested so far (Burkhoff et al., 1998). Throughout the
human hypothalamus, 25 times more Y1 binding sites
than Y2 binding sites were found. The number of binding
sites was moderate to low. This is rather surprising, as
the hypothalamus is highly enriched in both NPY cell
bodies and fibers. Perhaps other receptor subtypes will
ultimately appear to be present in higher amounts (Jacques
et al., 1997). Dumont et al. (1998, 2000) found a relative paucity of both Y1 and Y5 receptors in the human
brain, except for the dentate gyrus of the hippocampus
and the bed nucleus of the stria terminalis, where significant amounts of Y1-like and Y2-like receptors were
observed. Moderate levels of Y2/Y5 binding sites were
reported in the human PVN and dorsomedial nucleus
(Dumont et al., 2000). The NPY-Y5 receptor gene was
found to be expressed in the infundibular nucleus, PVN,
VMN and posterior hypothalamus (Jacques et al., 1998).
The suprachiasmatic nucleus (SCN; see Chapter 4) is
responsible for the circadian pattern in feeding behavior
(Bernardis and Bellinger, 1996). Animal experiments
indicate that the neurons of the SCN are involved in the
circadian control of the autonomous nervous system and
thus in the circadian regulation of glucose metabolism.
The SCN may exert these functions by influencing the
function of the PVN and dorsomedial nucleus (DMN;
Nagai et al., 1996) and other hypothalamic nuclei that
project to the parasympathetic dorsal motor nucleus of
the vagus or the sympathetic preganglionic spinal cord
neurons that innervate, e.g. the pancreas (Buijs et al.,
2001). The nucleus basalis of Meynert (NBM) contains
feeding cells, and stimulation of this area can mimic the
reward value of food (Rolls, 1984).
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(Satoh et al., 1997), possibly by decreasing the production of NPY in the arcuate nucleus (Stephens et al., 1995),
although activation of the alternative pathways should
also be considered (Eriksson et al., 1996). Plasma leptin
levels are significantly higher in obese subjects and
PraderWilli patients. These elevations are proportional
to the increased body-mass index (Carlson et al., 1999),
suggesting that some obese humans are resistant to leptin.
Either leptin deficiency or leptin resistance can cause
severe obesity in mice (Schwartz and Seely, 1997). Leptin
crosses the bloodbrain barrier by a saturable, receptormediated transport system (Couce et al., 1997). However,
it should be noted that the arcuate nucleus is presumed
to be situated outside the bloodbrain barrier. In the
arcuate nucleus of the rat, leptin binding increases twofold
after a 2-day fast (Baskin et al., 1999). Cerebrospinal
fluid (CSF) leptin concentrations in children reflect
plasma leptin concentrations, including the rise in leptin
levels during the advent of sexual dimorphism at puberty.
Only free leptin is detectable in CSF (Landt et al., 2000).
Arcuate nucleus NPY neurons and pro-opiomelanocortin
(POMC) neurons are principal sites of leptin-receptor
expression. Leptin increases the electrical activity of the
anorexic POMC neurons, while melanocortin has an
autoinhibitory effect on this circuit (Cowley et al., 2001).
In addition, leptin may not only act on the arcuate nucleus.
In obese rats the strongest leptin response was found in
the PVN (Woods and Stock, 1996). Electrophysiological
studies on rat PVN slices suggest that leptin acts as a
satiety signal to inhibit feeding as a result of its ability
to influence the excitability of PVN neurons (Smith
et al., 1998). Leptin activates CART neurons, which
mostly also contain POMC. Elmquist et al. (1997) found
activation as a result of leptin administration not only in
the PVN, but also in the VMN, DMN and ventral
premamillary nuclei. Leptin may also act via the tuberomamillary histaminergic neurons on feeding behavior
(Yoshimatsu et al., 1999). Experiments in rat indicate
that leptin decreases food intake induced by melaninconcentrating hormone (MCH), galanin or NPY (Sahu,
1998), suggesting that modulation of the postsynaptic
actions of these peptides is one of the mechanisms of
action of leptin. The circadian fluctuations in leptin
(Mantzoros, 2000) indicate a role of the suprachiasmatic
nucleus.
The possibility that leptin is produced not only by fat
cells, but also in the brain, should certainly not be
excluded (Reichlin, 1999). Leptin concentrations in the
internal jugular vein are significantly higher than arterial
(b) Leptin
Leptin (from the Greek word leptos = thin), a satiety
factor that is produced by fat cells, has a potent influence on central mechanisms of food intake and is an
essential chain in circuits that act as an adipostat. Leptin
is the product of the LEP gene (Zhang et al., 1994; Halaas
et al., 1995; Clapham et al., 2001). It informs the brain
about the size of the body fat depots by receptors that
are present in the arcuate nucleus. It reduces food intake
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levels in lean females and in obese (but not in lean) men

(Wiesner et al., 1999). Indeed, leptin mRNA was found
to be present in the rat hypothalamus and other brain
regions. Since leptin mRNA expression in the brain is
suppressed by fasting, a role for brain leptin in the central
regulation of appetite is suggested (Morash et al., 1999).
The leptin receptor occurs in at least five forms as a
result of alternative splicing. It is the long form that is
the most important for the regulation of the energy balance
(Clapham et al., 2001). In the rat brain the leptin receptor
is located in the arcuate nucleus, PVN, VMN and lateral
hypothalamic area. In addition, the olfactory bulb,
neocortex, cerebellar cortex, dorsal raphe nucleus, inferior olive, nucleus of the solitary tract, and the dorsal
motor nucleus of the vagus nerve also show immunoreactivity. Western blotting yields the expected 120-kDa
major band (Shioda et al., 1998). An immunocytochemical study of the human hypothalamus has shown
leptin-receptor staining in a number of human hypothalamic nuclei, i.e. the arcuate nucleus, SCN, mamillary
nucleus, PVN, DMN, supraoptic nucleus (SON), posterior nucleus, and the NBM. Moreover, the leptin-receptor
is found in extrahypothalamic sites such as the inferior
olivary nucleus and cerebellar Purkinje cells (Couce et
al., 1997; Burguera et al., 2000), as well as in the choroid
plexus, ependymal lining and small vessels wall. It was
hypothesized that leptin may cross the bloodbrain barrier
in this way (Couce et al., 1997). Indeed, high-affinity
transport systems mediating leptin uptake were found in
the rat hypothalamus and across the bloodCSF barrier.
High-affinity binding of leptin was also detected in the
choroid plexus. In contrast, low-affinity carriers for leptin
were found at the bloodbrain barrier outside the hypothalamus (Zlokovic et al., 2000). The gene for the leptin
receptor is mutated in fatty (fa/fa) rats and diabetic (db/db)
mice (Clapham et al., 2001).
The hormonal message of plasma leptin is transduced
by the NPY neurons of the arcuate nucleus, e.g. to CRH,
TRH and luteinizing hormone-releasing hormone (LHRH)
neurons, as shown in animal experiments. The latter
finding is a possible basis for coupling of the energy imbalance with menstrual irregularity and infertility (Costa
et al., 1997b; Gehlert and Heiman, 1997; see Chapter
23.2). Indeed, low leptin synthesis appeared to be associated with amenorrhea in underweight females. Apparently
a critical leptin level is needed, not only to trigger the
menarche (Matkovic et al., 1997), but also to maintain
menstruation (Kpp et al., 1997). Moreover, a rise of
endogenous circulating leptin concentrations precedes the
onset of puberty in humans (Mantzoros et al., 1997).

Information about the energy balance that is fed back to
the TRH and CRH neurons of the PVN determines consequent effects in thermogenesis and stress reactions.
Very high serum leptin levels beyond the expected
levels for body mass index are found in idiopathic
intracranial hypertension, a neurological disorder mainly
affecting obese females, and after hypothalamic surgery,
i.e. after craniopharyngeal removal (Lampl et al., 2002).
(c) Neuropeptides and hormones involved
The effects of leptin (Chapter 23b) and NPY (see Chapter
23a; Table 23.1) on appetite have been discussed previously. The peptide alpha-melanotropin (-MSH) is a
POMC-derived peptide (Fig. 23.2) that is produced in the
infundibular nucleus (Mihaly et al., 2000) and inhibits
feeding behavior by acting on the MC-4 receptor.
Opiates such as dynorphin and endorphin stimulate
food intake (Williams et al., 1991; Rohner-Jeanrenaud,
1995; Bernardis and Bellinger, 1996; Tritos et al., 1998b;
Lustig et al., 1999; Taylor, 1999; Stving et al., 2002).
A mouse knock-out for POMC developed hyperphagia
and obesity, defective adrenal development and altered
pigmentation (Barsh, 1999; Yaswen et al., 1999).
Moreover, MSH/ACTH 4-10, the core sequence of
all melanocortins, administrated intranasally to human
subjects, reduces body fat, plasma leptin and insulin levels
(Fehm et al., 2001). It may be of relevance to weight
changes after the age of 50 years that the POMC gene
expression is decreased in the infundibular nucleus of postmenopausal women (Abel and Rance, 1999). Inactivation
of this receptor by gene targeting results in mice that
develop a maturity onset obesity syndrome associated
with hyperphagia, hyperinsulinemia and hyperglycemia.
This syndrome recapitulates several of the characteristic
features of the agouti obesity syndrome as discussed
below (Huszar et al., 1997). In humans, mutations of the
G-protein-coupled MC-4 receptor gene are the cause of
obesity in some 5% of the subjects. Mutation carriers
have severe obesity, increased lean mass, increased linear
growth, hyperphagia, and severe hyperinsulinaemia.
Homozygotes are more affected than heterozygotes. The
major phenotype of MC4R mutations is binge-eating
(Vaisse et al., 1998; Yeo et al., 1998; Gu et al., 1999;
Hinney et al., 1999; Jacobson et al., 2002; Branson et al.,
2003; Farooqi et al., 2003). Multiple molecular mechanisms are involved in the disruption of MC4 receptor
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TABLE 23.1
Food consumption-regulating neuroactive compounds in the hypothalamus.
Localization cell bodies
Effect on food consumption
Alpha melanotropin (-MSH)

Agouti-related protein (AGRP)
Cocaine and amphetamine-regulated
transcript (CART)
Corticotropin (CRH), Urocortin
Dopamine
Dynorphin
Endorphins
Galanin
Ghrelin
Growth hormone releasing hormone (GHRH)
Histamine
Hypocretin 1 and 2 (or orexin A and B)
Leptin
Melanin-concentrating hormone (MCH)
Infundibular nucleus (Fig. 23.2)

Infundibular nucleus; coexpression in NPY neurons
Infundibular nucleus and many other hypothalamic
nuclei
Ventral tegmentum
Tuberal and caudal hypothalamus (Fig. 31.2)
Many hypothalamic nuclei
Arcuate nucleus
Tuberomamillary nucleus
Lateral hypothalamus and perifornical area
Fat tissue
Lateral, posterior hypothalamus and a number
of other hypothalamic areas
Locus coeruleus
Raphe nuclei
Periventricular nucleus
Noradrenaline
Neuropeptide-Y (NPY)
Oxytocin
Serotonin (5-HT)
Somatostatin
Active compound
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NPY neurons (Mihaly et al., 2000). Fasting increases

AGRP mRNA (Hahn et al., 1998a) and overexpression
of AGRP leads to obesity (Rossi et al., 1998b). In addition, agouti-related peptides, when administered centrally,
induce hyperphagia (Rossi et al., 1998b). In PraderWilli
syndrome (PWS) (Chapter 23.1) and nonsyndromic obese
patients, we did not find a significant change in AGRP
staining in the infundibular nucleus (Goldstone et al.,
2002, see Chapter 23.2; Fig. 23.8). Three single nucleotide
polymorphisms (SNPs) have been identified in the coding
region of the human AGRP. Two of these SNPs were
associated with susceptibility for anorexia nervosa (Vink
et al., 2001b).
Hypocretins 1 and 2, also known as orexins A and B,
a pair of hypothalamic peptides, also act on G-proteincoupled orexin 1 and 2 receptors (Kunii et al., 1999). The
peptides were called hypocretins because they were
produced in the hypothalamus and resembled the secretin
neuropeptides that help regulate gut function (Samson and
Resch, 2000). The word orexis means appetite. Orexin
A and B cell bodies are located in and around the lateral
and posterior hypothalamus and in the perifornical area
(Peyron et al., 2000; Chapter 14). These peptides stimulate food consumption and influence metabolic rate and
function by mutations, such as impaired cell surface

expression on reduced binding of the ligand (Yeo et al.,
2003). Injection of an MC-4 receptor agonist inhibits and
injection of an MC-4 receptor antagonist stimulates
feeding when injected directly into the rat PVN, where
the expression of this receptor is very high (Giraudo et
al., 1998). Observations in rat indicate that the satiety
effect of leptin is mediated by stimulation of the hypothalamic POMC system.
Agouti regulates hair color and body weight and acts
as a high-affinity, natural antagonist of the MC-1, MC-3
and MC-4 receptors (Rossi et al., 1998b). Mutations in
the agouti coat color gene cause obesity in mice (Fan et
al., 1997; Huszar et al., 1997; Schith et al., 1997; Barsh,
1999; Nagle et al., 1999). Mutations within the mahogany
locus suppress obesity of the agouti-lethal yellow mutant
mouse, but do not suppress the obese phenotype of the
MC-4 receptor null allele. The mahogany gene is
expressed in the ventromedial nucleus and mahogany can
suppress diet-induced obesity. The amino acid sequence
of mahogany protein suggests that it is a large, single
transmembrane-domain receptor-like molecule with a
short cytoplasmatic tail. There is an AGRP that is an
endogenous MC receptor antagonist that coexpresses in
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Fig. 23.2. The protein sequence of the pro-opiomelanocortin (POMC)-derived peptides is shown to illustrate the composition of the single peptides,
their position within the precursor POMC and their endoproteolytic cleavage. The first residues containing the signal peptide were given negative
numbers. Residues in dark gray represent the paired basic sites that serve as targets for PC1 and PC2; black arrows indicate preferential cleavage
by PC1; white arrows indicate preferential cleavage by PC2. The interaction of each peptide with the two sets of receptors and the functional roles,
where known, are shown. Note the exclusive binding of the MC2-R by corticotropin (ACTH) and the restricted affinity of gamma-melanotropin
(-MSH) to the MC3-R. Because the physiological role of -MSH is not clear, the affinities to the different MC receptors are not included.
Residues in light gray represent the binding cores of each peptide. MCR, melanocortin receptor; PC, prohormone convertase. (From Krude and
Grters, 2000, Fig. 1 with permission.)
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arousal. Prepro-orexin mRNA is upregulated after fasting

(Sakurai et al., 1998) and genetic ablation of orexin
neurons in mice results in obesity (Hara et al., 2001),
orexin may act as MC-4 receptor agonists and may also
be involved in autonomic and neuroendocrine regulation
(Samson and Resch, 2000). Recently it was found that a
mutation in the hypocretin (orexin) receptor 2 gene or a
disappearance of the hypocretin system is responsible for
narcolepsia (Lin et al., 1999; Peyron et al., 2000; Samson
and Resch, 2000; Hara et al., 2001; Chapter 28.4). It is
interesting though that narcolepsy patients have serum
levels of leptin that are more than 50% reduced, pointing
to the presence of an alteration in the regulation of food
intake and metabolism in this disorder (Schuld et al.,
2000).
Yet another factor that influences eating behavior is
galanin. It stimulates food consumption, preferentially
increasing the ingestion of fat and leaving the uptake of
carbohydrate and protein unaffected (Leibowitz, 1992;
Akabayashi et al., 1994). Galanin is overexpressed in the
PVN and median eminence of the obese Zucker rat (Beck
et al., 1993), which has no functional leptin receptor. This
peptide is present in the arcuate nucleus, SCN, sexually
dimorphic nucleus, PVN and tuberomamillary (TMN)
and supramamillary nuclei. In the human SON and SCN,
as well as in the PVN, galanin is colocalized with vasopressin, oxytocin or tyrosine hydroxylase (Gai et al.,
1990). From experimental studies in rat, it appears that
only the anterior parvocellular, galanin-containing PVN
neurons are involved in the metabolic and behavioral
processes of fat metabolism and ingestion (Wang et al.,
1998). In early postnatally overfed rats, excess weight
and hyperinsulinemia have been observed, accompanied
by an increased number of galanin-positive neurons in
the PVN at weaning. The galanin neurons in the PVN
may thus be involved where perinatal overfeeding is a
risk factor for excess weight and diabetes during life
(Plagemann et al., 1999).
Oxytocin release accompanies treatments known to
inhibit food intake (Verbalis et al., 1995), and oxytocin
neurons of the PVN are considered to be satiety cells (see
Chapter 23.1), probably acting by their projections to the
brainstem nuclei (Buijs et al., 1983). The increased oxytocinergic activity observed during depression might
therefore be related to the decreased food uptake in this
condition (Purba et al., 1996; Chapter 26.4), and the
decreased number of oxytocin neurons in the PVN of
PraderWilli patients may be responsible for their insatiable hunger (Swaab et al., 1995a; Chapter 23.1). On the
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other hand, the satiety effects of oxytocin are not without

controversy. One research group has shown that long-term
oxytocin subcutaneous treatment may result in increased
food intake and weight gain, a mechanism that is suggested
to be of possible physiological importance in lactationinduced hyperphagia (Bjrkstrand and Uvns-Moberg,
1996; Uvns-Moberg et al., 1998). In fact, oxytocin may
either increase or decrease food intake, depending on the
rat strain studied (Uvns-Moberg et al., 1996).
Endogenous corticosteroids play a pivotal role in
visceral adipose tissue deposition. Subjects with abdominal obesity are characterized by hyperactivity of the
hypothalamopituitaryadrenal (HPA) axis, which leads
to functional hypercortisolism (Pasquali and Vicennati,
2000a, b). Glucocorticoids stimulate NPY and inhibit
CRH, and this combination promotes food consumption
and therefore weight gain, e.g. in Cushings syndrome or
treatment with corticosteroids (Schwartz and Seely,
1977). However, the reversibility of the HPA axis changes
with weight loss, suggesting that these changes are consequences of rather than the cause of an expanding
intraabdominal fat deposit (Kopelman, 1999), and autonomic innervation of the adrenal and adipous tissue may
play a crucial role (Buijs and Kalsbeek, 2001). CRH and
urocortin inhibit food intake and are therefore considered
to be responsible for at least some of the changes in
eating behavior in stress and depression (Holsboer et al.,
1992; Raadsheer et al., 1995; Bradbury et al., 2000; see
Chapter 26.4). Judging by the data from transgenic
mice, the CRH receptor-1 does not, however, seem to
play a critical role in the basal regulation of ingestive
behavior (Mller et al., 2000a). The observation that CRH
in human CSF diminishes after feeding has been interpreted as not supporting the hypothesis that CRH is a
central satiety factor in human (Kasckow et al., 2001a).
However, CRH levels in CSF do not seem to reflect
hypothalamic CRH production (see Chapter 26.4d),
while some studies indicate that plasma and salivary
cortisol levels are diminished in severely obese patients
(Putignana et al., 2001). Others claim that basal cortisol
levels are normal in obese women. However, different
HPA-activity changes were observed in obese women in
relation to abdominal versus subcutaneous fat distribution.
A recently discovered satiety factor is the peptide
CART, which is produced in the DMN, SON and PVN,
posterior hypothalamus, premamillary nucleus, TMN,
infundibular nucleus, LHA, bed nucleus of the stria terminalis, amygdala, thalamus and cortex in the human brain
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(Hurd and Fagergren, 2000; Elias et al., 2001). In humans,

CART contains 116 amino acid residues. CART mRNA
is upregulated by leptin and the expressed CART is a
potent anorectic peptide that overrides the feeding
response induced by NPY (Thim et al., 1998). The
CART/POMC neurons innervate sympathetic preganglionic neurons in the spinal cord that may contribute to
the increased thermogenesis and energy expenditure and
the increased body weight that are observed after leptin
administration (Elias et al., 1998). CART administration
intracerebroventricularly (ICV) inhibits food intake,
induces the expression of c-Fos in the PVN and causes
a transient rise in plasma oxytocin levels in rat (Vrang
et al., 2000). This suggests that CART might act through
the oxytocinergic system to bring about its inhibitory
effects on feeding behavior. Oxytocin cells of the PVN
are considered to be satiety neurons (Swaab et al., 1995a).
Interestingly, preliminary observations by our group indicate that there is a tendency toward a reduction in CART
cell number in the infundibular nucleus in PWS (F.
Goezinne et al., unpubl. results).
MCH is produced in the LHA, perifornical area, tuberomamillary nucleus, posterior nucleus and zona incerta
(Pelletier et al., 1987; Bresson et al., 1989; Mouri et al.,
1993; Qu et al., 1996; Saito et al., 2000b; see Chapter
14). MCH is overexpressed in the hypothalamus of obese
mice and during fasting. ICV injection of MCH in rat
increases food consumption (Qu et al., 1996). Mice deficient for MCH have reduced body weight due to
hypophagia and an inappropriately increased metabolic
rate, despite the reduced amounts of leptin and POMC
mRNA in their arcuate nucleus (Shimada et al., 1998).
MCH is the cognate ligand for the orphan G-proteincoupled receptor SCL-1, which is expressed in the rat
ventromedial and dorsomedial nuclei (Chambers et al.,
1999; Saito et al., 1999). Apart from its role in feeding,
the MCH receptor may be involved in the regulation of
the HPA axis in stress, olfaction and anxiety (Saito et
al., 2000). There are at present two G-protein-coupled
receptors known for MCH (Sailer et al., 2001). MCHbinding sites are present in the human hypothalamus and
other brain areas (Sone et al., 2000). Neurotensin,
bombesin and glucagon-like peptide inhibit food intake,
and somatostatin increases feeding, while octreotide, a
long-acting somatostatin receptor agonist, promotes
weight loss, possibly by suppressing excessive insulin
secretion. Growth hormone-releasing hormone (GHRH)
stimulates feeding (Leibowitz, 1992). Ghrelin is an
endogenous growth hormone-release-stimulating peptide
that is produced in the rat arcuate nucleus. Ghre comes

from the Indo-European root for the word grow. It also
increases feeding in rats and stimulates NPY and AGRP
neurons (Nakazato et al., 2001; Lu et al., 2002). It is a
peptide of 28 amino acids, which acts through the endogenous ligand for the growth hormone secretagogue receptor
(Lu et al., 2002) and antagonizes leptin action through
the activation of the NPY/Y1 receptor pathway (Shintani
et al., 2001). Recently a mutation was found in the
preproghrelin sequence that corresponds to the last amino
acid in the mature ghrelin product in heterozygous obese
subjects, showing that the ghrelin gene could play a role
in the etiology of obesity (Lustig et al., 1999; Ukkola et
al., 2001). PWS patients have markedly elevated plasma
ghrelin levels, which may contribute to the severe hyperphagia and obesity associated with this syndrome
(Cummings et al., 2002; Chapter 23.1). In addition,
increased fasting ghrelin plasma levels are found in
patients with bulimia nervosa (Tanaka et al., 2002).
Ghrelin causes a hypothalamic release of GHRH,
CRH, arginine vasopressin (AVP), and NPY (Wren et
al., 2002).
Injection of serotonin (5-HT) suppresses carbohydrate
intake, with little or no change in protein and fat in freely
moving animals (Bernardis and Bellinger, 1996); but, in
the rat, serotonergic control of feeding behavior has been
designated both as suppressant and stimulant. A serotonergic disorder has been presumed in anorexia and
bulimia nervosa (Walsh and Devlin, 1998). Dopamine
and noradrenaline inhibit food intake and the VMNlesion syndrome may be partly if not completely due to
interruption of the aminergic innervation of the hypothalamus (see Chapters 9, 26.3; Bernardis and Bellinger,
1996). In genetically obese mice, there are hypothalamic
noradrenergic receptor changes and an increased noradrenergic activity is presumed (Boundy et al., 2000).
Histamine, derived from the TMN (Chapter 13),
suppresses feeding (Brown et al., 2001).
Moreover, a number of substances from the periphery
affect the balance of nutrient and energy homeostasis,
such as cholecystokinin (CCK) from the gastrointestinal
tract (Hopkins and Williams, 1997). Corticosteroids,
aldosterone, estrogens and the nutrients glucose, fatty
acids and amino acids, also affect the energy homeostasis
(Williams et al., 1991; Leibowitz, 1992; for leptin, see
Chapter 23b). In addition, sex hormones and sex
hormone-binding globulin may play a role in obesity and
may explain the increased abdominal obesity in
menopause-induced estrogen deficiency (Tchernof and
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Desprs, 2000). The anorectic action of estrogens in rat

is mediated by the central estrogen receptor- (Liang et
al., 2002). Insulin receptors are present in the human
hypothalamus (Hopkins and Williams, 1997). Mice with
neuron-specific disruption of the insulin receptor gene
show increased food intake and a diet-sensitive obesity,
with increases in body fat and plasma leptin levels
(Brning et al., 2000). In patients with suprasellar lesions,
documented pituitary, hypothalamic lesions, and profound
obesity, T3 supplementation weight loss was promoted
(Fernandez et al., 2002).
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humans than in mice. Treatment of this 9-year-old child

with recombinant leptin led to sustained reduction in
weight, predominantly as a result of a loss of fat. This
therapeutic response confirms the importance of leptin in
the regulation of body weight in humans and establishes
an important role for this hormone in the regulation of
appetite (Farooqi et al., 1999). Polymorphisms in the leptin receptor gene are associated with levels of abdominal
fat in postmenopausal overweight women (Wouters et al.,
2001). Another genetic defect was found in a woman with
extreme childhood obesity, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypocortisolism
and elevated plasma proinsulin and POMC concentrations,
but a very low insulin level. This disorder seems to be
based upon a mutation in the prohormone processing
endopeptidase, prohormone convertase 1 (PC1) (Jackson
et al., 1997). Severe early-onset obesity, adrenal insufficiency and red hair pigmentation were found to be caused
by POMC mutations (Krude et al., 1998; Krude and
Grters, 2000). The patients had severe early-onset obesity and red hair pigmentation due to mutations truncating the POMC molecule and leading to the complete lack
of ACTH and -MSH (Krude and Grters, 2000; MacNeil
et al., 2002). However, a cryptic trinucleotide repeat polymorphism in exon 3 of POMC that was associated with
elevated leptin levels, appeared not to be associated with
obesity (Rosmond et al., 2002). Mutations in the MC-4
receptor gene (MC4R) seem to be a common cause of
monogenic human obesity. Up to 46% of severely obese
humans have defects of the MC-4 receptor gene. Affected
individuals have hyperphagia in childhood, which loses
its intensity later in life. These individuals of normal
height, present with binge-eating as the major phenotype
characteristic. Some patients had cyclothymia or bipolar
affective disorder (Cone, 1999; Mergen et al., 2001;
Kobayashi et al., 2002; Branson et al., 2003; Farooqi et
al., 2003). A patient with both extreme obesity and bulimia
nervosa has been described, who has a haploinsufficiency
mutation in the MC-4 receptor (Hebebrand et al., 2002).
A SNP in the AGRP, a natural MC-4 receptor agonist, is
thought to increase the risk of developing anorexia nervosa (Vink et al., 2001b). In one patient with both extreme
obesity and bulimia nervosa, a haplo-insufficiency mutation was found in the MC-4 receptor (Hebebrand et al.,
2002). A novel MC-3 receptor mutation has been observed
in an obese girl and her father (Lee et al., 2002). However,
MC-3 receptor variantss are common and generally considered not to explain human morbid obesity (SchalinJntti et al., 2003). In a number of obese subjects a
(d) Molecular genetic factors involved in obesity

Human obesity certainly has an important inherited component. In fact, studies in twins, adoptees and families
indicate that 80% of the variance in body-mass index is
attributable to genetic factors (Rosenbaum et al., 1997).
The obesity gene map 2000 reports on the presence of
47 human cases of obesity caused by single-gene mutation in six different genes, including SIM1, a critical transcription factor for the formation of the SON and PVN
in mice. In addition, 24 Mendelian disorders exhibiting
obesity as one of their clinical manifestations have now
been mapped (Prusse et al., 2001), yet the genetic factors responsible for most obesity in the general population have remained elusive so far. As far as the single-gene
mutations are concerned, obese subjects with a mutation
in the gene that encodes for leptin (Montague et al., 1997;
Strbel et al., 1998) or for the leptin receptor (Clment
et al., 1998) have been described. The missense leptin
mutation described by Strbel et al. (1998) is associated
not only with morbid obesity but also with hypogonadism
and primary amenorrhea. The male patient never enters
the stage of puberty. The mutation described by Clment
et al. (1998) results in a truncated leptin receptor, lacking both the transmembrane and the intracellular domains.
In addition to their early-onset morbid obesity and lack
of pubertal development, patients who are homozygous
for this mutation also have reduced secretion of growth
hormone, growth retardation and central hypothyroidism.
The observations in subjects with mutations in the leptin
receptor and leptin itself suggest that leptin not only controls body mass but is also a necessary signal for the initiation of puberty in humans. However, since in a child
with congenital leptin deficiency there was no evidence
of substantial impairment in basal or total energy expenditure, and her body temperature was normal, leptin may
be less central to the regulation of energy expenditure in
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mutation in the preproghrelin gene was found that corresponds to the last amino acid of ghrelin (Ukkola et al.,
2001), but so far there is no good evidence that sequence
variants in the coding region of the ghrelin gene influence body weight (Hinney et al., 2002). However, growth
hormone secretogogues such as ghrelin may be important
for feeding. When the expression of the receptor for this
compound in the arcuate nucleus was blocked, the rats
had lower body weight and less adipose tissue than controls (Shuto et al., 2002). A glucocorticoid receptor polymorphism is associated with obesity and dysregulation of
the HPA axis (Rosmond et al., 2000). A patient with a
mutation in the transcription factor steroidogenic factor 1
had a complete sex reversal and developed obesity in late
adolescence (Ozisik et al., 2002).
PWS, which is characterized by obesity, hypotonia,
mental retardation and hypogonadism, is discussed in
Chapter 23.1. PraderWilli patients usually have a de
novo, paternally derived, deletion of the chromosome
region 15q11-13. In contrast, Angelmans syndrome is
generally due to a maternally derived deletion of the chromosome 15q11-13 region. Its clinical features comprise
severe mental retardation, postnatal microcephaly, macrostomia and prograthia, absence of speech and a happy
disposition. A group of patients has been reported who
lack most of these features, but present with obesity,
muscular hypotonia and mild retardation, i.e. features that
are also seen in PWS. The Angelman patients had an
apparently normal chromosome 15 of biparental inheritance but possibly an incomplete imprinting defect or
cellular mosaicism. For other eating disorders, such as
BardetBiedl syndrome, see Chapter 23.3.
and some authors propose that cultural factors are of great

importance (Bemporad, 1997). Moreover, morbid obesity
has been reported following encephalitis lethargica infection and other viral neurological infections (Nagashima
et al., 1992; Chapter 20.2). Animal models with human
adenovirus-induced adiposity also suggest the possibility
of viral involvement (Dhurandhar et al., 2000). In addition, Langerhans cell histiocytosis (Chapter 21.3) and
ventromedial hypothalamic lesions (Chapter 26.3) may
be accompanied by adipositas. Autoantibodies against MSH, ACTH, and LHRH have been found in anorexia
and bulimia nervosa (Fetissov et al., 2002). Both conventional and newer antipsychotics are associated with weight
gain. Among the newer agents, clozapine appears to have
the largest potential to induce weight gain, and ziprasidone the smallest (Allison et al., 1999).
Progressive wasting as found in cancer is considered
to be due to a disruption of the physiological mechanisms
controling energy intake. Cancer anorexia is multifactorial and may involve most of the neuronal signaling pathways modulating energy intake. Factors probably involved
are cytokines, such as tumor necrosis factor , interleukins-1 and -6, interferon-, leukemia inhibitory factor
and ciliary neurotrophic factor. They are proposed to
stimulate anorexigenic neuropeptides such as CRH in the
hypothalamus, and to inhibit neuropeptides of the orexogenic network such as NPY, galanin and opioids, and
hormones such as leptin. In addition, neurotransmitters
such as serotonin and dopamine are presumed to be
involved (Inui, 1999; Laviano et al., 2002). Animal experiments have shown that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated
by central MC4-R blockade (Marks et al., 2001).
(e) Epigenetic factors in obesity and anorexia cachexia

In addition to the genetic factors, epigenetic factors seem
to be involved in obesity as well. People exposed to
famine, during the first half of pregnancy, in the Dutch
hunger winter of 19441945, displayed significantly
higher obesity rates. Exposure to famine during the last
trimester of pregnancy and the first months of life,
however, resulted in significantly lower obesity rates
(Ravelli et al., 1976). A syndrome of intractable weight
gain may result from hypothalamic damage following
radiation for a brain tumor in children (Lustig et al.,
2003). A wide range of childhood aversions is associated
with elevated risk of developing eating disorders during
adolescence or early adulthood (Johnson et al., 2002a, b)
23.1. PraderWilli syndrome (PWS; MIM no.

176270, Fig. 23A)
(a) Symptoms and molecular genetics
In 1956, Prader, Labhart and Willi described a syndrome
in children characterized by grossly diminished fetal
activity and hypotonia in infancy, mental retardation
(mean IQ of 65) or learning disability, feeding problems
in infancy, and later insatiable hunger and gross obesity
(Fig. 23.3), hypogonadism and hypogenitalism. Unilateral
or bilateral cryptorchism is found in 80100% of male
PraderWilli patients. Additional features are a variety
of minor malformations, including a small forehead,
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almond-shaped eyes, triangular mouth, small hands and

feet, short height, decreased pigmentation of skin
and hair, which is probably of neural crest origin, and
ophthalmic disorders. PWS is the most frequent form of
human syndromal obesity (Apkarian et al., 1989; Smeets
et al., 1992; Mller, 1997; Butler et al., 1998; Eiholzer
et al., 2000). In the USA, PWS is also known as the H3O
syndrome, after the four essential features: hypotonia,
hypomentia, hypogonadism and obesity. The glucose
tolerance test result is often abnormal (Tolis et al., 1974).
Diagnostic criteria for PWS have been developed by
consensus and two scoring systems have been provided:
one for children aged between 0 and 36 months, and
another for children from 3 years onwards, into adulthood
(Holm et al., 1993).
The majority of PWS cases are sporadic, but familial
cases have been reported (McEntagart et al., 2000). In
70% of the patients a de novo deletion of the paternally
inherited chromosome 15q11-13 is present. About 28%
of PWS cases are due to maternal uniparental disomy,
that would result in a slightly milder phenotype with better
cognitive functions. Paternal deletion and maternal
uniparental disomy are functionally similar as they both
result in the absence of a paternal contribution to the
genome in the 15q11-13 region. A third, and the
most severe, phenotype with a high incidence of congenital heart disease are the patients with maternal uniparental
disomy 15 with mosaic trisomy 15 (Olander et al.,
2000). A few PWS cases with mosaicism for the deletion have been reported (Golden et al., 1999), but definite
evidence has not yet been found (Nicholls, 2000).
Less than 2% of the cases have an abnormality in the
imprinting process, which causes nonexpression of the
paternal genes in the PWS-critical region (ASHG/ACMG
Report, 1996; Brndum-Nielsen, 1997). In a 3-yearold, a cryptic interstitial duplication of the entire
PraderWilli/Angelman critical region was found. It was
of maternal origin. The phenotype included developmental mental delay, speech problems and seizures
(Thomas et al., 1999). Duplication, triplication and tetrasomy of the 15q11-q13 region has been reported with
varying degrees of clinical manifestation (Butler et al.,
2002). In a clinically atypical PWS patient, a rare,
balanced de novo translocation has been observed
(Conroy et al., 1997) and several cases with phenotype
overlapping with the PWS phenotype had maternal
uniparental disomy 14. Some PWS candidate genes have
been identified. The SNRPN (small nucleoriboproteinassociated polypeptide N) gene is probably part of the
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putative imprinting center that regulates the expression

of several genes in PWS transcriptional domain (Martin
et al., 1998a). An intact genomic region and/or transcription of SNRPN exons 2 and 3 seem to play a pivotal
role in the manifestations of the clinical phenotype in
PWS (Kuslich et al., 1999). However, other human cases
tend to exclude SNRPN as the causative gene for PWS
genotype (Conroy et al., 1997). In addition, the human
necdin gene, NDN, which is maternally imprinted and
located in PWS chromosomal region, was considered to
be a candidate gene (Jay et al., 1997). Although at first
necdin-deficient mice did not develop the hypogonadism,
infertility or obesity characteristics of PWS (Tsai et al.,
1999), later on Necdin mouse mutants were developed
that showed hypothalamic and behavioral alterations
reminiscent of the human PWS, including a reduction of
90% in oxytocin neurons and of 25% in LHRH-producing
neurons, increased skin-scraping activity (Muscatelli et
al., 2000), and a deficiency of respiratory drive (Ren
et al., 2003). Others claim that the imprinted genes
ZNF-127 and -127 AS may be associated with some of
the PWS features (Jong et al., 1999). In addition, there
is a small evolutionarily conserved RNA resembling C/D
box, small-nucleolar RNA, which is transcribed from
PWCR1, a novel imprinted gene in the PWS deletion
region, which is highly expressed in brain (De los Santos
et al., 2000).
PWS occurs in 1 of every 10,00025,000 births.
Epidemiologic studies have shown an increased incidence
of paternal preconceptional employment in hydrocarbonexposed occupations (gasoline/petrol) (Cassidy et al.,
1989; kefeldt, 1995; Martin et al., 1998a). The exact
causes of mental retardation, behavioral problems such
as fits of temper, depression and sudden aggression in
PWS children are not known, but the major symptoms
of this syndrome are seen as the result of hypothalamic
disturbances (Swaab, 1997). This fits in with the experimental data of Keverne et al. (1996), who showed that
cells that carry only paternal genes accumulate in clusters scattered through the hypothalamus, septum, preoptic
area and amygdala, while cells that carry only maternal
genes accumulate in the cortex and striatum. Misrouting
of retinal ganglion fibers at the optic chiasm a finding
previously only reported in forms of albinism was
claimed to be present in PWS (Creel et al., 1986) but
could not be confirmed in a later study (Apkarian et al.,
1989). The original observation does not, therefore,
appear to give a clue for changes in brain development
(see Chapter 18.5).
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Fig. 23.3. Characteristic pattern of obesity in a patient with PraderWilli syndrome. (From Kaplan et al., 1991, Fig. 1 with permission.)
(b) Hypothalamic abnormalities

Dysfunction of various hypothalamic systems, neuroendocrine and nonneuroendocrine, may be the basis of a
number of symptoms in PWS. Severe fetal hypotonia is
often already noticed by the mother during pregnancy;
the baby does not seem to move much. Apart from the
babys underactivity, its position in the uterus at the onset
of labor is often abnormal (either a transverse, face or
breech presentation). These abnormal presentations result
in a high percentage of assisted deliveries. In addition,
the percentage of asphyctic infants is at least 8 times
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higher than in the general population. It has often been

presumed that the fetal position is caused by hypotonia,
the child being too weak to move itself in the correct
position. However, there are other congenital disorders
in the hypothalamus and pituitary in which hypotonia
is not reported which are also accompanied by abnormal
presentation of the fetus at birth, such as anencephaly
and septo-optic dysplasia (De Morsier syndrome) (see
Chapters 8.1, 18.3b). The way the hypothalamus is
involved in fetal hypotonia is not known at present. The
timing of the moment of birth is often also abnormal; too
high a percentage of children with PWS are born either
prematurely or too late (Wharton and Bresman, 1989),
an abnormality also found in anencephaly (Chapter 18.1).
An abnormality of the hypothalamus, which plays a
central role in the childs timing of its own birth, may
explain these phenomena (see Chapter 8.1).
Abnormal function of nerve cells in the hypothalamus
containing LHRH is thought to be responsible for
decreased levels of sex hormones, resulting in cryptorchism in boys, hypoplastic external genitalia in children
of both sexes and delayed or incomplete pubertal
development, as well as decreased sexual behavior and
insufficient growth during puberty, resulting in short
stature (Hamilton et al., 1972; Wannarachue et al., 1975;
Cassidy et al., 1997; Mller, 1997; Burman et al., 2001).
It should be noted though that there is a considerable
degree of variation in the function of the hypothalamopituitarygonadal axis in PWS and also hypergonadotropic
hypogonadism secondary to cryptorchism has been
described (Tolis et al., 1974; Mller, 1997). Serum testosterone levels are uniformly low in male PWS, whereas
serum estradiol, LH and follicle-stimulating hormone
(FSH) levels in females are usually low, which is consistent with hypogonadotropic hypogonadism. The onset of
menstruation is often late in girls, if it occurs at all (Mller,
1997). It is not yet known whether the proposed abnormality in LHRH production is due to absence of the LHRH
neurons, or due to an abnormal location, or to a deficiency
in LHRH production or perhaps to the production of an
abnormal form of the hormone. Gonadal function may also
be normal in a small number of patients (Rubin and
Cassidy, 1988; Cassidy et al., 1997, Mller, 1997; Martin
et al., 1998a). In some rare cases, precocious puberty has
been observed, once even in combination with empty
sella syndrome. In 5% of cases, empty sella syndrome is
accompanied by hyperfunction of the pituitary (Linneman
et al., 1999). It is generally assumed that PWS patients are
infertile. However, one woman with PWS was reported to
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have given birth to a healthy baby girl, presumably related

to the treatment with a serotonin reuptake inhibitor
(kefeldt et al., 1999). In addition it was reported (Schulze
et al., 2001) that a 32-year-old woman with PWS had given
birth to a girl with Angelmans syndrome, due to a
maternal deletion on chromosome 15q11-13. Treatment of
hypothalamopituitarygonadal failure in PWS remains
a controversial issue. More recently, sex hormone
replacement therapy is given. This encourages the development of secondary sexual characteristics and potentially
improves bone mineral content and density. Given the
reports of pregnancy in a few PWS cases, care-givers
should, however, be aware of the possible need for
contraceptives. If aggressiveness in male PWS patients
during testosterone substitution increases, the substitution
should be stopped (Burman et al., 2001).
Short stature and delayed skeletal maturation are the
most frequent features of PWS, probably partly due to
hypogonadism (see above) and partly to a growth
hormone (GH) deficiency, and are seen in 90% of the
PWS patients (Angulo et al., 1996). Some PWS patients
have abnormally low spontaneous nocturnal GH and
insulin-like growth factor-I (IGF-1) serum levels and
blunted GH responses to pharmacological stimuli and to
GHRH, suggesting that hypothalamic dysfunction of this
axis may be a factor in the short stature (Costeff et al.,
1990; Cappa et al., 1993; 1998; Angulo et al., 1996;
Grosso et al., 1998; Eiholzer et al., 2000). In addition,
insulin-like growth factor (IGF) binding protein-3 levels
are low in PWS as compared to healthy obese children
(Eiholzer et al., 1998). GH deficiency is independent of
weight status (Thacker et al., 1998). The possibility that
short stature is due to a deficit at or above the level of
the pituitary is reinforced by the fact that GH treatment
stimulates body growth in PWS patients. In addition,
weight gain decreased and IGF-I (somatomedin C) and
insulin levels increased after GH treatment (Lee et al.,
1987; Angulo et al., 1991; Eiholzer et al., 1997; Hauffa,
1997; Lindgren et al., 1997b, 1998, 1999; Lindgren and
Ritzn, 1999; Myers et al., 1999; 2000; Lee, 2000). GH
therapy during a period of up to 4 years continued to give
beneficial effects on body composition and growth
velocity. Prior improvements in strength and agility were
sustained (Carrel et al., 2002). Interestingly, GH treatment
appeared to have psychological and behavioral benefits
also. Parents reported that the children were more alert,
had a more stable temperament, were more interested
in other children and were easier to handle than before
treatment (Lindgren et al., 1997b). However, the only
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difference in cognition or behavior reported in a recent

study was an increase in hyperactivity after growth
hormone intervention. In GH-deficient PWS children, the
overall mean height SD and weight SD changed from
2.2 to 0.8 and from 3.5 to 2.4, respectively, in a period
of 2 years of treatment (Angulo et al., 1996). The
determination of GH levels, either spontaneous nocturnal
ones or after stimulation tests (Grosso et al., 1998), in
venous plasma as an indicator of hypothalamic GHRH
release is used (Kimber et al., 1997). GHRH that is
produced in the arcuate nucleus (Ciofi et al., 1990; Fig.
23.4) was expected to be affected in PWS. However,
observations in postmortem material from our group have
shown that the number of GHRH-expressing neurons in
this nucleus is not decreased in PWS, and increased to
the same degree as it is in controls, due to chronic illness,
so there is no evidence that the GH deficiency in PWS
results from reduced GHRH cell number (Goldstone et
al., 2003).
The hypothalamopituitaryadrenal and thyroid axes
remain largely intact in PWS, and prolactin and cortisol
levels are generally normal (Tolis et al., 1974;
Wannarachue et al., 1975; Mller, 1997; Grosso et al.,
1998; lAllemand et al., 2002). Dehydroepiandtosterone
(DHEA), DHEA-S and androstenedione levels are elevated (Burman et al., 2001; lAllemand et al., 2002).
Premature adrenarche, characterized by growth of axillary hair and pubic hair is frequently observed in PWS
(Linnemann et al., 1999; Burman et al., 2001). One patient
has been reported with the rare combination of PWS and
congenital hypothyroidism caused by an ectopic sublingual thyroid gland. Although early initiation of thyroid
replacement therapy took place, she continued to suffer
from hypotonia and developmental delay, after which
PWS was discovered (Sher et al., 2002).
The observation of an aberrant control of body temperature in PWS is also interpreted as a hypothalamic
disturbance (Vela-Bueno et al., 1984). It should be
noted, however, that thermoregulatory disturbances are
not specific for this syndrome and may occur in any
neurodevelopmentally handicapped person (Williams
et al., 1994).
The abnormal ventilatory control during wakefulness
and sleep in patients with PWS may, apart from being
linked to sleep apnea, also be related to a hypothalamic
disorder, since this brain area modulates both hypercapnic
and hypoxic ventilatory responses (Menendez, 1999).
Leptin is a satiety factor that is produced by fat cells
and acts on the infundibular nucleus and other hypothal-
amic areas in order to inhibit food intake (see Chapter

23b) and was, therefore, presumed to be involved in
obesity in PWS. Plasma leptin levels are increased in
PWS, but this was generally in relation to the increased
body-mass index (Carlson et al., 1999). It was therefore
thought to be improbable that an explanation for the
increased food intake and obesity could be presented on
the basis of a disturbance in the leptin gene (Wallace et
al., 1999). However, subtle differences may be present
in leptin. The normal sex difference females have higher
leptin levels than males is not present in PWS, and it
is remarkable that the differences between obese and
nonobese PWS subjects are small and insignificant. In
fact, plasma leptin levels in nonobese male PraderWilli
subjects were nearly 5 times higher than in nonobese
control males (Butler et al., 1998). While a difference in
the hypothalamic response to leptin could not be excluded
on the basis of the study by Lindgren et al. (1997a), our
finding that there is less NPY in the infundibular nucleus
in PWS patients (see below) seems to exclude a gross
disturbance of the leptinleptin receptorNPY interaction
(Goldstone et al., 2002).
Leptin is presumed to inhibit NPY production in the
infundibular nucleus (see Chapter 23b). In order to see
whether an increased activity of NPY neurons in the
infundibular nucleus might explain the eating disorder in
PWS patients, we determined the amount of NPY in the
infundibular nucleus immunocytochemically, and NPY
mRNA, by means of an image-analysis system, in PWS
cases, nonsyndromic obese patients and controls. The
infundibular nucleus contains NPY cell bodies and an
extremely dense network of NPY fibers that generally do
not extend to the most ventral part of the median
eminence, which contains the portal capillaries. This indicates that most of the NPY fibers have central projections.
NPY immunoreactivity and mRNA are decreased in PWS
patients, to the same degree as in the other obese patients
(Figs. 23.5, 23.6, 23.8). NPY immunocytochemistry and
mRNA increases with longer disease duration (Goldstone
et al., 2002; Fig. 23.6). Apparently the insatiable hunger
in PWS is not due to increased NPY expression, as these
neurons show a normal reaction to the obese state and
disease duration of these patients. No increase was found
in the AGRP staining or mRNA in the infundibular
nucleus of PWS patients either (Fig. 23.7, 23.8). This
peptide, too, is upregulated with disease duration
(Goldstone et al., 2002; Fig. 23.7). AGRP is another
peptide that stimulates feeding and is colocalized with
NPY, but not with POMC (Figs. 11.3, 11.4). The
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Fig. 23.4. Growth hormone-releasing hormone (GHRH)-immunoreactive neurons in the infundibular nucleus of 3 controls (left column) and 3
PraderWilli syndrome (PWS) patients (right column). The top row shows the cases with the highest number of GHRH-immunoreactive neurons,
the middle row shows cases with the highest number of GHRH-immunoreactive neurons, the middle row shows cases with a median GHRH neuron
number and the last row represents the cases with the lowest GHRH-neuron number: (a) control case 96-030, (b) PWS case 43830, (c) control
case 85-124, (d) PWS case 96-000, (e) control case 80-271 and (f) PWS case 97-049. Scale bar 50 m. Note that there is a great variability in
number of GHRH neurons, both within the control group and in the PWS patient group. Although the PWS patients generally tended to have
fewer GHRH neurons and their staining tended to be less intense, this appeared to be due to differences in disease duration and not to PWS per
se. (cf. Goldstone et al., 2003, preparation by U. Unmehopa.)
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Fig. 23.5. Hypothalamic neuropeptide-Y (NPY) in human illness and obesity. NPY immunocytochemistry (ICC) staining in the infundibular nucleus
of control, PraderWilli syndrome (PWS) and non-PWS adults, with sudden death, premorbid illness duration of less than 2 wk and more than 6
wk. Note that NPY ICC staining increases with longer periods of illness, but that each illness duration levels are lower in both PWS and nonPWS obese subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 4 with permission.)
Fig. 23.6. Hypothalamic neuropeptide-Y (NPY) mRNA in human illness and obesity. Representative autoradiographs of NPY in-situ hybridization
in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more
than 5 wk. Note that NPY mRNA expression increases with longer periods of illness, but that at each illness duration levels are lower in PWS
or non-PWS obese subjects, compared with controls. 3V, third ventricle. (From Goldstone et al., 2002, Fig. 5 with permission.)
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Fig. 23.7. Hypothalamic agouti-related protein (AGRP) peptide in human illness and obesity. Representative autoradiographs of AGRP ICC staining
in the infundibular nucleus of control, PWS, and non-PWS obese adults, with sudden death, premorbid illness duration of less than 2 wk or more
than 5 wk. Note that AGRP ICC staining increases with longer periods of illness, and that levels are not increased in PWS or non-PWS obese
subjects, compared with controls. Bar 50 m. (From Goldstone et al., 2002, Fig. 6 with permission.)
peptide are increased to a level reported to stimulate

appetite and food intake (Cummings et al., 2002; Del
Parigi et al., 2002; Haqq et al., 2003). The possibility
that this peptide also has a source in the human brain
should be investigated.
The birth weight of PWS children is often too low, but
from age two onwards these children tend to grow fatter
than other children. Appetite control is exacerbated when
there is more severe mental retardation. The obesity may
be caused by an increased drive to eat as well as by an
impaired mechanism of satiation. Both functions are
controlled by the hypothalamus. Animal experiments have
shown that the parvocellular oxytocin neurons of the
hypothalamic PVN are crucial for the regulation of food
intake. Oxytocin release accompanied various treatments
that inhibit food intake (Verbalis et al., 1995). In the rat,
the oxytocin neurons of the PVN project to brainstem
nuclei, for example the nucleus of the solitary tract and
the dorsal motor nucleus of the nervus vagus (Buijs et
al., 1983; De Vries and Buijs, 1983; Voorn and Buijs,
1983). These connections are held responsible for the
satiety effects of oxytocin (Verbalis et al., 1995). Small
decreased NPY and AGRP content of the hypothalamus

indicates that the transport of information between the fat
cells and the infundibular nucleus to the PVN by the NPY
neurons will be largely intact, including leptin and leptin
receptors, and that abnormalities have to be searched for
in other peptide systems of the arcuate nucleus or in the
area of termination of the NPY fibers, such as the PVN
(Goldstone et al., 2002). Seemingly in contrast to our
data, kefeldt et al. (2001) reported that the NPY content
of CSF in PraderWilli children with a mean age of 8
years was higher. However, in two PWS infants of 6 and
8 months, we did not find the reduction in NPY either
(Goldstone et al., 2002). The developmental state may
thus be of crucial importance in these hypothalamic
peptide changes. Preliminary results from our group indicate that there is a reduction of CART-containing neurons
in the infundibular nucleus of PWS patients (F. Goezinne
et al., unpubl. observ.). Since CART inhibits feeding, this
observation has to be followed up.
A new putative factor involved in obesity in PWS is
ghrelin. This peptide is an orexigenic circulating hormone
implicated in meal-time hunger. The plasma levels of this
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Fig. 23.8. Hypothalamic neuropeptide-Y (NPY) is decreased and agoutirelated peptide (AGRP) is not increased in obesity. (A) NPY ICC
staining volume, (B) NPY mRNA expression by ISH; and (C) AGRP
ICC staining volumes, in the infundibular nucleus/median eminence
(INF/ME), in control, PraderWilli syndrome (PWS) and non-PWS
obese subjects. + represents females, hypogonadal females (postmenopausal or PWS), intact males, hypogonadal males (castrated
controls or PWS). Dashed line represents median for each group. Note
that, in obese subjects (PWS and non-PWS) compared with controls,
there is a significant reduction in NPY ICC staining and mRNA, but
no difference in AGRP ICC staining, when adjusting for significant
covariates. P-values: a Mann-Whitney test; b adjusting for differences in
premorbid illness duration by ANCOVA; cadjusting for differences in
premorbid illness duration and storage time by ANCOVA. (From
Goldstone et al., 2002, Fig. 2 with permission.)
lesions in the rat PVN cause overeating and obesity

(Leibowitz et al., 1981), suggesting that the PVN usually
has an inhibitory effect on eating and body weight. In
addition, stimulation of the medial parvocellular subdivision of the rat PVN elicits significant increases in gastric
acid secretion (Rogers and Hermann, 1986). Central
administration of oxytocin or oxytocin agonists inhibits
food intake and gastric motility in rat, whereas these
effects are prevented by an oxytocin receptor antagonist
(Rogers and Hermann, 1986; Arletti et al., 1989; Benelli
et al., 1991; Olson et al., 1991a, b). In a patient whose
PVN was bilaterally destroyed by a hypothalamic astrocytoma, obesity and hyperphagia were indeed reported
(Haugh and Markesbery, 1983). It should be noted,
however, that in this patient one side of the VMN was
also affected.
We have investigated whether a disorder of the PVN,
or, more particularly, of its putative satiety neurons the
oxytocin neurons might be the basis of the insatiable
hunger and obesity in PWS. Apart from gross obesity,
oxytocin neurons are also thought to be crucial for various
aspects of sexual behavior, including sexual arousal,
orgasm, sexual satiety and other aspects of sociosexual
interaction (Hughes et al., 1987; Murphy et al., 1987;
Argiolas, 1992; Arletti et al., 1992; Carter, 1992; Chapters
8f, 8g). The thionine-stained volume of the PVN appeared
to be 28% smaller in PWS patients and the total cell
number of the PVN is 38% lower than in controls (Swaab
et al., 1995a). Following immunocytochemistry, the
immunoreactivities for oxytocin and vasopressin are
decreased in PWS patients (Fig. 23.9), although the variation within the groups is high. A large and highly
significant decrease (42%) in the number of oxytocinexpressing neurons was found in all five PWS patients
(Fig. 23.10). The volume of the PVN containing the OXTexpressing neurons is 54% lower in PWS. The number
of vasopressin-expressing neurons in the PVN did not
change significantly (Fig. 23.9). The finding that volume
and total cell number and oxytocin cell number was so
much lower in PWS patients points to a developmental
hypothalamic disorder, and agrees with the hypothesis
that oxytocin neurons of the PVN may be good candidates for a physiological role as satiety neurons in
ingestive behavior, also in the human brain (Swaab et al.,
1995a). In addition, it seems worthwhile to investigate
whether it is possible to curb childrens appetites by
administration of oxytocin. It should be noted, though,
that the recent observation that oxytocin levels in CSF
of five PWS patients were just significantly elevated
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Fig. 23.9. In thionine-stained sections of the paraventricular nucleus (PVN), no qualitative differences were observed between controls (no. 81255;
A) and PWS patients (no. 43830; B). The staining of oxytocin (OXT) (C, D) and vasopressin (AVP) (E, F) was generally lower in PWS patients
(no. 43830; D, F) than in controls (no. 81255; C, E). G, H, Two PWS patients (no. 1 and 4) had intense and weak OXT staining (no. 93056; G)
and only negligible AVP staining (no. 93056; H) in the PVN. Bar 50 m. (From Swaab et al., 1995a, Fig. 1, with permission.)
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Fig. 23.10. Number of oxytocin-expressing (OXT) (left panel) and vasopressin-expressing (AVP) (right panel) neurons in the PVN of 27 controls
and 5 PraderWilli syndrome (PWS) patients. The values of the PWS patients are delineated by a minimum convex polygon. Note that the oxytocin
neuron number of these patients is about half of that of the controls (left panel), which is not the case for vasopressin (right panel). (From Swaab
et al., 1995a, Fig. 2 with permission.)
seems to be at odds with our observation in the PVN,

although it is of course possible that different subpopulations of oxytocin neurons in the PVN, with different
projection sites, react in a different way to the disease
process (Martin et al., 1998b). Clearly oxytocin should
be studied in more PWS patients, both in postmortem
hypothalamic material and in CSF.
It should be mentioned that, in two of seven of our
PWS patients, vasopressin neurons stained only weakly
(Swaab et al., 1995a) or not at all (Gabrels et al., 1994),
depending on the antibody used. In these two PWS
patients there was no staining with antibodies against 7B2,
a neuroendocrine chaperone preventing premature activation of the enzyme prohormone convertase (PC)2. Since
the precursor of vasopressin was present in these two
PWS patients (Fig. 23.11) and no PC 2 activity was found
in the SON and PVN, a processing enzyme disturbance
is presumed that also affects the 7B2 gene from the
paternal allele (Gabrels et al., 1994, 1997). The finding
that vasopressin expression is occasionally diminished in
PWS patients agrees with the demonstration of Miller et
al. (1996) that MRI shows a complete absence of the
posterior pituitary bright spot in 20% of these patients,
indicating a disturbed function of the hypothalamohypophysial system as found in patients with hypothalamic
diabetes insipidus (see Chapter 22.2). Whether a vasopressin defect is indeed present in those PraderWilli
patients that lack the posterior pituitary bright spot in
MRI should be proved by further observations.
The extensive calcifications found in the brain and
spinal cord of a 16-year-old boy with PWS are most probably an incidental finding not directly related to the
syndrome (Reske-Nielsen and Lund, 1992). In conclusion, so far hypothalamic research has revealed an intact
NPY/AGRP system in PWS syndrome that is inhibited
in a normal way by obesity, but the number of oxytocinexpressing neurons in the PVN is clearly diminished.
(c) Behavioral disorders
Behavioral problems are a frequent occurrence in PWS
(Curfs et al., 1991). Symptoms of mood disorder and
anxiety laminate the picture of PWS. They can, at least
partly, also be considered to be hypothalamic symptoms
(Chapter 26.4). In addition, temper tantrums and compulsive behavior such as skin-picking may be present (Martin
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Fig. 23.11. Paraffin sections of the supraoptic nucleus (SON) from PraderWilli syndrome patient 93-056 shows no immunoreactivity with antibody III-D-7 recognizing processed vasopressin (A), but very intense immunoreactivity with antibody PS41 recognizing neurophysin predominantly
in its processed form (B), and very intense immunoreactivity with antibody Boris Y-2 recognizing the glycopeptide part of the vasopressin precursor
(C). These data indicate a processing disorder. Bar 25 m. (From Gabrels et al., 1998b, Fig. 1 with permission.)
patients show hypersomnolence and little or no sleep

apnea, but REM-related oxygen desaturation is quite
common. In addition, abnormal REM sleep cycles, sleeponset REM periods and fragmented REM sleep with
multiple, brief REM periods are present (Kaplan et al.,
1991; Hertz et al., 1993; Clift et al., 1994; Richdale et
al., 1999; Manni et al., 2001). It is hypothesized that the
abnormal sleep findings in this syndrome are related to
a disturbance of the posterior hypothalamus (Hertz et al.,
1993; Manni et al., 2001). Clift et al. (1994) presume
that sleep apnea is also of some importance. An alternative explanation would be disturbed circadian functioning
(Vela-Bueno et al., 1984).
et al., 1998a; Holland et al., 2003). Moreover, psychosis

and bipolar illness have been reported in PWS cases, but
it is not clear whether they are more prevalent in PWS
than in the general population (Clarke, 1993; Clarke et
al., 1995; Descheemaeker et al., 2002). It is postulated
that in PWS an abnormal pattern in expression of a sexspecific imprinted gene on chromosome 15, such as in
maternal uniparental disomy, is associated with psychotic
illness in early adult life (Boer et al., 2002). Patients with
PWS may be especially vulnerable to the development
of cycloid psychosis that reacts favorably to lithium
(Verhoeven et al., 1998; Descheemaeker et al., 2002).
PWS is, moreover, associated with high rates of ritualistic behaviors, such as the need to ask or tell something,
insistence on routines, hoarding and ordering objects and
repetitive actions and speech (Clarke et al., 2002). In relation to the behavioral disturbances, the increased
concentrations of dopamine, 5-HT and metabolites may
be of relevance (kefeldt et al., 1998).
Another symptom that is present in 90% of the PWS
patients and may originate in the hypothalamus is the
excessive day-time hypersomnolence, accompanied by
snoring and early waking (Richdale et al., 1999). PWS
(d) Comorbidity
One case of KleineLevin syndrome has been described
in a boy with PWS (Gau et al., 1996). KleineLevin
syndrome is characterized by episodes of hypersomnia
and hyperphagia and considered to be a hypothalamic
syndrome (see Chapter 28.1). The small hypothalamus
observed in this patient with MRI (Gau et al., 1996)
supports the idea that this brain area is strongly affected.
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A case of multiple endocrine neoplasia (MEN) type 1

was found to be accompanied by PWS. MEN-1 (MIM
no. 131100) is a syndrome characterized by hyperplastic
or neoplastic disorder of endocrine organs. More than
90% of the affected subjects manifest hyperparathyroidism. Pituitary tumors and pancreatic endocrine tumors
are seen in 50% of the patients. Mutations of the MEN1
gene on chromosome 11q13 have been identified in most
of the affected subjects (Nakajima et al., 1999).
Four patients suffering from both PWS and Klinefelter
syndrome (47,XXY; see Chapter 24.4) have been
described. In the most recent case both parents contributed
to the chromosomal abnormalities, supporting the possibility of a coincidental association (Geffroy et al., 1998).
Symptoms characteristic of PWS have also been
described in a woman with a duplicated X chromosome,
random X-inactivation pattern and negative molecular
genetic studies for PWS (Monaghan et al., 1998). There
are also other observations indicating that on the proximal
long arm of the X-chromosome a gene or genes are located
that in case of malfunction result in obesity, mental retardation and small hands and feet (Tmer et al., 1998).
In addition, PWS patients with trisomy-X syndrome and
with XYY syndrome have been described (Honma et al.,
1999; Stalker et al., 2003).
23.2. Anorexia nervosa and bulimia nervosa

(Fig. 23B)
Anorexia nervosa is among the most disabling and lethal
of psychiatric disorders (Walsh and Devlin, 1998).
Anorexia nervosa was first described by Lasgue (1873)

and Sir William Gull (1873) (for references see Li Parry
Jones et al., 1994). The prevalence of eating disorders
among young females is about 0.3% for anorexia nervosa
and about 1% for bulimia nervosa (Hoek et al., 1995).
In fact, 93% of anorexia nervosa cases and 75% of bulimia
nervosa cases are found in women, an example of a clear
sex difference in psychiatric diseases (Chapter 1, Table
1.1). They are relatively rare disorders, with an incidence
rate of 0.8/10,000 for anorexia nervosa and 1.2/10,000
for bulimia nervosa. Comorbid psychiatric conditions
such as affective disorders, anxiety disorders, substance
abuse and personality disorders are frequently present
(Halmi, 2002). Cultural pressures are presumed by some
authors to play a role in the prevalence of these disorders, as indicated by cultural and historical differences in
prevalence (Bemporad, 1997; Walsh and Devlin, 1998).
Obstetric complications are mentioned as risk factors for
anorexia nervosa (Verdoux and Sutter, 2002). This
concerns in particular very early birth and birth traumas.
Fig. 23B. Alberto Giacometti (19011966) Piazza, 19471948 (cast 19481949). Bronze, 21 62.5 42.8 cm. Peggy Guggenheim Collection,
Venice (The Soloman R. Cuggenheim Foundation, New York); photograph by David Heald. Photograph 2003 The Solomon R. Cuggenheim
Foundation, with permission.
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The incidence of bulimia nervosa is lowest in rural areas

and highest in large cities (0.7/10,000 and 3.8/10,000
women per year, respectively). However, the epidemiological comparisons between different periods are full of
pitfalls (Wakeling, 1996). No ruralurban differences
were found for anorexia nervosa (Hoek et al., 1995).
There is no indication of a secular increase in the incidence of anorexia nervosa (Fombonne, 1995), but the
incidence of bulimia nervosa tends to increase (Hoek et
al., 1995). The incidence of mortality among anorexia
nervosa patients is generally said to range between 5 and
20%. However, in a long-term survival study in Rochester
(New York), anorexia nervosa patients did not differ from
controls. So the overall mortality was not increased
(Korndrfer et al., 2003). On average, less than one-half
of the anorexia patients recover, whereas one-third
improved. Twenty percent remain chronically ill (Barry
and Klawans, 1976; Ratnasuriya et al., 1991; Licinio et
al., 1996; Steinhausen, 2002). Suicide attempts are
frequent (27.8% of the women), often serious, and
multiple. Women who attempted suicide had higher
severity of depressive and general symptoms and more
impulse-disordered conducts.
Evidence is emerging that both anorexia and bulimia
nervosa are familial and that clustering in families may
arise partly from genetic transmission of risk (Kaye et
al., 1999; Strober et al., 2000; Wade et al., 2000;
Brambilla, 2001). Twin studies in bulimia indicate
substantial genetic variance (44%) and do not support a
strong role for shared environmental effects (Rowe et al.,
2002). A single patient with extreme obesity and bulimia
nervosa had a haplotype-insufficiency mutation in the
MC-4 receptor (Hebebrand et al., 2002) and significant
linkage was found on chromosome 10 in families with
bulimia nervosa (Bulik et al., 2003). SNPs in the AGRP
gene were found to be associated with an increased
susceptibility for anorexia nervosa and are presumed to
be caused by a defective suppression of the MC-4
receptor, leading to a decreased feeding signal (Vink et
al., 2001b). One patient has been described with both
bulimia nervosa and extreme obesity, and a haploinsufficiency mutation in the MC-4 receptor (Hebebrand et al.,
2002). Allele 13 of the polymorphic microsatellite marker
D11S911 is significantly overrepresented in the anorexia
nervosa population, and the UCP2/UCP3 genes on chromosome 11q13 are thought to play a role in the control
of energy expenditure and thermogenesis (Campbell et
al., 1999). Modest evidence for linkage of anorexia
nervosa with chromosome 4 and better evidence with
181
linkage with chromosome 1p was obtained (Grice et al.,

2002). Candidate genes for anorexia nervosa in the
1p3336 linkage region are the serotonin 1D and delta
opioid receptor loci (Bergen et al., 2003). In addition, a
5-HT2A promotor polymorphism has been reported in
anorexia nervosa (Sorbi, 1998), but a combined analysis
of 316 trios from six European centers did not reveal any
evidence for a significant role of the 5-HT2A gene in
anorexia nervosa (Gorwood et al., 2002). The frequency
with which the H (high) allele of the enzyme catecholO-methyltransferase occurs is significantly higher in
anorexia nervosa patients than in those not affected.
Individuals that are homozygous for the H allele run a
two-fold increased risk of developing anorexia nervosa
(Frish et al., 2001). Anorexia nervosa was found to be
associated with a polymorphism in the novel norepinephrine transporter gene promotor polymorphic region
(Urwin et al., 2002). Also variability in the estrogen
receptor- may contribute to the genetic susceptibility to
anorexia nervosa. An association was found between the
heterozygous genotype of the G1082A polymorphism and
anorexia nervosa (Eastwood et al., 2002). Genetic factors
also substantially contribute to the comorbidity between
anorexia nervosa and major depression (Wade et al.,
2000). Patients with congenital adrenal hyperplasia
compound heterozygotes for mutations/deletions of the
CYP21A2 gene may be at risk for anorexia nervosa
(Brand et al., 2000). Alterations in transmitters as biological factors involved in the pathogenesis of anorexia and
bulimia have been proposed repeatedly. Especially noradrenaline and 5-HT levels are lower in bulimia
(Brambilla, 2001). Moreover, 5-HT transporter availability is impaired in the hypothalamus (Tauscher et al.,
2001). Concerning the latter, studies show that postsynaptic hypothalamic-pituitary serotonergic pathways
are altered in anorexia, and that many differences tend
to persist despite a weight increase. After recovery,
anorexics still have increased levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of
serotonin. This suggests the existence of brain-related
serotonergic activation in the brain (Brewerton and
Jimerson, 1996; Kaye et al., 1998). In addition, increased
activity of the dopaminergic system in anorexia nervosa
has been hypothesized (Barry and Klawans, 1976).
Anorexia patients are more likely to be born in March
to June; a seasonal effect that may, e.g. be due to viral
factors (Waller et al., 2002). In 74% of anorexia and
bulimia patients, autoantibodies against -MSH, ACTH
and LHRH are found. It is not clear how they are involved
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in the pathogenesis of these disorders (Fetissov et al.,

2002).
Sociocultural factors (e.g. media and peer influences),
family factors (e.g. enmeshment and criticism, negative
affect, low self-esteem and body dissatisfaction) are often
mentioned as causal factors in eating disorders (Polivy
and Herman, 2002), although hard evidence for such
factors is lacking. In the lay press it is often stated that
anorexia nervosa is caused by the visually ideal body
image as perceived by girls watching extremely thin
fashion models. There has been a recent study on the
impact on eating behaviors and attitudes following
prolonged introduction of television among media-naive,
ethnic adolescent Fijian girls. Key indicators of disordered eating were significantly more prevalent following
exposure, and narrative data revealed the subjects interest
in weight loss as a means of modeling themselves after
television characters. This indeed suggests a negative
impact of television on disordered eating attitudes and
behaviors in a media-naive population (Becker et al.,
2002). However, clinical diagnoses were not sought in
this study, so that we do not know whether the introduction of television may indeed have induced anorexia
or bulimia nervosa in this population.
On the other hand, a study of six blind patients
has been published: the patients developed anorexia
nervosa but had been blind since infancy, which
suggests that eating disorders can develop independently
of cultural conceptions of feminine appearance (Sharp,
1993).
. . . It is not known whether minor cytologic changes occur
in any part of the hypothalamus to correspond with these
functional disturbances.
(Sheehan and Kovacs, 1982)
The well-known anorexia nervosa of girls seems to me on
careful observation to be a melancholia occurring where
sexuality is underdeveloped.
(Sigmund Freud in The Origin of Psychoanalyisis:
Letters to Wilhelm Fleiss, 1959)
(a) Symptoms
Anorexia nervosa is characterized by a series of hypothalamic symptoms (for review see Kaplan and Garfinkel,
1988), of which it is often not yet clear whether they are
related and primarily due to a hypothalamic process, or
state-related and secondary to the cachectic process (Kaye
et al., 1998; Stving et al., 2001). Depressed affect and

disturbance of body image have been reported prior to
the onset of anorexia in a 14-year-old girl (Morgan
and Lacey, 1996), which argues against the idea that
these symptoms are secondary to the cachectic process.
The same holds true for amenorrhea (see ii, below).
Many of these symptoms also occur in bulimia. In fact,
the two disorders are closely related: some 15% of the
patients with anorexia nervosa develop bulimia nervosa
(Ratnasuriya et al., 1991). The fact that third ventricle
enlargement in anorexia nervosa is greater than that of
the lateral ventricles supports the idea of hypothalamic
involvement (Golden et al., 1996). The putative hypothalamic symptoms include:
iiv(i) Eating disturbances and weight loss. Neuroimaging
shows morphological and functional alterations that
are at least partly reversible after weight gain. The
reversible shrinkage of the brain (pseudoatrophy)
also affects the pituitary gland. PET reveals caudate
hyperactivity. It is tempting, but purely speculative,
to relate the increased caudate dopamine activity to
the well-known increased body activity of these
patients (Barry and Klawans, 1976). Several mild,
rightleft asymmetries have been reported in
bulimia nervosa (Herholz, 1996). Body image
distortion is a core symptom and often persistent,
and it continues to pose a threat of relapse, even
after weight recovery. Images of their own body
induce an activation of the right amygdala and other
components of the fear network, as shown by
fMRI (Seeger et al., 2002).
iv(ii) Altered levels of steroid hormones, i.e. reduced
plasma concentrations of estradiol are found not
only in anorexia but also in bulimia nervosa. In
addition, secondary amenorrhea, decrease in libido,
and loss of secondary sexual characteristics are
observed (Kaplan and Garfinkel, 1988; Raboch
and Faltus, 1991; Monteleone et al., 1999; 2001;
Cotrufo et al., 2000; Stving et al., 2001). Primary
amenorrhea occurs in only 411% of cases (White
et al., 1993). In about 20% of cases, amenorrhea
takes place before a great deal of weight loss occurs.
Menstrual irregularities and amenorrhea also
occur in a high proportion (more than 30%) in
patients with a normal weight bulimia syndrome
(Ramacciotti et al., 1997). A strong association has
been found between bulimia and polycystic ovary
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syndrome (Chapter 24.1d): ultrasonography indicates that some 75% of patients with bulimia have
polycystic ovaries. Changes in bulimic eating may
mirror changes in ovarian morphology. The two
conditions may be linked by changes in peripheral
insulin sensitivity (Morgan et al., 2002). Even
in the absence of overt menstrual disturbances,
altered LH secretion elicited by LHRH stimulation
is found, with a more severe impairment in purging
than in nonpurging normal-weight bulimia
(Ramacciotti et al., 1998). Thus amenorrhea cannot
be adequately explained solely on the basis of
weight loss, which seems to be in favor of a primary
hypothalamic process. Low levels of gonadotropins
are generally reported and are possibly related
to the low leptin levels (see point xi, below). Both
bulimic and anorexia nervosa patients who are
underweight demonstrate an ACTH secretion
pattern that resembles that of prepubertal girls.
In this light it is interesting that anorexia and
cachexia go together with signs of hyperactivity in
the subregion of the hypothalamic infundibular
nucleus, i.e. the subventricular nucleus, probably
due to a lack of inhibitory feedback action of
sex hormones on this nucleus (see Chapter 11;
Hart, 1971). From a follow-up of anorexia nervosa
women, it appeared that they had only one-third
of the expected fertility, that the rate of prematurity
among their offspring was twice as high, and
that perinatal mortality was 6 times higher than
expected. So far no explanation has been given
for these reproductive disorders (Brinch et al.,
1988). There is also a relationship between the
phase of the menstrual cycle and bulimia symptoms.
The symptoms are exacerbated in both the midlateral and premenstrual phases (Lester et al., 2003)
indicating a role for steroid hormones.
Testosterone plasma levels are reported to be
increased in women with bulimia nervosa in one
study, and a positive correlation is found between
testosterone plasma levels and aggressiveness in
patients but not in controls (Cotrufo et al., 2000).
In another study, testosterone levels were decreased
in anorexia and unchanged in bulimia. Neuroactive
steroids such as 3,5-tetrahydroprogesterone,
DHEA and DHEAS exhibited increased plasma
levels in that study, both in anorexia and bulimia
(Monteleone et al., 2001).
183
(iii) The HPA axis is generally found to be hyperactive

in anorexia and bulimia (Licinio et al., 1996;
Monteleone et al., 1999; Cotrufo et al., 2000;
Neudeck et al., 2001). Although cortisol secretion
is not found to be markedly higher in anorexia
nervosa patients than in matched controls, and no
relationship has been found with cognitive functions
in a later study (Seed et al., 2002), various other
studies, with both plasma and salivary hormone
assays, have shown that there is an overdrive of the
HPA axis (Putignano et al., 2001). Bingeing and
vomiting in bulimic patients was associated with
modest increases in cortisol secretion (Weltzin
et al., 1991; Galderisi et al., 2003) and increased
DHEA(S) levels (Galderisi et al., 2003), while
normal-weight bulimic women showed normal
circadian ACTH and cortisol variations and levels
(Vescovi et al., 1996). A recent study showed that
elevated cortisol secretion followed exacerbation of
bulimic symptoms (Lester et al., 2003). Anorexia
and bulimia nervosa patients often have a marked
hypercortisolism but normal plasma ACTH. When
CRH was given, hypercortisolism was associated
with a marked reduction in plasma ACTH as a
response to the elevated levels of cortisol. When
these patients were studied shortly after their body
weight had been restored, hypercortisolism had
disappeared, but the abnormal response to CRH
remained unchanged. On the other hand, at least 6
months after the loss of weight had been corrected,
their responses returned to normal. These observations suggest that hypercortisolism in anorexia
reflects a defect at or above the level of the
hypothalamus (Gold et al., 1986). In addition,
CSF levels of CRH of anorexia patients are elevated
(Hotta et al., 1986; Kaye, 1996), which may also
reflect a change in extrahypothalamic rather than in
hypothalamic function (see Chapter 26.4). It should
be noted that CRH administration to experimental
animals may produce many of the symptoms
of anorexia nervosa, such as hypothalamic hypogonadism, decreased sexual activity, decreased
feeding behavior, hyperactivity and depression
(Holsboer et al., 1992; Kaye, 1996; Licinio et al.,
1996; see Chapter 26.4).
It has been hypothesized that self-starvation
through physical activity would activate the HPA
axis. Stimulated CRH activity would subsequently
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activate the reward system consisting of dopaminer2
gic neurons in the ventral tegmentum, whose
3
terminals are located in the nucleus accumbens.
4
Cortisol would enhance the reward by stimulating the
5
release of dopamine in this nucleus. Self-starvation
6
would thus be rewarding (Bergh and Sdersten,
7
1996; Wheatland, 2002). Evidence for such a vicious
8
circle as the pathogenic mechanism of anorexia
9
nervosa, however, has yet to be collected.
101 ii(iv) The hypothalamopituitarythyroid axis is hypo1
active in anorexic patients (Leslie et al., 1978).
2
The alterations fit into the euthyroid sick syndrome
3
(see Chapter 8.6). Thyroid volume is markedly
4
reduced in anorexia nervosa. Thyroid atrophy could,
5
hypothetically, be involved in a vicious circle main6
taining anorectic or depressive symptomatology
7
(Stving et al., 2001). The TSH response in anorexic
8
patients is often low or delayed. Following weight
9
recovery, TRH responses often continue to be
201
abnormal. The thyrotropin (TSH) response to TRH
1
of bulimic patients is blunted. In normal-weight
2
bulimic patients, T4, T3 and TSH levels are also
3
lower, as is the response to TRH (Kiyohara et al.,
4
1988; Schreiber et al., 1991b). These observations
5
contradict the idea that thyroid axis hypoactivity is
6
a result of malnutrition and support the idea of a
7
primary hypothalamic process.
8
iii(v) Basal GH levels are elevated in anorexia and IGF9
I levels are lower, probably due to the state of
301
malnutrition. GH response to GHRH, however, was
1
normal, indicating a disturbance at the hypothalamic
2
level in anorexia and bulimia. A hypothalamic
3
subsensitivity of postsynaptic D-2 receptors and a
4
presynaptic dopamine hypersecretion has been
5
proposed (Casanueva et al., 1987; Brambilla et al.,
6
2001; Stving et al., 2001) but not proven. The
7
enhanced growth hormone secretion in anorexic
8
patients is the result of an increased frequency of
9
secretory pulses superimposed on an enhanced tonic
401
secretion. These changes suggest the presence of
1
both an increased number of GHRH discharges and
2
a decreased somatostatin tone (Scacchi et al., 1997;
3
Stving et al., 2001). Indeed, the GHRH secreto4
gogue ghrelin was found to be elevated, both in the
5
anorexia nervosa, binge eating/purging-type and in
6
bulimia nervosa purging-type patients. Vomiting
7
may have a strong effect on this gastric peptide.
8
Since this gastric hormone is also an efficient
911
orexigenic factor, the increase of ghrelin levels

could be considered an adaptive mechanism,
promoting energy intake and fat stores (Tanaka et
al.,2003; Tolle et al., 2003). Bingeing and vomiting
in bulimic patients was associated with reduced GH
secretion (Weltzin et al., 1991).
ii(vi) Bingeing and vomiting in bulimic patients is accompanied by moderate prolactin increases according
to some authors (Weltzin et al., 1991), and with
reduced plasma prolactin concentrations according
to others (Monteleone et al., 1999; Cotrufo et al.,
2000). More attention should be paid to their
possibly altered circadian rhythms (see ix).
i(vii) Neurohypophysial disorders are present in anorexia
nervosa. A syndrome of partial diabetes insipidus
has been reported and vasopressin seems to be
secreted erratically, independent of plasma sodium
levels (Gold et al., 1983). The response to hypertonic saline is abnormal. The hyperintense MRI
signal in the posterior part of the pituitary was
reported not to be abnormal (Herholz, 1996).
However, an anorexia patient with high serum
vasopressin levels and an absence of the posterior
pituitary bright spot on MRI has also been described,
indicating increased release of vasopressin (Sato
et al., 1993). In addition, anorexic patients are
not able to excrete a large volume of water (Russell
et al., 1966), indicating hypersecretion of vasopressin. Moreover, hypersecretion of vasopressin
and reduction of oxytocin have been reported in
CSF of underweight anorexics (Demitrack et al.,
1989). The elevation of CSF vasopressin was
confirmed in women who had recovered from
anorexia nervosa/bulimia nervosa. In patients
recovered from bulimia nervosa, elevated CSF
vasopressin may be related to having a life-long
history of major depression (Frank et al., 2000).
There is impairment of the oxytocin response to
challenging stimuli, such as oestrogens and insulin
in underweight anorectic women. After complete
weight recovery, the oxytocin response, too, was
regained. This neuroendocrine abnormality thus
seems to be associated with starvation and/or weight
loss. The reduced CSF levels of oxytocin in
anorexics (Demitrack et al., 1989) were not
expected, because of the feeding behavior inhibiting
effect of this peptide (Swaab et al., 1995a).
Although a later study showed increased CSF
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oxytocin levels, they may be related to the use of

birth control pills and not to the eating disorder in
some bulimia patients (Frank et al., 2000).
(viii) The basal temperature is unusually reduced, and
the temperature regulation in heat and cold is
disturbed. Heat and cold intolerance have, however,
also been found due to weight loss (Vela-Bueno
et al., 1984);
ii(ix) In anorexia, circadian variation of blood pressure
is absent. This reverts to normal after refeeding
(Awazu et al., 2000). In anorectic patients, not only
were leptin levels low; their relative diurnal variation was strikingly reduced in one study (Stving
et al., 2001), or qualitatively altered (Herpertz
et al., 1998); while, in another study (Herpertz et
al., 2000), diurnal secretion patterns were found to
be preserved, even in the severe state of emaciation. Also, the levels of plasma cortisol often show
a loss of the normal diurnal rhythm (Hotta et al.,
1986; Herpertz et al., 1998), pointing to a disorder
in the circadian timing system. However, others
reported that the circadian variations in cortisol
remained the same despite an increase in the mean
levels of cortisol (Balligand et al., 1998). Hypercortisolism in underweight anorexics reflects
hypersecretion of hypothalamic CRH rather than
primary glucocorticoid resistance (Kling et al.,
1993). Hypercortisolism is presumed to cause a loss
of circadian rhythms (Awazu et al., 2000). Our
observation that corticosteroid treatment of patients
for different reasons decreases vasopressin mRNA
in the SCN (Liu et al., 2003, submitted) agrees with
this idea. In a subsample of bulimia patients who
experienced reversed symptoms such as hypersomnia and hyperphagia when they were depressed,
low plasma cortisol levels were observed. These
lower levels may, however, have been due to circadian phase alterations (Levitan et al., 1997).
Prolactin, ACTH, -endorphin and melatonin circadian rhythms are also disturbed in anorexia and
bulimia nervosa according to some studies (Ferrari
et al., 1990; Kaye, 1996; Pacchierotti et al., 2001)
and the circadian rhythm of leptin is completely
abolished (Balligand et al., 1998). Bulimic women
have blunted nocturnal prolactin patterns (Weltzin
et al., 1991). Other studies report that the circadian
rhythm of melatonin was unaltered in bulimia and
anorexia (Brown, 1992), and that the nocturnal
185
Fig. 23.12. Seasonal variation in binge eating, purging and feeling worst
among 31 bulimic and 31 comparison subjects. Binge eating (a), purging
(b), and feeling worst (c) were determined according to the modified
seasonal pattern assessment questionnaire. Number of dark hours was
defined as 24 h minus the average photoperiod for each month.
(a) A significant group effect (F = 103.99, df = 1, 60, p < 0.001), month
effect (F = 9.91, df = 11, 50, p < 0.001) and group by month interaction (F = 7.06, df = 11, 50, p < 0.001) were found. The correlation
between number of dark hours and likelihood of binge eating was
significant (r = 0.97, df = 12, p < 0.001).
(b) A significant group effect (F = 83.77, df = 1, 60, p < 0.001), month
effect (F = 3.99, df = 11, 50, p < 0.001) and group by month interaction (F = 2.76, df = 11, 50, p < 0.007) were found. The correlation
between number of dark hours and likelihood of purging was significant (r = 0.94, df = 12, p < 0.001).
(c) A significant group effect (F = 6.46, df = 1, 60, p < 0.02) and group
by month interaction (F = 2.50, df = 11, 50, p < 0.02) were found.
The correlation between number of dark hours and likelihood of
feeling worst was significant (r = 0.92, df = 12, p < 0.001). (Blouin
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secretion of melatonin was significantly greater in
2
anorectics (Arendt et al., 1992; Luboshitzky et al.,
3
2001), or even that there was an enhanced circa4
dian rhythm of melatonin in anorexia nervosa with
5
higher diurnal and nocturnal plasma melatonin
6
levels (Tortosa et al., 1989). That the night levels
7
of serum melatonin in patients with anorexia are
8
increased was confirmed by Manz et al. (1990).
9
Since, a significant decrease in melatonin secretion
101
has been found, coexisting with depression in
1
patients with eating disorders, which may at least
2
partly explain the variable results in the literature
3
on this topic (Kennedy et al., 1990; Brown, 1992).
4
A clear seasonal pattern has been reported in the
5
signs and symptoms of bulimia nervosa. Bingeing
6
behavior and mood disorders were found to be
7
closely associated with the photoperiod in that the
8
symptoms are the most severe in winter and the
9
least severe in summer (Blouin et al., 1992; Fig.
201
23.12). Such seasonal changes are not present in
1
anorexia nervosa (Lam et al., 1996a). In bulimic
2
patients with worsening of mood and eating symp3
toms in winter, bright white light therapy was effec4
tive for both symptoms (Lam et al., 1994), an
5
important observation that has so far not gained
6
much following. However, it should be noted that
7
Pasternak and Zimmerman (2002) did not find
8
higher rates of bulimia in winter in an outpatient
9
psychiatric practice in the USA.
301 iii(x) Various peptides that are involved in the regulation
1
of food intake (Chapters 11, 23c) show alterations.
2
Reduced CSF -endorphin levels have been found.
3
This peptide stimulates feeding behavior (Kaye,
4
1996). Plasma -endorphin concentrations were sig5
nificantly higher in bulimic than in control subjects
6
at all time points (Vescovi et al., 1996). Since nalox7
one has some effects in the treatment of anorexia
8
(Moore et al., 1981), the opiate system, too, should
9
have research attention. It is not remarkable that ele401
vated CSF levels of NPY have been found in anorec1
tics (Krysiak et al., 1999), since this peptide is
2
upregulated by lower levels of leptin (see Chapter
3
23b) (Kaye, 1996; Krysiak et al., 1999). Galanin is
4
an orexigenic peptide that stimulates appetite and
5
fat consumption. The galanin level in the CSF of
6
recovered anorexia nervosa patients is lower than
7
that of controls, and may thus play a role in food
8
restriction and fat avoidance (Frank et al., 2001).
911
Leptin is a satiety factor that is produced by fat
cells. The protein is encoded by the LEP gene and

acts on the arcuate nucleus and other hypothalamic
areas to reduce food intake (see Chapter 23b). Both
serum and CSF leptin levels are lower in anorexia
nervosa patients but appropriate to body-weight
decrease. However, altered transport of leptin over
the bloodbrain barrier is presumed. Weight gain in
anorexia patients leads to steep increases in leptin
plasma levels. Low leptin levels are also associated
with amenorrhea. A critical leptin level seems to be
needed to maintain menstruation (Grinspoon et al.,
1996; Hebebrand et al., 1997; Kpp et al., 1997;
Balligand et al., 1998; Herpertz et al., 1998; Stving
et al., 1998; Mantzoros, 2000). Recently, increased
fasting plasma levels of ghrelin have been reported
in patients with bulimia nervosa; this peptide stimulates eating (Tanaka et al., 2002).
ii(xi) Using single photon emission computed tomography
(SPECT), a reduced hypothalamic and thalamic
5-HT transporter availability was found in bulimia
nervosa. The impaired 5-HT transporter availability
was more pronounced with longer duration of the
illness (Tauscher et al., 2001). The association with
the presence of 5-HT2A promotor polymorphism
in anorexia (Sorbi et al., 1998) may be related to
such alterations. Because elevated concentrations
of 5-HIAA were found in the CSF of anorexia
and bulimia nervosa patients after recovery, altered
5-HT metabolism is proposed to be a trade-related
characteristic (Kaye et al., 1998) and may be the
basis of the therapeutic effects of SSRIs.
i(xii) One of the most paradoxical features of anorexia
nervosa is that, during periods of extreme caloric
restriction and weight loss, the majority of patients
display abnormally high levels of physical activity.
Interestingly, in many kinds of animals, heightened
locomotion is a behavioral marker of sensitivity to
stress (Davis et al., 1999b).
(xiii) Whether the elevated pain threshold in anorexia nervosa, bulimia nervosa and binge-eating disorder
(Raymond et al., 1999; see Chapter 23.3) is based
upon a hypothalamic pain mechanism (Chapter 31)
remains to be investigated.
(b) Hypothalamic tumors mimicking anorexia nervosa
The possibility that anorexia and bulimia may primarily
be a hypothalamic disease is reinforced by a number of
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case histories of patients who were, after they had been

diagnosed to suffer from anorexia and sometimes
subjected to psychotherapy, at autopsy, found to have a
tumor in the hypothalamus. These cases not only include
a number of children that had atypical anorexia, but also
adults with a typical diagnosis of anorexia nervosa.
In cases of anorexia it may be difficult to differentiate
between psychogenic and organic causes. Psychological disturbances without neurological manifestations
may be due to occult intracranial tumors masquerading
as anorexia nervosa (DeVile et al., 1995). In a neonate,
an obstinate anorexia and a subsequent failure to gain
weight had been present since birth. At autopsy, at 6
months of age, an astrocytoma, probably originating from
the meninges and occupying the third ventricle, was
found. The tumor was not sharply demarcated from the
hypothalamic regions and was continuous with the
meninges (Kagan, 1958). A 10-year-old child with a diagnosis of major depression and atypical anorexia nervosa
was found to have a teratoma in the hypothalamic region
(Chipkevitch and Fernandes, 1993). DeVile et al. (1995)
describes three boys with tumors affecting the hypothalamus and invading the brainstem, causing psychological
dysfunction and anorectic symptoms without initial neurological signs. The CT scans of all three patients were
normal. The children suffered from, respectively, a craniopharyngioma, a disseminating pineal germinoma, and a
low-grade astrocytoma. A 13-year-old girl with anorexia
nervosa was found to have an infiltrating tumor in the
left hypothalamic area. The symptoms abated after the
tumor was irradiated (Weller and Weller, 1982).
In various adult patients who had been diagnosed to
suffer from anorexia nervosa, it also turned out to be a
tumor that appeared to be the cause. A 22-year-old girl
with a psychiatrists diagnosis of anorexia nervosa
suddenly lost consciousness, had an epileptic fit and died
in coma. She had been obsessed by her weight. Her condition deteriorated after learning that her father suffered
from an inoperable carcinoma. She probably also suffered
from diabetes insipidus and had developed pneumonia.
In retrospect, she suffered from hypopituitarism. She
had a hypothalamic tumor, atypical pinealoma (no tumor
cells were found in the pineal gland), seminoma, dysgerminoma or atypical teratoma (Clinicopathological
Conference, 1973).
Another case was that of a 62-year-old woman who
became extremely cachectic and refused to eat. According
to a psychiatrist she had anorexia nervosa. At autopsy,
her brain revealed a cystic lesion on the wall of the
187
third ventricle at the level of the infundibulum, which

was bordered medially by normal ependymal and subependymal tissue. The cyst had caused a decrease in
hypothalamic substance. The lateral hypothalamic nuclei
showed paucity of neurons (White and Hain, 1959).
A 22-year-old woman with anorexia nervosa first went
through a phase of nonspecific and inconsistent signs and
symptoms such as sleep disturbances and increased fluid
intake. The psychodynamic features were the most
striking, but the characteristics of the ventromedial hypothalamic syndrome complicated the psychiatric picture;
she had urges to kill people and induced vomiting whenever she overate. Eventually the intractable headaches and
loss of visual fields pointed to a hypothalamic tumor. The
craniopharyngioma was removed (Climo, 1982).
Yet another case report concerns a 25-year-old woman
with a history of secondary amenorrhea and weight loss.
Her father had died six months earlier, after which she
had begun to lose weight. A diagnosis of anorexia nervosa
was made. She suffered from sudden losses of consciousness, with low blood sugar levels and died 2 weeks later
from an infection. The hypothalamus contained a small,
0.5-cm-diameter, circumscript astrocytoma immediately
posterior to the optic chiasm and to the right of the tuber
cinereum (Lewin et al., 1972).
Although these case histories show that all the signs
and symptoms of anorexia nervosa can be found in
patients with a hypothalamic tumor, including the characteristic that the psychodynamic features are the most
outstanding, it should be noted that these are rare cases
and that the majority of the hypothalamic tumors are not
associated with symptoms of anorexia nervosa.
(c) Association with other disorders
Comorbidity between eating disorders and other psychiatric diseases is common, e.g. with depression, anxiety
disorders, oppositional defiant disorder and substance
abuse (Rowe et al., 2002). Bulimia has been found to be
associated with Parkinsons disease (Rosenberg et al.,
1977). Bulimia disappeared in these Parkinson patients
following L-DOPA treatment. This indicates that a
disorder of the dopaminergic system might be a basis for
the change in appetite in bulimia (Rosenberg et al., 1977),
but no direct data on this possibility are available. The
presence of bulimia in Parkinson patients may also fit in
with the idea that oxytocin neurons of the paraventricular nucleus are satiety cells (Swaab et al., 1995a),
because their number decreases in Parkinsons disease
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(Purba et al., 1994). Bulimia may also be present in

borderline personality disorder. In addition, a greater lifetime presence of binge eating was found among survivors
of the Nazi concentration camps, who survived a period
of extreme food deprivation (Favaro et al., 2000).
Moreover, a 28-year-old man with anorexia and bulimic
eating behavior had a hydrocephalus internus, presumably due to a stenosis of the aquaduct (Pauls et al., 1991).
Anorexia nervosa associated with Klinefelters syndrome
has been described in several cases (El-Badri and Lewis,
1991). Primary amenorrhea occurs in 411% of the
anorexia cases. In case of primary amenorrhea, Kallmann
syndrome, for instance, should be excluded (White et al.,
1993). Medicine-induced eating disorders have been
reported with fluoxetine, clozapine, apomorphine and
amphetamine (Barry and Klawans, 1976; Morgan and
Lacey, 1996). For bulimia associated with KleineLevin
syndrome, see Chapter 27.1.
On clinical grounds, it is difficult to distinguish
anorexia nervosa from Simmonds pituitary cachexia
(Richardson, 1939). Simmonds disease was described
to arise from adenohypophysial failure, but was later
also found to occur in patients with an intact pituitary,
but with tumors or inflammatory processes in the region
of the third ventricle (Kagan, 1958). Heterozygous
carriers for Wolframs syndrome (see Chapter 22.6)
have also been hospitalized for anorexia (Swift et al.,
1991). Moreover, a case with acute pandysautonomia
presented with the diagnosis anorexia nervosa (Okada,
1990).
Since hypothalamic tumors may fully mimic anorexia
nervosa (Chapter 23.2b), one should, in the case of eating
disorders, look, in postmortem tissue, for hypothalamic
conditions that may be involved in the etiology, such as
autoimmune processes. The case of anorexia nervosa of
the bulemic subtype in a 14-year-old girl following withdrawal of oral prednisolone used in the treatment of
asthma (Morgan and Lacey, 1996) supports the possibility of an autoimmune process underlying this condition
(although this possibility is not mentioned as such by the
authors). No great changes in peripheral immunocompetence are generally found in anorexia nervosa (Marcos et
al., 1997; Staurenghi et al., 1997). However, in one case
of anorexia nervosa, vacuolization of the TMN was
observed with moderate gliosis and myelinization of the
vessels. The vacuolization and gliosis extended to the
paraventricular nuclei and the massa intermedia, where a
strong microglial reaction was observed (Martin, 1958).
This observation points to the possibility of a central
immune process as a basis of anorexia nervosa, a concept

that is reinforced by changes in cytokine levels observed
in anorexia and bulimia nervosa (Holden and Pakula,
1996). The possibility that anorexia and bulimia nervosa
are based upon a hypothalamic autoimmune process is
strongly supported by the presence of autoantibodies
against hypothalamic neuropeptides (Fetissov et al.,
2002), and by the five patients mentioned in the literature
who were successfully treated with corticosteroids and
ACTH (Wheatland, 2002).
(d) Therapy
For light therapy in bulimia nervosa, see Chapter 23.2a
(ix). Cognitive psychotherapy is the treatment of choice
in anorexia nervosa (Halmi, 2002) and is reported to be
effective in 6070% of the individuals with bulimia
nervosa, while fluoxetine reduces binge frequency,
although the relapse rate is considerable (Walsh and
Devlin, 1998). Psychoanalytical and family therapy are
said to be of specific value in the outpatient treatment of
adult patients with anorexia (Dare et al., 2001). In a
randomized controlled trial, 16 patients with anorexia and
bulimia were trained to eat and recognize satiety by using
computer support. Fourteen patients (75%) of the treatment group went into remission in the mean time of 14.7
months, while only 1 untreated control went into remission. Only 7% of those who were treated with this method
to remission relapsed, while 93% remained in remission
for 12 months, so this method seems to be effective
(Bergh et al., 2002).
Selective 5-HT reuptake inhibitors are not very useful
when anorexia nervosa patients are malnourished and
underweight. When given after weight restoration, these
medicines may reduce the extremely high rate of relapse
seen in anorexia (Brewerton and Jimerson, 1996; Kaye,
1997; Kaye et al., 1998). In addition, fluoxetine adds a
modest beneficial effect to cognitive-behavioral therapy
in bulimia nervosa (Stunkard, 1997; Walsh et al., 1997).
In bulimia nervosa, cognitive behavioral therapy seems
to be superior to imipramine alone. In anorexia nervosa
the progress in treatment is modest. Family therapy seems
to be more effective than standard, individual supportive
therapy. In addition, tricyclic antidepressants are effective (Brambilla, 2001). When patients recover from
anorexia nervosa, insulin hypersensitivity remained the
insulin response to the meal was blunted and apparently
delayed. There may be a persistent alteration in pancreatic
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Fig. 23C. Ren Magritte, Le Sorcier (autoportrait), 1951. Huile sur toile, 35 46. Galerie Isy Brachot, Bruxelles 1992. By C.H. Adagp
et Flammarion 4, Paris 6, 19 rue Visconti. Imprim en France XF 1055. (Reproduced with permission Ren Magritte Le Sorcier,
c/o Stichting Beeldrecht.)
dominates; whereas, in the second syndrome, neurological

complications are very unusual (Soliman et al., 1996).
Because of the overlapping phenotypes between Bardet
Biedl syndrome and LaurenceMoon syndrome, Beales
et al. (1999) proposed the name polydactyly-obesitykidney-eye syndrome as a unifying descriptive label.
BardetBiedl syndrome (BBS MIM no. 209900) is genetically heterogeneous, with six known loci: BBS1 (11q13),
which is the most frequent one, accounting for about
50% of the cases, BBS2 (16q21), BBS3 (3p13-p12),
BBS4 (15q22.3-q23) and BBS5 (2q31) (Haider et al.,
1999; Woods et al., 1999; Young et al., 1999; Mykytyn
et al., 2002). In families from New Foundland, mutations
in the chaperone-like gene MKKS were found to cause
obesity, retinal dystrophy and renal malformations associated with BardetBiedl syndrome, while mutations in
BBS1 to -5 were excluded (Katsanis et al., 2000). BBS6
is caused by mutations in the gene MKKS (Mykyntyn
et al., 2001). Mutations in the MKKS gene also cause
McKusickKaufman syndrome, which is related to
BardetBiedl syndrome (Schaap et al., 1998; Mykytyn
function, or alternatively this may be a trait marker for

anorexia nervosa (Brown et al., 2003b).
23.3. Other eating disorders (Fig 23C)
(a) LaurenceMoon/BardetBiedl syndrome
LaurenceMoon/BardetBiedl syndrome is a rare
(1:1,000,000), heterogeneous disorder that includes the
following cardinal symptoms: obesity starting at 23
years, hypogenitalism, mental retardation (predominantly
verbal), retinitis pigmentosa (which becomes apparent
around 8 years), short stature, renal abnormalities and
polydactyly or syndactyly. The disorder is also associated
with diabetes mellitus, hypertension and congenital heart
disease (Stoler et al., 1995; Soliman et al., 1996; Beales
et al., 1999). The syndrome has an autosomal recessive
mode of inheritance (Lerner et al., 1995). It is suggested
that this syndrome comprises two disorders: the Laurence
Moon syndrome, and the BardetBiedl syndrome. In the
first syndrome, polydactyly is rare and spastic paraparesis
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et al., 2001, 2002). In spite of the obesity and hypogonadism in LaurenceMoon/BardetBiedl syndrome, there
is so far only little and inconsistent evidence that lesions
of the hypothalamus may account for these conditions.
In some older case histories fewer large cells were
reported in the tuberal nuclei, fewer cells in the corpora
mamillaria, and slight demyelination of the optic tracts
and chiasm. Also, moderate paraventricular gliosis has
been reported, but other studies mention the hypothalamus to be normal (McLoughlin and Shanklin, 1967).
Systematic work with quantitative state-of-the-art techniques is needed to establish whether there is indeed
hypothalamic involvement in this disorder.
(b) Biemonds syndrome
absence of mental retardation, and the combined occurrence of nerve deafness, diabetes mellitus and chronic
nephropathy. Analysis of the family data is compatible
with an autosomal recessive mode of inheritance, and the
multiple clinical manifestations are, therefore, explained
on the basis of homozygosity for mutant genes at a single
autosomal locus (Goldstein and Fialkow, 1973). The gene
ALMS1, which contains sequence variations, including
four frameshift mutations and two nonsense mutations,
segregates with Alstrms syndrome in six unrelated families (Collin et al., 2002).
(d) Night eating syndrome
Biemonds syndrome type 2 is a recessive inherited condition (MIM no. 210350) comprising mental retardation,
coloboma, obesity, polydactyly, hypogonadism, hydrocephalus and facial dysostosis. Clinically the disorder is
closely related to BardetBiedl syndrome. Several related
clinical forms are distinguished as new nosological entities (Verloes et al., 1997). Short stature and delayed sexual maturation are features also present in BardetBiedl
syndrome. The growth disturbance may partly be due to
the defective testosterone secretion. The presence of an
empty sella has also been described in this syndrome.
Hypogonadism can be attributed in this disorder to
primary gonadal failure with or without hypothalamicpituitary disfunction. Obesity is the major determining
factor of hyperinsulinemia, also in BardetBiedl syndrome
(Soliman et al., 1996). Molecular studies indicate that the
syndrome is genetically heterogeneous with major loci at
chromosome 11q, 15q, 16q and a rare locus at 3q. The
genes have not yet been cloned (Schaap et al., 1998).
A new, related eating disorder that is different from

anorexia nervosa, bulimia nervosa and binge eating, is
the night eating syndrome. It is characterized by morning
anorexia, evening hyperphagia and insomnia and occurs
during periods of stress. Its prevalence has been estimated
at 1.5% in the general population and some 27% of
severely obese persons. The mood of the night eaters falls
during the evening. There are circadian changes, such as
an attenuation of the night-time rise in melatonin and
leptin and elevated levels of plasma cortisol (Birketvedt
et al., 1999). Night-time awakenings are far more common
among night eaters than among controls and more than
half the number of the awakenings are associated with
food intake. The typical neuroendocrine characteristics
are an attenuation of nocturnal rises in melatonin and
leptin and increased diurnal secretion of cortisol. The
CRH-induced ACTH and cortisol response are reduced
in night eaters (Birketvedt et al., 2002). Observations that
light improves the symptoms of night-time eating
syndrome (Friedman et al., 2002) should be further tested
in controlled studies.
(c) Alstrms syndrome
(e) Binge eating disorder
Alstrms syndrome is characterized by profound blindness due to retinal degeneration, infantile obesity,
deafness, diabetes mellitus due to resistance to the action
of insulin, and slowly progressive nephropathy. Males
have a unique variety of hypogonadism in which normal
secondary sexual characteristics occur despite small
testes, low plasma testosterone and elevated gonadotropins. The features that distinguish Alstrms syndrome
from the LaurenceMoon/BardetBiedl syndrome are the
A new diagnostic concept that has provisional status in

DSM-IV is binge eating disorder. Like bulimia nervosa
it has binge eating as a central feature, but there is little
or no weight-control behavior, such as self-induced
vomiting and laxative misuse. Some 40% of the binge
eating disorder cohort met criteria for obesity in a 5-year
follow-up, and this group of patients is highly prevalent
(130% among often extremely obese subjects seeking
weight-loss treatment) (Dingemans et al., 2002; Hsu
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et al., 2002). The rate of childhood emotional abuse is

some 23 times more prevalent in this eating disorder
than in a normative adult female sample. No other forms
of childhood maltreatment, such as physical or sexual
abuse, or emotional or physical neglect, were increased
in binge eating disorder (Grilo and Masheb, 2002). Bingeeating is a major characteristic of subjects with a mutation
in the MC4 receptor (Branson et al., 2003). The treatment of choice is currently cognitive behavioral treatment,
but interpersonal psychotherapy, self-help and SSRIs
seem effective (Dingemans et al., 2002).
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(f) Miscellaneous
Other eating disorders include Frlichs syndrome and
the related ventromedial hypothalamic syndrome (Chapter
26.3), KleineLevin syndrome (periodic somnolence and
morbid hunger; Chapter 28.1) and PraderWilli-like
syndrome, which have a different genetic background
(Chapter 23.1d).
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CHAPTER 24
Reproduction, olfaction and sexual behavior (Figs. 24A, B)
Long before the human species appeared, the pinnacle of

evolution was already the brain as it had been before
mammals appeared, before land vertebrates, before vertebrates. From this point of view, everything else in the
multicellular animal world was evolved to maintain and
reproduce nervous systems that is, to mediate behavior,
to cause animals to do things. Animals with simple and primitive or no nervous system have been champions at surviving,
reproducing, and distributing themselves, but they have
limited behavioral repertoires. The essence of evolution is
the production and replication of diversity and more than
anything else, diversity in behavior.
T.H. Bullock (1984)
The central peptide for reproduction, luteinizing

hormone-releasing hormone (LHRH), is synthesized as a
92-amino acid precursor that is subsequently cleaved to
form the decapeptide LHRH. Pulsatile LHRH acts at
the LHRH receptor on gonadotropic-hormone-containing
neurons in the pituitary and is required to maintain
gonadotropin synthesis and secretion. Acute administration of LHRH induces a marked release of LH and
follicle-stimulating hormone (FSH). However, chronic
administration of LHRH induces an inhibition of the
gonadal axis through the process of downregulation of
pituitary receptors for LHRH. This is the basis for application of LHRH in gynecology and oncology, e.g. in
treating mamillary, ovarian, endometrial and prostate
cancer and hamartomas (Chapter 19.3). The pituitary
gonadotropins LH and FSH stimulate steroid production
and gametogenesis in males and females. Genetic
abnormalities have been identified on all levels of
the hypothalamopituitarygonadal axis (Ackerman
et al., 2001). The distribution of the LHRH (=
GnRH)-synthesizing neurons and fibers in the hypothalamus and adjacent areas is described in Chapters 11 and
24.2, as well as by Stopa et al. (1991) and Duds
Fig. 24A. Pregnant woman. Marc Chagall, 1913. Stedelijk Museum,

Amsterdam, in bruik-leen van: Instituut Collectie Nederland (with
permission.)
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Fig. 24B. Activating effects of sex hormones on the brain. Arend van Dam, with permission.
et al. (2000). LHRH is present in the human brain in

three isoforms (Chen et al., 1998; Yahalom et al., 1999).
The human hypothalamic LHRH pulse-generating mechanism is located entirely within the mediobasal
hypothalamus, as shown by in vitro perfusion techniques
(Rasmussen, 1992). The frequency and amplitude of
LHRH pulses determine gonadotropin subunit gene
expression and secretion of pituitary LH and FSH. During
ovulatory cycles, an increase in LHRH frequency (more
than 1 pulse per hour) during the follicular phase favors
LH synthesis prior to the LH surge, while, after ovulation, luteal steroids slow LHRH pulses to favor FSH
synthesis. Thus, a changing frequency of LHRH stimulation is one of the mechanisms involved in differential
gonadotropin secretion during ovulatory cycles (Seminara
et al., 1998; Marshall et al., 2001).
A large number of factors modulate the function of the
LHRH neurons, and thus the LH pulsatile secretion. As
found in many species, also in young healthy men, light
exposure increases LH secretion (Yoon et al., 2003).
Genetic abnormalities have been identified on all levels
of the hypothalamopituitarygonadal axis (Ackerman et
al., 2001). The sequential acceleration and deceleration
of the LHRH pulse generator and subsequent LH pulse
frequency during the menstrual cycle are to a certain
degree determined by cyclic changes in endogenous
opioid peptides such as -endorphin, probably derived
from the infundibular nucleus (Ferin et al., 1984; Gindoff
et al., 1987; Kalra et al., 1997; Chapter 31.1). In postmenopausal women this inhibitory opioid tone on LHRH
release diminishes, as appears from the decreased proopiomelanocortin mRNA expression in the infundibular
nucleus (Abel and Rance, 1999). In addition, estradiol
and progesterone act at a hypothalamic site to modulate
LHRH signals. Estradiol primarily affects the amplitude,
while progesterone decreases the frequency of the LHRH
pulse (Ferin et al., 1984). Participation of a number of
hypothalamic neurotransmitters/neuromodulators in the
release of LHRH is apparent, i.e. neuropeptide-Y (NPY),
GABA, galanin, excitatory amino acids, substance-P,
and nitric oxide (Kalra et al., 1997; Duds et al., 2000;
Duds and Merchenthaler, 2002), and catecholamines
modulate the LHRH release. Tyrosine hydroxylase
containing terminals, possibly coming from the supraoptic
(SON), paraventricular (PVN) and periventricular nuclei
are found on LHRH neurons (Duds and Merchenthaler,
2001). Melatonin inhibits the hypothalamopituitary
gonadal axis before the onset of puberty (Lavie and
Luboshitzky, 1997; Chapter 4.5d). Moreover, melatonin
secretion is increased in patients with LHRH deficiency,
irrespective of its etiology (Kadva et al., 1998). Testosterone decreases melatonin secretion to normal levels in
these patients (Luboshitzky et al., 1995, 1996, 1997a),
indicating that pineal function is altered in relation to
the gonadal status. High training activity and dark
photoperiod independently suppress ovarian function
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(Ronkainen et al., 1985). The strongly diminished

estrogen levels in postmenopausal women induce hyperactivity of LHRH neurons (Wise, 1998; Chapter 11f).
In the human male, testosterone exerts both direct and
indirect feedback on LH secretion, whereas its effects on
FSH appear to be mediated largely by aromatization to
estradiol, which is thus the predominant regulator in
FSH secretion (Hayes et al., 2001). There is an attenuation of LH and testosterone secretory pulse amplitude,
and disruption of their orderly patterns of release in
healthy older men (Veldhuis, 2000). Testosterone levels
decline with age in men, but not so dramatically, and
with great interindividual variability (Sternbach, 1998;
Feldman et al., 2002), resulting in a moderate stimulation
of LHRH neurons (Chapter 11f). Bioavailable testosterone
decreases 0.53% per year in men. Dehydroepiandrosterone sulfate (DHEAS) and estrone also decline with
age, whereas dihydrotestosterone rises (Feldman et al.,
2002). The decline of free testosterone in men already
starts when men are in their 30s and 40s. In addition, the
circadian rhythm of testosterone flattens out in the elderly
(Baulieu, 2002; Chapter 4.3).
Functional MRI (fMRI) studies show that sexual
arousal in males, but not in females, is accompanied by
an activation of the right hypothalamus (Arnow et al.,
2002; Karama et al., 2002). This technique does not allow
determination of exactly which hypothalamic structures
are involved. Interestingly, in patients with psychogenic
erectile dysfunction, sublingual administration of apomorphine caused extra activation of the hypothalamus during
video sexual stimulation. Apomorphine acts on the
oxytocinergic neurons in the paraventricular nucleus,
which plays a key role in regulating penile erection
(Chapter 8g; Montorsi et al., 2003). There is a strong
correlation between testosterone levels and male sexual
activity, both in cross-sectional and longitudinal studies.
In addition, correcting testosterone deficiency in hypogonadal men improves sexual desire, activity and mood
(Anderson et al., 1992a; Wang et al., 2000a; Yates, 2000).
Testosterone not only stimulates both male and female
sexual behavior, it is also enhanced by sexual behavior.
Although the salivary testosterone levels in males are
much higher (7.4 ng/dl) than in females (1.4 ng/dl), in
both sexes a similar increase in testosterone levels is
found across the evening when there is intercourse, and
a decrease when there is no intercourse (Dabbs and
Mohammed, 1992). This relationship between testosterone and coitus must, however, be regarded as tentative
in view of the studies finding no change in testosterone
195
levels (Meisel and Sachs, 1994). Interestingly, men with

paraphilia have a prompt reduction or total abolition of
all paraphilic activities, while being treated with a longacting analogue of LHRH that serves to reduce
testosterone levels (Rosler and Witzum, 1998). A curious
finding is that expectant fathers have lower testosterone
and cortisol levels, more frequently detectable estradiol
levels, and elevated prolactin levels. The functional
meaning of these changes for fatherhood is not known
at present (Berg et al., 2001).
The ovaries provide approximately half the circulating
testosterone in premenopausal women (Shifren et al.,
2000). The disappearance of androgens such as
androstenedione, testosterone, DHEA and DHEAS after
ovariectomy and adrenalectomy in women is accompanied by a complete loss of libido, whereas substitution
of androgens maintains sexual desires and fantasies after
surgical menopause. Circulating levels of androgens
decline gradually with increasing age and the circadian
rhythm of testosterone disappears in older age (Bremner
et al., 1983). Prudent administration of testosterone to
healthy premenopausal women causes increases in vaginal
arousal, genital sensations and lust (Shifren et al., 2000;
Tuiten et al., 2000; Davis and Tran, 2001; Schill, 2001).
Around the menopause in women there is a continuous
rise in serum FSH and LH and a concomittant fall in
estradiol and estrone levels (Overlie et al., 1999). Some
publications report a decline of androstendione and testosterone 3 years before menopause (Overlie et al., 1999),
while others observe a small rise of these two androgens
in postmenopausal women (Jiroutek et al., 1998). Sex
hormones are thought to play a role in cognition also,
although the literature on the possible effects of estrogens in Alzheimers disease is certainly still controversial
(see Chapter 29.1b). In older men low estrogen and high
testosterone levels predict better performance on several
tests of cognitive function (Barrett-Connor et al., 1999a).
Testosterone has a differential effect on cognitive function, inhibiting spatial abilities while improving verbal
fluency in eugonadal men (OConnor et al., 2001).
Apart from regulating sex hormones (see below and
Chapter 24.5), neuropeptides play a role in sexual
behavior, as has been shown, mainly, but not only in
animal experiments. A facilitatory role for sexual behavior
is assigned to corticotropin (ACTH), alpha-melanotropin
(-MSH) and oxytocin. Oxytocin is acutely released after
orgasm in men, while vasopressin plasma levels remain
unaltered (Krger et al., 2003; see Chapter 8g). Erectogenesis occurs via the MC-4 receptor and may involve
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oxytocinergic pathways (Martin et al., 2002). In contrast,

an inhibitory effect on sexual behavior has been found
for opioid peptides, CRH, cholecystokinin and NPY (see
also Chapter 24.5b). The results of tests with galanin
contrast with those of LHRH (Argiolas, 1999).
24.1. Disorders of gonadotropic hormone regulation
A woman who does not have regular menstrual periods will
endure great suffering and eventually death if the problem
is left untreated.
Hippocrates, cited by Warren and Fried, 2001.
(a) Hypogonadotropic hypogonadism

Patients with hypogonadotropic hypogonadism manifest
irreversible pubertal delay, infertility and low serum levels
of FSH and LH. Hypogonadotropic hypogonadism may
have a number of different congenital causes, including
genetic ones (for reviews see Whitcomb and Crowley,
1993; Yen, 1993; Warren, 1996; Hayes et al., 1998;
Seminara et al., 1998). Increased melatonin levels were
found in patients with hypogonadotropic hypogonadism
(Luboshitzky and Lavie, 1999). In its turn, melatonin
suppresses the gonadal axis (Chapter 4.5).
Mutations have been identified in 510% of the patients
with hypogonadotropic-hypogonadism (Layman, 1999a).
Although no specific mutations have been found in the
LHRH gene so far (Layman, 1999a, b), hypogonadism,
involving the LHRH locus (Achermann et al., 2001a, b),
has been described in some patients with 8p deletions. A
family has been described with hypogonadotropic hypogonadism without anosmia with compound heterozygous
mutations of the pituitary LHRH receptor genes. The
disorder was transmitted as an autosomal recessive trait.
One mutation in the first extracellular loop of the receptor
dramatically decreased LHRH binding to its receptor. The
other mutation, in the third intracellular loop, did not
modify the binding of the hormone but decreased the activation of phospholipase C (De Roux et al., 1997; Layman,
1999a, b). Kallmanns syndrome, characterized by hypogonadotropic hypogonadism and anosmia and based on,
e.g. an X-linked recessive mutation of the KAL gene, is
discussed in Chapters 24.2 and 24.3. Moreover, patients
have been described with hypogonadotropic hypogonadism, inherited obesity, abnormal glucose homeostasis,
hypocortisolism, a very low plasma insulin level and
elevated plasma proinsulin and pro-opiomelanocortin
due to a mutation of the endopeptidase prohormone
convertase 1 (PCSK1), which prevents the processing

of various prohormones (ORahilly et al., 1995; Jackson
et al., 1997). A few families have been described with
autosomal recessive mutations in the leptin gene or the
leptin receptor gene (see Chapter 23). In addition to
morbid obesity, these patients had hypogonadism and did
not progress to puberty, suggesting that leptin not only
controls body mass but is also a necessary signal for the
initiation of puberty in human (Clement et al., 1998;
Strbel et al., 1998).
PraderWilli syndrome is dealt with in Chapter 23.1
and Klinefelters syndrome in Chapter 24.4. The fertile
eunuch syndrome represents a partial LHRH deficiency
with preservation of spermatogenesis (Hayes et al., 1998;
Seminara et al., 1998). Moreover, LaurenceMoon/
BardetBiedl, Biemond II and Alstrms syndromes
(Chapter 23.3) are characterized by hypogonadotropic
hypogonadism, possibly due to an abnormality in LHRH
secretion accompanied by mental retardation, obesity,
retinitis pigmentosa and often by dysmorphic extremities
(Whitcomb and Crowley, 1993; Yen, 1993; Warren, 1996;
Young et al., 1999). In addition, hypogonadotropic hypogonadism is frequently associated with X-linked congenital
adrenal hypoplasia, an autosomal recessive disease due
to mutations of the DAX-1 gene (NROB1). This gene is
a member of the nuclear hormone receptor family, located
on chromosome Xp21, and is responsible for the normal
development of the hypothalamopituitarygonadal axis.
More than 60 different mutations have been described in
the DAX gene so far (Layman, 1999a, b; Achermann
et al., 2001a, b). DAX-1 is an orphan nuclear receptor
that is expressed in the adrenal gland, ventromedial hypothalamus and pituitary gonadotropins. NROB1 mutations
abrogate its ability to act as a transcriptional repressor of
steroidogenic factor-1, also an orphan nuclear receptor
(Achermann et al., 2001a, b). Although it is not clear at
present whether the origin of this disorder is pituitary,
hypothalamic or both, the successful induction of pubertal
gonadotropins and sex steroid concentrations after therapy
with pulsatile LHRH in some cases suggests a hypothalamic origin. This was, however, not confirmed by others
(Seminara et al., 1999). In affected males an intrinsic
defect in the spermatogenesis may be present which is
not responsive to gonadotropin therapy (Seminara et al.,
1999). It is interesting to note that a patient with this
disorder showed the normal neonatal increase in testosterone levels, possibly stimulated by human chorionic
gonadotropin (HCG) from the placenta (Takahashi et al.,
1997; Bassett et al., 1999; Caron et al., 1999; Wang
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et al., 1999). PROP1 gene mutations lead to combined

hypogonadotropic hypogonadism and pituitary deficiency,
and HESX1 mutations to septo-optic dysplasia (Chapter
18.3b). Idiopathic hypothalamic syndrome of childhood
and hypothalamic atrophy are rare disorders, described
in Chapters 32.1 and 32.2, respectively. Salla disease,
due to sialic acid storage, may also be accompanied by
hypogonadotropic hypogonadism (Grosso et al., 2001).
The most common cause of adult onset of hypogonadotropic hypogonadism in males is a tumor of the
hypothalamic-pituitary region, such as a pituitary tumor,
which often goes together with acquired erectile dysfunction (Citron et al., 1996; Ben-Jonathan and Hnasko, 2001).
Prolactinoma cause amenorrhea, infertility, decreased
libido and increased anxiety and depression. Adult-onset
hypogonadotropic hypogonadism may also be due to craniopharyngioma (Chapter 19.5) or hypothalamic tumors
such as germinoma (Chapter 19.2), astrocytoma (Chapter
19.4) or hamartoma (Chapter 19.3). Hypothalamic hypogonadism is found in 32% of adult patients who received
radiation therapy for brain tumors outside the hypothalamic-pituitary region (Arlt et al., 1997; Chapter 25.3).
Insulin-dependent diabetes has been associated with
reproductive impairment in both men and women. The
neuroendocrine lesion may be at the level of the hypothalamus (Baccetti et al., 2002).
Rather rare diseases in which an infiltrating process is
involved in hypogonadotropic hypogonadism include
neurosarcoidosis (Murialdo and Tamagno, 2002; Chapter
21.1), histiocytosis-X (also called Langerhans-cell histiocytosis or HandSchllerChristian disease; Chapter
21.3), and lymphocytic hypophysitis, an autoimmune
process that may cause amenorrhoea in combination with
polyuria (Chapters 22.1, 22.2). Exceedingly common are
infectious disorders of a viral or bacterial nature that lead
to hypogonadotropic hypogonadism. In addition, alcohol
may not only act directly on the testes but also affect the
LHRH neurons.
Moreover, head injuries, especially those sustained in
head-on automobile collisions, can cause hypothalamic
damage resulting in hypopituitarism and elevated prolactin levels. While mildly elevated prolactin levels can
cause interruptions in LHRH secretion in women, this is
unusual in men. Whiplash injury may cause transsection
of the pituitary stalk. A few cases with amenorrhea, sexual
immaturity and a history of head trauma have been
described. In a 17-year old girl, provocative testing of
the pituitary revealed intact pituitary function with
hypothalamic insufficiency. MRI demonstrated loss of
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the hypothalamic infundibulum. Traumatic damage to the

infundibulum or pituitary stalk is supposed to lead to
hypothalamic atrophy (Grossman and Sanfield, 1994). A
male patient with hypothalamic hypogonadism and
growth hormone deficiency associated with pituitary stalk
amputation was treated with intermittent administration
of LHRH. The treatment initially improved LH, FSH and
testosterone secretion. However, within 3 years of the start
of the treatment, LHRH failed to be effective any longer
(Mori et al., 1998).
Features that distinguish the failure of pituitary cells
from a lack of hypothalamic releasing hormones are: (i)
hyperprolactinemia, (ii) pituitary hormone deficiencies in
provocative testing, i.e. when exogenous pulsatile LHRH
invokes LH and FSH secretion, (iii) visual impairment,
(iv) diabetes insipidus, and (v) behavioral manifestations
(Yen, 1993; MacColl et al., 2002). In addition, (vi)
pulsatile LHRH administration may be used to assess the
functional integrity of pituitary gonadotropin (Begon et
al., 1993). For therapeutic considerations of hypothalamic
hypogonadism, see Hayes et al. (1998). In hypogonadotropic hypogonadal men, testosterone replacement
may improve both sexual function and mood (Wang
et al., 2000a).
Secondary amenorrhea or hypothalamic amenorrhea is
a form of hypogonadotropic hypogonadism that may
occur after severe dieting, heavy physical training or
intensely emotional events, and places women at a greatly
increased risk of stress fractures, osteopenia, osteoporosis
and other bone complications (Warren and Fried, 2001).
Strenuous physical exercise, particularly in runners,
strongly affects the hypothalamopituitarygonadal axis
function in women and only mildly in men. The increased
CRH drive in this condition may play a role in the pathogenetic mechanism of this type of amenorrhea, since
serum testosterone is also reduced by chronic glucocorticoid therapy. Anabolic steroid use by athletes may also
cause a hypogonadal state (MacAdams, 1986). Idiopathic
hypothalamic hypogonadism (Bchter et al., 1998) in
weight-stable nonathletic women may be due to subclinical eating disorders (Laughlin et al., 1998; Chapter
23.2). The condition may be effectively treated by LHRH
(Begon et al., 1993; Schopohl, 1993). The phrase functional hypothalamic amenorrhea refers to the presumed
nonorganic nature and the reversibility of this form of
secondary amenorrhea. The presence of identifiable
psychogenic factors in some cases and the reversal of
the amenorrhea following counseling is mentioned as
an argument for a suprahypothalamic site as a primary
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cause in psychogenic amenorrhea, but neither the

hypothalamus nor the suprahypothalamic structures
that would be involved have ever been studied in this
disorder. A slow frequency of LH pulses is typical in
these patients (Genazzani et al., 2001; Marshall et al.,
2001). Multihormonal abberations occur in this syndrome
and opiate systems are presumed to be involved, since
some patients have shown LH secretion improvements
following naloxon or naltrexone (Wildt et al., 1993; Yen,
1993).
A multitude of neuroendocrine changes are described
in secondary amenorrhea. Patients suffering from this
syndrome show an increased activation of the hypothalamopituitaryadrenal (HPA) axis as appears from higher
basal hormone levels and from an augmented adrenal
hormone response to CRH administration. Changes in the
adrenal androgen enzymatic pathway are presumed to be
present (Genazzani et al., 2001). The hypersecretion of
cortisol due to an increased CRH drive in these patients
may be reversed by naloxon. Both the increased CRH
drive and the increased nocturnal melatonin levels may
contribute to the inhibition of LHRH secretion (Nappi et
al., 1993; Yen, 1993; Luboshitzky and Lavie, 1999).
Animal experiments have shown that increased CRH may
either directly or indirectly inhibit LHRH release. Cortisol
secretion is higher in women with functional hypothalamic amenorrhea than in women with other causes of
anovulation or in eumenorrheic women. These observations thus underscore the concept that functional
hypothalamic amenorrhea develops in response to stressinduced alterations in the hypothalamus (Berga et al.,
1997). In addition, increased serum levels of melatonin
have been reported (Luboshitzky et al., 2001). Although
the 24-h serum prolactin levels in psychogenic amenorrhea are lower, the sleep-associated increments are
greater. Growth hormone is preferentially increased
during the nocturnal hours (Yen, 1993). A specific correlation exists between body-weight loss and the occurrence
of amenorrhea. Functional hypothalamic amenorrhoea
may be a consequence of low-calorie intake as observed
in anorexia nervosa (see Chapter 23.2) and intensive
physical exercise (Couzinet et al., 1999). Leptin levels in
women with functional hypothalamic amenorrhea are
significantly lower than in controls, even in those who
have a normal body weight and body-mass index (Andrico
et al., 2002). A critical leptin level, produced by fat cells,
is necessary to maintain menstruation, as shown in
anorectic patients (Kpp et al., 1997; Chapter 23.2). NPY
from the infundibular nucleus is presumed to play a
crucial role in this relationship. This peptide, which stimulates food intake, is inhibited by leptin (Chapter 23). In
rhesus monkey the LHRH pulse generator activity is
inversely related to the activity of the NPY gene, and
central administration of an NPY antagonist to juvenile
animals elicits precocious LHRH release. NPY thus seems
to restrain the onset of puberty. The gonadotropin
deficiency that is due to malnutrition is partial and
may be reversible after improvement of nutritional
intake and body composition (Couzinet et al., 1999).
Patients with weight-loss amenorrhea and no signs of
anorexia nervosa have an augmented growth hormonereleasing hormone (GHRH)-induced growth hormone
response. Some of them have reduced levels of insulinlike growth factor-I (IGF-I) (Genazzani et al., 1996).
Despite normal thyrotropin (TSH) levels, T3 and T4 are
significantly reduced (Yen, 1993), which may also
contribute to the amenorrhea. In functional hypothalamic
amenorrhea, a reduced thyroid-binding, globulin-binding
affinity explains the disparity between normal levels of
free T3, free T4 and binding proteins in the face of
reduced levels of total T3 and T4 (Domininguez et al.,
1997). Nocturnal melatonin secretion is three-fold
increased (Yen, 1993).
Women with functional hypothalamic amenorrhea, in
addition, show increased cognitive dysfunction and
psychiatric morbidity. They have greater difficulty coping
with daily stress and more often have a history of psychiatric disorders. Indeed, 31% meet the criteria for major
depression, and 19% for generalized anxiety disorder
(Giles and Berga, 1993). In those women who recovered
from functional hypothalamic amenorrhea, the body-mass
index increased or remained stable, while this index
decreased or remained stable in women who did not
recover in an 8-year follow-up. The body-mass index
plays a fundamental role in the resolution of this disorder
(Falsetti et al., 2002).
In men, adult-onset idiopathic hypogonadotropic hypogonadism is an extremely rare neuroendocrine disorder.
Normal puberty is followed by a postpubertal or adult
decrease in libido and fertility, pulsatile LH and low serum
testosterone. The function of the pituitarygonadal axis is
restored and the erectile and ejaculatory disorders respond
well to exogenous LHRH replacement. A cause for this
condition has so far not been found (Seminara et al., 1998;
Kobayashi et al., 2002).
Amenorrhea in anorexia nervosa and bulimia nervosa
is dealt with in Chapter 23.2. The critical blood level of
leptin that is necessary to trigger reproductive ability in
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women and to maintain menstruation (Kpp et al., 1997)

may not be maintained in these disorders. It is, moreover, interesting from an evolutionary point of view that
the desert-dwelling hunter-gatherers of the !Kung San
(Bushman) population of Botswana in the Kalahari
desert, South Africa, have a seasonal suppression of
ovulation in relation to the seasonal changes in nutrition,
body weight and activity (Yen, 1993). In mitochondrial
encephalopathies gonadal dysfunctions are found, i.e.
amenorrhea, impotence, and poor development of
secondary sexual characteristics. Several hypothalamopituitary dysfunctions are found in these patients (Chen and
Huang, 1995). Menstrual disorders are also observed in
patients with hereditary glucocorticoid resistance
(Lamberts, 2001).
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the rhesus monkey embryonic olfactory placode release

LHRH in a pulsatile manner at approximately 50-min
intervals. This indicates that the pulse generator for LHRH
is present within these neurons (Terasawa et al., 1999).
The marked increase in amplitude of LHRH-induced
LH pulses at puberty is accompanied by much more
modest changes in frequency (Seminara et al., 1998).
The response of the free -subunit of LH to LHRH administration distinguishes prepubertal individuals with a
functional hypothalamic hypogonadism from adult
males with a permanent hypogonadotropic hypogonadism
(Mainieri et al., 1998).
Delayed puberty occurs in 1% of the population and
may result from decreased LHRH release or gonadal
failure. The most common cause of a permanent absence
of pubertal development is Kallmanns syndrome, which
combines failure of LHRH activity and impairment of
the sense of smell (Chapters 24.2, 24.3). The cause of
Kallmanns syndrome is proposed to be a lack of production of adhesion molecules coded by the KAL gene
(KAL1), located at Xp22.3, which prevent the LHRH
neurons from migrating from the nasal placode to the
hypothalamus (Styne, 1997). Delayed puberty is also
found in Klinefelters syndrome (Chapter 24.4), Noonans
syndrome (Chapter 18.6) and in female carriers of NROB1
mutations (Ackermann et al., 1999; Seminara et al., 1999).
Precocious puberty is the appearance of any sign
of secondary sexual maturation, such as pubic hair,
before the age of 8 years (or menarche before the age of
9 years) in girls and 9 years in boys. The female-to-male
ratio is approximately 10:1 (Partsch and Sippell, 2001;
Table 24.1). Central precocious puberty is, by definition, physiologically normal but chronologically early,
resulting from hypothalamic LHRH secretion. True,
LHRH-dependent or central precocious puberty is
induced by the activation of the hypothalamic LHRH
pulse generator. Most girls (95%) and nearly 50% of boys
have idiopathic true precocious puberty, for which the
therapy of choice is the administration of LHRH agonists
that inhibit the pulsative release of gonadotropins (Styne,
1997). Before the advent of LHRH analogues, cyproterone acetate was widely used for the treatment of
idiopathic precocious puberty. Although this treatment
was usually well tolerated, liver toxicity has been recognized as a complication of long-term use (Garty et al.,
1999). Following discontinuation of LHRH therapy in
boys with precocious puberty due to hypothalamic hamartomas (see Chapter 19.3 and below), these boys reentered
puberty (Feuillan et al., 2000).
(b) Disorders of puberty

While the exact mechanism that triggers the onset of
augmentation of LHRH is still unclear, potential factors
involved include decreased melatonin production
(Chapter 4.5d), metabolizing enzymes responsible for
LHRH secretion, neurotransmitters such as noradrenaline,
NPY, which restrains the onset of puberty, aspartate,
GABA, glutamate, glial growth factors such as transforming growth factor-, and metabolic signs such as
leptin (Seminara et al., 1998; Ebling and Cronin, 2000).
A male patient with prelingual deafness due to a connexin26 gene mutation also had a partial hypogonadotropic
hypogonadism. This supports the possible role of
connexins, the constitutive proteins of gap junctions, in
puberty initiation. Connexins may play a part in the coordination and synchronization of LHRH release (Houang
et al., 2002).
The onset of puberty is associated with increases in
gonadotropin and sex steroid levels. The first sign of
puberty is a sleep-entrained activation of the reproductive axis (Hayes et al., 1998). Serum LH and FSH levels
increase with developing puberty and show day/night
rhythms with pulsatile secretions. Serum testosterone
levels in boys increase with developing puberty and show
a diurnal rhythm with an augmentation in the early
morning. However, there is already some diurnal rhythmicity of LH, FSH and testosterone much earlier on,
i.e. from 4 to 5 years of age; although serum LH, FSH
and testosterone in pubertal boys are higher than in prepubertal boys, and the preparation for the onset of puberty
in boys thus seems to begin at the age of 45 years
(Mitamura et al., 1999). LHRH neurons cultured from
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TABLE 24.1
Etiology of central precocious puberty (gonadotropin-dependent, true precocious puberty).
Category
Underlying disease
Permanent precocious puberty

Idiopathic true or central
precocious puberty
Sporadic
Familial (gain of function mutation of LH receptor)
CNS tumors, abnormalities or lesions
Dysmorphic syndromes
Chemical effects
CNS maturation with central precocious
puberty secondary to prolonged sex
steroid exposure
Transient precocious puberty
Variants of pubertal development

(partial or incomplete precocity)
Hypothalamic hamartoma (Chapter 19.3)

Tumors (Chapter 19): astrocytoma, craniopharyngioma, ependymoma, glioma often associated
with neurofibromatosis, Langerhans cell histiocytosis, LH-secreting adenoma, pinealoma
Congenital malformations: arachnoid cyst, suprasellar cyst, phakomatosis, hydrocephalus
( spina bifida), myelomeningocele, septo-optic dysplasia
Acquired disease: inflammatory CNS disease, abscess, radiation, chemotherapy, headtrauma,
empty sella, vascular lesion
WilliamsBeuren syndrome, McCuneAlbright syndrome, Klinefelter syndrome (Chapter 24.4)
Following diabetic ketoacidosis, hyperglycinemia
Congenital adrenal hyperplasia
Sex steroid-producing tumors
Male-limited precocious puberty (constitutively activated LH receptor)
Idiopathic sporadic
Arachnoid cyst (Chapter 19.10)
Hydrocephalus (Chapter 18.7)
Premature thelarche
Premature pubarche
Premature menarche
Adapted from Partsch and Sippell, 2001 and Grumbach, 2002.
A familial form of precocious puberty limited to males,

with gain-of-function mutations of the LH receptor,
has been reported (Grosso et al., 2000). A cranial MRI
is indicated in central precocious puberty since it may be
caused by CNS tumors of the suprasellar and pineal areas
(Chapters 17.3, 19.1, 19.4; Ng et al., 2003), possibly by
factors secreted by the tumors that advance the tempo
of LHRH maturation (Rivarola et al., 2001). Radiation
therapy (Chapter 25.3) may also cause true, central
precocious puberty. Optic and hypothalamic gliomas,
often associated with neurofibromatosis (Chapter 19.4)
and a patient with precocious puberty has been described
with a neurofibromatosis type 1 in the presence of a hypothalamic hamartoma (Biswas et al., 2000), Langerhans
cell histiocytosis (Municchi et al., 2002), astrocytomas
(Chapter 19.4) and, in rare cases, with craniopharyngiomas (Chapter 19.5) or suprasellar arachnoid cysts
(Chapter 19.10), may also be the cause of true precocious puberty. Hamartomas of the tuber cinereum contain
LHRH neurosecretory neurons and may be associated
with true precocious puberty, often before the age of
3 years (Chapter 19.3). In addition, precocious puberty
may occur secondary to encephalitis, brain abscess, static

cerebral encephalopathy, sarcoid granulomas, tuberculous
granulomas of the hypothalamus with and without
tuberculous meningitis, histiocytosis, head trauma,
cerebral atrophy, focal encephalomalacia (Styne et al.,
1997; Beswick et al., 2002), or following an acute
cerebral complication of diabetic ketoacidosis (TubianoRufi et al., 1992). The association between precocious
puberty and partial empty sella is exceptional, which
is not surprising, as it combines hypoplasia and hyperfunction of the pituitary (Zucchini et al., 1995).
Precocious puberty also occurs 5.5-fold more often
than expected in Klinefelters syndrome (Bertelloni
et al., 1999; Chapter 24.4). Also other chromosomal
abnormalities may lead to central precocious puberty
such as triple-X syndrome, three copies of the
PraderWilli syndrome region on chromosome 15q-1113, and a duplication of the long arm of chromosome 9
(Grosso et al., 2000). Moreover, children with hydrocephalus or arachnoid cysts may have true precocious
puberty (Styne, 1997; Starzyk et al., 2003). Precocious
puberty that later failed to progress was reported in
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idiopathic hypothalamic syndrome of childhood (Chapter

32.1). In an 11-month-old girl, precocious puberty was
observed together with nonketotic hyperglycinemia, probably due to an effect of glycine on N-methyl-D-aspartate
(NMDA) receptors. Repression of pubertal development
during anticonvulsant therapy with GABA agonists
suggests that the stimulatory effect of glycine can be overcome by GABA receptor-mediated inhibition. This idea
has been confirmed in animal experiments (Bourguignon
et al., 1997). Precocious puberty has also been described
in children raised in an environment with malnutrition
who were adopted after the age of 3 years (Styne, 1997).
Girls with a premature pubarche have lower birth weight
than normal girls. The girls who subsequently develop
functional ovarian hyperandrogenism have even lower
birth weights. The lowest birth weights are found in girls
with premature pubarche who also have pronounced
hyperinsulinism. This combination of symptoms thus
indicates an increased risk of a polyendocrine-metabolic
disorder (Ibez et al., 1999). In addition, patients with
McCuneAlbright syndrome, consisting of polyostotic
fibrous dysplasia, caf-au-lait pigment, autonomous
disorders (see Chapter 30), various forms of endocrine
hyperfunctions including a risk for developing acromegaly, may have precocious puberty. In girls there is
a 50% probability of peripheral precocious puberty at
4 years of age (De Sanctis et al., 1999) by estrogen
hypersecretion (Feuillan et al., 1995; Syed and Chalew,
1999). McCuneAlbright syndrome is based upon an activating missense mutation at cordon 201 of the GNAS
gene encoding the -subunit of the G protein (GS),
which stimulates the adenylcyclase, intracellular cyclic
AMP and, subsequently, precocious steroid production
and pituitary gigantism. In addition, elevated sex
hormones, hyperthyroidism, hyperprolactinemia and
hypercortisolism have been described in this disorder
(Tinschert et al., 1999). Ketoconazole has been used to
block gonadal steroidogenesis (Syed and Chalew, 1999).
Decreased melatonin levels were observed in precocious
puberty (Luboshitzky and Lavie, 1999), suggesting that
this inhibitory factor has stopped to suppress the gonadal
axis.
Menstrual bleeding during the neonatal period is
commonly related to the withdrawal of maternal estrogens
and not to precocious puberty. Vaginal bleeding has also
been reported in female infants with congenital adrenal
hyperplasia due to a treatment-induced activation of the
hypothalamic-pituitaryovarian axis. A decline of adrenal
androgens after glucocorticoid treatment results in an
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increase in gonadotropin levels, which then triggers the

occurrence of menses (Uli et al., 1997).
(c) The hypothalamopituitary gonadal axis in aging
and menopause
Age at menopause has a strong genetic component that
is influenced by estrogen receptor polymorphism (Weel
et al., 1999). One theory on the genesis of menopause is
that it is due to the ovarian exhaustion of follicles. Others
maintain that the hypothalamus is the pacemaker that
initiates the cascade of events leading to menopause. Hot
flushes already occur in normally cycling women during
the fourth decade, when there are still many follicles
present in the ovary. In addition, the finding of the change
of rhythmicity of many neurotransmitters with age has
led to the hypothesis that the deterioration of the biological clock, the suprachiasmatic nucleus (SCN), underlies
such desynchronization (Wise et al., 1996). Indeed, we
have found a loss of circadian and seasonal changes in
the SCN after the age of 50 years (Chapter 4.3a).
The first hormonal change that indicates the onset
of menopause is a rise in FSH, based upon increased
LHRH activity in the hypothalamic infundibular nucleus.
The increase in LHRH secretion occurs despite the 30%
decrease in LHRH pulse frequency with aging (Hall and
Gill, 2001). Typical symptoms of the acute climacteric
syndrome are vasomotor phenomena, e.g. hot flushes,
night sweats, and psychosomatic symptoms such as poor
concentration, memory impairment, loss of confidence and
insomnia (see Chapter 11f).
In aging men total and free testosterone gradually
decline as gonadotropins increase, while there is an
attenuation of the LH and testosterone secretory pulse
amplitude, and an associated disruption of their orderly
patterns of release. Detailed research showed that the
LH pulsing mechanism in healthy older men maintains
an increased mean frequency and lower amplitude of
bursting activity, a reduced uniformity of serial LH
pulse-mass values, and an impaired variability among
interpulse-interval lengths (Keenan and Veldhuis, 2001).
In the elderly, the circadian testosterone rhythm attenuates a pattern that is observed for many circadian rhythms
(Chapter 4.3). The decreased testosterone levels roughly
parallel the decline in sexual activity, libido and potency.
Aging and hormonal changes were more strongly related
to sexual activity and nocturnal erections than to
libido (enjoyment, drive and thoughts) (Davidson et al.,
1983; Veldhuis, 2000; Schill et al., 2001). Using total
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testosterone criteria, the incidence of hypogonadal testosterone levels increased to about 20% of men over 60,
30% over 70 and 50% over 80 years of age, and even
greater percentages when free testosterone index criteria
were employed (Harman et al., 2001). Testosterone
administration to elderly men improved spatial cognition
(Janowsky et al., 1994). Androgen supplementation for
3 months in older men with partial androgen deficiency,
using a transdermal dehydrotestosterone gel, demonstrated the expected androgenic effects but no change in
physical or cognitive functioning (Ly et al., 2001).
(d) Polycystic ovary syndrome
Polycystic ovary syndrome is a common disorder in which
multiple ovarian cysts are associated with menstrual
disorders, bilaterally enlarged ovaries, subfertility, hyperandrogenism such as hirsutism and acne, and often central
obesity and hyperinsulinemia. Gonadotropin concentrations are high, with a high ratio of LH to FSH, excessive
ovarian androgen production, chronic anovulation and
acyclic estrogen production in the prototype form of the
syndrome, the SteinLeventhal type of polycystic ovary
syndrome (Hall et al., 1998). LH pulses have a persistently accelerated frequency and higher amplitude of
pulses and favor LH synthesis, hyperandrogenism and
impaired follicle maturation (Marshall et al., 2001).
Heightened LHRH drive of gonadotropin secretion and a
steroid-permissive milieu appear to jointly promote LH
secretion. Positive feedback of estrogens is also implied
(Barontini et al., 2001). An insensitivity of the hypothalamic LHRH pulse generation to estradiol and
progesterone is present in polycystic ovarian syndrome
(Hall et al., 1998). Hypotheses explaining the disorder
include an abnormality on the level of the hypothalamus,
and it has been suggested that it may originate during
intrauterine development. Animal experiments have
shown that the pattern of gonadotropin release by the
hypothalamus is programmed by the concentration of
androgens during early development. Female rats exposed
to high androgen levels during development have
persisting changes in sexual physiology, including an
ovulatory sterility and polycystic ovaries (Cresswell et
al., 1997). However, observations in androgen-treated,
female-to-male transsexuals show that the histology of
the ovaries met the criteria for the diagnosis of polycystic
ovaries, which shows that elevated levels of androgens
in adulthood alone may also induce polycystic changes
(Pache et al., 1991). Women with polycystic ovary
syndrome have increased melatonin secretion, which is

associated with their increased testosterone levels
(Luboshitzky et al., 2001). In addition, multifaceted
dysregulation of the HPA axis is present in this syndrome
(Invitti et al., 1998). The abnormalities of the HPA axis
are presumed to be central in origin and abdominal obesity
may play a key role in the hyperactivity of the HPA axis
when tested with naloxone. There does not appear to be
any altered sensitivity of the HPA axis to opioids
(Ciampelli et al., 2000). Alternatively, polycystic ovary
syndrome may be primarily an ovarian disorder of
androgen secretion (Rosenfield, 1997).
Familial clustering of cases suggest that genetic factors
are present (Goudas and Dumesic, 1997). There is familial
aggregation of hyperandrogenemia, with or without
oligomenorrhea in polycystic ovary syndrome kindreds.
In affected sisters only half have oligomenorrhea and
hyperandrogenemia, characteristic of polycystic ovary
syndrome, whereas the other half have hyperandrogenemia per se (Legro et al., 1998). Several genes and
pathways have been implicated in this syndrome.
Evidence is present for a role for the insulin gene
minisatellite, for the genes encoding the insulin receptor
substrate protein-2, for an the association with insulin
variable number of tandem repeats, and for the gene
encoding for P450 cholesterol side-chain cleavage in
polycystic ovary syndrome and in the mechanism of
excessive androgen secretion in this syndrome (Franks et
al., 1997; Xita et al., 2002), and for an interstitial deletion of the long arm of chromosome 11 (Meyer et al.,
2000).
One study has proposed that there are two common
forms of polycystic ovary syndrome that probably have
different origins in intrauterine life. First, obese, hirsute
women with polycystic ovaries have an ovarian secretion
of androgens that is higher than normal. They also have
high LH levels and are associated with high birth weight
and maternal obesity. Secondly, thin women with polycystic ovaries have altered hypothalamic control of
LH release, which is found with prolonged gestation;
and they have high LH but normal androgen levels. The
hypothesis is that an altered hypothalamic-pituitary setpoint for LH release occurred in the second type as
a consequence of long gestation and the presence of a
placental failure associated with postmaturity leading to
an increased exposure of androgens (Cresswell et al.,
1997). This hypothesis should be further explored, and
the hypothalamic changes caused in development still
have to be shown. It has also been proposed that a low
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hypothalamic dopamine tone is involved in the inappropriate LH and prolactin secretion. In addition, changes in
prolactin bioactivity may play a role in the development
of hyperinsulinemia (Hernndez et al., 2000). A case has
been described of a woman with idiopathic intracranial
hypertension, polycystic ovary syndrome and visual loss
(Au Eong et al., 1997). A subset of women with polycystic ovarian syndrome may develop hirsutism and
virilization in pregnancy, especially in the context of
reproduction techniques such as in vitro fertilization (De
Bustros and Hatipoglu, 2001).
One of the widely used therapies for polycystic ovary
syndrome is an estrogen/progesterone combination.
However, also LHRH agonists and antiandrogens are used
(Toscano, 1998). Administration of progesterone can
slow down LHRH pulse secretion, favor FSH secretion
and induce follicular maturation (Marshall et al.,
2001). In obese women with polycystic-ovary syndrome
D-chiro-inositol, a fungal metabolite, induced ovulation
and decreased testosterone levels (Nestler et al., 1999).
Both clinical and animal experimental observations indicate that electroacupuncture may be an effective
treatment.
There is a close association between bulimia nervosa
(Chapter 23.2) and polycystic ovary syndrome, in that
some 75% of bulimic women seem to have this syndrome.
The connection between the two conditions may be
explained by altered peripheral sensitivity for insulin
(Morgan et al., 2002).
203
that human olfactory sensibilities are in decline. Some

70% of human olfactory receptor genes are pseudogenes (Keverne, 1999). Axons from the olfactory neurons
course through the cribiform plate of the etmoid bone,
and synapse in the olfactory bulb. From the olfactory
bulb, axons project predominantly to the periform cortex
in the medial aspects of the temporal lobes via the lateral
olfactory tract (Figs. 24.1, 24.2). These connections with
the temporal cortex may be crucial in the development
of olfactory deficits in Alzheimers disease (see below).
There are some very small leftright connections transporting olfactory information in the rostral part of the
anterior commissure (Sylvester, 1986). In addition, axons
project from the olfactory bulb to structures of the limbic
system, including the anterior olfactory nucleus, preperiform cortex, periamygdaloid complex and the
olfactory tubercle (Figs. 24.1, 24.2). Widespread
connections with many other areas, including the hypothalamus, spring from these brain regions. Electrical
responses have been recorded in the medial and lateral
hypothalamus in these brain areas after electrical and
odorant stimulation of the olfactory bulb (Martzke et al.,
1997). The olfactory bulb is innervated cholinergically
by the nucleus basalis of Meynert (Price, 1990).
In contrast to the main olfactory connections, the
vomeronasal organ (see below) projects to the accessory
olfactory bulbs, and from there directly to the hypothalamus (Tirindelli et al., 1998).
(b) Anosmia
24.2. Olfaction, anosmia, the vomeronasal organ

(Jacobsons organ) and the embryology of LHRH
neurons
Anosmia can result from a congenital defect, inflammation, head trauma or neoplasm. Congenital anosmia is
defined as a complete inability, present from birth, to
smell. It arises secondarily to abnormal embryological
development of the olfactory system. The disorders range
from holoprosencephaly (Chapter 18.3) via Kallmanns
syndrome (Chapter 24.3), to congenital anosmia, the
mildest manifestation of the arhinencephalic spectrum.
Aplasia or hypoplasia of the olfactory bulbs is revealed
by MRI in the case of isolated congenital anosmia.
Outgrowth of the fibers from the neurosensory cells of
the olfactory pits is necessary for the later induction
of the olfactory bulbs and tracts. In congenital anosmia
this outgrowth appears to be arrested prematurely for
unknown reasons between 7 and 16.5 weeks of gestation.
The migration deficiency may be a subtle abnormality of
the nasal placodes that normally allow their invagination
and, in case of a disorder, prevent the growth and contact
Give me a man with a good allowance of nose . . . I always

choose a man, if suitable otherwise, with a long nose.
Napoleon Bonaparte
(a) Olfaction
Odor perception is the result of stimulation of bipolar
neurons in the olfactory mucosa by volatile chemicals. A
family of approximately 1000 genes coding for odorant
receptors with seven transmembrane helices was discovered. Individual olfactory neurons express a single
receptor that recognizes a limited range of ligands. There
is a striking convergence of all the neurons expressing
one type of receptor to one or a few glomeruli (Tirindelli
et al., 1998). However, molecular genetic studies suggest
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Fig. 24.1. Olfactory structures within or in close relation to the anterior perforated space. Whereas the monkey (A) has a clearly identifiable olfactory tubercle (Tu), it is more difficult to identify a tubercle in the human (B, C, D). The region indicated by an asterisk in D is usually referred
to as the olfactory trigone. Note the continuation between the olfactory peduncle (o. ped.) and the olfactory tract (olf) in the monkey (A). The
olfactory tract continues in a caudolateral direction towards the limen insulae (white arrowhead) where it makes a sharp bend to enter the temporal
lobe. The olfactory tract is more difficult to appreciate in the human (D). The large arrow in B points to the anterior choroidal artery and the
small arrows to striate arteries. AO, anterior olfactory nucleus; Ant perf., anterior perforated space; db, diagonal band; GR, gyrus rectus; olfs,
olfactory sulcus; opt, optic tract; ox, optic chiasm; U, uncus. (From Sakamoto et al., 1999, Fig. 1 with permission.)
of the neurosensory cells with the telencephalon. Without

that contact the formation of the the olfactory bulbs and
tracts never occurs. Alternatively, a deficiency in the
molecules necessary for the growth and contact of the
olfactory nerves may be the cause of this disorder, as is
proposed for Kallmanns syndrome. It should be noted,

though, that congenital anosmia is not accompanied by
hypogonadism. This means that the LHRH neurons have
reached their normal destination; some connection
between the olfactory pits and the telencephalon should
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In patients with mild cognitive impairment, olfactory

identification deficits, particularly with a lack of awareness of olfactory deficits, may even have clinical utility
as an early diagnostic marker for Alzheimers disease
(Devanand et al., 2000). In this respect it may be
mentioned that in cognitive-unimpaired elderly people
a substantial number of tangles has been observed
in the anterior olfactory nucleus, and that the number of
tangles increases markedly in very mildly demented cases
(Price, 1990). In mildly affected Alzheimer patients, odor
detection limits for pyridine were in the normal range,
but recognition of a broad spectrum of odors was
disturbed (Koss et al., 1987; Rezek, 1987). More recently,
Wang et al. (2002) found not only that a group of mildly
cognitively impaired patients showed a worse sense of
smell in a cross-cultural smell-identification test, but also
that subjects with an apolipoprotein E (ApoE) -4 allele
were unable to identify as many odors as the subjects
without the -4 allele. In a meta-analysis of olfactory
deficits in Alzheimers disease and Parkinsons disease,
odor identification, recognition and detection threshold
were found to be severely disturbed in a similar way
(Mesholam et al., 1998). However, a later study, in which
impaired odor in patients was followed by neuropathological investigation, came to a different conclusion about
anosmia in Alzheimers disease than earlier studies, in
which no neuropathological validation took place. Patients
with Lewy bodies, either in the brainstem or in the
cerebral cortex, were more likely to be anosmic than
those with Alzheimers disease or controls. Patients with
Alzheimers disease were not more likely to be anosmic
than controls, nor was anosmia associated with the degree
of neurofibrillary tangles as assessed by Braak stage.
Among patients with Lewy bodies, overall cortical Lewy
body scores and Lewy body density in the cingulate were
higher in those who were anosmic. Consensus clinical
criteria for dementia with Lewy bodies had a sensitivity
of 64% and specificity of 89%. In the absence of
Alzheimers disease, the sensitivity was even 100%
(McShane et al., 2001). A substrate is present for anosmia
in Parkinsons disease, since Lewy neurites and Lewy
bodies are found in the olfactory system, i.e. in the
olfactory bulb, olfactory tract and anterior olfactory
nucleus .
An esthesioneuroblastoma, or olfactory neuroblastoma,
is a rare, malignant neuroectodermal tumor originating
from neurosensory receptor cells in the nasal mucosa. A
case has been described of inappropriate vasopressin
secretion by such a tumor (Mller et al., 2000b).
Fig. 24.2. Higher magnification view of anterior perforated space.

Although a vague bulge appears behind the anterior olfactory nucleus
(AO), it is highly questionable if this should be considered to be homologous with the olfactory tubercle in macrosmatic mammals (see text).
The surface topography only hints at the presence of an olfactory tract
(between arrows) and its bend (white arrowhead) at the region of the
limen insulae. (From Sakamoto et al., 1999, Fig. 2 with permission.)
thus have been present during early development. Since

an increased rate of sporadic Kallmanns syndrome is
found in families with congenital anosmia, variable penetration of the same gene is presumed (Assouline et al.,
1998).
(c) Neurological and psychiatric diseases
Large numbers of neurological and psychiatric diseases
have been reported to be accompanied by olfactory
dysfunction. Examples are: Alzheimers disease, Downs
syndrome, Korsakoffs syndrome, Huntingtons disease,
amyotrophic lateral sclerosis, schizophrenia, obsessivecompulsive disorder, Kallmans syndrome (Chapter 24.3),
epilepsy, AIDS, neurosarcoidosis (Kieff et al., 1997;
Chapter 21.2) and closed head injury, which are reported
to be accompanied by olfactory dysfunction. Anosmia
and olfactory bulb and tract atrophy are also characteristics of Wolframs syndrome (Dean et al., unpubl. results;
Chapter 22.7). However, little is known about the exact
site of the lesions in the different brain diseases in case
of anosmia (Martzke et al., 1997). In schizophrenia, olfactory deficits were particularly found in the subgroup with
severe polydipsia and hyponatremia (Kopala et al., 1998).
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As a periscope from the diencephalon, the vomero-nasal

system may monitor exogenous hormones, pheromones.
Wysocki (1979)
(d) Olfaction and sex: the vomeronasal organ and the

LHRH neurons of the preoptic area
Over 100 years ago, in his text book Psychopathia
Sexualis, Von Krafft-Ebing described how olfactory
stimuli frequently initiated sexual excitement. Von KrafftEbing suggested a close proximity of the olfactory and
sexual centers (Casanova et al., 2002).
The vomeronasal organ is sensitive to certain airborne
chemical signals defined as pheromones or vomeropherins. Mammalian pheromones are naturally occurring,
species-specific volatile compounds that are secreted into
the environment in sweat or urine by one individual of
a species. They stimulate the vomeronasal organ and exert
a behavioral or physiological response in another individual of the same species (Berliner, 1996). The
vomeronasal organ responds to exposure to pheromones
from the skin of the opposite sex and produces changes
in LH by activation of the accessory olfactory system and
the pulsatile release of LHRH neurons in the preoptic
hypothalamus (Berliner et al., 1996). In the rat, the
vomeronasal organ and the vomeronasal pathway are
sexually dimorphic ; sex differences are present in the
structures that receive vomeronasal input, e.g. the medial
amygdala, the medial preoptic area, the ventromedial
hypothalamic nucleus and the ventral region of the
premamillary nucleus. In addition, sex differences have
been described in the rat accessory olfactory bulb, bed
nucleus of the accessory olfactory tract, and bed nucleus
of the stria terminalis. The vomeronasal organ thus acts
in a sex-specific way as an additional sensory system
(sixth sense), using the hypothalamus and adjacent structures as a link. It affects psychophysiological homeostasis,
hormonal responses and autonomic reflexes by transmitting neural impulses to the hypothalamus. Vomeropherins
induce a reduction of cardiac and respiratory rate, increase
the conductance of the skin and increase -rhythm of the
EEG. In addition, increases in parasympathetic tone, an
amelioration of anxiety, and changes in LH and FSH
levels have been observed (Berliner, 1996). Menstrual
synchrony is often reported by all-female living groups
and by mothers, daughters and sisters who are living
together. Pheromones are held responsible for this
phenomenon (McClintock, 1971; see below). The
vomeronasal organ is often damaged when plastic

surgeons rebuild noses.
Functional anatomy and histology. It is still generally
claimed that adult humans do not have a vomeronasal
organ or an accessory olfactory bulb, but that they would
be present in the human fetus, where they disappear before
birth (e.g. Price, 1990; Savic et al., 2001). Although this
is not correct according to quite a number of publications
(see below), recent papers also state that the presence of
only very few neurons and the lack of vomeronasal nerve
bundles suggest that the vomeronasal epithelium, unlike
in other mammals, is not a sensory organ in adult humans
and has already regressed in the fetus halfway through
gestation (Trotier et al., 2000). However, electrical autonomic and psychological responses constitute evidence
for a selective and sensitive response from the adult
human vomeronasal organ (Meredith, 2001). The accessory olfactory bulb is absent in adult humans and it is
thus uncertain exactly how pheromone signals reach the
human brain (Keverne, 1999; Savic et al., 2001).
The first description of the vomeronasal organ or
Jacobsons organ, in a wounded soldier, was given in
1703 by the Dutch anatomist F. Ruijsch, while L.
Jacobson, after whom the organ was named, published
his findings in animals in 1811 (Johnson et al., 1985).
The vomeronasal organ is enclosed in a cartilaginous
capsule that is separated from the main olfactory epithelium. It consists of a pair of blind tubular diverticula,
which are found on the most anterior part at the inferior
margin of the nasal septum (Fig. 24.3). The closed tubes,
28 mm long, which run in the lamina propria of the
septal mucosa, in the anteroposterior direction, are blind
posteriorly and usually open anteriorly into the nasal
cavity (Fig. 24.4). The vomeronasal pit is usually
observed 1 cm dorsal to the columella and 12 mm above
the floor of the nose (Moran et al., 1991; Keverne, 1999).
Using a headlight and Killians nasal speculum, the
opening of the vomeronasal organ can be macroscopically seen in some 40% of the adults (Moran et al., 1991)
and with an endoscope and repeated observations in 73%
of the population (Trottier et al., 2000). No trend toward
involution with increasing age (Johnson et al., 1985) has
been observed. The vomeronasal pit measures up to 2
mm (Johnson et al., 1985). The duct of the vomeronasal
organ is filled with fluid. The cavernous tissue of this
organ undergoes cyclic swelling and emptying under the
influence of the autonomic innervation, nitric oxide and
vasoactive intestinal polypeptide nerve fibers. Novel
stimuli activate the pump-like action for stimulus access.
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In this way pheromones, dissolved in the fluid, reach

the receptor cells (Tirindelli et al., 1998; Keverne,
1999).
In most cases the organ has a crescentic lumen on
coronal section, with the neuroepithelium on the medial
wall, while the remaining epithelium is respiratory in type
(Johnson et al., 1985). Within the duct the mucosa is tall,
ciliated and pseudostratified and differentiates into
receptor cells and basal cells. Goblet cells are sometimes
present (Johnson et al., 1985; Keverne, 1999). The
chemosensitive bipolar neurons, the primary sense
neurons of the vomeronasal system, possess apical
microvilli and are located in a neuroepithelium. They send
a dendrite to the site of the stimulus and an axon to
the brain. Like the olfactory receptor neurons, the
vomeronasal receptor neurons turn over during the life
of an individual and are replaced by new neurons derived
from the basal cells. The posterior end of the vomeronasal
organ is lined by an epithelium that contains three distinct
cell types: (1) basal cells, (2) dark cells, and (3) light
cells, which have a round, euchromatic nucleus with
a pronounced nucleolus and a clear cytoplasm with a
pronounced Golgi apparatus (Moran et al., 1991; Keverne,
1999; Fig. 24.5). These cells are most probably the
neurons that subserve the sensory function. The vomeronasal organ neurons contain neuron-specific enolase
and protein gene product 9.5, like the olfactory receptor
neurons, but no olfactory marker protein (Takami et al.,
1993). The latter observation was confirmed by Trottier
et al. (2000). In that study it was found that most
cells of the vomeronasal epithelium expressed keratin.
No nerve bundles were found with anti-S100, and there
was a lack of neurons, raising doubt again about the
functional significance of this organ in adults. However,
functional studies show fundamental differences between
the receptor for odor and pheromones. So far, two
families of seven transmembrane vomeronasal organ
receptors have been identified that appear to activate
inositol 1,4,5-triphosphate, in contrast to cyclic adenosine
monophosphate. They consist of some 40 and 100 genes,
respectively. Two multigene families of G protein-linked
receptors (V1 and V2) are each expressed in a distinct
region of the vomeronasal organ. Probably one receptor
is expressed in each sensory neuron. One receptor displays
some kind of sexual dimorphism (Tirindelli et al., 1998;
Keverne, 1999).
Embryology. The vomeronasal groove appears in the
human embryo at 37 days postovulation. At 41 days the
olfactory nerve is organized into two plexuses, one lateral
Fig. 24.3. Localization of the vomeronasal cavities (indicated by arrows)

in humans, as they were illustrated in the last centuries. (A) Frederic
Ruysch, in 1703, was the first to indicate, with two bristles (*), the
existence of these canalibus nasalibus. He wrote, in Latin: On
both sides of the anterior and inferior part of the nasal septum appears
the opening of a duct. I have not read about the existence and
utility of that in authors: I consider it serves for the secretion of mucus
(translation by courtesy of Annick Le Guerer). (B) Anton Klliker,
in 1877, gave the exact position of these cavities in the nasal septum
of adult cadavers. (C) Potiquet, 1891, was the first to study the
position and length of these cavities in living adult subjects. He
inserted a stylet (*) to estimate the length of the vomeronasal cavity
that extended toward the back. (from Trottier et al., 2000, Fig. 1 with
permission.)
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Fig. 24.4. Coronal section through an adult human septum. On the left, the closing vomeronasal pit can be seen, and on the right, the duct (H&E
80). (From Johnson et al., 1985, Fig. 6 with permission.)
and one medial, the latter mingled with the terminalvomeronasal complex. The olfactory bulb is visible at 44
days, while by 48 days the distinction between olfactory
bulb, and nuclei and terminal and vomeronasal nerves
can be observed. At 57 days the olfactory and terminalvomeronasal fibers are easily distinguishable. The
terminal ganglion is a sensory ganglion with an autonomic contingent. It is attached to the vomeronasal system
(Bossy, 1980; Figs. 24.6, 24.7). In the ganglion terminalis, the LHRH-immunoreactive cells are outnumbered
by the other neurons (Schwanzel-Fukuda and Pfaff, 1994).
The vomeronasal fibers are gathered into two posterior
filaments that arrive at the vomeronasal ganglion, in the
dorsomedial part of the olfactory bulb, and end in the
medial part of it. Both the somata and the axons of about
70% of all terminal neurons are immunoreactive for
LHRH and they appear to provide direct input to LHRH
neurons in the basal forebrain, medial preoptic nucleus
and other anterior parts of the hypothalamus that regulate
neuroendocrine functions (Boehm et al., 1994; MontiBloch et al., 1994). The central processes of the terminal
and vomeronasal fibers enter the brain medial and caudal

to the olfactory bulb, and in the supraoptic area, septal
nuclei, olfactory lobe and islands of Calleja (Bossy, 1980;
Schwanzel-Fukuda and Pfaff, 1994). Neuronal cell adhesion molecule (N-CAM) is expressed in both sets of
sensory neurons. These cell adhesion molecules are
thought to be involved in stabilization connections
(Schwanzel-Fukuda et al., 1996; Keverne, 1999; Figs.
24.8, 24.9, 24.10). However, in the N-CAM knock-out
mouse, migration of LHRH neurons was not overly
affected (Rugarli, 1999).
Like the vomeronasal organ itself, nerve cells of
the terminal nerve have their embryological origin in the
medial olfactory placode. Neuron-specific enolase and
LHRH-immunoreactive cells migrate from the primordial
vomeronasal organ into the basal forebrain and preoptic
hypothalamus (Boehm et al., 1994; Berliner et al., 1996),
following the course of the terminal and vomeronasal
nerves (Schwanzel-Fukuda and Pfaff, 1994). A notable
exception occurs in individuals with Kallmanns
syndrome, one of its features being a lack of development
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Fig. 24.5. Electronmicrograph of the vomeronasal organ epithelium. The dark cells (D) have elliptical, heterochromatic nuclei. The cytoplasm in
the apical domain of the cells contains mucigen-like granules (M). The light cells have round, euchromatic nuclei (N). Note the membranelimited vesicles (V) with contents of moderate electron density in the supranuclear cytoplasm. Golgi stacks (G) are abundant. Several slender
microvilli (arrow) extend from the cell surface into the lumen (LU) of the VNO. Small basal cells (B) sit atop the basement membrane (BM).
2100. (From Moran et al., 1991, Fig. 6 with permission.)
of the vomeronasal organnervus terminalis complex (see

Chapter 24.3). At 5 weeks after conception, LHRH was
found in the human hypothalamus (Aksel and Tyrey,
1977). LHRH-expressing neurons were observed in the
vomeronasal organ at 812 weeks of gestation. At later
stages (1819 weeks) only few or no (19 weeks) LHRH
cells were found close to the vomeronasal organ, which

suggests migration of these cells (Kjaer and Fischer
Hansen, 1996). Although it has not been established that
all human LHRH neurons originate in the nasal placode,
two LHRH neuron populations have been found in
the rhesus monkey fetus that are both derived from the
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Fig. 24.6. Semischematic representation of the main features related to the stage development. Stages 1115 and 18: transverse sections; stages
19, 20, 22, and 23: sagittal sections. CB, cellular buds; LD, lens disc; ND, nasal disc; NF, nasal field; ON, olfactory nerve; RN, rostral neuropore; TG, terminal ganglion; TVN, terminal-vomeronasal nerve; VNG, vomeronasal groove; VNO, vomeronasal organ; VX, vessels. (From Bossy,
1980, Fig. 2 with permission.)
olfactory placode. The one that occurs earlier migrates

mainly to extrahypothalamic sites, i.e. apart from the
septum, preoptic region and stria terminalis, also to the
medial amygdala, internal capsule and globus pallidus.
In contrast the later-occurring LHRH neurons migrate to
the preoptic area and basal hypothalamus and are considered to regulate the pituitarygonadal axis (Quanbeck et
al., 1997). Also in the adult human hypothalamus, an
accumulation of LHRH neurons and fibers was observed,
not only in the infundibular and preoptic region, but also
in additional locations in extrahypothalamic regions
(Stopa et al., 1991). LHRH in extrahypothalamic regions
may be involved in nonreproductive functions. A subpopulation of the LHRH neurons shows colocalization
with galanin (Kalra et al., 1997), and LHRH neurons
colocalizing -endorphin have been described in the
arcuate nucleus, the lamina terminalis and the septopreoptic area of human fetuses of 1726 weeks of gestation
(Leonardelli and Tramu, 1979). The LHRH content of

the female fetal hypothalamus shows a peak at 2225
weeks and declines after 26 weeks of gestation. In male
fetuses a decline of LHRH content was observed from
1433 weeks. From 3438 weeks, LHRH content rose to
the highest levels attained during gestation. A sex difference is thus already present in human fetal LHRH
development (Siler-Khodr and Khodr, 1978). LHRH
neurons, cultured from the embryonic olfactory placode
of the rhesus monkey, release LHRH in a pulsatile manner
at 50 min intervals, supporting the idea that the LHRH
pulse generator is situated within these neurons (Terasawa
et al., 1999).
For the distribution of LHRH neurons in the preoptic
septal region, diagonal band of Broca, lamina terminalis
and periventricular and infundibular nuclei of the adult
human brain, see Rance et al. (1994) and Duds et al.
(2000).
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Fig. 24.7. Schematic representation of the nervous olfactory structures at the stage 23. AON Anterior olfactory nucleus; EL, ependymal layer;
EGL, external granular layer; EML, external molecular layer; IGL, internal granular layer; IML, internal molecular layer; LOF, lateral olfactory
fila; MCL, mitral cell layer; ML, marginal layer; MOF, medial olfactory fila; MSN, medial septal nucleus; OV, olfactory ventricle; PL, plexiform
layer; TG, terminal ganglion; TN, terminal nerve; VNG, vomeronasal ganglion; VNN, vomeranasal nerve; VNO, vomeronasal organ; I, accessory
olfactory formation. According to Humphrey (1940), the external granular layer of this formation is deep and does not mix with the vomeronasal
fibers, in contrast to the intermingling of olfactory fibers and external granular layer of the olfactory bulb. (From Bossy, 1980; Fig. 3 with
permission.)
rienced as an odor. These signals also have immediate

or delayed effects on the neuroendocrine reproductive
systems of other humans (Weller, 1998). Although the
role of the vomeronasal system in aspects of human mothering has been presumed, only indirect evidence for such
a function is available at present.
Negative potentials with the characteristics of receptor
potentials are recorded from the surface of the vomeronasal organ epithelium, in response to vomeropherins
in a sex-dependent way. In contrast, no sexual dimorphism
Effects of vomeropherins. Humans, like other animals,

emit odors from many parts of the body, such as the axillary area. Olfactory information seems to be quite specific.
A mother can identify the odor of her infant or older
child by smelling at a T-shirt worn previously by the
child. In turn, infants prefer their own mothers breasts
or axillary pads. Children can discriminate between odors
and prefer their mothers odor and the body odors of
other kin. Chemical signals from one human can also be
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Fig. 24.8. Microprojection drawings of serial, 8 m sagittal sections through the brain and nasal regions of an approximately 42-day-old human
embryo. Every 10th section through the migration route, on one side, was drawn. N-CAM-immunoreactive cells are represented by open circles,
and N-CAM-immunoreactive fibers by dashed lines. LHRH-immunoreactive cells are represented by black dots. The olfactory pit (OP) has invaginated to form the beginnings of the nasal cavity. N-CAM-immunoreactive cells and fibers form a distinctive plexus or network across the developing
nasal septum, linking the epithelium of the olfactory pit (OP) with the forebrain (F), and forming a scaffold along which LHRH cells migrate
into the forebrain. The migration route is composed of N-CAM-immunoreactive cell bodies (represented by open circles) or axons (dashed lines)
of the olfactory (sections 77 and 87) and vomeronasal and terminal nerves (sections 97, 107, 177), extending from the epithelium of the olfactory
pit to the forebrain. At 42 days LHRH-immunoreactive cells are seen primarily in the ganglia of the terminal nerve (NTg), and along the caudal
part of the cellular aggregate below the forebrain (sections 97, 107, 117). At this age a few LHRH cells enter the brain with central roots of the
terminal nerve and may be seen in the medial basal forebrain. (From Schwanzel-Fukuda et al., 1996, Fig. 5 with permission.)
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Fig. 24.9. (1) A luteinizing hormone-releasing hormone (LHRH)-immunoreactive cell (red-brown) is seen in the epithelium of the medial olfactory pit (MOP). Forty-two-day-old human embryo, 8-m sagittal section. Scale bar 7 m. (2) Low-power photomicrograph showing neural cell
adhesion molecule (N-CAM)-immunoreactive cells (blue-gray) in the intermediate and basal layers of the epithelium of the medial part of the
olfactory pit (MOP). Both N-CAM (blue-gray) and LHRH-immunoreactive cells (red-brown, arrow) are seen in ganglia of the terminal nerve
(nervus terminalis, NTg) in the nasal mesenchyme (NM). Large, round cells characteristic of the medial components of the migration route. Fortytwo-day-old human embryo, 8-m sagittal section. Scale bar 45 m. (3) a. Low-power photomicrograph, shows a few LHRH-immunoreactive
cells (arrows) along the broad swath of N-CAM-immunoreactive cell bodies and neurites which extend from the epithelium of the olfactory pit
(OP) and form an aggregate in the nasal mesenchyme (NM) below the forebrain and the developing olfactory bulb (OB). In serial sections, the
N-CAM-immunoreactive axons of the olfactory nerves, which make up a part of the aggregate, are seen in contact with the developing olfactory
bulb. Forty-two-day-old human embryo, 8-m sagittal section. b. Higher magnification of the same section shows some of the LHRH-immunoreactive cells (red-brown) along the caudal part of the migration route. Scale bar 90 m in a, 7 m in b. (From Schwanzel-Fukuda et al., 1996, Fig.
1 with permission.)
was found for olfactory epithelial responses by MontiBloch et al. (1994). The steroidal vomeropherin, pregna4,20-diene 3,6-dione (PDD), delivered as pulses in an
airstream, produces dose-dependent changes of the
electrovomerogram, but had no such effects on the nasal
respiratory or olfactory epithelium. However, a sex
difference was observed in the sensitivity to the odor

of androsterone. A smaller number of females than
males became insensitive to this compound (Dorries et al.,
1989), suggesting the presence of sex differences also
in the olfactory epithelium. The vomeropherin PDD
decreased LH and FSH pulsatility in males, but not in
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Fig. 24.10. (A) In contrast to the fairly extensive distribution of the low sialic acid-containing N-CAM, the polysialated PSA-N-CAM is found in
particular parts of the migration route. In this photomicrograph, PSA-N-CAM immunoreactivity is seen in fascicles and clusters just outside the
epithelium of the medial olfactory pit, in the nasal mesenchyme. LHRH-immunoreactive neurons (red-brown, arrows), are seen in these clusters
and fascicles. Forty-two-day-old human embryo, 8-m sagittal section. Scale bar 25 m. (B) PSA-N-CAM-immunoreactive fibers (light gray, solid
arrow) are seen along the caudal part of the cellular aggregate (CA) below the rostral forebrain (F), together with a few LHRH-immunoreactive
neurons (red-brown, open arrows). A number of blood vessels (bv) and small, darkly stained red blood cells (rbc) are seen nearby. Compare the
distribution of PSA-N-CAM here with that of N-CAM in Fig. 24.9(3). Forty-two-day-old human embryo, 8-m sagittal section. (C) This section,
adjacent to that seen in (B), was treated with a neuraminidase before incubation in primary antiserum to PSA-N-CAM (see controls). The absence
of PSA-N-CAM reaction product (solid arrow) confirms the specificity of our antibodies. LHRH-immunoreactive neurons (red-brown, open arrows)
are seen along the caudal part of the cellular aggregate (CA) and in a cluster on its ventral border. Scale bar 45 m in (B) and (C). (From
Schwanzel-Fukuda et al., 1996, Figs. 8 and 9 with permission.)
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females, showing a sex-dependent functional connection

between the vomeronasal organ and the hypothalamic
LHRH neurons. Prolactin levels were not significantly
affected. In addition to the effects on gonadotropin
pulsatility, autonomic effects have been found as well after
vomeronasal organ stimulation. These include decreased
respiratory frequency, increased cardiac frequency and
event-related EEG changes. In addition, decreased skin
temperature has been found (Monti-Bloch et al., 1994,
1998; Berliner et al., 1996).
Research pioneered by McClintock (1971) has shown
that the menstrual cycle of women who are roommates
or close friends tend to converge with time. Although the
vomeronasal organ has been proposed to be the most
likely candidate system of communication between
the women, this has not been proven until recently;
however, vomeropherins seem to be involved. Stern and
McClintock (1998) collected body odor on cotton pads
from female donors. These pads were wiped under the
nose of recipient women, who were asked not to wash
their faces for the next 6 h. The timing of the ovulation
and menstruation of the recipients did indeed change
systematically. Odors taken on the day that the donors
ovulated and the two following days delayed ovulation,
whereas odors from women in the follicular phase of the
ovulatory cycle shortened both the time to ovulation and
the length of the menstrual cycle. The interpretation of
these data is still under debate (McClintock, 1999;
Whitten, 1999).
Recent positron-emission tomography (PET) studies
have shown that smelling an androgen-like compound
activates the hypothalamus of women, with the center of
gravity in the preoptic and ventromedial nuclei. Men, in
contrast, activate the PVN and dorsomedial nuclei when
smelling an estrogen-like substance, showing a substrate
for a sexually dimorphic reaction to pheromones (Savic
et al., 2001; Fig. 24.11).
Fig. 24.11. Smelling of odorous sex hormone-like compounds causes
sex-differentiated hypothalamic activations in humans. Activated clusters superimposed on a standard brain. The Sokoloff color scale
illustrates z values (0.04.5). The clusters were thresholded at 3.1; thus,
only regions with z > 3.1 and cluster size > 0.8 cm3 are shown. (A) A
derivative of testosterone (AND) versus AIR in females. (B) A derivative of estrogens (EST) versus AIR in females. (C) EST versus AIR
in males. Subjects right side is to the left. The Talairach coordinates
are given. The same brain sections are shown for the two contrasts
within each sex group to illustrate the lack of hypothalamic activation
with AND in males and EST in females. Only the significant clusters
(p < 0.05) are shown. The AND versus AIR in males showed no clusters at p < 0.05 and is therefore not illustrated. (From Savic et al., 2001,
24.3. Kallmanns syndrome

Kallmanns syndrome, first described by Maestro de San
Juan in 1856 and subsequently by Kallmann et al. in 1944
(Izumi et al., 1999), is an inherited disorder, defined by
the joint occurrence of hypogonadotropic hypogonadism
and anosmia. Affected patients may exhibit, e.g. cerebellar ataxia, nerve deafness, retinitis pigmentosa, color
blindness, synkinesia, nystagmus, and mental retardation
(Hochberg et al., 1982; Rugarli and Ballabio, 1993; Gu
et al., 1998), but high IQs have also been reported
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(Bobrow et al., 1971). In addition, dysplasia of the hippocampus has been reported in two cases of Kallmanns
syndrome, making it clear that the affected systems are
not limited to the hypothalamus. Male Kallmann patients
do not show an interest in the opposite sex, do not fall
in love and have no libido. An absence of homosexuality
has been reported, but the study included only 13 patients
(Bobrow et al., 1971; Wakeling, 1972; Parhar et al., 1995).
In female patients, the differential diagnosis anorexia
nervosa with primary amenorrhea should be considered
(White et al., 1993). Although many cases of Kallmanns
syndrome are sporadic, autosomal dominant, autosomal
recessive and X-linked recessive inheritance patterns
have also been described, which indicates genetic heterogeneity. An autosomal locus for Kallmanns syndrome
has been proposed at chromosome 8p11.2 (Vermeulen
et al., 2002). The incidence of Kallmanns syndrome has
been estimated at 1:10,000 males and 1:50,000 females,
which was interpreted to indicate that the X-linked form
is the most frequent one (Rugarli and Ballabio, 1993;
Birnbacher et al., 1994). However, more recent data
indicate that the X-linked form of Kallmanns syndrome,
which is due to characterized mutations, is the least
common of the three modes of inheritance (Gu et al.,
1998; Maya-Nuez et al., 1998).
(a) Molecular genetics and migration
Genetic defects have been observed in X-linked
Kallmanns syndrome, in a critical region of about 70 Kb
in the Xp22.3 region in less than 50% of the patients.
This localization has led to the assignment of the KALX
or KAL1 gene to a specific 680 amino acid-secreting part
within this region (Legouis et al., 1994; Izumi et al., 1999;
Rugarli, 1999). Patients with Kallmanns syndrome
carrying small deletions or single-base mutations within
the KAL gene, a translocation or a duplication, have been
described (Hardelin et al., 1993; Rugarli and Ballabio,
1993; Izumi et al., 1999, 2001; Rugarli, 1999; Sderlund
et al., 2002). Final validation of the KAL gene was established with the discovery of nine unique point mutations
in this gene (Seminara et al., 1998; Izumi et al., 2001).
In addition, the complementary DNA (cDNA) of the
candidate gene KALIG-1 (Kallmanns syndrome interval
gene-1), which has been isolated from the same area,
Xp22.3. Two brothers with Kallmann syndrome inherited
a 3500-bp deletion from their mother that was entirely
confined to the KALIG-1 gene (Bick et al., 1992;
Caviness, 1992). The sequence revealed homology with
the N-CAM, indicating that the KALIG-1 gene may

encode a new type of neuronal migration factor. The
KAL1 gene encodes an extracellular matrix glycoprotein
of compound molecular structure called anosmin-1, which
belongs to the class of cell adhesion molecules. Anosmin1 is present in various extracellular matrices, such as
interstitial matrices and basement membranes. Later in
embryonic life, KAL1 expression becomes restricted to
definite neuronal populations (Hardelin, 2001). Anosmin1 may not only play a role in migration of olfactory and
LHRH neurons and in the differentiation of the olfactori
bulb, but also in the development of synkinesia and renal
agenesis, which are seen in the X-linked form of
Kallmanns syndrome (Jansen et al., 2000; Massin et al.,
2003). A nonsense mutation was found in exon 13 of the
KAL gene, encoding the region of the fourth fibronectin
type III repeat of anosmin-1, which results in an apparently nonfunctional truncated protein (Jansen et al., 2000).
In X-linked Kallmanns syndrome, gonadotropin apulsity
is consistent with complete arrest of LHRH neurons at
the nasal-forebrain junction. However, the low levels of
LH and FSH that have been reported in cases of autosomal Kallmanns syndrome suggest that a few LHRH
neurons have successfully reached their destination in the
hypothalamus (MacColl et al., 2002). In addition to the
X-linked form, autosomal dominant and recessive
kindreds with Kallmanns syndrome have been reported.
These cases do not have a completely apulsatile LH secretion, like the patients with a KAL mutation, but rather
enfeebled, but present, LHRH-induced LH pulses
(Oliviera et al., 2001). One siblingship has been described
where the brother and sister both had Kallmanns
syndrome (anosmia and deficiency of LHRH), and the
woman also had streak ovaries. Linkage analysis showed
that a gene other than KAL1 at Xp22.3 was implicated
in this mutation (Persson et al., 1999). Moreover, autosomal forms of Kallmanns syndrome with complex
chromosomal translocations have been reported (Kroisel
et al., 2000). In fact, both autosomal recessive and autosomal dominant modes of transmission have been
described in addition to the X-linked form, and many
sporadic cases have been reported (Izumi et al., 1999).
Consequently, other genes than the Xp22.3 region should
be involved in more than 50% of the cases of Kallmanns
syndrome.
The KAL gene is expressed in the olfactory bulb and
in various other parts of the brain (Rugarli et al., 1993;
Lutz et al., 1994). Upregulation of transcription of the
KAL gene was found in chickens at the moment when
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the first synaptic contacts between the olfactory axons

and mitral cells were established, which may suggest that
the primary defect in Kallmanns syndrome lies in
neuronal interaction and/or synaptogenesis rather than in
migration. In addition to functions such as adhesion molecule, chemoattractant, and proinvasive factor, KAL was
proposed to function as a target-derived stop signal for
olfactory neurons (Rugarli, 1999). The observation in
humans that at 45 days of embryogenesis, when the KAL
gene is not yet expressed, the olfactory nerves have
already begun their migration from the nasal epithelium,
suggests that the KAL gene is not necessary for early
migration. Rather, a defect in neuronal interaction may
take place, i.e. when the LHRH neurons enter the olfactory bulb and/or at the moment when contact is established
between the incoming olfactory axons and the central
neurons of the bulb (Seminara et al., 1998). The migration defect may consequently be secondary to the lack of
contact between the olfactory nerves and the forebrain
(Rugarli and Ballabio, 1993; Rugarli et al., 1993), and
the retrograde degeneration of the olfactory nerve may
thus be the result of this lack of contact (Seminara et al.,
1998). It has also been presumed that part of the role of
the normal Kallmann gene product may be a suppression
of a Y gene product (Parhar et al., 1995).
Subsequently a mutation was found in the KAL gene
part that encodes for the C-terminal portion of a
fibronectin type III gene that may be involved in axonal
pathfinding (ONeill et al., 1998). In addition, the KAL1-encoded protein anosmin-1 was found to be a transient
and regionally restricted component of extracellular
matrices during organogenesis in humans. Anosmin-1 was
detected in many organs, including some forebrain
regions. In the olfactory bulb the protein was detected
from week 5 onward. The protein was restricted to the
olfactory bulbs and the medial walls of the primitive cerebral hemispheres along the rostrocaudal migratory
pathway of the LHRH neurons at 6 weeks. The protein
seems to act as a local rather than a long-range cue during
organogenesis (Hardelin et al., 1999).
217
been described (Dissaneevate et al., 1998). Patients with

partial LHRH deficiencies and incomplete sexual development have been described in the past as fertile eunuchs
(Rugarli and Ballabio, 1993). Although gonadotropin
deficiency in Kallmanns syndrome is generally said
to be an isolated endocrine disorder, some patients with
this syndrome may have osmoreceptor dysfunction and
abnormal thirst regulation, indicating more extensive
hypothalamic involvement than previously appreciated
(Hochberg et al., 1982).
In addition to hypogonadism, patients with Kallmanns
syndrome exhibit either nonselective anosmia or hyposmia, due to aplasia or hypoplasia of the olfactory bulbs
and tracts. Neuroimaging by MRI provides accurate in
vivo demonstration of arrhinencephalia, i.e. absence of
the olfactory bulb, olfactory tracts and olfactory sulcus
(Rugarli and Ballabio, 1993; Vogl et al., 1994). The
receptor cells of the olfactory mucosa cannot innervate
the absent olfactory bulb in Kallmanns syndrome and
this disorder is therefore characterized by axonal degeneration, neuronal immaturity and the formation of
intraepithelial neuromas (Schwob et al., 1993). Yet at
least some olfactory neurons are functionally mature in
the olfactory epithelium of Kallmann patients (Rawson
et al., 1995) and normal olfactory bulbs are found in 25%
of Kallmanns syndrome patients (Seminara et al., 1998).
Typically, patients with hypogonadotropic hypogonadism
and anosmia have been diagnosed with Kallmanns
syndrome and those with normal olfaction have been diagnosed with idiopathic hypogonadotropic hypogonadism.
However, both of these presentations (i.e. with and
without anosmia) can occur in the same family, thus
demonstrating the variability of expression of this trait
(Seminara et al., 1998).
The pathogenetic basis of the association between
hypogonadism and anosmia in Kallmanns syndrome
seems to be a migration defect of LHRH neurons (see
above). LHRH neurons and olfactory neurons both originate in the olfactory placode. The olfactory placode forms
the olfactory epithelium from which the olfactory neurons
project to the mitral cells of the olfactory bulb. During
development, LHRH neurons migrate from the medial
olfactory pit along the terminal nerves and across the
olfactory bulb to the hypothalamus and adjacent areas
(Parhar et al., 1995; Schwanzel-Fukuda et al., 1996). The
presence of LHRH neurons has been demonstrated in the
human fetal hypothalamus, by 59 weeks of gestation,
although functional connections between these neurons
and the portal system are not established until 16 weeks
(b) Functional deficits

Gonadotropin deficiency in Kallmanns syndrome is due
to a reduced secretion of LHRH by the hypothalamus.
LHRH deficiency may be partial or complete. In the
complete form, both FSH and LH levels are low, and
there is no evidence of sexual maturation. A few
Kallmann patients with a pubertal LHRH response have
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(Aksel and Tyrey, 1977; Seminara et al., 1998). Whether

these LHRH neurons, that are present during early human
embryogenesis, indeed originate from the olfactory pits
has not been proven. The hypothesis that one of the guidance molecules of migrating neurons would be deficient
in Kallmanns syndrome was supported by histopathological findings in a 19-week-old human fetus with
X-linked Kallmanns syndrome. The outgrowth of the
olfactory axons was prematurely arrested in a tangle of
nerve fibers in the fetal meningal, between the cribiform
plate and the forebrain. LHRH-containing neurons were
found to be dammed up at the dorsal surface of the
cribiform plate. Migration was arrested at the distal end
of the olfactory nerves and the neurons accumulated in
the meningeal tissue (Schwanzel-Fukuda et al., 1989,
1992, 1996; Rugarli et al., 1993; Parhar et al., 1995; Fig.
24.6). A possible radiological correlate of arrested
neuronal migration in Kallmanns syndrome has been
found as heterotopic tissue in this place (Rugarli and
Ballabio, 1993). Based on these findings, it has been
proposed that the Kallmanns syndrome gene would
encode a factor involved in the migration and targeting
of LHRH and olfactory neurons, respectively. In mice it
has subsequently been established that N-CAM marks the
migration route for LHRH (Parhar et al., 1995), and the
properties of the KAL1 gene (Hardelin, 2001) confirm
this concept.
Some patients with Kallmann syndrome may have

osmoreceptor dysfunction and abnormal thirst regulation
(Hochberg et al., 1982), which may be related to the
observation of Itoh et al. (1997) that the SON neurons
showed hypertrophy. This activation can at least be partly
due to a lack of sex hormones (Ishunina et al., 2000;
Chapter 8c).
The missing hormones have been substituted by exogenous testosterone or estrogens to induce puberty
(Dissaneevate et al., 1998). Kallmanns syndrome can be
effectively treated with pulsatile LHRH. Even in a
Kallmanns syndrome patient as old as 43 years, not only
androgenization but also spermatogenesis could be
induced.
Interestingly, a variant of Kallmanns syndrome has
been reported in which endogenous gonadotropin secretion recovers spontaneously in later life. Spontaneous
onset of endogenous gonadotropin secretion, evidenced
by progressive normalization of testicular volume, and of
serum testosterone concentration, occurred in these men
over a period of years. This means that Kallmann patients
should be reassessed (off androgen replacement therapy)
to identify those who no longer require treatment (Quinton
et al., 1999).
(c) Endocrine disorders
In 1942, Klinefelter described a man with gynecomastia

and infertility, whose Leydigs cells nevertheless appeared
to be normal. He had a low to normal urine excretion
of 17-ketosteroids and an increased urinary excretion
of FSH. About half of the Klinefelter patients have
decreased testosterone levels, while the other half
have normal testosterone values (Yoshida et al., 1997).
Lower testosterone values may even be present already
at birth (Srensen et al., 1981; Smyth and Bremner,
1998). Cells of the buccal mucosa of Klinefelter males
appeared to contain an extra chromatin mass, later termed
sex-chromatin or Barr body, which turned out to be a
second X chromosome (47,XXY). Klinefelters syndrome
is the most common sex chromosome disorder (Smyth
and Bremner, 1998). Mosaic and polysomic-X variants
of Klinefelters syndrome are present in 1020% of
the patients. Patients with the XXYY karyotype constitute about 3% of the chromatin-positive males. The
incidence of this variant is estimated to be 1:50.000 male
births (Bertelloni et al., 1999; Matsuoka et al., 2002).
Although it has been proposed to name the 47,XXY
The pituitary of a Kallmanns syndrome patient shows

scant gonadotrophs only weakly staining for LH and
FSH, with fewer and smaller secretory granules. Growth
hormone, too, stains less intensely, but the other pituitary
hormones seem to be normal (Kovacs and Sheehan, 1982;
Itoh et al., 1997). In the hypothalamus the lateral tuberal
nuclei are undeveloped (Kovacs and Sheehan, 1982;
Itoh et al., 1997). Both studies reported that the nucleus
subventricularis, the ventral part of the infundibular
nucleus, showed hypertrophy, most probably due to a
stimulation of sex hormone receptor-containing neurons,
as is also observed in menopause and other conditions
that display a lack of sex hormones (see also Chapter
11f). The neurons of the tuberomamillary nucleus
were described as unusually numerous according to
Kovacs and Sheehan (1982), whereas Itoh et al. (1997)
reported the tuberomamillary complex neurons to be
unusually few, which makes clear that systematic quantitative studies of the Kallmann hypothalamus are needed.
24.4. Klinefelters syndrome or testicular dysgenesis
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karyotype Klinefelter disease and to call the other

variant genotypes/phenotypes Klinefelters syndrome,
the latter term will be used here for all variants.
Anenploidy involving the X chromosome results either
from nondysjunction during the first or second meiotic
divisions, or from mitotic nondysjunction in the developing zygote. In 53% of cases the cause is paternal
nondysjunction at the first meiotic division, in 34% it is
the first maternal meiotic division; 9% of cases were
secondary to abnormalities during the maternal second
meiotic division. The frequency of 47,XXY is about 1/500
male conceptions but only 1/1000 male live births
(Schwartz and Root, 1991; Smyth and Bremner, 1998).
In one Klinefelter fetus, holoprosencephaly (see Chapter
18.3) was found (Armbruster-Moraes et al., 1999), and
one 46,XY/47,XXY mosaic Klinefelter patient had a
Rathkes cleft cyst with hypothalamic panhypopituitarism, partial diabetes insipidus and other endocrine
disorders (Gotoh et al., 2002).
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(1997) study the mean frequency of intercourse was

significantly higher than in the control group, possibly
because this was a selection of patients who came with
the chief complaint of male infertility. Wakeling (1972)
reported evidence of homosexual behavior in 4 of 11
Klinefelter patients, which agrees with the idea that sexual
orientation develops as a result of interaction of sex
hormones and nerve cells (see Chapter 24.5). This observation seems to contrast, however, with an older report
mentioning that only 2 of 30 Klinefelter patients were
homosexual (Pasqualini et al., 1957). The small numbers
in either study do, however, not allow a final conclusion
about this topic.
Klinefelters syndrome is the most common cause of
hypogonadism in males. However, due to causes other
than chromosomal abnormalities, often types of hypogonadal patients had a more marked hypogonadism
and more severe impairment of secondary sexual development than the Klinefelter patients (Wakeling, 1972).
Testosterone levels from umbilical cord blood of infants
with an XXY have been found to be lower than those of
controls, so that decreased testosterone function may be
present already in fetal life. Yet, postnatal pituitary
gonadal function is remarkably normal until the later
phases of puberty (Smyth and Bremner, 1998). In the
first stages of pubertal development, testosterone levels
of Klinefelter patients are still in the normal range.
Progressive hyalization and fibrosis of the seminiferous
tubules begins before puberty. By ages 1214, basal LH
and FSH levels start to increase, then, from this age
onwards, testosterone levels stay below the midnormal
adult range (Hsueh et al., 1978; Raboch and Mellan, 1978;
Schwartz and Root, 1991; Smyth and Bremner, 1998).
The attenuated testosterone feedback in Klinefelters
syndrome is responsible for the greatly amplified pituitary
responsiveness to the trophic action of LHRH and this,
in part, may lead to the increased LH and FSH levels
(Goh and Lee, 1998). Elevations in sex hormone-binding
globulin levels in Klinefelters syndrome lead to decreased
free testosterone concentrations. Plasma estradiol levels
are often elevated (Yoshida et al., 1997) and an increase
in the estradiol to testosterone ratio may be responsible
for gynecomastia (Schwartz and Root, 1991). Both normal
and blunted TSH responses to TRH have been reported
in Klinefelters syndrome; basal prolactin levels are
generally normal (Hsueh et al., 1978; Schwartz and Root,
1991). In Klinefelters syndrome significant circannual
rhythms are present for testosterone and FSH, but not
for LH, prolactin or TSH (Bellastella et al., 1986a, b).
(a) Clinical presentation

Males with 47,XXY are found during prenatal genetic
testing in neonatal screening programs and during evaluation of hypospadias, microphallus, cryptorchism
(Schwartz and Root, 1991) or infertility (azoospermia).
Damage to the testicular Leydigs cells and seminiferous
tubules can be seen as early as the 1st year of life (Hsueh
et al., 1978). Klinefelters syndrome features include a
smaller head circumference. At school age Klinefelters
may have learning problems and behavioral disorders;.
in adolescence they may develop gynecomastia (present
in 3060%), tallness, low weight, small testes, sparse
body hair and an eunuchoid habitus. Puberty is often
delayed; on the other hand, precocious puberty also
occurs in Klinefelters syndrome. In fact, the association
between Klinefelter and precocious puberty is 5.5fold higher than expected. In some Klinefelter boys,
precocious sexual development is due to peripheral
endocrine active malignancies; in one boy a hamartoma
of the third ventricle was found, and a pineal tumor
in another. Central precocious puberty may also
occur in the XXXY and XXYY variants (Bertelloni et
al., 1999).
About 67% of the Klinefelter patients have some type
of sexual function disturbance (Schwartz and Root, 1991;
Srensen, 1992; Von Mhlendahl and Heinrich, 1994;
Smyth and Bremner, 1998). Klinefelter patients are generally said to have a weak libido, but in Yoshida et al.s
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As in other cases of hypogonadism, increased nocturnal

melatonin secretion has been found that can be normalized by testosterone treatment (Luboshitzky et al., 1997;
Caglayan et al., 2001). The latter authors showed that
the increased melatonin levels are due to a change in
melatonin metabolism, rather than to a change in melatonin secretion.
Until recently, donated sperm or adoption were the
options for infertile parents. However, also successful
intracytoplasmic injection of sperm, obtained from testicular biopsy samples from patients with Klinefelters
syndrome have been published. The finding of some spermatozoa with an extra X chromosome implies that
Klinefelters syndrome may be transmissible by such
techniques and is a point of serious concern (Amory et
al., 2000).
(b) Psychosocial problems
Learning disabilities, a low IQ, averaging 82, behavioral
problems, psychological distress and (generally mild)
mental deficiency have all been found in Klinefelters
syndrome, as have neuromaturational lag, reduced
language skills and dyslexia. Sexual activity generally
begins at the usual age. Behavioral and psychiatric disorders include aggressiveness, alcohol abuse and abuse of
other substances, criminal behavior, depression, personality disorders and schizophrenia. Speech and language
delays have an impact on development. The verbal and
language deficits associated with Klinefelters syndrome
are found to be associated with a reduction in left temporal
lobe gray matter, while a history of testosterone supplementation increases verbal fluency scores and preserves
the left temporal lobe volume (Patwardhan et al., 2000).
It should be noted, moreover, that it has been stated
that the diagnosis of Klinefelters syndrome is said
not to denote an increased likelihood of criminality,
psychopathology or mental retardation. Some 6.3% of
Klinefelter patients are diagnosed as having schizophrenia
and 5.8% as having psychoses of an uncertain type.
Testosterone replacement therapy might have positive
effects on mood, sexual behavior, self-esteem and other
behavioral problems in some subjects (Pasqualini et al.,
1957; Johnson et al., 1970; Wakeling, 1972; Nielsen et
al., 1988; Mandoki et al., 1991; Schwartz and Root, 1991;
Srensen, 1992; Smyth and Bremner, 1998). Some cases
of anorexia nervosa associated with Klinefelters
syndrome have been described (El-Badri and Lewis,
1991).
24.5. Sexual differentiation of the brain and sexual

behavior
We must remember that all our provisional ideas in
psychology will one day be explained on the basis of organic
substrates. It seems then probable that there are particular
chemical substances and processes that produce the effects
of sexuality and permit the perpetuation of individual life.
(Sigmund Freud, On Narcissism)
(a) Mechanism of sexual differentiation of the brain

Sexual differentiation of the brain is thought to be
imprinted or organized by hormonal signals from the
developing male gonads. On the basis of animal experiments, this process is presumed to be induced by
androgens during development, following conversion to
estrogens by P-450 aromatase (Fig. 24.12). Aromatase
is present throughout the human brain, including the hypothalamus, both in men and women (Sasano et al., 1998).
Male sexual differentiation of the human brain is thought
to be determined in the two first periods during which
sexually dimorphic peaks in gonadal hormone levels are
found, viz: (i) during gestation, and (ii) during the perinatal period, while (iii) from puberty onwards, sex
hormones alter the function of previously organized
neuronal systems (activating effects) (for references see
Forest, 1989; De Zegher et al., 1992; Swaab et al., 1992a).
In late gestation, the male fetus is exposed to both high
concentrations of testosterone from the fetal testes and
high levels of estrogens from the placenta. After the
inhibitory effect of maternal estrogens wanes, postnatally,
the infants gonadotropins predominantly LH increase
significantly, a process that starts around 1 week after
birth. In response there is a rapid rise in testosterone until
some 6 months after birth.
The female fetus is also exposed to estrogens from the
placenta. In postnatal female infants, the surge of FSH
is predominant, giving rise to an increase in estradiol,
24 months postnatally. FSH secretion begins to decline
by 12 months of age (Quigley et al., 2002).
Studies in primates indicate that the period of the
neonatal testosterone peak is a critical period in the
process of sexual and behavioral development (Mann and
Fraser, 1996). Testosterone is formed in the fetal Leydig
cells in the testicle from about 8 weeks of gestation
on (Hiort, 2000). The possible importance of the male
testosterone surge for sexual differentiation of the brain
following aromatization to estrogens agrees with the
observations that girls whose mothers were exposed to
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Fig. 24.12. Schematic overview of the interconversions and relations between steroids with androgenic and estrogenic properties. DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 5-ADIOL, 5-androstene-3,17-diol (DHEA after reduction at the 17 position); 4-ADION,
4-androstene-3,17-dione; TESTO, testosterone; DHT, 5-dihydrotestosterone. The arrows indicate the possible conversions in the human body.
(From Thijssen, 2002, Fig. 1 with permission.)
hypothalamus of the child, but by chorionic gonadotropins

from the placenta as well, since a normal neonatal increase
of testosterone was found in a patient with hypogonadism
based upon a DAX-1 gene mutation, which causes hypogonadotropic hypogonadism (Takahashi et al., 1997).
Although both sexes are prenatally exposed to high
estrogen concentrations, only males are subjected to high
levels of androgens (Quigley et al., 2002). In human
neonates the testosterone level is 10-fold higher in men
than in women at 3441 weeks of gestation (De Zegher
et al., 1992). Although the peak in serum testosterone in
boys at 13 months postnatally approaches the levels seen
in adult men, most testosterone is bound to globulin. Yet
the amount of free testosterone in male infants is about
one order of magnitude larger than that in female infants
at this time (Bolton et al., 1989). During the adrenarche,
i.e. from 7 years of age to the onset of puberty, the adrenal
starts to produce more androgens, predominantly DHEA
and DHEAS. After the age of 8 years, testosterone
from the adrenal also starts to rise, while a small but
significant testicular production of testosterone is also
present in prepubertal boys (Forest, 1989). Although the
testosterone peak during puberty (Forest, 1989) is generally thought to be involved in activation rather than
diethylstilbestrol during pregnancy run a higher risk

of developing bi- or homosexuality (Ehrhardt et al.,
1985; Meyer-Bahlburg et al., 1995), and that girls with
congenital adrenal hyperplasia, producing high levels of
testosterone, are at risk for homosexuality or gender-identity problems (Money et al., 1984; Dittmann et al., 1992;
Meyer-Bahlburg et al., 1996; Zucker et al., 1996; Table
24.2) (see below). An association has been found between
an estrogen receptor- gene polymorphism and personality traits such as nonconformity in women (Westberg
et al., 2003), pointing to effects of estrogens on brain
development. Estrogens, produced locally by aromatase,
are thought to participate in numerous biological functions, including sexual differentiation of the brain.
Aromatase is found throughout the adult human brain
with the highest levels in the pons, thalamus, hypothalamus and hippocampus. The amount of aromatase mRNA
is also highest in the hypothalamus, thalamus and amygdala, and alternative splicing is found also. However, no
difference in aromatase mRNA was detected between
the four men and two women studied (Sasano et al.,
1998). Such a study has, however, so far not been
performed in larger series or in development. The neonatal
peak of testosterone is probably not only induced by the
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TABLE 24.2
Factors that influence sexual differentiation of the human brain.
Gender identity (transsexualism)
Chromosomal disorders
Phenobarbital/diphantoin
Hormones
Social factors?
Rare: 47XYY (male-to-female), 47XXX (female-to-male). Microdeletion on

Y-chromosome in 1 male-to-female transsexual (Hengstschlger et al., 2003).
Steroidogenic factor-1 mutations (give sex-reversal, no transsexuality; Achermann et al., 2001a, b;
Ozisik et al., 2002).
Klinefelter XXY male-to-female (Sadeghi and Fakhrai, 2000).
Twin studies (Sadeghi and Fakhrai, 2000; Coolidge et al., 2002).
Genomic imprinting (Green and Keverne, 2000).
(Dessens et al., 1999)
Intersex (Zucker et al., 1987; Reiner, 1996), micropenis (Reiner, 2002)
Cloacal exstrophy (Zucker, 2002; Zderic et al., 2002)
5--Reductase deficiency, 17-hydroxy-steroid-dehydrogenase-3 deficiency (Imperato-McGinley et al.,
1979, 1991; Wilson, 1999).
CAH girls with gender problems (Meyer-Bahlburg et al., 1996; Zucker et al. 1996).
More polycystic ovaries, oligomenorrhea and amenorhea are found in transsexuals (Futterweit et al.,
1986).
Complete androgen-insensitivity syndrome results in XY heterosexual females (Wisniewski et al., 2000).
However: in congenital deficiency of estrogens due to aromatase deficiency or estrogen resistance,
gender identity is not affected (Smith et al., 1994; Morishima et al., 1995; Carani et al., 1997, 1999;
Faustini-Fustini et al., 1999; Rochira et al., 2001).
(Bradley et al., 1998) not effective: John/Joan/John case (Diamond and Sigmundson 1997; CohenKettenis and Gooren, 1999)
Sexual orientation (homosexuality, heterosexuality)

Genetic factors
Twin studies (Kallmann, 1952; Bailey and Bell, 1993).
Molecular genetics (Hamer et al., 1993; Hu et al., 1995). However, see Rice et al. (1999).
Hormones
CAH girls (Money et al., 1984; Dittmann et al., 1992; Zucker et al., 1996)
DES (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995)
Male-to-female sex reassignment (Bailey et al., 1999)

Chemicals
Nicotine prenatally increases the probability of lesbianism (Ellis and Cole-Harding, 2001).
Immune response?
Social factors?
Golombok et al.,
Homosexual orientation in men is most likely to occur in men with a high number of older brothers and
shorter stature (Bogaert, 2003).
Stress during pregnancy (Ellis et al., 1988; Bailey et al., 1991; Ellis and Cole-Harding, 2001).
Raising by transsexual or homosexual parents does not affect sexual orientation (Green, 1978;
1983).
organization, the neuron number of the female domestic

pig hypothalamus to our surprise showed a twofold
increase in a sexually dimorphic hypothalamic nucleus
around puberty (Van Eerdenburg and Swaab, 1991),
which means that, although this phenomenon may have
been programmed earlier, late organizational effects can
at present not be excluded. Few data are available on the
exact period in development when the human brain differentiates according to sex. Brain weight is sexually
dimorphic from 2 years postnatally onwards, taking
differences in body weight between boys and girls into
account (Swaab and Hofman, 1984). Sexual differentiation of the human sexually dimorphic nucleus of the
preoptic area (SDN-POA) becomes apparent between 4
years and puberty (Swaab and Hofman, 1988, Chapter
5). A similar late sexual differentiation was found in
darkly staining posteromedial components of the bed
nucleus of the stria terminalis (Allen et al., 1990; Chapter
7). The sex difference in the size of the central subdivision of the bed nucleus of the stria terminalis (BSTc)
(Chapter 7.1) only becomes significant in adulthood
(Chung et al., 2002). Concluding one might say that the
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limited evidence that is currently available suggests that

sexual differentiation of the human hypothalamus
becomes apparent between 2 years of age and adulthood,
depending on the area involved. This may, of course, be
based upon processes that were programmed much earlier,
for instance by a peak in sex hormone levels in mid-pregnancy or during the neonatal period (see above). On the
basis of existing prenatal serum samples from their
mothers, it appeared that, indeed, higher androgen exposure in the second trimester of fetal life may masculinize
a girls behavior (Udry et al., 1995).
Although estrogens, derived from testosterone by aromatization (Fig. 24.12), are considered to be the major
mediator for androgenization of the brain during development in rodents, testosterone itself may be of major
importance for sexual differentiation of the human brain.
In the first place, both sexes are exposed to high levels
of estrogens during fetal life, while it is only the males
who are subjected to high androgen levels (Quigley
et al., 2000). Moreover, the androgen receptor, located
on the X-chromosome at Xq11-12, may be mutated in
such a way that the subject has a complete androgeninsensitivity syndrome. The pre- and postnatal hormone
testosterone surge normally found in male infants most
probably also occurs in these children. Apparently
the normal surge requires hypothalamic expression of
androgen receptors (Quigley et al., 2002). This is at least
clear for the postnatal testosterone surge (Bouvattier et
al., 2002).
In spite of normal testis differentiation and androgen
biosynthesis, the phenotype has a normal female external
and behavioral appearance (Batch et al., 1992; Thiele et
al., 1999). Phenotypic women with complete androgeninsensitivity syndrome perceive themselves as highly
feminine. They do not have gender problems and largely
report their sexual attraction, fantasies and experiences
as being female and heterosexual (Wilson, 1999;
Wisniewski et al., 2000). This means that for the development of human male gender identity and male
heterosexuality, direct androgen action on the brain seems
to be of crucial importance, and that the aromatization
theory may even be of secondary importance for human
sexual differentiation of the brain. The observation by
Mackle et al. (1993), that DNA sequence variation in the
androgen receptor is not a common determinant of sexual
orientation at first sight, seems to be at variance with this
idea, but it should be noted that the DNA variations in
that study did not prevent normal androgenization of the
subjects studied, so that there was no loss of function of
223
this receptor. The point of view that aromatization may

be less important than we thought agrees with the lack
of gender problems in a brother and sister with aromatase
deficiency due to an inactivating mutation of the P-450
gene and in a 27-year-old man with a mutation of the
CYP gene (of which aromatase cytochrome is a product),
were accompanied by psychosexual orientation appropriate for their genetic and phenotypic sex (Morishima et
al., 1995; Rochira et al., 2001; Carani et al., 1997; 1999;
Faustini-Fustini et al., 1999; Hermann et al., 2002).
Moreover, a 28-year-old man with estrogen resistance due
to a mutation of the estrogen-receptor gene was described
as tall, with continued linear growth in adulthood, incomplete epiphysal closure and increased estrogen and
gonadotropin levels. A change in a single base pair in
the second exon of the estrogen-receptor gene was found.
However, the patient reported no history of gender-identity disorder, had strong heterosexual interest and normal
male genitalia. The elevated serum estrogen levels are
explained by a possible compensatory increase in
aromatase activity in response to estrogen resistance
(Smith et al., 1994; Rochira et al., 2001). On the one
hand, the heterosexual XY females resulting from the
complete androgen-insensitivity syndrome (Wisniewsky
et al., 2000) and the male gender heterosexual behavior
of patients with 5-reductase-2 or 17-hydroxysteroid
dehydrogenase-3 deficiency (Imperato-McGinley et al.,
1991, 1997; Wilson et al., 1993; Wilson, 1999) indicate
that a direct action of testosterone may be more important than that of dihydrotestosterone (DHT) (Fig. 24.12)
for male heterosexual psychosexual development. The
affected 46,XY individuals have normal to elevated to
high plasma testosterone levels with decreased DHT
levels. They have ambiguous external genitalia at birth,
so that they are often raised as girls. Virilization occurs
at puberty, frequently with a gender role change. These
subjects demonstrate that exposure of the brain to testosterone during development and at puberty appears to have
a greater impact in determining male gender identity than
do sex of rearing and sociocultural influences (ImperatoMcGinley and Zhu, 2002). The relative contributions of
the different sex hormones and other nonhormonal factors
on sexual differentiation of the human brain should clearly
be a focus for future research, including a more detailed
endocrine and psychosexual investigation of the patients
with mutations in aromatase or sex hormone receptors.
Not only may sex hormones affect sexual differentiation of the brain; on the basis of animal experiments it
is expected that all compounds that influence hormone
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or neurotransmitter metabolism in development may also

affect sexual differentiation of the brain (Pilgrim and
Reisert, 1992; Swaab and Boer, 2001). Indeed, prenatal
nicotine exposure was found to increase the probability
of lesbianism. Also prenatal stress disrupts the hormonal
milieu in which the fetal brain is sexually differentiating
and feminizes/demasculinizes the males sexual orientation (Ellis and Cole-Harding, 2001). Although young
adult male mice that were prenatally exposed to alcohol
were found to have a decreased preference for females
and an increased preference for males (Watabe and Endo,
1994), little support was found for such an effect of
prenatal alcohol exposure on sexual orientation in humans
(Ellis and Cole-Harding, 2001). Rats exposed to some
drugs (e.g. barbiturates) during development show deviations in testosterone levels, persisting into adulthood
(Ward, 1992). This agrees with the finding of Dessens et
al. (1999) that children born of mothers who were exposed
to anticonvulsants such as phenobarbital and diphantoin
have an increased probability of transsexuality (see
below). Exposure of rats to drugs such as opiates leads
to behavioral changes, despite apparently normal adult
gonadal hormone levels (Ward, 1992). Similar observations in human sexual differentiation have not yet been
reported. However, a study on gender role behavior in
children of 42 months of age showed that maternal stress
during pregnancy was accompanied by more masculine
behavior not only in girls, but also in both boys and girls,
older male or female siblings, parental adherence to traditional sex roles, maternal use of tobacco or alcohol during
pregnancy, and maternal education (Hines et al., 2002).
What these factors mean for gender and sexual orientation in adulthood remains to be seen.
It is of great interest that, in addition, there is recent
animal experimental evidence for primary genetic control
of sexual differentiation that does not involve sex
hormones. Results obtained from cultures of embryonic
rat brain indicate that dopaminergic neurons may develop
morphological and functional sex differences in the
absence of sex steroids (Pilgrim and Reisert, 1992). For
such hormone-independent effects, the most likely candidates are those genes located on the nonrecombining part
of the Y-chromosome and believed to be involved in
primary sex determination of the organism. Two candidate genes are the two testis-determining factors, ZFY
and the master switch for differentiation of a testis SRY;
they are putative transcription factors. We have shown
that SRY and ZFY are transcribed in hypothalamus and
frontal and temporal cortex of adult men and not in
women. It may well be possible that they function as sexspecific cell-intrinsic signals that are needed for full
differentiation of a male human brain, and that continuous expression throughout life may be required to
maintain sex-specific structural or functional properties
of differentiated male neurons. Sexual differentiation of
the human brain may thus be a multifactorial process,
although a role of SRY and ZFY in this process still needs
to be proved (Mayer et al., 1998a). An alternative mechanism could be the actions of an imprinted X-linked locus
(Skuse, 1999). Recent clinical studies on human subjects
with mutations in genes involved in sexual differentiation also point to the possibility that the interaction
between estrogens and brain development may not be the
only mechanism involved in the development of male
gender and sexual orientation. In fact, the data obtained
so far indicate that in case of congenital deficiency of
estrogens in humans due to aromatase deficiency or
estrogen resistance, gender identity and sexual orientation are not affected (Carani et al., 1999; Faustini-Fustini
et al., 1999; see above). The relative contributions of the
different sex hormones and other nonhormonal factors on
sexual differentiation of the human brain should clearly
be a focus for future research.
(b) Sexual differentiation, the hypothalamus and
amygdala
My brain? Its my second favourite organ.
Woody Allen
Sex differences in the hypothalamus and other limbic

structures are thought to be the basis of sex differences
in sexual arousal (Kamara et al., 2002), in reproduction
(e.g. copulatory behavior in both sexes, the menstrual
cycle in women), gender identity (i.e. the feeling one
is either male or female), gender identity disorders
(transsexuality) and sexual orientation (homosexuality,
heterosexuality, bisexuality) (Gooren et al., 1990; Swaab
et al., 1992a; Swaab and Hofman, 1995; Chapters 5, 6,
7). In addition, desinhibited sexual activity and paraphilias
have been reported following lesions in the hypothalamus
and septum (Miller et al., 1986; Frohman et al., 2002).
The PVN in rat, and in particular its oxytocin neurons
(see Chapter 8g), is involved in erectile functions in
copula. In monkey, too, penile erection is induced
by elective stimulation of the PVN (MacLean and
Ploog, 1962). Not only oxytocin but also -MSH
induces erection in rats after intracerebroventricular injection (Mizusawa et al., 2002). In humans, evidence
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supporting the role of melanocortin receptors in sexual

function derives from two double-blind, placebocontrolled phase I clinical trials, with the nonselective
melanocortin receptor agonist MTII. Subcutaneous lowdose administration of MTII was proerectile in men, with
organic (hypercholesterolemia, obesity, hypertension),
and psychogenic (no organic cause identified) erectile
dysfunctions. In addition, it was shown that the MC-4
receptor mediates proerectile events in rodents (MacNeil
et al., 2002; Van der Ploeg et al., 2002). For penile
erections initiated by psychogenic stimuli, the medial
amygdala, the PVN, and to a lesser extent the BST are
involved, while medial preoptic lesions in the rat have
little, if any, effect on this type of erections (Liu et al.,
1997b). Sexual arousal and orgasm produce long-lasting
alterations in plasma prolactin concentrations, both in men
and women (Exton et al., 1999), which might be related
to postorgasmic loss of arousability (Bancroft, 1999),
indicating a role of the medial-basal hypothalamic
dopamine neurons.
There is extensive animal experimental literature that
shows that the medial preoptic area of the hypothalamus
is a key structure for male and female copulatory behavior
(Pilgrim et al., 1992; Yahr et al., 1994; McKenna, 1998),
and that the hypothalamus is involved in seminal vesicle
contractions at coitus (Cross and Glover, 1958). Electrical
stimulation of the preoptic area in monkeys induces penile
erection (MacLean and Ploog, 1962). Although the exact
role of its subarea, the SDN-POA, in these functions is
less clear (Chapter 5), Gorski (2003) reported that electrical stimulation of the rat SDN-POA markedly enhanced
male sexual behavior. Hypothalamic structures involved
in sexual orientation in experimental animals is scarce
(Kindon et al., 1996; Paredes et al., 1998). Paredes and
Baum (1995) found that lesions of the medial preoptic
area/anterior hypothalamus in the male ferret not only
affected masculine coital performance, but also heterosexual partner preference. Perkins and colleagues have
shown that testosterone, estrone and estradiol plasma
concentrations are higher in female-oriented rams than in
homosexual rams. In the preoptic area the aromatase
activity is higher in the female-oriented than in the maleoriented rams, indicating again the possible importance
of the preoptic area in sexual orientation (Resko et al.,
1996). Edwards et al. (1996b) have observed a decrease
in partner preference in male rats following a lesion of
the BST. The number of estrogen receptors in the amygdala is similar in both homosexual rams and ewes but
lower than the receptor content in heterosexual rams,
225
while the estrogen receptor content of the hypothalamus,

anterior pituitary and preoptic area of these two groups
does not differ. These data suggest that the amygdala
might also play a role in sexual orientation. Indeed, in
some KlverBucy syndrome cases due to damage of the
temporal lobe, the patients behavior is reported to change
from heterosexual to homosexual, indicating that the
temporal lobe might be of importance for sexual orientation (Terzian and Dalle Ore, 1955; Marlowe et al., 1975;
Lilly et al., 1983). Also, there are a few case histories of
changing sexual orientation, from heterosexual to
pedophilic or homosexual, on the basis of a lesion in the
hypothalamus or in the temporal lobe, from which the
amygdala has strong connections to the hypothalamus
(Miller et al., 1968). There is no information available
on the exact nature of the preoptic and amygdala neuronal
systems and connections that may be involved in sexual
orientation. Data on the hypothalamus in relation to
gender identity in animals are, of course, nonexistent (for
alterations in the BSTc in male-to-female transsexuals,
see Chapter 7).
There are a few studies in the medical literature that
implicate the hypothalamus and adjoining structures in
various aspects of sexual behavior. Direct electrical or
chemical stimulation of the septum may induce a sexually motivated state of varying degrees up to penile
erection in men and building up to an orgasm in both
sexes (Heath, 1964). Markedly increased sexual behavior
has been observed following the placement of the tip of
a ventriculoperitoneal shunt into the septum in two cases
(Gorman and Cummings, 1992). Meyers (1961) has
described a loss of potency following lesion in the septofornicohypothalamic region. Electrical stimulation of
the mamillary body in monkeys induces penile erection
(MacLean and Ploog, 1962; Poeck and Pilleri, 1965).
Precocious puberty and hypersexuality have been reported
following lesions in the posterior part of the hypothalamus, and hypogonadism is an early sign of pathology
in the anterior part of the hypothalamus (Bauer, 1954,
1959; Poeck and Pilleri, 1965; Chapter 19.1). In particular hamartomas that affect the posterior region of the
hypothalamus, i.e. those that are pendulated and attached
to the region of the corpora mamillaria, may cause
precocious puberty (Valdueza et al., 1994a; Chapter 19.3).
In addition, precocious puberty is found in cases of pineal
region tumors that produce gonadotropins (Chapter 19.7).
A German stereotactic psychosurgical study (Mller
et al., 1973) reported on 22 male, mainly pedo- or
ephebophilic (i.e. preferring pubertal boys) homosexuals
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(n = 14), and 6 cases with disturbances of heterosexual

behavior (hypersexuality, exhibitionism or pedophilia).
In 12 homosexual patients a lesion was made in the
right ventromedial nucleus of the hypothalamus. In 8
patients homosexual fantasies and impulses disappeared.
According to this paper, in 6 patients a vivid desire for
full heterosexual contacts occurred after the operation.
In one pedophilic patient, bilateral destruction of the
ventromedial nucleus was performed and he lost all
interest in sexual activity after the operation. The heterosexual patients reported a significant reduction of their
sexual drive. Unilateral ventromedial hypothalamotomy
in 14 cases treated for aggressive sexual delinquency
caused a decrease in sexual drive (Dieckmann et al., 1988;
Albert et al., 1993). Although at first sight these studies
appear to suggest that the human ventromedial nucleus
of the hypothalamus is indeed involved in sexual orientation and sexual drive, they are highly controversial from
an ethical point of view, and methodologically deficient
(Heimann, 1979; Rieber and Sigusch, 1979; Schorsch und
Schmidt, 1979; see also Chapter 9).
(c) Transsexuality and other gender identity problems
Re: new phalloplasty technique proposal; seeking surgeon.
P.S. I am interested in a neophallus uncircumcized in appearance. So I am looking overseas, since a natural uncircumcized
penis is more common in Europe than in the U.S.
(From a letter of a female-to-male transsexual to D.F.S.)
The first definition of the term transsexualism dates from

1953, coined by Benjamin, who associated biological
normality with the conviction of belonging to the opposite sex and sex-reassignment request. In this sense, the
transsexual is characterized by an unshakeable conviction
of belonging to the opposite sex, presenting a most
extreme gender identity disorder. Gender identity (gender
identity refers to an identity experience expressed in terms
of masculine or feminine belongingness, independent of
the anatomical reality of the sex) is therefore totally in
disharmony with corporal reality, forcing the individual
to request sex-reassignment surgery. Gender-related traits
may also resemble those of the opposite sex in transsexuals (Lippa, 2001). Transsexualism as a particular
nosological category (gender dysphoria syndrome) was
included in the Diagnostic and Statistical Manual of
Mental Disorders III (DSM-III) in 1980, but was then
removed from DSM-IV, where it was assimilated into
sexual identity disorders. DSM-IV no longer adopts the
view that the difference between transsexuals and other
forms of gender dysphoria is an interesting differential

criterion. Therefore, as a consequence, highly heterogeneous cases are regrouped together in DSM-IV (Michel
et al., 2001).
Transsexuality often becomes overt early in development. Parents of boys with gender identity disorders often
report that, from the moment their sons could talk, they
insisted on wearing their mothers clothes and shoes, were
interested exclusively in girls toys and played mainly
with girls (Cohen-Kettenis and Gooren, 1999). At present
between 77% and 80% of the transsexuals in the
Netherlands receive surgical and/or hormonal treatment,
and less than 0.4% express regrets about their sex reassignment. These are all male-to-female transsexuals (Van
Kesteren et al., 1996). The annual incidence of transsexuality in Sweden has been estimated to be 0.17 per
100,000 inhabitants. The prevalence rates vary from
1:10,000 to 1:100,000 for men and 1:30,000 to 1:400,000
for women. The sex ratio (genetic male to female) varies
from country to country and with age between 1.4:1 and
3:1 (Landn et al., 1996; Van Kesteren et al., 1996;
Cohen-Kettenis and Gooren, 1999; Garrels et al., 2000;
Michel et al., 2001).
There is little information about the factors that may
influence gender and cause gender identity disorders and
transsexuality in humans (Cohen-Kettenis and Gooren,
1999; Table 24.5.1). The disparate maternal aunt to uncle
ratio in male transsexuals has been hypothesized to be
due to genomic imprinting (Green and Keverne, 2000).
There are only a few reports that have found chromosomal abnormalities in transsexuals. Six cases of
male-to-female transsexuals with 47,XYY chromosome
and one female-to-male transsexual with 47,XXX have
been reported (Turan et al., 2000). A phenotypically
female baby with 46,XY sex-reversal, persisting
Mllerian structures, and a primary adrenal failure, was
reported to have a mutation of steroidogenic factor-1.
Subsequently a heterozygous frameshift mutation has
been described with 46,XY sex-reversal and cliteromegaly, but no uterus, raising the possibility that other
mutations of this transcription factor might have milder
or tissue-specific effects in humans. So far these mutations
concern complete sex-reversal and not transsexuality
(Achermann et al., 2001a, b). Moreover, transsexualism
has been reported in a Kleinfelter (XXY) male (Sadeghi
and Fakhrai, 2000). Genetic aberrations are generally
indetectable in transsexuals when G-banded karyotypes
are analyzed, and evidence has been presented that
molecular-cytogenetic alterations affecting the androgen
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receptor gene region or the SRY region do not play a

role in transsexualism. One carrier of a microdeletion on
a Y-chromosome has been detected out of a series of 30
male-to-female transsexuals (Hengstslger et al., 2003).
In addition, pairs of monozygotic female twins have
requested sex reassignment, and twin studies and familial
cases of gender identity problems are reported, suggesting
a genetic basis for this disorder (Green, 2000; Sadeghi
and Fakhrai, 2000; Coolidge et al., 2002). The claim
of Drner et al. (2001), that in transsexuals a partial
21-hydroxylase deficiency may be present, has yet to be
confirmed. Although only a minority of the transsexuals
has an underlying endocrine abnormality (Meyer et al.,
1986), there are some indications of a possible disorder
of the hypothalamopituitarygonadal axis in some transsexuals that may have a basis in development, such as a
high frequency of polycystic ovaries, oligomenorrhea and
amenorrhea in female-to-male transsexualism (Futterweit
et al., 1986; Sadeghi and Fakhrai, 2000). These observations may be explained by a difference in the interactions
between hormones and the developing brain. Dessens
et al. (1999) have reported that 3 children born of a group
of 243 women exposed to the anticonvulsants phenobarbital and diphantoin were found to be transsexuals, while
there were a few other subjects with gender dysphoria/
cross-gender behavior. Gender problems thus occur
remarkably often, in view of the rarity of this disorder.
This exciting observation on the effect of compounds
that are known to alter steroid hormone levels in animal
experiments has to be examined further. In this respect
it is of interest to note that phenobarbital has been widely
used as prophylactic treatment in neonatal jaundice and
greatly elevates the postnatal rise in testosterone (Forest
et al., 1981). There has not, however, been a follow-up
on gender identity disorders so far. Also, endocrine
disruptors, present in food and water, may be considered
with respect to gender-identity problems, such as, e.g.
veterinary growth promoters such as resveratrol, a phytoestrogen that is present in grapes and wine and that is an
agonist for the estrogen receptor (Gehm et al., 1997;
Skakkebaek et al., 2000). Long-term effects of endocrine
disruptors on human brain and behavior differentiation
have, however, not been studied so far. In 1996, MeyerBahlburg et al. reported a gender change from female to
male in four 46,XX individuals with classic congenital
adrenal hyperplasia. Congenital adrenal hyperplasia,
characterized by high androgen levels during prenatal
development in 90% due to a defect in 21-hydroxylase,
indeed constitutes a risk factor for the development of
227
gender-identity problems (Slijper et al., 1998). However,

others found only a small increase in risk of atypical
gender identity in girls with cogenetical adrenal hyperplasia (Berenbaum and Bailey, 2003). Although it should
thus be emphasized that the majority of women with this
disorder may not experience a marked gender-identity
conflict, the odds ratio that a genetic female with this
disease would live, as an adult, in the male social
role, compared with genetic females in the general population, was found to be 608:1 (Zucker et al., 1996). These
observations support the view that intrauterine or perinatal exposure to abnormal levels of sex hormones
may permanently affect gender identity. The finding that
both male and female transsexuals were more often
non-right-handed than controls is also consistent with
the theory of altered prenatal sex hormone origin for
transsexualism (Green and Young, 2001).
Aside from the biological factors considered during the
pre- and perinatal periods, various psychological and
social aspects are presumed to play an important role in
the etiology of transsexualism. Psychological theories can
be placed in two distinct categories: one envisaging transsexualism as the result of a nonconflictual process where
gender identity is precociously fixed, and the other
considering transsexualism as a conflictual process where
gender identity is not fixed and continues to remain
ambiguous throughout development (Michel et al., 2001).
These theories still await data supporting them.
The concept of sexual neutrality at birth, after which
the infants differentiate as masculine or feminine as a
result of social experiences, was proposed by Money
et al. (1955a, b). Gender inprinting was presumed to start
at the age of 1 year and to be already well established
by 34 years of age (Money and Erhardt, 1972). Observations on children with male pseudohermaphroditism due
to 5--reductase-2 deficiency were supposed to support
the influence of life experience on psycho-sexual
make-up (Al-Attia, 1996). However, the conclusion in the
available literature is that there is no solid evidence for
parental influences on the etiology of transsexuality
(Cohen-Kettenis and Gooren, 1999). A classic report
which originally strongly influenced the opinion that the
environment plays a crucial role in gender development
was that described by Money of a boy whose penis was
accidentally ablated at the age of 8 months, during a
phemosis repair by cautery, and who was subsequently
raised as a female. Orchiectomy followed within a year
to facilitate feminization and further surgery to fashion a
full vagina was performed later. Initially this individual
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was described as developing into a normally functioning

female. Later, however, it appeared that the individual
had rejected the sex of raising and switched at puberty
to living as a male again and requested male hormone
shots, a mastectomy and phalloplasty. At the age of 25
he married a woman and adopted her children. This
famous JohnJoanJohn story, although it is just one case,
illustrates that there is little, if any, support for the view
that individuals are sexually neutral at birth and that
normal psychosexual development is dependent on the
environment (Diamond and Sigmundson, 1997). In a
second case of penile ablation, in which the decision was
made to reassign the patient to female and raise the baby
as a girl, the remainder of the penis and testes were
removed at a slightly earlier stage (7 months). Although
her adult sexual orientation was bisexual and even though
she was mainly attracted to women, her gender identity
was female. The different outcome as compared to the
former case is explained by the authors on the basis
of the decision to reassign the sex at a younger age
(Bradley et al., 1998). Male patients with cloacal extrophy
have a herniation of the urinary bladder and hindgut and
the anatomy leaves them aphaleic in the majority of the
cases. In a group of 8 male patients that were gender
reassigned as females in the neonatal period, at least in
3 instances gender identity has been questioned by the
patients themselves (Zderic et al., 2002) supporting
the early programming of gender identity by biological
factors and arguing against a dominating role of the social
environment.
The observation that in a longitudinal series of 16
hormonally normal 46xy males assigned to female sexof-rearing at birth due to the absence of a penis 8 have
spontaneously declared themselves male and 15 fall very
close to the male-typical spectrum of gender roles (Reiner,
2002) leads to the same conclusion.
Reiner et al. (1996) described a 46,XY child with mixed
gonadal dysgenesis, one immature testis, hypoplastic
uterus and clitoral hypertrophy, who was raised without
stigmatization as a girl, but who declared himself male
at the age of 14. Following corrective surgery and testosterone substitution, he lived as a boy despite the social
factors that were clearly in favor of maintaining the
assigned sex. Apparently the deficient testis has been able
to organize the brain during development, even though
the hormone levels were prenatally so inadequate that
ambiguity of the genitalia was induced. A child with true
hermaphroditism and 45X (13%) 47XYY (87%) sex chro-
mosome mosaic pattern in blood, uterus, fallopian tubes,

phallus, testicular tissue and epididymis, was assigned the
male sex at birth. At 5 weeks the decision was made to
reassign him to female. At 9 months an operation was
performed to make the genitalia female, at 13 months the
testicle was removed and at 5 years another operation was
done to make the genitalia female. She was raised as a
girl, but had masculine interests and when she was around
8 years of age she declared that God had made a mistake
and that she should have been a boy. Apparently the
male sex hormones to which she had been exposed in
utero had imprinted the male gender, although the authors
also presumed postnatal psychosocial factors to have
played a role (Zucker et al., 1987). Despite sex assignment, genital organ correction soon after birth,
psychological counseling of parents and intensive
psychotherapy, 13% of the intersex children in the study
of Slijper et al. (1998) developed a gender-identity
disorder. Yet only one girl (2%) failed to accept the
assigned sex. The ImperatoMcGinley syndrome, based
upon DHT deficiency due to 5-reductase-2 deficiency,
also shows that exposure to testosterone during development has a greater impact on male gender identity than
the sex of rearing and sociocultural influences (ImperatoMcGinley and Zhu, 2002).
We have found a female-sized central nucleus of the
BSTc in male-to-female transsexuals. These data were
confirmed by neuronal counts of somatostatin cells, the
major neuron population in the BSTc and total cell
number in the BSTc. Changes in adult hormone levels
could not explain this difference (Zhou et al., 1995c;
Kruijver et al., 2000; Chung et al., 2002; see Chapter 7).
These observations support the hypothesis that gender
identity develops as a result of an interaction between the
developing brain and sex hormones. Much to our surprise,
however, the sex difference in BSTc volume did not
become overt until adulthood (Chung et al., 2002). The
explanation for the discrepancy between the late occurrence of a sex difference in the volume of this nucleus
and the early occurrence of gender problems in transsexualism necessitates further research. Possibly
functional sex differences in the BSTc may precede the
structural sex differences in the course of development.
In male-to-female transsexuals a redirection of the P300
amplitude in the left frontal and temporal areas was found.
In addition, a delay of the P300 latency was observed at
the central frontal region (Papageorgiou et al., 2003),
pointing to alterations in cortical circuits.
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(d) Homosexuality
229
increases the occurrence of bi- or homosexuality in girls

whose mothers received DES during pregnancy (Ehrhardt
et al., 1985; Meyer-Bahlburg et al., 1995) in order to
prevent miscarriage (quod non). DES was given between
1939 and the 1960s to millions of pregnant women (TitusErnstoff et al., 2003). However, these authors could not
confirm an increase in the likelihood of homosexual
behavior in DES-exposed girls or boys in adulthood. The
ratio of the 2nd to 4th finger digits, a measure ascribed
to the organizational actions of prenatal androgens, was
significantly lower in the homosexual males and females
as compared to heterosexuals. This observation suggests
that homosexual males and females have been exposed
to elevated levels of androgens in utero (Rahman and
Wilson, 2003). Whether environmental estrogens from
plastics can influence sexual differentiation of the human
brain and behavior is, at present, in debate but certainly
not established. However, the observation that masculine
behavior increases in boys with number of years of
maternal sport fish consumption (Sandberg et al., 2003)
is consistent with this possibility. In addition, phytoestrogens, such as resveratrol, present in grapes and wine,
and an agonist for the estrogen receptor, should be considered in this respect (Gehm et al., 1997).
Homosexual orientation is most likely to occur in men
with a high number of older brothers and a shorter stature.
One biological mechanism that could explain this
phenomenon is an immune response in women pregnant
with successive male fetuses (Bogaert, 2003).
Prenatal nicotine exposure has masculinizing/
defeminizing effects on sexual orientation of female
offspring and increases the probability of lesbianism (Ellis
and Cole-Harding, 2001).
Maternal stress is thought to lead to increased
occurrence of homosexuality in boys, particularly when
the stress occurs during the first trimester (Ellis et al.,
1988; Ellis and Cole-Harding, 2001), and girls (Bailey et
al., 1991). As an interesting case history of this prenatal
environmental factor, Weyl (1987) has mentioned that
Marcel Prousts mother was subjected to the overwhelming stress of the Paris commune during the 5th
month of her pregnancy in 1871, and that Mary, Queen
of Scots, the mother of the homosexual king of England,
James I, toward the end of the 5th month of pregnancy,
had the terrifying experience that her secretary and special
friend Riccio was killed. Although postnatal social factors
are generally presumed to be involved in the development of sexual orientation (Byne and Pearson, 1993;
Thou shalt not lie with mankind, as with womankind: it is

abomination. Leviticus XVIII, 22
If a man has intercourse with a man as with a woman, both
commit an abomination, They must be put to death. Leviticus
XX,13
Xq28 Thanks for the genes, mom (seen on T shirts in the
USA)
Sexual orientation is influenced by quite a number of

genetic as well as nongenetic factors (Table 24.2). Genetic
factors appear from studies in families, twins and through
molecular genetics (Kallmann, 1952; Bailey and Bell,
1993; Hamer et al., 1993; Hu et al., 1995; Turner, 1995;
Pillard and Bailey, 1998; Bailey et al., 1999). Hamer and
colleagues found linkage between DNA markers on the
X chromosome and male sexual orientation. Genetic
linkage between the microsatellite markers on the X chromosome, i.e. Xq28, was detected for the gay male
families, but not for the lesbian families (Hamer et al.,
1993, Hu et al., 1995). In a follow-up study, Rice et al.
(1999) studied the sharing of alleles at position Xq28 in
52 Canadian gay male sibling pairs by four markers.
Allele and haplotype sharing for these markers was not
increased more than expected, which did not support
the presence of an X-linked gene underlying male homosexuality. In a reaction to this paper, Hamer (1999)
stated that: (i) the family pedigree data from the Canadian
study supported his hypothesis, (ii) that three other available Xq28 DNA studies found linkage also, and (iii) that
the heritability of sexual orientation is supported by
substantial evidence independent of the X chromosome
data. In a meta-analysis of the four available studies,
he found a significant linkage. Rice et al. (1999)
responded extensively and remained convinced that an
X-linked gene could not exist in the population with any
sizeable frequency. This controversy will undoubtedly
continue for a while longer. The claim of Drner et al.
(2001), that in homosexual men a partial 3-hydroxysteroid dehydrogenase deficiency may be present, has to
be confirmed.
Sex hormones during development also have an influence on sexual orientation, as appears from the increased
proportion of bi- and homosexual girls with congenital
adrenal hyperplasia (Money et al., 1984; Dittmann et al.,
1992; Meyer-Bahlberg et al., 1996). Then there is diethylstilbestrol (DES), a compound related to estrogens that
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Zucker et al., 1996), solid evidence in support of such

an effect has not yet been reported. The observation that
children raised by lesbian couples or by transsexuals
generally have a heterosexual orientation (Green, 1978;
Kirkpatrick et al., 1981; Golombok et al., 1983) does not
support the possibility of the social environment in which
the child is raised as an important factor for determining
sexual orientation, nor is there scientific support for the
idea that homosexuality has psychoanalytical or other
psychological or social learning explanations, or that it
would be a lifestyle choice (Ellis, 1996). Various hypothalamic structures are structurally different in relation
to sexual orientation, i.e. the SCN, INAH-3 and the
commissura anterior (see Chapter 4.4), suggesting that a
difference in hypothalamic neuronal networks that occur
in development may be the basis of differences in sexual
orientation.
The human hypothalamus is claimed to produce an
endogenous Na+K+ ATPase inhibitor, digoxin. In homosexual men, a decreased circulating digoxin level has been
found (Kurup and Kurup, 2002). It is not clear what the
exact relationship is between changes in digoxin levels
and alterations in hypothalamic nuclei.
(e) Sexual dysfunction in hypothalamopituitary
disorders
Hypothalamopituitary disorders often interfere with the
expression of sexuality. In fact, a decreased sexual desire
was significantly present in 7090% of the adult males
with a pituitary tumor.
One-third of these patients report decreased sexual
desire even as the first symptom of the tumor. Decreased
sexual drive is the first symptom in 50% of men with
pituitary tumors accompanied by hyperprolactinemia. In
addition, sexual desire is absent or decreased in two-thirds
of the women with hypothalamopituitary disorders. This
problem is recorded for 84% of the women with hyperprolactinemia and for only 33% of those with normal
serum prolactin. Almost all these women have amenorrhea
(Lundberg and Hulter, 1991; Lundberg and Brattberg,
1992; Ben-Jonathan and Hnasko, 2001; Chapter 24.1). As
men age, there is a decrease in total and free testosterone
levels and an associated increase in gonadotropin levels,
while a decrease in sexual activity is also notable
(Davidson et al., 1983). Although the hormonal changes
during aging are generally considered to contribute only
to a minor degree to the decline in sexual function in men,
there are many studies that show the relationship between
testosterone levels and sexual activity. Testosterone

increases the incidence of all types of male sexual activity
in hypogonadal men, whereas the antiandrogen cyproteron
acetate inhibits sexual activity (Davidson et al., 1982;
Albert et al., 1993; Yates, 2000; Chapter 2.4). There is
also clear evidence that testosterone modulates sexual
behavior in women: adrenalectomy decreases sexual
activity and testosterone replacement restores it (Albert
et al., 1993; Tuiten et al., 2000; Chapter 24).
Disturbed sexual behavior has, moreover, been reported
in a number of different neurological and psychiatric
disorders (Chandler and Brown, 1998), such as rabies
(Dutta, 1996; Chapter 20.1), encephalitis lethargica
(Chapter 20.2), multiple sclerosis (Chapter 21.2),
Wolframs syndrome (Chapter 22.7), PraderWilli
syndrome (Chapter 23.1), anorexia nervosa and bulimia
nervosa (Chapter 23.2), Kallmanns syndrome (Chapter
24.3), Klinefelters syndrome (Chapter 24.4), depression
(Chapter 26.4), Downs syndrome (Chapter 26.5),
KleineLevin syndrome (Chapter 28.1) and Parkinsons
disease (Chapter 29.3). Antipsychotic treatment in schizophrenia results in more sexual disturbances in men than
in women (Hummer et al., 1999). In multiple sclerosis
(Chapter 21.3) sexual dysfunction is typically characterized by diminished libido, erectile and ejaculatory
dysfunction in men, and poor lubrication and anorgasmy
in women. However, in some cases hypersexual behavior
and paraphilias have been associated with lesions in the
hypothalamus and septum (Frohman et al., 2002). In
depression (Chapter 26.4) sexual activity per se is said
not to be reduced during the depressed state. Rather, loss
of sexual interest appeared to be related to the cognitive
set of depressive symptoms, i.e. loss of sexual satisfaction. Nocturnal penile tumescence alterations may be
more trait-like than state-like in depression (Nofzinger et
al., 1993).
A newly discovered group of neurological and reproductive disturbances is due to mutations in sex hormone
receptors or aromatase. A complete androgen-insensitivity
syndrome leads to a normal female external and behavioral
appearance (see Chapter 24.5a). Some abnormalities of
the androgen receptor result in the syndrome of androgen
resistance, which goes together with normal male
differentiation. More recently, mutations of the androgen
receptor have also been described in a form of Kennedys
disease, a motor neuron disease. In Kennedys disease
(X-linked bulbospinal muscular atrophy), a trinucleotiderepeat expansion occurs in exon A of the androgen receptor
gene (MacLean et al., 1995). Subjects with Kennedys
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disease have normal virilization, although progressive

gynecomastia, testicular atrophy and infertility may occur
(MacLean et al., 1996). In addition, mutations of the estrogen receptor may cause estrogen resistance.
Cases of female pseudohermaphroditism, hypergonadotropic hypogonadism and multicystic ovaries have
been reported to be associated with missense mutations
in the gene encoding aromatase (P450). One 14-year-old
girl did not develop breasts, the clitoris was enlarged, and
circulating androgens and gonadotropins were high,
causing hyperstimulation of the ovaries (Conte et al.,
1994). Female pseudohermaphroditism has been found to
be caused by placental aromatase deficiency. Maternal
serum levels of estrogens were low and those of androgens were high in the third trimester, causing maternal
virilization and pseudohermophroditism of the female
fetus (Shozu et al., 1991). Another mutation of the human
gene encoding for aromatase P450 has been reported in
male and female siblings. During both pregnancies the
mother exhibited signs of progressive virilization. The
girl had nonadrenal female pseudohermaphrodism at birth
and developed progressive virilization at the age of
puberty, had pubertal failure with no signs of estrogen
action, hypergonadotropic hypogonadism and polycystic
ovaries. The brother was 204 cm tall. He was sexually
mature, had elevated testosterone levels, low estrogen
levels and high gonadotropins. Interestingly, the psychosexual orientation of both brother and sister was reported
to be appropriate for their phenotypic sex (Morishima
et al., 1995). There has also been a publication on
two mutations in the CYP19A1 gene that were responsible for aromatase deficiency in an 18-year-old girl with
ambiguous genitalia at birth, primary amenorrhea, sexual
infantilism and polycystic ovaries (Ito et al., 1993). No
information is present on the sexual differentiation of the
hypothalamus in such subjects.
231
Pedophiles show significantly lower baseline plasma

cortisol and prolactin concentrations and a higher body
temperature than normal volunteers. The chlorophenylpiperazine (mCPP)-induced cortisol responses are significantly greater in pedophiles than in normal volunteers.
In normal volunteers, mCPP induces a hyperthermic
response, whereas in pedophiles no such response is
observed. mCPP induces different behavioral responses
in pedophiles than in normal men. In pedophiles, but not
in normal men, mCPP increases the sensations of feeling
dizzy, restless and strange and decreases the sensation
of feeling hungry. It is hypothesized that the results are
compatible with a decreased activity of the serotonergic
presynaptic neuron and a 5-HT2 postsynaptic receptor
hyperresponsivity (Mozes et al., 2000). The possibility
that pedophilia is based on a different interaction between
sex hormones and the developing brain has to be investigated. In cases of hypothalamic glioma, a patients sexual
orientation changes from heterosexual to pedophilia
(Miller et al., 1986), indicating that the hypothalamus
should be a focus for such research.
Stereotactic hypothalamotomy aimed at the ventromedial nucleus has been performed during the detention of
violent sexual offenders. Sexual drive is reported to be
markedly reduced and no relapses occur. Side effects
include strong feelings of hunger and weight gain
(Dieckmann and Hassler, 1977). In one patient, agitation
followed by unconsciousness and hemiparesis resulted
from a hemorrhage into the third ventricle after removal
of the electrode after such an operation. Another patient
became unconscious but later recovered. Stereotactic
hypothalamotomy is not only a risky operation, but also
a very controversial one, both from an ethical and from
a scientific point of view.
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CHAPTER 25
Hypothalamic lesions following trauma and

iatrogenic lesions
25.1. Head/brain injury
be accompanied by central leptin insensitivity (Patel

et al., 2002).
Trauma may cause posterior lobe hemorrhage, ischemia
in the anterior part of the hypothalamus, and destruction
or avulsion of the pituitary stalk, followed by hypopituitarism. Post-traumatic diabetes insipidus is generally
transient (Horvath et al., 1997) and may be accompanied
by hypernatremia (Rehman and Atkin, 1999). However,
when the lesion affects the hypothalamus, traumatic
brain injury caused by, e.g. a gunshot wound, may be
permanent (Alaca et al., 2002). In addition, the syndrome
of inappropriate antidiuretic hormone secretion
(SchwartzBartter syndrome; Chapter 22.6a) has been
frequently reported following head injury. Interleukin-6
(IL-6) may be the mediator through which vasopressin
neurons are stimulated in this syndrome following
head trauma (Gionis et al., 2003). The syndrome of
inappropriate vasopressin secretion was found to be
related to subdural hematoma, and a marked association
has been observed with skull fractures in the frontotemporal region, extending to the base of the skull, which
would suggest hypothalamic dysfunction as a cause of the
syndrome. The effects of this syndrome may be edema,
nausea, vomiting and irritability, confusion, lethargy,
coma and the occasional seizure, as well as raised intracranial pressure. The syndrome disappears with fluid
restriction and/or administration of hypertonic saline
(Twijnstra and Minderhoud, 1980). In some 40% of the
closed head injuries, two main types of hypothalamic
lesions have been described: microhemorrhages and
ischemia lesions. The lesions occur in a somewhat
haphazard manner throughout the anterior hypothalamus,
but the microhemorrhage tends to be located subependymally in the paraventricular nuclei, in the lateral
hypothalamus, amongst the fibers of the median forebrain
Wallace LaBaw was a physician who in 1964 sustained

a closed brain injury himself (Kapur, 1997), and who
wrote an interesting account of his feelings of intense
anger (sham rage), temperature dysregulation, and
hunger and memory problems. His defecatory urge
and sexual drive and ability had gone, and he had
emotional problems. Although he assumed, probably
correctly, hypothalamic involvement, the location of the
lesions was not documented.
A number of neuroendocrine changes indicating
hypothalamic involvement have, however, been reported
following head injury. There appears to be a rapid but
variable activation of the hypothalamopituitaryadrenal
(HPA) axis after head injury. Some authors report an
association between the severity of head injury and the
extent of the HPA axis response. Others indicate that
there is a relationship between plasma cortisol levels and
patient outcome. Experimental data indicate the exclusive
presence of a corticotropin-releasing hormone (CRH)
response (and thus an absence of vasopressin response)
following traumatic brain injury (Grundy et al., 2001).
Increased HPA axis activity is a key characteristic
in depression (Chapter 26.4a, d). In this connection it
may be of great importance that the risk of depression
remains elevated for decades following head injury
and seems to be the highest in those who suffered severe
head injury (Holsinger et al., 2002). In the acute phase
of severe head injury, increased growth hormonereleasing hormone (GHRH) and somatostatin release
may be present. The resulting increased insulin-like
growth factor (IGF-I) levels suggest that these changes
may be advantageous for recovery (De Marinis et al.,
1999). Traumata of the hypothalamopituitary system may
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bundle, in the supraoptic nuclei (SON), and in the region

of the median eminence. Pituitary infarcts or hemorrhages
are frequently present in these patients, in both the anterior
and the posterior lobe (Crompton, 1963; Neil-Dwyer
et al., 1994). Following closed head injury, diabetes
insipidus, and clinical signs as well as symptoms of
hypopituitarism frequently occur. An example is a patient
who had hypopituitarism 1 year after a basilar skull fracture due to an automobile accident. Endocrinologically
provocative testing indicated that the patients hypopituitarism was secondary to hypothalamic insufficiency
or interruption of the pituitary portal circulation (Woolf
and Schalch, 1973).
In addition, autonomic hypothalamic disorders are
found post-trauma. Hypothermia due to hypothalamic
dysfunction has been described (Ratcliffe et al., 1983).
A patient was able to sweat normally, but during
cold stress he was unable to maintain core temperature.
Four years after the original head injury, a CT scan
demonstrated damage in the hypothalamus. As patients
with traumatic brain injury go through the stages of
recovery, acute hypothalamic instability occurs, usually
in the form of autonomic dysfunction syndrome (also
known as neurostorming or diencephalic seizures or
paroxysmal sympathetic storm; Chapter 30). The usual
manifestation are intermittent episodes of diaphoresis,
tachycardia and hypertension. The syndrome is managed
with short-acting opiates or benzodiazepines and then
subsequently with antihypertensives, dantrolene and
bromocryptine. Other causes of acute hypothalamic instability are the neuroleptic malignant syndrome (Chapter
25.2), malignant hyperthermia (Chapter 30.2) and lethal
catatonia. The patients all present with signs and symptoms of hypothalamic instability (Thorley et al., 2001).
After fatal head injury, histological evidence of
neuronal damage was found in the nucleus basalis
of Meynert (NBM). Reduced levels of choline acetyltransferase were observed in the cortex, indicating a
loss of cholinergic innervation. Dysfunctioning of this
system is thought to contribute to deficits of memory and
cognition after head injury (Murdoch et al., 2002). In a
review of case-control studies, Fleminger et al. (2003)
confirmed that head injury is a risk factor for Alzheimers
disease. The NBM damage may well contribute to this
association.
A case of avulsion of the optic chiasm is described in
Chapter 17.2b. Intractable obesity has been reported after
radiation therapy for leukemia or brain tumors. These
patients with hypothalamic obesity demonstrate excessive
insulin secretion. Octreotide (a long-acting somatostatin

receptor agonist) administration promoted weight loss in
these patients, possibly through reductions in -cell
insulin release.
After pituitary/hypothalamic surgery, children are not
only at risk of developing hormonal deficiencies and
obesity, but also of hypersomnolence. The (often severe)
daytime sleepiness is not the result of inappropriate
hormone replacement (Snow et al., 2002). In a 15year-old girl, a delayed sleep-phase syndrome developed following traumatic brain injury. The sleepwake
rhythm was delayed by almost half a day and returned
to normal following treatment with 5 mg of melatonin
(Nagtegaal et al., 1997). One patient experienced a lack
of REM sleep during hypothalamic injury following
excision of a craniopharyngioma (Rehman and Atkin,
1999). Neurosurgery for hypothalamopituitary masses
frequently causes growth hormone deficiency (Corneli et
al., 2002).
Following hypothalamic injury, psychiatric symptoms
are common, including attacks of rage, laughing and crying, excessive sexuality, antisocial behavior, hallucinations, coma or somnolence (with posterior lesions) or
pathological wakefulness (with anterior lesions), excessive
salivation, and bradycardia (Rehman and Atkin, 1999).
Whiplash injury may lead to a syndrome characterized
by insomnia, impaired concentration and memory, fatigue,
neck pain and headache. The injury may cause transection of the pituitary stalk. Cases with amenorrhea, sexual
immaturity and a history of head trauma have been
described. In a 17-year-old girl, provocative testing of
the pituitary revealed hypothalamic insufficiency and
intact pituitary function. MRI demonstrated loss of the
hypothalamic infundibulum, which may lead to hypothalamic atrophy (Grossman and Sanfield, 1994). In
chronic whiplash syndrome patients with delayed melatonin onset, melatonin administration advances melatonin
onset and sleepwake rhythm.
The great variability in outcome that is generally
observed after traumatic brain injury is only partly
explained by age and estimated damage. Genetic factors,
too, determine the outcome; i.e. apolipoprotein E-4
genotype predicts a poor outcome (Friedman et al., 1999).
25.2. Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a rare but severe side
effect of neuroleptics (Caroff and Mann, 1993). The
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incidence is estimated to be 0.51% of all patients

exposed to neuroleptics (Guz and Baxter, 1985).
Neuroleptic malignant syndrome is characterized by
extrapyramidal signs and hyperthermia. It was first
described and named by Delay and Deniker (1968).
Other autonomic manifestations are pallor, diaphoresis,
blood pressure instability, tachycardia and tachypnea.
It is frequently associated with confusion, agitation
and hypertonicity of skeletal muscles (Addonizio et al.,
1987; Thorley et al., 2001). The symptoms may culminate in stupor and coma, and death occurs in some 20%
of the cases (Hendersen and Wooten, 1981; Jones and
Dawson, 1989). This syndrome has often been described
in young, acutely psychotic patients and has also
been called lethal catatonia or fatal catatonia, acute lifethreatening catatonia or fatal hyperthermia syndrome
(Kish et al., 1990).
The syndrome may in fact represent an iatrogenic form
of fatal catatonia and is an uncommon complication
of therapy with dopamine receptor blocking agents
such as phenothiazines or other neuroleptics, especially
with long-acting (depot) neuroleptic dopamine-depleting
drugs. Others consider lethal catatonia to be a precursor
of neuroleptic malignant syndrome (Thorley et al., 2001).
Neuroleptic malignant syndrome has also been reported
following discontinuation of an L-DOPA-carbidopa
combination (Horn et al., 1988; Jones and Dawson, 1989;
Kish et al., 1999), metoclopramine or lithium (Addonizio
et al., 1987; Goekoop and Knoppert-Van der Klein, 1990),
following the cessation of dopaminergic drugs in patients
with Parkinsons disease (Jones and Dawson, 1989), and
in hypothalamic instability following traumatic brain
injury (Thorley et al., 2001). In addition, the syndrome
can even develop with continued antiparkinsonian
medication. Hot weather, dehydration, the premenstrual
period and the use of lithium may be risk factors for
the development of this disorder (Jones and Dawson,
1989).
The pathogenetic mechanism of the neuroleptic malignant syndrome remains unclear. In one instance this
syndrome was attributed to a respiratory infection (Itoh
et al., 1995). The syndrome is characterized by increased
muscular activity and a hypothesized hypothalamic disturbance that would impair heat dissipation (Morris et al.,
1980; Henderson and Wooten, 1981). It has been proposed
that neuroleptic malignant syndrome is of central origin,
while malignant hyperthermia (Chapter 30.2) is of peripheral origin, i.e. due to prolonged muscle contraction
on the basis of a primary deficit in the muscle (Guz
235
and Baxter, 1985; Jones and Dawson, 1989). It has also

been suggested that the neuroleptic malignant syndrome
would result in a disturbance in the hypothalamicadrenal
axis, which is associated with excessive catecholamine
secretion (Feibel and Schiffer, 1981).
There is a lack of systematic therapeutic studies, but
dopamine agonists were reported to reduce mortality
significantly (Caroff and Mann, 1993). In addition, several
reports have pointed to the usefulness of electroconvulsive therapy in neuroleptic malignant syndrome. One case
has been reported where a dramatic improvement indeed
occurred after electroconvulsive therapy. The tremor was
alleviated after the first application of electroconvulsive
therapy and the neuroleptic malignant syndrome symptoms and psychiatric symptoms disappeared after the
fourth application of this therapy. It has been suggested
that this therapy is effective because it enhances the
turnover rate of dopamine and serotonin (Nisijima et al.,
1996), but, of course, many other transmitter systems are
affected by this treatment.
In four cases, brain autopsy has so far not shown any
consistent or specific abnormality (Henderson and Wooten,
1981), while no abnormal histological hypothalamic
findings were reported in three other cases (Kish et al.,
1990). In two cases that were presumed to have chronic
neuroleptic malignant syndrome on clinical grounds
(92-003; 94-094), we could not find a hypothalamic lesion
either. In one case in the literature, scattered, petechial
subarachnoid hemorrhages were reported to occur all
over the brain, and similar tiny parenchymal and perivascular hemorrhages were also seen in the hypothalamus.
These abnormalities were acute, minimal, nonspecific,
possibly agonal and of uncertain significance (Jones and
Dawson, 1989). The possible association of neuroleptic
malignant syndrome with striatonigral degeneration has
been reported in other cases (Gibb, 1988; Hayashi et al.,
1993; Itoh et al., 1995). There is one interesting, positive neuropathological report on the possible involvement
of the hypothalamus in this syndrome (Horn et al., 1988).
Microscopic examination revealed bilateral foci of
pycnosis, disintegration of neurons, and sponginess of the
neuropil in the hypothalamus. The changes were limited
to the lateral hypothalamus and lateral tuberal nuclei
(Fig. 25.1), but a few pycnotic nuclei were also seen
in the ventromedial hypothalamic nucleus. In addition,
widespread small foci of nuclear pycnosis were found in
the cerebral cortex that were most probably secondary to
the extremely elevated body temperature. Neuroleptic
syndrome has also been reported in patients with cell loss
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died of malignant neuroleptic syndrome, higher guanosine triphosphate cyclohydrolase activity was found,
which suggests a possible involvement of biopterin
metabolism in the pathophysiology of this syndrome
(Ichinose et al., 2003). More systematic neuropathology
of patients with this syndrome will be needed in order
to link the symptoms, and in particular heat stroke, to the
localization of hypothalamic or other lesions that are
involved in the mechanism of heat loss and influenced
by dopamine (Caroff and Mann, 1993).
25.3. Hypothalamic injury by radiation
Fig. 25.1. Circumscribed foci of an early necrosis in the hypothalamus
of a patient who died of neuroleptic malignant syndrome. ON, optic
nerve; LHA, lateral hypothalamic area; T, tuberal nuclei (probably
nucleus tuberalis lateralis); III, third ventricle; VM, ventromedial
nucleus. Hematoxylin and eosin staining; approximately 12. Arrows
indicate necrosis. (From Horn et al., 1988, Fig. 1, with permission.)
in the NBM, with lesions in the anterior cingulate gyri

and mamillary bodies, or with periventricular nuclei in
the hypothalamus or in brainstem areas, perhaps as a
result of interruption of dopaminergic tracts passing
through these regions (Caroff and Mann, 1993). In one
patient, who died after 4.5 months of suffering from
neuroleptic malignant syndrome, a complete loss of cerebellar Purkinje cells and a moderate reduction of granular
neurons were observed, both of which were considered
to be heat-induced central nervous system injuries (Lee
et al., 1989). The strong loss of large NBM lesions and
the resulting decrease in choline acetyltransferase in the
cerebral cortex in patients with malignant neuroleptic
syndrome has also been reported in a larger-scale sample
of schizophrenic patients. Conceivably, the brain cholinergic abnormality in malignant neuroleptic syndrome
might have been due to pre-existing developmental
dysfunction and may thus lead to a reduced capacity of
the brain to respond adequately to stress and/or
neuroleptic-induced receptor blockade (Kish et al., 1990),
and temperature changes (see Chapter 2). Moreover, a
marked reduction in hypothalamic norepinephrine content
was observed in patients with malignant neuroleptic
syndrome. Norepinephrine is involved in the regulation
of body temperature and the decreased hypothalamic
levels are proposed, on the basis of animal experiments,
to be secondary to the rise in temperature (Kish et al.,
1990). In the hypothalamus of Parkinson patients who
(a) Hypothalamic symptoms following radiation of

tumors
Following previous external radiation, not only of
pituitary tumors (Shalet, 1982), but also of tumors some
distance away from the adenohypophysis such as posterior
fossa tumors, neuroendocrine disturbances have been
found, ranging from isolated growth hormone deficiency
to panhypopituitarism. The nature of radiation injury is
generally thought to be based upon direct neural injury,
vasculitis due to radiation, and multifocal microvascular
thrombosis due to chemotherapy and secondary gliosis
(Ciesielski et al., 1994; Spoudeas et al., 2003). Progressive
neural injury can occur following a latent interval of 6
months to several years after radiation (Perry-Keene et
al., 1976; Shalet, 1982). The endocrine complications may
occur late (Shalet, 1982; Abayomi et al., 1986). Growth
hormone regulation is particularly affected, not only
following radiation of the pituitary-hypothalamic region
but also after radiation of posterior fossa tumors
(Spoudeas et al., 2003). The regulation of growth hormone
release is predominantly under the control of GHRH
and somatostatin (Shalet et al., 1982; Peacey et al.,
1998; Chapter 18.6). Hyperprolactinemia is one of the
most common dysfunctions in adult female patients
with nasopharyngeal carcinoma treated with radiotherapy. MRI revealed no structural abnormality in the
hypothalamopituitary region of these patients (Lau
et al., 2001). In children, the prevalence of true
precocious puberty is increased after cranial radiation
for local tumors or leukemia. Even radiotherapy aimed
at the pituitary gland may result in true precocious
puberty. Several papers underscore that early puberty
occurs in children who were treated with high-dose
cranial irradiation. In addition, these children often have
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growth hormone deficiency and impaired linear growth.

Moreover, they are at risk for adrenal insufficiency and
may develop hypothyroidism. Treatment with growth
hormone and an LHRH agonist is often indicated and
should be considered at a young age (Styne, 1997; Mller
et al., 1998a; Oberfield and Garvin, 2000; Daniel, 2002;
Spoudeas et al., 2003). Hypothalamic radiation doses
higher than 51 Gy are a risk for the development of
obesity in children (Lustig et al., 2003).
In a study on 32 patients of between 6 and 65 years
old who had received cranial radiotherapy for brain
tumors 213 years earlier, at doses of 39607020 rad
(39.670.2 Gy), 28% had thyroid deficiency and 62%
had low serum total or free thyroxine (T4) or total
triiodothyronine (T3) levels. Seventy percent of the
adult women had oligomenorrhea and 50% had low
estradiol concentrations. Of the adult men 30% had
low serum testosterone levels. Mild hyperprolactinemia was present in 50% of the patients. One
patient had panhypopituitarism (Constine et al., 1993).
Other authors, too, pointed to the high frequency of
thyroid disturbances (Pasqualini et al., 1987). It should
be added that patients with hypopituitarism are at risk
for premature mortality due to cardiovascular disease
(Rosn and Bengtsson, 1990; Markussis et al., 1992;
Rosn et al., 1993). In addition to endocrine changes,
intellectual and cognitive capabilities are affected in
these subj-ects (Ciesielski et al., 1994). Concerning
the effect of radiation therapy on IQ, the risk of
adversely affecting the intellectual status of the
survivors is clear when subjects are treated with a
greater irradiation volume at a young age, while no
influence of the location of the tumor was detected
(Mulhern et al., 1992). Growth hormone deficiency
may contribute to the cognitive disorder of these
patients (Blow et al., 2002).
A controlled, cross-sectional study to assess frequency
and clinical impact on endocrine dysfunction has been
performed in 32 long-term survivors, aged between 25
and 66 years, of primary brain tumors outside the hypothalamopituitary region, which were studied for 111
years after radiotherapy with a mean total dose of
62.3 2.8 Gy (mean local dose pituitary 51.1 12.1 Gy
and hypothalamus 57.0 7.8 Gy). Fifty-two percent of
the patients reported symptoms suggestive of hypothyroidism and 26% showed evidence of hypothalamic
hypothyroidism. These patients had significantly lower
serum baseline cortisol levels and dehydroepiandrosterone
sulfate (DHEAS) than controls. Forty-seven percent
237
of the male patients and only 6% of the controls suffered

from erectile dysfunction, 42% of the patients had
hypothalamic hypogonadism. Twenty-nine percent of
the patients presented with hyperprolactinemia, and 4
women concurrently suffered from oligoamenorrhea.
A high frequency of clinical complaints was observed
in the survivors, and this had a significant impact on
their well-being, such as cognitive impairment and
reduced drive (Arlt et al., 1997). Growth hormone
deficiency may contribute to mental distress and cognitive
dysfunction (Blow et al., 2002). Cranial irradiation
for childhood acute lymphoblastic leukemia results in
subtle ovulatory disorder in some patients (Bath et al.,
2001).
The lesion-producing pituitary deficiency in cranial
radiation patients is more likely to be situated in the hypothalamus than in the pituitary. This idea is supported by
raised serum prolactin levels (Shalet, 1982; Constine
et al., 1993), by the occurrence of true precocious puberty
and by some sleep disturbances. Since the hypothalamus
has nuclei that develop relatively late, i.e. in the postnatal period, such as the sexually dimorphic nucleus of
the preoptic area (SDN-POA) (Chapter 5.2), the suprachiasmatic nucleus (SCN) (Chapter 4.2b), and the bed
nucleus of the stria terminalis (BST) (Chapter 7), this
structure may thus be very sensitive to radiation. Despite
all these arguments, hypothalamic neuropathology
following radiation injury has so far not been systematically studied in postmortem tissue, either in children or
in adults.
Disturbances of the circadian regulation of sleep and
wakefulness argue for the idea that damage as a result of
craniospinal irradiation administered to cure childhood
malignancy does not only occur at the level of the
pituitary, but also at that of the hypothalamus. High-dose
cranial radiation therapy in childhood is associated with
both objective (actigraphy) and subjective (questionnaire)
changes in the sleepwake rhythm in adulthood.
Surprisingly, a strongly increased sleep duration and a
higher amplitude sleepwake rhythm with less fragmentation was found in young adults who received cranial
radiation during childhood, showing that the function of
the SCN was intact. The increase in the duration of sleep
may, however, indicate hypothalamic damage. In spite of
this apparently good sleep, patients, particularly those
with low growth hormone and high prolactin and leptin
levels, experienced an increased difficulty in overcoming
drowsiness and getting started in the morning. Since
young adults with isolated growth hormone deficiency
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also showed increased total sleep time, at least part

of the sleep disturbances may be due to pituitary
damage.
(b) Tumors after whose treatment these symptoms were
found
Following field radiation of hypothalamic/chiasmatic
gliomas, growth hormone deficiency, hypogonadotropic
hypogonadism, hypoadrenalism and diabetes insipidus
have been reported (Collett-Solberg et al., 1997).
Long-term follow-up of patients treated for optic
pathway tumors with radiotherapy, especially young
children and patients with neurofibromatosis-1, showed
major sequelae, such as cerebrovascular complications
and severe intellectual disabilities. The two most frequent
endocrine deficiencies were growth hormone deficiency
and precocious puberty (Cappelli et al., 1998). In
acromegaly the frequency of growth hormone pulses is
increased, and this is interpreted by several authors as
evidence that acromegaly is due to a primary hypothalamic abnormality with secondary development of a
pituitary neoplasm. There are, however, also arguments
in support of the idea that acromegaly is due to a primary
pituitary defect. Radiotherapy is excellent at halting tumor
growth, but the slow reduction of growth hormone
concentration, damage to the normal hypothalamic
pituitary axis necessitating life-long replacement hormone
therapy and the recent evidence to suggest lack of normalization of IGF-I are obvious disadvantages. Radiotherapy
is proposed to lead to a reduction, or even a complete
loss of endogenous hypothalamic somatostatin tone
(Peacey et al., 1998).
Patients with nasopharyngeal carcinoma treated with
irradiation more than 5 years before had hypothalamic
hypothyroidism with low free T4 and normal thyrotropin
(TSH). TSH appeared to have decreased bioactivity,
which was restored by prolonged TRH administration.
These observations indicate that endogenous TRH
deficiency after irradiation of the hypothalamohypophyseal region may not always be a transient phenomena
(Lee et al., 1995). In fact, progressive impairment of
hypothalamic-pituitary functions occurring after cranial
irradiation for nasopharyngeal carcinoma can be demonstrated already 1 year after radiotherapy, using estimated
doses of 39.8 Gy to the hypothalamus and 61.7 Gy to
the pituitary. One year after radiotherapy, there was a
significant decrease in the integrated growth hormone

response to insulin. In male patients basal and simulated
follicle-stimulating hormone (FSH) levels increased,
and luteinizing hormone (LH) decreased, suggesting
a decreased LH-releasing hormone (LHRH) pulse
frequency. The peak serum TSH response to TRH became
delayed in 28 patients, suggesting a defect in TRH release.
After 2 years, the basal T4 and plasma cortisol levels
had significantly decreased and further impairment in
the secretion of growth hormone, FSH, LH, TSH and
corticotropin (ACTH) had occurred (Lam et al., 1987).
Hyperprolactinemia associated with oligomenorrhea is
found especially in women. Adults who had received
cranial irradiation in childhood as part of their treatment
for acute lymphoblastic leukemia not only had decreased
growth hormone levels but also hyperleptinemia. Leptin
levels were significantly higher in the group with the
lower growth hormone levels. Whether the hyperleptinemia was due to growth hormone-deficiency or to
radiation-induced leptin resistance is not known (Brennan
et al., 1999a). Cranial irradiation for childhood acute
lymphoblastic leukemia may result in subtle ovulatory
disorder (Bath et al., 2001).
Long-term neuroendocrine deficiencies following
craniospinal irradiation for childhood medulloblastoma
preferentially take place in the growth hormone axis
(Abayomi and Sadeghi-Nejad, 1986). Eight years after
therapy with 35 Gy, some 70% of the adult subjects
(median age 25 years) had impaired growth hormone
secretion, and 35% had an absolute growth hormone
deficiency. Young age at treatment was a determinant of
growth hormone deficiency in adulthood. In contrast, only
20% showed impairment of the hypothalamopituitary
thyroid or gonadal axis. Central adrenal insufficiency
was not observed, while basal prolactin levels were
normal in all subjects. Whether the localization of the
damage of the growth hormone axis is at the hypothalamic
or at the pituitary level, or both is still a matter of debate
(Heikens et al., 1998). Long-term endocrine surveillance
seems to be mandatory following craniospinal irradiation,
not only for the growth hormone axis. Although radiationinduced ACTH deficiency is relatively uncommon, it may
be life-threatening and should be ruled out (Abayomi and
Sadeghi-Nejad, 1986).
Children with posterior fossa tumors remained severely
growth hormone deficient until some 11 years after cranial
irradiation. A few of these children also had partial ACTH
insufficiency or hypopituitarism (Spoudeas et al., 2003).
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Fig. 25.2. Effect of hypophysectomy on the supraoptic nucleus (SON). Nissl-stained sections through the SO of a normal subject (a) and of two
patients who had been hypophysectomized for 4 months (b) and 8 years (c). Note the great loss of nerve cells in the nucleus after hypophysectomy.
Or, optic tract. (From Daniel and Prichard, 1975, Fig. 37, with permission.)
of these astrocytomas are high-grade (Collett-Solberg

et al., 1997).
(c) Yttrium (Y)-90 implantation in the pituitary

A few decades ago, pituitary ablation by stereotactic
transnasal yttrium-90 implantation was carried out in
patients with advanced metastatic mammary carcinoma
in order to curtail the effect of sex hormones on such
tumors. Varying degrees of water intoxication (Chapter
22.6), and ultimately diabetes insipidus (Chapter 22.2),
followed this operation. A decrease in the number of
neurons in the SON and paraventricular nucleus (PVN)
was found in patients who died between 5 and 20 months
after the operation. The occurrence of diabetes insipidus
was related to neuronal loss in the SON and PVN, and
to the decreased volume of the SON and PVN (Habener
et al., 1966). Saccular aneurysms causing hypopituitarism
have been described as a complication of yttrium-90
implantation for pituitary adenomas.
(e) Vascular complications

Radiation can cause delayed (up to 20 years later) vascular
complications, such as small-vessel obliterative vasculopathy an important cause of radiation necrosis.
Radiation-induced microscopic vascular anomalies or
telangectasia may cause hemorrhages, and large vessel
damage may manifest itself as occlusive cerebrovascular
disease, or cause intracranial fusiform aneurysms. In
chronic occlusive large-vessel disease of arteries of the
circle of Willis, abnormal capillary network (moyamoya)
vessels may develop at the basis of the brain due to
radiation therapy (Sinsawaiwang and Phanthumchinda,
1997). Moyamoya disease may lead to massive cerebral
hemorrhage (Oka et al., 1981; see Chapter 19.4).
(d) Postradiation tumors
(f) Other complications
As a consequence of radiotherapy for pituitary adenoma

or craniopharyngioma, astrocytomas may arise in the
hypothalamic region after some 10 years. The majority
Intrasellar herniation of the third ventricle has been

described following radiation of pituitary adenoma
(Kobayashi et al., 1996). In addition, radiation necrosis
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Fig. 25.3. Effects of hypophysectomy and of pituitary stalk sectioning on the paraventricular nucleus (PV). Parasagittal Nissl-stained sections
through the PV of a normal subject (a), and of a patient who died 8 years after hypophysectomy (b). Note the great loss of PV neurons. AC,
anterior commissure; F, anterior column of fornix; IF, interventricular foramen; PV, paraventricular nucleus; SR, supraoptic recess of third ventricle.
(From Daniel and Prichard, 1975, Fig. 38, with permission.)
of the optic pathways, hypothalamus and brainstem has

been described following irradiation of a pituitary
adenoma (Delattre et al., 1986).
25.4. Lesion of the pituitary stalk
Following surgical hypophysectomy or pituitary stalk
sectioning, the SON and PVN show a marked nerve cell
loss that is usually more pronounced in the SON than in
the PVN (Daniel and Prichard, 1975; Figs. 25.2 and 25.3).
Similar changes are found in the SON and PVN when
the stalk is interrupted by metastases (Duchen, 1966;

Chapter 19.9). Pituitary stalk sectioning has been used to
inhibit hypothalamic stimulation of the pituitary, e.g. in
the treatment of metastatic cancer of the breast or diabetic
retinopathy. Many of the SON and PVN neurons
disintegrate and die by the end of the 2nd week after the
operation, and at 3 weeks a loss of nerve cells is definitely
apparent. After 3 months, dying cells are a rarity (Daniel
and Prichard, 1972, 1975). Morton (1970) found a cell
loss of 25% at 3 weeks after the operation. After 3 months,
50% of the nerve cells had disappeared. In contrast to
Daniel and Prichard (1975), Morton (1961, 1970) found
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a continuing cell loss until about a year after the operation,

when approximately 20% of the nerve cells remained.
Some discrepancies in the literature concerning cell loss
may be due to the fact that individual variability in cell
number in the SON and PVN is considerable (see Chapter
8). No close relationship has been found between the
length of the remaining stalk and the number of residual
cells in the SON and PVN. In the SON and PVN of
stalk-sectioned patients gliosis has been reported. An
accumulation of Gomori-positive neurosecretory material
was reported to occur within a week after the operation;
this increased staining disappeared after a month (Daniel
and Prichard, 1972, 1975). The immediate effect of stalk
sectioning is a venous infarction of the neural tissue of
the stump, due to thrombosis of the long portal vessels.
Because the arterial blood flow is not cut off by the
operation, an intense congestion of the blood vessels in
the stump occurs, as well as an extravasation of blood.
Necrosis of neuronal tissue may involve irregular areas
higher up, up to the junction of the stalk and the optic
chiasm. Hemorrhages may extend into the hypothalamus,
around the infundibular recess (Daniel and Prichard, 1972,
1975). Diabetes insipidus usually starts 1 day after the
operation (Seckl et al., 1990). After a month, the stalk
has regenerated and is almost normal in appearance.
Patchy innervation and hemosideration granules are
observed. After a year, the stalk is reinnervated
throughout, although less abundantly, and with a finercaliber fiber than can be found in a normal stalk. In some
cases where the pituitary stalk has been transected, a
newly formed, small ectopic miniature neurohypophysis
is found at the proximal stump of the transected stalk.
The ectopic posterior lobe secretes vasopressin and shows
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a high-intensity signal on T1-weighted MRI images

(Daniel and Prichard, 1975; Fujisawa et al., 1987a). In
hypothalamic nuclei other than the SON and PVN, no
changes have been reported after stalk sectioning,
although not only diabetes insipidus but also hypopituitarism was found after this operation. The cells of
the pars tuberalis usually survive. Postpartum hypopituitarism may go together with a similar strong loss of
SON and PVN neurons as observed following stalk
sectioning (Whitehead, 1963; see Chapter 22.1).
Following suprasellar removal of the pituitary, first a
polyuria occurred, which was probably due to the acute
damage of the hypothalamoneurohypophysial system.
This phase was followed by a period of normal urine
levels that could be explained by the release of preformed
vasopressin. The occurrence of permanent polyuria was
frequent but unpredictable. From animal experiments it
is estimated that if less than 515% of the SON cells
remained in the SON, polyuria would occur (Lipsett
et al., 1956).
Metastases are common in the neurohypophysis. They
may cause diabetes insipidus (Schubiger and Haller,
1992). Interruption of the stalk and neurohypophysis by
such metastases may lead to neuronal loss and gliosis in
the SON and PVN (Duchen, 1966; Chapter 19.9).
Damage to the pituitary stalk in the fetus was proposed
to lead to perinatal abnormalities such as breech presentation, forceps delivery and asphyxia. It also accompanies
idiopathic pituitary dwarfism. However, it may well be
that pituitary stalk damage in fact occurs much earlier
in the fetus, and that such a developmental defect
subsequently leads to perinatal problems (see Chapters
18.4 and 18.6).
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CHAPTER 26
Hypothalamic involvement in psychiatric disorders
Geisteskrankheiten sind Gehirnkrankheiten.

W. Griesinger, 1861
1997), proving that the tumor had caused the symptoms.

Alpers (1937) has described a case of a dermoid cyst
in the third ventricle that severely damaged the hypothalamus, causing severe personality changes and
mood swings. The changes generally consisted of maniclike reactions such as euphoria, motor restlessness, push
of speech and flight of ideas; also, it was quite easy
to elicit rage in this subject. In the older literature, this
type of reaction was also reported following operations
for hypophyseal adenoma. Alpers (1940) has reported
emotional negativism in the case of craniopharyngioma
of the hypothalamic region, and violent psychomotor
agitation (rage) in the case of a glioma. Another
case involving an epidermoid cyst extending into the
hypothalamus showed mood swings, from euphoria to
mild depression, accompanied by bouts of weeping and
laughing (for attacks of laughter see Chapter 26.2).
Hypothalamic stimulation leads to sympathetic effects and
profound anxiety in patients (Alpers, 1940). On the basis
of lesions, the posterior hypothalamus is held responsible
for changes in personality and mood (Alpers, 1937). The
episodic rage (Chapter 26.9) and emotional instability
may be attributed to structures in the ventromedial area
(Chapter 26.3). Patients with a third ventricular colloid
cyst or tumor without hydrocephalus may manifest disturbances of memory (imprinting and retrieval), emotion
and personality (euphoria or apathy) that improve once
the tumor has been removed. The symptoms may be
attributed to compression or to vascular compromise of
the diencephalon (Williams and Pennybacker, 1954;
Lobosky et al., 1984). Intermittent explosive disorder,
hypersexual behavior and hallucinations have been found
in cases of deteriorated work performance due to a craniopharyngeoma or prolactinoma (Carrol and Neal, 1997).
Hypothalamic tumors causing symptoms of anorexia
Do not consult the gods to discover the directing soul, but

consult an anatomist. Galenus, 2nd century
Emotion moves us, hence the world itself. Sir Charles
Sherington, cited by Gano et al., 1970.
26.1. Psychiatric symptoms due to tumors of the

third ventricle
Observations that unsuspected tumors of the region of
the third ventricle give rise to predominant psychiatric
symptoms confirm the view that the hypothalamus plays
a significant role in emotional expression. Malamud
(1967) has studied a group of seven patients, four of
whom had first been diagnosed to be schizophrenic, two
suffered from psychoneurosis and one from manic excitement (Table 26.1). Although these conditions were all
due to tumors, only the illness in case 13 was initiated
by seizures, and only here could some evidence of an
organic disturbance be found also. In all but the terminal
stages of the remaining cases was the clinical course
dominated by the psychiatric disorder.
Visual hallucinations have been described in a patient
with a hypothalamic astrocytoma that affected the preoptic area bilaterally and the tuberal region of the
hypothalamus at one side (Haugh and Markesbery, 1983).
One patient with an isolated absence of the septum pellucidum presented with schizophrenic psychosis (Supprian
et al., 1999). Another one, a 9-year-old boy, with a history
of behavioral problems and worsening psychosis appeared
to suffer from a choroid plexus papilloma. When examined 1 year after the operation, it transpired that he had
not experienced any hallucinations since the operation
and his behavior was within normal limits (Carson et al.,
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TABLE 26.1
Tumors in the region of the third ventricle.
Case no.
Psychiatric diagnosis
Location of tumor
Diagnosis of tumor
12
13
14
15
16
17
18
Schizophrenia
Schizophrenia
Schizophrenia
Psychoneurosis
Manic excitement
Psychoneurosis
Schizophrenia
Intraventricular
Periventricular
Floor of third ventricle
Roof of third ventricle
Roof of third ventricle
Subependymoma
Glioblastoma multiforme
Craniopharyngioma
Craniopharyngioma
Craniopharyngioma
Colloid cyst
Colloid cyst
From: Malamud N. (1967) Psychiatric disorder with intracranial tumors of limbic system. Arch Neurol 17:113123.
nervosa are discussed in Chapter 23.2 and other symptoms

of tumors in the regions of the third ventricle such as
transient global amnesia (Sorensen, 1995), akinetic
mutism (Ross and Stewart, 1981), somnolence, altered
levels of consciousness (Davison and Demuth, 1946;
Coffey, 1989) and coma (Cairns, 1952) are discussed in
Chapter 19.1b).
26.2. Attacks of laughter (gelastic epilepsy)
(Fig. 26A)
An honoured gentleman brought his wife to this city to
get the advice of Messrs. Le Grand, Duret and myself
(physicians), to find why she wept and laughed without
reason, and no one could cure her. We treated her with
many remedies but could accomplish little; finally he took
her away in the same state she had come. Ambroise Par
(15101590), cited by Altshuler and Wisdom, 1999.
Gelastic epilepsia (gelos = mirth) is defined as laughter

that is inappropriate, stereotyped and not precipitated by
either a specific humorous or nonspecific stimulus.
Convulsive laughter thus lacks an affective component
(Money and Hosta, 1967). The laughter attacks may
appear on their own or in conjunction with other types
of convulsions (Iannetti et al., 1992) and are characterized
by a sudden, paroxysmal onset, a self-limiting nature and
a correlation with abnormal cortical discharges (Black,
1982). The spells may be accompanied by hypoapnea,
repeated cooing respirations, giggling and smiling,
and occur as frequently as every 1520 min (DiFazio and
Davis, 2000). Some patients have the symptom of a
pressure to laugh but often without actually laughing.
The symptom is regarded as pleasant and sometimes it
is associated with a sense of happiness (Sturm et al.,

2000). Gelastic epilepsy is more common in children than
in adults (Askenasy, 1987). It may sound like normal
laughing, resemble a caricature of laughter (giggle) or be
alternated with crying (Black, 1982). The duration of
the laughter attacks is usually short, i.e. less than 30 s.
Cognitive deterioration and behavioral problems are
common (Sturm et al., 2000) in gelastic epilepsy, which
is often associated with precocious puberty and mental
retardation (Cascino et al., 1993).
Main causes of gelastic epilepsy are: hypothalamic
hamartomas (Chapter 19.3), pituitary tumors, astrocytomas of the mamillary bodies, dysraphic conditions and
neoplasms of the posterior fossa (Iannetti et al., 1992;
Arroyo et al., 1993; Al-Herbish et al., 1997; Colover,
2000; Coppola et al., 2002). In addition, the cingulate
cortex may be the origin (Munari et al., 1995). Gelastic
epilepsy is only observed in relation to the type of
hypothalamic hamartomas that are broadly attached to the
mamillary bodies, i.e. type IIa and IIb of Valdueza et al.,
1994a (see Chapter 19.3; Fig. 19.7). Gelastic seizures
have been found in a 2-year-old girl with multiple brain
anomalies , including tectal tumor (possibly hamartoma),
multiple subependymal nodules and holoprosencephaly
(Akman et al., 2002). One boy has been described with
gelastic epilepsy, precocious puberty, hypothalamic
hamartoma and agenesis of the corpus callosum
(Alikchanov et al., 1998). Pathological laughing and crying also occurs in some 10% of multiple sclerosis patients
in a chronic-progressive stage (Feinstein et al., 1997). In
addition, laughing seizures have been reported in a child
with tuberous sclerosis due to a neoplasma arising from
the floor of the left lateral ventricle extending downwards
into the hypothalamus (Gunatilake and Harendra De Silva,
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Fig. 26A. Mischievous woman (Edma Balzs), Life and Work.

Published 1998 by Robert, Susan and John Balzs, Robert, Susan and John Balzs, ISBN: 0-9532750-1-9. (With permission.)
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D.F. SWAAB
1995). In a 4-month-old infant with Wests syndrome,

gelastic seizures in clusters have been observed; smile-like
episodes developed every few seconds. PET showed
hypoperfusion bilaterally in the hypothalamus, and interictal hypsarrhythmia and ictal EEG revealed desynchronization; ACTH was effective. Wests syndrome is
characterized by infantile spasms, mental retardation and
hypsarrhythmia (chaotic, high-amplitude slow waves,
sharp waves and spikes) on EEG. In this case Wests
syndrome was due to perinatal hypoxia followed by hypothalamic hemorrhage (Kito et al., 2001). Gelastic seizures
have also been associated with third-ventricle papillomas,
tumors of the pineal region, traumas, lesions of the
ventromedial nucleus area, encephalitis, meningitis, lipid
storage disease (Iannetti et al., 1992), pseudobulbar palsy
and psychiatric illness (Altshuler and Wisdom, 1999).
Gelastic epilepsy is also found to be associated with
general temporal lobe epilepsy (Arroyo et al., 1993).
Intense sexual feeling (orgasmolepsy) has been reported
in some of these cases in association with the laughing fits
(Purdon, 1950; Sethi et al., 1976; Holmes et al., 1980;
Jacome et al., 1980). It is not clear exactly how the temporal lobe attacks may be related to altered hypothalamic
functions. During the laughing attacks there can be a loss
of consciousness (Cascino et al., 1993).
Although it is clear that hypothalamic hamartomas are
associated with gelastic seizures, it was not believed for a
long time that the hypothalamus could be the origin of the
seizures, since attempts to remove the hypothalamic lesion
failed to control the seizures (Pallas et al., 1969; Cascino
et al., 1991; Arroyo et al., 1993). However, later it was
found that gelastic fits are strictly linked to ictal discharges
that start and may remain well localized in the hamartoma,
as shown by stereotactically implanted intracerebral
multielectrodes (Munari et al., 1995). Moreover, SPECT
demonstrates a dramatic ictal uptake in the area of the
tumor, with normalization during the postictal phase
(DiFazio and Davis, 2000). Since hyperperfusion of the
hypothalamopituitary region is observed by SPECT,
together with an ictal pulse of gonadotropins, 17-estradiol and growth hormone, this means that at least
neighboring areas are also influenced and that these
seizures may cause paroxysmal dysfunction of the
hypothalamopituitary axis (Arroyo et al., 1997). Gelastic
seizures spread from the hypothalamus through hypothalamusamygdala connections and spread to mesial
temporal structures, causing complex partial seizures and
a pattern of symptomatic generalized epilepsy with tonic,
atonic and other types of seizures in association with slow
spike and wave discharge and cognitive deterioration

(Berkovic et al., 1997; Sturm et al., 2000).
Gelastic seizures that have their basis in a hypothalamic hamartoma are accompanied by an abrupt rise in
blood pressure and respiratory rate, increased levels of
growth hormone, norepinephrine and cortisol, without
modification of corticotropin (ACTH) or epinephrine,
which indicates an abrupt increase in the activity of the
sympathetic system (Tinuper et al., 1994). It should be
noted here that a normal, mirthful laughter experience
reduces serum levels of cortisol, 3, 4-dihydroxyphenyl
acetic acid (DOPAC), epinephrine and growth hormone
(Berk et al., 1989).
The existence of a center for laughter in or near the
hypothalamus has been postulated on the basis of
the effects of: (i) astrocytomas (Iannetti et al., 1992);
(ii) hamartomas involving the floor of the hypothalamus
(see Chapter 19.3); (iii) a case of an aneurysm,
compressing the corpora mamillaria and elevating the
floor of the anterior part of the third ventricle; (iv) a case
of a tumor between the posterior wall of the tuber
cinereum and the posterior margins of the mamillary
bodies, leaving all hypothalamic nuclei intact; and
(v) neurosurgical provocations of outbursts of laughter
when swabbing blood from the floor of the third ventricle
(Purdon, 1950; Duckman and Chao, 1957).
Usually the response of gelastic seizures to antiepileptic
drugs is poor. One case of tuberous sclerosis with gelastic
seizures has been reported that disappeared after treatment
with ACTH (Go, 1999). Surgical resection and stereotactic radiofrequency ablation of hamartomas have been
performed (see Chapter 19.3). In addition, luetinizing
hormone-releasing hormone (LHRH) antagonists, gamma
knife radiation and stimulation of the left vagal nerve
have been performed (see Chapter 19.3).
26.3. Ventromedial hypothalamus syndrome and the
effect of lesions on aggression
Following invasion of a tumor into the area of the ventromedial hypothalamic nuclei (VMN), a tetrad of symptoms
have been described, i.e. (i) episodic rage, (ii) emotional
lability, (iii) hyperphagia with obesity and (iv) intellectual deterioration. Memory loss is the most prominent
feature of intellectual decline. Lesion of the descending
columns of the fornix and mamillary bodies may be
important in this respect, but a primary role for the VMN
in memory has also been postulated (Reeves and Plum,
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1969; Climo, 1982; Flynn et al., 1988; Fig. 26.1). A young

woman with anorexia nervosa due to a craniopharyngioma reported urges to kill people (Climo, 1982). Indeed,
experimental lesions of the VMN area in animals produce
rage and excessive eating, and, in a child with massive
leukemia infiltration at the level of the VMN of the hypothalamus, violent hunger, and obesity were reported. In
addition to tumors, encephalitis, tuberous sclerosis and
vascular lesions have been found to cause hypothalamic
obesity (Bastrup-Madsen and Greisen, 1963; Coffey,
1989). It should be noted, though, that lesions that are
restricted to the VMN do not produce obesity in rats. It
is therefore presumed that damage to the nearby noradrenergic bundle or its terminals might be responsible for
obesity (Gold, 1973). Moreover, it should be mentioned
that, in a patient with hyperphagia and obesity whose
VMN was unilaterally lesioned by a hypothalamic astrocytoma, the paraventricular nucleus (PVN) was bilaterally
involved (Haugh and Markesbery, 1983), which may
also have caused these symptoms (see Chapter 23.1). In
addition to rage attacks in patients with VMN area lesions,
marked oscillations between inappropriate laughter and
crying have been reported (Chapter 26.2).
If VMN lesions indeed have such a notable effect on
the production of episodic rage, emotional instability,
hyperphagia with obesity and memory loss, it is remarkable, to say the least, that none of these signs and
symptoms have been mentioned following stereotactic
destruction of the VMN in patients with sexual deviations or in drug addicts. Even in the patient who
underwent bilateral destruction of the VMN, the only
effect reported was a loss of all interest in sexual activity.
The authors explicitly state that psycho-organic disturbances did not occur in any of the patients, although they
do not define the exact nature of the disturbances
they looked for (Mller et al., 1973). One may thus
indeed wonder whether structures in the vicinity of
the VMN instead of the VMN itself may be essential
for the development of a ventromedial hypothalamus
syndrome. This possibility is reinforced by the observation of a post-traumatic patient with a lesion in the
dorsomedial hypothalamic nucleus who had hyperphagia
(Shinoda et al., 1993). Moreover, in the rat, aggression
can come from an area below the fornix, just lateral and
frontal to the VMN in the hypothalamus. This area almost
completely coincides with the intermediate hypothalamic
area (Kruk et al., 1998; Chapter 14c). On the other hand,
a 3-year-old boy who developed obesity on the basis of
encephalitis had a severe bilateral outfall of the neurons
247
Fig. 26.1. In the course of several years, a young woman developed

marked obesity and hyperphagia, associated with aggressive behavior.
At autopsy, she was found to have a hematoma that destroyed the
ventromedial nucleus. Diagrammatic representation of the tumor
projected on midsagittal plane. ac, anterior commissure; al, ansa
lenticularis; DM, dorsomedial nuclear region; F, fornix; HL, lateral
hypothalamus; I, infundibular stalk; ic, internal capsule; mi, massa intermedia; Mm, mamillary body; ME, median eminence; o ch, optic chiasm;
ot, optic tract; Pa, paraventricular nucleus; ph, pallidohypothalamic tract;
PH, posterior hypothalamus; pi, pineal body; Pr, preoptic region; t,
thalamus; VM, ventromedial nuclear region; zi, zona incerta; and III,
third ventricle. (From Reeves and Plum, 1969; Fig. 3, with permission.)
of the VMN (Wang and Huang, 1991), which argues for

some role of the VMN in eating behavior.
In 1901 Frlich described the case of a 12-yearold boy with a pituitary tumor, sexual immaturity,
hypogonadism and obesity, probably caused by a craniopharyngioma (Carmel, 1980). Later this condition was
called dystrophic adiposo-genitalis syndrome. The
hypogonadism and dwarf growth were probably due
to pituitary deficiencies, while the adiposity is presumed
to be due to a VMN lesion by the tumor, so that
Frhlichs syndrome as an entity has become obsolete
(Drukker, 1967). The most common cause of the combination of hypogonadism and adiposity is, indeed, a
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craniopharyngioma (Sheehan and Kovacs, 1982). It is not

clear what the hypothalamic involvement might be in fat
boys or girls with small genitals that are often said to
have pseudodystrophia adiposogenitalis or pseudoFrhlichs syndrome (Drukker, 1967). Later they develop
into normal adults. A transitory functional disturbance of
the satiety center, the gonadotropin center and temporary, excessive corticotropin-releasing hormone (CRH)
production have been presumed (Sheehan and Kovacs,
1982) but have not been established.
There is one report on the opposite effect of the
symptom, episodic rage, which belongs to the VMN
tetrad, i.e. a calming effect of posterior hypothalamic
lesions, but in fact these lesions were situated just behind
the VMN level. In 51 patients with violent, aggressive
or restless behavior, bilateral lesions were made in an
area 15 mm lateral from the wall of the third ventricle
in the ergotropic triangle. The triangle was in lateral
view, bordered by the midpoint of the intercommissural
line, the rostral end of the aqueduct and the anterior border
of the mamillary body (this means that the major part of
the lesion was in fact situated just behind the hypothalamus). Electrical stimulation of this area caused a rise in
blood pressure, tachycardia and maximum pupillary
dilatation. After bilateral electrocauterization of this area,
a marked calming effect was found in 95% of the cases.
There was a tendency to a decrease in sympathicotonia
or an increase in parasympathicotonia (Sano et al.,
1970). Similar lesions made by Schvarcz et al. (1972)
in 11 patients who had suffered episodes of severe
hetero- and/or autoaggressiveness with violent, destructive behavior have resulted in marked improvement
without aggressive crises or violent behavior, with social
readaptation in 7 cases, improvement in 3 cases and no
improvement in 1 case. As is often the case in such
stereotactic experimental operations, one can doubt the
scientific strength of these observations.
26.4. Depression and mania (Fig. 26B)
Deep grief is mortal. That is to say deadly. Shakespeare.
It should be generally known that the source of our delight,
our joy, laughter and entertainment, as well as of our grief,
pain, fear and tears, is no other than the brain. This organ
in particular allows us to think, to see, to hear, and to distinguish the ugly from the beautiful, evil from good, pleasurable
from disagreeable. The brain is also the seat of madness
and insanity, and of the fears and terrors that assail us,
often at night, but sometimes during the day; the cause of
sleeplessness and somnabulism lies there, of thoughts that

fail to emerge, of obligations forgotten and of strange
phenomena.
After Hippocrates, ca. 460377 v. Chr. in:
Corpus Hippocratium.
Major depressive disorders are considered to have a

neurochemical basis in multiple signaling pathways in
different brain areas, and various regional selective
impairments of structural plasticity have been reported
(Manni et al., 2001). At least seven interacting hypothalamic peptidergic systems are currently considered
to be involved in symptoms of depression, as well as
3 aminergic transmitter systems that innervate the
hypothalamus.
(a) Depression and neuropeptides
The role of neuropeptides in depression is summarized:
(1)
Depressive illness is presumed to result from an

interaction between the effects of environmental
stress and genetic/developmental predisposition.
The hypothalamopituitaryadrenal (HPA) axis,
a key system in stress responses, is considered
to be the final common pathway for a major
part of the depressive symptomatology. The set
point of the HPA axis activity and other central
systems is programmed by genotype but can be
changed to another level by developmental influences and early negative life events. Long-lived
hyper(re)activity of the CRH neurons resulting
in increased stress responsiveness is seen in
these individuals (De Kloet et al., 1997; Heim and
Nemeroff, 2001). Promising animal experimental
models for depression, i.e. maternal deprivation
in neonatal rats, are based upon such a mechanism (Pihoker et al., 1993; Fujioka et al., 1999).
Prenatal stress in rat may lead to permanently
enhanced CRH mRNA expression in the offspring
(Fujioka et al., 1999), and prenatal environmental
chemical stressors such as smoking by the mother
during pregnancy may sensitize a person for
depression, especially children who were either
light or heavy at birth (Clark et al., 1996, Clark,
1998). Both hyper- and hypocortisolism may arise
as a consequence of fetal programming of the HPA
axis during intrauterine life (Kajantie et al., 2002).
Animal experiments and observations in human
indicate that aversive experiences, both in utero
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Fig. 26B.
249
Albrecht Drer, Melencolia I, 1514, Staatliche Museen zu Berlin Preuischer. Kulturbesitz, Kupferstickkabinett, with permission.
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and in the neonatal period, result in sustained HPA

axis activation and in sensitization of emotional
and HPA axis responses to subsequent stress.
Maternal stress beginning at infancy and concurrent stress on preschoolers is accompanied by
sensitization of the childrens HPA axis response
to subsequent stress exposure (Checkly, 1996;
Holsboer and Barden, 1996; Nemeroff, 1996;
Carlson and Earls, 1997; Kraemer, 1997; Clark,
1998; Essex et al., 2002). Stressful life events such
as bereavement, child abuse and early maternal
separation are also risk factors for depression,
anxiety disorder, or both. Childhood physical or
sexual abuse is an important early stressor that
may predispose individuals to adult-onset depression with permanent hyperactivity. Borderline
personality disorder often shows depressive symptoms. A substantial number of these patients show
recurrent brief depression (De la Fuente et al.,
2002) and a high coincidence of childhood abuse.
Interestingly, chronically abused borderline
patients had a significantly enhanced ACTH and
cortisol response to the dexamethasone/CRH challenge test compared with nonabused subjects (De
Bellis et al., 1999; Weiss et al., 1999; Goodyer et
al., 2000; Heim et al., 2000; Heim and Nemeroff,
2001; Wise et al., 2001; Rinne et al., 2002).
In addition, small size at birth leads to an
alteration in set point of the HPA axis and
an increased cortisol responsiveness and risk of
depression in adulthood (Phillips, 2001; Thompson
et al., 2001). The risk of depression remains
elevated for decades following head injury in
adulthood and seems to be the highest in those
who have had a severe head injury (Holsinger
et al., 2002). Additive effects for the risk to
develop depression are personal disappointment,
negative life events, bereavement and stress,
reflected in high daily levels of cortisol or dehydroepiandrosterone (DHEA) (Goodyer et al., 2000;
Harris et al., 2000). However, patients with major
depressed disorders and personality disorders
such as avoidant, schizoid, self-defeating, passiveaggressive, schizotypical and borderline personalities are found to have a normal suppression of
cortisol following dexamethasone administration
(Schweitzer et al., 2001). In contrast to the increased
cortisol levels in major depression, a mirthful
laughter experience reduces serum cortisol (Berk
et al., 1989). Indeed, a good environment is not

a luxury, it is a necessity for optimum brain
development and the prevention of depression. In
addition, there are genetic risk factors involved.
Members of families with a high incidence of
depression showed a primary functional defect in
corticosteroid signal transduction (Holsboer et al.,
1995).
All the environmental and genetic risk factors
for depression ultimately appear to go together
with increased HPA axis activity in adulthood.
On the other hand, when patients are treated with
antidepressants or electroconvulsive therapy, or
when they show spontaneous remission, the HPA
axis function returns to normal (Nemeroff, 1996).
In adulthood, the HPA axis is activated not only
by stressful events, but also by proinflammatory cytokines such as interleukin-6 or exogenous
interferon- that activates such cytokines (Cassidy
and OKeane, 2000). The CRH neurons of the
PVN that regulate the HPA axis are indeed strongly
activated in depression (Raadsheer et al., 1994c,
1995; Figs. 26.2, 26.3 and 26.6) and there is
dexamethasone resistance in the great majority of
depressed patients (Dinan, 1994; Holsboer, 2000).
These findings are of particular interest, not only
because CRH is the central drive to the stress
response, but also because there are similarities
between signs and symptoms of major depression
and the behavioral effects of centrally administered CRH in laboratory animals and in transgenic
mice with CRH overproduction. It is therefore
presumed that antidepressants might elevate mood
through their long-term inhibitory effect on the
HPA axis (Barden et al., 1995; Plotsky et al., 1998;
Holsboer, 2000, 2001). In this connection it is also
interesting to note that depressed patients with
HPA axis hyperactivity are less responsive to
psychotherapy (Thase et al., 1996). In relation
to the hyperactivity of the CRH neurons and
vasopressin and oxytocin neurons in depression
(see below), it is of considerable interest that both
placebo treatment and the selective serotonin reuptake inhibitor (SSRI) fluoxetine cause a decrease
in hypothalamic metabolic rate as measured by
PET scanning (Mayberg et al., 2002).
(2, 3) The vasopressin and oxytocin neurons in the PVN
of patients with major depression or bipolar
disorder are activated, and this activation may have
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Fig. 26.3. The total number of CRH-expressing neurons in the PVN

of human subjects at different ages. , 10 control subjects; , 6 bipolar
or major depressed patients; , 2 non-major depressed subjects with
either an organic mood syndrome or a depressive episode not otherwise
specified. Note the high number of neurons expressing CRH in bipolar
and major depressed patients. (From Raadsheer et al., 1994c, Fig. 2,
with permission.)
Fig. 26.2. Total hybridization signal for human corticotropin-releasing

hormone (CRH)-mRNA (arbitrary units) in the paraventricular nucleus
(PVN). Bars indicate median values per patient group. The PVN of the
Alzheimer patients (n = 10) contained significantly more (MW; U = 23.0,
W = 0.78, Z = 2.0, p = 0.04) CRH-mRNA than that of comparison
subjects (n = 10). The amount of radioactivity in depressed patients
(n = 7) was significantly higher than in comparison cases (MW; U = 7.0,
W = 91.0, Z = 2.7, p = 0.006) and Alzheimers disease patients (MW;
U = 23.0, W = 0.78, Z = 2.0, p = 0.05). (From Raadsheer et al., 1995,
Fig. 2, with permission.)
functional consequences for the activation of the

HPA axis. Vasopressin is known to potentiate the
effects of CRH. Von Bardeleben and Holsboer
(1989) have already postulated that increased
release of vasopressin into the portal capillaries in
depression enhances the action of CRH at the
pituitary level, and cerebrospinal fluid (CSF) CRH
and vasopressin levels are associated with a diminished response of the pituitary to CRH (Newport
et al., 2003). Moreover, depression is associated
with enhanced pituitary vasopressinergic responsivity (Dinan et al., 1999). Because of their central
(4)
251
effects, oxytocin neurons have been connected to

the eating disorders in depression (Purba et al.,
1996). Although the literature has been quite
controversial so far, oxytocin seems to have an
inhibitory effect on ACTH release in various
species, including human (Legros, 2001). The
reduced number of nitric oxide synthase-containing
neurons in the PVN of depressed patients is
supposed to be related to the increased release of
CRH, oxytocin and vasopressin from this nucleus
(Bernstein et al., 1998). In the supraoptic nucleus
(SON), no change is found in depression
(Bernstein et al., 2000).
The suprachiasmatic nucleus (SCN), the clock of
the hypothalamus, normally shows strong circadian
and circannual variations in neuronal activity
(Hofman and Swaab, 1992b, 1993) which are
supposed to be related to circadian and circannual
fluctuations in mood and to sleeping disturbances
in depression. In addition, biological rhythms are
disturbed in depression (Chapter 26f; Van Londen
et al., 2001). A disorder of SCN function, as
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(5)
(6)
(7)
D.F. SWAAB
apparent from the decreased amount of vasopressin

mRNA in this nucleus, may not only be the basis
of the circadian and sleeping disorders in depression, but also contribute to hyperactivity of the
CRH neurons (Zhou et al., 2001). It is presumed
that the decreased activity of the SCN in depression is due to the increased corticosteroid levels
that are known to inhibit SCN function (Liu et al.,
2003, submitted; Figs. 26.4, 26.5 and 26.6). Data
on changes in melatonin excretion in depression
are controversial (Chapter 4.5e; Kripke et al.,
2003).
Depressed patients have alterations in the hypothalamopituitarythyroid axis (Musselman and
Nemeroff, 1996). Basal thyrotopin (TSH) and
thyroxin levels are found to be altered in melancholic and major depressed patients (Maes et al.,
1993b). Moreover, thyroid hormones may increase
the efficacy of antidepressant drugs (see below).
In CSF of depressed patients, somatostatin is
decreased in a state-related way, while in suicide
attempters somatostatin levels are significantly
increased. The source of these peptide changes still
ought to be established (Westrin et al., 2001).
The number of -endorphin-containing neurons in
the infundibular nucleus (Chapter 11) and the
number of -endorphin innervated neurons in
the PVN are lower in depressed patients (Bernstein
et al., 2002b).
Fig. 26.4. Estimated total amount of arginine vasopressin (AVP)

mRNA in the suprachiasmatic nucleus (SCN; expressed as masked area
of silver grains) of the controls and the corticosteroid-exposed subjects
(CST). The bars and error lines represent the mean and standard error
of the mean (SEM). (From Liu et al., 2003, submitted.)
1992), but it has yet to be elucidated whether the

serotonergic innervation of the hypothalamus is crucial
in this respect. Some conditions, such as major depression,
violent suicide and SAD are presumed to be related to
the rhythmicity of 5-HT function (Cappiello et al., 1996).
(b) Amines in the hypothalamus and depression

Patients with depression have alterations in serotonin (5HT), noradrenaline and dopamine production by the brain
(Lambert et al., 2000). The hypothalamus is strongly
innervated by the noradrenergic, dopaminergic and
serotonergic systems, neurotransmitter systems that are
considered to play vital roles in the pathogenetics of
depression. The slightly lower prolactin plasma levels
in patients with seasonal affective disorder (SAD) are
consistent with a hypothalamic dopamine disregulation
in this disorder (Oren et al., 1996). Indeed, increased
dopamine levels were observed in the hypothalamus of
suicide victims who died as a result of carbon monoxide
poisoning or drug overdose. However, the possibility that
these changes are secondary to hypoxia or due to drug
effects should be considered (Arranz et al., 1997).
Impulsive aggression and suicidal behavior have been
related to a decreased serotonergic activity (Coccaro,
Fig. 26.5. Daynight fluctuation in the total amount of AVP mRNA

of the SCN in controls and in the glucocorticoid-exposed subjects (CST).
Note that at any moment of the day the values for CST are lower than
those of controls. (From Liu et al., 2003, submitted.)
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With respect to the seasonal and circadian fluctuations

in mood, the circannual and day/night fluctuations in
hypothalamic content of 5HT and dopamine (Carlsson
et al., 1980a; Chapter 1.3) may be of particular interest.
The rhythmic circadian and circannual fluctuations in
amines suggest that the hypothalamic SCN may drive
the aminergic neurotransmitter system rather than the
other way around. Noradrenaline is increased in the hypothalamus of depressive suicides and suicides who were
alcoholics (Moses and Robins, 1975). Depression in
suicide victims was also found to be related to the
presence of supersensitive 2A-adrenoceptors in the
hypothalamus and prefrontal cortex (Meana et al., 1992;
Oren et al., 1996), although other data indicated a
decrease in postsynaptic 2-adrenoreceptor responsive-
253
ness in depression (Mokrani et al., 1997). There are many

possible interactions between the peptidergic and
aminergic networks and endocrine changes in depression.
Corticosteroids exert a variety of effects on aminergic
neurotransmission (Holsboer and Barden, 1996), probably
by the widely distributed corticosteroid receptors (De
Kloet et al., 1997). Moreover, CRH neurons innervate
dopaminergic neurons (Thind and Goldsmith, 1989),
which might be an additional route for HPA axis influence
on monoaminergic systems. Light therapy is presumed
to act on the SCN but also affects serotonergic and
noradrenergic neurotransmissions. The maintenance of
light therapy-induced remission from depression in
patients with seasonal mood cycles seems to depend on
the functional integrity of the brain serotonergic system,
Fig. 26.6. Depression; schematic illustration of an impaired interaction

between the decreased activity of vasopressin neurons (AVP) in the
suprachiasmatic nucleus (SCN) and the increased activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular
nucleus (PVN). The hypothalamopituitaryadrenal (HPA) system is activated in depression and affects mood, via CRH and cortisol. We found
a decreased amount of vasopressin (AVP) mRNA of the SCN in depression. The decreased activity of AVP neurons in the SCN of depressed
patients is the basis of the impaired circadian regulation of the HPA
system in depression. Moreover, animal data have shown that AVP
neurons of the SCN exert an inhibitory influence on CRH neurons in
the PVN. Increased levels of circulating glucocorticoids decrease AVP
mRNA in the SCN, which will result in smaller inhibition of the CRH
neurons. In the light of our data we propose the following hypothesis
for the pathogenesis of depression. In depressed patients, stress acting
on the HPA system results in a disproportionally high activity of the
HPA system because of a deficient cortisol feedback effect due to the
presence of glucocorticoid resistance. The glucocorticoid resistance may
either be caused by a polymorphism of corticosteroid receptor or by a
developmental disorder. Also AVP neurons in the SCN react to the
increased cortisol levels and subsequently fail to inhibit sufficiently the
CRH neurons in the PVN of depressed patients. Such an impaired negative feedback mechanism may lead to a further increase in the activity
of the HPA system in depression. Both high CRH and cortisol levels
contribute to the symptoms of depression. Light therapy activates the
SCN, directly inducing an increased synthesis and release of AVP that
will inhibit the CRH neurons. Antidepressant medication generally
inhibits the activity of CRH neurons in the PVN. ACTH, corticotropin.
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suggesting that this system may be involved in the

mechanisms of the action of light therapy (Neumeister
et al., 1997). Whether hypothalamic changes are responsible for the loss of sexual satisfaction in depression and
nocturnal penile tumescence abnormalities (Nofzinger
et al., 1993) remains to be studied. Some animal experiments suggest that histamine, the product of the
tuberomamillary nucleus (Chapter 13), increases anxiety.
Winston Churchill described depression as the black
dog (Nemeroff, 2001).
(c) Other factors and brain structures involved in the

pathogenesis of depression
Environmental stress and developmental factors, including
a genetic basis, are involved in the pathogenesis of
depression and cause hyperactivity of the HPA axis
(Chapter 26.4a). Those patients who were born in the
northern hemisphere in MarchMay and those born in
the southern hemisphere in SeptemberNovember
have the highest prevalence of suicidal and depressive
symptoms. Second-trimester prenatal exposure to influenza is given as an example of this seasonal fluctuation
(Joiner et al., 2002). Moreover, a clear gender difference
is present in depression. The prevalence, incidence and
morbidity risk is higher in females than in males (Regier
et al., 1988; Table 2.2), suggesting the organizing or
activating action of sex hormones.
The high proportion of depression-like neuroendocrine, polysomnographic or psychometric features
are conspicuous findings observed in 32% of the healthy
first-degree relatives of patients with an affective disorder
hypothesized to be due to a disturbed receptor function
and indicate a genetically transmitted risk factor
(Holsboer et al., 1995; Holsboer, 2000; Krieg et al., 2001)
such as corticosteroid receptor polymorphism, which
leads to corticosteroid resistance. Increased levels of
cortisol or DHEA, which are risk factors for depression,
may thus also be based upon genetic factors (Goodyer
et al., 2000). Interestingly, results of an analysis of twin
studies suggest a heritability of the cortisol levels of 62%
(Bartels et al., 2003). Although mutations, singlenucleotide polymorphisms and glucocorticoid receptor
variants have been found, no association with depression
or other psychiatric disorders has been reported. However,
such an association has in fact hardly been studied so far
(DeRijk et al., 2002). Polymorphisms in the 5-HT transporter promotor and in genes encoding for 5-HT receptors
5-HT2A and 5-HT2C and tryptophanhydroxylase do not

play a major role in the pathogenesis of SAD according
to some studies (Johansson et al., 2001; see below),
although according to others this may be a vulnerability
factor (Praschak-Rieder et al., 2002). Carriers of the
5-HT2C ser allele were 12 times more likely to have
major depression in Alzheimers disease (Holmes et al.,
2003). The apolipoprotein E (ApoE) 2 allele is significantly less frequently found in depressive illness and is
associated with a later mean age at onset. In contrast,
subjects with depressive symptomatology in Alzheimers
had a higher frequency of the ApoE 2 allele (Holmes
et al., 1996b). In Alzheimer patients the ApoE 4 allele
is associated with depression in women, but not in men
(Mller-Thomsen et al., 2002). Evidence of anticipation
for bipolar disorder may be explained by the presence of
unstable trinucleotide CAG/CTG repeats that expand
from one generation to the next (Vincent et al., 1999).
Seasonality of the winter type of depression also seems
to run in families (Madden et al., 1996). A 5-HT transporter promoter polymorphism (Sher et al., 1999) and
-7 nicotine receptor polymorphisms (Stassen et al.,
2000) are known to be associated with this type of depression. In addition, it is hypothesized that mutations or
allelic variations in clock genes might contribute to
the symptoms of depression in SAD and subgroups of
major depression (Bunney and Bunney, 2000). Desan
et al. (2000) have reported a single-nucleotide polymorphism in the CLOCK gene, in addition to a preference
for activity in the evening, but it is not associated
with depression. A polymorphism in the clock gene
NPAS2 appeared, however, to be associated with SAD
(Johansson et al., 2003). An insertion/deletion polymorphism in the angiotensin-1-converting enzyme gene
leads to higher HPA axis activity during major depressive periods (Baghai et al., 2002). For the increased risk
factor for depression in heterozygous Wolfram patients
(Swift et al., 1991; see Chapter 22.7). There is also
preliminary evidence for a role of the Wolfram syndrome1 (WFS1) gene in the pathophysiology of impulsive
suicide (Sequeira et al., 2003). Patients with cyclothymia
or bipolar affective disorder are present in families with
morbid obesity due to mutations of the melanocortin 4
receptor (Mergen et al., 2001). Genetic factors also seem
to contribute substantially to the comorbidity between
major depression and anorexia nervosa (Wade et al.,
2000).
Prenatal famine in middle or late gestation is a risk factor
for major depression, as shown in studies on subjects
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exposed to the Dutch Hunger winter of 19441945. The

effects were demonstrated for men and women and for
unipolar and bipolar affective disorders (Brown et al.,
2000). Whether long term dysfunctions of the HPA axis
are present in these subjects has yet to be elucidated.
Several hormonal factors may also be involved.
Prenatal diethylstilbestrol (DES) exposure increases the
risk for depression (Meyer-Bahlburg and Ehrhardt, 1987),
while in addition growth hormone-deficient children are
at risk for depression and react favorably to growth
hormone treatment (Stabler et al., 1996; Chapter 18.6).
Hypertension is accompanied by high levels of a feeling
of hopelessness (Everson et al., 2000), possibly due to
the increased activity of the CRH neurons found in this
condition (Goncharuk et al., 2002). Depression is common
after stroke. The severity of mood disorders in stroke is
increased in patients with left prefrontal frontal cortex
lesions or with right posteriodorsal lesions (Robinson
et al., 1984; Iacoboni et al., 1995). Postmortem studies
have provided morphological evidence for the involvement of the prefrontal cortex in depression. Cell loss takes
place in the subgenual prefrontal cortex and cell atrophy
is found in the dorsolateral and orbitofrontal cortex
(Rajkowksa, 2000). Moreover, the number of glial fibrillary acetic protein (GFAP) positive astrocytes is decreased
in the dorsolateral prefrontal cortex of young depressed
patients and increased in older depressed patients
(Miguel-Hidalgo et al., 2000). PET and SPECT studies
have shown that bilateral hypometabolism of the orbitalinferior prefrontal lobe occurs in most types of depression,
regardless of the origin of the depression (George et al.,
1993; Mayberg et al., 2002; Morris et al., 1996a, b;
Galynker et al., 1998). It is a matter of debate whether
these metabolic changes in the cortex in depressed
patients are cause or effect of the disorder, since increased
levels of glucocorticoids inhibit prefrontal cortex metabolism (Fulham et al., 1995; Brunetti et al., 1998) and
glucocorticoid receptor dysregulation is found in the
neocortex and hippocampus of patients with depression
(Webster et al., 2002). In the pathogenesis of depression,
the interaction between the prefrontal cortex and the
HPA axis is crucial. On the one hand, the prefrontal
cortex inhibits the HPA axis, as is clear from the lesions,
particularly of the left prefrontal cortex, which may
go together with symptoms of depression and hypercortisolism. On the other hand, the hypercortisolism that
occurs in depression will inhibit prefrontal cortex activity,
and these two effects might even reinforce each other
(Swaab et al., 2000).
255
Major depressive syndrome has a high (45%) prevalence rate in Alzheimer patients, and may thus be among
the most common mood disorders of late life (Zubenko
et al., 2003). What the increased HPA axis activity that
we observed in Alzheimer patients (Raadsheer et al.,
1995) may contribute to this syndrome should be investigated. Depression is considered to be a risk factor for
the later development of Alzheimers disease (Green
et al., 2003).
Major depression with melancholic features includes
sustained anxiety, dread for the future, and hyperarousal,
which are proposed to be based not only on hyperactivity
of the CRH system, but also on hyperactivity of the locus
coeruleus-norepinephrine system (Gold and Chrousos,
2002; Wong et al., 2000). These two systems are also
interconnected. Noradrenaline injection into the rat PVN
causes an increase in CRH heteronuclear RNA (Itoi
et al., 1999). In connection with the strong noradrenergic
innervation of the PVN and other hypothalamic structures,
it is of great interest that a number of observations
suggested the presence of a relationship between the
degree of the loss of neurons in the locus coeruleus and
the occurrence of depression, in Alzheimer patients. In
demented patients with major depression significantly
more degenerative neurons in the locus coeruleus are
reported than in nondepressed demented patients,
although this finding has not been substantiated by
morphometry (Zubenko and Moossy, 1988). Patients with
Alzheimers disease are reported to have fewer neurons
at the middle and rostral level of the locus coeruleus than
nondepressed Alzheimer patients according to Zweig et
al. (1988). Frstl et al. (1992) have also reported lower
neuronal counts in the locus coeruleus of depressed
Alzheimer patients compared with nondepressed subjects.
Zubenko et al. (1990) have subsequently reported a
10- to 20-fold reduction of noradrenaline in the cortex of
demented patients with major depression compared with
demented patients who were not depressed. However,
recent studies by our group in which we placed special
emphasis on longitudinal psychiatric evaluation of the
symptoms, matching for the clinical symptoms of
dementia severity, matching for neurological comorbidity
and for the severity of cortical Alzheimer pathology, and
using image-analysis assisted morphometry, could not
confirm these results. The mean number of neurons
in the locus coeruleus was higher in controls than in
depressed and nondepressed Alzheimer patients, while
between the two latter groups no significant differences
were found. Also the noradrenaline levels in the cortex
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of depressed dementia patients did not differ from those

of nondepressed Alzheimer patients (Hoogendijk et al.,
1999a, b). The discrepancy with the previous papers is
probably partly based upon the debatable way degeneration was defined: by combining scores and using
one-tailed testing (Zubenko and Moossy, 1988), but the
major problem seems to be the insufficient matching of
the degree of dementia in the other papers (Hoogendijk
et al., 1999a, b).
In suicide victims 38% fewer pigmented locus
coeruleus neurons have been reported. The reduction is
localized in the rostral two-thirds of the locus coeruleus.
It is, however, not established whether the loss of
noradrenergic neurons is indeed associated with an underlying major depression (Arango et al., 1996). Two other
studies have examined the number of locus coeruleus
neurons in suicide victims. Biegon and Fieldust (1992)
have reported reduced intensity of tyrosine hydroxylase
immunoreactivity but no difference in the number of
immunoreactive cells in suicide victims. Ordway et al.
(1994) have found an increase in the concentration of
tyrosine hydroxylase and no difference in the number
of pigmented neurons. However, the neuron counting was
only performed on two or three sections of the locus
coeruleus per case, not taking into consideration the
rostrocaudal differences in this nucleus. Thus, so far, a
consistent change does not seem to be present in the locus
coeruleus of depressed patients.
Opioid peptides are known to exert an inhibitory
influence on the HPA axis in humans. The increased HPA
axis activity in depression is associated with a reduced
opioid tone as shown from a reduced cortisol and ACTH
response to naloxone in depressed patients. A reduced
endogenous opioid tone may explain why some depressed
patients self-medicate with opiates (Burnett et al., 1999).
The opiate systems in the postmortem human brain have,
however, not yet been studied in connection with depression. Cannabis can induce mood changes (Tsai et al.,
2001). Moreover, leptin levels (see Chapters 11d and 23b)
are low in depressed patients, while the body mass index
is normal. This alteration may be related to the changes
in appetite, food intake and weight, that are frequently
observed in depression (Kraus et al., 2001).
Interleukin-2 and interferon- therapy in hepatitis C
or cancer patients is frequently associated with depressive
symptoms (Capuron et al., 2000; Wichers and Maes,
2002). Major depression is accompanied by an acutephase response including increased plasma interleukin-1
levels (Owen et al., 2001). The mechanism whereby inter-
leukin may induce depression remains elusive at present.

In addition, alterations in melatonin secretion patterns
have been reported in depression (Pacchierotti et al.,
2001). Lower nocturnal bilirubin levels were found in
patients with winter seasonal depression. Circulating
bilirubin is thought to serve as a photoreceptor (Oren
et al., 2002a). For the controversial relationship between
a reduced hippocampal volume (Bremner et al., 2000) in
depressed patients and activation of the HPA axis, see
Chapter 8.5b, e.
In children with gelastic seizures (Chapter 26.2) and
hypothalamic hamartoma (Chapter 19.3) a high proportion of mood disorders are found (Weissenberger et al.,
2001).
(d) CRH neurons and the symptoms of depression (Fig.
26.6)
Both major depressed patients and patients with bipolar
depression show a much stronger CRH neuron activation
than aged controls or Alzheimers disease patients, as
shown by the fourfold increase in total number of cells
expressing CRH (Fig. 26.3), the increased total number
of CRH neurons showing vasopressin colocalization and
the increased amount of CRH mRNA in the PVN
(Raadsheer et al., 1994c, 1995; Fig. 26.2). The observation that the number of non-vasopressin-coexpressing
CRH neurons increases more in major and bipolar depression than the number of vasopressin-coexpressing CRH
neurons (Raadsheer et al., 1994c) seems to indicate that
different subtypes of CRH neurons are present in humans
and that these are activated differentially in depressed
patients (Raadsheer et al., 1995). This view is supported
by the different alteration found in multiple sclerosis
(Chapter 21.2c) and the finding of two subtypes of
CRH neurons in the PVN of experimental animals
(Whitnall et al., 1993). One type colocalizes vasopressin
and projects to the rat median eminence, whereas the
other type does not coproduce vasopressin and projects
to the brainstem and spinal cord (Sawchenko and
Swanson, 1982). Although in the rat the proportion
of nonneuroendocrine neurons represent only a minor
subpopulation of the CRH neurons in the PVN (Swanson
et al., 1983; Mezey et al., 1984), our data indicate that,
if the same principle goes for humans, this proportion
may be considerably larger in our species. However, this
principle still has to be confirmed for the human brain.
At present there are various additional arguments for
the increased HPA axis activity in depression. Increased
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plasma and salivary cortisol and cortisone levels,

increased urinary free cortisol excretion and disturbed
dexamethasone suppression, decreased corticosteroid
receptor function, enhanced adrenal response to ACTH,
blunted pituitary ACTH response to CRH, and adrenal
and pituitary enlargement in depression also indicate HPA
axis hyperactivity in this disorder (Krishnan et al., 1991a;
OBrien et al., 1996; Rubin et al., 1996; Modell et al.,
1997; Maes et al., 1998; Holsboer, 2000; Weber et al.,
2000a). The smaller pituitary volumes found in one study
in patients with bipolar disorder (Sassi et al., 2001)
and the urinary hyposecretion of cortisol in a small group
of elderly depressed patients (Oldehinkel et al., 2001)
are difficult to explain. The combined dexamethasone/
CRH test does not only identify, with high sensitivity, a
dysfunction of the HPA axis in depression, the elevated
cortisol response in the test is also correlated with a
four- to six-fold higher risk for relapse than in individuals
who had a depression but subsequently showed a normal
cortisol response (Zobel et al., 2001). It is of particular
interest that the adrenal weight increase in suicide victims
is accounted for specifically by increases in the weight
of the left adrenal gland (Szigethy et al., 1994). The
unilateral activation is consistent with the proposed
functional importance of adrenal innervation for regulation of the sensitivity for ACTH of these glands in
rat (Buijs et al., 1999). It should be noted, though, that
there is individual variability in the degree of HPA
axis activation (see also Fig. 26.2). The increased basal
plasma cortisol levels are present only in some 25%
of the subjects with major depression, while 66% show
nonsuppression of cortisol to dexamethasone (Young
et al., 2001). In a recent study, Brunner et al. (2002)
did not find any indication for an activation of the HPA
axis in depressed patients, including suicide attempters,
on the basis of the dexamethasone/CRH test, or of
plasma cortisol levels. Indeed, most patients with major
depression are not hypercortisolemic when studied crosssectionally; however, this does not rule out clinically
significant periods of excessive exposure to glucocorticoids. Urinary free cortisol excretion may be elevated for
21 days out of a month in depressed patients, compared
with 45 days per month in control subjects. Moreover,
plasma cortisol levels fluctuate strongly over the day and
are elevated and normal at different times of the day in
depressed patients (Gold et al., 2002). Moreover, the HPA
axis is not overtly abnormal in chronic depression, not
even when tested with a sensitive dexamethasone/CRH
test (Watson et al., 2002). Subjects with psychotic major
257
depression have higher cortisol levels throughout the

afternoon than subjects with nonpsychotic major depression, which may also contribute to the variability in
cortisol level (Belanoff et al., 2001). In younger depressives adrenal steroid abnormalities are also apparent when
the developmentally sensitive steroid DHEA that is a
precursor for testosterone and estrogens is determined
(Goodyer et al., 1996, 1998). Scott et al. (1999a) have
found lower dehydroepiandrosterone sulfate (DHEAS)
but no DHEA plasma levels in depressive patients.
Elevated baseline cortisol levels are related not only to
mood disorders, but also to cognitive impairment in
depressed patients (Van London et al., 1998a).
In some studies CRH levels in CSF are reported to be
higher in major depression than in mania, anxiety or
controls (Banki et al., 1992; Mitchell et al., 1998; Wong
et al., 2000). There is certainly the possibility that the
increased CSF CRH levels reported are due to the stress
of the anticipation of the lumbar puncture or the puncture
itself (Geracioti et al., 1992). When lumbar CSF is
continuously sampled, thus avoiding a stress response,
CSF CRH levels are found to be strikingly reduced in
depressed patients (Geracioti et al., 1992). In postmortem
cisternal CSF, elevated CRH levels have been measured
in suicide victims that have an underlying depression
(Arat et al., 1989). However, Brunner et al. (2002) did
not find a difference in lumbar CSF CRH levels in
drug-free, depressed suicide attemptees compared with
nonattemptees in this study, and could thus not confirm
the earlier observation of increased CSF CRH levels in
suicide victims by Arat et al. (1989). Although there is
a close association between CSF CRH levels and alterations in the HPA axis in depression (Newport et al.,
2003), one may wonder what proportion of CSF CRH
comes from the PVN. CRH is produced not only in
the PVN, but also in extrahypothalamic areas and in the
spinal cord. CRH levels in extra-hypothalamic sites may
return to near normal during remission (Mitchell, 1998),
indicating their role as a state marker. CSF CRH may,
at least for the most part, represent fluctuations in extrahypothalamic CRH such as from the neocortex, limbic
and brainstem regions rather than in hypothalamic CRH
(Gottfries et al., 1995; Mitchell, 1998; Arborelius et al.,
1999; Vythilingham et al., 2000; Galard et al., 2002). The
locus coeruleus of depressed subjects contains elevated
CRH concentrations. This brain area receives CRH input
from the central nucleus of the amygdala and from
pontine-medullary projections (Bissette et al., 2003). The
observation that CSF CRH levels are increased in anxiety
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and depression, even though in anxiety there is supersuppression of cortisol following dexamethasone and
there is nonsuppression in depression (Boyer, 2000),
pleads for the idea that CSF CRH levels do not necessarily
reflect HPA axis activity. Another observation supporting
the idea that CRH in CSF is derived from other sources
than the HPA axis is that, in spite of the fact that in posttraumatic stress disorder the HPA axis is strongly
suppressed (Yehuda et al., 1995a, b), CRH levels in CSF
are increased (Bremmer et al., 1997; Kasckow et al.,
2001b). Finally, although the HPA axis is activated in
Alzheimers disease (Chapter 8.5b; Fig. 26.2), some
authors have reported decreased CRH levels in the CSF
(Geracioti et al., 1992; Gottfries et al., 1995), although
others did not confirm this (Martignoni et al., 1990; Banki
et al., 1992; Nemeroff, 1996; Valenti, 1996). Concluding,
alterations in HPA axis activity do not seem to be directly
reflected by CSF CRH levels.
There is also uncertainty about the source of plasma
CRH, which is increased in depression (Cataln et al.,
1998). However, the observation that plasma CRH levels
increase in depression and decrease following dexamethasone suppression (Galard et al., 2002) make this
measurement a promising tool that should be studied
further.
An important argument for the crucial role of CRH is
that symptoms resembling depression, e.g. decreased food
intake, decreased sexual activity, disturbed sleep and
motor behavior and increased anxiety, can be induced in
experimental animals by intracerebroventricular injection
of CRH (Holsboer et al., 1992). In addition, antidepressant
drugs attenuate the synthesis of CRH, possibly by
stimulation of corticosteroid receptor expression (Fischer
et al., 1990; Brady et al., 1991, 1992; Delbende et al.,
1991; Reul et al., 1993; Nemeroff, 1996; Reus, 1997).
Moreover, the CRH concentrations in CSF in healthy
volunteers (Veith et al., 1993) and the CRH levels in CSF
of depressed patients (De Bellis et al., 1993; Heuser
et al., 1998) decrease due to antidepressant drugs;
although, as has been argued before, CSF CRH is
probably not, or only partly, derived from the hypothalamus but mainly from other sources, such as the cortex
(Vythilingam et al., 2000; see also before). Lastly, a
transgenic mouse model with an overproduction of
CRH appeared to have increased anxiogenic behavior. i.e.
symptoms that are usually related to major depression,
which could be counteracted by injection of CRH
antagonist (Stenzel-Poore et al., 1994). CRH-receptor
antagonists are also suggested to be useful for the treat-
ment of melancholic depression (Grammatopoulos and

Chrousos, 2002). A mouse with a genetic deletion of
the CRH1 receptor has reduced anxiety-like behavior
(Contarino et al., 1999). An interesting new compound
in depression research is urocortin, a CRH-related peptide
(Chapter 8.5) also has anxiogenic-like properties in animal
experiments (Behan et al., 1997; Moreau et al., 1997) and
the presence of CRH-binding protein in the brain that
also binds urocortin (Behan et al., 1997).
The sum of the arguments mentioned above leads to
the CRH hypothesis of depression (Fig. 26.6), i.e. that the
hyperactivity of a subgroup of CRH neurons that does not
project to the median eminence but into the brain may be
activated in depression and induce the symptoms of this
disorder. The recent development of selective, smallmolecule CRH1 receptor antagonists, which block the
effects of CRH both in vitro and in vivo, suggest that these
compounds may be effective in the treatment of mood and
anxiety disorders (OBrien et al., 2001b). In an open trial,
one of these compounds (R121919) led to a 50% reduction in depressive symptoms, comparable with that
obtained with a selective 5-HT reuptake inhibitor (Keck
and Holsboer, 2001). There are, however, also observations that may call this concept into question and point
rather to the importance of glucocorticoids (Fig. 26.6). A
few studies have reported that glucocorticoid antagonists
may be effective in the treatment of major depression
(Murphy, 1997; Wolkowitz et al., 1999). Inhibitors
of cortisol production such as metyrapone, aminoglutethamide or ketoconazole, when administered to major
depressed patients, may result in clinical success,
which was not to be expected if not cortisol but CRH
would indeed cause the symptoms (Reus, 1977; Fava,
1994; Murphy, 1997). The antiglucocorticoids DHEA
and DHEAS are also studied for their positive antidepressant and cognition-enhancing effects in mood
disorders (Reus et al., 1997; Wolkowitz et al., 1997). The
antiglucocorticoid mifepristone is effective in treating psychotic depression, producing clinically relevant responses
in some patients in a few days (Gold et al., 2002). The
effectiveness of these new compounds may depend on the
type of depression that is being treated (also see below).
In addition, such compounds induce so many unspecific
effects, also at the central level, that the interpretation
allowed by some of these experiments is limited (Holsboer
and Barden, 1996). On the other hand, the observation that
a significant improvement in mood is observed in patients
with treatment-resistant depression who receive dexamethasone in addition to their antidepressant treatment
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appears to be in favor of hyperactive CRH neurons playing

a causal role in the symptomatology of depression (Dinan
et al., 1997). The finding that acute hydrocortisone
infusion is associated with rapid and robust reduction in
depressive symptoms (De Battista et al., 2000) reinforces
this conclusion.
The increased drive of the HPA axis in depressed
patients could be mediated either by CRH, by vasopressin
or by both. Indeed, both CRH receptor antagonists
and cortisol synthesis inhibitors or corticosteroid receptor
antagonists may be effective in depressed patients
(Holsboer, 2000; Gold et al., 2002). Whether disinhibition
of sexual behavior is a side effect of CRH antagonists in
depressed patients as observed in Syrian hamsters
following intracerebroventricular administration (Jones
et al., 2002) is not yet known. Gold et al. (1995) and
Gold and Chrousos (2002) propose that the classic form
of major depression, i.e. melancholic depression, that
goes with decreased food intake, insomnia, lack of affective responses to external events and a general state of
pathological hyperarousal, is due to hyperactivity of CRH
neurons. Hypercortisolemia is consistently observed in
melancholy. The adrenal is hyperresponsive to ACTH and
hypertrophic, while the pituitary cells are appropriately
responsive to glucocorticoids. In contrast, atypical
depression a state of hyperphagia, hypersomnia,
enhanced affected responsiveness to external stimuli,
lethargy and fatigue would be based upon increased levels
of corticosteroids and decreased levels of CRH (Gold
et al., 1995). In this context it is of interest that women
not only are more at risk than men for major depression
(Chapter 1, Table 1), but also have a significantly higher
glucocorticoid and mineralocorticoid receptor mRNA
expression than men in the temporal lobe and prefrontal
cortex (Watzka et al., 2000). In addition, a well-known
side effect of glucocorticoids is depression. A third of
the patients receiving glucocorticoids experience significant mood disturbances and sleep disruption. Up to 20%
report psychiatric disorders, including depression, mania
and psychosis (Mitchell and OKeane, 1998). Moreover,
atypical depression is found in a large proportion of
patients with Cushings disease. Patients with long-term
Cushings syndrome are especially at risk for such
psychopathology (Dorn et al., 1995; Gold et al., 1995).
The fact that atypical depression is so often seen in
Cushings syndrome indicates that in these patients
cortisol causes this type of depression rather than ACTH
or CRH. This conclusion is supported by a small study
that shows that depression can be treated by ketoconazole,
259
an antiglucocorticoid (Wolkowitz et al., 1999) and by

the observation that metyrapone successfully treats
depression in Cushing patients (Checkley, 1996).
However, it should be noted that, also after correction of
hypercortisolism in Cushings syndrome, atypical depression frequently continues to be present. Suicidal ideation
and panic may increase (Dorn et al., 1997a). The pituitary
shows a profoundly exaggerated plasma ACTH response
to CRH in Cushings disease, despite pronounced hypercortisolism. This indicates that the pituitary is grossly
unresponsive to glucocorticoid negative feedback. A
relationship has also been found between hypercortisolism
and violent suicidal behavior. Both in patients who have
recently attempted suicide and in those with a history of
suicidal behavior increased urinary cortisol excretion and
a decreased noradrenergic function is observed (Van
Heeringen et al., 2000). Also patients with winter depression and chronic fatigue syndrome meet all the criteria
for an atypical depression. In these patients hypofunctional CRH neurons are postulated (Joseph-Vanderpool
et al., 1991; Gold et al., 1995; Chapter 26.6), but so
far the hypothalamus of these patients has not been
investigated. In multiple sclerosis (MS), a disease with
an increased incidence of depression, the blunted plasma
ACTH response to vasopressin reflects a relative shift
from CRH to vasopressin modulation of pituitary adrenal
function (Gold et al., 1995), which fits in with our finding
of increased numbers of neurons colocalizing arginine
vasopressin (AVP) and CRH in MS (Erkut et al., 1995;
see Chapter 21.2c).
The consistent presence of increased HPA axis activity
in depression raises the question of the possible pathogenetic mechanisms underlying the activation of this
axis. An imbalance in the ratio between mineralocorticoid and glucocorticoid receptors has been shown in
depressed patients (Young et al., 2003), but it is not clear
whether this is cause or effect. Impaired negative feedback control of the HPA axis and adrenal hypertrophy
are frequent signs of a subgroup of depressed patients
(Checkley, 1996; Modell et al., 1997). It coincides with
episodes of depression and, at least partially, reverses
after recovery from psychopathology. Some observations
suggest that the impaired negative feedback effect of
corticosteroids on the HPA axis in a number of healthy
probants at risk for affective disorder is caused by a
disturbed corticosteroid receptor function, indicating a
genetically transmitted risk factor (Holsboer et al., 1995;
Holsboer, 2000). Genetic variations (polymorphisms) of
the glucocorticoid receptor are hypothesized to explain
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that only some 50% of the depressed patients show

hypercortisolemia (Checkley, 1996; Holsboer, 2000). The
expected mutations, deletions and other changes in
the glucocorticoid receptor gene for the presence of glucocorticoid resistance have, however, not yet been found
(Brnnegrd et al., 1996; Holsboer, 2000). A developmental effect inducing altered feedback control of the
HPA axis persisting in adulthood is an alternative possibility that may lead to acquired glucocorticoid receptor
resistance in some areas (Brnnegrd et al., 1996; De
Kloet et al., 1997; De Bellis et al., 1999) and receptor
hypersensitivity in other brain areas (Nemeroff, 1996).
Several types of developmental sequela might be considered in this respect. Depression and anxiety have been
found to be more frequent in the sons and daughters of
women who had been treated with DES during pregnancy
(Vessey et al., 1983; Brown et al., 1995b) and in children
of mothers who were pregnant during the hunger winter
in the Netherlands during the second world war (Susser
et al., 1992, 1996). However, so far the HPA axis has
not been investigated in these patients. In addition,
psychological stress in development may have permanent
activating effects on the HPA axis (see Chapter 26.4a).
The observation that the adrenal corticosteroid DHEA
improves depression ratings as well as memory performance in elderly depressed patients (Wolkowitz et al.,
1997) has yet to be confirmed in double-blind trials. These
observations seem to be at odds with the increased
DHEAS plasma levels observed in depressed patients
(Heuser et al., 1998).
(e) Oxytocin and vasopressin neurons and the
symptoms of depression
As discussed previously, CRH and vasopressin are
colocalized in an increased number of PVN neurons in
depressed patients (Raadsheer et al., 1994c). We found
not only an increased number of vasopressin-coexpressing
CRH neurons in depression, but also an increase in the
total number of vasopressin and oxytocin-expressing
neurons in the PVN, of 56% and 23%, respectively,
indicating an increased production of these peptides
(Purba et al., 1996). In depressed patients the plasma
vasopressin and cortisol levels correlate positively
(Brunner et al., 2002). These observations thus confirm
the postulate of Von Bardeleben and Holsboer (1989)
that the action of CRH in depression is enhanced by
vasopressin. In addition, depression is associated with an
enhanced pituitary vasopressinergic responsivity (Dinan
et al., 1999). During chronic stress the upregulation of

vasopressin released into the portal system may be critical
for sustaining corticotroph responsiveness in the presence
of high circulating glucocorticoid levels. V1b receptor
mRNA levels and coupling of the receptor to phospholipase C are stimulated by glucocorticoids (Aguilera and
Rabadan-Diehl, 2000). Indeed Van Londen et al. (1997)
have reported increased plasma levels of vasopressin
in depressed patients. The melancholic patients have
higher plasma levels than the nonmelancholic patients.
There appears to be a vague relationship between
plasma vasopressin levels and psychomotor retardation
and a significantly inverse relationship between these
levels and neuroticism (Van London et al., 1997, 1998b).
Interestingly, in melancholic patients, increased vasopressin levels in plasma correlates with a weak 24-h
periodicity of body temperature (Van Londen et al., 2001).
The oxytocin plasma levels of depressed patients only
show a trend toward higher levels in this study. In another
study Van Londen et al. (1998a) report that patients with
higher vasopressin plasma levels perform better in a
number of memory tests.
Inder et al. (1997) have found that increased vasopressin levels are associated with suicide attempts.
Adolescents who are at risk of making suicide attempts
appear to display significant elevations of cortisol prior
to sleep onset, a time when the HPA axis is normally
most quiescent (Mathew et al., 2003). Patients displaying
clearly increased activity of the HPA axis in midafternoon
have elevated vasopressin levels, as do patients who
attempt suicide. Since patients who recently attempted
suicide also have increased urinary cortisol excretion (Van
Heeringen et al., 2000), various data seem to support
the possible synergistic effects of vasopressin and CRH,
both on the level of the pituitary when released in the
portal system and on a behavioral level when released
centrally (Inder et al., 1997). Also, De Winter et al. (2003)
have found that patients with anxious-retarded depression
have a significantly elevated vasopressin level and a
high correlation between vasopressin and cortisol levels.
On the other hand, a recent study did not confirm
the increased plasma levels in depression and suicide
attempts (Brunner et al., 2002), making vasopressin levels
as a marker for suicide of questionable value at this
moment.
The possibility that chronically elevated vasopressin
levels may be involved in the induction of depressive
symptomatology is supported by the case of a 47-year-old
man with an esthesioneuroblastoma with paraneoplastic
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secretion of vasopressin that was associated with the onset

of a first episode of major depression. The man displayed
chronically elevated plasma vasopressin levels due to
paraneoplastic vasopressin secretion by the tumor.
Depressive symptoms improved markedly after surgical
resection of the tumor and subsequent normalization of
plasma vasopressin levels. However, surprisingly, the
chronically elevated vasopressin levels also led to a
marked desensitization of the HPA axis (Mller et al.,
2000b).
Heuser et al. (1998) have not observed a changed CSF
vasopressin level in depressed patients, nor did they see
a change in those levels due to antidepressant therapy. It
is not clear how the lower CSF vasopressin levels reported
earlier in depression (Gjerris et al., 1985) fit into these
observations. The idea that activation of both the CRH
and vasopressin neurons is related to the symptoms of
depression is reinforced by the observation of De Bellis
et al. (1993), who found a significant decrease in
CSF levels, not only of CRH, but also of vasopressin
levels, accompanied by a decrease in the Hamilton
Depression Scale ratings following fluoxetine treatment.
The therapeutic effects of this selective 5-HT reuptake
inhibitor may thus be related to diminution of these two
arousal-promoting neuropeptides.
Animal experiments have indicated that not only
vasopressin, but also oxytocin may potentiate the effects
of CRH (Yates and Maran, 1974; Gillies and Lowry,
1979; Carlson et al., 1982; Gillies et al., 1982; Vale
et al., 1983a; Muir and Pfister, 1988; Makara, 1992).
However, in later experiments an inhibitory effect of
oxytocin on ACTH release was established and later
confirmed in various species (Legros, 2001). Oxytocin
thus seems to act as an antistress hormone in human
(Carter, 1998). In the rat, oxytocin neurons that coexpress
CRH are present in the PVN (Sawchenko et al., 1984;
Pretel and Piekut, 1990), but in the human PVN this
coexistence has not been studied. Such a coexistence may
be of particular importance, since in the rat stress
increases oxytocin release in the hypothalamic PVN
(Nishioka et al., 1998), and animal experiments have
implicated oxytocin as a possible central mediator of
CRH-induced anorexias (Olson et al., 1991a, b). Even
though Van Londen et al. (1997) have found only a trend
toward higher peripheral plasma levels in these patients,
our finding that oxytocin neurons in the PVN of depressed
patients seem to be activated may be of relevance for its
central effects (Purba et al., 1996), since the oxytocin
cells of the PVN are putative satiety neurons of the brain
261
(Swaab et al., 1995a; cf. section 8.3), Centrally acting,

increased vasopressin and oxytocin cell activity might
thus contribute to mood changes, suicide, decreased food
intake and cognitive alterations.
However, as a possible confounder in the studies on
changes in oxytocin in depression, one should keep in
mind that selective 5-HT reuptake inhibitors produce
increased oxytocin plasma levels (Uvns-Moberg et al.,
1999).
(f) Biological rhythms in mood disorders
Rhythm and Blues. Healy, 1987.
The theory that chronobiological mechanisms play a role

in the pathogenetic mechanism of depression is based on
the classic diurnal variation of depressive state, early
morning awakening and seasonal modulation of onset. In
addition, this theory is supported by the antidepressant
and occasionally mania-inducing effects of manipulations
of the sleepwake cycle and exposure to light. Several
other observations point to a relationship between sleep
disturbances and depression. Delayed sleep phase
syndrome, a disorder that reflects probably an abnormality
in the entrainment of the sleepwake cycle is often associated with major depression (Regestein and Monk, 1995).
Some authors therefore even seek the primary cause of
depression in an abnormal functioning of the circadian
pacemaker (Van den Hoofdakker, 1994). Interestingly,
one of the characteristics of jet lag is exhaustion with
mild depression, pointing again to a strong link between
affecting disorders and circadian rhythms (Katz et al.,
2001). The finding that melatonin may improve not only
sleep, but also mood (De Vries and Peeters, 1997; JeanLouis et al., 1998; Lewy et al., 1998a; Bellipanni et al.,
2001) supports the idea of involvement of the circadian
system.
In a normal population, strong seasonal effects in mood
are observed. Depression scores are highest in winter and
lowest in summer. Hostility, anger, irritability and anxiety
also show strong seasonal effects. Seasonal fluctuations
in depression scores differ for males and females
(Harmatz et al., 2000). In Norway, admission for depression has a significant monthly variation, with the highest
peak in November for men and in April for women
(Morken et al., 2002). The sex differences in such rhythms
may be related to the sex differences in sex hormone
receptors in the SCN (Fernndez-Guasti et al., 2000;
Kruijver and Swaab, 2002). However, higher rates of
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onset of major depression in spring or fall, higher rates

of depressive symptoms or rates of atypical depression,
or higher rates of suicidal ideation in spring were not
observed in an outpatient psychiatric practice in the USA
(Posternak and Zimmerman, 2002). The mixed support
for seasonal changes in depression (and also in suicidal
symptoms) may be due, at least partly, to the months of
birth, as a confounding factor, as shown by a study
of participants currently living in Australia, some of
whom were born in the northern hemisphere. Those born
in SeptemberNovember in the southern hemisphere
showed the highest suicidal and depressive symptoms
than those born in the northern hemisphere in March
May. Season of birth may thus be a risk factor for
depressive and suicidal symptoms (Joiner et al., 2002).
The classic melancholic symptom of diurnal variation
of mood is not specific for endogenous depression, but is
also found, for example, in reactive depression or SAD.
However, the type of diurnal variation (i.e. morning low,
evening low, indifferent pattern) can change from day to
day in a given patient. Sleep can vary with mood state.
Decreased sleep duration predicts that the next mornings
mood will be manic or hypomanic in patients with rapidcycling bipolar disorder (Leibenluft et al., 1996). Diurnal
variations are also present in suicide occurrence. Apart
from biological factors, sociorelational factors are
presumed to contribute to the diurnal suicide risk by age
and gender (Preti and Miotto, 2001). A fairly constant
finding that demonstrates a disturbance of circadian
rhythms in depression is a decrease in circadian amplitude
of body temperature, plasma cortisol, plasma corticosterone, noradrenaline, thyrotropin (TSH) and melatonin
(Soutre et al., 1989; Van den Hoofdakker, 1994; Weber
et al., 2000a; Pacchierotti et al., 2001; Van Londen et al.,
2001). Changes of the circadian timing system are agedependent. Evening cortisol dysregulation has been found
more frequently in child and adolescent major depression
patients who exhibit suicidal behavior and sleep dysregulation (Pfeffer et al., 1989; Dahl et al., 1991).
Increased vasopressin plasma levels in depressed patients
are correlated with a weak 24-h periodicity of body
temperature (Van Londen et al., 2001). Comparison of
multiple circadian rhythms during depression and after
recovery have suggested that a blunted amplitude is the
main chronobiological abnormality (Wirz-Justice, 1995).
This may be due to the increased cortisol levels, which
inhibit SCN function (Liu et al., 2003, submitted; Figs.
26.426.7). Depressed patients display sleep disturbances
(Rieman et al., 1994) and a less rhythmic, more chaotic
pattern of cortisol release (Madjirova et al., 1995; Yehuda

et al., 1996). Not only are the ACTH and cortisol levels
found to be higher in depressed patients, but also the
frequency of pulses of these hormones is higher during
the evening. It has been hypothesized that these changes
are due to circadian alterations, possibly caused by
changes in mineralocorticoid receptor capacity and function (Deuschle et al., 1997a, b). Altered diurnal rhythms
in salivary cortisol and DHEA have also been observed
in 8- to 16-year olds with major depression (Goodyer
et al., 1996). Cortisol secretion patterns were found to be
normal in adolescents with major depression, with the
exception of elevated cortisol levels around sleep onset
(Dahl et al., 1991). Significant seasonal and circadian
rhythms have, moreover, been described in the occurrence
of (violent) suicide. It is presumed that the yearly rhythms
in ambient temperature or light, and the light/dark
cycle can serve as Zeitgeber for the endogenous rhythms
(Maes et al., 1993a, c; Altamura et al., 1999). Interestingly,
subjects that have strong seasonal fluctuations in mood
also have stronger weekly mood cycles (Reid et al.,
2000), indicating a possible function of the SCN in such
rhythms, too.
Some forms of affective illness have a pattern of
periodic recurrence, linked to, e.g. hormonal cycles,
characteristic sleep disturbances or diurnal or circannual
mood fluctuations. The prevalence rate for seasonal
affective disorder (SAD) is some 10% of the depressed
patients, with higher rates for the more northerly countries
and lower rates for the southerly ones (Wicki et al., 1992).
Two types of seasonal mood changes have been described
in temperate zones, i.e. (1) depression regularly occurring
in fall and winter, and (2) depressive episodes in the
summer (Neumeister et al., 1997). In the tropics a
different pattern of seasonal mood changes is observed,
with a high prevalence of summer SAD and a low
prevalence of winter SAD. Almost half of the tropical
population feels worse in summer, probably in
response to temperature but not duration of daylight
(Sriseerapanont and Intraprosert, 1999). On the mainland
of China, several variations in mood are common. Also
in this country, summer difficulties are more common
than winter difficulties, according to a survey of Chinese
medical students (Han et al., 2000). In various countries,
seasonal fluctuations in suicide rates have been described
(Maes et al., 1993a, c; Castrogiovanni et al., 1998;
Altamura et al., 1999), but in England and Wales this
pattern seems to have diminished or even vanished,
presumably because of changes in lifestyle (Yip et al.,
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Fig. 26.7. The number of arginine vasopressin-immunoreactive (AVP-IR) neurons (A) and the mask area of silver grains of the AVP mRNA (B)
in the suprachiasmatic nucleus (SCN) in control subjects (n = 11) and depressed subjects (n = 11). The error bars indicate the SD. Note the change
in the balance between the presence of more AVP and less AVP mRNA in depression. There is probably a disorder of the transport of AVP that
leads to accumulation of the peptide, in spite of the decreased production rate. (From Zhou et al., 2001, Fig. 2, with permission.)
occurred more frequently after eastbound flights (WirzJustice, 1995), also suggests a relationship between
circadian phase changes and mood changes. One may
presume that a basis for such changes might be found
in the effect of corticosteroids on circadian timing
(Madjivora et al., 1995). We have indeed observed an
inhibitory effect of corticosteroids on vasopressin mRNA
in the SCN (Liu et al., 2003, offered; Figs. 26.426.6).
The sensitivity of the biological clock to the phaseshifting action of light is the same in depressive patients
and controls. In contrast to sleep deprivation, moderate
shifts of circadian rhythm do not act as mood-changing
stimuli. This does not argue for an important role of
circadian phase disturbances underlying depressive mood
(Gordijn et al., 1998). In addition, in a 120-h forced
desynchrony protocol, no significant differences are
observed between SAD patients and controls in the period
length or in the timing of the endogenous circadian
temperature minimum. This study supports neither
the proposed disorder of the pacemaker in SAD nor the
psychological or physiological variables investigated
(Koorengevel et al., 2003). Alternatively it has been
proposed that the mood disturbances should be seen as
resulting from changes in the phasing of external
2000). An important distinction in this respect is that

seasonality is found to be present in violent but not in
nonviolent suicides. The violent suicides peak in spring
and summer, whereas the lows occur in winter (Maes
et al., 1993b). Also, in southeastern Australia, a clear
seasonal pattern is found that is positively linked with
prevailing levels of sunlight. The incidence of suicide has
a zenith in the spring and summer, and a nadir in winter
(Lambert et al., 2003).
There is also seasonal variation in manic episodes in
bipolar disorder. The frequency of such episodes peaks
in early spring, with a nadir in late fall. Mixed manic
admissions peak in late summer and have a nadir in
November (Cassidy and Carroll, 2002).
Various mechanisms are proposed to be the basis of
SADs. Whether periodically recurring depressions are
indeed based upon primary disturbances in the SCN (see
Chapter 4) is unresolved (for a review, see Wirz-Justice,
1995). For the pathophysiology of SAD, disturbances in
SCN function such as a phase delay, amplitude change
and poor entrainment have been suggested (Oren et al.,
1996; Teicher et al., 1997). The observation that incidence
of hospitalization for depression is higher after westbound
flights than after eastbound ones, whereas hypomania
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Zeitgebers rather than of an abnormality of the clock itself

(Healy and Waterhouse, 1995). Wehr et al. (2001) have
reported the presence of a signal of change of season
in patients with SAD. In patients with SAD the duration
of the nocturnal period of active melatonin secretion
is longer in winter than in summer, but in healthy volunteers there is no change. The data shows that patients
with SAD generate a biological signal of change of season
that is absent in healthy volunteers and that is similar
to the signal that mammals use to regulate seasonal
changes in their behavior. An interesting observation is
that the serotonin metabolites in the jugular vein are
lowest in winter, and that the turnover of serotonin in
the brain rises with increased luminosity (Lambert
et al., 2002), suggesting that the SCN may act via the
serotonergic system on seasonal mood changes. The
observation, in Japan, that suicide rates are affected
by latitude, i.e. that total yearly sunshine is related to
suicide rate (Terao et al., 2002), may be based upon a
similar mechanism.
There are at present 3 lines of research that support
the role of genetic factors in the etiology of SAD: (i)
familiality: there is a tendency for seasonal changes in
mood and behavior to run in families; especially seasonality of the winter type shows such a predisposition
(Madden et al., 1996); (ii) heriditability, based upon twin
studies that indicate that genetic factors explain about
29% of the variance in seasonality; and (iii) molecular
genetics, showing that a 5-HT transporter promoter
polymorphism is associated with SAD and with higher
levels of seasonality (Sher et al., 1999). Neither the latter
nor other 5-HT-related systems appear, however, in a later
study to play a major role in the pathogenesis of seasonal
affective disorder (Johansson et al., 2001). A recent paper
indicates, however, the importance of a polymorphism in
the clock gene NPAS2 for the occurrence of SAD
(Johansson et al., 2003). Although a major hypothesis is
that SAD is triggered by photoperiod variation, recent
observations indicate that the influence of latitude on the
prevalence of SAD is small, and that other factors such
as climate, genetic vulnerability and sociocultural context
can be expected to play a more important role (Mersch
et al., 1999). There is probably no seasonal variation in
the occurrence of bipolar disorder (Partonen and
Lnnqvist, 1996).
Recent observations from our group suggest that in
major depressed patients normal diurnal rhythm in the
number of vasopressin neurons in the SCN has disappeared (Fig. 26.8), the number of neurons expressing
vasopressin has increased and the amount of vasopressin

mRNA has decreased (Fig. 26.7). This indicates a
decreased synthetic and transport activity of the vasopressin neurons of the SCN (Zhou et al., 2001). Since
vasopressin neurons from the rat SCN were shown to
inhibit CRH neurons in the PVN (Kalsbeek et al., 1992;
Gomez et al., 1997), the observed disorder of this class
of SCN neurons in depression may contribute to the
increased activity of CRH neurons in depression (see
above). The number of neurons staining in the SCN for
nitric oxide synthesis or neurophysin are also decreased
in depressed patients (Bernstein et al., 2002a), indicating
impairment of the SCN in this disorder. In addition we
observed a decreased nuclear size of vasoactive intestinal
polypeptide (VIP) neurons in the SCN of depressed
patients, indicating a changed metabolism in the neurons
that are primarily involved in entrainment (J.N. Zhou,
unpubl. results). The old observations that CSF VIP levels
are decreased in depression (Gjerris et al., 1984) fit in
with the idea that the SCN is less active in this disorder,
although certainly not all VIP in the CSF will come from
the SCN.
Also pineal gland function is changed in depressed
children and adolescents according to some studies, but
this point is at present controversial (see Chapter 4.5e).
Several studies have shown that evening/nocturnal
levels of melatonin are decreased in depression, SAD
and unipolar depression (Fountoulakis et al., 2001;
Pacchierotti et al., 2001). Abnormalities in melatonin
secretion have been found in a subgroup of euthymic
bipolar and unipolar patients (Nurnberger et al., 2000),
and in postmenopausal women with a family history of
depression (Tuunainen et al., 2002). However, some
studies show an increase in melatonin levels (Shafii
et al., 1996) or excretion (Kripke et al., 2003). After
lights-out the melatonin blood levels rise more in
depressed patients than in controls. Moreover, the rise
was stronger in depressed patients with psychosis (Brown,
1996). In addition, higher melatonin levels have been
reported to occur during the manic phase in patients with
a bipolar depression (Penev and Zee, 1997). However,
the majority of studies show a decrease in nocturnal serum
or urine melatonin levels or a phase shift in the melatonin
peak in depressed adults (Brown, 1996). This would fit
with the observation that CRH increases in at least some
depressed patients (see above) and inhibits melatonin
levels (Kellner et al., 1997). A few other studies, however,
show no difference in melatonin levels and rhythms
(Penev and Zee, 1997; Voderholzer et al., 1997). Normal
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(g) Light therapy and the circadian system

These studies provide the best evidence to date that light
is an effective antidepressant in SAD. Dr. Wirtz-Justice
said she hopes the studies will help overcome lingering
scepticism by those physicians who regard light therapy as
not molecular enough, a bit too Californian-alternative, a
bit too media-overexposed, merely a placebo response by
mildly neurotic middle-aged women who dont like nasty
drugs. Light therapy, she notes, is an outpatient treatment,
lacks major adverse effects, and is cost-effective. Whatever
its mode of action, she asserts, it demands inclusion in
the antidepressant armamentarium, now.
Anna Wirtz-Justice. Arch Ge. Psychiatry,
October 1998, Commentary
A state-dependent disorder of circadian rhythmicity characterizes acute episodes of major depression, as appears,
e.g. from hormone measurements and sleep detection
(Linkowski et al., 1987). A strong argument for a close
relationship between the pathogenetic mechanism of
depression and the circadian timing system is the effectiveness of light therapy in SAD (Wirz-Justice, 1995;
Wileman et al., 2001), in pharmacological treatmentresistant, rapid cycling affective disorders (Kusumi et al.
1995) and in patients with nonseasonal affective disorders
(Yamada et al., 1995; Prasko et al., 2002). According to
some authors, the effect of bright-light therapy on winter
depression takes at least 3 weeks before it becomes
apparent (Eastman et al., 1998) but would already act
after 1 week according to others (Prasko et al., 2002;
W.J.G. Hoogendijk, personal communication). After
treatment with light, a significantly greater improvement
is reported in patients with seasonal depression than in
patients with a nonseasonal pattern of depression.
However, another study has reported similar effects of
light treatment in seasonal and nonseasonal depression
and the effects are faster than psychopharmacological
treatment (Kripke, 1998). The latter finding has been
confirmed by Prasko et al., 2002. Physical exercise is
effective in alleviating depressive symptoms, but is
much more effective when combined with bright light
(Leppmk et al., 2002). Depressed patients treated with
morning bright light do not show significant differences
from those treated with evening bright light in one study
(Thaln et al., 1997), or between bright white light at
10,000 lx and dim-red light at 500 lx. For both groups of
patients, symptoms reduced by more than 40% during the
4 weeks of the trial. In another study in patients with
SAD, bright-light exposure immediately on awakening
was found to be more effective (Lewy et al., 1998b).
Fig. 26.8. A. Number of vasopressin-immunoreactive (AVP-IR)

neurons plotted against clock time at death of each individual (11
depressed subjects, and 11 control subjects). B. Area of masked silver
grain plotted against clock time of death of each individual. The
difference between depressed and control subjects is present at different
points of the day and there is no overlap between the two groups when
you take the clock time at death into account (From Zhou et al., 2001,
Fig. 3, with permission.).
circadian profiles have been measured for cortisol, TSH

and prolactin in patients with SADs (Oren et al., 1996;
Lewy et al., 1998b), observations that should be extended
in large, well-controlled studies. Administration of melatonin to depressed patients and to perimenopausal and
menopausal women has reduced insomnia and improved
mood (De Vries and Peeters, 1997; Bellipanni et al.,
2001).
In normal human controls, hypothalamus daynight
fluctuations in 5-HT are present (Carlson et al., 1980a).
It has so far not been elucidated whether these circadian
changes are altered in depressed patients, and what the
relationship to the changes in HPA axis activity may be.
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Terman et al. (2001) have found that the antidepressant

effect of light therapy is potentiated by early morning
administration, best done 8.5 h after melatonin onset or
2.5 h after the sleep midpoint. A positive total sleep deprivation response in major depressed patients can be
predictive of beneficial outcome of subsequent light
therapy (Fritzsche et al., 2001). An abnormal architecture of non-REM sleep seems to be a state marker of
those patients who benefit from bright-light treatment
(Palchikov et al., 1997). In addition, the occurrence of at
least two consecutive, seasonally recurring major depressive periods has been found to predict improvement with
light (Dittmann et al., 1994). A limitation of studies with
light is the question of what the right placebo is. Red
light, as used in various light-therapy studies (Prasko et
al., 2002) might not be an ideal placebo (Wileman et al.,
2001). Surprisingly, exposure to infrared light is as effective as exposure to bright white light, which questions
the specific role of visible light in the treatment of SAD
(Meesters et al., 1999).
Dawn simulation with gradually increasing bedside
light in the morning has also given promising results.
Although the effects on mood are less marked than lightbox treatment, they are equally persistent (Lingjaerde
et al., 1998). Another study has even reported that dawn
stimulation is associated with greater remission and
response rates compared with placebo and compared with
bright-light therapy (Avery et al., 2001).
All these observations reinforce the theory that chronobiological mechanisms play a role in the pathogenetic
mechanism of depression. Moreover, a placebo-controlled
study has shown that bright-light treatment decreases
depression in institutionalized older people (Sumaya
et al., 2001). Another study of healthy office employees
during winter has shown that repeated bright-light exposure improves vitality and reduces depressive symptoms.
The beneficial effect is observed not only in healthy
subjects with season-dependent symptoms, but also in
those not experiencing the seasonal variation (Partonen
and Lnnqvist, 2000). Bright-light exposure during winter
appears thus to be effective also when it comes to
improving the health-related quality of life and alleviating
distress in healthy subjects (Partonen and Lnnqvist,
2000). Extraocular light therapy in SAD patients does not
exceed its placebo effect (Koorengevel et al., 2001).
The mechanisms involved in bright-light treatment are
still under investigation. Data from our group indicate a
decreased synthesis and transport of vasopressin in the
SCN of depressed patients (Zhou et al., 2001; Figs. 26.7
and 26.8). Since vasopressin neurons of the SCN inhibit

CRH production in the PVN (Kalsbeek et al., 1992;
Gomez et al., 1997), this may contribute to the activation
of CRH neurons in depression. Light therapy may stimulate the SCN neurons and thus restore the inhibition of
the CRH neurons (Fig. 26.6). Measurements of light
exposure have shown that complaints of seasonal mood
variations are not caused by a differential pattern in brightlight exposure compared with normal exposure. Whether
an increased vulnerability of patients with SAD is due to
a more fragile affective state or to a lower sensitivity to
light remains to be determined (Guillemette et al., 1998).
Light visions can effectively be used to prevent the development of SAD. Since rapid tryptophan depletion reverses
the antidepressant effect of bright-light therapy in patients
with SAD, the therapeutic effects of bright-light might
involve a serotonergic mechanism (Lam et al., 1996b;
Neumeister et al., 1997). Measurements of 5-HT metabolites in the jugular vein show that this is indeed the case.
The production of 5-HT in the brain rises rapidly with
increased luminosity (Lambert et al., 2002). Other data
indicate that additional effects may also be involved (Fig.
26.6), such as responses of sleep-regulating, circadian,
energy-regulating and sympathicoadrenal systems that
may be responsible for at least part of the favorable
therapeutic response to bright light (Putilov, 1998).
Exposure to bright light during the early hours of darkness not only delays the nocturnal melatonin peak, but
also decreases cortisol concentrations and changes in
growth hormone, prolactin and nocturnal vasopressin
secretion (Kostoglou-Athanassiou et al., 1998a). Light
therapy also reduces the urinary output of norepinephrine
and its metabolites in autumn/winter seasonal depression
(Anderson et al., 1992b). Some authors do not consider
light to be antidepressant per se, but rather a way to
reverse the phase delay that occurs in the winter (Lewy
and Sack, 1996). Circulating nocturnal bilirubin levels
are lower in patients with winter seasonal depression.
Since bilirubin may serve as a photoreceptor, this
molecule, too, may be involved in the mechanism of light
therapy (Oren et al., 2002a).
A specific example of the importance of circannual
rhythms in a disease process and the effectiveness of light
is present in the symptoms of bulimia nervosa (see also
Chapter 23.2; Fig. 23.12). Not only binge and purge
behavior vary with the season, but also mood is worse
in the winter period (Blouin et al., 1992). Bright-light
treatment appears to be effective for both eating behavior
and mood in this disorder (Lam et al., 1994). In addition,
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in a case report, bright-light therapy is reported to be

comparable with or superior to treatment with previous
medications for depression in a patient with schizoaffective disorder with recurring depressive episodes in
winter (Oren et al., 2001).
As with all effective therapies, light therapy may also
have side effects, although these are rare. There may
be risks for the eyes when light exposure lasts for an
extended period of time (Rem et al., 1996), and mania
and suicide have also been described as possible consequences of this therapy (Kripke, 1998; Meesters and
Letsch, 1998). Short-term, 10,000-lx light therapy often
produces mild side effects such as headaches or vision
problems, but they are neither serious nor prolonged and
generally do not interfere with the treatment (Kogan
et al., 1998). There is increased risk in light damage to
the lens and retina if depressed patients are treated with
bright light concurrently with treatment with antidepressant or neuroleptic drugs. Certain drugs, such as iprindol
and chlorpromazine, which have absorptions longer than
295 nm, can, moreover, act as photosensitizers, resulting
in enhanced damage to the eye (Wang et al., 1992).
267
people with sleepwake disturbances (Jean-Louis et al.,

1998) and significantly decreases depression ratings in a
patient with insomnia (De Vries and Peeters, 1997) and
in a small group of patients with winter depression (Lewy
et al., 1998a), supporting the presence of a causal link
between circadian rhythm and mood disorders. On the
other hand, slow-release melatonin improves the sleep
quality in major depressive disorder, but has no effect on
the rate of improvement in symptoms of depression,
although it is effective in improving sleep (Dolberg
et al., 1998). Controlled-release melatonin also significantly improves the quality of sleep and vitality in subjects
with subsyndromal seasonal affective disorder, but attenuates improvement in subjects with weather-associated
changes in mood and behavior (Leppmki et al., 2003).
Although electroconvulsive therapy (ECT) causes a rise
in plasma vasopressin, oxytocin, prolactin and neuropeptide FF levels, these surges are not associated with
clinical improvements, seizure duration, time to orientation or memory test performance. This does not support
the hypothesis that vasopressin or oxytocin surges
contribute to the mechanism of action of ECT (Devanand
et al., 1998; Sundblom et al., 1999). In fact, on the basis
of our finding of increased vasopressin and oxytocin
production in depression (Purba et al., 1996), one may
even expect the reverse to be the case. A recently reported,
effective nonpharmacological antidepressant therapy is
high-density negative air ionization. The effective
range, optimum dose and mechanism of action remains
uncertain as of 2002 (Terman et al., 1998). Repetitive
transcranial magnetic stimulation (rTMS) of the left
dorsolateral prefrontal cortex has also been found to be
useful in the treatment of medication resistant depression
(George et al., 1996, 2000; McCann et al., 1998; Davidson
et al., 1999; Berman et al., 2000; Eschweiler et al., 2000),
although some double-blind controlled stimulation studies
have not found a difference between real and sham rTMS
(Loo et al., 1999). A meta-analysis of controlled studies
indicates, however, that the anti-depressant effects of
rTMS are fairly robust from a statistical point of view.
However, effect sizes are heterogenous and the durability
of the effects is largely unknown (Burt et al., 2002).
Interestingly, in in vivo experiments in rat, using microdialysis, rTMS of the frontal brain reduces the vasopressin
release in the PVN area by up to 50% (Keck et al., 2000).
In healthy subjects rTMS leads to a mild decrease in
serum cortisol and TSH levels. These changes may
explain at least part of the effect of rTMS (Evers et al.,
2001). However, a combined dexamethasoneCRH test
For the rest of my life I will reflect on what light is.

Albert Einstein, 1917.
(h) Other therapeutic interventions

Antidepressant drugs may act on the HPA axis (Fig. 26.6),
but they may also involve the circadian timing system.
It has been suggested that antidepressant drugs may shift
the circadian period, but the evidence is not consistent
(Healy and Waterhouse, 1995). In addition, carbachol may
mimic the effect of light (Healy and Waterhouse, 1995),
and lithium seems to act on the SCN (Mason and Biello,
1992), which supports the possible involvement of this
brain structure in depression. It has also been shown that
lithium induces subsensitivity to light (Carney et al.,
1988), reinforcing the idea that the mechanism of action
is via the circadian system. Although it has been suggested
that oxytocin release by selective serotonin reuptake
inhibitors may be an important contributing factor for the
clinical profile of such antidepressants (Uvns-Moberg
et al., 1999), one might, on the one hand, expect an
opposite effect on eating disorders on the basis of our
findings of increased oxytocin activity in depression
(Purba et al., 1996), but on the other hand, oxytocin
indeed seems to act as an antistress hormone (Legros,
2001). Melatonin treatment improves mood in elderly
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after rTMS has shown a persistent HPA-system hyperactivity, and thus a high risk of relapse. This argues for
immediate maintenance therapy in the patients responding
to this treatment (Zwanzger et al., 2003).
Following transcutaneous electrical nerve stimulation
(TENS), Alzheimer patients and nondemented elderly
persons feel less depressed (Scherder et al., 1995a, b, c,
2000). Vagus nerve stimulation has been delivered by the
NeuroCybernetic Prothesis system to treatment-resistant
depressed patients. The open trial results suggest that this
new technique had antidepressant effects in these patients
(Rush et al., 2000). Randomized controlled studies are
now needed. A recent paper has reported that electrical
stimulation of the subthalamic nucleus in Parkinson
patients is antidepressive (Schneider et al., 2003).
However, several other studies report depression and
even suicide as side effects of this type of deep-brain
stimulation (Chapter 15.1).
Sleep disorders are common in depression.
Interestingly, patients with abnormal sleep profiles have
significantly poorer clinical outcomes with respect to
symptom ratings, attrition rates and remission rates than
the patients with normal sleep profiles (Thase et al., 1997).
Sleep deprivation in depressed patients improves mood
for 1 day, which clearly demonstrates that the interaction
between sleep and mood is not an epiphenomenon but
that changes in sleep pattern have pathogenic significance
(Wirz-Justice, 1995). In addition, a positive total sleep
deprivation response in major depressed patients may
predict a beneficial outcome of subsequent light therapy
(Fritzsche et al., 2001). Sleep deprivation is accompanied
by a fall in testosterone levels and an increase in
TSH levels. The latter change is significantly correlated
to the clinical response (Baumgartner et al., 1990a, b).
The curative effect of sleep deprivation is due to changes
in the circadian rhythm (Madjirova et al., 1995). Also,
in healthy young subjects, subjective mood is influenced
by a complex and nonadditive interaction of circadian
phase and duration of prior wakefulness. The nature of
this interaction is such that moderate changes in the timing
of the sleepwake cycle may have profound effects
on subsequent mood (Boivin et al., 1997). A similar
relationship appears also from the observation that exogenous shifts in timing of the sleepwake cycle in healthy
subjects may induce dysphoric mood.
Placebo effects are extremely important in the treatment
of depression. It has been proposed that 5075% of
the efficacy of antidepressant medication represents the
placebo effect. Changes in brain function as measured
by PET or quantitative EEG indicate that placebo

effects partly overlap with the effects of an antidepressant
medicine. For instance, an increased metabolism is
observed in both treatments in the prefrontal cortex, and
a decreased metabolism in the hypothalamus. However,
differences between the reaction of the various brain areas
are also observed (Leuchter et al., 2002; Mayberg et al.,
2002).
(i) The thyroid axis
At present there are several lines of evidence that suggest
that the hypothalamopituitarythyroid (HPT) axis
may play an important role in depression. First, early
investigations have already shown a markedly depressed
mood in a majority of patients with primary hypothyroidism and other thyroid diseases (Asher, 1949;
Henley and Koehnle, 1997). The diffuse atrophy of the
thyroid gland in anorexia nervosa is presumed to be
involved in the depressive symptomatology in that
disorder (Stving et al., 2001). In addition, in patients
with hypothyroidism, partial substitution of triiodothyronine (T3) may improve mood and neuropsychological
function (Bunevicius et al., 1999). Moreover, subtle
changes in the HPT axis have been described in depressed
patients. The most consistent observation in depression
is a slightly elevated plasma concentration of thyroxine
(T4) and decreased plasma TSH, with a blunted response
to stimulation with thyrotropin-releasing hormone (TRH).
Basal TSH and thyrotoxin levels correlate with the
severity of the depression, but the hyperthyroxinemia is
at present unexplained (Gold et al., 1981; Holsboer et al.,
1986; Styra et al., 1991; Maes et al., 1993b; Jackson,
1998; Kirkegaard and Faber, 1998). However, others have
reported that at least the large majority of depressive
patients are euthyroid (Lingjaerde et al., 1995), or that
there is no association between thyroid dysfunction and
depression (Engum et al., 2002). Yet, in postmortem
tissue of patients with unipolar major depression, we
found a decreased amount of TRH mRNA in the PVN
(Alkemade et al., 2003), which may be due to the higher
levels of circulating corticosteroids.
In addition to elevated CSF levels of TRH (which may
reflect extrahypothalamic sources and was not confirmed
in a later study; Roy et al., 1994), an abnormally high
rate of thyroid peroxidase antibodies, a condition known
as symptomless autoimmune thyroiditis, has been
observed (Roy et al., 1994; Musselman and Nemeroff,
1996; Pop et al., 1998). A community-based study has
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pointed to thyroid peroxidase antibodies as a determinant

of depression rather than biochemical thyroid dysfunction
(Pop et al., 1998). Evidence of T-cell dysfunction in SAD
patients supports the hypothesis that SAD may involve
subtle autoimmune dysregulation (Raitiere, 1992).
In pre-pubertal and early pubertal boys with major
depression (in contrast to adult depressive patients; see
below), lower T4 levels and lower T3 uptake were found
(Dorn et al., 1997b). Especially in rapid cycling bipolar
disorder, a high proportion of patients with thyroid
hypofunction were reported (Cowdry et al., 1983; Bauer
et al., 1990). Although other studies could not confirm
the commonly cited relationship between subclinical
hypothyroidism and rapid cycling bipolar illness (Post
et al., 1997; Cole et al., 2002b), they have provided further
evidence that patients with bipolar disorder are particularly sensitive to variation in thyroid hormone function
within the normal range. Subjects with lower thyroid
function have longer times to remission. In a group
of patients with major depression or bipolar disorder,
peripheral TSH levels are found to be inversely related
to global and regional cerebral blood flow and cerebral
glucose metabolism (Marangell et al., 1997a). It seems
as if only a particular subgroup of depressed patients may
have changes in the HPT axis.
A low TSH response to TRH in the presence of normal
serum thyroid hormone levels is observed in SAD (Coiro
et al., 1994). This reflects a defect in the central regulation
of the HPT axis that may, in some patients, be a trait
marker (Loosen and Prange, 1982). A circannual pattern
of both HPT function and mood are observed in antarctic
conditions. These observations indicate that in winter
depression a state of relative central nervous system
hypothyroidism is present (Palinkas et al., 2001). In a
recent study of 105 subjects with major depression, the
low or blunted TSH response to TRH challenges was
present, but it was not an impressive discriminator
between depressed and control subjects (Sullivan et al.,
1997). Daily fluctuations of T4 are the only variables
significantly different between depressed and control
subjects, and a significant relationship has been observed
between this parameter and treatment outcome (Sullivan
et al., 1997). In untreated depression the diurnal variation
in serum TSH is attenuated (Kirkegaard and Faber, 1998).
These data point again to the SCN as a crucial structure
in depression and to a relationship between the SCN and
the thyroid axis in the pathogenesis of depression.
In connection with the possible involvement of the
TRH neurons in depression, it should be noted that TRH
269
is not only released into the portal capillaries to regulate

the neuroendocrine HPT axis, but also TRH fibers project
into the brain and terminate in many hypothalamic and
extrahypothalamic areas, where TRH acts as a neurotransmitter or neuromodulator (Fliers et al., 1994; Chapter
8.6). Changes in the function of centrally projecting TRH
fibers are not necessarily reflected in changes in the
peripheral HPT axis. Intravenous TRH administration has
an antidepressive action (for references see Jordan et al.,
1992), although most controlled studies do not confirm
these findings (Marangell et al., 1997b), which may be
due to the short half-life of TRH and the effective
bloodbrain barrier for the peptide. However, a doubleblind crossover study has revealed rapid and clinically
robust improvements in mood and suicidality of
intrathecal TRH given to refractory depressed patients
(Marangell et al., 1997b), confirming the antidepressant
action of TRH, at least in a subgroup of patients.
It has also been reported that T3 or T4 augments
the efficacy of various antidepressants. T3 increases the
rapidity of action of tricyclic antidepressant agents and
is as effective as lithium in converting tricyclic nonresponders to responders (Stein and Avni, 1988; Aronson
et al., 1996; Musselman and Nemeroff, 1996). Support
for the efficacy of adjunctive T3 treatment has been found
in a sample of 14 patients suffering from refractory
depression (Birkenhger et al., 1997). Thyroid hormones
may potentiate antidepressant therapy in about onequarter to two-thirds of the treatment-resistant depressed
patients (Joffe et al., 1995; Henley and Koehnle, 1997;
Jackson, 1998). Patients with the lowest pretreatment
evening TSH secretion also have the lowest rates of
antidepressant response (Duval et al., 1996). How exactly
the change in thyroid-axis function may contribute
to treatment resistance in some depressed patients,
which subgroup of depressed patients may respond to
thyroid hormones, and what the mechanism behind the
relationship to HPA axis changes is, should be further
investigated.
There is growing information to explain the HPT axis
changes in depression and the possible beneficial effects
of T3 medication. The active thyroid hormone in the brain
is T3, which is derived locally from T4 due to the
deiodination by type II 5deiodinase (DII) (Henley and
Koehnle, 1997; Jackson, 1998; Kirkegaard and Faber,
1998). Endocrine observations suggest that CRH and TRH
regulation are at least partly under joint control (Holsboer
et al., 1986). Glucocorticoid excess suppresses TSH. The
demonstration of glucocorticoid receptor expression by
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TRH cells in the rat PVN and the presence of a glucocorticoid response element in the TRH gene suggests that
the inhibitory effect of glucocorticoids on TSH secretion
involves downregulation of TRH cells in the PVN. This
possibility is supported by studies in rats after adrenalectomy, showing increased CRH mRNA and TRH
mRNA in the PVN. After dexamethasone treatment, both
messengers are markedly reduced (see Jackson, 1998).
By inference, hypercortisolism in depression may lead to
suppression of the central component of the HPT axis,
explaining the low plasma concentrations of TSH. An
additional effect of hypercortisolism may be decreased
activity of DII, leading to decreased bioavailability of
T3 in the CNS. This might be the basis for the potential
of T3 as effective comedication in nonresponders to
antidepressants. In this respect the recent study by
(Bunevicius et al., 1999) showing beneficial effects of
replacement of a fraction of T4 by T3 in the treatment
of hypothyroidism on mood and well-being, is of interest.
Organ-specific tissue concentration of T4 and T3 cannot
be restored by T4 alone after thyroidectomy (EscobarMorreale et al., 1995). A possible alternative explanation
is the reduction in transthyretin, a transport protein to T4.
This protein, synthesized by the choroid plexus and
secreted into the CSF, is reduced in depressed patients
(Sullivan et al., 1999). This could also contribute to brain
hypothyroidism in depression. It is also noteworthy that
TRH is under a constant inhibition by 5-HT, while T3
treatment increases the 5-HT levels in the cerebral cortex
of the rat. Both effects may play a part in the pathogenesis and alleviation of depression. Several antidepressants,
including tricyclic antidepressive drugs and lithium,
increase DII activity and in this way may contribute also
to the alleviation of depression. Whether the increased
HPA axis activity, decreased DII or decreased 5-HT
activity are primary in (subgroups of) depressed patients
remains to be elucidated (Jackson, 1998; Kirkegaard and
Faber, 1998). The consequences of decreased thyroid
activity during lithium therapy in major depression
(Bschor et al., 2003) need further study.
With respect to the changes observed in the thyroid
axis in depression it is curious that the TRH lateralization
found in the PVN and VMN of the hypothalamus, with
higher concentrations of TRH in the left side (BorsonChazot et al., 1986), was not observed in a subsequent
study on suicide victims (Jordan et al., 1992). It should
be noted, however, that the controls of the latter study
were the same historical ones as those used for the paper
by Borson-Chazot et al. (1986), so that the original
observation of TRH asymmetry in the PVN of controls

still needs to be confirmed.
(j) Sex hormones, depression, premenstrual syndrome,
antepartum depression and postpartum mood disorder
Unipolar depression and dysthymia are twice as common
in women as in men (Seeman, 1997; Piccinelli and
Wilkinson, 2000), which may point to either an organizing
or an activating effect of sex hormones in the pathogenesis of depression. The observation that adults with a
history of prenatal exposure to DES have an increased
risk for depression argues for an effect of prenatal estrogens in the organization of brain systems that are involved
in affective disorders (Meyer-Bahlburg and Erhardt,
1987). Depression is considered to be more common in
women, specifically during times of changing sex
hormone levels, such as premenstrual, antepartum and
postpartum levels, and during transition to the menopause
(Young and Korszun, 2002). Interestingly, M. Bleuer
suggested, as early as 1919, that hormone treatment could
be a potential antidepressant (Holsboer, 2000). In
untreated depressed female patients significantly higher
plasma concentrations of testosterone, androstenedione
and dehydrostestosterone were found. These findings
are best explained as a consequence of an overstimulation
of the adrenal glands in hypercortisolemic depressed
patients. In contrast to women, depressed men seem to
show decreased testosterone levels. In males, the activation of the HPA axis in depression may negatively affect
gonadal function at every level of regulation (Albert
et al., 1993; Baischer et al., 1995; Schweiger et al., 1999;
Sternbach, 1998; Weber et al., 2000b). In the infundibular
nucleus, juxtapositions of CRH fibers are found, which
form multiple contacts with LHRH neurons. This may be
a substrate of such effects (Duds and Merchenthaler,
2002c). In severely depressed patients, testosterone
levels are lower (Heuser, 2002) and older men with
lower bioavailable testosterone levels are more depressed
(Barrett-Connor et al., 1999b). In addition, low testosterone levels are found in men with dysthymic disorder
(Seidman et al., 2002). Both testosterone level and
androgen receptor polymorphism are related to the risk
middle-aged men run of becoming depressed. Men who
have low total testosterone levels and a shorter CAG
codon repeat length in the androgen receptor have a
greater likelihood of becoming depressed (Seidman et al.,
2001). In connection with the observed decreased sex
hormone levels in depressed men, it is interesting that,
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in body builders who take supraphysiological doses of

testosterone, testosterone levels have a strong negative
correlation with depression scores (Dickerman and
McCobathy, 1997). Studies in anabolic androgenic steroid
users show that some of them develop manic or aggressive reactions to these drugs. Supraphysiological doses
of testosterone indeed increase ratings of manic symptoms
in normal men (Pope et al., 2000). Depression can also
be associated with the use of oral contraceptives,
pregnancy and menopause (Parry and Newton, 2001).
An interaction between sex hormones and the serotonergic system has been proposed (Rubinow et al., 1998),
and we recently found a colocalization of estrogen
receptor- and CRH in the human PVN (Bao et al., 2003,
submitted), but exactly how sex hormones interact with
the mechanisms involved in the pathogenesis of depression should be studied in the future. An interesting new
development in this respect is that neurosteroid levels in
plasma change during depression (Romeo et al., 1998).
The sexual function and mood of hypogonadal men that
receive testosterone replacement improves (Seidman
and Walsh, 1999; Wong et al., 2000). However, there
are not enough controlled studies at present that indicate
that testosterone administration is effective in mood disorders (Sternbach, 1998). In women with depression, the
blood levels of estradiol are significantly lower, which
has been hypothesized to be due to the inhibiting effect
of the HPA axis on the reproductive axis, in a way resembling that observed in stress and CRH administration
(Young et al., 2000). Not only is the estradiol level lower
in depressed women, but also the luteinizing hormone
(LH) pulsatility frequency is slower and dysrhythmic
(Meller et al., 2001). The estrogen decrease in postmenopausal women may be a factor in both the
pathogenesis of late-life depression and in response to
therapy. Estrogen replacement therapy may make women
with Alzheimers disease less vulnerable to depression
(Carlson et al., 2000) and may augment a fluoxetine
response in elderly depressed patients (Schneider et al.,
1997). On the other hand, it should be noted that estrogen
substitution in postmenopausal women with depressive
symptoms is effective in some studies but not in others
(Rubinow et al., 1998; Rasgon et al., 2001). The addition of progestins during sequential hormonal replacement
therapy causes negative mood and physical symptoms,
symptoms that are accentuated by increasing the estrogen
dose (Bjrn et al., 2003).
Premenstrual syndrome or premenstrual dysphoric
disorder is characterized by depression, anxiety and
271
mood swings during the last week of the luteal phase.

Correlations have been reported between the premenstrual
or menstrual phase and violent crimes, death as a result
of accident or suicide, accidents, admission to hospital
with psychiatric problems, taking a child to a medical
clinic, and loss of control of aircraft and plane crashes
in which the women pilots were said to be menstruating
at the time of the crash (Parlee, 1973). A polymorphism
in the 5-HT transporter promotor gene region may be a
vulnerability factor for this disorder (Praschak-Rieder et
al., 2002). Premenstrual dysphoric syndrome is characterized by disturbances in the timing and secretion
patterns of circadian rhythms and their response to
critically timed light administration, and interventions
with bright light improve mood in these patients (Parry
and Newton, 2001). Although there is at present no
conclusive evidence that premenstrual dysphoric disorder
is indeed associated with abnormalities in the levels of
sex hormones, both suppression of ovarian function by
LHRH agonists or surgical oophorectomy are effective
treatments for this type of mood disorder (Steiner, 1996;
Rubinow et al., 1998). The observation that no differences are present in plasma levels of ACTH, -endorphin,
cortisol or free testosterone does not support a primary
endocrine abnormality in women with premenstrual
syndrome (Bloch et al., 1998). Timing rather than
quantitative measures of cortisol secretion are different
in premenstrual dysphoric subjects, both during the
menstrual cycle and in response to sleep-deprivation
interventions (Parry et al., 2000). Moreover, on the basis
of animal experiments, neurosteroids have been proposed
as potential etiological factors in this syndrome (Britton
and Koob, 1998) and such effects would not be reflected
in peripheral hormone changes. The fluid retention in
the premenstrual syndrome has been proposed to be
related to increased vasopressin levels (Reid and Yen,
1981). This peptide indeed shows fluctuation during the
menstrual cycle (Chapter 8f), but the relationship between
these fluctuations and psychological symptoms of the
premenstrual syndrome has not been shown as yet. Sleep
deprivation may help to correct underlying circadian
rhythm disturbances during sleep in premenstrual
dysphoric disorder (Parry et al., 1999).
Antepartum depression is found in some 5% of pregnant women. This condition may be a risk factor for
development of preeclampsia and is the strongest
predictor of postpartum depression. Maternal depressive
symptoms during pregnancy may lead to behavioral
changes in the child (Oren et al., 2002b). The safety of
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pharmacological treatment of depression of pregnant

women is controversial because of the possible behavioralteratological effects (Swaab and Boer, 2001). It is
therefore of great practical interest that an open trial has
shown that morning light therapy may be effective as an
antidepressant during pregnancy (Oren et al., 2002b). A
randomized controlled trial is needed to confirm these
promising data.
In the commonly occurring postpartum mood disorders
such as postpartum blues, depression and psychosis,
gonadal hormones have often been presumed to be of
pathogenetic importance. The postpartum estrogen
withdrawal state has often been held responsible for
this disorder. However, available studies show a lack of
evidence that serum sex hormones account for mood
disturbances in these women. Yet, estradiol might be
effective in its treatment. The hypothesis that the postpartum drop in melatonin secretion is responsible for this
disorder (Sandyk, 1992b) has so far not been supported
by clinical evidence. On the other hand, two women,
both suffering from a major depressive episode with
postpartum onset, were effectively treated with bright
light (Corral et al., 2000). Alterations in the HPA axis
that can be attributed to childbearing show remarkable
similarity to those observed in depressed women.
Postpartum women are also at risk for HPT axis dysfunction that may increase the vulnerability for affective
disorders (Sichel et al., 1995; Wisner and Stowe, 1997).
It has been proposed that placental CRH might play a
role in these endocrine alterations. The third trimester of
human pregnancy is characterized by a hyperactive HPA
axis, possibly driven, at least partly, by progressively
increasing circulating levels of CRH-binding protein
(see Chapter 8.5a). A suppressed hypothalamic CRH
neuron would be present postpartum that gradually returns
to normal, while hypertrophic adrenal cortices become
progressively down-sized. The central suppression of
postpartum hypothalamic CRH secretion is presumed to
cause an increased vulnerability to the affective disorders
observed during this period. The suppressed ACTH
response to ovine CRH may serve as a biochemical
marker of the postpartum blues or depression (Magiakou
et al., 1996).
Depressive symptoms are common during the
transition to menopause, and there are suggestive data
that estrogen deficiency may increase the susceptibility
for depression (Birkhuser, 2002). Perimenopause may
be a period of risk for mood disturbances that generally
do not represent major depression. In fact, depressive
disorders do not occur more frequently during perimenopause (Banger, 2002).

Estrogen replacement therapy improves mood in
perimenopausal women (Soares et al., 2001) and
postmenopausal women (Birkhuser, 2002). In addition,
there are some indications that estrogens may improve the
effect of SSRIs in postmenopausal women (Birkhuser,
2002).
(k) Mania
I am unable to describe exactly what is the matter with me;
now and then there are horrible fits of anxiety, apparently
without cause, or otherwise a feeling of emptiness and fatigue
in the head . . . . and at times I have attacks of melancholy
and of atrocious remorse. There are moments when I am
twisted by enthusiasm or madness or prophecy, like a Greek
oracle on the tripod. And then I have great readiness of speech.
Vincent van Gogh (18531890), cited by Blumer, 2002.
As in depression, an association has been reported

between early traumatic experiences and mania (Levitan
et al., 1997). In addition, there are seasonal fluctuations,
since admissions for mania peak in the summer, and fewer
admissions occur in winter. It has been proposed that
increasing exposure to light may play a role in the onset
of manic episodes and that the sensitivity of the eye may
facilitate this effect. Supersensitivity to light has been
proposed as a possible trademark of manic depressive
illness. Melatonin levels of manic depressive patients
drop to half the levels of normal controls, while lithium
induces subsensitivity to light (Carney et al., 1988). Manic
reactions to the use of anabolic androgenic steroids have
also been reported (Pope et al., 2000).
In his review of secondary or organic mania,
Cummings (1986) suggests that focal lesions and degenerative disorders of deep midline structures such as basal
ganglia, thalamus and hypothalamus are associated with
manic symptoms. Vincent van Gogh (18531890), who
is presumed to have suffered from temporal lobe epilepsy,
had not only two distinct periods of depression but
also clearly bipolar aspects in his history (Blumer,
2002). Abnormalities in the HPA axis and HPT axis
are found not only in depression, but also in mania. We
have observed the same hypothalamic changes in CRH,
vasopressin and oxytocin in three patients with a bipolar
disorder as we had seen in major depression (Raadsheer
et al., 1994c, 1995; Purba et al., 1996). Patients with
mania have elevated CSF levels and urinary excretion of
cortisol, similar to depressed patients. Mixed manics, i.e.
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patients that have both manic and depressive symptoms,

even have significantly higher morning plasma cortisol
levels, postdexamethasone plasma levels and CSF cortisol
than pure manics. Afternoon plasma cortisol and CSF
cortisol correlates significantly with depressed mood,
while urinary free cortisol correlates with anxiety. None
of the cortisol measures correlates with mania or agitation
scores (Stokes and Spikes, 1991). In addition, patients
with first-episode mania demonstrates significantly larger
third ventricular volumes (Strakowski et al., 1993),
pointing to strong hypothalamic functional or structural
changes. Srensen (1986) has reported increased CSF
levels of vasopressin in mania, while others have shown
hypersecretion of vasopressin and its neurophysin not
only in CSF, but also in plasma in manic patients (Legros
and Ansseau, 1992). These observations warrant further
study of the hypothalamic nuclei in mania.
273
found. Increased cortisol is significantly associated with

behavioral problems in boys and girls (Hessl et al., 2002).
In addition, increased melatonin levels are found in
fragile-X syndrome, during both the night and the day,
possibly due to overactivity of the sympathetic nervous
system (Gould et al., 2000). Fragile-X syndrome has also
been associated with autistic disorder (Andres, 2002),
and about 7580% of the patients with autism are mentally
retarded (Van Karnebeek et al., 2002; Chapter 27.2).
Hypothalamic involvement is presumed (but not shown)
in LaurenceMoonBiedlBardet and Biemond syndrome,
comprising mental retardation, coloboma, obesity,
polydactyly, hypogonadism, hydrocephalus and facial
dysostosis (Chapter 23.3). Obesity, muscular hypotonia
and mild mental retardation have been the symptoms by
which a number of children presented who were initially
suspected of having PraderWilli syndrome but who were
found, by molecular genetic analysis, to suffer from
Angelman syndrome (Gillessen-Kaesbach et al., 1999).
In fetal Minamata disease, a toxic encephalopathy due
to environmental mercury poisoning, slight neuronal
regressive changes are observed in the hypothalamus, but
no decrease in the number of nerve cells. In addition,
perivascular infiltration of lymphocytes has been noted
in this region (Matsumoto et al., 1965).
Hypothalamic systems involved. The hypothalamus
may indeed be frequently affected in mental retardation,
since in 77% of the idiopathic cases the third ventricle
is found to be larger than normal (Prassopoulos et al.,
1996).The possible involvement of neuroendocrine
factors in mental retardation is also illustrated by the fact
that infantile hypothyroidism may lead to this condition
(Loosen, 1992). Thermoregulatory defects that may have
a hypothalamic origin are also found in various types of
neurodevelopmentally handicapped children (Williams
et al., 1994), and menopause occurs some 4 years earlier
in women with intellectual disability (Seltzer et al., 2001),
pointing to the involvement of LHRH. The circadian
system is also often affected. In fragile-X syndrome,
increased melatonin levels are found (Gould et al., 2000).
A 5-year-old boy with an unspecified form of mental
retardation had an extremely low secretion of melatonin,
but there was a circadian cortisol rhythm. A congenital
deficiency of melatonin secretion was presumed and
supplemental melatonin therapy proved effective for
treating his non-24-h sleepwake syndrome (Acaboshi
et al., 2000). Mentally handicapped children experience
frequent sleeping problems (Quine, 1991; Hoban, 2000;
Chapter 30.7) that frequently react favorably to melatonin.
26.5. The hypothalamus in mental deficiency

Without folly there is no pleasure in life. Erasmus, The
Praise of Folly
More brain, O Lord, more brain! George Meredith,
Modern Love
Brain malformations account for a significant percentage

of patients with mental retardation. Reported estimates
of brain malformations from postmortem studies range
from 34 to 98% (Shaw, 1987; Schaefer et al., 1994).
These data, of course, depend on the sensitivity of
the techniques used. Hypothalamus-related abnormalities
may be present. Persistence of the cavum septum
pellucidum is a marker of cerebral dysgenesis. It is found
in 15% of adults with mental retardation and in 02% of
normal subjects. In contrast, a cavum vergae is seen with
the same frequency in normal and retarded populations
(Bodensteiner et al., 1998; Chapter 18.8). A hypoplastic
anterior commissure has been found in a mentally
retarded patient (Shaw, 1987). Hypothalamic changes
have been described before in various causes of mental
retardation such as septo-optic dysplasia (see Chapter
18.3) and related disorders (Miyako et al., 2002),
Noonans syndrome (Chapter 18.6), hypothalamic hamartomas (Weissenberger et al., 2001; Chapter 19.3),
tuberous sclerosis (Chapter 19.8), PraderWilli syndrome
(23.1), Kallmann syndrome (24.2) and Klinefelters
syndrome (24.3). Subjects with fragile-X syndrome have
an abnormal HPA axis function (Wisbeck et al., 2000).
Especially in males, higher levels of salivary cortisol were
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Institutionalized children can become less irritable,

calmer, happier and more content. They may also
socialize better and become more attentive with improved
cognitive abilities (Gordon, 2000; Hayashi, 2000; Ross
et al., 2002). Sleep in mentally retarded people living in
a rehabilitation center at a northern latitude, i.e. in Finland,
is more fragmented in winter than in summer. Daily
artificial light exposure during the dark season is proposed
as therapy (Lindblom et al., 2002). Moreover, eating
disorders, probably with a hypothalamic origin, leading
to either obesity or underweight, are frequently observed
in adults with intellectual disabilities (Gravestock, 2000;
Chapter 23). Morgan (1939) described the diencephalon
of 16 brains of institutionalized cases of mental deficiency. Cell densities were determined in various
hypothalamic nuclei. In all but three cases the third
ventricle was compressed inwardly and in some cases
parts of the walls of the ventricle were fused. There
was evidence of chronic leptomeningitis in 6 cases
(proliferation of fibroblasts and endothelial cells, presence
of macrophages and sometimes of lymphocytes). Subependymal proliferation of glia was present in 11 cases.
Only 2 cases showed normal ependyma of the third
ventricle and normal meninges at the base of the brain.
With one exception, i.e. the nucleus tuberomamillaris, a
reduction of cell density was consistently found in all
hypothalamic nuclei. Since the cytoarchitecture of the
hypothalamic nuclei was normal, cell reduction was
presumed to have occurred in development. Cell density
in the PVN was reduced by about 40%. In Downs
syndrome patients, the largest cells of the PVN were
almost entirely absent. Cell density in the supraoptic
nucleus (SON) was reduced by 35%. The nucleus
tuberalis lateralis was affected to a larger degree than any
other cell group in the hypothalamus; here cell density
reduction was 52% (Morgan, 1939). These observations
need confirmation using modern techniques.
Downs syndrome. Originally described by Langdon
Down in 1866, Downs syndrome (trisomy-21) is the
most commonly viable aneuploidy and one of the most
frequently identified causes of mental retardation. There
are various hypothalamic disorders in Downs syndrome.
Growth retardation, which is most marked in early
childhood and adolescence, is one of the cardinal features
of Downs syndrome (Hestnes et al., 1991). Both the
growth hormone system and hypothyroidism may
contribute to the growth retardation in Downs syndrome.
Somatic growth retardation is thought to be due to a
partial growth hormone deficiency secondary to hypo-
thalamic dysfunction. A precocious impairment of the

cholinergic tuberoinfundibular pathways is presumed to
lead to somatostatin hyperactivity and to lower growth
hormone responsiveness to growth hormone-releasing
hormone (GHRH) (Beccaria et al., 1998). Levodopa and
clonidine, drugs that stimulate hypothalamic GHRH
release, do not sufficiently stimulate growth hormone
release in Downs syndrome patients. Furthermore, a
normal growth hormone response was found after GHRH
administration to Downs syndrome patients. These observations indicate a partial hypothalamic dysfunction in
Downs syndrome (Castells et al., 1996). Although growth
hormone plasma levels in Downs syndrome children are
normal, insulin-like growth factor (IGF)-I levels do not
rise during early childhood and remain low throughout
life. Thus patients with Downs syndrome have a selective IGF-I deficiency similar to that reported in pygmies.
This might account for the growth retardation in Downs
syndrome, since growth hormone does not regulate
growth direct, but via IGFs. It has been proposed that
there is a delay in the development of the IGF system in
Downs syndrome that results in a diminished sensitivity
to growth hormone. Treatment of the partial growth
hormone deficiency with human growth hormone appears
to accelerate growth in children with Downs syndrome;
their IGF-I levels are restored to normal. Downs
syndrome children have microcephaly, associated with
retardation of brain growth. Interestingly, IGFs are also
considered to be growth factors for the developing brain
and maintenance hormones for the mature brain. Increases
in head circumference after human growth hormone
therapy have indeed been reported in Downs syndrome.
However, whether early growth hormone therapy does
indeed have a positive influence on brain growth and
function of the brain is unknown at present. It is possible
that the bloodbrain barrier for growth hormone and IGFs
might prevent such effects (Castells et al., 1992). In the
hypothalamus of three Downs syndrome subjects with
trisomy-21 (1229 years of age) Wisniewski and Bobinski
(1991) have found gliosis and a very low cell density
in the arcuate (= infundibular) nucleus and VMN.
The authors relate this defect to the growth hormone
deficiency in Downs syndrome. It seems worthwhile
to repeat these observations on larger numbers of
Down syndrome patients and to obtain data on the volume
of these hypothalamic structures in order to estimate
total cell numbers, and to determine the total number of
GHRH stained neurons that are located in the arcuate
nucleus (see Chapter 11). The sex of the patients should
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be taken as a possible confounding factor in follow-up

studies, because of the sex differences in aging and
Alzheimers pathology present in this area (see Chapter
11, and below). Various studies show that the prevalence
of thyroid diseases is increased in Downs syndrome
(Jaruratanasirikul et al., 1998; Karlsson et al., 1998). The
variation in prevalence in the literature may be related
to the age variation among the subjects studied. Karlsson
et al. (1998) have reported that 50% of Downs syndrome
children develop hypothyroidism at a young age, i.e.
before the age of 8 years, while thyroid autoimmunity
was only found in one case in the group studied.
Hypothyroidism might, in addition to IGF-I deficiency,
be another reason for growth retardation in Downs
syndrome. A higher average TSH level is found in
Downs syndrome (Hestnes et al., 1991). Most patients
who develop hypothyroidism after 8 years of age have
thyroid autoantibodies. Hypothyroidism may give symptoms that are difficult to distinguish from the symptoms
found in Downs syndrome. Although a few patients with
Downs syndrome may develop thyrotoxicoses associated
with high concentrations of TSH receptor antibodies,
thyroxine replacement treatment should in general be
encouraged in Downs syndrome, even in marginal
hypothyroidism (Karlsson et al., 1998). In addition,
gonadal insufficiency, reduced male fertility, and poor
psychosexual differentiation are well-known neuroendocrine characteristics of Downs syndrome. Small
testes and markedly elevated levels of folliclestimulating hormone (FSH) and LH, indicative of some
primary gonadal insufficiency in boys, as well as normal
testicular size and normal FSH, LH and testosterone levels
have been reported. Estradiol is elevated in male patients.
Moreover, pubertal development is reported to be delayed
in female patients, but others have found a menarcheal
age corresponding to that of the mothers (Campbell
et al., 1982; Hestnes et al., 1991; Arnell et al., 1996).
Menopause occurs 4 years earlier in Downs syndrome
than in the control population. This may be both a
reflection of premature or accelerated aging and a risk
factor for estrogen-related diseases such as heart disease,
depression and dementia (Seltzer et al., 2001). Cortisol
levels seem to be normal (Arnell et al., 1996) and
prolactin levels are significantly elevated in Downs
syndrome (Hestnes et al., 1991). Vasopressin expression
has increased strongly in the temporal lobe of fetal
Downs syndrome brains, at a stage when brain choline
acetyltransferase (ChAT) activities still indicate normal
cholinergic function (Labudova et al., 1998). The lower
275
body temperature in Downs syndrome and sleep

disorders also indicate hypothalamic disturbances (Hoban
2000; Holtzman and Simon, 2000).
Alzheimer changes were described for the first time in
Downs syndrome patients in 1929 (Struwe, 1929).
Female, middle-aged Downs syndrome individuals have
an earlier onset and a more severe form of Alzheimers
disease, which correlates with higher neocortical neurofibrillary tangle densities. Senile plaque counts show no
significant sex differences in plaque counts (Raghavan
et al., 1994). Especially in older Downs syndrome
patients in the hippocampus, a strong reduction is detected
in nicotine binding and ChAT activity (Court et al., 2000).
The strong Alzheimer changes that occur in the hypothalamus of presenile demented Downs syndrome
patients are described in Chapter 29.1 and the cholinergic
deficit in Downs syndrome patients in Chapter 2.5. A
histaminergic deficiency has been found in the prefrontal
cortex of both Alzheimers and Downs syndrome
patients, indicating that the tuberomamillary nucleus
is affected (Schneider et al., 1997). These Alzheimer
changes in Downs syndrome, together with the earlier
menopause experienced in this syndrome (Schupf et al.,
1997), indicate an accelerated aging in Downs syndrome.
Downs syndrome subjects have smaller corpora mamillaria (Raz et al., 1995) and a 50% smaller anterior
commissure. The latter is considered to be a congenital
malformation (Sylvester, 1986); however, both structures
may also be smaller because of the degenerative
Alzheimer changes in the temporal lobe (cf. Chapters 6.3
and 16C).
She was a perfectly normal girl before 12 months. Then
she lost all of her abilities, and we never got her back. A
mother of a child with Rett syndrome.
Adv Pediatr 1993; 40: 217224.
Retts syndrome. Retts syndrome (1966) is a progressive

disorder that affects early brain growth between infancy
and the 5th year of life with a prevalence of
1:10,0001:22,000. The disease affects mainly, if not
exclusively, girls. Girls with Retts syndrome are
generally reported to be normal at birth, but a loss of
communication skills develops soon after and abnormal
stereotypical movements appear. The survival rate in
reduced to 70% by 35 years of age. Deceleration of head
growth is noticeable between 2 and 4 months of age.
However, head circumference is already smaller at birth,
and perinatal abnormalities are reported in 25% of patients
(Leonard and Bower, 1998), indicating that these children
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are already compromised at birth. The disease is

associated with autistic behavior, cortical atrophy, loss
of speech, stereotyped hand movements mimicking
hand-washing, severe mental deficiency, gait apraxia and
cortical and extrapyramidal dysfunction. Seizures, scoliosis and breathing disturbances such as periodic apnea
during wakefulness may become evident (Armstrong,
1997; Miyamoto et al., 1999). Sleep disorders are
commonly observed and both free-running rhythms and
fragmented sleep patterns have been described. These
disorders can be treated effectively with melatonin
(McArthur and Budden, 1998; Miyamoto et al., 1999;
Yamashita et al., 1999; Hoban, 2000). Sleep time and
sleep efficiency are improved by melatonin (McArthur
and Budden, 1998). Arrested neuronal development, e.g.
on the basis of a lack of appropriate trophic factors, is
presumed. Neuropathology shows a generalized brain
atrophy involving the cerebrum and cerebellum, without
evident general cell loss, inflammation, gliosis or migration defects. Neurons are reduced in size, and there is a
reduction in number and size of cholinergic neurons in
the nucleus basalis of Meynert (NBM) and a reduction
in the melanin-containing neurons of the substantia nigra.
Biochemical studies have shown a decrease in ChAT and
other cholinergic markers in the neocortex, hippocampus,
thalamus and basal ganglia. This neurodevelopmental
disorder is presumed to have its greatest effect upon the
cholinergic system during the first years of postnatal life.
In the prefrontal cortex of Retts syndrome patients, a
reduced quantity of nerve growth factor was observed
(Lipani et al., 2000). This observation agrees well with
the atrophy in the NBM, as these neurons need nerve
growth factor from the cortex for their metabolism (see
Chapter 2.5). Although most cases of Retts syndrome
are sporadic, a few familial cases and a striking concordance in twins point to a genetic component. One study
has suggested that the disorder may be located in two
loci, one of which is autosomal (possibly chromosome
11) and one on the X-chromosome (Armstrong, 1997;
Naidu, 1997; Wenk, 1997a, b). Recently, mutations in
the X-linked MECP2 (methyl CpG binding protein 2 (Rett
syndrome)) gene were indeed identified in some sporadic
Retts syndrome patients. Familial cases are an X-linked
dominant disorder that maps on Xq28. A candidate gene
is the transcription-silencing MECP2. It contains mutations in 77% of Retts syndrome patients. The encoded
protein is a global transcriptional repressor (Xiang et al.,
2000; Dunn and Macleod, 2001; Shastry, 2001). One
must, however, recognize that about 99.5% of cases are
sporadic and that MECP2 testing is not positive in all

individuals. The probands mother is not routinely tested,
because about 90% of the sporadic cases have paternally
derived MECP2 mutations (Singer and Naidu, 2001).
Other syndromes. In SmithMagenis syndrome, due
to a deletion on chromosome 17p11-2, mental retardation,
aggression, tantrums and sleep disturbances are found.
The melatonin-secretion cycle is completely inverted,
starting around 6 a.m. and with a peak around midday.
Tantrums occur when melatonin increases, and sleep
attacks take place around the melatonin peak (McBride,
1999; De Leersnyder et al., 2001).
Multiple neuroendocrine disorders are observed in
Salla disease, which is characterized by increased excretion of sialic acid, mutations in the SLC17A5 gene,
psychomotor retardation and ataxia, combined growth
hormone deficiency and hypogonadotropic hypogonadism
(Grosso et al., 2001).
26.6. Obsessive-compulsive disorder
Obsessive-compulsive disorder afflicts 2% of the population (Altemus et al., 1992). Patients are plagued by
recurrent intrusive thoughts that often involve the fear
that some potential danger has been left unchecked or
that they are about to perform an act that is harmful to
themselves or others. Compulsive, stereotyped repetitive
behaviors, such as handwashing, are often conducted to
magically forestall the imagined danger and relieve
anxiety. The patients lives are so persistently focused on
obsessive thoughts and compulsive rituals that it impairs
their daily functioning (Altemus et al., 1992).
Obsessive-compulsive disorder was once considered to
be a psychological disorder or neurosis, but is now considered to be a neurobiological disorder with various
etiological factors (Swedo et al., 1997). In this condition
increased metabolism occurs in the frontal lobes, caudate
nucleus and cingulate gyrus (Rapoport, 1988). There are
familial and sporadic cases. Among the familial cases,
some appear to be related to Tourettes syndrome
(Leckman et al., 1994). Obsessive-compulsive disorder in
families with an eating disorder follows a Mendelian
dominant model of transmission (Cavallini et al., 2000).
Poststreptococcal autoimmunity has been postulated as
another etiological factor. Indeed, an association has
been found between obsessive-compulsive disorder and a
trait marker of rheumatic fever susceptibility (D8/17)
(Swedo et al., 1997). Also the observation that treatments
such as plasmapheresis, intravenous immunoglobulins and
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immunosuppressive doses of prednisone, lead to immediate, significant improvements (Allen et al., 1995) points
to an immunological mechanism. In addition, children
with obsessive-compulsive disorder, antistreptococcal
antibodies and antineuronal antibodies are effectively
treated with penicillin (Swedo et al., 1994). Higher rates
of obsessive-compulsive disorder are observed in patients
with thyroid diseases (Placidi et al., 1998).
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with clomipramine hydrochloride (Altemus et al., 1994).

In a later study, no significant differences were observed
between the obsessive-compulsive disorder patients
and controls in CSF oxytocin or neuropeptide Y levels
(Altemus et al., 1999). In conclusion, clear and consistent
differences in CSF vasopressin and oxytocin levels are
probably not present in this disorder.
In addition, CSF CRH levels are significantly elevated
in patients with obsessive-compulsive disorder (Altemus
et al., 1992). For men with this disorder, this observation
has been confirmed (Fossey et al., 1996). A similar
increase is found in anorexia nervosa patients. In this
connection it is interesting that many patients with
obsessive-compulsive disorder show evidence of concurrent major depression, in which similar CRH elevations
in CSF have been reported, although it is questionable
whether the source of this CRH is indeed the hypothalamus (see Chapter 26.4). Increased secretion of the
stress hormones vasopressin and CRH are presumed
to contribute to persistent behavior, a narrow focus of
attention and exaggerated grooming behavior (Altemus
et al., 1992; McDougle et al., 1999). During treatment of
obsessive-compulsive disorder with clomipramine, CSF
levels of CRH decreases (Altemus et al., 1994). However,
the fact that Swedo et al. (1992) did not find a relationship
between CSF CRH levels and obsessive-compulsive
disorder symptom severity does not fit into these observations. No clear disturbance of circadian rhythmicity is
observed for plasma melatonin, cortisol or temperature
in this disorder (Millet et al., 1998); however, somatostatin levels in CSF are increased (McDougle et al., 1999).
The hypothalamus of obsessive-compulsive disorder
patients has never been studied.
(a) Neuroendocrine changes

Several hypothalamic systems have been reported to have
changed in this condition, although these alterations are
far from settled. The levels of vasopressin in the CSF of
patients suffering from obsessive-compulsive disorder
have been found to be significantly elevated, as is the
secretion of plasma vasopressin in response to hypertonic
saline administration. Moreover, most patients show a
loss of the normal relationship between vasopressin levels
and osmolality. Patients with anorexia nervosa show a
qualitatively similar dysregulation. A significant positive
correlation has been found between CSF vasopressin
levels and the dopamine metabolite HVA in these patients,
as in schizophrenia (Altemus et al., 1992). However,
Leckman et al. (1994) did not find differences in
CSF concentrations of vasopressin in this syndrome.
And in contrast with the data mentioned above, Swedo
et al. (1992) have reported a negative correlation between
vasopressin CSF levels and several ratings of obsessivecompulsive disorder. Increased oxytocin CSF levels were
found in a subset of these patients. In this subset the CSF
oxytocin levels were correlated with the severity of
the obsessive-compulsive disorder. The authors speculate
about the possible role of central oxytocin in cognition,
grooming, affiliation and sexual behavior and how these
behaviors are disrupted in some forms of obsessiveconvulsive disorders (Leckman et al., 1994). Swedo
et al. (1992) have found that the oxytocin CSF levels are
positively correlated to depressive symptoms in this
disorder. On the basis of the observed increased CSF
levels of oxytocin in obsessive-compulsive disorder, one
may wonder why oxytocin treatment (Altemus et al.,
1992) would be a good strategy to ameliorate obsessivecompulsive disorder; but it would, of course, concur with
data of Swedo et al. 1992. In addition, it is difficult to
reconcile the reported increased CSF levels of oxytocin
(Leckman et al., 1994) and vasopressin (Altemus et al.,
1992) in obsessive-compulsive disorder with the decrease
in the CSF levels in these patients following treatment
(b) Neuroendocrine therapies

Ansseau et al. (1987) have reported symptomatic
improvement in one patient with obsessive-compulsive
disorder following treatment with oxytocin. This improvement was concurrent with the development of severe
memory disturbances, supporting the possible amnestic
properties of the peptide. However, the patient also
developed psychotic symptoms. Since then a number of
authors have reported no appreciable effects of oxytocin
in obsessive-compulsive disorder (Salzberg and Swedo,
1992; for references see Epperson et al., 1996). One
patient felt that oxytocin decreased his compulsions and
stated: I didnt check or count my steps when I left the
bathroom just now that is the first time in as long as
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I can remember (Salzberg and Swedo, 1992). However,

in 1-week- or 6-week-treatment double-blind placebocontrolled studies, no effect of oxytocin on obsessivecompulsive disorder symptoms has been observed (Den
Boer et al., 1992; Epperson et al., 1996). The overall
results of the oxytocin therapy thus do not appear to
be convincing at present. Naloxone, an opioid receptor
antagonist, does not alter symptom severity. However,
serotonin reuptake inhibitors seem to be effective in a
large proportion of patients with obsessive-compulsive
disorder (McDougle et al., 1999).
26.7. Anxiety disorders
(a) Panic disorder
In panic disorder, anxiety manifests itself as recurrent,
unexpected panic attacks and associated avoidance and
worry related to the possible recurrence, consequences or
health implications of the attacks. One-third to one-half
of patients with panic disorder have agoraphobia. Panic
disorder is also often associated with other anxiety disorders such as social and simple phobia. Epidemiological
data have shown a lifetime prevalence of panic disorder
of 1.63%, mean age of onset 20 years and a two-fold
higher risk for females. Panic disorder is highly familial
and an autosomal dominant pattern of inheritance with
incomplete penetrance has been proposed for panic
disorder. In addition, an interstitial duplication of chromosome 15q24-26 (named DUP25) was found to be
significantly associated with panic, agoraphobia, social
phobia and panic disorder in nonfamilial cases. DUP25
is present in 7% of the control subjects and is proposed
to be a susceptibility factor for panic disorder. The penetrance for the various phenotypes is between 37% and
63%. Other putative susceptibility genes mentioned are
MAOA and CCK (Gratacs et al., 2001). The MAOA G
941T polymorphism is associated with generalized
anxiety disorder but not with panic disorder (Tadic et al.,
2003). There is also evidence that experiencing traumatic
events during childhood and adulthood is associated
with panic disorder (Gorman et al., 2000). Moreover, a
pathogenetic role of birth seasonality has been found
(Castrogiovanni et al., 1999).
Different brain circuits have been hypothesized to be
involved in the pathogenesis of panic disorder, including
the hypothalamus, which is central in the reaction of the
adrenals and autonomic nervous system in this disorder
(for reviews see Coplan and Lydiard, 1998; Gorman

et al., 2000). Moreover, higher rates of panic disorder
have been found in thyroid-diseased patients (Placidi
et al., 1998). Anxiety disorder patients in remission are
free of psychopathological problems, but they are at risk
for future psychiatric episodes. Various data suggest that
panic attacks might be partly attributable to exaggerated
physiological responses to environmental stresses. Indeed,
during a laboratory stress test, patients have greater
increases in plasma cortisol levels than controls (Leyton
et al., 1996). Patients with panic disorder are characterized by overnight hypercortisolemia and increased activity
in ultradian secretory episodes (Abelson and Curtis,
1996a). Another study has shown increased basal total
plasma cortisol, free plasma cortisol and salivary cortisol
levels in panic disorder (Wedekind et al., 2000). Various
observations, moreover, not only indicate hypercortisolemia in panic disorder, but also a normalization of
cortisol levels with symptom remission. The HPA axis
is, however, not only a state marker in panic. A pretreatment dexamethasone suppression test as well as shifts
in ACTH circadian rhythm and cortisol secretion can
predict subsequent relapse with medication discontinuation, the patients subjective assessments of their own
functioning, and greater social and occupational disability
years later. Thus, the HPA axis activity may also mark
traits associated with long-term vulnerability and functioning. It should also be mentioned that panic patients
have elevated overnight cortisol secretion. The cortisol
elevations are more pronounced during the night and also
occur mainly in the more severely ill panic patients.
Others have found a subtle but significant elevation of
saliva cortisol levels during spontaneous panic attacks,
however, without a relationship with the severity of the
attack or the severity of the illness. In addition, patients
with frequent panic attacks have reduced ACTH/cortisol
ratios and an altered ACTH circadian cycle, suggesting
a more chronic central overdrive of the HPA axis
(Abelson and Curtis, 1996b; Bandelow et al., 2000a, b).
Moreover, hypercortisolinemia, escape of plasma cortisol
from dexamethasone suppression and enlargement of the
adrenal cortex indicate a dysregulation of the HPA axis.
Untreated, nondepressed panic disorder patients fail to
show blunted ACTH or cortisol responses to CRH. In
fact, the responses are subtly enhanced in that they are
more rapid than those of controls. After 12 weeks of
alprazolam treatment, repeated testing found cortisol
levels similar to those of controls (Abelson et al., 1996;
Curtis et al., 1997). CRH-receptor antagonists have been
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suggested as possible treatment for anxiety disorder

(Grammatopoulos and Chrousos, 2002). No changes in
CSF CRH levels are observed in panic disorder (Fossey
et al., 1996), but one may wonder whether this gives any
information on the functional state of hypothalamic CRH
neurons, since CRH in CSF may, to a large degree, be
derived from extrahypothalamic sources (Chapter 26.4).
It is hard to explain why Stones et al. (1999), in contrast
to the other observations, have found lower salivary
cortisol levels in panic disorder patients and an unresponsiveness to novel situations. It should be noted,
though, that in panic induced by CO2 inhalation, plasma
cortisol levels do not increase but actually decrease
significantly (Sinha et al., 1999). These observations
lend support to the idea that the pathophysiological
mechanisms underlying CO2-induced panic are different
from those underlying general or anticipatory stress.
Acidbase disturbances may be relevant in panic disorder
(Coplan and Lydiard, 1998). Patients with panic disorder
experience panic attacks after intravenous lactate infusions. On the basis of animal experiments, it is presumed
that the organum vasculosum lamina terminalis may be
the primary site that detects lactate infusions, activating
an anxiety response in a compromised dorsomedial
nucleus (Shekhar and Keim, 1997). However, the hypothalamus of panic patients has so far never been studied.
This brain structure does indeed seem to be of interest,
because a patient with a cyst in the third ventricle exhibited anxiety periods (Lobosky et al., 1984). Moreover,
blood pressure is elevated in fully remitted panic disorder
patients (Leyton et al., 1996) and atrial natriuretic factor
is increased in patients with panic disorder. This peptide
inhibits the CRH-stimulated release of ACTH in humans
(Kellner et al., 1992; Dieterich et al., 1997). Increased
nocturnal melatonin has been found in panic disorder
patients (Brown, 1996; Pacchierotti et al., 2001). There
are also other neuroendocrine disturbances in this
disorder. Blunted growth hormone responses to clonidine,
yohibine, GHRH, caffeine and glucose challenge have
been observed. These data indicate a hyporesponsive
hypothalamic growth hormone system in panic disorder
(Uhde et al., 1992).
Benzodiazepines and, in particular, alprazolam produce
substantial improvement in clinical status, accompanied
by nearly full reduction of pretreatment hypercortisolemia
(Abelson et al., 1996). In addition, more than 3 decades
ago Klein observed that imipramine was effective (Coplan
and Lydiard, 1998). Effective cognitive behavioral
therapies have also been reported (Gorman et al., 2000).
279
(b) Social anxiety disorder

Social anxiety disorder is conceptualized as a chronic
neurodevelopmental illness, with excessive fear and/or
avoidance of situations in which an individual feels
scrutinized by others and is fearful of a negative evaluation by others. There is a low concordance rate for social
anxiety in monozygotic twins, suggesting that genetics
may play a limited role in its development. In adulthood
no peripheral HPA axis pathological change is evident,
in contrast to panic disorder. Psychological stressors such
as mental arithmetic and a short-term memory test
performed in front of an audience resulted in a significantly higher cortisol response in patients with a
generalized social phobia than found in controls (Condren
et al., 2002).
26.8. Fatigue syndromes
. . . Neurasthenia, indeed, has been the central Africa of
medicine an unexplored territory into which few men enter,
and those few have been compelled to bring reports that
have been neither credited nor comprehended . . .
George Beard, 1880, from Demitrack, 1994.
(a) Chronic fatigue syndrome

For research purposes the Center for Disease Control and
Prevention (CDC) has proposed a working case definition
for chronic fatigue syndrome , neurasthenia or benign
myalgic encephalomyelitis. Patients must have persistent
or relapsing debilitating fatigue for at least 6 months
without any medical diagnosis that would explain the
clinical presentation. The fatigue should cause a reduction
in activity of at least 50%. Symptom criteria also include
an abrupt onset, low-grade fever, arthralgia, myalgia,
painful adenopathy, postexercise fatigue, neuropsychological complaints and sleep disturbances (Demitrack,
1994; Krupp and Pollina, 1996). The prevalence is
estimated to be 112 patients per 100,000 (Buskila, 2001).
The neurotransmitter systems probably involved in
the mechanism of central fatigue in chronic disease
are noradrenaline, 5-HT and CRH (Swain, 2000).
Many symptoms experienced by these patients are similar
to those experienced by patients who have received
long-term glucocorticoid therapy and are undergoing
steroid withdrawal (Adler et al., 1999). Moreover, low
blood pressure has frequently been reported (Demitrack,
1997). Subjects with chronic fatigue syndrome have
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normal core body temperature, despite frequent selfreports of subnormal body temperature and low-grade
fever (Hamilos et al., 1998). In addition, the observed
T-cell activation indicates the presence of an immunedysregulation disorder (Bell, 1994). This disorder is
accompanied by a relative resistance of the immune
system to dexamethasone (Kavelaars et al., 2000) and
angiotensin-converting enzyme plasma levels are
increased. This enzyme is a marker not only for sarcoidosis (Chapter 21.1), but also for diseases involving blood
vessels (Bell, 1994). Moreover, abnormalities in essential
fatty acid incorporation into phospholipids have been
found (Gray and Martinovic, 1994).
Chronic fatigue syndrome often starts following a
significant period of stress and is worsened by exercise.
Acute infections can evolve into chronic fatigue syndrome, and an influenza-like onset of this syndrome is
more common in winter than in other seasons (Natelson,
2001). Antibody titers to a variety of viral agents may be
present in CSF, including antibodies to herpes, cytomegalovirus and measles virus. However, no single virus has
been identified as the cause of chronic fatigue syndrome
(Krupp and Pollina, 1996). No circulating autoimmune
antimuscle or anti-CNS antibodies in chronic fatigue
syndrome have been found (Plioplys, 1997). In some
studies, patients with chronic fatigue syndrome are
reported to have significantly more abnormal scan results
than head trauma/headache controls. The abnormalities
are predominantly either single or multiple small areas
of increased T2 signal in white matter or evidence of
ventricular or sulcal enlargement (Natelson et al., 1993;
Schwartz et al., 1994; Lange et al., 1999). Others have
not confirmed these findings (Greco et al., 1997). Patients
with chronic fatigue syndrome have, moreover, more
defects throughout the cerebral cortex, as revealed by
SPECT scans, than normal subjects (Schwartz et al.,
1994). In addition, there is a significant reduction of the
perfusion to several areas of the cortex (Costa et al., 1992;
Ichise et al., 1992), but in particular to the hypothalamus
and pons in patients with chronic fatigue syndrome (Costa
et al., 1992).
In spite of the nearly ubiquitous presence of depression,
a functional deficit in the HPA axis is found in chronic
fatigue syndrome rather than hyperactivity (Demitrack,
1997; Cleare, 2003). Scott et al. (1999c) have found,
by CT scanning, that the adrenals in this disorder are
50% smaller. A reduction in evening basal plasma glucocorticoid levels and urinary free cortisol excretion has
been reported in chronic fatigue patients, while plasma

ACTH levels are higher (Poteliakhoff, 1981; Demitrack
et al., 1991; Scott et al., 1999a). Furthermore, these
patients have an enhanced sensitivity to exogenous
ACTH and a blunted response to CRH, which may be
compatible with a mild insufficiency of the HPA axis.
The observation that DDAVP (desmopressin) augments
the CRH-mediated pituitary-adrenal responsivity may
relate to increased vasopressin regulation of the HPAaxis in this syndrome (Scott et al., 1999b; Cleare et al.,
2001). Although glucocorticoid deficiency is generally
considered to be central in the symptomatology of this
syndrome (Poteliakhoff, 1981; Demitrack, 1994; Adler
et al., 1999; Cleare, 2003), some relatively recent studies
could not replicate the reduced HPA-axis activity in
this syndrome by measurement of daily salivary cortisol
secretion (Young et al., 1998) and plasma cortisol
levels were not found to be different from control levels
either (Scott et al., 1999a). Furthermore, in contrast
to previous studies, adrenal sensitivity to infused ACTH
was found to be normal (Adler et al., 1999) and the
decreased 24-h urinary cortisol excretion of patients
with fibromyalgia could not be replicated either (Maes
et al., 1998). Reviewing the literature, Parker et al.
(2001) statesd that one-third of the studies report baseline cortisol values to be significantly low, usually in
one-third of patients. One may presume that more
differences might appear if provocation tests of the HPA
axis had been used, since reduced HPA function in
such tests is more consistent (Parker et al., 2001). Also,
differences in dietary sodium or environmental stresses
may have played a role in the discrepancies (Adler et al.,
1999). This possibility is supported by the observation
that vasopressin infusion in chronic fatigue patients
produces a reduced ACTH response, which is explained
by reduced hypothalamic CRH secretion that acts
synergistically with vasopressin on the pituitary level
(Altemus et al., 2001). Comparing different types of
stress, it is concluded that chronic fatigue patients are
capable of mounting a sufficient cortisol response, but
that there is a subtle dysregulation of the HPA axis at
the central level that becomes overt as a result of or
through a lower ACTH response. In all tests these patients
had significantly reduced baseline ACTH levels (Gaab
et al., 2002).
Subtle changes in the HPA axis are also indicated by
the observation that the majority of chronic fatigue
syndrome patients have a serum DHEA-S deficiency,
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while cortisol and DHEA levels were found to be either

normal (Kuratsune et al., 1998; De Becker et al., 1999)
or lower (Scott et al., 1999a; Cleare, 2003). A blunted
serum DHEA response to intravenous ACTH has been
observed (De Becker et al., 1999). DHEA-S is one of the
most abundantly produced hormones. It is secreted by
the adrenal and is a precursor of sex steroids. These data
agree with the opinion of Cleare et al. (2001) that
hypocortisolism in chronic fatigue syndrome is secondary
to reduced adrenal gland output. Since DHEAS has, in
addition, central effects (cf. Scott et al., 1999a; Cleare,
2003), its deficiency may be related to the core symptoms
of chronic fatigue syndrome.
In addition, basal plasma levels of 3-methoxy4-hydroxyphenylglycol (MHPG), a norepinephrine
metabolite, are lower and basal plasma levels of 5hydroxyindoleacetic acid (5-HIAA), a 5-HT metabolite,
are significantly higher in patients with chronic fatigue
syndrome than in controls (Bell, 1994). Enhanced
serotonergic activity is a consistent finding (Parker et al.,
2001). The decreased MHPG levels reflect an increase in
sympathetic activity which could explain at least part of
the fatigue of the syndrome (Bell, 1994). On the basis
of a study on cardiovascular control in chronic fatigue
syndrome, an autonomic imbalance with sympathetic
predominance has been hypothesized (Pagani and Lucini,
1999). On the other hand, Adler et al. (1999) have found
an impairment of the sympathoadrenal response to hypoglycemia. A hypofunction of the sympathetic nervous
system has been described by several authors and could
contribute to adrenal insufficiency (Neeck and Crofford,
2000). Moreover, a significant reduction in the prolactin
response to hypoglycemia has been noted (Demitrack,
1997), indicating dopamine involvement.
Some 20% of patients with chronic fatigue syndrome
describe excessive thirst as a minor symptom. Vasopressin
secretion is erratic in patients with postviral fatigue syndrome. Moreover, the baseline vasopressin plasma level
in these patients is lower than in controls (Bell, 1994).
The diurnal change in cortisol levels is less pronounced
in chronic fatigue syndrome than in controls. Morning
cortisol levels are lower and evening levels higher
(MacHale et al., 1998), indicating a deficient SCN
paraventricular nucleus interaction. Moreover, exhaustive
exercise interferes with normal entrainment to 24-h
Zeitgebers in chronic fatigue syndrome patients, but not
in controls. The patients have a lengthening of the mean
circadian period, while the period remains unchanged in
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controls (Ohashi et al., 2002). However, Adler et al.

(1999) have found a normal diurnal rhythm of the HPA
axis under basal conditions in these patients. In addition,
continuous recordings of core body temperature using an
ingestible radio-frequency transmitter pill did not reveal
any clear differences from controls (Hamilos et al., 2001).
It has been suggested that the sleep disorders in chronic
fatigue syndrome may result from melatonin deficiency.
However, in contrast to this assumption, higher nocturnal
melatonin levels were found in these patients (Knook et
al., 2000). and melatonin levels were normal in another
study (Korszun et al., 1999). The observation that
melatonin and bright-light phototherapy are ineffective in
chronic fatigue syndrome sufferers (Williams et al., 2002)
agrees with the idea that the circadian system is not
seriously affected. There is no indication of an abnormal
function of the hypothalamopituitary-gonadal axis in
chronic fatigue syndrome (Korszun et al., 2000).
In approximately one-third of the patients with chronic
fatigue syndrome, low dose hydrocortisone reduces
fatigue levels in the short term (Cleare et al., 1999; Adler
et al., 2002), which seems a rational therapy since the
mild hypocortisolism reported in this disorder. In a later
study the improvement in fatigue seen in some patients
with chronic fatigue syndrome during hydrocortisone
treatment was accompanied by a reversal of the blunted
cortisol response to human CRH (Cleare et al., 2001).
However, as Scott et al. (1999a) pointed out, the administration of hydrocortisone as a therapeutic measure
may further lower the levels of DHEA and DHEAS.
The observations of favorable effects of corticosteroids
should still be confirmed in controlled longterm followup studies. Although such a treatment was also associated
with some improvement in symptoms in another study,
the degree of adrenal suppression, the modest benefit,
and the overlap of symptoms between chronic fatigue
syndrome and glucocorticoid therapy, and the other side
effects of glucocorticoids are thought to preclude their
practical use for this disorder (McKenzie et al., 1998;
Jeffcoate, 1999; Adler et al., 2002). In a pilot experiment
it was found that daily administration of DHEA-S induced
marked improvements in the daily activities and a reduction of their symptoms (Kuratsune et al., 1998).
Although there are thus several reports implicating
the hypothalamus in the chronic fatigue syndrome, such
as a putative deficiency of the HPA axis (Demitrack
et al., 1991; Demitrack, 1997), a reduction of the perfusion
of the hypothalamus (Costa et al., 1992), endocrine
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abnormalities of hypothalamic or pituitary function (Bell,

1994), upregulation of 5-HT receptors in the hypothalamus (Bakheit et al., 1992), problems with temperature
regulation and disturbed circadian hormone profiles
(MacHale et al., 1998), the functional anatomy of the
hypothalamus itself has so far not been studied in postmortem material.
The debate as to whether chronic fatigue syndrome is
psychiatric or organic no longer appears to be useful.
The neuroendocrine alterations found in at least some
of these patients strongly argue in favor of the latter
possibility. The fact that cognitive behavioral therapy led
to improved clinical outcomes in patients with chronic
fatigue syndrome, does, of course, not mean that this
syndrome is psychological in origin (Natelson, 2001).
Patients with chronic fatigue syndrome and post-Lyme
syndrome share many features, including symptoms of
severe fatigue and cognitive deficits. However, the latter
are particularly apparent in patients with post-Lyme
syndrome (Gaudino et al., 1997).
Symptoms that are comparable with those of chronic
fatigue syndrome, and with those of work-related
syndromes, are found in burnout patients. They do,
however, not have blunted cortisol levels. On the contrary,
their morning cortisol levels are elevated. The severity
of mental exhaustion is associated with the degree of
early morning cortisol level elevation. In addition, higher
resting heartrates are observed in burnout patients (De
Vente et al., 2003).
(b) Fibromyalgic syndrome
A rheumatologic syndrome characterized by a widespread
musculo-skeletal pain and tenderness, fatigue, neurovegative symptoms and sleep disturbances, fibromyalgic
syndrome is related and may even be identical to the
chronic fatigue syndrome, although lower numbers of
patients showed abnormal suppression to dexamethasone.
Furthermore, according to a number of investigations,
these patients show reduced diurnal fluctuations of glucocorticoid levels, reduced free cortisol excretion, impaired
reactivity of the HPA axis to challenge reduced vasopressin response to water deprivation challenge (Hudson
et al., 1984; McCain and Tilbe, 1989; Griep et al., 1993,
1998; Demitrack, 1997; Lentjes et al., 1997; Wikner
et al., 1998; Cutolo and Straub, 2000; Buskila, 2001).
Moreover, the patients have increased sympathetic and
decreased parasympathetic system tones (Buskila, 2001)
and low DHEAS levels were reported (Dessein et al.,

2000). Fibromyalgia and irritable bowel syndrome coexist
in many patients (Buskila, 2001).
Since fibromyalgia patients display a hyperactive
ACTH response to CRH and to insulin-induced hyperglycemia, the existence of a deranged negative feedback
control of cortisol was proposed. These patients appeared
indeed to have an increased cortisol feedback resistance,
presumed to be combined with a reduced CRH synthesis
or release in the hypothalamus (Lentjes et al., 1997). A
later study did not observe a change in the 24-hour urinary
excretion of cortisol, however (Maes et al., 1998) and
even elevated basal levels of the ACTH and cortisol were
found by others (Neeck, 2000). Some other studies claim
that fibromyalgia is characterized by hyperactivity of the
HPA axis, possibly driven and sustained by stress exerted
by chronic pain (Neeck and Crafford, 2000). A defect in
the descending spinal cord pathways that modulate pain
sensation has been hypothesized, therefore, to be present
in fibromyalgia.
Reduced nocturnal melatonin levels were reported that
were presumed to play a role in the sleep disturbances,
in fatigue during the day, and in a changed perception
of pain (Wilkner et al., 1998). However, contrary to earlier
reports, Korszun et al. (1999) found significantly higher
night-time plasma melatonin levels. No abnormalities in
the function of the hypothalamopituitary-gonadal axis
were found by Korszun et al. (2000), but Neeck (2000)
reported increased levels of not only FSH, but also of
lowered basal levels of estrogens, androgens, insulin-like
growth factor-1, somatomedin C, and free triiodothyronine (T3) (Geenen et al., 2002).
The occurrence of daytime somnolence in fibromyalgia
patients is one of the most important symptoms. The
occurrence is linked to a greater severity of the symptoms
of the disease and to more polysomnographic alterations
(Sanzi-Puttini et al., 2002). Typical non-REM disturbances are present. Slow-wave sleep abnormalities appear
to be more important than REM sleep disturbances.
Both the histaminergic tuberomamillary system and the
SCN have been hypothesized to participate in these
changes (Pillemer et al., 1997; Griep et al., 1998), and a
stimulatory serotonergic influence of the serotonergic
system on the HPA axis is presumed (Neeck, 2000).
However, direct evidence for a disturbance in these
systems in fibromyalgia is currently lacking. One third
of the patients has an impaired reaction of growth
hormone following insulin-induced hypoglycemia and
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arginine stimulation, suggesting an impaired hypothalamic

somatotropic reactivity (Dinser et al., 2000).
Substance-P, an important nociceptive neurotransmitter,
is elevated in the CSF of fibromyalgia patients and not
in patients with chronic fatigue syndrome, while metenkephalin levels are low (Pillemer et al., 1997).
Beneficial strategies in fibromyalgia include graded aerobic
exercise, cognitive behavior, stress reduction therapies,
tricyclic antidepressants, growth hormone replacement and
DHEAS replacement (Dessein et al., 2000). In a placebocontrolled study of glucocorticoids in fibromyalgia, no
favorable effect was found (Adler et al., 2002).
In general, little support is obtained from the literature
for hormone supplementation therapy in case of fibromyalgia (Geenen et al., 2002).
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26.9. Aggressive behavior

the world was against him (patient with a medial
hypothalamic tumor.
Alpers, 1937)
(a) Developmental factors involved in clinical disorders

associated with aggression
Genetic, developmental and environmental developmental factors play a role in later levels of aggression. That
the levels of aggression in adult life may at least to some
degree be determined by genetic factors appears from, e.g.
the study by Brunner et al. (1993), who described a large
Dutch kindred with a form of X-linked mild mental
retardation, in which all the affected males showed aggressive and sometimes violent behavior, arson, attempted
rape and exhibitionism, which are proposed to be due to
changes in the monoamine oxidase type A (MAO-A) locus
in Xp11.23-11.14. On the other hand, children with a genotype conferring high levels of MAO-A expression are less
likely to develop antisocial behavior when maltreated
during childhood (Caspi et al., 2002). Moreover, individual differences in aggressive disposition were shown to
be associated with an intronic polymorphism of the
tryptophan hydroxylase gene in a nonpatient sample of
volunteers. This gene codes for the rate limiting enzyme
in 5-HT biosynthesis (Manuck et al., 1999). Large-scale
screening studies have refuted the earlier claims that
Kleinfelters syndrome patients (Chapter 24.4) are prone
to criminal behavior (Smyth and Bremner, 1998).
Various developmental factors may determine the later
degree of aggression. Minor physical abnormalities in
newborns that result from some form of genetic transmission or insult during early pregnancy predict short
attention span, peer aggression and impulsivity at 3 years
of age (Waldrop et al., 1978) and recidivistic violent
behavior later (Kandel et al., 1989). In children with
gelastic seizures (Chapter 26.2) and hypothalamic hamartomas (Chapter 19.3a), high rates of aggression are found
(Weissenberger et al., 2001). A rare syndrome that probably affects the hypothalamus has been described in two
unrelated boys who suffered from adipsic hypernatremia,
inappropriately low plasma vasopressin levels, possibly
due to a selective osmoreceptor dysfunction, hyperprolactinemia and an exaggerated prolactin response to
TRH, associated with aggressive behavior. No intracranial
lesions were found (Dunger et al., 1985). Moreover,
(c) Postviral fatigue syndrome

Another closely related syndrome is postviral fatigue
syndrome. It is a chronic disorder with an acute onset
and a fluctuating course that occurs either sporadically or
in epidemics. The disease follows an acute viral infection
and is characterized by overwhelming fatigue. As a rule
there is a variable degree of myalgia. Most patients
develop, in addition, a number of other symptoms that
suggest hypothalamic dysfunction, including changes
in body weight and appetite, minor fluctuations in
body temperature, excessive sweating, a reversed pattern
of sleep, excessive sleep, impaired libido, menstrual
irregularities, depression, and sometimes fluid retention.
Secretion of vasopressin may be erratic in these patients
as appeared from the lack of correlation between serum
and urine osmolality and plasma vasopressin levels and
the baseline vasopressin levels are low (Bakheit et al.,
1993; Bell, 1994). In addition, an increased sensitivity of
hypothalamic 5HT receptors was found. The buspirone
challenge test to determine the functional activity of hypothalamic 5-HT receptors showed upregulation of these
receptors in patients with postviral fatigue syndrome, and
not in those with primary depression. An increased
prolactin response to this serotonin reuptake inhibitor was
found in these patients, most of whom had objective
evidence of muscle damage. In contrast, a significantly
lower prolactin response to buspirane was found in
patients with a primary depression (Bakheit et al., 1992).
Patients with primary adrenal failure (Addisons
disease) have increased daytime fatigue, but no more day
time sleepiness than normal (Lvs et al., 2003).
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pregnancy or obstetric complications are associated

with conduct problems in childhood and with antisocial
personality disorder or frank criminality in adulthood. In
particular birth complications in combination with early
child rejection predisposes to violent crime. The rates
of crime are particularly high in a subgroup of subjects
with early neuromotor deficits and unstable family
environments (Kandel and Mednick, 1991; Raine et al.,
1994, 1996). A combination of pregnancy complications
and inadequate parenting increases the risk of violent and
nonviolent offending only slightly. However, inadequate
parenting was experienced by 5 times as many cohort
members than was the combination of inadequate
parenting and pregnancy complications (Hodgins et al.,
2001). In addition, prenatal exposure to wartime famine
during the first or second trimester is associated with an
increased risk of violent antisocial personality disorder
(Neugebauer et al., 1999). A higher potential for physical
aggression is found following exposure to androgen-based
synthetic progestins during gestation (Reinisch, 1981) and
an increased risk factor for conduct disorder, delinquency,
and attention-deficit conduct disorder of the offspring is
observed following maternal smoking during pregnancy
(Rantakallio et al., 1992; Wakschlag et al., 1997;
Fergusson et al., 1998; Brennan et al., 1999b; HellstrmLindahl and Nordberg, 2002). For women who smoke
more than 10 cigarettes per day from the 4th month of
pregnancy, it can be predicted almost with certainty that
their children will show behavioral problems, including
delinquency, 16 years later, according to Bagley (1992).
A recent study suggests that the association between
maternal smoking during pregnancy and conduct disturbance symptoms in boys may be attributed to the
transmission of a latent conduct disorder factor rather
than to a direct effect of smoking (Silberg et al., 2003).
Low HPA axis activity as is apparent from plasma or
salivary cortisol is also a correlate of severe and persistent
aggression in children and adolescents as seen in conduct
disorder (McBurnett et al., 2000; Pajer et al., 2001). In
children with opposite defiant disorder or conduct
disorder, the adrenal androgen functioning, as measured
by DHEAS levels is elevated. These children are at risk
for criminality and antisocial personality disorder in
adulthood. It is speculated that the HPA axis is activated
due to stress or genetic factors (Van Goozen et al., 2000b).
An exciting possibility is that adults with refractory
anxiety and/or maladaptive behavior, high DHEAS and
low cortisol levels have late-onset congenital adrenal
hyperplasia that reacts favorably to treatment of the
endocrine disorder. Ketoconazole normalizes DHEAS

and decreases the level of anxiety and aggressive
behavior. In victims of intimate-partner physical and
sexual violence, the mean cortisol levels are significantly
decreased (Seedat et al., 2003). The various data on the
possible organizing effects of testosterone on aggressive
behavior in humans are not always in agreement (Mazur
and Booth, 1998). Although in violent men testosterone
levels are not different from those of nonviolent men, the
testosterone levels in violent men correlated significantly
with hostility. Individuals whose life histories involve
numerous antisocial behaviors tend to have higher testosterone levels (Aromki et al., 1999). In another study
personality disorder criminals with multiple offences had
high serum testosterone levels (Rsnen et al., 1999). The
use of anabolic androgenic steroids may also lead to
aggressive reactions (Pope et al., 2000) and accompany
antisocial personality traits (Yates, 2000). The aggressiveness in early childhood autism is presumed to be due
to excessive brain opioid activity (Leboyer et al., 1992).
Aggression, hypersexuality and violent rape attempts have
been reported as manifestations of rabies (Gmez-Alonso,
1998). The combination of head injuries, perinatal
difficulties, parental psychopathology (e.g. as indicated
by the presence of a schizophrenic parent and social
deprivation particularly as manifested by the failure of
the physician to diagnose or appropriately treat psychiatric
illness or CNS dysfunction, or to failure of society to
provide adequate support is sufficient to create a young
offender. This combination of factors occurs frequently
(Lewis et al., 1979). Moreover, aggression has been
described in attention-deficit hyperactivity disorder
(Jensen and Garfinkel, 1988; Siponmaa et al., 2001),
pervasive developmental disorder not otherwise specified,
Aspergers syndrome, Tourettes syndrome (Siponmaa
et al., 2001) and neurosarcoidosis (Bona et al., 1998;
Chapter 21.1).
Aggressive behavior appears as a component of
numerous neuropsychiatric diseases including Alzheimers
disease, affective disorders, schizophrenia, tertiary syphilis,
brain tumors, temporal lobe epilepsia, encephalitis, normalpressure hydrocephalus, traumatic brain injury, mental
retardation, stroke, infection, developmental disorders,
MS, Parkinsons and Huntingtons disease. Such behavior
usually falls into the category of defensive rage and is
linked to the limbic hypothalamic-midbrainperiaquaductul gray axis (Ryan, 2000; Gregg and Siegel, 2001),
although the structural basis is usually far from proven.
Hypothalamic hamartoma (Chapter 19.3) frequently lead
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to oppositional defiant disorders and significant rates

of aggression (Weissenberger et al., 2001). A rare cause of
aggressive behavior is idiopathic hypothalamic dysfunction, a paraneoplastic syndrome (Chapter 32.1; Ouvrier
et al., 1995).
285
hypothalamus. One case has been reported of a man with

a tumor in the medial hypothalamus who flew into a rage
when somebody dared to argue with him. Other cases are
known, but the behavioral descriptions are less complete.
Some indication that mediohypothalamic lesions may
cause aggressive behavior comes from the unilateral
hypothalamic lesions in sex offenders some of which
would display considerable affective excitability and lack
of control and appeared to be less inhibited than before
the operation (see Chapter 24.5; Albert et al., 1993). After
surgical removal of a craniopharyngioma and damage of
the ventral hypothalamus, a 32-year-old man developed
a tetrad of neurobehavioral changes, consisting of episodic
rage, emotional lability, hyperphagia with obesity and
memory impairment with intellectual decline. Not only
did he verbally abuse the family, hospital staff and fellow
patients, but also impulsively destroyed the contents
of a garage, a pool table, patio doors, door bolts,
bedroom windows, water fountains, fire extinguishers and
numerous pieces of furniture. Caretakers were often
injured during attempts to intervene, although the unprovoked violence was rarely directed specifically at
individuals (Flynn et al., 1988). A 22-year-old woman
with anorexia nervosa due to a craniopharyngioma has
reported that she had urges to kill people (Climo, 1982).
In the rat, aggression can be induced by a hypothalamic
attack area below the fornix, just lateral and frontal
of the VMN in the hypothalamus. This area almost
completely coincides with the intermediate hypothalamic
area and the ventrolateral pole of the hypothalamic VMN
(Roeling et al., 1994; Kruk et al., 1998). Neoplastic
destruction of the VMN has indeed been associated with
unplanned impulsive aggression (Ryan, 2000).
The SCN is presumed to be responsible not only for
day/night rhythms, but also for circannual rhythms
(Chapter 4.3) and may thus be involved in rhythmic occurrence of aggressive behavior. Suicide, which can be
considered to be self-directed aggression, occurs more
frequently during the day than during the night (Altamura
et al., 1999). Aggression toward others is mainly observed
in the evening and at night (Laubichler and Ruby, 1986).
Profound diurnal activity disturbance with increased
diurnal physical activity is found in alcoholic, impulsive,
violent offenders with intermittent explosive disorder
(Virkkunen et al., 1994). In the United States, an annual
rhythm has been found in rapes, assaults and battering
of women, with maximum values in summer. In contrast,
there is a virtual absence of seasonal changes in numbers
of murders. A close relationship has been found between
(b) Hypothalamic structures involved

A number of hypothalamic structures and transmitter
systems seem to be involved in aggression. Animal experiments have shown that, after cortical ablation, stimulation
of the posterior lateral hypothalamus elicits sham rage,
a combination of hissing, pilo-erection, pupil dilation
and extension of the claws. Electrical stimulation of the
median preoptic area or the sexually dimorphic nucleus
within this area (Chapter 5) in the rat may also elicit or
enhance aggression (Merari and Ginton, 1975; Gorski,
2002). Stimulation of the human medioposterior or
caudolateral hypothalamus during neurosurgical procedures elicits fear or horror (Carmel, 1980). Tumors in the
human septal area are also associated with a heightened
defensiveness. Patients have been described with
outbursts of temper and violence and have become
increasingly irritable, unreasonably angry, abusive
verbally and threatened physicians. She attacked her
husband with a paring knife (Albert et al., 1993). Some
patients have been incarcerated and even died whilst
in jail, sentenced because of hypersexuality, fetishism,
sexually assaulting a minor and other aberrant sexual
behaviors; they were later found to have (by MRI or
autopsy) multiple sclerous lesions in the hypothalamus,
septum and other brain areas (Frohman et al., 2002).
Von Economo (see Chapter 20.2) has suggested that
encephalitis lethargica in the anterior part of the hypothalamus is related to aggression. Aggression in humans
increases with tumors in the medial hypothalamus. Reeves
and Plum (1969) have described a 20-year-old woman
with a hamartoma that had destroyed the ventromedial
hypothalamus. She developed bulimia, obesity, amenorrhea and diabetes insipidus. In addition she developed
outbursts of aggression, hitting, scratching or biting
examiners who approached, indicating that the midhypothalamus plays a role in such aggressive behaviors.
Another case is that of a 26-year-old woman who showed
hyperphagia, obesity and aggressive behavior due to a
hypothalamic astrocytoma in the region of the midhypothalamus (Haugh and Markesbery, 1983). A number
of other cases have been reported where heightened
aggression is associated with a tumor in the medial
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assaults, battering and rapes on the one hand and ambient

temperature on the other. Human violence seems thus to
be influenced by environmental factors such as light and
temperature (Michael et al., 1983, 1986). Yearly rhythms
in ambient temperature or light/dark cycles can serve
as Zeitgebers (Altamura et al., 1999). This idea is
reinforced by the observation that, under rigorously
controlled laboratory conditions and a constant photoperiod, male rhesus monkeys show a clear annual cycle
of aggression toward their female partners. Aggression is
most severe between August and October, which corresponds with the time when plasma testosterone reaches
maximum levels, and with the mating season, when
aggression increases normally in the wild (Michael and
Zumpe, 1978). Schreiber et al. (1991a) have reported the
presence of seasonal rhythms in the opening dates of
wars. They base their analysis upon 2,121 acts of hostility.
In the Northern hemisphere, the annual opening dates
of wars show a peak in August and a nadir in January,
while an inverse pattern is seen in the annual rhythms
of wars in the Southern hemisphere, with a peak in
DecemberFebruary and a nadir in July. A constant rate
of acts of hostility is found throughout the year around
the line of the equator. Elongation of the daily photoperiod may thus induce increases in affective
aggressiveness. Several studies have reported seasonal
variations in suicide with annual and semiannual rhythms.
In the Netherlands, train suicides also appeared to be
influenced by season (Van Houwelingen and Beersma,
2001). One study has shown seasonality to be present in
violent, but not in nonviolent suicide. Peaks are present
in MarchApril and August in younger and elderly
persons, respectively, and lows in DecemberJanuary
(Maes et al., 1993a). The latter study could, however, not
confirm the seasonality for homicide, as reported by
Smolensky et al., 1983. In the study of Morken and
Linaker (2000) a seasonal rhythm in violent incidents
was found with one peak in MayJune and one in
OctoberNovember.
Excessive cholinergic stimulation (perhaps acting on
receptors within the hypothalamus) may promote serious
aggression in man. In the intact animal, attack behavior
can be facilitated by injecting acetylcholine into the
hypothalamus, while a cholinergic blocker will eliminate
a biting attack, even in naturally aggressive cats or
rats (Bear, 1991). One interesting case study comes from
a scientist who treated his pets with a tick powder
containing a potent cholinesterase inhibitor. His cat initiated predatory stalking and began to kill birds and mice
in large numbers. The scientist developed a concomittant

rage that led to uncharacteristic violent arguments on
many subjects, accompanied by flushing and threats.
The aggressiveness led a long-time companion to flee the
house. Within a week of terminating the use of the
cholinesterase inhibitor, aggression ceased in both cat and
man (Bear, 1991). On the other hand, cholinergic deficit
in the cortex of Alzheimer patients correlates with aggressive behavior (Minger et al., 2000). Animal experiments
and increased vasopressin levels in CSF in humans
suggest that central vasopressin plays a facilitary role
in aggressive behavior, while 5-HT may play a role in
inhibiting aggressive behavior in personality-disordered
individuals. The relationship between the CSF vasopressin
levels and a life history of aggression is stronger among
male than among female subjects. In addition, central
catecholaminergic, opiate and ACTH systems are considered to play a role in aggression (Brunner et al., 1993;
Coccaro et al., 1998; Manuck et al., 1999; Ryan, 2000).
Concerning the latter compounds, it is of interest that, in
patients displaying violent suicidal behavior, both in those
who have recently attempted suicide and in those with a
history of suicidal behavior, increased cortisol excretion
and reduced noradrenalin functioning are observed (Van
Heeringen et al., 2000). In addition, oppositional deficient disorder, also combined with attention deficit
disorders, is accompanied by low cortisol levels in children (McBurnett et al., 2000; Kariyawasam et al., 2002).
Perpetrators of domestic violence without alcohol dependence have lower CSF 5-HIAA levels (George, 2001),
while the serotonergic system interacts in various ways
with hypothalamic and endocrine systems. For instance,
alcoholic, impulsive offenders with antisocial personality
disorder have low CSF 5-HIAA and ACTH levels
(Virkkunen et al., 1994).
(c) Sex hormones and aggression
Men in society are much more aggressive than women,
yet under laboratory conditions similar propensities
toward aggression are found. The between-sex differences
are about one-third to one-half of the within-sex standard
deviation. Although 80% of the homicides in North
America are committed by males, this sex difference is
not reflected by homicide within marriage. Apparently
the situation in which aggression is committed is an
important influence on these sex differences (Albert
et al., 1993). In addition, in women correlations have
been reported between the premenstrual or menstrual
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phase and violent crimes and suicides (Parlee, 1973),

indicating a relationship between hormones of the gonadal
axes and violence. Women with bulimia nervosa have
increased plasma testosterone levels that correlate with
aggressiveness in patients but not in controls (Cotrufo
et al., 2000).
A link between testosterone and aggressive behavior
in humans has often been presumed and some studies
indeed claim such a relationship (e.g. Dabbs et al., 1987;
Ryan, 2000). For instance. in competitive hockey,
outbursts of violent behaviors as a response to threat show
a positive correlation with serum testosterone levels
(Scaramella and Brown, 1978). In addition, it has been
found that individuals who have a history of numerous
antisocial life histories tend to have higher testosterone
levels (Aromki et al., 1999). Perpetrators of domestic
violence with alcohol dependence have higher CSF testosterone levels than such perpetrators without alcohol
dependence or healthy controls (George et al., 2001). In
addition, higher CSF levels are observed in alcoholic,
impulsive offenders with antisocial personality disorder.
However, the serum testosterone levels of high- and
low-aggression individuals do not differ consistently,
aggression does not change at puberty when testosterone
levels increase, nor does aggression increase in hypogonadal males when testosterone is substituted. Aggression
also does not seem to increase in hirsute females, even
though testosterone levels may double, and castration or
antiandrogen administration in men is not associated with
a consistent decrease in aggression. The antiandrogen
cyproterone acetate inhibits sexual activity but not aggression (Albert et al., 1993). A number of studies have
indicated that following castration a substantially reduced
recidivism rate is found in sexual offenders. In addition,
cyproterone acetate may reduce deviant sexual arousal as
shown in, e.g. a case study on a sadistic homosexual
pedophile of 23 years of age with a serious, chronic
organic brain syndrome (Bradford and Pawlak, 1987).
Aggression in humans has, according to some authors, a
number of features in common with defensive aggression
seen in nonprimate mammals, rather than having its
biological roots in hormone-dependent aggression based
on testosterone (Alpers, 1937; Albert et al., 1993; see
also citation at the beginning of Chapter 26.9).
Mazur and Booth (1998) share the doubts expressed
by Albert et al. (1993) that circulating testosterone directly
affects human aggression, i.e. the intentional infliction of
physical injury. Instead, they favor the hypothesis that
high or rising testosterone encourages dominant behavior
287
intended to achieve or maintain high status (implying

power, influence and valued prerogatives). Sometimes
dominant behavior is aggressive, its apparent intent being
to inflict harm to another person, but often dominance is
expressed nonaggressively. Sometimes dominant behavior
takes the form of antisocial behavior, including rebellion
against authority and the breaking of laws. Measurement
of testosterone predicts many of these dominant or antisocial behaviors testosterone levels, aggressiveness and
antisocial behavior all peak in the late teens and early
twenties, and then slowly decline throughout adult life in
men. However, the causal role of testosterone remains
an unanswered question. Testosterone not only affects
behavior, it also responds to it. Testosterone rises in the
face of a challenge. After a competition testosterone rises
in winners and declines in losers. In prepubertal boys
with a conduct disorder, the adrenal androgen levels of
DHEAS and androstenedione were elevated, suggesting
that adrenal androgens may play a role in the onset and
maintenance of aggression in young boys (Van Goozen
et al., 1998b). Aggression in two men with dementia and
aggressive physical behavior was recuced after treatment
with conjugated estrogen or diethylstilbestrol (Ryan,
2000).
(d) Stereotactic hypothalotomy
It is alarming to know that hundreds, if not thousands,
of patients have undergone primary or secondary stereotactic posteromedian hypothalamotomy for untreatable
aggressiveness, with claims of high improvement rates.
The operation was based upon the animal experimental
observation that sham rage arose from the hypothalamus (see above). Some surgeons preferred primary
unilateral hypothalamotomy (Sano et al., 1970; Schvarcz
et al., 1972; Schvarcz, 1977), whereas others performed
bilateral amygdalatomy as a first step and proceeded 812
weeks later with secondary unilateral hypothalamotomy
in those cases where the first operation had not been
successful (Ramamurthi, 1988). The patients were
reported to become calm, passive, and tractable, and
showed decreased spontaneity. Intelligence was not
impaired (Sano et al., 1966). However, quantitative data
are lacking. Amazingly, many of the patients were
children under the age of 15 years, and even as young
as 6 or 7 years, who had developed aggressive behavior
as a result of some insult of the brain. Although it is
not clear, on the basis of scientific evidence, that this
region is related to aggressive behavior, the target
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area for the stereotactic operations in the posteromedian

hypothalamus was identified by autonomous stimulation
effects (Chapter 30) such as a rise in blood pressure, pulse
rate, apnea and ocular movements. This area was called
the ergotropic triangle, based upon the subdivision
made by Hess. It lies more than 1 mm and less than
5 mm lateral to the lateral wall of the third ventricle,
where it occupies a triangle formed by the midpoint of
the intercommissural line, the rostral end of the aqueduct
and the anterior border of the mamillary body. The
larger part of the lesion side thus lies posterior to the
hypothalamus, but the area includes at least the posterior
part of the posterior hypothalamic nucleus (Sano et al.,
1966, 1970; Ramamurthi, 1988; Sano and Mayanagi,
1988; Chapter 13.3). Also children with low IQ and a
wild form of aggressiveness (oligophrenia erethica or
agitated idiocy) have undergone such operations where
lesions of less than 6 mm in diameter are made. After
the operation all the auto- and heteroaggression disappeared. Agitation also improved enormously, and these
children were said to be able to live at home and mix
with other children (Arjona, 1974; Rubio et al., 1977;
Laitinen, 1988). The patients became tame and passive

and showed decreased spontaneity. The latter two
symptoms improved within the 1st month. The patients
were not emotionally flat; but restlessness lessened. In
addition, this operation was performed on schizophrenic
patients with extremely severe restlessness, agitation
and autodestructiveness, with good results, according
to Laitinen (1988), who concludes I feel that posteromedial hypothalamotomy is one of the most rewarding
psychosurgical interventions. At this moment we can
only point to the risks of such operations (Sramka

and Ndvornk, 1975; Rubio et al., 1977), to their poor
scientific basis and evaluation, to the unacceptable ethical
problems involved and to the fact that this procedure has
not been confirmed or accepted in the meantime.
I am convinced that if we succumb to the temptation to use
violence in our struggle for freedom, unborn generations
will be the recipients of a long and desolate night of
bitterness, and our chief legacy to them will be a neverending reign of chaos.
Martin Luther King, from
The Words of Martin Luther King, 1958.
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D.F. Swaab, author
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CHAPTER 27
Schizophrenia and autism
I believe that the great diseases of the brain . . . will be

shown to be connected with specific chemical changes in
neuroplasm . . . It is probable that by the aid of chemistry,
many derangements of the brain and mind, which are at
present obscure, will become accurately definable and
amenable to precise treatment, and what is now an object
of anxious empiricism will become one for the proud exercise
of exact science.
J.L.W. Thudicum. A Treatise on the Chemical
Constitution of the Brain Based throughout
upon Original Researches (1884)
and Lawrie, 1995; ODwyer, 1997; Rantakallio et al.,

1997; Squires, 1997; Van Os and Selten, 1998; Vincent
et al., 1999; McNeil et al., 2000; Zornberg et al., 2000;
Verdoux and Sutter, 2002). A meta-analysis revealed
three groups of obstetric complications to be significantly
associated with schizophrenia: (i) complications of
pregnancy (bleeding, diabetes, rhesus incompatibility,
preeclampsia); (ii) abnormal fetal growth and development (low birth weight, congenital malformations,
reduced head circumference); and (iii) complications of
delivery (uterine atony, asphyxia, emergency cesarean
section). However, pooled estimates of effect sizes were
generally less than 2 (Cannon et al., 2002). In addition
one may presume that the increased frequency of obstetric
complications may be the first sign of a disorder of brain
development in schizophrenia, rather than that birth
complications have a negative impact on brain development and increase the risk of schizophrenia (see Chapter
8.1). No significant association has been found between
prenatal exposure to the maternal stress of the Dutch flood
disaster of 1953 and the risk of nonaffective psychosis
(Selten et al., 1999a), but the stress of war is a risk factor
for schizophrenia (Van Os and Selten, 1998). It has been
proposed that jet lag may elicit psychosis and even schizophrenia (Katz et al., 2001). A significant relationship is
found between season and schizophrenia incidence, which
may be related not only to viral infections, but also to
parental procreational habits (Battle et al. 1999; Suvisaari
et al., 2001). However, neither influenza nor measles is
predictive of schizophrenia prevalence (Battle et al.,
1999). In addition, no relationship has been observed
between second-trimester exposure to the 1957 influenza
Our hope for the future lies . . . in organic chemistry or in an

approach to (psychosis) through endocrinology. Today this
future is still far off, but we should study analytically every
case of psychosis because the knowledge thus gained will
one day direct the chemical therapy. Sigmund Freud in a
letter to Marie Bonaparte, 1930 (cited by Nemeroff, 1998).
27.1. Schizophrenia
Als ik mijn pillen niet meer neem, word ik meer schizo
dan freen. Kees Winkler.1
(a) A developmental disturbance

Schizophrenia is considered to be a multifactorial
disorder of brain development in which various risk
factors may play a role, such as genetic factors (see
below), chromosome 22q11 deletion (Chow et al., 2002),
advanced paternal age (Malaspina et al., 2002a), viral
infections, metabolic factors during pregnancy or early
childhood, prenatal exposure to maternal stress or
obstetric complications (Susser et al., 1992, 1996; Geddes
Without my pills I am more schizo than phrenic.
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Fig. 27A.
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Malle Babbe. Frans Hals (1582/831666). Kat. Nr. 801 C, Staatliche Museen, Berlin, Gemldegalerie. Photograph: Jrg P. Anders,
with permission.
pandemic and risk of nonaffective psychosis in the Dutch

population (Selten et al., 1999b), which does not support
the possible relationship between maternal influenza and
schizophrenia reported by others. The first episode of
schizophrenic psychosis appears to be spared any seasonal
fluctuations (Strous et al., 2001). Exposure to nutritional
deficiency, which is a risk factor for schizophrenia, during
fetal life in the Dutch hunger winter, is associated with
decreased intracranial volume and with an increase in
brain abnormalities, predominantly white-matter hyper-
intensities (Hulshoff Pol et al., 2000). Another observation in favor of developmental sequelae in schizophrenia
is that the risk of developing not only schizophrenia, but
also a schizoid personality is increased following prenatal
exposure to famine (Hoek et al., 1998). In addition, breastfeeding postpones the onset of schizophrenia (Amore
et al., 2003).
Various genetic factors may play a role. 22q11 deletion
syndrome is a genetic syndrome associated with an
increased risk of developing schizophrenia (Chow et al.,
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2002). Some 6.3% of Klinefelter patients (see Chapter

24.4) are diagnosed as suffering from schizophrenia, and
5.8% of having a psychosis of uncertain type (Wakeling,
1972). A high frequency of 7-nicotine receptor
polymorphism has been reported in schizophrenia. It is
presumed not only to be involved in the pathogenesis
of this disorder, but also to be responsible for the
heavy smoking habits of schizophrenics (Stassen et al.,
2000). Moreover, catechol-O-methyl transferase gene
polymorphism was found to influence the susceptibility
to schizophrenia in a Japanese family (Ohmori et al., 1998;
Weinbergen et al., 2001), while polymorphism in the
tyrosine hydroxylase (TH) gene (Ishiguro et al., 1998)
or in the promotor region of the neurotrophin-3 gene
(Hattori et al., 2002) was found not to play a major role
in the genetic predisposition to schizophrenia by others. It
has been proposed that the different risk factors mentioned
above may lead to changes in membrane phospholipid
metabolism and fatty acid levels, as well as alterations in
metabolism in certain brain areas (Horrobin et al., 1991;
Pettegrew et al., 1991). Because children of women with
schizophrenia are genetically predisposed to schizophrenia, it is of considerable interest that these children
are also at risk for adverse pregnancy outcome. Children
of women with schizophrenia are generally of lower birth
weight, shorter gestational duration and increased risk of
prematurity compared with the general population
(Bennedsen et al., 1999). A major source of new mutations in humans is the male germ line, with mutation rates
monotonically increasing as the fathers age at conception
advances, possibly because of accumulating replication
errors in spermatogonial cell lines. Paternal age is also a
strong and significant predictor of schizophrenia that
might thus also be associated with mutations in the
paternal germ line. The odds of schizophrenia in offspring
of fathers that are 45 years old are 2.8 times as great as
in offspring of fathers aged 2024 years of age (Malaspina
et al., 2001, 2002a; Dalman and Allebeck, 2002).
The high frequency of structural brain abnormalities
reported in schizophrenia agrees with the developmental
hypothesis. Enlargement of the ventricles, reduction of
brain volume of temporal gyri, of gray matter, hippocampal and of entorhinal cortical volume have been
reported. In contrast, the striatum is enlarged. Moreover,
according to some studies, the massa intermedia or
adhesio interthalamica (Chapter 6.2) is more frequently
absent in female schizophrenic patients than in controls
(Nopoulos et al., 2001), a difference that is not present
in male schizophrenic patients (Meisenzahl et al., 2002).
291
In fact, factors that produce normal sexual dimorphisms

in the brain may be associated with modulating insults
that produce schizophrenia (Goldstein et al., 2002).
Cytoarchitectural abnormalities have been observed in
the hippocampus and entorhinal cortex; also structures
adjacent to the hypothalamus are affected. MRI and CT
scans reveal a higher proportion of midline cerebral
malformations in schizophrenia, such as cavum vergae
and cavum septum pellucidum (Scott et al., 1993;
see Chapter 18.8) and isolated absence of the septum
pellucidum (Supprian et al., 1999). The prevalence of a
cavum septum pellucidum has been found repeatedly
to be increased in schizophrenia (Rajarethinan et al.,
2001). In an MRI study, the prevalence was 2630%
for schizophrenic patients (Fukuzako and Kodama, 1998;
Kwon, 1998) and 19% for schizotypical personality
disorder, while in controls the prevalence was 10%
(Fukuzako and Kodama, 1998; Kwon et al., 1998). In
another MRI study, the frequency of enlarged cavum
septum pellucidum was 13% in patients with childhoodonset schizophrenia compared with 1% in healthy
volunteers. Two of the three patients with an enlarged
cavum septum pellucidum had complete nonfusion
of the septal leaflets, underlining the hypothesis that a
developmental disorder may lie at the basis of schizophrenia (Nopoulos et al., 1998). Failure of fusion of the
cavum septum pellucidum is associated with thought
disorder in schizophrenia (Kirkpatrick et al., 1997) and
with poor prognosis (Fukuzako and Kodama, 1998). The
combination of cavum septum pellucidum and schizophrenia has been linked to hemizygous chromosome
22q11 deletion (Catch 22 syndrome) and to partial trisomy
of chromosome 5 (Vataja and Elomaa, 1998). However,
there are also studies that do not confirm a higher prevalence of cavum septum pellucidum in schizophrenia
(Hagino et al., 2001). In the anterior commissure a
reduction in fiber density is found in female but not in
male schizophrenia patients (Highley et al., 1999).
Olfactory deficits are found in particular in the subgroup
of schizophrenic patients with severe polydipsia and
hyponatremia (Kopala et al., 1998). In deficit syndrome,
i.e. schizophrenic patients with enduring negative symptoms, an olfactory dysfunction was found (Malaspina
et al., 2002b). Schizophrenic patients have not only
functional olfactory deficits, but also structural ones. The
olfactory bulb is 23% smaller than in comparison subjects
(Turetsky et al., 2000). Patients without an adhesio interthalamica had significantly higher scores for negative
symptoms (Meisenzahl et al., 2002).
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Patients with schizophrenia are no more prone to the

development of Alzheimers disease than the general
population (Bozikas et al., 2002).
(b) Hypothalamic involvement
The intersecting lines above the pituitary fossa were intended
by Leonardo da Vinci (14521519) to show the senso comune
(common sense). This position corresponded approximately
to the third ventricle of the brain and, interestingly, was
supposedly the locus of the soul in those days (Pevsner,
2002).
The possible involvement of the hypothalamus in the

symptomatology of this psychosis is suggested by those
cases that were first diagnosed as schizophrenia but
appeared to have a tumor of the hypothalamic region
(Malamud, 1967; Table 26.1). Psychotic symptoms have
also been observed in patients with other hypothalamic
disorders. In PraderWilli syndrome, a hypothalamic
syndrome with mental retardation (Chapter 23.1),
psychotic episodes have been described, but it is not clear
whether they are indeed more prevalent in this syndrome
(Clarke, 1993; Clarke et al., 1995). Hallucinations also
occur in acute intermittent porphyria (Chapter 28.3),
narcolepsy and diencephalic tumors (Carroll and Neal,
1997). An astrocytoma of the visual pathway can lead to
visual hallucinations (Haugh and Markesbery, 1983).
Moreover, neurosarcoidosis, a disease that preferentially
affects the hypothalamus (Chapter 21.1), has been
confused with schizophrenia (Bona et al., 1998).
Hallucinations were found in one case of Nasu-Hakola
syndrome with hypothalamic hemorrhage (Kobayashi
et al., 2000). In spite of the fact that hypothalamic
processes may lead to schizophrenic symptoms, the
neuropathology of the hypothalamus in schizophrenia has
received only little attention. Stevens (1982) has reported
increased, patchy fibrillary gliosis in the periventricular
nuclei of the hypothalamus, bed nucleus of the stria
terminalis, septal nuclei, substantia innominata, diagonal
band of Broca and preoptic area in schizophrenic patients,
suggesting previous or low-grade inflammation, as is
found, e.g. secondary to an infectious or immunological
disorder. There was no active inflammatory activity in
these patients. A morphometric study has shown that the
left, but not the right, mamillary body is significantly
larger in schizophrenic patients, whereas neuronal
numbers are the same on both sides (Briess et al., 1998).
Loss of the large, presumably cholinergic neurons of
the nucleus basalis of Meynert has been described (Kish

et al., 1990). Several neuroradiological and scanning
studies have shown not only enlargement of the lateral
ventricles in schizophrenia, but also atrophy of the
periventricular gray matter surrounding the third ventricle
at the level of the sulcus hypothalamicus (Lesch and
Bogerts, 1984). Cullberg and Nybck (1992) have found
that third-ventricle enlargement is significantly associated
with the persistence of auditory hallucinations in patients
with schizophrenia. In addition, Jones et al. (1994) have
shown that there is an association between larger third,
but not lateral, ventricular size in affective psychosis.
Staal et al. (2000) have found no difference in thirdventricle volume between schizophrenic patients and
their healthy siblings. However, both have higher third
ventricle volumes than the comparison subjects. From a
follow-up study, it was concluded that enlargement of the
third ventricle appeared to relate to poor outcome in schizophrenia (Staal et al., 2000).
(c) Hypothalamic neurotransmitters, neuromodulators
and neurohormones
I emerged from irrational thinking ultimately without medicine
other than the natural hormonal changes of aging.
John Nash, Nobel laureate, who developed
schizophrenia at age 32.
The dopamine hypothesis has dominated schizophrenia

research for a long time. Increased dopamine activity
would lead, in particular, to the positive symptoms of
schizophrenia (Tandon, 1999). Dopamine has been called
the wind of the psychotic fire (Laruelle and AbiDargham, 1999). However, the new atypical antipsychotic
drugs improve glutaminergic transmission (Rao and
Klsch, 2003), and it is also becoming clear now that many
other neurotransmitter and neuromodulatory systems are
affected in different brain areas, including the hypothalamus. Various changes in vasopressin and oxytocin neurons and levels have been reported in schizophrenia. Mai
et al. (1993), have observed strongly decreased numbers
of neurophysin-containing neurons in the paraventricular
nucleus of untreated schizophrenic patients, but not in their
supraoptic nucleus (SON). Unfortunately, the staining
used by these authors did not distinguish between vasopressin- neurophysin or oxytocin neurophysin. Polydipsia
and polyuria are relatively common in drug-free schizophrenic patients. Neuroleptic treatment is associated with
a further significant increase in urine volume (Lawson
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et al., 1985). Complex changes in water metabolism with

possible involvement of vasopressin have been reported
in schizophrenia (Spigset and Hedenmalm, 1995).
Compulsive water drinking and polyuria are found in some
20% of chronic schizophrenics (Legros and Ansseau,
1992). Water intoxication is a serious problem in many
patients suffering from a chronic psychiatric illness, as are
polydipsia and hyponatremia (Goldman et al., 1988;
Verghese et al., 1993; McKenna and Thompson, 1998; see
Chapter 22.3). So far, these phenomena seem to be due to
unexplained defects in urinary dilution, osmoregulation or
water intake and in the secretion of vasopressin.
A reset osmostat and upregulation of vasopressin
receptors in the kidney has been presumed (Goldman
et al., 1988; Goldman, 1999). For reasons that are not quite
clear, 35% of chronic schizophrenic patients are hyponatremic, develop the syndrome of inappropriate antidiuretic
hormone secretion (SIADH) and experience life-threatening episodes of water intoxication that may lead to
seizures, delirium, irreversible neurologic defects, coma
and death (Spigset and Hedenmalm, 1995; Goldman et al.,
1997). Hyponatremia occurs particularly if patients are
treated with drugs that reduce free water clearance, such
as carbomazepine and phenothiazines. Acute severe
hyponatremia leads to convulsions and coma. Chronic
schizophrenic patients with chronic antipsychotic medication develop abnormal vasopressin, aldosterone and
atrial natriuretic peptide secretion during anesthesia for
abdominal surgery (Kudoh et al., 1998). Exaggerated
vasopressin responses to osmotic stimulation have also
been reported in comparison with nonpolydipsic schizophrenic patients with normal suppression of vasopressin
levels after drinking. The osmotic threshold for thirst falls
below that for vasopressin release, so that drinking to suppress plasma osmolality fails to suppress vasopressin
release and therefore constant hypotonic diuresis develops
(Goldman, 1999).
The pathophysiology of abnormal thirst in schizophrenics is unknown, but may be based upon a defect in
the central integration of thirst in the higher centers, rather
than on a lesion in the osmoreceptors (McKenna and
Thompson, 1998). Polydipsia is present in some 20% of
chronic psychiatric inpatients and hyponatremia in more
than 10% (De Leon, 2003). In the group of polydipsic
schizophrenic patients, psychotic exacerbations are associated with chronic hyponatremia and with enhanced
plasma levels of vasopressin. The exacerbated psychosis
seems to be responsible for the enhanced vasopressin
release. However, in a group of closely matched, nor-
293
monatremic schizophrenic patients, vasopressin levels

rose only a little, if they rose at all (Goldman et al., 1997).
Moreover, Frederiksen et al. (1991) have not observed a
difference in hypothalamic vasopressin content in
schizophrenic patients. There is also no consensus as far
as the circulating levels of neurohypophysial hormones
in schizophrenic patients are concerned (Legros and
Ansseau, 1992). Both the basal levels and the apomorphine challenge test indicated decreased vasopressinergic
and increased oxytocinergic functions in one study
(Legros et al., 1992). Reduced vasopressin levels and
their corresponding neurophysin levels have also been
observed in CSF and plasma (Sarai and Matsunaga,
1989); while, in contrast, schizophrenic patients have
been reported by others to excrete less water after water
loading, which suggests vasopressin hypersecretion
(Goldman et al., 1988; Legros and Ansseau, 1992; Spigset
and Hedenmalm, 1995; see also Chapter 22.6). Indeed,
plasma vasopressin levels are found to be increased in
acutely psychotic patients (Raskind et al., 1978). In
schizophrenic patients who underwent elective lower
abdominal surgery, abnormally high secretion of vasopressin was observed during anesthesia (Kudoh et al.,
1998). Although Beckmann et al. (1985) did not find
differences in vasopressin levels in the CSF in schizophrenia, the increased oxytocin levels in schizophrenic
patients they reported have been confirmed by Legros and
Ansseau (1992). CSF oxytocin levels in patients treated
with neuroleptics and those from whom neuroleptics were
withdrawn were unaltered in another study, suggesting
that neither schizophrenia nor neuroleptic medication
changed these neuropeptide levels (Glovinsky et al.,
1994). Yet it should be noted that various observations
indicate antipsychotic medicines might affect the activity
of the vasopressinergic system. Psychotropic drugs such
as thiothrix, amitriptylene, thioridazine and chlorpromazine might cause inappropriate antidiuretic hormone
secretion. Irreversible neurological symptoms and even
coma have been reported as a result of such effects
(Ajlouni et al., 1974; Tildesley et al., 1983; Ananth
and Lin, 1987). Also animal experiments point to a
stimulation of SON and paraventricular nuclei (PVN) in
rats treated with neuroleptics (Ireland and Connell, 1990).
In addition, electroconvulsive therapy (ECT) results in a
rise of vasopressin levels both immediately after ECT and
1 week after the last ECT (Narang et al., 1973). However,
in one patient with schizophrenia and the syndrome of
inappropriate vasopressin secretion, the hyponatremia was
found to end after recovery from psychosis by ECT
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(Suzuki et al., 1992), suggesting that hyponatremia is

related to the disease process. Consequently, a major task
is to try to distinguish disease- and treatment-related
effects in the reported hypothalamic alterations in schizophrenic patients in future research.
Neuroleptics may facilitate vasopressin secretion
(Spigset and Hedenmalm, 1995; Chapter 22.6) and
dopamine may be a vasopressin-release inhibiting or
stimulating factor (Lightman and Forsling, 1980; Chapter
8.2). An interesting question is therefore whether the
expression of TH in vasopressin neurons is involved in
such effects. In order to investigate which effects schizophrenia and the use of neuroleptics have on the activity
of vasopressin neurons in schizophrenic patients we
measured TH, mRNA and neurosecretory activity, using
the size of the Golgi apparatus in the arginine vasopressin
neurons of the dorsolateral SON of drug-treated schizophrenic patients and sex- and age-matched controls (in
collaboration with M.T. Panayotacopoulou and Y.
Malidelis, University of Athens, Greece). Significant
differences were found neither in the amount of general
protein synthetic activity of the vasopressin neurons
of the SON, nor in the total amount of vasopressin
mRNA, nor in the number of TH-immunoreactive neurons
of schizophrenic patients as compared to controls. A
stimulation of vasopressin production consequently does
not seem to be the explanation for the complex changes
in water metabolism reported in schizophrenic patients,
such as compulsive water drinking, polyuria or symptoms
of the syndrome of inappropriate antidiuretic hormone
secretion (unpubl. observation).
The typical onset of schizophrenia during late adolescence and early adulthood, during which there is a flood
of estrogens and testosterone to the brain, and the additional small peak around the age of 45 years, when
estrogen levels drop (Riecher-Rssler, 2002), has raised
interest in possible hypothalamopituitarygonadal abnormalities in this disorder. Indeed, menstrual irregularities,
a greater variation in cycle length, a later menarche,
loss of hair, mid-cycle bleeding and hirsutism have been
reported in schizophrenia (Kamstra and Fujii, 2000;
Riecher-Rssler, 2002).
Estrogens are presumed to constitute a protective factor
for schizophrenia that might be at least part of the explanation of the sex differences in this disorder. Moreover,
women suffering from schizophrenia have significantly
lower estradiol levels and experience the first onset
or recurrence of a psychotic episode more often in a
low-estrogen phase of the cycle. However, hypothalamic

downregulation of estrogen levels due to the stress of
acute hospitalization must be borne in mind as a possible
explanation of this phenomenon (Huber et al., 2001).
Although administration of transdermal estradiol appears
to have a positive impact on psychotic symptoms in
women with schizophrenia (Kulkarni et al., 2000), and
in postmenopausal schizophrenic women treated with
antipsychotic medication (sex hormone replacement
therapy may help to reduce negative but not positive
symptoms; Lindamer et al., 2001), the presumed protective effect of estrogens does not fit in with the increased
incidence of schizophrenia around puberty. Alternatively,
androgens may consequently be considered as a risk factor
for schizophrenia.
A number of other neuroendocrine abnormalities have
been reported in schizophrenia, although they may be
at least partly influenced by medication. Some, such
as an abnormal growth hormone response to thyrotropin
(TSH) and luteinizing hormone-releasing hormone
(LHRH) in adolescents, but not in adults, may indeed
reflect developmental changes. Some patients on longterm neuroleptic therapy show low insulin-like growth
factor-I (IGF-I) levels, pointing to a possible interference
with the growth hormone axis (Melkersson et al., 1999).
There is a high prevalence of thyroid function test
abnormalities in chronic schizophrenia that may, at least
partly, be due to a central disorder of the hypothalamopituitarythyroid system (Othman et al., 1994). Some
abnormalities seem to be related more directly to the
prognosis of the disease process: a rapidly neurolepticresponsive and type of psychotic disorder with a good
prognosis appears to be associated with blunted TSH
response to thyrotropin-releasing hormone (TRH) and a
blunted growth hormone response to apomorphine; a relatively drug-resistant psychotic disorder, whose response
requires several weeks of neuroleptic treatment, appears
to be associated with an excessive growth hormone
response to apomorphine (Garver, 1988). Both basal and
stimulated prolactin secretion, which are largely under
dopamine control, are said to be normal in schizophrenic
patients (Nemeroff, 1991), although in schizophrenic
patients on long-term neuroleptic therapy, prolactin levels
are elevated in 50% of the women and 1020% of the
men (Melkersson et al., 1999; Kaneda and Fujii, 2000).
The normal gradual activation of the hypothalamopituitaryadrenal (HPA) axis between 12 and 20 years
may provide an increased risk for schizophrenia in the
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pubescent period (Walker et al., 2001). Stress and

the development of a schizophrenic psychosis are inextricably related (Gispen and De Wied, 2000). The
sensitivity of the dexamethason/corticotropin-releasing
hormone (CRH) test (about 80%) greatly exceeds that of
the standard dexamethasone-suppression test (2544%)
(Heuser et al., 1994b). Schizophrenic patients, like other
psychiatric patients, are generally reported to release
significantly more cortisol and corticotropin (ACTH)
after dexamethason and additional CRH administration.
Glucocorticoid receptors are decreased in the cortex and
hippocampus (Webster et al., 2002). These observations
indicate that psychiatric patients are more prone to altered
glucocorticoid feedback regulation during the acute illness
episode. There is also evidence of a decreased response
of the HPA axis in schizophrenic patients to psychological
stress or to the stress of lumbar puncture (Jansen et al.,
1998; Gispen and De Wied, 2000). Neuroleptics may
influence HPA axis function (Kaneda and Ohmori, 2002).
In addition, an exaggerated ACTH response to acute
metabolic stress exposure is observed in schizophrenic
patients who are given 2-deoxyglucose (Elman et al.,
1998). A relationship seems to exist between negative
symptoms of schizophrenia and nonsuppression in the
dexamethasone test (Altamura, 1996). It should be noted
that, in spite of the fact that 36% of their schizophrenic
patients fulfilled the criteria for major depression, the
dexamethasone suppression rates were very low in the
study by Ismail et al. (1998), suggesting that depression
in schizophrenia may have a different neuroendocrine
profile than in major depressive disorder. Patients who
are nonsuppressors on the dexamethasone test are more
likely to be free of symptoms in a follow-up of up to
1 year. Nonsuppression is thus a prognostically favorable
sign (Coryell and Tsuang, 1992). Higher cortisol plasma
levels accompany lower metabolic rate in the hypothalamus as measured by PET scanning (Wik, 1996).
The reduced number of nitric oxide synthase-containing/
NADP-diaphorase neurons in the PVN of schizophrenic
patients is interpreted as being related to an increased
release of CRH, vasopressin and oxytocin (Bernstein
et al., 1998). Also, Bernstein et al. (2000) have failed to
find a change in activity of this enzyme in the SON of
schizophrenic patients. The concentration of CSF-CRH
is slightly but significantly higher in schizophrenic
patients (Banki et al., 1987), but the source of this
CRH i.e. PVN or an extrahypothalamic site such as the
cerebral cortex is not known. Leptin (see Chapters 11d
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and 23b) plasma levels are decreased in schizophrenic

patients, while the body mass index remains normal. This
may be related to the alterations in food intake, appetite
and weight frequently observed in schizophrenia.
In chronic schizophrenics, in addition to abnormal
dexamethasone suppression, abnormal diurnal variations
of cortisol levels are found. Those patients with abnormal
diurnal cortisol variations gave higher scores for some
negative symptoms (Kaneko et al., 1992). In addition,
patients with more disturbed sleep and less robust circadian rhythms perform more poorly on neuropathological
tests (Martin et al., 2001). These results show that not
only the HPA axis is disturbed in schizophrenia, but
possibly also, in a subgroup of patients, the suprachiasmatic nucleus. Indeed, there are several observations
showing changes in the circadian rhythm in schizophrenia, suggesting a disturbed functioning of the
suprachiasmatic nucleus (SCN) in this condition. The
mesor of dopamine is higher in schizophrenic patients
than in healthy subjects, while the mesor of prolactin
and TSH is lower in drug-free schizophrenic patients than
in healthy ones. In addition, a significant phase-advance
of serum tryptophan, prolactin and melatonin concentrations was found in schizophrenic women (Rao et al.,
1994, 1995). In another study Van Cauter et al. (1991)
have concluded, however, that pituitary-adrenal function
and circadian timekeeping are normal in schizophrenic
men, but that prolactin secretion is hyperresponsive
to the physiological stimulus of onset of sleep. In
drug-free paranoid schizophrenic patients plasma melatonin circadian rhythm is completely absent, whereas the
24-h profile of plasma cortisol is preserved (Monteleone
et al., 1992). On the other hand, on the basis of diurnal
rhythms in plasma dehydroepiandosterone (DHEA), a
clear distinction can be made between schizophrenic
subjects and controls (Erb et al., 1981). The circadian
rhythm disturbances in schizophrenic patients are related
to levels of illumination, lifestyle factors, behavioral
factors, psychiatric symptoms and medication. Although
these relations are complex, the strong relationship
between sleep and circadian rhythms and functioning
(Martin et al., 2001) make biological clock disorders a
clinically relevant topic in schizophrenia research.
The most consistent sleep disturbance in schizophrenia
is an increased sleep latency. Interestingly, the hypocretin
levels in the CSF of schizophrenic patients correlate
significantly and positively with sleep latency (Nishimo
et al., 2002). The neuropeptide hypocretin is produced in
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the perifornical area of the lateral hypothalamus (Chapter

14) and involved in narcolepsy (Chapter 28.4).
A hypothalamic system that may be involved in the
pathogenesis of schizophrenia is the tuberomamillary
nucleus, the source of histamine in the brain, and its sites
of termination. Although on the one hand the favorable
effect of histamine injections in schizophrenic patients
and some quite indirect evidence indicate decreased
activity of the histaminergic system (Heleniak and
ODesky, 1999), the elevated levels of histamine metabolites in the CSF of patients with chronic schizophrenia
(Prell et al., 1995) suggest, on the other hand, increased
activity of the tuberomamillary neurons. Histamine type2 receptor binding is found to be moderately higher in
the globus pallidus of schizophrenic patients that are
treated with neuroleptics (Martinez-Mir et al., 1993),
and a few schizophrenic patients show symptomatic
improvements following a histamine type-2 antagonist
(Kaminsky et al., 1990; Rosse et al., 1995; Whiteford
et al., 1995; Deutsch et al., 1997). Interestingly, recently
allelic variation in the histamine H2 receptor gene has
been found with an association with schizophrenia
(Deutsch et al., 1997). Moreover, downregulation of the
histamine H1 receptor has been found in the prefrontal
cortex of schizophrenic patients (Nakai et al., 1991).
It is of interest that the atypical, antipsychotic drug
clozapine has an affinity for histamine too (Stevens,
2002). Postmortem studies on untreated schizophrenic
patients and placebo-controlled, double-blind trials are
necessary to confirm the possible involvement of the
tuberomamillary histaminergic neurons in this disease
process.
A number of observations indicate that the cholinergic
activity may be reduced in schizophrenia. The cholinergic
nucleus basalis of Meynert (NBM) shows atrophy, cell
loss and other degenerative changes (Von ButtlarBrentano, 1952; Kish et al., 1990; Caroff and Mann, 1993).
Some of the earliest pharmacological treatments included
cholinergic agents. The cholinergic system exerts a
damping effect on the positive symptoms associated with
increased dopaminergic activity and an intensification of
negative symptoms, and, on the basis of pharmacological
studies, an increased cholinergic activity in schizophrenia
is presumed (Tandon, 1999). The involvement of the
cholinergic system in schizophrenia is thus controversial.
An enhanced rate of pineal and habenular calcifications
and decreased pineal hydroxyindole-O-methyltransferase
(HIOMT) activity is observed in schizophrenic patients.
Since these alterations are related to increased third
ventricular width, it has been hypothesized that periventricular damage, in particular to the PVN in schizophrenia,
might account for the enhanced calcifications (Sandyk,
1990, 1992a). The increased frequency of pineal calcifications in schizophrenia is also supposed to be related to
the diminished nocturnal melatonin secretion that has
been reported by various authors in schizophrenic patients
(Fanget et al., 1989; Monteleone et al., 1992; Sandyk,
1992a; Brown, 1996; Pacchierotti et al., 2001), but the
relationship between pineal calcifications and decreased
melatonin production is controversial (Chapter 4.5).
Possible medication effects are, however, important, since
in the rat haloperidol is found to increase pineal gland
melatonin levels (Gaffori et al., 1983). Pineal deficiency
in schizophrenia is more evident in chronic disease
(Vigano et al., 2001). Therefore, it is of the utmost importance that the observation of decreased nocturnal rise
of melatonin in schizophrenia has been confirmed in
drug-free patients (Robinson et al., 1991), although in a
later study only a phase-advance of melatonin levels was
found (Rao et al., 1994), which may contradict the former
observations. On the other hand, a smaller pineal gland
has been observed in schizophrenia using MRI (Bersani
et al., 2002), which is in agreement with the earlierreported, diminished nocturnal melatonin levels. The
observation that high-dose melatonin may exacerbate
psychosis in schizophrenia (Miles and Philbrick, 1988;
Pachierotti et al., 2001) makes the possible relationship
between the pineal gland and schizophrenia of even higher
interest.
No significant differences have been found in the hypothalamic content of neurotensin, somatostatin, galanin,
vasopressin, neuropeptide-Y, peptide YY, delta sleepinhibiting peptide or TRH in schizophrenic patients
(Frederiksen et al., 1991; Nemeroff, 1991; Breslin et al.,
1994). However, aberrant -endorphin metabolism
has been found in the hypothalamus of these patients
(Wiegant et al., 1992), and the number of -endorphincontaining neurons in the PVN and the innervation of
PVN neurons by -endorphin-containing fibers is reduced
in schizophrenic patients (Bernstein et al., 2002). A
statistically significant but not clinically apparent decrease
in schizophrenic symptoms appears after intravenous
injection of -endorphin (Berger et al., 1981). The
concentrations of - and -endorphins, but not that of
-endorphin, were elevated. As the biological activity
of -endorphins is disturbed, the antipsychotic effects of
-type endorphins in schizophrenic patients is presumed
to be based upon a deficiency of this type of endorphin
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in schizophrenia (Wiegant et al., 1992). Winblad et al.

(1979) have found reduced concentrations of 5-HT in the
hypothalamus of demented schizophrenics which were
not believed to be due to the neuroleptic treatment.
Increased levels of norepinephrine were found in the
bed nucleus of the stria terminalis, ventral septum and
mamillary body in postmortem tissue of schizophrenic
patients (Farley et al., 1978). One might wonder to what
degree the autonomic disturbances reported in schizophrenia (Zahn et al., 1997) may be due to hypothalamic
disturbances.
From estimation of metabolites in the peripheral blood,
upregulation of the hypothalamic digoxin-mediated
isoprenoid pathway is proposed in schizophrenia (Kumar
and Kurup, 2001b).
In conclusion, quite a number of morphological,
physiological and endocrine disturbances point to a
considerable hypothalamic involvement in schizophrenia.
However, neither the enlarged third ventricle size
(Chapter 27b) nor the various hypothalamic changes
reported in schizophrenia constitute any scientific justification for hypothalamotomy, which has been performed
in schizophrenic patients (Balasubramaniam and Kanaka,
1975).
297
complications are also mentioned as risk factors (Verdoux

and Sutter, 2002). Autism is associated with specific
hereditary disorders such as untreated phenylketonuria,
fragile-X disorder, chromosome 15q duplications and
tuberous sclerosis (Schroer et al., 1998; Insell et al., 1999;
Nelson et al., 2001). Increased incidence of thyroid
disease of the parents has been proposed as a preconceptional factor for autistic children (Coleman, 1979;
Gillberg and Coleman, 1992). On the basis of studies
in families and twins, and based on cytogenetics and
molecular genetics it is now thought that genetic influences are dominant underlying factors. The relative risk
of first relatives is about 100-fold higher than the risk in
the normal population and the concordance in monozygotic twin is about 60% (Andres, 2002). Piven (1997)
has calculated that the broad heritability is more than
90%. Chromosome anomalies have been reported in
autism to involve almost all chromosomes and many
types of rearrangements (Van Karnebeek et al., 2002).
Numerous candidate genes have been proposed on the
basis of their possible functional role in neurotransmission
(Korvatska et al., 2002). Abnormalities of chromosome
15q11-13 have emerged as a common cause. This is also
the region of the Angelmans and PraderWilli syndromes
(Andres, 2002). Candidate genes in this region include
the three genes for GABAA receptor subunits (Schroer
et al., 1998; Wolpert et al., 2000). The regions of chromosome 7q31-35 and 16p13-3 also emerge as significant
regions (International Molecular Genetic Study of Autism
Consortium 1998; Lauritsen and Ewald, 2001). Another
candidate gene is WNT2, which is located on the long
arm of chromosome 7 (Wassink et al., 2001). A candidate gene on chromosome 7q is the vasoactive intestinal
peptide receptor 2 (Asano et al., 2001). In one case an
association of a xeroderma pigmentosa group C-splice
mutation on chromosome 3 and autistic behavior has been
described (Khan et al., 1998).
A strong (6573%) decrease in the nicotinic acetylcholine receptor has been found in the frontal and parietal
cortex and cerebellum in autism. This concerns a selective
loss of 4 and 2 immunoreactivity. These data indicate
a disorder in the cholinergic basal nuclei (Court et al.,
2000; Perry et al., 2001). The cortical muscarinic receptor
was only 30% lower. No differences have been found in
choline acetyltransferase (ChAT) or acetylcholine esterase
activity (Perry et al., 2001). The vertical limb of the
diagonal band of Broca shows a decreased cell density
and small neurons that are markedly reduced in number
(Baumann and Kemper, 1985; Baumann, 1991; Kemper
27.2. Autism
Autism is a developmental disorder characterized by
stereotypical, repetitive behaviors, disturbed social interactions (extreme autistic loneliness) and difficulties in
verbal and nonverbal communications. The incidence of
autism is generally reported at less than 0.1%. Affected
boys outnumber girls by about 4:1 and the children show
a range of cognitive defects. Approximately 7585%
of these children function at a retarded level (Insell
et al., 1999; Van Karnebeek et al., 2002). Impairment
of reciprocal social interactions, verbal and nonverbal
communication, and age-appropriate activities and
interests become evident before the age of 35 years. The
causes of autism are heterogeneous, including a major
genetic factor (see below) and environmental insults,
infectious causes (e.g. rubella, cytomegalovirus and
herpes simplex (Korvatska et al., 2002), teratogenic
influences (e.g. phenylketonuria, fetal alcohol syndrome,
neonatal jaundice with kernicterus). Perturbations occurring near the time of neural tube closure can lead to
autistic manifestations (Van Karnebeek et al., 2002),
while arachnoid cysts (Tantam et al., 1990) and obstetric
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and Baumann, 1998). The cholinergic system is thus

clearly affected in autism.
A few observations indicate that the hypothalamus is
affected in autism. Case reports have indicated several
neuroendocrine disorders in some autistic patients.
Gingell et al. (1996) have described a boy with childhood
autism as defined by ICD-10. At 18 months of age, he
was found to have a deficiency of antidiuretic hormone.
He failed to respond to TRH and had a suboptimal growth
hormone response. CT scans showed a small pituitary
gland with a large CSF space around it. He received
thyroxine, hydrocortisone, desmopressin (DDAVP) nasal
spray and growth hormone injections. The boys history
revealed delays in development and continence. His
language functioning development and social interaction
abilities were impaired, and there was evidence of
restricted and repetitive stereotyped patterns of behavior.
In addition he showed hyperphagia. The function of
the vasopressin receptor 1A polymorphisms observed in
autism (Kim et al., 2002) needs further study. Hashimoto
et al. (1991) have found that the basal TSH levels and
the response of TSH to TRH is lower in autistic patients
than in the controls. Mean prolactin levels do not differ.
In addition, growth hormone levels are below the normal
range and the L-DOPA-stimulated or insulin-stimulated
peak of growth hormone is delayed in autistic children.
The clonidine-induced growth hormone peak is premature
(Realmuto et al., 1990; Ragusa et al., 1993). These
findings are interpreted as pointing to abnormalities in
both dopaminergic and noradrenergic neurotransmission
in autism, but primary hypothalamic defects should not
be excluded. In the CSF of children with autism, IGF-I
levels are decreased. It is not known whether IGG-I in
the CSF is derived from the brain or produced in the
periphery (Vanhala et al., 2001). In addition, male autistic
children have lower plasma oxytocin levels than controls.
Inferences to possible central changes in oxytocin release
leading to behavioral disorders in autism have been drawn
(Modahl et al., 1998). In addition to decreased plasma
oxytocin levels, increased plasma levels of oxytocin at
the C-terminal site with 3 amino acids was found. This
suggests changes in processing by prohormone convertases (Green et al., 2001). In addition, abnormalities of
vasopressin levels have been described (LeBoyer et al.,
1992). Since oxytocin and vasopressin are involved in
social behaviors (see Chapter 8), Insel et al. (1999) have
proposed a connection between changes in these peptides
and autism. They also mention an unpublished report
indicating that systemic administration of oxytocin to
autistic children would increase social interaction. In a

randomized double-blind trial, oxytocin infusion over
a period of 4 h significantly reduced repetitive behaviors
(Hollander et al., 2003).
There are also data that indicate that autism in some
children may accompany a dysfunction of the HPA
axis. An abnormal diurnal cortisol rhythm or abnormal
dexamethasone-suppression test results were found more
frequently in poorly developed cases. The authors
interpreted these changes in terms of a disorder of the
serotonin (5-HT) metabolism (Hoshino et al., 1987),
but this is not necessarily the case. The defect may
also be primarily situated in the hypothalamic nuclei.
On the other hand, serotonin reuptake inhibitors reduce
persevering symptoms and aggression and improve
language use and general functioning in adult autistics
(McBride et al., 1996). Kulman et al. (2000) have reported
significantly lower melatonin levels in autistic children
and an absence of the nocturnal increase in this hormone.
A case study of an autistic child with severe mental
retardation has been reported who, when given melatonin
at 9 p.m. experienced early morning wakening and
fragmented night sleep; while, when melatonin was given
at 11 p.m., night sleep was prolonged and sleepwake
rhythm improved (Hayashi, 2000). On the other hand,
Chamberlain and Herman (1990) have proposed that
a subgroup of autistic individuals have a hypersecretion
of pineal melatonin. According to these authors, this could
initiate a cascade of events, including hyposecretion
of pituitary pro-opiomelanocortin and a hypersecretion of
hypothalamic opioid peptides and 5-HT. Hypersecretion
of melatonin might also inhibit the release of CRH, which
would, in its turn, result in hyposecretion of pituitary
ACTH and of -endorphin. Le Boyer et al. (1992) have
indeed reported abnormalities in plasma -endorphin
levels in autism. Symptoms of early childhood autism
may result from excessive brain opioid activity, since the
orally effective opioid antagonist naltrexone has yielded
some promising therapeutic results (Leboyer et al., 1992).
Whether the discrepancy with the data of Chamberlain
and Herman (1990) can be explained by the existence of
different subgroups of autistic patients or age effects still
has to be studied.
Neonatal blood concentrations of vasoactive intestinal
polypeptide, calcitonin gene-related peptide and the
neurotrophin nerve growth factor and neurotrophin 4/5
are increased, but it is not clear from which organ, let
alone brain area, these compounds are derived (Nelson
et al., 2001).
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Aspergers syndrome lies within the autistic spectrum

and is characterized by greater clumsiness, floppiness
of limbs and less-impaired language development. It is
associated with intellectuality. There is a male preponderance, and the syndrome has been associated with
mental retardation, Tourettes syndrome, aminoaciduria,
Marfans syndrome, epilepsy and a colloid cyst of
the third ventricle. A developmental defect of midline
structures may be the basis of this syndrome (Tantam
et al., 1990). A patient with Aspergers syndrome, central
diabetes insipidus, empty sella and primary polydipsia
(i.e. compulsive drinking) has been described (Raja et al.,
1998). Aspergers syndrome may also be found in juvenile
and young-adult mentally disordered offenders (Siponmaa
et al., 2001). In a randomized trial, oxytocin appeared to
reduce repetitive behaviors in patients with Aspergers
disorder (Hollander et al., 2003). Sleep disturbances
are common in Aspergers syndrome; in an open trial,
melatonin appeared to improve sleep patterns and behavioral measures (Paavonen et al., 2003), but these results
need to be confirmed in a controlled study.
Some patients with hypothalamic hamartomas (see

Chapter 19.3) have severe autistic behaviors. Interestingly,
striking improvements of these behaviors are observed
during treatment with intermittent left vagal nerve stimulations (Murphy et al., 2000). Sleep disturbances in autism
have been successfully treated with light therapy, chronotherapy (Hoban, 2000) and melatonin (Hayashi, 2000).
In spite of the neuroendocrine alterations that have been
reported in autism, only a few areas of the hypothalamus
have so far been studied. The autistic brains show
increased cell-packing density and reduced nerve cell
size, e.g. in the mamillary body and the medial septal
nucleus (Bauman and Kemper, 1985; Bauman, 1991).
These abnormalities noted in brains from autistic patients
appear to have been acquired early in development. In
addition, numerous swollen axon terminals (spheroids)
are located in the cholinergic basal nuclei the NBM
and diagonal band of Broca in a number of hypothalamic
nuclei: infundibular nucleus, mamillary body, PVN,
dorsomedial nucleus, ventromedial nucleus, and posterior
and lateral hypothalamus in the neocortex, thalamus and
brainstem. These abnormalities suggest a defect in axonal
transport or synaptic transmissions (Weidenheim et al.,
2001).
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CHAPTER 28
Periodic disorders
The symptoms of a variety of disorders whose cause is

unknown and that recur regularly are called periodic
diseases. Depending on the most prominent clinical
feature, they are called, e.g. periodic fever or periodic
hypothermia, as found, e.g. in Shapiro syndrome (Chapter
28.2), periodic somnolence and morbid hunger, as seen
in KleineLevin syndrome (Chapter 28.1), periodic
neutropenia, cyclic vomiting or periodic apnea during
wakefulness as seen in Rett syndrome (Chapter 2.5;
Naidu, 1997). Cluster headache has a highly distinctive
cyclic recurrence pattern (Chapter 31.3a). Recurrent
nocturnal headaches that awaken the patients from sleep
at a consistent time have been described as the hypnic
headache syndrome (Newman et al., 1990; Chapter
31.3c). Episodes of stupor of unknown origin may also
be recurring. During such periods the EEG shows a
physiological sleep pattern and the endogenous benzodiazepine receptor ligand endozepine-4 levels may be
elevated 40 to 300 times in plasma and CSF (Tinuper
et al., 1994). A patient with a circadian pattern of episodes
of stupor is described in Chapter 4.6). In addition, cases
of menstruation-linked hypersomnia have been described
(see below). Circadian and circannual disorders that
probably find their origin in the suprachiasmatic nucleus
are discussed in Chapter 4. For periodic aspects of depression, see Chapter 26.4f. Although vasomotor disturbances
may often be present in headaches, the pathogenetic
mechanism and the brain structures involved in other
periodic disturbances are unknown (Reimann, 1951).
There are, however, also a number of periodic disorders
for which there are good indications (narcolepsy is an
example of this) that the hypothalamus is involved. They
are discussed in this chapter.
28.1. KleineLevin syndrome (periodic somnolence

and morbid hunger)
Attention was first drawn to this disorder by Kleine
(1925), who described five patients with periods of
excessive sleep, day and night, two of whom also had an
excessive appetite, while Levin (1929) confirmed Kleines
observations and described a young man with attacks
of sleepiness and pathological hunger. Critchley (1962)
preferred the name periodic hypersomnia and megaphagia and described it as a syndrome composed of
recurring episodes of undue sleepiness lasting some days,
associated with an inordinate intake of food and often
with abnormal behavior. Adolescent males are affected
exclusively or even predominantly, although some girls
with similar symptoms have been described (Duffy and
Davison, 1968; Gilligan, 1973; Malhotra et al., 1997). In
a case of menstruation-linked periodic hypersomnia,
an increased turnover of serotonin has been observed
(Billiard et al., 1975). The onset is in adolescence and in
general the syndrome eventually disappears spontaneously. However, Critchley (1962) has pointed out that
a number of female patients did not fulfil the criteria,
such as one girl of 7 years who had a pseudotumor
following a diencephalic disturbance, women with attacks
corresponding to the menstrual periods, women with
comparable symptoms following encephalitis. Although
four female patients with the classic triad, i.e. hypersomnolence, hyperphagia and hypersexuality, have been
described (Kesler et al., 2000), it remains questionable
whether female patients with somnolence without recurring megaphagia in association with each menstruation
should be considered as cases of KleineLevin syndrome.
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Gadoth et al. (2001) have found a mean age at onset

of 16 years, but records of older patients exist (Badino
et al., 1992). The average period between attacks is
6 months, but intervals of 6 years have been described,
e.g. in a student aviator (Wygnanski et al., 1996). The
mean duration of a single hypersomnolent period is
12 days (Gadoth et al., 2001). During a period of
somnolence the patient can always be aroused and wakens
spontaneously to empty the bladder. Sleep recordings
during a hypersomnolent period show frequent awakenings from sleep stage 2 (Gadoth et al., 2001). Psychiatric
manifestations such as sexual disinhibition, confusion,
agitation, depersonalization, forgetfulness, disturbed sense
of time, vivid imagery and visual and auditory hallucinations are frequent. Waking fantasies of a bizarre
and crudely sexuosadistic nature are common (Kahn and
Johnson, 1987).
The association between sleep disturbance, increased
food intake, disordered sexual behavior, a loss of normal
diurnal variation of plasma cortisol, abolished corticotropin (ACTH) and cortisol responses to insulin-induced
hypoglycemia, high values of thyrotropin (TSH) and
prolactin, absent TSH response to thyrotropin-releasing
hormone (TRH), luteinizing hormone (LH) abnormalities,
and abnormal secretion of growth hormone during the
hypersomnia episodes suggests reversible hypothalamic
dysfunctions. On the basis of the hormonal changes, a
reduced hypothalamic dopaminergic tone is presumed
(Duffy and Davison 1968; Gilligan, 1973; Gadoth et al.,
1987; Fernandez et al., 1990; Chesson et al., 1991; Fenzi
et al., 1993; Malhotra et al., 1997; Mller et al., 1998b).
It should be mentioned, however, that other brain areas
may also be functionally altered (Landtblom et al., 2002)
and that a study of five KleineLevin syndrome patients
did not reveal any evidence of hypothalamic neuroendocrine or circadian dysfunction. Although these
authors found increased melatonin levels in all patients
during symptomatic periods (Mayer et al., 1998b), this
was not confirmed by Gadoth et al. (2001) in one patient
during an attack. In agreement with the clustering of
hypothalamic symptoms in a number of studies, perivascular lymphocytic infiltration and microglial proliferation
nodules have been found in the hypothalamus, particularly
in the floor of the third ventricle, but also in the thalamus,
and periaqueductal gray, amygdala and temporal lobe.
The infiltrated cells reacted with antibodies against
macrophages and T cells (Fig. 28.1; Takrani et al., 1976;
Carpenter et al., 1982; Fenzi et al., 1993). It should be
noted, though, that there are only a few cases with such
Fig. 28.1. (a) Microglial nodule in the posterior hypothalamic nucleus

of a patient with KleineLevin syndrome (hematoxylin and eosin,
210). (b) Anti-HAM 56 antibody showing immunoreactivity of
microglial cells and their dendritic processes. ABC method. (From Fenzi
et al., 1993, Fig. 2, with permission.)
neuropathological changes in the hypothalamus that had

unusual clinical features (Katz and Ropper, 2002),
including two cases involving girls. The structural lesions
in the hypothalamic area reported in some cases of
KleineLevin syndrome, i.e. hypodense lesions in the
suprasellar cistern, suggesting an infundibular lipoma and
a large and asymmetrical mamillary body, need to be
confirmed in other cases (Landtblom et al., 2002). The
relapsing course of the disease, the neuropathological
findings, the younger age at onset, and the high allele
frequency of HLA-DQB1*0201 suggest an immunemediated process with selective involvement of the
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diencephalon and midbrain structures (Dauvilliers et al.,

2002). Prevalence of T lymphocytes points to an unknown
viral antigen. In fact, in 3550% of cases of KleineLevin
syndrome, the onset is preceded by respiratory tract infection, acute viral encephalitis or vaccination (Merriam,
1986; Fenzi et al., 1993; Salter and White, 1993;
Pike and Stores, 1994). Epstein-Barr and varizella-zoster
virus have been mentioned in this connection (Mller
et al., 1998b). This raises the possibility that a dormant
neurotropic virus is activated and causes the attack.
In addition, the syndrome has been related to affective
disorders on the basis of a positive therapeutic response
to lithium (Lemire, 1993; Pike and Stores, 1994). A recent
report mentioned, for the first time, two familial cases: a
brother and a sister who developed their symptoms
in early adolescence, within 5 months of each other,
and who shared the HLA-DR2 haplotype, suggesting a
potential hereditary cause (Katz and Ropper, 2002).
KleineLevin syndrome has been associated with
various other disorders. Two cases of KleineLevin
syndrome with Aspergers syndrome have been described
(Berthier et al., 1992). Moreover, the syndrome has
been seen in association with head trauma (Visscher
et al., 1989), thalamic and multiple cerebral infarctions,
and multiple sclerosis (MS). In a 9.5-year-old Prader
Willi patient (Chapter 23.1) in whom the diagnosis
was confirmed, showing 15q12 deletion from the
paternal chromosome, the clinical features of Kleine
Levin syndrome have also been described, i.e. periodic
hypersomnia and hyperphagia. MRI revealed a small
hypothalamus (Gau et al., 1996). The relationship between
these two syndromes deserves further study. A 54-yearold man has been reported who developed the symptoms
of KleineLevin syndrome at the age of 50. Four years
later Parkinsonian symptoms appeared. The hormonal
changes supported the hypothesis that a reduced hypothalamic dopaminergic tone was present in symptomatic periods. The presence of Parkinsonian symptoms
suggests a general dopaminergic dysfunction in that
patient (Mller et al., 1998b). In addition, a 20-year-old
man has been described who presented with episodes of
daytime hypersomnia, orthostatic hypotension, psychotic
behavior, compulsive masturbation and abnormalities
of eating habits. From a clinical point of view, it was
suspected that he suffered from KleineLevin syndrome.
However, eventually it turned out the patient had MS
(Testa et al., 1987). One case of KleineLevin syndrome
induced by triazolam has been described (Menkes, 1992)
and one unusual female case of recurrent acromegaly,
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accompanied by KleineLevin syndrome, which developed 10 months after single-field radiation therapy,
and Munchausen syndrome with self-inflicted anemia
(Jungheim et al., 1999). An overlap between Kleine
Levin syndrome and narcolepsy (Chapter 28.5) is present
(Gordon, 1992). For a differential diagnosis of Kleine
Levin syndrome, see Khan and Johnson, 1987.
Amphetamine (methylfenidate, Ritalin), (Duffy and
Davison, 1968; Gilligan, 1973; Visscher et al., 1989) and,
for menstruation-linked periodic hypersomnia, estrogens
(Billiard et al., 1975) have been proposed as therapy.
28.2. Spontaneous periodic fever, hypothermia,
Shapiro syndrome and periodic Cushings syndrome
Two hypothalamic centers are generally presumed to act
reciprocally to maintain body temperature. The anterior,
preoptic/septal center controls heat dissipation by
stimulating a caudal hypothalamic region which induces
vasodilatation and perspiration (see Chapter 30.1).
Persistent hypothermia or poikilothermia due to thermoregulatory dysfunction with associated hypothalamic
damage are well recognized, and acute brain dysfunction
with hypothalamic involvement may cause transient
hypothermia (Kloos, 1995; see Chapter 30.2). There are
various hereditary periodic fever syndromes, such as:
(i) familial Mediterranean fever, which maps to the short
arm of chromosome 16. At least 28 mutations in the
Mediterranean fever (MEFV) gene have been described.
Colchicine prevents febrile attacks in the majority of the
patients; (ii) Hyper-IqD-syndrome, which maps to the
long arm of chromosome 12; and (iii) tumor necrosis
factor (TNF)-receptor associated periodic syndrome or
familial Hibernian fever, which maps to the short arm
of chromosome 12. Patients with these disorders respond
to high doses of oral prednisone (Drenth and Van der
Meer, 2001).
Chronic recurrent fever of central nervous system
(CNS) origin is extremely rare. Recurrent and periodic
febrile syndromes have been described under various
names, such as Reimans syndrome, Welff syndrome,
hypothalamic attacks, and autonomic (diencephalic)
epilepsy. It has been postulated that in periodic fever the
hypothalamic thermostat is reset to a higher level by an
as yet unexplained central mechanism. A case has been
described where the symptoms began on awakening and
followed a 30-day cycle of fever. This disorder may be
accompanied by behavioral disturbances (Van Hilten
et al., 1997).
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In 1929 Penfield reported a patient with a thirdventricle tumor, markedly increased intracranial pressure
and a defect of the corpus callosum. He proposed that
mechanical irritation would lead to diencephalic autonomic epilepsy; symptoms including flushing, diaphoresis,
and a fall in temperature. Abnormal EEG findings and
manifest seizures have been reported. On the other hand,
the response rate to anticonvulsants is lower than expected
for an epileptic phenomenon (Kloos, 1995). Patients with
diencephalic epilepsy may have various lesions in the
hypothalamus such as angiomas, ischemia, infections,
neoplasm, metabolic derangements and trauma (Klein
et al., 2001). Periodic hypothermia has been observed in
combination with agenesis of the corpus callosum
(Shapiro syndrome). This disturbance is considered to
be the result of a localized arrest in development of
the lamina terminalis (Guihard et al., 1971; Nol et al.,
1973). Several authors have reported the association of
paroxysmal hypertension with spontaneous periodic
hypothermia and Shapiro syndrome (Kloos, 1995). Nol
et al. (1973) have described a patient with Shapiro
syndrome who had severe neuronal loss and nonspecific
fibrillary gliosis in the arcuate nucleus and premamillary
region. The testes exhibited a dense interstitial fibrosis.
Mitoses in the seminal tubules were rare and no Leydig
cells could be observed. These abnormalities may be
related to lesions in the infundibular nucleus, since this
nucleus produces luteinizing hormone-releasing hormone
(LHRH) (see Chapter 11). In a variant of Shapiros
syndrome, there was a malformation of the corpus
callosum, hypoplasia of the anterior commissure and
absence of the septum pellucidum and columns of the
fornix. The patient had episodic sweating and shivering
with reduced temperature (Klein et al., 2001).
Spontaneous periodic hypothermia has also been
described when hypothalamic abnormalities are present
that affect structures related to thermoregulation (Nol
et al., 1973) and very rarely without an obvious brain
lesion. During episodes varying from hours to weeks,
with a periodicity from hours to years (the episodes have
been described as periodic, recurrent, intermittent, remittent), these patients have active heat dissipation through
vasodilatation and sweating and decreased generation of
heat. Generally no abnormalities of thirst or water metabolism are noted during or between the episodes (Kloos,
1995). The pathophysiological mechanism of spontaneous
periodic hypothermia remains unknown, but degenerative,
irritative, neurochemical or structural abnormalities have
been presumed. Engel and Aring (1945) have described
an 18-year-old boy with repeated paroxysms of coldness,

shivering, pallor of extremities, fluctuating hypertension,
oliguria, tachycardia and spiking temperature followed by
abrupt temperature reduction toward normal values
accompanied by profuse perspiration and flushing. Also
his genitals were underdeveloped. Autopsy revealed cystic
degeneration of the dorsomedial nucleus of the thalamus,
the internal medullary lamina and the lateral nuclei of the
right thalamus, while the hypothalamus itself was intact.
The authors proposed that the thalamic lesion would have
interrupted corticohypothalamic association fibers. Fox
et al. (1970) have described a young man with repeated
episodes of hypothermia, who had defects in heat
conserving mechanisms of peripheral constriction and
shivering. Necropsy revealed fibrillary gliosis in the
anterior hypothalamus, i.e. in the preoptic and septal
nuclei and in the medial hypothalamic area, the optic
chiasm and the optic tracts. The cause of the gliosis
was not apparent. There were no vascular, inflammatory
or neoplastic lesion in the vicinity. Intermittent neurochemical dysfunctions have also been presumed to be
possible causal mechanisms of periodic hypothermia.
Catecholamine levels have sometimes been found to be
elevated and clonidine might be effective in treating
some patients. Dysfunction of vasopressin and endogenous opioids have also been presumed (Kloos, 1995).
An inflammatory process, e.g. an autoimmune process,
seems unlikely in view of the failure of exogenous steroids
to be effective and the absence of histological data
supporting such a possibility. An infectious etiology is
also unlikely given the prolonged antibiotic trials and the
lack of supportive histological data (Kloos, 1995).
We have seen one case of spontaneous periodic hypothermia (NHB 94010). She had hibernation periods
for 30 years, consisting of hypothermia combined with
slow, passive behavior, diabetes insipidus, and leuco- and
thrombocytopenia. In summer the symptoms abated
and the need for vasopressin substitution lessened. She
died of respiratory insufficiency, disturbed coagulation
and bleeding from a rupture of the pulmonary artery.
At autopsy no gross brain abnormalities were found.
The neurohypophysis contained some groups of brown
pigmented cells that are typical of a granular cell tumor
or choristomas. These tumors are, however, generally
considered to be asymptomatic (Chapter 22.1). The hypothalamus did not show abnormal microscopic anatomy,
so an explanation for this condition was not found.
In a 14-year-old boy with a suspected hypothalamic
lesion, periodic release of ACTH and adrenal cortico-
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steroids has been reported. He had cyclic manifestations

of nausea, vomiting, fever, emotional disturbances and a
marked change in weight. Associated findings during the
attacks were facial plethora, hypertension, abnormal
glucose tolerance, elevated plasma ACTH and adrenal
hyperfunction. The patient can thus be considered to have
periodic Cushings syndrome. The disease process was
effectively suppressed by dexamethasone treatment and
chlorpromazine. The authors thought it unlikely that
dexamethasone had an anti-inflammatory effect on the
primary lesion (Wolff et al., 1964).
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exacerbations with discrete hypothalamic changes was

reported (Suarez et al., 1997). He expired after being in
septic shock. Sections through the hypothalamus revealed
a reduction larger than 75% in the number of neurons
with reactive astrocytosis in the SON and a reduction
larger than 90% in the PVN at the level of the median
eminence. In this case, damage to the SON and PVN
during AIP exacerbations was also presumed to lead at
first to an increase in circulating vasopressin. The cerebral
cortex, hippocampus, basal ganglia, thalamus, cerebellum,
midbrain, pons and medulla were unremarkable. In the
kidney a general autopsy revealed over 75% of sclerotic
glomeruli with advanced tubulointerstitial atrophy and
interstitial fibrosis characteristics of end-stage renal
disease. A 50-year old man had AIP with severe postural
hypotension, hallucinations and inappropriate antidiuretic
syndrome. A reduction of about two-thirds of the neurons
in the SON and PVN occurred, as well as mild astrogliosis
and vacuolar changes that did not contain neurosecretory
substance in most of the remaining neurosecretory cells
(Stein et al., 1972). A 19-year-old pregnant girl with AIP
died of pneumonia. She had inappropriate secretion of
antidiuretic hormone and neuronal loss in the SON and
PVN (Kerr, 1973).
Other hypothalamic abnormalities in AIP concern the
regulation of growth hormone. Administration of glucose
to patients with AIP often produces a paradoxical rise in
the level of circulating growth hormone. In other patients
the magnitude of the normal decline of growth hormone
in response to glucose has been reported to be less. These
changes are also probably due to hypothalamic damage
(Perlroth et al., 1966).
28.3. Acute intermittent porphyria

Acute intermittent porphyria (AIP) is a rare inborn error
of metabolism with a prevalence of 1.54 per 100,000
and characterized by widespread lesions in the nervous
system. The disease is inherited in an autosomaldominant fashion with a women to men ratio of 3 : 2.
Biochemically it is characterized by deficiency of the
enzyme hydroxymethylbilane synthase (Suarez et al.,
1997) and excretion of porphyrin precursors in the urine.
Clinically the disease manifests itself in the form of
widespread neurological abnormalities with abdominal
pain, constipation, nausea, vomiting, tachycardia, hyporeflexia, seizures, cranial nerve involvement, hypertension
and fever. Frequently psychiatric manifestations included
weakness, delirium, depression and psychosis (Suarez
et al., 1997). Since AIP patients with seizures had significantly lower melatonin levels than AIP patients without
seizures, melatonin was proposed to have a protective
effect on seizures (Bylesj et al., 2000; see also Chapter
28.5b). This possibility still has to be tested in a systematic
way. In an autopsy of a 19-year-old girl with AIP,
selective demyelination of the fasciculus gracilis in the
cervical segment of the spinal cord, vagus nerve and
the rostral optic tracts was found (Perlroth et al., 1966).
The latter explains the patients blindness. In addition,
the syndrome of inappropriate vasopressin secretion was
found in this patient. An inflammatory lesion was seen
in the median eminence and neurohypophysial stalk. In
the supraoptic (SON) and paraventricular nucleus (PVN),
respectively, 95% and 65% neuronal loss was found. The
inappropriate vasopressin secretion was considered to
be due to the fact that vasopressin leaked from the
degenerating hypothalamo-neurohypophysial system,
while diabetes insipidus was suspected in the terminal
stage of this patient. Another case of a 41-year-old patient
with multiple episodes of hyponatremia during AIP
28.4. Narcolepsy
Sleep, eat and be merry.
Orla Smith.
Narcolepsy is a chronic, disabling sleep disorder that

affects 1 in 2000 individuals and consists of daytime
sleepiness and sleep attacks, generally with a short
duration of not more than 10 min or so that occurs several
times a day. The patients are easily wakened (by touch
or by calling them by name). The attacks are usually
coupled with cataplexy (i.e. a sudden diminution of
muscle tone, triggered by emotions; Fig. 28.2) and hypnagogic or hypnopompic hallucinations (i.e. hallucinations
occurring in the process of falling asleep or while waking
up). These hallucinations can be visual or auditory and
are usually frightening. In addition, paralysis may occur.
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Fig. 28.2. Top: a cataplectic attack in a patient with narcolepsy, here

elicited by laughter. Note that the paralysis is not instantly complete;
the patient is able to reach out his arms to break the fall. Below:
cataplectic attack in a hypocretin-receptor-2 mutated Doberman pinscher.
The attack was triggered by the excitement from receiving a piece of
palatable food. The attack is partial; the most obvious weakness is in
the hindlimbs. (From Overeem et al., 2002, with permission.)
Most cases of narcolepsy start during adolescence and

it is human leukocyte antigen (HLA)-associated, i.e.
with HLA-DR2/DQB1*0602 and DQA1*0102 (Kadotani
et al., 1998; Peyron et al., 2000; Van den Pol, 2000;
Lin et al., 2001; Ripley et al., 2001; Thorpy, 2001).
The HLA-DQB1*0602 frequency is increased in
narcolepsy with typical cataplexy (93% versus 17%
in controls), and present in 56% of the narcoleptic patients
without cataplexy (Mignot et al., 2002). Because of the
tight HLA association, the disorder has been suggested
to be autoimmune in nature (Overeem et al., 2001;
Thorpy, 2001). Hypocretin neurons are localized in the
perifornical region in the human brain (Moore et al., 2001;
Fig. 28.3). Their number was estimated to be between
15,000 and 80,000 neurons (Peyron et al., 2000).
Recently it has been established by positioning cloning
that an autosomal recessive mutation of the hypocretin
(orexin) receptor 2 gene (HCRT2) is responsible for
the genetic form in a well-established canine model, in
Doberman pinschers and Labrador retrievers (Kadotani
et al., 1998; Lin et al., 1999). In addition, hypocretin
knockout mice exhibit narcolepsy (Chemelli et al., 1999),
and modafinil, an antinarcoleptic drug, activates orexincontaining neurons. The hypocretin neurons are known
to project to brainstem regions linked to motor inhibition
as well as to the locus coeruleus (norepinephrine), raphe
nucleus (serotonin), laterodorsal tegmental nuclei (acetylcholine) and ventral tegmentum (dopamine) (Peyron
Fig. 28.3. Section of the hypothalamus of a 58-year-old male control

patient (NHB 98-090) stained with rabbit anti-orexin A 1:1250 (Phoenix
Pharmaceuticals) according to the ABC method, with DAB-nickel ammonium sulfate as substrate. The fornix is surrounded by immunoreactive
orexin neurons and fibers in the lateral hypothalamic perifornical area.
Bar 50 m. (Preparation U. Unmehopa and H. den Hartog.)
et al., 2000; Van den Pol, 2000; Moore et al., 2001;

Thorpy, 2001). In human narcolepsy the hypocretin
neurons have disappeared (Peyron et al., 2000).
Hypocretin-1 levels have been reported to be absent
or dramatically decreased in the CSF of the majority of
patients suffering from narcolepsy (Nishino et al., 2000,
2001; Melberg et al., 2001; Ripley et al., 2001).
Hypocretin (CSF) levels below 110 pg/ml are diagnostic
for narcolepsy, while values above 200 pg/ml are
considered normal. Krahn et al. (2002) found that undetectable hypocretin-1 levels were highly specific for
HLA-DQB1*0602 positive narcolepsy patients with
cataplexy, whereas Ebrahim et al. (2003) also report
deficient hypocretin-1 levels in CSF of patients with
monosymptomatic narcolepsy. Hypocretin deficiency
was also observed in a case of Niemann-Pick type C
with cataplexy (Kanbayashi et al., 2003). Intermediate
levels were observed in primary hypersomnia patients
and patients with various acute neurological conditions,
such as GuillainBarr syndrome and myxedema coma
secondary to Hashimoto thyroiditis (Mignot et al, 2002;
Ebrahim et al., 2003). Krahn et al. (2002) have found
that undetectable hypocretin-1 levels are highly specific
for HLA-DQB1*0602-positive narcolepsy patients with
cataplexy, whereas Ebrahim et al. (2003) also report
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deficient hypocretin-1 levels in CSF of patients with

monosymptomatic narcolepsy. An MS patient has been
reported with a new plaque in the hypothalamus who
developed acute hypersomnia accompanied by undetectable hypocretin CSF levels (Iseki et al., 2002). In a
case of acute disseminated encephalomyelitis with hypersomnia and hyperintense lesions in the hypothalamus,
decreased hypocretin levels were found in the CSF
(Kubota and Kanbayashi, 2002). Low hypocretin levels
by others have also only been found in a few cases of
GuillainBarr syndrome, and low but detectable levels
were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma
and CNS infections (Ripley et al., 2001; Kanbayashi
et al., 2002a, b). Plasma hypocretin-1 levels are also
supposed to be lower in most (but not all) narcolepsy
patients than in age- and gender-matched normal controls
(Higuchi et al., 2002). The finding that low plasma levels
of orexin-A-like immunoreactivity may be a marker for
the reactivity of sleep apnea (Nishijima et al., 2003) needs
to be followed-up. Increased hypocretin-1 levels are found
in the CSF of patients with restless legs syndrome. The
increased CSF levels were most striking in the early-onset
form of this sleep disorder (Allen et al., 2002).
Immunocytochemical and in situ hybridization data
indicate that there is a substantially (8595%) reduced
number of neurons producing hypocretins in narcoleptics
(Peyron et al., 2000; Thannickal et al., 2000; Van den
Pol, 2000). The detection of increased glial fibrillary
acidic protein (GFAP) immunostaining of astrocytes in
the perfornical hypocretin area of the brain of narcoleptics
(Thannickal et al., 2000; Van de Pol, 2000) argues in
favor of some type of neuronal degeneration. However,
Peyron et al. (2000) could not confirm the presence of
hypothalamic gliosis in narcolepsy. The reason for this
discrepancy is not clear at present. Clearly more patients
in different phases of the disease should be studied. Some
rare polymorphism in the prepro-orexin was claimed to
be associated with narcolepsy (Gencik et al., 2001) and
a mutated signal sequence of hypocretism in a child with
narcolepsy (Peyron, 2000). However, in contrast to animal
models, most cases of narcolepsy are not familial (Siegel,
1999). It is thus unlikely that a high proportion of human
narcoleptics have a mutation or a polymorphism responsible for narcolepsy, either in the Hcrt gene or in the
HCRT-1 or -2 receptors (lafsdttir et al., 2001).
Narcoleptic patients were reported to have bilateral
decreases in hypothalamic gray matter, using voxel-based
morphometry and MRI (Draganski et al., 2002). How this
307
finding relates to the observations in the hypocretin

system is, at present, not clear.
Hypocretins are not only involved in narcolepsy but
also in eating behavior and metabolism (see Chapter 23c).
The bodymass index is increased in narcolepsy patients,
indicating altered energy homeostasis (Schuld et al., 2000;
Dahmen et al., 2001). Since leptin levels in serum, are
reduced in narcoleptic patients by more than 50% and
increased in CSF, narcolepsy seems to be accompanied
by complex alterations in the regulation of food intake
and metabolism (Schuld et al., 2000; Nishino et al., 2001;
Kok et al., 2002). In narcoleptic patients, hypocretin
deficiency is accompanied by a disruption of the circadian
distribution of growth hormone-releasing hormone
release, in such a way that they secrete about 50% of
their growth hormone during the day, whereas controls
secrete only 25% of their growth hormone during that
period (Overeem et al., 2003). This, and these patients
propensity to fall asleep during the day, supports the
notion that the function of the suprachiasmatic nucleus
(SCN) is disturbed in this disorder.
A large number of brain structures may be functionally
or structurally affected in narcolepsy. In canine narcolepsy, neuronal degeneration is found in the amygdala,
diagonal band of Broca, substantia innominata, preoptic
regions and medial septum (Siegel et al., 1999). In the
CSF of narcoleptic patients, substance P and somatostatin,
5-hydroxyindoleacetic acid (5-HIAA) and vanillylmadelic
acid (VMA) are decreased, while homovanillic acid
(HVA) is increased. These changes seem to be related to
the severity of the clinical symptoms of narcolepsy
(Strittmatter et al., 1996a). Levels of serotonin and
5-HIAA in the hypothalamus of autopsied narcolepsy
patients are significantly increased, whereas their molar
ratio does not change (Kish et al., 1992).
Symptomatic narcolepsy is not human leucocyte
antigen-associated (Aldrich and Naylor, 1989). When
CNS disorders and narcolepsy occur together, hypothalamopituitary pathology is the most common
association. Association with KleineLevin syndrome,
MS, diencephalic sarcoidosis, angioma, encephalitis,
periventricular ependymal gliosis in the hypothalamus,
pituitary adenomas, nonspecific hypothalamic endocrine
syndromes and head trauma have been reported (Erlich
and Itabashi, 1986; Aldrich and Naylor, 1989; Gordon,
1992; Clavelou et al., 1995; Malik et al., 2001). Narcolepsy
has also been described in a 37-year-old man with tissue
typing HLA-DR2 and DQ1 and hypothalamic neurosarcoidosis, in particular in the septal region, in the nucleus
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basalis of Meynert (NBM) and the rostral part of the

amygdala (Servan et al., 1995). In addition, two cases of
children with severe narcolepsy secondary to brain tumors
have been reported. These children had suprasellar
tumors and hypothalamic obesity, so that the hypothalamic
hypocretin system may have been affected (Marcus et al.,
2002). A young man has been described who developed
narcolepsy after a massive hypothalamic stroke. The lesion
included much of the region where hypocretin is produced,
and his CSF levels of this neuropeptide were low. A
loss of the hypocretin system seems, consequently,
also to be the cause of secondary narcolepsy (Scammell
et al., 2001).
A close association has been described between REM
sleep behavior disorder and narcolepsy. Sleep motor
dyscontrol in narcolepsy may start as a non-REM sleep
parasomnia in childhood and then the onset of narcolepsy
might represent the turning point for its intrusion into
REM sleep (Schenk and Mahowald, 2002). REM sleep
disturbances are associated with narcolepsy, and animals
studies have shown that the hypothalamus is involved in
REM sleep regulation (Aldrich and Naylor, 1989). On
the other hand, cortisol and melatonin show normal
profiles, suggesting that the function of the circadian
timing system is preserved (Van Cauter and Spiegel,
1997), although there is a loss of circadian rhythmicity
in leptin levels in narcoleptic patients (Kok et al., 2002).
In addition, narcolepsia may be associated with psychosis (Howland, 1997). In schizophrenic patients the CSF
hypocretin levels correlate positively and significantly
with sleep latency, one of the most constistent sleep
abnormalities seen in this disorder (Nishino et al., 2002).
28.5. Epileptic seizures
Hypothalamic involvement in epileptic seizures appears
from (a) the occurrence of circadian patterns of ictal
manifestations (Ellis, 1992) and their relationship to sleep,
(b) the release of hypothalamic and pituitary hormones
in relation to seizures, (c) epileptic seizures in case of
hypothalamic hamartomas (see also Chapter 19.3a and
26.2) and (d) hypothalamic changes in patients with
epilepsy, reported in a few autopsy cases.
(a) Epilepsy, diurnal rhythms and sleep
As early as 1929, Langdon-Down and Brain reported that
two-thirds of epileptics manifested a marked difference
Fig. 28.4. Circadian distributions of seizures in a patient with

intractable epilepsy who maintained an hour-by-hour seizure diary for
over 5 years, denoting occurrence of either episodes of confusion and
orofacial automation or episodes of abrupt left hand pain. Location of
ictal foci were then documented by intracranial EEG using bilateral
hippocampal depth electrodes and bilateral subdural strip electrodes.
Whereas right temporal lobe seizures usually occurred diurnally, right
parietal lobe seizures occurred nocturnally and out of phase with
temporal seizures. Seizures clustered near times of transitions from sleep
to wakefulness from either foci. Parietal lobe seizures also clustered at
times habitually marked by transitions from wakefulness to sleep. (From
Quigg, 2000, Fig. 3, with permission.)
in the diurnal and nocturnal incidence of their convulsions. Sleep may indeed profoundly modify epileptic
seizures and interictal epileptic EEG activity. In partial
epilepsy, circadian influences are obvious (Autret et al.,
1997; Quigg et al., 1999; Fig. 28.4). Janz (1962) has
described three types of courses of major seizures
governed by the sleepwake cycle: (1) grand mal attacks
predominantly following waking, (2) grand mal epilepsies
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mainly after falling asleep and (3) grand mal epilepsies

with irregular dispersed attacks. Frontal brain injuries lead
mainly to sleep epilepsy, parietal lesions mainly to irregular epilepsy, while no correlations could be established
for awakening epilepsy. On the other hand, there are
several reasons to anticipate that the limbic seizures of
mesial temporal lobe epilepsy due to hippocampal sclerosis (Chapter 29.7b) will alter circadian rhythms (Quigg
et al., 1999).
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(cf. Sperling et al., 1986; Rao et al., 1989), a failure of

prolactin to rise consequently does not exclude a diagnosis
of complex partial seizures. Thus prolactin measurements
do not help to differentiate frontal lobe complex partial
seizures from psychogenic attacks of pseudoseizures: a
failure to find increased postictal prolactin levels does not
exclude the diagnosis of epilepsy (Laxer et al., 1985;
Wroe et al., 1989; Meierkord et al., 1992).
Norepinephrine, vasopressin and oxytocin, unlike
prolactin, remain low during the aura and only rise during
the generalized convulsions and motor features. During
the state of postictal confusion norepinephrine remained
high, but vasopressin and oxytocin decreased (Meierkord
et al., 1994).
Hyposexuality has been described in association with
temporal lobe epilepsy and in patients that underwent
temporal lobectomies. Hyposexuality in men may be
associated with low levels of LH and elevated prolactin
levels. Antiepileptic drugs may add to the hyposexuality,
since they enhance testosterone metabolism (Schachter,
1994). Abnormal menstrual function and infertility has
been reported in epileptic women. They may have LH,
FSH, and testosterone concentrations suggestive of polycystic ovarian syndrome.
Melatonin is presumed to have anticonvulsant properties (Bazil et al., 2000; Bylesj et al., 2000). Saliva
melatonin levels are reduced in patients with intractable
temporal lobe epilepsy at baseline and increase threefold
following seizures (Bazil et al., 2000). In patients with
severe intractable seizures, melatonin was confirmed to
have antiepileptic properties. This effect is proposed
to be based upon its antioxidant activity as a free radical
scavenger (Peled et al., 2001), but a more probable
explanation is that melatonin is acting through the GABA
and benzodiazepine receptor (Rohr and Herold, 2002).
A novel class of antiepileptic drugs is also represented
by the effects of TRH. TRH treatment has been reported
to be efficacious in intractable epilepsies such as infantile
spasms, LennoxGastaut syndrome, myoclonic seizures
and other generalized and refractory partial seizures
(Kubek and Garg, 2002). The hypothalamopituitary
adrenal (HPA) axis is also of interest in epilepsy, since
corticotropin-releasing hormone (CRH) is a potent proconvulsant, particularly in the immature brain, while
ACTH and corticosteroids have been studied mainly as
anticonvulsants, useful in the treatment of infantile
spasms. Fluctuations in the function of the various components of the HPA axis may thus play a part in the circadian
fluctuations in seizures (Quigg, 2000).
(b) Epilepsy and hormone release

Postictal elevation of serum prolactin levels has been
found following tonic-clonic seizures and in focal epileptic
seizures of temporal origin (Meierkord et al., 1992). In
addition, following generalized tonic-clonic convulsions, increased plasma levels of ACTH, -endorphin,
-lipotropin, LH, follicle-stimulating hormone (FSH;
values increased in women only), growth hormone,
vasopressin and cortisol were found (Dana-Haeri et al.,
1983; Pritchard et al., 1983, Aminoff et al., 1984; Wyllie
et al., 1984; Laxer et al., 1985; Wroe et al., 1989;
Schachter, 1994). The mechanism underlying the
hormonal discharges is presumed to be a spread of ictal
discharges to hypothalamic structures that regulate
anterior and posterior pituitary functions. Amygdaloid
discharges might also be a basis for such hypothalamic
alterations in view of the strong hypothalamic projections
of this structure (Morales et al., 1995). In unilateral
temporal epileptia without secondary generalization,
growth hormone and prolactin release were not affected
(Matthew and Woods, 1993).
In infants, seizures had variable effects on serum
prolactin levels. Marked prolactin increases were only
noticed with focal tonic seizures and temporal involvement (Morales et al., 1995). In adults, prolactin plasma
levels may already rise during the aura of a limbic seizure
and may stay high during the phase of onset of generalized convulsions, cessation of motor features and the state
of postictal confusion (Meierkord et al., 1994). Meierkord
et al. (1992) found that six of the eight complex partial
seizures of temporal origin were associated with a marked
rise in prolactin plasma levels at 10 min after onset,
compared with a rise in only one of eight frontal lobe
complex seizures (two of temporal and three of frontal
lobe origin) was associated with a marked rise in prolactin
levels. Although this difference in prolactin response may
help in the clinical differentiation between these seizures
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(c) Hypothalamic hamartomas and epilepsy

Hypothalamic hamartomas (Chapter 19.3) are malformations containing hypothalamic neurohormones. They may
cause gelastic seizures or attacks of laughter (Chapter
26.2). There may be later development of focal seizures,
including complex partial seizures and a pattern of
symptomatic generalized epilepsy with tonic, atonic and
other seizure types in association with slow spike
and wave discharge and cognitive deterioration. Since the
time of Hughlings, Jackson focal seizures were, however,
supposed to be due to discharges in cortical gray matter,
and generalized seizures were supposed to arise from
a central midline pacemaker. A midline hypothalamic
hamartoma causing Lennox both focal and symptomatic
generalized patterns of epilepsy thus seemed hard to
fit in. However, hypothalamic hamartomas were shown
to be intrinsically epileptogenic by direct ictal EEG
recordings, increased ictal SPECT hyperperfusion in
the hamartoma, hypothalamic region and thalamus only.
Electrical stimulation reproduced the gelastic events and
stereotactic radiofrequency lesioning of the hamartoma
resulted in seizure remission. Laughing seizures thus
represent true diencephalic epileptic seizures (Kuzniecky
et al., 1997; Delalande et al., 2001; Chapter 19.3), while
this is a questionable term for the diencephalic epilepsy
described by Penfield (1929; see Chapter 28.5a and
below). They may even give rise to pseudotemporal lobe
seizures, i.e. seizures that begin in the hypothalamic
hamartoma and spread by connections to the amygdala
and produce focal temporal ictal discharges. Seizures do
not, in addition, disappear after temporal resection. There
may be absence attacks, tonic, atonic and tonic-clonic
seizures with slow spike and wave discharge. These
patterns are explained by the connections of the hypothalamus with the thalamus and the cortex (Berkovic
et al., 1997; Kuzniecky et al., 1997).
The pathogenesis of the epileptic seizures is unknown,
but in patients with hypothalamic hamartomas and
intractable epilepsy, large, dysplastic ballooned neurons
are observed. Dysplastic lesions are considered to be
intrinsically epileptogenic. An alternative pathogenetic
mechanism may be the production of certain peptides, such as metenkephalin by the hamartoma, or the
displacement of adjacent structures. Hypothalamic hamartomas with slow spike and wave discharge might also
cause progressive mental decline, possibly through
damage to the mamillary bodies or thalamus. Epilepsy
may be effectively treated by completely removing the
hamartoma (Berkovic et al., 1997; Kuzniecky et al.,

1997). An alternative therapy for medical refractory
epilepsy secondary to hypothalamic hamartomas is intermittent stimulation of the left vagal nerve (Murphy et al.,
2000).
(d) Hypothalamic pathology in epilepsy
Mesial temporal sclerosis is the major pathological abnormality in about 60% of patients with intractable temporal
lobe epilepsy. A strong concordance between changes in
the mamillary bodies, fornix and hippocampus was found
in an MRI study, pointing to an important role of these
structures in temporal lobe epilepsy (Ng et al., 1997).
In autopsy cases of epileptic patients, mamillary body
atrophy has been reported, thought to be due to deafferentation of the mamillary bodies in patients with mesial
temporal sclerosis (Kim et al., 1995; Mamourian et al.,
1995). This relationship is not without controversy,
however (see Chapter 17).
In an old study (Morgan, 1930), the clearest reduction
in cell numbers in epilepsy has been reported to occur in
the substantia grisea (periventricular gray), followed by
the nucleus tuberalis lateralis. Chromatolysis and gliosis
are generally found in these nuclei; and neuronophagia
is a common feature. The tuberomamillary nucleus is
affected to a lesser extent; the paraventricular nucleus
shows a varying amount of chromatolysis. Confirmation
of these hypothalamic changes in epileptic patients has
not been looked for since 1930. There is evidence that
histaminergic neurons (localized in the tuberomamillary
nucleus) (see Chapter 13) may control the excitability of
neurons and inhibit the generalization of epileptic
discharges. In this respect it is interesting that PET studies
have revealed abnormal amounts of H1-receptors around
the epileptic focus in complex partial seizures. Children
are more sensitive than adults to proconvulsive side
effects of drugs with H1-receptor antagonistic properties.
This agrees with the observation that the CSF concentration of histamine in a group of children with febrile
convulsions was lower than in another group of febrile
children without convulsions, which suggests a protective
effect of histamine against excessive neuronal excitation
(Tuomisto et al., 2001).
Penfield (1929) first used the term diencephalic
epilepsy for paroxysmal attacks of autonomic disbalance,
e.g. flushing, diaphoresis and temperature drop in a patient
with a cholesteatoma compressing the anterior hypothalamus and thalamus, causing intermittent hydrocephalus.
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It is presumed that injuries to the dorsal medial nucleus

of the thalamus and its connections are responsible for
this disorder (Solomon, 1973). A patient with a hypothalamic astroblastoma with autonomic seizures has also
been described in the older literature. The tumor was
311
localized between the roots of the fornices and the corpora

mamillaria. The tumor did, however, also infiltrate the
thalamus so that it is not known whether the hypothalamic
structures can be held responsible for diencephalic
epilepsy (McClean, 1934).
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CHAPTER 29
Neurodegenerative disorders
4 allele and Alzheimers disease does not seem to be

mediated by vascular factors. The ApoE 4 allele, elevated
cholesterol, and high blood pressure seem to be independent risk factors for Alzheimers disease (Kivipelto
et al., 2002; Lindsay et al., 2002).
Having Alzheimers disease means dying twice first the

mind dies, then the body.
. . . is not your father grown incapable / of reasonable
affairs? Is he not stupid / with age and altring rheums?
Can he speak? Hear? / know man from man? Dispute his
own estate? / Lies he not bed-rid? And again does nothing
/ But what he did being childish? Shakespeare, A Winters
Tale, Act IV, scene 4, 390 (Fogan, 1989).
(a) Conventional neuropathology

As sisters, we made the hard choice not to have children.
Through brain donation, we can help unravel the mysteries
of Alzheimers disease and give the gift of life in a new way
to future generations.
(Sister Rita Schwalbe; Snowdon, 2001; Fig. 29B).
29.1. Alzheimers disease and the hypothalamus

(Fig. 29A)
The brain is said to degrade gracefully. A computer is
brittle. Even a little damage to it, or a small error in its
program may cause havoc. A computer degrades catastrophically
(F. Crick. 1995, p. 178).
The involvement of the hypothalamus in aging and AD

is suggested by the increased volume of the third ventricle
with age (Murphy et al., 1992b) in spite of the decline
of cerebrospinal fluid (CSF) production and turnover rates
(Rubenstein, 1998). In AD, the third ventricular volume
increases by 74%, as compared to age-matched controls
(Tanna et al., 1991). Moreover, it is interesting that the
degree of dementia expressed as mini-mental state scores
correlates negatively with the volume of the third ventricle
(Wahlund et al., 1993). In addition to general brain
atrophy (Fig. 29B), MRI has shown atrophy of the hypothalamus, mamillary bodies, fornix, septal area and basal
forebrain in AD (Callen et al., 2001).
Using conventional stainings on the hypothalamus, the
classic Alzheimer changes are only modest. The presence
of some silver-stained neurofibrillary tangles (NFTs)
(Hirano and Zimmerman, 1962; Ishii, 1966) and a few
thioflavin S-positive (Rudelli et al., 1984; Saper and
German, 1987) and congophilic neuritic plaques
(Simpson, 1988) have been described. Some neuritic
plaques containing amyloid may be found in the nucleus
basalis of Meynert (NBM), in the diagonal band of Broca
Alzheimers disease (AD) is a multifactorial disease that

has age as the major risk factor. The presence of
apolipoprotein E (ApoE) 4 alleles is responsible for some
17% of the cases. Mutations in the amyloid precursor
protein presenilin 1 and 2 genes contribute less than 1%
to the prevalence of AD. The age at onset of AD is highly
hereditary (4060%), although ApoE has an effect on this
parameter (Tol et al., 1999). The ApoE 4 allel is also
associated with depression in female Alzheimer patients
but not in male patients (Mller-Thomsen et al., 2002).
Moreover, linkage is found on chromosome 6 and 10
(Li et al., 2002). Additional possible risk factors are sex,
sex hormones, smoking, education, cardiovascular disorders (Chapter 19.1b; De la Torre, 2002; Swaab et al.,
2002), brain-derived neurotrophic factor polymorphism
(Riemenschneider et al., 2002; Ventriglia et al., 2002),
interleukin-1 (IL-1A) polymorphism (Pirskanen et al.,
2002), and accumulation of mitochondrial DNA mutations (Li et al., 2002). The association between the ApoE
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Fig. 29 A.
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End stage of Alzheimers disease. Patient in fetal position. (With permission from the relatives of the patient, given to Dr. E.J.A.
Scherder.)
(DBB), and in the septal nuclei (Rudelli et al., 1984),

albeit not in large quantities (Chapter 2.3; Arnold et al.,
1991; Sassin et al., 2000). However, in the NBM and
DBB of Alzheimer patients, a considerable number of
NFTs may be present (Arnold et al., 1991). In the NBM
the first single silver-staining cytoskeletal abnormalities
are found very early in the Alzheimer process, i.e. in
Braak stages I and II, before any amyloid deposits are
found in this particular nucleus. It starts as isolated
filaments that aggregate to a spherical NFT. In stages III
and IV some ghost tangles are seen (Sassin et al., 2000).
Only occasionally are silver-staining NFTs found in the
preoptic area and anterior hypothalamus. At the tuberal
level, silver-stained tangles are scattered throughout
the hypothalamus, but they generally tend to avoid the
paraventricular and supraoptic nucleus (PVN, SON) and
the nucleus tuberalis lateralis (NTL). Only in a small
percentage of patients are NFTs found in the PVN and

SON (Schultzes et al., 1997a). The Alzheimer changes
in the infundibular nucleus depend on sex and age.
Argyrophylic neurofibrillary pathology was found in the
great majority of old men and only in a small percentage
of women, independent of the presence of Alzheimer
pathology in the neocortex (Schultz et al., 1996, 1997a,
b, c, 1999). In Alzheimer patients a few tangles are found
in the ventromedial nucleus (VMN). By contrast, large
numbers of NFTs are present in the dorsomedial nucleus,
in neurons surrounding the medial edge of the fornix and
the mamillothalamic tract, and in the large tuberomamillary neurons (Braak et al., 1996, Chapter 13.2). The
number of large, histamine-containing neurons of the
TMN is reduced in AD (Nakamura et al., 1993), which
is in agreement with the histaminergic deficit reported in
the cortex of Alzheimer patients. The silver-stained
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Fig. 29 B.
315
Brain of Alzheimer patient (top) and control (bottom). Note the atrophy of the Alzheimer brain. (From the Netherlands Brain Bank,
photograph G. van der Meulen.
neurofibrillary changes in the TMN (Chapter 13) start at

Braak stage IV and quite late in the NTL (Chapter 12),
i.e. at Braak stage VI (Braak and Braak, 1991). The medial
mamillary nucleus is relatively sparsely involved in
Alzheimer changes, but NFTs and neuritic plaques (NPs)
are present and the lateral nucleus is usually free of them
(Grossi et al., 1989; Braak et al., 1996; see Chapter 16.c).
However, the volume of the mamillary body as measured
by MRI is clearly diminished in Alzheimer patients
(Sheedy et al., 1999). For olfactory deficits in AD, see
Chapter 24.2b.
(b) Sex differences and sex hormones

According to some studies, the prevalence of AD is higher
in women than in men (Bachman et al., 1992; Brayne et
al., 1995; Fratiglioni et al., 1997; Launer et al., 1999;
Letenneur et al., 2000). In contrast, a study by Hebert
et al. (2001) did not reveal a sex-specific risk for AD,
but suggested that the excess number of women with this
disease was due rather to the longer life expectancy
of women. Lindsay et al. (2002) and Gatz et al. (2003)
did not find an association of AD with sex either, but a
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Dutch study indicated that after the age of 90 years

the incidence of AD is higher for women than for men,
while the incidence of vascular dementia is higher in men
than in women in all age groups (Ruitenberg et al., 2001).
Our observation of an increased number of NBM
cells containing hyperphosphorylated tau in women, as
compared to men (Salehi et al., 2000), and the association
found between AD and a locus on the X-chromosome,
support the presence of sex differences in AD. In addition,
estrogen receptor- (ER) polymorphisms PvuII and
XbaI are associated with the risk of developing cognitive
impairment (Yaffe et al., 2002); CAG-repeat polymorphism of the androgen receptor is associated with
AD in men (Lehmann et al., 2003); the DXS1047 202bp allele on the X-chromosome is twice as common
among Alzheimer cases as among controls (Zubenko
et al., 1998); and an increased risk by a factor of 7.6 has
been observed in homozygous individuals with the PPXX
ER genotype (Brandi et al., 1999). Moreover, there
is an interaction between estrogen receptor- and -
polymorphisms and the risk of developing AD (Lambert
et al., 2001).
Lower endogenous estradiol levels are correlated
with poor cognitive, behavioral and functional status in
older but undemented individuals (Farrag et al., 2002;
Senanarong et al., 2002; Wolf and Kirschbaum, 2002).
In women, higher estradiol levels as well as higher testosterone levels are associated with better verbal memory.
Moreover, estradiol is associated with a diminished
susceptibility to interference (Wolf and Kirschbaum,
2002). In elderly, nondemented men, higher free testosterone levels are associated with better scores on visual
and verbal memory, visuospatial functioning, and visuomotor scanning, and with a reduced rate of longitudinal
decline in visual memory (Moffat et al., 2002; Wolf and
Kirschbaum, 2002). Several studies have reinforced the
idea that the postmenopausal decrease in estrogen levels
may be an important factor in triggering the pathogenesis
of the disease, since women with high serum concentrations of bioavailable estradiol are less likely to develop
cognitive impairment than women with low concentrations (Inestrosa et al., 1998; Manly et al., 2000; Yaffe et
al., 2000b). In men, the Rotterdam study has not found
a clear association between estradiol levels and risk of
dementia, but in women higher levels of estradiol are
associated with increased risk of dementia (Geerlings
et al., 2003). In AD patients Cunningham et al. (2001)
have found higher serum levels of estrone and androstenedione, but not of testosterone or estradiol. The increased
levels of androstenedione in AD have been confirmed,

but serum estradiol levels are nonsignificantly increased
in women with Alzheimers disease in another study
(Rasmuson et al., 2002). The negative observations on
possible differences in sex hormone levels in AD patients
agree with our small pilot study (Table 8.5I and II). Yet
an interesting relationship has been observed between
CSF levels of estradiol and -amyloid. Estradiol CSF
levels are lower in AD patients than in controls, and
within the Alzheimer group the estradiol levels are
inversely correlated with A-42 concentrations. This
observation has been interpreted as corresponding to the
beneficial effects of estrogen replacement therapy on AD
(Schnknecht et al., 2001). In addition, women with
AD who are not taking estrogen replacement therapy are
vulnerable to depression (Carlson et al., 2000).
Estrogen replacement therapy (ERT) as a preventive
measure for AD is becoming increasingly controversial.
Epidemiological evidence, randomized controlled trials,
and cross-sectional and longitudinal studies have indeed
indicated that ERT in postmenopausal women is effective
in protecting against a decline in verbal memory in healthy
postmenopausal women and in preventing and delaying
the onset of AD (Henderson et al., 1996; Stephenson
et al., 1996; Tang et al., 1996; Costa et al., 1999; Slooter
et al., 1999; Van Duijn, 1999; Sherwin, 2002). In one
study, the overall efficacy of hormone replacement
therapy was similar for cognition and mood, but larger
for activities of daily living (Yoon et al., 2003). No effect
on cognition was observed after 4 years of hormone
therapy (Grady et al., 2002), and others have reported a
small but clinically meaningful cognitive decline
following estrogen plus progesterone treatment (Rapp
et al., 2003). In contrast, long-term treatment exceeding
10 years of hormone replacement seems to have positive
effects (Zandi et al., 2002). ERT is also reported to
improve cognitive performance in patients with AD
by enhancing the response to the acetylcholinesterase
inhibitor tacrine (Schneider et al., 1996), and by influencing the vesicular acetylcholine transporter (Smith
et al., 2001). Beneficial effects of ERT on cognition and
on noncognitive psychiatric signs have been reported in
some studies but not in others, possibly at least partly
depending on ApoE genotype (Haskell et al., 1977;
Hogervorst et al., 2000; Yaffe et al., 2000a; LeBlanc
et al., 2001; OConnor et al., 2001; Seshadri et al., 2001;
Tan and Pu, 2001; Kyomen et al., 2002; Lindsay et al.,
2002). Between 2000 and 2003, a number of randomized
controlled trials in AD patients did not show meaningful
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effects of estrogens (Henderson et al., 2000; Hogervorst

et al., 2000; Mulnard et al., 2000; Wang et al., 2000b).
Raloxifene, a selective estrogen-receptor modulator, given
for a period of 3 years to postmenopausal women with
osteoporosis, did not affect cognitive scores (Yaffe et al.,
2001). However, other trials have shown enhanced
cognitive functioning, following estrogen treatment, in
postmenopausal, nondemented women and women with
AD (Asthana et al., 1999; Carlson et al., 2001). In a
recent Danish study (Lkkegaard et al., 2002), hormone
replacement therapy appeared to postpone age-related
decline in cognitive functioning, partly in concentration
and partly in visuomotor function. However, women
treated with this therapy had better cognitive performance
already prior to treatment. On the other hand, women
who received estrogen plus progesterone therapy from
the age of 65 years and older ran an increased risk of
dementia (Shumaker et al., 2003). There is thus a need
for long-term, randomized controlled trials with estrogens,
starting immediately in the postmenopausal period in
mentally unaffected women, in order to get more information on the prevention of AD. At least part of the
controversial literature on the possible positive effects
of sex hormones in AD may be based upon the different
effects that different sex hormones may have on different
brain areas, depending on, e.g. age and sex. This is a
good a reason for more basic studies on the estrogen and
androgen neuronal systems that are involved in memory
processes.
A clear sex difference in the formation of Alzheimer
changes, either stained for hyperphosphorylated tau or by
silver, is observed in the hypothalamus. A dense network
of large, dystrophic neurites with NFTs interspersed
among them was observed in the median eminence (ME)
and adjacent infundibular (= arcuate) nucleus (Chapter
11, Fig. 11.3). The terminal-like fibers form a perivascular
plexus of bouton-like structures around the vessels of the
pituitary portal system. This neurofibrillary pathology
reveals a striking sex difference. From 60 years onwards,
the frequency of the neurofibrillary lesions in the
infundibular nucleus of male subjects rises from 22% to
90%, while such lesions are observed in only 810% of
the women (Schultz et al., 1997a, b, c, 1999; Fig. 29.1).
It is tempting to explain the sex difference in Alzheimer
changes in the infundibular nucleus in relation to the
strong activation of this structure in postmenopausal
women, as is evident from the hypertrophy of the neurons,
their increased production of neuropeptides, the increase
in nucleolar size, and the presence of multiple nucleoli
317
Fig. 29.1. The percentage of men affected by mediobasal hypothalamic (MBH) pathology markedly increases from the age of 60 to 90
years. A marked or severe degree of MBH pathology was identified in
30% of all men at this age (not shown). In contrast, only a small
percentage of elderly women are affected. (From Schultz et al., 1997a,
Fig. 3a, with permission.)
(see Chapter 11f). In addition, nuclear spheroids are

found that are cytoplasmic protrusions in the nucleus
of the activated infundibular nucleus neurons of postmenopausal women (Hirabayashi et al., 1979). Activation
of the infundibular neurons of postmenopausal women
seems to protect these women from Alzheimer changes,
a phenomenon paraphrased use it or lose it (Swaab,
1991).
In the NBM of women there are a larger proportion
of neurons that contain hyperphosphorylated tau than in
the NBM of men (Salehi et al., 1998c). The ApoE 4
allele is associated with shorter survival in men but not
in women with AD (Dal Forno et al., 2002).
(c) Downs syndrome
Downs syndrome patients reach their highest mean IQ
at the age of 6 months (IQ80). There is a decrease in
IQ with age. At the age of 11 years, the IQ has decreased
to 40 (Annern et al., 1990), indicating premature brain
aging in Downs syndrome. This possibility is reinforced
by the observation that Downs syndrome patients experience menopause at an earlier age (Schupf et al., 1997).
317
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The smaller corpora mamillaria (Raz et al., 1995) and

anterior commissure (Sylvester, 1986) may be due to
degenerative changes in the temporal cortex (see Chapters
6.3 and 16c). Neuroendocrine changes are described in
Chapter 26.5.
Alzheimer changes are generally present in middleaged Downs syndrome patients. They were described in
Downs syndrome patients for the first time in 1929
(Struwe, 1929) and have been confirmed many times since
then. Female Downs syndrome patients have an earlier
onset and a more severe form of AD, which correlates
with higher neocortical neurofibrillary tangle counts rather
than with plaque density (Raghavan et al., 1994). In the
hypothalamus of middle-aged Downs syndrome patients,
similar but often very pronounced Alzheimer changes are
found, accompanied by a cholinergic deficiency in the
NBM (see Chapter 2.5). In the NTL of Downs syndrome
patients of between 49 and 59 years old, a variable amount
of A has been observed; while Alz-50 stains this nucleus
strongly, both for cell bodies and neuropil threads (Van
de Nes, 1995; Thesis, Chapter V).
Fig. 29.2. The mean of Alz-50 load (A) and mean percentage of
Alz-50 stained neurons (B) in men and women. Note that female subjects
showed a significant increase in the mean percentage of Alz-50-stained
neurons compared with men. *p = 0.039. (From Salehi et al., 1998c,
Fig. 3, with permission.)
(d) Hyperphosphorylated tau and -amyloid

Although the occurrence of the classic silver-staining
Alzheimer changes in the hypothalamus is modest, antibodies that recognize pretangle cytoskeletal changes in
cell bodies, dystrophic neurites, neuropil threads and
congo-negative anti--protein/A4 (A)-immunoreactive
amorphous senile plaques are present in considerable
amounts (Standaert et al., 1991; Swaab et al., 1992b; Van
de Nes et al., 1993, 1994, 1998; Salehi et al., 1995b).
However, the disposition of A in the diencephalon,
including the NBM, does not occur until relatively late,
i.e. in the third phase of -amyloidosis (Thal et al., 2002).
Several antibodies for cytoskeletal changes in AD
reveal, in principle, similar staining patterns in the
hypothalamus. This holds true, e.g. for antibodies against
paired helical filaments (PHF) e.g. anti-PHF serum 60e
and the monoclonal antibody Alz-50, both directed against
normal and abnormally phosphorylated tau; the monoclonal antibody tau-1, which recognizes tau, and the
monoclonal antibody 3-39, which recognizes ubiquitin
(Swaab et al., 1992b). The sensitive antibody AT8, which
recognizes hyperphosphorylated tau, was later used in
many other studies (e.g. Schultz et al., 1996, 1997a, b).
MCI has similar properties (Van Leeuwen et al., 2000).
In our studies, staining of the neuropil threads and
dystrophic neurites in Alzheimer patients was most
conspicuous following Alz-50 staining (Swaab et al.,

1992b). The epitope on tau protein recognized by the
monoclonal antibody Alz-50 is discontinuous and requires
both an N-terminal segment and the microtubule binding
region for efficient binding to this antibody (Carmel
et al., 1996). On the other hand, Alz-50 staining of
Alzheimer changes should be distinguished from crossreactivity seen with this antibody in some normal neurons
and thin beaded neurites, e.g. in the PVN, periventricular
and arcuate nucleus and terminals around the portal
vessels in the stalk/median eminence region of young,
healthy controls (Byne et al., 1991; Swaab et al., 1992;
Van de Nes et al., 1994). This control staining is due
to cross-reactivity with an unknown compound in somatostatin-containing neurons (Van de Nes et al., 1994). The
distribution over the hypothalamus and adjoining areas,
such as, e.g. the bed nucleus of the stria terminalis,
of both amorphic plaques stained by anti-A and
cytoskeletal changes as revealed by Alz-50, is quite
characteristic, as shown in Tables 29.1 and 29.2 (Van de
Nes et al., 1998). A few AT8-immunoreactive neurons
are already present in the NBM at Braaks stages I and
II. The density of such lesions is moderate in stage III
and tends to be severe in stage IV (Sassin et al., 2000).
In advanced Braak stages, the subthalamic nucleus
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TABLE 29.1
Immunocytochemical staining of amorphous plaques and -amyloid cores in the hypothalamus.
Controls
1
Alzheimers disease patients

2
10
++*
+
+*
++
++
NA
++*
Chiasmatic region of the hypothalamus

SON
CG
SDN
SCN
PVN
PVA
ME
NA
Tuberal region of the hypothalamus

DMN
VMN
TG
TMN
NTL
NTI
+
++
+
+*
+*
+++*
+++*
++
+*
++
++
++
+++
+
+
++
++
++
+
+
+
+
+
+
+
++*
+++*
+
+++
++
+
+
++
+++
+
+++
++
+*
++
++
++*
+
++
+
+
+
++
+
Adjoining areas
NBM
DBB
BSTc
BSTl
BSTm
ACC
CI
NA, not available; , no or negligible staining; , few; +, small amount; ++, considerable amount; +++, large amount.
* Congophilic -amyloid cores were present but their amount was too low to score. The antibodies SP28 and 1G102 revealed a similar staining.
(Adapted from Van de Nes et al., 1998.)
occur relatively late, i.e. in the third phase of the evolution of -amyloidosis (Thal et al., 2002).
A-positive amorphic plaques are found in the
following nuclei of Alzheimer patients: the central gray,
the sexually dimorphic nucleus of the preoptic area (SDNPOA), the tuberal gray, the dorsomedial hypothalamic
nucleus, the VMN, the tuberoinfundibular nucleus, the
TMN, and the NTL, as well as in all subnuclei of
the bed nucleus of the stria terminalis (BST), the NBM
and DBB, nucleus accumbens (ACC), islands of Calleja
and in the corpus mamillare. It should be noted, though,
that amorphous plaque density in the NBM in AD was
found to be in the same range as that of a 90-year-old
(Chapter 15a) shows neurons accumulating hyperphosphorylated tau (Mattila et al., 2002).
(e) A immunoreactivity (Table 29.1)
The hypothalamus in AD is seeded with amorphic plaques
that do not contain epitopes corresponding to other
regions of the amyloid protein precursor (APP) than
the A4 region in contrast to the A4-reactive plaques in
the cortical areas and hippocampus that are dominated
by those that exhibit immunoreactivity for regions of the
APPs outside the A4 region (Standaert et al., 1991).
However, the A-deposits in the diencephalon and NBM
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control (Van de Nes et al., 1998; Thal et al., 2002),

emphasizing the absence of a clear border between normal
aging and AD. Other regions, such as the SON, suprachiasmatic nucleus (SCN), periventricular area (PVA) and
ME, remain devoid of A staining (Van de Nes et al.,
1994, 1998; Stopa et al., 1999). While, in the NBM, NFTs
are already present in Braak stage I, amyloid deposits are
found only in Braak stage II and later stages (Sassin
et al., 2000; Thal et al., 2002). In the NTL, considerable
amounts of amorphous A deposits were mainly found
in young Alzheimer patients of 52 years and younger. In
different areas the amorphic plaques have a different
morphology (Van de Nes, 1995, Thesis, Chapter V; Van
de Nes et al., 1998).
Anti-A-reactive blood vessels are only found in some
Alzheimer patients in the ACC, the central nucleus of the
BST (BSTc) and the TMN. These A deposits are applegreen birefringent with Congo red, and thus represent
congophilic angiopathy. Congophilic senile plaques are
rare in the hypothalamus but are sometimes seen in areas
indicated by an asterisk in Table 29.1. Ghost tangles,
indicative of cell death, are only rarely seen in AD patients
in the chiasmatic gray (CG) and tuberal gray (TG). They
stain positive with anti-A, but not with Alz-50.
(f) Abnormally phosphorylated tau (Table 29.2)
In general, the SON and PVN do not show Alzheimer
pathology (Swaab et al., 1992b). Using the antibody AT8
in a small subpopulation of elderly subjects, neurofibrillary pathology has been observed in the PVN (7.5%)
and SON (4.5%) (Schultz et al., 1997a). In addition, early
cytoskeletal changes, as revealed by antibodies against
abnormally phosphorylated tau (i.e. AT8, PHF-1 and
Alz-50) are observed in some fibers and Herring bodylike structures in the neurohypophysis of some patients,
even if the brain is devoid of Alzheimer changes (Schultz
et al., 1997b).
Alz-50 immunoreactivity showing cytoskeletal changes
in perikarya and dystrophic neurites is present in a number
of hypothalamic nuclei of Alzheimer patients and elderly
controls. The staining ranges from intense in the NTL to
generally none in the SON (Table 29.2; Swaab et al.,
1992b; Van de Nes et al., 1993, 1994, 1998). Presenile
Alzheimer patients have less Alz-50 staining in the
NTL than senile AD patients (Van de Nes, 1995).
Accumulation of hyperphosphorylated tau is also found
in the subthalamic nucleus (Chapter 15a) in advanced
Braak stages (Mattila et al., 2002). It should be noted
that, to the experienced eye, staining of dystrophic

neurites with Alz-50 is not superior to that obtained with
the Bodian conventional silver-staining method.
The sex-specific argyrophilic neurofibrillary changes
in the ME and infundibular nucleus as observed by
Gallyas silver stainings have been confirmed by antibodies that show the relationship with abnormally
phosphorylated tau such as AT8 (Schultz et al., 1996)
and Alz-50 (Chapter 11).
The presence of Alz-50 and A staining is not
necessarily correlated in the various hypothalamic nuclei.
For instance, the hypothalamus and BSTc of a young
Alzheimer patient (patient 7; Table 29.1) showed
relatively intense A staining and little Alz-50 staining
(Table 29.2). The SCN in AD remains entirely negative
for A, but some staining of neuropil threads is found
with Alz-50, while this nucleus shows a clear functional
disorder (see Chapter 4.3). Double staining of Alz-50
and A does not show a topical relationship between
amorphic plaques and cytoskeletal changes either, so that
the pathogenetic mechanism giving rise to these two
hallmarks does not seem to be causally related (Van de
Nes et al., 1998). In addition, the amount of A staining
does not differentiate between controls and Alzheimer
patients (Standaert et al., 1991; Van de Nes et al., 1998).
In the hypothalamus and adjacent areas, the difference
between Alzheimer patients and controls is most obvious
in the NBM when this structure is immunocytochemically
stained for pretangles or by, e.g. Bodian. The discrepancies between the localization of A accumulation and
(pre)tangle formation in the various brain structures
is one of the arguments against the amyloid cascade
hypothesis as the central mechanism in the pathogenesis
of AD (Swaab et al., 1998; Van de Nes et al., 1998;
Sassin et al., 2000; Mudher and Lovestone, 2002).
(g) Relationship between Alzheimer neuropathology
and decreased metabolism
In addition to NFTs and plaques, decreased neuronal
activity is one of the major characteristics of AD (Swaab
et al., 1998). Using the size of the Golgi apparatus (GA)
as a histological parameter of chronic metabolic activity
changes in neurons, the hypothalamus appears to contain
several nuclei that are differentially affected in AD.
For instance, the SON is generally not affected by
AD changes and even shows hyperactivity during aging,
in both controls and AD patients (Swaab et al., 1992b;
Lucassen et al., 1994; Chapter 8.3; for a sex difference
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TABLE 29.2
Alz-50 staining for hyperphosphorylated tau of dystrophic neurites (D) and perikarya (P) in the hypothalamus.
Controls
1
Alzheimers disease patients

2
10
D,P
+ D,P
+D,P
+ P,D
D,P
D,P
P
P
D,P
P
++ D,P
++ D.P
+ D,P
+ P,D
+P
NA
D,P
+ D,P
+P
Chiasmatic region of the hypothalamus

SON
CG
SDN
SCN
PVN
PVA
ME
NA
Tuberal region of the hypothalamus

DMN
VMN
TG
TMN
NTL
NTI
D,P
D,P
D,P
D,P
+ D,P
+ D,P
+ D,P
+ D,P
+ D,P
+ D,P
D,P
D,P
D,P
D,P
+ D,P
D,P
++ D,P
P
++ D,P
+++ D,P
+ D,P
+ D,P
++ D,P
++ D,P
+++ D,P
+ D,P
D,P
+ D,P
+ D,P
++ D,P
D,P
D,P
D,P
D
P
P,D
+ P,D
++ D,P
++ D,P
+ D,P
D,P
+ D,P
P,D
P,D
++ D,P
+ D,P
P
P
P,D
P
++ D,P
+ D,P
+ D,P
D,P
+ D,P
D,P
+ D,P
++ D,P
++ D,P
+ D,P
D,P
D,P
+ D,P
P
++ D,P
++ D,P
+ D,P
D,P
+D,P
+ D,P
+D,P
Adjoining areas
NBM
DBB
BSTc
BSTl
BSTm
ACC
CI
The order of the letters D or P is related to the relative density of the Alz-50-positive dystrophic neurites of perikarya. The first letter presents
the highest relative density. (Adapted from Van de Nes et al., 1998.)
different stages of neurofibrillary degeneration and

neuronal activity has been investigated, as well as the
question of the possible cause or effect of such a relationship. In order to do so, the relationship between GA
size and the different stages of AD changes were assessed
for the following characteristics:
see Chapter 8.d). Only in a small part of the population

are some cytoskeletal alterations observed in the SON
and PVN (Schultz et al., 1997a); this in contrast to the
NBM (Chapter 2), which generally shows clear signs of
neuronal atrophy (Rinne et al., 1987), cytoskeletal alterations (Swaab et al., 1992b; Van de Nes et al., 1993) and
some NP formation (Rudelli et al., 1984). The changes
in the NBM are, however, certainly not as outspoken as
those in the CA1 area of the hippocampus, a brain region
which is clearly affected by cell death (West et al., 1994)
and contains an abundance of NFT and a moderate amount
of NPs (Mann et al., 1985b). In the hypothalamic and
hippocampal tissue from controls and AD patients, the
possible presence or absence of a relationship between
Hardly any AD hallmarks

The SON of the hypothalamus generally appears to be
spared in AD (Chapter 8.3). No classic AD neuropathology is present in the large majority of the patients,
and even using antibody Alz-50 as an indicator of early
cytoskeletal alterations (Bancher et al., 1989), no staining
of SON neurons is generally found (Swaab et al., 1992b;
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Fig. 29.3. Supraoptic nucleus of an Alzheimer patient (NHB 96009, male, 86 years of age; Braak stage 3) with a relative, rare involvement of
some neurons in the Alzheimer process. Brown staining for hyperphosphorylated tau by AT8 in some cells and dystrophic neurites. (Preparation,
T. Ishunina.) Bar 50 m.
Van de Nes et al., 1993). Only in a small number of

Alzheimer patients are some cytoskeletal changes present
in the SON and PVN (Schultz et al., 1997a; Fig. 29.3).
Furthermore, there is no cell loss in the SON, either
in aging or AD (Goudsmit et al., 1990; Van der Woude
et al., 1995). In the SON signs of hyperactivation with
aging were even found (Hoogendijk et al., 1995; Van
der Woude et al., 1995). As shown by Lucassen et al.
(1994), there is indeed a significant increase in activity,
as measured by an increased size of the GA, of vasopressinergic neurons of the SON during aging, both in
controls and AD patients, supporting the idea that
activation of neurons might protect them against AD
changes (Swaab, 1991; Chapter 8.3). Since these
studies, we have found that the increased activity of SON
neurons during the course of aging is restricted to women

(Ishunina et al., 1999). One may wonder, therefore,
whether the cytoskeletal changes observed in the SON of
a few individuals (Schultz et al., 1997a) may also be a
sexually dimorphic phenomenon.
Early cytoskeletal alterations
Tau proteins belong to the microtubule-associated
proteins. It has been suggested that the occurrence of
early cytoskeletal changes due to abnormal phosphorylation of tau as found by a variety of antibodies would
precede the appearance of neurofibrillary degeneration as
shown by silver staining (Bancher et al., 1989; Braak
et al., 1994). Abnormal phosphorylation of tau proteins
as found in AD patients may lead to a failure of
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of the GA. Although diminished somatostatin staining

may indicate a start of decreased metabolic activity (Van
de Nes, 1995, Thesis, Chapter V), pretangle AD changes
were not accompanied by reduced metabolic activity as
measured by the size of the GA.
Late cytoskeletal alterations (NFTs)
The appearance of early cytoskeletal alterations is
presumed to be followed by the formation of NFTs that
are detectable by silver staining (Bancher et al., 1989).
The finding (see above) that there is no clear relationship
between the appearance of early cytoskeletal alterations
and protein synthetic ability as measured by the size
of the GA in the NTL raises the question of whether
AD changes and decreased metabolism are related in
areas with late stages of cytoskeletal alterations, i.e. NFTs
and NPs, such as the NBM, TMN and CA1 area of the
hippocampus.
The NBM is an area of the basal forebrain which is
clearly affected in AD (Chapter 2.3). This nucleus shows
not only early cytoskeletal alterations, as indicated by
Alz-50 staining (Fig. 29.4), but also some silver-staining
NFTs and NPs, and some -amyloid accumulation in AD
(Rudelli et al., 1984; Swaab et al., 1992b; Van de Nes
et al., 1993, 1994; Sassin et al., 2000). Although it was
suggested initially that this area shows a dramatic cell
death in AD (Whitehouse et al., 1982, 1983b), it turned
out that degeneration in the NBM is mainly characterized
by cell atrophy rather than by cell death (Pearson
et al., 1983; Rinne et al., 1987; Gilmor et al., 1999;
Chapter 2.4). A significantly decreased size of the GA is
found in NBM neurons in AD, suggesting that protein
synthetic activity of NBM neurons is strongly reduced
in this brain area (Salehi et al., 1994). The decreased
expression of the high-affinity neurotrophin receptors, the
trks, in the NBM (Fig. 29.5) in AD may be a crucial
phenomenon in the decreased metabolic rate in these
neurons. AD patients with one or two ApoE 4 alleles
have an extra decrease in metabolic rate, which fully
agrees with the more severe cholinergic deficit in the neocortex of these patients and their increased risk to get AD
(Salehi et al., 1998a; Fig. 29.5). TMN neurons are clearly
affected in AD by NFTs (Nakamura et al., 1993; Chapter
13) in this area of the hypothalamus. As shown by Salehi
et al. (1995a), metabolic activity is also significantly
reduced in AD. This observation agrees with the decreased
hypothalamic, hippocampal and cortical histamine levels
found in AD patients (Schneider et al., 1997; Panula et
al., 1998), and supports the existence of a relationship
Fig. 29.4. Immunocytochemical staining of Alz-50 in the NBM of an

Alzheimer patient with apolipoprotein E 3/4. Note the clear staining
of cell bodies, dystrophic neurites and neuropil threads. Scale bar
28 m. (From Salehi et al., 1998c, Fig. 1, with permission.)
tau proteins to bind to microtubules (Lee et al., 1991).

This is presumed to result in a failure to maintain axonal
transport and neuronal shape.
The hypothalamic NTL shows strong cytoskeletal
alterations, as appears from the intense staining of NTL
neurons by the antibodies Alz-50 and MC1 (both against
hyperphosphorylated tau, tau-1 (against tau) and 3-39
(against ubiquitin) (Swaab et al., 1992b; Van de Nes
et al., 1993; Chapter 12). Interestingly, silver-stained
NFTs and NPs are rare in the NTL of AD brains (cf.
Kremer, 1992b). The NTL thus represents a brain area
that shows only the early stage of AD changes and does
not generally progress towards classic silver staining
of neuropathological AD hallmarks (Swaab et al., 1992b;
Chapter 12.2b), in spite of the fact that in other regions
of the brain of the Alzheimer patient full blown
neuropathology is present. This makes the NTL a very
suitable structure for a study of the relationship between
the presence of pretangles and changes in neuronal
activity. In the NTL, decreased staining of somatostatin,
its major neuropeptide, often seems to precede the
cytoskeletal changes (Van de Nes, 1995). As shown by
Salehi et al. (1995b), there is no reduction in neuronal
activity in this area in AD. Furthermore, comparison of
the intensity of Alz-50 staining with Golgi apparatus size
does not show a clear relationship between these two
parameters. This indicates that strong cytoskeletal
alterations in the NTL are not necessarily accompanied
by decreased neuronal activity as measured by the size
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Fig. 29.5. The proportion of neurons stained by Trk antibodies in

controls and Alzheimers disease (AD) patients. Note the strong reduction in the proportion of TrkA-expressing neurons in AD, which is
followed by TrkB and TrkC. * p 0.00001; ** p 0.009; *** p 0.004.
(From Salehi et al., 1996, with permission.)
between AD pathology and decreased neuronal activity.

It has been proposed that the decreased histaminergic
activity in AD and Downs syndrome is due to the
decreased levels of histamine-releasing factor that is found
in various brain regions (Kim et al., 2001b). The observation of Airaksinen et al. (1991b) that histaminergic
neurons in the TMN seldom contain NFTs, may well be
explained by the loss of histamine in the affected
TMN neurons. The CA1 area of the hippocampus, too,
is strongly affected by AD changes (West et al., 1994)
and shows strongly decreased neuronal activity in AD
patients (Salehi et al., 1995c), but this structure will not
be extensively discussed here.
The pretangle stage of AD changes is not necessarily
related to clear changes in metabolic rate, as indicated
by our GA studies in the NTL. However, the clear reduction in GA size in AD affected NBM, TMN and CA1
neurons supports the idea that decreased neuronal activity
and the occurrence of the classic AD changes often go
together. Of course this does not necessarily mean that
these two types of changes are also causally related. On
the contrary, observations on the hippocampus reveal that,
in principle, these two groups of Alzheimer changes are
independent of each other. In CA1 neurons of Alzheimer
patients, the neuronal activity is strongly diminished.
However, this is independent of the presence or absence
of NFTs in the neurons (Salehi et al., 1995c). Moreover,
the presence or absence of adjacent plaques in CA1
Fig. 29.6. The size of the mean Golgi apparatus in controls and
Alzheimer patients with apolipoprotein E (ApoE) genotype 3/3
compared with Alzheimer patients with ApoE genotype 3/4 and 4/4.
Note the clear reduction in the size of Golgi apparatus in Alzheimer
patients with one or two ApoE 4 alleles, compared with Alzheimer
patients without ApoE 4 alleles. There is no significant difference
(P = 0.760) in Golgi apparatus size between Alzheimer patients with
one ApoE 4 allele and two 4 alleles. (From Salehi et al., 1998a,
Fig.2, with permission.)
does not affect metabolic rate in the neurons of this area

either (Salehi et al., 1998b). The classic neuropathological
hallmarks (the NFTs and NPs) consequently do not seem
to induce decreased metabolic rate.
Reactivation of hypothalamic structures in AD
In conclusion, it appears that decreased neuronal activity
is one of the major hallmarks of AD, accompanying the
classic neuropathology. This makes it attractive to study
the question whether restimulation of the affected
neuronal systems is, in principle, possible in this disorder.
The fact that the infundibular nucleus suggests a strong
and lasting (up to 100 years of age) neuronal activation
in postmenopausal women (Chapter 11f) suggests that
activation of neurons in older age can be achieved. The
activation of the infundibular nucleus in postmenopausal
women is accompanied by protection against Alzheimer
changes in this area that are hardly ever seen in older
women, whereas such changes are present in up to 90%
of the older men (Schultz et al., 1997a, b, c, 1999).
The SCN seems an excellent target for clinical reactivation studies, since its main function, i.e. the regulation
of circadian rhythmicity, can be monitored. A decreased
number of neurons expressing vasopressin (Fig. 29.7),
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Fig. 29.7. In both presenile (n = 7) and senile (n = 8) Alzheimer patients the volume of the vasopressin subnucleus of the suprachiasmatic nucleus
(A) and the number of vasopressin-expressing neurons (B) is significantly decreased when compared with young (n = 14) or old (n = 9) agematched controls. In presenile Alzheimer patients only 10% of the number of neurons expressing vasopressin n controls is found. *** p > 0.001,
* p > 0.02 (MannWhitney U-test). (Unpublished data, D.F. Swaab.)
rhythm of 14 Alzheimer patients indeed showed an

improvement in its coupling to Zeitgeber, following
TENS treatment (Van Someren et al., 1998; Scherder et
al., 1999b). Concluding, both specific stimulation of the
SCN by light, and more general peripheral stimulation
of the central nervous system by TENS improve circadian rhythms in early and midstage Alzheimer patients,
which indicates increased activity of the biological
clock. Recent studies indicate that bright-light therapy in
demented elderly individuals improves not only circadian
rhythmicity but also daytime cognitive performance
(Yamadera et al., 2000; Graf et al., 2001).
neurotensin and vasoactive intestinal peptide (VIP)

neurons of the SCN in AD (Chapter 4.3; Swaab et al.,
1985; Zhou et al., 1995b; Stopa et al., 1999) have been
found. In addition, it is clear from the neurofibrillary
changes, from the increased number of glial fibrillary
acidic protein (GFAP)-positive astrocytes (Swaab et al.,
1992b; Van de Nes et al., 1993, 1994, 1998; Stopa et al.,
1999) and from the 3 times lower amount of vasopressin
mRNA in the SCN of Alzheimer patients (Liu et al.,
2000b; Fig. 29.8) that the SCN is affected by AD. The
alterations observed in the SCN are accompanied by a
disruption of circadian rhythms (see Chapter 4.3), nightly
restlessness, and a phase delay in body temperature
rhythm (Harper et al., 2001). Indeed, stimulation of the
SCN by light improves circadian rhythmicity, decreases
behavioral disturbances such as nightly restlessness (Van
Someren et al., 1998; Chapter 4.3) and can even improve
cognitive performance (Yamadera et al., 2000). In addition, as both direct and indirect spinal projections to the
SCN have been described in the rat, we investigated
whether transcutaneous electrical nerve stimulation
(TENS) could improve circadian rhythm disturbances in
AD patients. The actigraphically obtained rest-activity
(h) Hypothalamic changes in neuroactive substances

in AD
Neuropeptides
The changes in the vasopressin and VIP neurons in the
SCN in AD patients are described in Chapter 4.3 (see
also Figs. 29.7 and 29.8). The vasopressin-producing
neurons in the SON and PVN generally remain intact in
AD (Van der Woude et al., 1995) and the vasopressinergic
neurons even appear to be activated in the course of aging
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Fig. 29.8. Daynight fluctuations in vasopressin (AVP) mRNA in the suprachiasmatic nucleus (SCN) expressed as a masked area of silver grains
in controls and in Alzheimer patients (AD). Note that at any moment of the day the values for AD patients are lower than those for controls.
(From Liu et al., 2000b, Fig. 3, with permission.)
(see Chapters 8d and 8.3). Yet, some studies report

changes in circulating vasopressin and oxytocin levels in
AD although these data are somewhat equivocal (see
Chapter 8.3). The vasopressin CSF levels do not change
in dementia according to some authors (Jolkkonen et al.,
1989; Gottfries et al. 1995) and are increased (Tsuji
et al., 1981) or reduced according to others (Sundquist
et al., 1983; Srensen et al., 1983, 1986; Mazurek et al.,
1986; Olsson et al., 1987; Gottfries et al., 1995). The fact
that the type of dementia is often not specified may have
contributed to these discrepancies. Alterations in osmoreceptor function and vasopressin unresponsiveness to
metoclopramide point to alterations in the cholinergic
input and/or to changes in the control of processing or
release of vasopressin in AD (Norbiato et al., 1988;
Lipponi et al., 1990). An impaired vasopressin response
to changes in plasma osmolality has been found, but the
vasopressin response to hypotension in AD is normal
(Norbiato et al., 1988; Chapter 8.3). The changes in vasopressin regulation can, however, probably not simply be
primarily attributed to damage of the hypothalamic
neurosecretory neurons in AD, as has been proposed in
the literature, since their number remains intact in AD
(see Chapter 8.3). In agreement with an intact neurose-
cretory vasopressin system is the stable vasopressin innervation that is observed in the locus coeruleus and
parabrachial nucleus (Van Zwieten et al., 1994, 1996).
Although in an older paper a reduction of vasopressin
levels has been found in Brodmann areas 4, 7 and 10
(Fujiyoshi et al., 1987), increased vasopressin levels are
measured in the frontal lobe, temporal lobe and occipital
lobe of Alzheimer patients (Leake et al., 1991; Labudova
et al., 1998). In the choroid plexus we found an increase
in vasopressin-binding sites (Korting et al., 1996). A
substantial proportion of night-time incontinence in the
nursing home residents may be due to changes in circadian
regulation (Chapter 4.3b), possibly based on a deficiency
in vasopressin production and/or excretion (Ouslander
et al., 1998).
Clinical trials with vasopressin-like substances in AD
were based on the positive action of vasopressin in
memory processes, as shown in animal experiments. The
effects of vasopressin analogues on memory disorders in
AD have largely been negative, although some positive
trials have also been reported (Jolles, 1983; Perras, 2003).
That a double-blind, placebo controlled multicenter trial
with the vasopressin analogue DGAVP (Org 5667) did
not show any improvement in clinical rating scales or
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psychometric tests in Alzheimer patients (Wolters et al.,

1990) is in agreement with the intactness of the SON and
PVN as observed in our studies of these structures
(Chapter 8.3). Moreover, we should be aware that the
administration of vasopressin analogues is not without
danger: paranoid psychosis has been reported as a side
effect of desmopressin (DDAVP) in an Alzheimer patient
(Collins et al., 1981).
The decreased plasma concentrations of estrogenstimulated neurophysin in Alzheimer patients (Christie
et al., 1987) do not seem to be due to neuronal degeneration of the oxytocin neurons in the PVN, also because
these neurons seem to stay intact (see Chapter 8.3; Wierda
et al., 1991). Moreover, oxytocin levels are increased
in the hippocampus and temporal cortex and normal in
various other brain areas (Mazurek et al., 1987). CSF
levels of oxytocin are unchanged according to one study,
and decreased according to another (Gottfries et al., 1995;
Valenti, 1996). Yet a stable oxytocin innervation, originating in the PVN, and vasopressin innervation of the
parabrachial nucleus have been found in AD patients (Van
Zwieten et al., 1996), despite the fact that pervasive
neuropathological Alzheimer changes are observed in
Alzheimer patients in this brain area. These changes are
presumed to cause autonomic dysfunction and perhaps
even contribute to the mortality in these patients (Parvizi
et al., 1998).
Various other neuropeptide changes have been reported
in the hypothalamus in AD. Galanin and neuropeptide-Y
concentrations in the hypothalamus increase in AD
(Gottfries et al., 1995). This agrees with the fact that
weight loss is common in AD, and is even predictive of
mortality (Chapter 23c). Leptin is also decreased in
Alzheimer patients, but not inappropriately for the weight
loss (Power et al., 2001). CRH neurons in the PVN are
moderately activated in AD (Raadsheer et al., 1995, see
Chapter 8.5). The decreased CSF levels of CRH that have
been reported to occur in AD by some authors (Gottfries
et al., 1995; Heilig et al., 1995), but not by others
(Martignoni et al., 1990; Banki et al., 1992; Nemeroff,
1996; Valenti, 1996), might thus reflect extrahypothalamic changes rather than PVN changes (Gottfries et al.,
1995). Whether the CRH increase in CSF in Alzheimer
patients is indeed present only in association with major
depression in AD (Valenti, 1996) still has to be confirmed.
In the hypothalamus of Alzheimer patients, neurotensin, substance P, and concentrations of -melanotropin
(MSH), cholecystokinin (CCK), thyrotropin-releasing
hormone (TRH), luteinizing hormone-releasing hormone
327
(LHRH) and VIP (but see Chapter 4.4) are unaltered

(Ferrier et al., 1983; Arai et al., 1984a, b, 1986; Nemeroff,
1989; Gottfries et al., 1995), although extrahypothalamic
-MSH is reduced in Alzheimer patients (Catania et al.,
2000). In CSF, VIP levels are reduced in AD (Valenti,
1996). Somatostatin levels in the hypothalamus of
Alzheimer patients decrease according to some authors,
and increase or stay the same according to others
(Nemeroff et al., 1989; Gottfries et al., 1995, Heilig
et al., 1995; Valenti, 1996). Muhlbauer et al. (1986)
have found an increase in opioid peptide levels in the
CSF of AD patients. According to some, the CSF and
plasma levels of -endorphin decrease in AD (Kaiya
et al., 1983; Heilig et al., 1995), whereas those of ACTH
increase. According to others, the levels of -endorphin
and -lipoprotein remain the same or increase in this
disorder (Franceschi et al., 1988; Nappi et al., 1988). In
general, however, the CSF levels of neuropeptides yield
only very limited information, probably because of the
different brain structures that contribute to these levels
and that may show differential changes in AD.
Hormones and receptors
Also various endocrine alterations indicating hypothalamic changes have been reported in Alzheimer patients.
Plasma and salivary cortisol levels are increased in AD
and vascular dementia (Davidson et al., 1988; Masugi
et al, 1989; Swanwick et al., 1998; Murialdo et al., 2000;
Umegaki et al., 2000; De Bruin et al., 2002; Rasmuson
et al., 2002; Chapter 8.5b). Although some studies
indicate that cortisol levels may even increase in an early
stage of AD and may be related to cognitive decline
(Umegaki et al., 2000), others have not found increased
salivary cortisol levels in mild cognitive impairment, a
condition that is considered to be an increased risk for
AD (Wolf et al., 2002). The salivary cortisol levels are
also correlated with severity of disease, as measured
by the mini-mental state examination, and the global
deterioration scale (Giubilei et al., 2001). Hypercortisolinemia in AD appears to be related to the clinical
progression of the disease but not to aging or length of
survival (Weiner et al., 1997). The increased HPA axis
activity is presumed to contribute to neurodegenerative
changes in aging and AD, a hypothesis we could not
confirm (see Chapter 8.5e).
There is a linear relationship between plasma and CSF
cortisol levels (Fig. 1.14; Erkut et al., 2003, submitted).
Indeed, also CSF cortisol levels are increased in AD
(Swaab et al., 1994c; Erkut et al., 2003, submitted). While
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an increased cortisol in postmortem CSF was only found

in presenile AD patients (Swaab et al., 1994c), in lumbar
puncture, CSF cortisol levels were found to be elevated
in an ApoE-dependent way. The presence of 1 or 2 alleles
of 4 was accompanied by higher cortisol CSF levels, in
both AD patients and controls (Peskind et al., 2001).
In AD, CRH mRNA was found to be increased in the
PVN (Raadsheer et al., 1995), causing hyperactivity
of the HPA axis (see also Chapter 8.5b, e). How
the increased HPA axis activity may contribute to the
very high prevalence (45%) of major depression in
AD (Zubenko et al., 2003) should be further investigated.
Cortisol increase may generate leptin insensitivity (Olsson
et al., 1998). A recent study indicates that increased glucocorticoid production is an early feature of AD and may
be secondary to enhanced metabolic clearance of cortisol
by A-ring reduction (Rasmussen et al., 2001). In demented
patients with delirium, HPA axis feedback was found to
be disturbed (Robertsson et al., 2001). On the basis of
the inflammatory hypothesis of AD, low-dose (10 mg)
prednisone was given to Alzheimer patients for 1 year,
albeit without any effect on cognitive decline (Aisen,
2000; Aisen et al., 2000). However, after a moderate or
high-dose regimen of prednisolone given to nondemented
patients, the concentrations of A in CSF decreased,
indicating a decreased A production or an increased A
degradation in the brain (Tokuda et al., 2002).
Plasma growth hormone levels are higher in the
morning and plasma TSH concentrations are higher
through the day in Alzheimer patients. On the other
hand, plasma T3, T4 and rT3 are in the normal range
(Christie et al., 1987). A past history of thyroid dysfunction is a risk factor for AD (Smith et al., 2002).
Since an epidemiological study suggests that subclinical
hyperthyroidism in elderly people increases the risk of
dementia and AD (Kalmijn et al., 2000), a detailed study
of the hypothalamopituitarythyroid axis seems to be
worthwhile.
Melatonin levels in blood, CSF and pineal gland are
decreased in AD (Chapter 4.5; Skene et al., 1990; Uchida
et al., 1996; Magri et al., 1997; Liu et al., 1999). In
particular the nocturnal increase in melatonin secretion
is impaired (Ferrari et al., 2000). Moreover, daytime
melatonin levels are increased in Alzheimer patients and
do not react to bright light (Ohashi et al., 1999). Melatonin
levels in postmortem CSF are already decreased in the
earliest stages of AD, i.e. between Braak stages 0 and I
(Zhou et al., 2003; Fig. 29.9). This observation has yet
to be followed up in plasma or saliva. In this connection
Fig. 29.9. Melatonin levels in postmortem cerebrospinal fluid (CSF)

in relation to the progression of Alzheimers disease as indicated by
Braak stages. Note that the decrease in CSF melatonin levels already
begins in those aged control subjects that are in the early stages of
Alzheimers disease (Braak stage I). (From Zhou et al., 2003.)
it is of considerable interest that CSF and plasma levels

correlate significantly (Rousseau et al., 1999). It should
be noted here that melatonin functions as an antioxidant
and neuroprotector (Pappolla et al., 2000; Reiter et al.,
2000; Tan et al., 2000) and that it is capable of inhibiting
the formation of amyloid fibrils in vitro (Pappolla et al.,
1998, 2000). It also prevents the interaction of ApoE 4
and A, and thus the formation of -sheet structures and
amyloid fibrils (Poeggeler et al., 2001). The decreased
melatonin levels in AD may thus be clinically relevant.
In a case report on a monozygotic twin with AD, and in
a small retrospective study in Alzheimer patients, melatonin had a beneficial effect on memory function, sleep
quality and reduced sundowning (Brusco et al., 1998,
2000). In a double-blind, randomized placebo-controlled
trial of 6 mg melatonin in patients with dementia and
sleep disturbances for 2 weeks, no evidence was found
for improvement of sleep (Serfaty et al., 2002). More
long-term, well-controlled studies are needed on the
possible effects of melatonin in AD.
Circulating DHEAS levels are generally found to be
decreased in AD (Ferrari et al., 2000; Hillen et al.,
2000; Murialdo et al., 2000; Chapter 8.5c), but unchanged
levels have been reported also (De Bruin et al., 2002).
Others have even observed increased DHEAS levels in
AD patients (Rasmuson et al., 2002). DHEAS is
believed to antagonize noxious glucocorticoid effects
and to exert neuroprotective activity. In addition,
the decreased DHEAS levels correlate to changes in
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hippocampal perfusion in dementia (Murialdo et al.,

2000). A variety of steroids can be synthesized in the
brain and are known as neurosteroids. While Brown et
al. (2003a) have found increased DHEA and pregnanolone
levels in the hypothalamus of AD patients, Weill-Engerer
et al. (2002) have found decreased DHEAS and unaltered
pregnanolone sulfate levels. Clearly more data is needed
that differentiates between the different hypothalamic
regions. A small pilot study has not found significant
improvement of cognitive performance of DHEA in AD
patients (Wolkowitz et al., 2003).
Serum concentrations of LH and follicle-stimulating
hormone (FSH) are significantly elevated in patients with
AD. Testosterone decreases in dementia patients (Bowen
et al., 2000; Short et al., 2001). These observations agree
with the observations that higher levels of bioavailable
estradiol protect against AD (Chapter 29.1b). Elevated
gonadotropin levels are especially high in Downs
syndrome patients (Bowen et al., 2000).
In the NBM of Alzheimer patients, the proportion
of neurons showing nuclear staining for both ER- and
ER-, and cytoplasmic staining for ER-, were markedly
increased. In AD, the percentage of ER- nuclearpositive neurons increases only in women but not in men
(Ishunina and Swaab, 2001; Fig. 29.10). In the vertical
limb of the DBB, increased nuclear staining for ER- was
also found (Ishunina and Swaab, 2003). Although these
observations suggest the presence of a substrate for estrogen replacement therapy acting in interaction with the
cholinergic system, there may be serious doubt about
the efficacy of estrogen replacement therapy in Alzheimer
patients, because each area in the brain seems to react in
a different way to the lack of sex hormones and the aging
process (see Chapter 29.1b, where also the possible
changes in sex hormone levels in AD are discussed).
329
choline acetyltransferase activity correlates significantly

with the attention/registration scores. Hippocampal
choline acetyltransferase activity correlates only with
recent memory scores (Pappas et al., 2000). The cholinergic deficit in AD correlates not only with cognitive
impairment, but also with behavioral disorders such as
hyperactivity and aggression in Alzheimer patients
(Minger et al., 2000). The left NBM of one Alzheimer
patient was electrically stimulated over a period of
9 months, without any obvious clinical effect. However,
glucose metabolism at the ipsilateral, temporal and
parietal cortex was preserved in this stimulated patient,
while it decreased elsewhere in the cortex (Turnbull et
al., 1985), a possible basis for a positive effect that should
be extended in well-controlled studies. For cholinergic
deficiency in Downs syndrome patients, see Chapter 2.5.
Amines
Concerning the amines, reduced concentrations of serotonin, norepinephrine and increased monoamine oxidase
(MAO)-B activity have been observed in the hypothalamus (Gottfries et al., 1983); however, this has not been
confirmed by Sparks et al. (1991). The hypothalamic
decrease in noradrenaline (Arai et al., 1984b) correlates
with the severity of dementia and emotional disturbances
(Adolfson et al., 1979). The dopamine content of the
hypothalamus is unchanged in AD (Adolfsson et al.,
1979; Gottfries et al., 1983). However, because of the
strong heterogeneity of the hypothalamus, it is difficult
to interpret the overall levels of peptides or amines, and
immunocytochemical or in situ hybridization studies are
needed. Histaminergic deficits have been reported in the
cortex and hypothalamus of Alzheimers and Downs
syndrome patients. This indicates that the TMN is, indeed,
functionally affected in these disorders (MazurkiewiczKwilecki and Wsonwak, 1989; Schneider et al., 1997;
Panula et al., 1998; see also Chapter 13). In addition, the
in vivo histamine H1-receptor binding as measured by
PET is significantly decreased, particularly in the frontal
and temporal areas of the AD brain. Moreover, the
receptor binding correlates closely to the severity of the
disease (Higuchi et al., 2000). Two studies have shown
a delay in onset of AD among histamine H2-receptor
antagonists (Anthony et al., 2000).
Melatonin levels are decreased in AD, which is
most probably related to the high percentage of these
patients showing sundowning agitation. Supplementing
melatonin improves sleep and suppresses sundowning
(Cardinali et al., 2002; Chapter 4.3, 4.5e).
Acetylcholine
In the hypothalamus of demented patients, choline acetyltransferase levels are reduced, as is expected from the
observation that the cholinergic neurons of the NBM
and DBB are functionally affected by AD (Chapter 2;
Carlsson et al., 1980b; Candy et al., 1983; Minger et al.,
2000). In the neocortex of patients with AD, there is no
apparent reduction of nicotinic acetylcholine receptor
subunit mRNA, but there is loss at the protein level,
especially of the -4 subunit (Court et al., 2000, 2001).
The choline acetyltransferase activity in the medial frontal
and inferior parietal cortex significantly correlates with
scores on the graphomotor/praxis factor. Medial frontal
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Fig. 29.10. Immunocytochemical staining of ER in the NBM of AD patients (A; 91091) and of their matched controls (B; 98081, D; 94074).
Note intensive nuclear staining in AD patients as compared to controls. Bar 25 m. (From Ishunina and Swaab, 2001, Fig. 1, with permission.)
Autonomic changes and weight loss

Autonomic dysfunction, such as orthostatic hypotension,
has been mentioned as a possible complication of AD
(Siennicki-Lantz et al., 1999); in addition, weight loss is
a common problem. Changes in appetite, food preference
and eating habits are frequent occurrences (Ikeda et al.,
2002). The risk of weight loss, which is a predictor of
mortality among subjects with AD (White, 1998; Power
et al., 2001), tends to increase with severity and progression of the disease. Leptin is appropriately decreased in
AD (Power et al., 2001). The exact neurobiological basis
is not known for either the autonomic dysfunction or the
weight loss in AD.
29.2. Dementia with argyrophilic grains
Argyrophilic grain disease was first reported as an
adult-onset dementia. Recent studies have emphasized
personality change, emotional imbalance and memory

problems as clinical features (Togo et al., 2002b). In
the brains of individuals with adult-onset dementia,
Braak and Braak (1987b, 1989) have found a particular cytoskeletal abnormality, i.e. small, spindle-shaped
argyrophilic grains scattered throughout the neuropil. This
pathology could, according to Braak and Braak (1987b,
1989), best be recognized in silver impregnations such
as the modified Gallyas silver iodide technique (Schultz
et al., 1998), but one can visualize them even better with
phosphorylation-dependent antibodies such as Alz-50 or
AT8, which also label neurons that remain unstained by
silver preparations (Fig. 29.11; Schultz et al., 1998).
Indeed, the grains contain abnormally phosphorylated tau
protein (Ghebremedhin et al., 1998b). Argyrophilic brain
disease appears to be characterized by 4 repeats in the
microtubule binding domain (Togo et al., 2002a). The
argyrophilic grains cannot be recognized in Congo red or
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Fig. 29.11. Nucleus tuberalis lateralis of a patient with dementia with argyrophilic grains. NHB 95034, male, 75 years. Note the Alz-50 staining
(hyperphosphorylated tau) of a neuron and grains. Bar 50 m.
phylic grain disease and dementia, personality changes

and emotional imbalance may be typical features of this
disorder (Togo et al., 2002b).
The argyrophylic grains are often accompanied by
Alzheimer changes and can therefore best be recognized
in or below Braak stage III. The grains are not specific;
they can also be found in other neuropathological
disorders, including Picks disease, Lewy body disease,
corticobasal degeneration and progressive supranuclear
palsy (Togo et al., 2002a). The argyrophilic grains have
been found not only as exclusive pathology, but also in
combination with NPs, NFTs and neuropil thread, and
together with Parkinsonian pathology (Fig. 29.7) (Braak
and Braak, 1987b, 1989). Dementia with argyrophilic
grains should be distinguished from atypical forms of
progressive supranuclear palsy with 25-nm straight
tuberofilamentous structures (Masliah et al., 1991). The
thioflavin S stainings. In addition, mainly within the white

matter, close to the cortical gray matter, tau-positive
oligodendrocytes (coiled bodies) of silver-stained filaments are observed in this condition. Both argyrophilic
grains and coiled bodies contain dense accumulations of
straight filaments with a diameter of 913 nm in the electron microscope (Braak and Braak, 1987b, 1989; Itagaki
et al., 1989; Ghebremedhin et al., 1998). Argyrophilic
grain disease is not a rare disorder. In unselected material
it is present in a similar frequency to AD; its prevalence
increases with age and clinically it may appear as
personality changes and/or deterioration of intellectual
capabilities (Braak and Braak, 1998b). The frequency of
this disorder is estimated on the basis of several other
series, present in some 5% of dementia brains, a frequency
that is similar to that in nondemented cases. Although
there is thus no obligatory relationship between argyro331
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argyrophilic grains show an elongated body with coneshaped poles, occasionally giving off a short, thread-like
profile. The argyrophilic grains are found in abundance
in CA1 of the hippocampus, in the entorhinal cortex, in
the basolateral nuclei of the amygdala and in the hypothalamic lateral tuberal nucleus. The septum and the BST
contain modest amounts of grains. Of the hypothalamic
nuclei, the NTL (Chapter 12) shows the most severe
involvement (Fig. 29.8), whereas the VMN is affected to
a moderate degree, and the TMN shows only a few grains
(Braak and Braak, 1987b, 1989; Schultz et al., 1998).
The subthalamic nucleus (Chapter 15a) shows a clear,
hyperphosphorylated tau accumulation in argyrophilic
grain disease (Mattila et al., 2002). In addition, conspicuous accumulation of tau-positive oligodendrocytes
(coiled bodies) and interfascicular, thread-like fibers are
present in the column of the fornix. This pathology is not
visible in silver preparations, and absent in AD (Schultz
et al., 1998). The slender neuropil threads (dystrophic
neurites) can easily be distinguished from the coarse and
distended argyrophilic grains. The characteristic argyrophilic grains may go together with the sex-dependent
Alzheimer changes in the infundibular nucleus (Chapter
11.g, 29.1) which are also found in male controls and
male Alzheimer cases (Schultz et al., 1998).
A controversial association has been found between
the ApoE 2 allele and argyrophylic grain disease.
Individuals affected by this disease revealed a higher
frequency of the 2 allele (22%) than controls (2%)
(Ghebremedhin et al., 1998b). In contrast, ApoE allele
frequencies were found to be similar to those in controls
in cases with relatively pure argyrophylic grain disease,
while in those with concurrent Alzheimer pathology the
allele frequencies were similar to those in AD, i.e. more
frequently ApoE4 was found. This supports the notion
that argyrophylic grain disease is different from AD (Togo
et al., 2002a).
29.3. Parkinsons disease
. . . excessive salivation was to become the greatest
tribulation of my life (anonymous, 1952. The account by an
anonymous doctor of his Parkinsons disease).
Various genetic factors play a role in the development

of Parkinsons disease. There are many cases in which
an autosomal dominant hereditary factor seems to predispose for Parkinsons disease. A susceptibility gene has
been located on chromosome 4q21-23; another locus for
autosomal dominantly inherited Parkinsons disease

has been localized on chromosome 2p13 (Gasser, 1998).
In addition, a gene has been cloned for an autosomal
recessive type of familial Parkinsonism that had been
mapped on the long arm of chromosome 6 (Mizuno
et al., 1998). Missense mutations have been identified in
the -synuclein gene, which codes for a presynaptic
protein thought to be involved in neuronal plasticity, and
-synuclein (SNCA) is a major component of Lewy bodies
(Chase, 1997; Polymeropoulos et al., 1997; Spillantini
et al., 1997, 1998c; Lippa et al., 1998). Moreover, some
cases are linked to mutations in the parkin (PARK2) and
ubiquitin C-terminal hydrolase L1 gene (Solano et al.,
2000). In addition to SNCA and PARK 28, several other
chromosomal regions of interest are present (Foltynie
et al., 2002). In elderly people the ApoE 2 allele
increases the risk of Parkinsons disease, in particular
with dementia (Harhangi et al., 2000). Age at onset
appears to be highly heritable in Parkinsons disease
(4060%), and linkage is found on chromosome 1p, 6
and 10 (Li et al., 2002).
There is a male preponderance in Parkinsons disease.
Men and women acquire the disease at the same mean
age, have the same progression and die at the same age,
whereas in the general population women have a longer
life expectancy than men. It is not known what factor
lowers the life expectancy of women to that of men when
they get Parkinsons disease (Diamond et al., 1990).
The most obvious feature of Parkinsons disease is
the loss of dopaminergic melanin-laden neurons in the
substantia nigra. However, it is not a typical dopaminergic disease, since on the one hand, other dopaminergic
systems remain intact (e.g. the tuberoinfundibular neurons
in the hypothalamus: see below) while, on the other hand,
other transmitter systems and hypothalamic structures, the
septum, DBB, NBM and TMN, are affected as well. The
predilection sites include the entorhinal region, the CA2
sector of the hippocampal formation, the limbic nuclei of
the thalamus, anterior cingulate areas, agranular insular
cortex (layer VI) and the amygdala (Braak et al., 1996).
Loss of cholinergic innervation may underlie dementia in
Parkinsons disease, and there are a few smaller studies
that suggest that treatment with cholinesterase inhibitors
may be effective in the treatment of dementia associated
with Parkinsons disease (Emre, 2003).
In the Parkinson-dementia complex of Guam, a
cholinergic deficit was also observed (Masliah et al.,
2001). In the hypothalamus a decrease in the number of
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oxytocin-expressing neurons (Purba et al., 1994), neuronal

loss in the SON and an increased somatic, nuclear and
nucleolar size of the remaining neurons (Ansorge et al.,
1997) have been observed in Parkinsons disease. The
presence of Lewy bodies in hypothalamic nuclei (see
below) also indicates that this brain structure is affected.
After several years of treatment with levodopa and
other drugs, motor fluctuations ranging from bradykinesis
to hyperkinesia develop in many patients with Parkinsons
disease. A double-blind study has shown that bilateral
implantation of embryonic dopaminergic neurons into the
putamen may result in some clinical benefit in young but
not in older Parkinson patients (Freed et al., 2001). In
other transplantation studies, the degree of improvement
may be the same as after a sham operation (De la FuenteFernndez et al., 2002). Both electrical stimulation and
lesioning of the subthalamic nucleus (Chapter 15) can be
effective treatments for Parkinsons disease. Unilateral
and bilateral lesions in the subthalamic nucleus have been
performed in small series of Parkinson patients with
a good improvement of Parkinsonism. In practice, the
current procedure of choice is the chronic electrical
stimulation of the subthalamic nucleus. However, this is
an expensive treatment, and the effectiveness of electrical
stimulation versus lesioning has not been studied in a
controlled trial (Kumar et al., 1998; Limousin et al., 1998;
Krack et al., 2000; Guridi and Obeso, 2001; Thobois
et al., 2002). How deep-brain stimulation of the subthalamic nucleus works is not clear at present. However, PET
studies in Parkinsonian patients seem to exclude that
this method increases striatal dopamine release (Hilker
et al., 2003).
Both levodopa (L-DOPA) treatment and stimulation
of the subthalamic nucleus may lead to general mood
elevation, and even induce euphoria or a psychotic state.
In a few patients mirthful laughter has been reported as
a side effect (Krack et al., 2001; Thobois et al., 2002).
In addition, stimulation of this nucleus causes increased
heart rate (Kaufmann et al., 2002). However, the main
side effect is the occurrence or worsening of depression
(Thobois et al., 2002). Also, suicide attempts should
be considered as a side effect of bilateral subthalamic
stimulation (Doshi et al., 2002; Fig. 29.12).
Hyperactivity of neurons in the subthalamic nucleus
has also been postulated to be involved in the pathogenesis
of Parkinsons disease (Rodriguez et al., 1998; Kaufman
et al., 2002), but no damage has been found in this brain
structure in Parkinsonian patients (Chapter 15).
333
Fig. 29.12. Electrode tip (arrow) in the subthalamic nucleus (sth) of

a patient (NHB 00-073, female, 59 years of age) who committed suicide.
Symptoms of hypokinesia and stiffness had started 9 years earlier. The
woman had been depressed for 6 years before death and had attempted
suicide 5 years before death. Bilateral implantation of electrodes in the
subthalamic nucleus took place 2 years before death. Motor symptoms
responded well to stimulation. Neuropathological diagnosis: olivoportocerebellar atrophy with degeneration of the substantia nigra
(multisystem atrophy). Cg, cingulate gyrus; cc, corpus callosum; dm,
mediodorsal nucleus of the thalamus vl, ventrolateral posterior nucleus
of the thalamus; ci, capsula interna; cr-c, crus cerebri; ot, optic tract
(damaged in this section.)
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(a) Autonomic symptoms

Several autonomic and endocrine symptoms in Parkinsons
disease suggest hypothalamic involvement. Examples
of autonomic disturbances are dizziness, salivation,
seborrhea, excessive sweating, constipation, sphincter
disturbances, dysphagia, orthostatic hypotension, blue
mottled skin and other vasomotor abnormalities, low
resting skin temperatures, heat intolerance, sleep disorders, depression, impotence and disruption of sleep
(Appenzeller et al., 1971; Gross et al., 1972; Sandyk, 1989;
Takahashi, 1991; Mathias, 2002). Disturbances of autonomic functions are an integral part of the manifestations
of Parkinsons disease and have already been included in
the original description of the disease by James Parkinson,
although there is controversy about this point (Koike and
Takahashi, 1997). Autonomic disorders may, of course,
not only develop as a result of hypothalamic pathology,
but may also be due to changes in the brain stem or
sympathetic ganglia. Measurements of the relationship
between blood pressure and pulse rate seem to reflect an
imbalance between the sympathetic and parasympathetic
nervous system (Murata et al., 1997). According to some
authors, cardiovascular reflexes in Parkinson patients are
already disturbed in early stages of the disease (stages 1
and 2 on the Hoehn and Yar scale). Some 80% of the
patients have abnormalities in heart rate in response to
postural change, a function known to be mediated via the
parasympathetic innervation of the heart (Awerbuch
and Sandyk, 1992). Whether hypothalamic innervation
of the vagusambiguous complex is indeed involved in
these Parkinson symptoms still has to be investigated.
Orthostatic hypotension may not only be the result of
sympathetic dysfunction, but can also be a side effect
of levodopa. Other authors conclude, however, that cardiovascular autonomic dysfunction in Parkinsons disease is
mild, mainly affects blood pressure responses, and occurs
only in advanced cases (Van Dijk et al., 1993).
Other symptoms of hypothalamic involvement in
Parkinsons disease are weight gain or weight loss.
Bulimia has been found in Parkinsons disease, and the
bulimia decreases concomitantly with clinical improvement during levodopa treatment (Gasparinin and Spinnler,
1975; Rosenberg et al., 1977). However, more often
weight loss has been observed in Parkinsons patients
not treated with levodopa (Rosenberg et al., 1977;
Aimard et al., 1984). A case of a 54-year-old man with
KleineLevin syndrome who also developed Parkinsonian
symptoms has been reported (Mller et al., 1998b;
Chapter 28.1), suggesting a general dopamine deficiency

at the basis of the symptoms of this patient.
(b) Sleep and circadian rhythms
Sleep disturbances in Parkinson patients are much more
common than in controls and have been attributed to both
the disease and its therapy (Askenasy, 1993; Chaudhuri
et al., 2002). Sleep disturbances correlate with increased
severity of the disease (Kumar et al., 2002). As Parkinson
in his 1817 book phrased it: The tremulous motion of
the limbs occur during sleep and augment until they
awaken the patient (Askenasy and Yahr, 1990). A reversal
of sleep pattern and a normalization of muscle activity
during sleep may occur with dopaminergic treatment
(Askenasy and Yahr, 1985). Parkinson patients experience insomnia, parasomnias, such as REM sleep behavior
disorders, vivid dreaming, nightmares, psychosis, or
excessive daytime somnolence, specifically excessive
daytime sleepiness and sleep attacks (Larsen and
Tandberg, 2001; Kumar et al., 2002). The study by Van
Hilten et al. (1993) has shown that, although the light
prevalence of sleep disturbances in patients with
Parkinsons disease may be largely explained by normal
aging, the severity of disrupted sleep maintenance is more
marked in the patients with Parkinsons disease than in
healthy contemporaries. Nocturia, pain, stiffness, and
problems with turning in bed are well recognized causes
of disrupted sleep in Parkinsons disease. Sleep disruption
in mildly to moderately affected Parkinsons patients may
also be caused by a dose-dependent effect of levodopa
or dopamine agonists on sleep regulation (Van Hilten
et al., 1994; Larsen and Tandberg, 2001). However, in
more severely affected Parkinson patients, these drugs
have a beneficial effect on nocturnal disabilities (e.g.
problems with turning over in bed, pain and stiffness)
that may cause sleep disruption. As the progression of
Parkinsons disease evolves, the beneficial effect of
levodopa or dopamine agonists on nocturnal disabilities
predominate over their dose-dependent disrupting effect
on sleep regulation. No evidence was found for the association of fatigue with any circadian factor (Van Hilten
et al., 1993). Both movements and tremor of Parkinson
patients show a very clear circadian pattern, the tremor
becoming subclinical during the night. The circadian
rhythm of the movements and body core temperature in
idiopathic Parkinson patients was normal (Van Someren
et al., 1993; Pierangeli et al., 2001), so that the SCN,
at least in the studied group of patients subjected to
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stereotactic subthalamic lesions, seems to be largely

intact. Indeed, already since the turn of the century, the
disappearance of Parkinsonian tremor during the night
has been known to be a constant phenomenon. Plasma
melatonin in Parkinson patients was also found to be
in the normal control range (Critchley et al., 1991). In
levodopa-treated Parkinson patients, the circadian plasma
level changes in melatonin were very similar to those in
age-matched controls, except for a phase advance of the
nocturnal melatonin elevation in the Parkinson group
(Fertl et al., 1991; Bordet et al., 2003). In one paper,
a flattened diurnal cortisol secretory curve has been
reported in Parkinson patients, whereas strangely
enough an intact diurnal profile was found in the same
study in Alzheimer patients (Hartmann et al., 1997;
compare Chapter 4.3). One Parkinson patient with a
48-h sleepwake cycle has been described (Mikami
et al., 1987). In addition, by way of preliminary results
it was mentioned that the normal increase in urinary
volume occurring during the day was not observed in
patients with Parkinsons disease (Hineo et al., 1992). On
the other hand, Parkinsons disease is associated with a
loss of circadian rhythm of blood pressure, increased
diurnal blood pressure variability and postprandial
hypotension (Bruguerolle and Simon, 2002). The
increased occurrence rate of glaucoma in Parkinsons
disease (Bayer et al., 2002a) may result in a diminished
input to the SCN and to some alterations in circadian
rhythms. However, the body of evidence indicates that
circadian rhythms are largely intact in Parkinson patients.
Excessive daytime sleepiness, i.e. sudden onset of
sleep, is not the result of pharmacotherapy but is related
to the pathology of Parkinsons disease (Arnulf et al.,
2002). Rather unexpectedly a significantly higher
narcolepsy score was found in Parkinson patients. This
was viewed as being due to dopaminergic medication
(Happe et al., 2001). It is not known whether the
hypocretin neurons in the lateral hypothalamus are
affected in this disorder (see Chapter 28.4).
335
suggests that the prevalence of moderate or severe major

depression is lower than the previously assumed substantial proportion of patients with Parkinsons disease with
less-severe depressive symptoms (Tandberg et al., 1996).
Nonsuppression following dexamethasone frequently
occurs, which indicates increased activity of the CRH
neurons (Kostic et al., 1990; Rabey et al., 1990; Meco
et al., 1991) and thus hypothalamic involvement (see
Chapters 8.5, 26.4). It should be noted, though, that the
dexamethasone suppression test in Parkinson patients
does not differentiate well between those with depression
and those with dementia (Rabey et al., 1990), so that
disorders in other brain areas or neurotransmitter systems
may affect the dexamethasone suppression test in these
patients. In contrast to idiopathic depression (see Chapter
26.4), we did not find an increased number of CRHexpressing neurons in the PVN of Parkinson patients
with depression as compared to a nondepressed group
of Parkinson patients (Hoogendijk et al., 1998). The
most probable explanation is that depression in
Parkinsons disease has a different neurobiological basis
from that of idiopathic major depression (see before).
The fact, for instance, that the severity of vegetative
symptoms increases with advancing Parkinson, but mood
and self-reproach do not (Huber et al., 1990), and
the fact that the correlation between the severity of
motor impairment and depression in Parkinsons disease
is poor (Mayeux et al., 1984), may point toward a
psychological, reactive contribution to the etiology of
Parkinsons disease expression.
(d) Hormones and neuropeptides in the hypothalamus
Endocrine control is also impaired in Parkinsons disease
as indicated by abnormal glucose tolerance and abnormal
secretion of prolactin, TSH, growth hormone and
increased CSF levels of MSH (Brown et al., 1973; Shuster
et al., 1973; Eisler et al., 1981; Cusimano et al., 1991).
Idiopathic Parkinsons disease without autonomic defects
can be differentiated from multiple system atrophy by
stimulation of growth hormone release by clonidine.
Clonidine is a centrally active 2-adrenoceptor agonist
that raises growth hormone levels in healthy controls and
Parkinson patients, but not in patients with multiple
system atrophy. This indicates a specific hypothalamic
-adrenoceptor deficit in the latter disorder (Kimber
et al., 1997). Alterations in melatonin regulation have
also been reported (Catal et al., 1997). In addition, a
diminished number of oxytocin-containing neurons was
(c) Depression
Depression symptoms are frequently encountered in
Parkinsons disease (Cummings, 1992; Tandberg, 1997;
Happe et al., 2001), but their type and clinical course are
different from idiopathic depression (Mayeux et al.,
1984). Greater anxiety and less self-punitive ideation
(Cummings, 1992) distinguish Parkinsons depression
from other depressive disorders. Recent research also
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observed in the PVN (Purba et al., 1994) and vasopressin

blood and CSF levels were reported to be decreased in
Parkinsons disease in some studies (Sundquist et al.,
1983; Olsson et al., 1987). Indeed, a decreased number
of neurons in the SON was found in Parkinsons disease.
These neuroendocrine changes may be related to the
disturbed circadian renal fluid handling and blood pressure adaptation of Parkinson patients (Ansorge et al.,
1997). With respect to the alterations in antidiuretic
hormone levels and the colocalization of vasopressin and
tyrosine hydroxylase in the SON and PVN (see Chapter
8) it should also be noted that levodopa has, at least in
some Parkinson patients, an effect on renal blood flow,
and causes an increased urinary potassium excretion,
which causes hypokalemia. The mechanism of these
effects is not known (Finlay et al., 1971; Granrus et al.,
1977). Pro-opiomelanocortin peptides, CRH and growth
hormone-releasing hormone levels remain unaltered in
the hypothalamus of Parkinson patients (Conte-Devolx
et al., 1985; Pique et al., 1985), but MSH CSF levels
increase in Parkinsons disease (Catania et al., 2000).
Slightly higher cortisol levels associated with gait
deficit have been reported in Parkinsonism (Charlett
et al., 1998). Interestingly, some clinical studies suggest
that Parkinson symptoms may be exacerbated after
menopause, and transdermal 17-estradiol appeared to
have slight antiparkinsonian effects, without consistently
altering dyskinesias. Others failed to observe that
hormone replacement therapy delayed or alleviated the
symptoms (Blanchet et al., 1999; Shulman, 2002).
It is presumed that changes in the dopaminergic
systems might contribute, at least partly, to the reported
endocrine alterations, because dopamine is the major
prolactin-inhibiting factor, the secretion of MSH and
growth hormone are under dopaminergic control (Brown
et al., 1973), and oxytocin release is regulated by
dopamine also (Bridges et al., 1976; Clarke et al., 1979;
Lightman et al., 1982; Bjrklund and Lindvall, 1984). In
addition, dopamine levels in the hypothalamus decrease
by 3550% in Parkinsons disease (Conte-Devolx et al.,
1985; Pique et al., 1985; Uhl et al., 1985), probably
due to nigral degeneration rather than to degeneration
of the tuberoinfundibular dopaminergic system of
the hypothalamus itself. The number of hypothalamic
dopaminergic neuroendocrine neurons, as identified
by their melanin content, remains stable in Parkinsons
disease (Matzuk and Saper, 1985), in contrast to those in
the substantia nigra. Also, the presence of tyrosine
hydroxylase-positive neurons in the hypothalamic PVN
was not affected in Parkinsons disease (Purba et al.,

1994), supporting the notion that dopaminergic neurons
in the mesencephalon, but not in the hypothalamus, are
affected in Parkinsons disease.
Although the autonomic, sleep, mood and endocrine
changes suggest hypothalamic involvement, it must be
stated that no firm link between any of these changes in
Parkinsons disease have been related to deficiencies
in particular hypothalamic nuclei so far. In addition,
hypothalamic compensatory actions to overcome
dopamine deficiency may be responsible for symptoms
of Parkinsons disease (Sandyk, 1989).
(e) Lewy bodies in the hypothalamus and adjacent
areas
Lewy bodies are hyalin cytoplasmatic neuronal inclusions
that occur in nerve cell somata and processes. Trtiakoff
(1919) first described corps de Lewy in the substantia
nigra (for reference see Gibb, 1986). Lewy bodies are surrounded by a light halo and the core often stains differentially and can be stained by anti-ubiquitin in various
brain areas (Kremer and Bots, 1993; Purba et al., 1994).
The major components of Lewy bodies are abnormally
phosphorylated neurofilaments affecting the cytoskeleton.
Additional components include ubiquitin and -synuclein,
which normally occurs in the presynaptic membrane
(Braak and Braak, 2000). The presence of Lewy bodies
is generally considered to be a marker for nerve cell
degeneration in Parkinsons disease (Langston and Forno,
1978). However, Kremer and Bots (1993) have shown
that the NTL did contain Lewy bodies but did not show
neuronal loss in Parkinsons disease. Purba et al. (1994)
have shown the opposite: an absence of Lewy bodies in
the PVN accompanies a decreased number of oxytocinexpressing neurons in this nucleus in Parkinsons disease.
Although these two observations raise doubts about the
direct importance of the presence of Lewy bodies for
the process of neurodegeneration, it remains, of course, a
crucial neuropathological marker for the diagnosis of
Parkinsons disease. On the other hand, Lewy bodies
are not specific for this disorder, since they also turn
up as incidental findings at autopsy in 710% of normal
individuals over the age of 60 and in postencephalitic
Parkinsons syndrome. Lewy bodies are also seen in
Parkinson-dementia complex, HallerverderSpatz syndrome and progressive nuclear palsy (Ohama and Ikuta,
1976). They are rarely found in olivocerebellar atrophy
and in Joseph disease (Gibb, 1986). In diffuse Lewy body
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disease, the cortex is also involved, and dementia, paranoid

delusions and hallucinations may be present (Gibb, 1986).
Although a high frequency of visual hallucinations has
been confirmed in Parkinson patients with Lewy bodies in
the cortex, a clear relationship between the postmortem
neuropathological findings and the clinical presence
of psychopathology or dementia has not been observed
(De Vos et al., 1995).
Lewy bodies are found in different hypothalamic nuclei
(Den Hartog Jager and Bethlem, 1960; Langston and
Forno, 1978; Gibb, 1986). Lewy himself described, in
1912, serpentine or elongated bodies, not only in the
dorsal motor nucleus of the nervus vagus, but also in
the NBM, where they are still called Lewy neurites
(Chapter 2.6; Braak and Braak, 2000). They occur in
Braak stage 34 (Braak et al., 2003). Loss of neurons
in the NBM was first described by Lewy in 1913, even
before cell loss was reported in the substantia nigra
(Whitehouse, 1986). Indeed, there is degeneration of the
ascending cholinergic pathways in Parkinsons disease.
Deficits in nicotinic receptors have been reported in the
caudate nucleus, putamen, neocortex, substantia nigra and
ventral tegmental area (Court et al., 2000). In addition,
Lewy bodies are present in the periventricular nucleus,
dorsomedial nucleus, TMN (which contains the highest
concentration of Lewy bodies and Lewy neurites in the
hypothalamus) and the BST, while far fewer Lewy bodies
are found in the mamillary bodies and NTL (Kremer and
Bots, 1993; Braak and Braak, 2000; Braak et al., 2003).
In the latter nucleus, Lewy bodies appear to be quite
variable: regular, lamellated, distorted or elongated (intraneuritic) forms are seen. Since Lewy bodies vary in size,
as Kremer and Bots (1993) have pointed out, the impression that the TMN contains more Lewy bodies than
the NTL might, at least partly, be due to the fact that
Lewy bodies in the former nucleus are clearly larger,
which increases their sampling probability. Unbiased
morphometric techniques should therefore be used to
obtain a reliable estimation of the different amounts in
the different hypothalamic nuclei. On the other hand,
the TMN is, without any doubt, severely affected by
Lewy bodies in Parkinsons disease (Braak et al., 2003).
Although the term destruction has been used in this
connection (Braak et al., 1996), it should be noted that
this term is only based upon the presence of abundant
amounts of Lewy body and Lewy neurites and not on
neuronal death. The Lewy bodies would develop in the
TMN quite early on in the disease process and are often
more pronounced than in the basal forebrain nuclei.
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The histaminergic innervation of the substantia nigra is

increased in Parkinsons disease. Although these nerve
fibers are thinner and have enlarged varicosities, these
observations agree with a relatively intact TMN in
Parkinsons disease (Anichtchik et al., 2000). Lewy
bodies have also been found in the hypothalamic lateral
area and posterior nucleus (Ohama and Ikuta, 1976). The
mamillary nuclei are virtually spared any Parkinsonspecific changes (Braak et al., 1996).
The olfactory bulb, olfactory tract and the cells of the
olfactory nucleus are never the sole sites involved in
Parkinson-related pathology (i.e. Lewy neurites and Lewy
bodies), precluding that the olfactory system would be
the site of induction of this disorder (Del Tredici et al.,
2002).
29.4. Huntingtons disease
Huntingtons disease (HD) is an autosomal, dominantly
inherited neurodegenerative disorder, which is characterized by hyperkinetic involuntary movements (chorea),
intellectual impairment and selective neuronal loss in
the striatum and cerebral cortex (Reddy et al., 1999). The
hypothalamic subthalamic nucleus is involved in
the production of chorea (Chapter 15a; Weiner, 1997).
The molecular basis of HD is an expanded sequence
of 36 to 121 CAG repeats, the sequence that codes
for glutamine, with the median being 44 in a gene on
chromosome 416.3 (Huntington Dis. Coll. Res. Group,
1993; Kremer et al., 1994; Reddy et al., 1999). A significant negative correlation was found between the length
of the repeat and the age of onset for the total cohort. In
late-onset HD, the median upper allele size for the CAG
repeat was 42, with a range of 3848 repeats. The
variation of repeat length accounts only for about 7% of
the variation in age of onset for persons over the age
of 50 years (Andrew et al., 1993; Kremer et al., 1993a;).
For patients who had an age of onset above 60 years, no
such significant correlation was found. There is evidence
for area specific instability of the CAG-repeat lengths in
affected brain regions, such as the basal ganglia and
cerebral cortex. The cerebellar cortex displayed the lowest
degree of CAG mosaicism (Telenius et al., 1994). The
protein encoded for is huntingtin. It is normally located
in the cytoplasm, whereas the mutant form is also found
in the nucleus (Reddy et al., 1999). Huntingtin is of
unknown function, but colocalizes with microtubules,
vesicles and synaptic compounds, suggesting a role in
cellular transport and neurotransmission (Di Prospero and
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Tagle, 2000). An NH2-terminal fragment of the mutated

huntingtin has been localized to neuronal intranuclear
inclusions and dystrophic neurites in the Huntington
cortex and striatum, which are preferentially affected in
this disease. Ubiquitin is also found in these neuronal
intranuclear inclusions, suggesting that abnormal huntingtin is targeted for proteolysis but is resistant to
removal, so that this process is incomplete (DiFiglia
et al., 1997). However, the exact mechanism of neurodegeneration in HD is not yet clear (Ross, 1997;
Di Prospero and Tagle, 2000).
There are endocrine and autonomic abnormalities
pointing to hypothalamic involvement in HD. In addition,
hypothalamic involvement in HD is presumed on the
basis of sleep disturbances and a strong weight loss in
conjunction with adequate caloric intake (Kremer, 1992a).
Mean basal levels of growth hormone (Durso et al., 1983a,
b) and nocturnal growth hormone levels (Murri et al.,
1980) are found to be increased. In addition, growth
hormone responses to dopamine agonists (Caraceni et al.,
1977; Mller et al., 1979; Durso et al., 1983a), glucose
(Podolsky and Leopold, 1974), insulin (Keogh et al.,
1976; Phillipson and Bird, 1977; Lavin et al., 1981),
arginine (Leopold and Podolsky, 1975) and muscimol
(Durso et al., 1983a) are exaggerated. Since the paradoxical growth hormone rise after glucose loading only
occurs in some HD patients (Diepen, 1962; Podolsky
and Leopold, 1975; Kremer et al., 1989), impaired growth
hormone regulation seems to be a feature of only some
of the HD patients. Plasma cortisol has been reported to
be low in some HD patients (Bruyn et al., 1972), whereas
the cortisol rise during an insulin tolerance test occurs
earlier (Lavin et al., 1981). However, other studies found
elevated basal cortisol and ACTH levels in HD patients
(Heuser et al., 1991). The CSF levels of -endorphin
decrease in HD (Kaiya et al., 1983). Retarded menarche
in female HD patients (Oepen et al., 1963) and increased
levels of LHRH in the median eminence of female HD
patients but not of male HD patients (Bird et al., 1976)
have been reported; yet 24-h curves of LH secretion seem
to be normal (Durso et al., 1984). Prolactin, FSH, LH,
total T4, T3 uptake and TSH are also normal in HD
(Kremer, 1992a), as are hormone responses after TRH
and LHRH (Lavin et al., 1981). In addition, PD patients
who were deprived of water retain their ability to concentrate urine (Lavin et al., 1981), which points to an intact
hypothalamoneurohypophysial system.
The greater fall in mean blood pressure on tilting in
HD patients (Aminoff and Gross, 1974) is suggestive
of sympathetic dysfunction. The same goes for the

observation of Den Heijer et al. (1988) of an impaired
rise in diastolic blood pressure to sustained hand grip.
Parasympathetic dysfunction may be indicated by an
increased papillary light reflex latency (Den Heijer et al.,
1988). Disturbed sleep patterns with increased sleep
latency, reduced sleep efficiency, frequent nocturnal
awakenings, more time spent awake, and less slow-wave
sleep have also been found in HD patients (Wiegand
et al., 1991). So far these changes have not been related
to hypothalamic abnormalities.
Striking emaciation in HD patients has been shown in
clinical follow-ups (Sanberg et al., 1981), anthropometric
studies (Farrer and Yu, 1985) with dietary assessment
(Morales et al., 1989), as well as in a postmortem study
of 217 cases (Oepen, 1963). HD patients lose weight and
become cachectic, in conjunction with adequate dietary
intake (Sanberg et al., 1981; Morales et al., 1989) or even
increased carbohydrate intake (Farrer and Yu, 1985);
many patients even have a ravenous appetite (Bruyn,
1968). HD patients are less engaged in strenuous activity
than controls (Farrer and Yu, 1985) and tend to lose more
weight in their final hypokinetic stages than in their earlier
hyperkinetic stages (Sanberg et al., 1981). Also, the
curious finding of an inverse relationship between the age
of onset of HD and milk consumption in Dutch choreics
(Buruma et al., 1987) may reflect the increased caloric
intake of these patients.
Hypothalamic changes in Huntingtons disease
On the basis of a few cases and qualitative observations,
changes are presumed in the SON and PVN (Schpe,
1940; Vogt and Vogt, 1951), and in the VMN (Bruyn,
1973) and TMN (Schpe, 1940), while quantitatively no
significant neuronal loss is found in the NBM (Clark
et al., 1983). W. Wahren was the first to report the striking
cell loss in the NTL (Wahren, 1952; Wahren 1964). This
finding was followed up, in great detail, by Kremer
(1992a), who found that the NTL is indeed consistently
affected in HD. He found a neuronal loss of up to 90%
in the NTL of HD patients. The remaining neurons
showed features of degeneration and there was astrocytosis with an unchanged number of astrocytes, whereas
the number of oligodendrocytes was reduced by 40%.
The large neurons of the TMN are well preserved (Kremer
et al., 1990). The log-transformed neuronal counts in
the NTL of HD patients correlate closely with age at
death (r = 0.66, p < 0.01; Fig. 29.10) and age of onset
(r = 0.78, p < 0.001), but not with the duration of the
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disease. Patients who die young or who first display motor

disturbances at an early age have a great deal fewer
neurons left than patients who die in old age. Neuronal
loss in the NTL is not related to striatal changes (Kremer
et al., 1991a). It had already been reported by Wahren
(1964) that cell death in the NTL of Huntington patients
with an early onset (i.e. before the age of 60) is
more pronounced. In the neurites and perikarya of the
NTL, somatostatin 1-12 immunoreactivity is abundantly
present. In Huntingtons disease, somatostatin immunoreactivity is greatly reduced (Fig. 29.11), whereas
neostriatal somatostatin neurons escape destruction in this
disorder. In general, higher staining intensity is present
in Huntington patients who have more NTL neurons left
than in those who have fewer NTL neurons left. The data
obtained so far suggest that NTL neurons cease to express
somatostatin-like peptides quite some time before their
actual disappearance (Timmers et al., 1996).
In Huntington patients the levels of histamine H2receptor binding sites are found to be markedly decreased
in virtually all brain regions investigated, particularly in
the putamen and globus pallidus lateralis. The loss of
binding sites is related to the grade of the disease
(Martinez-Mir et al., 1993). Since the TMN does not
show a clear cell loss in this disorder (Kremer et al.,
1993), a functional change of the histaminergic system
may be expected in Huntingtons disease.
339
abnormal gaze and gait (ataxia), and loss of recent

memory. With abstinence and high dosage of thiamine,
the acute phase of Wernickes syndrome clears. However,
approximately 25% of the patients develop severe memory
disorders: the Korsakoff syndrome or Korsakoff psychosis
(Fadda and Rosetti, 1998).
Wernickes encephalopathy is characterized clinically
by the triad of ophthalmoplegia, nystagmus and ataxia,
and by a confusional state, while in 82% of cases polyneuropathy is found. Neuropathologically Wernickes
encephalopathy is characterized by hemorrhagic lesions
in the walls of the third and fourth ventricles and Sylvius
aqueduct and is caused by thiamine deficiency (Spillane
and Riddock, 1947; Haak et al., 1990; Blansjaar et al.,
1992; Victor, 1994; Ming et al., 1998). In addition,
subnormal temperatures that are likely to be due to an
involvement of the posterior hypothalamus, including the
mamillary bodies, have been reported. The physiological
thermostat seems to have been reset at a lower level
(Koeppen et al., 1969; Haak et al., 1990). Moreover, the
direct toxic effect of alcohol on the thyroid gland may
be relevant in this respect. This results in a compensatory
activation of the hypothalamopituitary axis (HPA axis)
with increased thyrotropin (TSH) release and a blunted
response to the TRH test, due to a downregulation of
pituitary TRH receptors. A reduction in total thyroxine
(T4) and total and free triiodothyronine (T3) are, moreover,
consistent findings during early abstinence. Also, other
hormonal and neurotransmitter disturbances have been
described. Acute and chronic alcohol consumption can
affect the HPA axis and the hormonal stress response.
Plasma cortisol increases have been observed concurrently with alcohol consumption, and also during
the alcohol withdrawal period. In abstinent alcoholics,
baseline plasma cortisol generally returns to normal
values (Umhau et al., 2001; Chapter 8.5d). In male
alcoholics sustained increases in serum free and total
testosterone levels are found in the presence of inadequately raised LH concentrations. A relative insensitivity
toward testosterone might contribute to the high prevalence of sexual dysfunction in this group of patients
(Hasselblatt et al., 2003). Poorer cognitive performance
in alcoholics is related to more withdrawals and higher
cortisol level during a withdrawal. Altered stress regulation of the HPA axis is also related to attenuated stress
cortisol responses (Errico et al., 2002). In alcoholism,
lower levels of 5-HT and 5-HIAA and MAO-B have been
detected in the hypothalamus(Carlsson et al., 1980b). The
patient described by Haak et al. (1990) probably had a
29.5. Wernickes encephalopathy, Korsakoffs

psychosis and MarchiafavaBignami disease
Alcoholism is a genetically influenced disorder; twin
studies have estimated a hereditability of 5060% for
alcoholism. The neuropeptide Y (NPY) is involved in
appetite, reward, anxiety and energy balance (Chapter
11.23). The functional Leu7Pro polymorphism in the NPY
gene is a risk factor for alcohol dependence (Lappalainen
et al., 2002).
Chronic alcoholics perform less well in several learning
and memory tests. Approximately 10% of chronic alcoholics develop an amnestic disorder Korsakoffs
syndrome or alcohol-associated dementia (Fadda and
Rossetti, 1998). In 1881 Wernicke described four cases
of encephalopathy and ophthalmoplegia in adults with
malnutrition who at autopsy were found to have characteristic hemorrhagic lesions (Spillane and Riddock, 1947;
Hazell et al., 1998; Figs. 29.1229.14). Wernickes
encephalopathy is an neurological crisis characterized by
mental confusion, impairment of spatial organization,
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Fig. 29.13. Number of remaining nucleus tuberalis lateralis (NTL)

neurons (NE) related to age at death in 16 Huntingtons disease (HD)
cases () and 12 controls (circ). For the controls the mean is indicated
(dashed line), as well as the normal range (mean 2 SD; shaded area);
there was no age-related decline: NE = 61.450 31.8 age; n = 12;
r = 0.071; NS. For the HD patients, NE did correlate with age:
NE = 6.9 + 0.038 age; n = 16; r = 0.66; p < 0.01. (From Kremer et al.,
1991a, Fig.1, with permission.)
temporarily inappropriately high release of vasopressin

and a decreased release of prolactin-inhibitory factor,
CRH and somatostatin. In Wernickes encephalopathy
active (acute and subacute) and inactive (chronic) cases
are distinguished. The term active is used to indicate
continuing thiamine deficiency at the time of death
(Torvik et al., 1982). Wernickes encephalopathy is
caused by thiamine (vitamin B1) deficiency and may be
due to alcoholism, malnutrition or eating disorders,
chemotherapy in cancer patients, or hyperemesis gravidarum or long-term extensive vomiting for other reasons.
The patients may respond dramatically to thiamine
replacement. Activity of the thiamine-dependent enzyme
-ketoglutamate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme is significantly reduced in
autopsied brain tissue from patients with Wernickes
encephalopathy. Animal studies suggest that such enzyme
deficits result in focal acidosis, cerebral energy impairment, depolarization due to increased glutamate release,
and so to excitotoxicity (Hazell et al., 1998). Wernickes
encephalopathy has also been seen in patients on total
Fig. 29.14. A and B: Comparison of anti somatostatin 1-12 (S320)

immunoreactivity in the hypothalamus of a control (control subject 2)
(A) to that of a HD patient (no. 10) (B). Note that in the control hypothalamus subdivisions of the NTL are intensively stained by S320,
whereas there is no staining at all in the NTL area of the HD patient.
Staining intensity of the ventromedial nucleus (vmn) does not differ.
HD patient no. 10: S320 immunoreactivity is absent in the NTL (C),
whereas in the vmn beaded fibers are still present (D). All sections
were pretreated by microwave heating. fx, fornix; ntl, nucleus tuberalis
lateralis; ci, internal capsule; to, optic tract; tv, third ventricle. Bars 2.5
mm in A, B; 10 m in C, D. (From Timmers et al., 1996, Fig. 3, with
permission.)
parenteral nutrition due to multivitamin shortage. MRI

may reveal lesions in the mamillary bodies and other
brain structures (Charness and DelaPaz, 1987; Hahn
et al., 1998b; Ming et al., 1998). The neuropathological
lesions of Wernickes encephalopathy are found at
autopsy in 0.82.8% of the population, and in up to 12.5%
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of the alcoholics, although Wernickes encephalopathy

is diagnosed in less than 0.040.13% of all hospital
admissions (Harper et al., 1983; Charness and DelaPaz,
1987). This discrepancy may be caused by the absence
of the classical triad-oculomotor dysfunction, ataxia and
encephalopathy (Charness and DelaPaz, 1987; Victor,
1994).
Despite adequate therapy, many inactive Wernickes
encephalopathy cases develop Korsakoffs psychosis, an
often irreversible syndrome of selective anterograde and
retrograde amnesia, confabulations, and severe learning
disabilities. The memory impairment is persistent and irreversible (Kahn and Crosby, 1972; Charness and DeLaPaz,
1987; Blansjaar et al., 1992). However, Korsakoffs
psychosis may also evolve without an antecedent episode
of Wernickes encephalopathy (Blansjaar et al., 1992;
Victor, 1994). Wernicke-Korsakoff syndrome patients of
alcoholic etiology with an Apoe-4 genotype are prone
to global intellectual deficits (Muramatsu et al., 1997).
The distinction between Korsakoffs psychosis and
alcohol dementia may not always be clear (Torvik et al.,
1982). Destructive bilateral lesions of the septal areas or
in the mamillary bodies interfere with the memory of
recent events. Craniopharyngiomas may also produce
Korsakoffs syndrome in adults when they compress the
two mamillary bodies (Kahn and Crosby, 1972). One
patient with tumor masses in both mamillary bodies and
medial thalamus revealed anterograde, but no retrograde
memory disturbances (Kapur et al., 1996).
The lesions of Wernickes encephalopathy occur
symmetrically, e.g. in the mamillary bodies (Figs. 29.11,
29.12 and 29.13), the hypothalamus adjacent to the third
ventricle, the aqueduct and the fourth ventricle (Hazell
et al., 1998). However, lesions also occur in other brain
areas. The number of immunoreactive vasopressin
neurons in the SON and PVN, and the volume of the
SON and PVN decreases (Fig. 29.15 and 29.16) in
Wernickes encephalopathy. This explains why alcoholics
respond inappropriately, with suppressed vasopressin
levels under osmotic stress (Harding et al., 1996). During
a 280-day period of abstinence in alcoholics, basal vasopressin levels stayed suppressed. It is presumed that this
may contribute to dysregulation of the HPA axis, mood,
memory, addiction behavior and craving (Dring et al.,
2003). Tau-positive granular and fibrillary inclusions are
frequently present in the magnocellular neurons of the
NBM in alcoholics without Wernickes encephalopathy.
In addition, increased peroxidase activity is found in
all Wernicke alcoholics in neurons of the NBM and
341
in neighboring astrocytes (Cullen and Halliday, 1995).

Ventricular enlargement and sulcal widening is found
in 34% and 21% of cases, respectively (Harper, 1983;
Jacobson and Lishman, 1990). Generalized alcoholic
brain atrophy is present and cerebellar atrophy is
frequently found (Torvik et al., 1982). Microscopic findings include extravasation of red blood cells (diapedesis)
into the perivascular space. In some instances they extend
into the parenchyma to form ball macrophages or
hemorrhages. Acute lesions are characterized by hemorrhage, and perivascular interstitial hemorrhage underlies
the petechial hemorrhages (Figs. 29.1229.14). The
endothelial cells become hypertrophic (Harper, 1983);
moreover, loss of neuropil, reactive proliferation of
macrophages, astrocytes, and microglia, demyelination,
neuronal loss and, occasionally, spongy necrosis and
hemorrhages are found (Koeppen et al., 1969; Harper,
1983; Charness and DelaPaz, 1987; Blansjaar et al. 1992;
Victor, 1994). In addition, acute cases of Wernickes
encephalopathy starting 2 weeks before death have been
described, with ballooned neurons in the mamillary
bodies. In one case focal necrosis was observed; the
affected neurons were reactive for phosphorylated neurofilament and synaptophysin, but ubiquitin and B
crystallin expression were not detected. The mamillothalamic tract appeared to be normal, while there was
a marked associated microglial reaction. It is proposed
that these changes reflect an early stage in the development of Wernickes encephalopathy (Freiesleben et al.,
1997). Chronic lesions are characterized by atrophy of
the mamillary bodies with brownish discoloration.
This is a relatively specific macroscopic feature encountered in up to 99% of autopsies (Torvik et al., 1982;
Harper, 1983; Charness and DeLaPaz, 1987; Victor,
1994). Histologically the changes vary from barely visible
tissue destruction, with gliosis in the central parts of the
mamillary bodies, to subtotal destruction of the tissue
(Torvik et al., 1982). Shrunken mamillary bodies, the
most specific macroscopic lesion of chronic Wernickes
encephalopathy, can be identified by means of MRI
imaging. The mean mamillary body volume as measured
by MRI is 5264 mm3 in controls, 4046 mm3 in
Alzheimer patients and 2124 mm3 in Wernicke patients
(Charness and DeLaPaz, 1987; Charness, 1999; Sheedy
et al., 1999). Mamillary body shrinkage is related to the
severity of cognitive and memory dysfunction (Sullivan
et al., 1999). However, in alcoholism alone, without
amnesic disorder, mamillary body atrophy also occurs.
These lesions thus presumably develop before the patients
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Fig. 29.15. Wernickes encephalopathy. Upper figure: characteristic vascular disturbances in mamillary bodies. Material from a patient who died
in a prisoner-of-war camp in the Far East. Frozen section. Benzidine stain, 8. Lower figure: same patient vascular lesions in floor of the third
ventricle ( 50). (From Spillane and Riddock, 1947, Fig. 18 and 19, with permission.)
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A rare complication of alcoholism, defined by a

degeneration of the corpus callosum and the anterior
commissure is MarchiafavaBignami disease (primary
degeneration of the corpus callosum). The clinical picture
shows great variation. The course may be acute, rapidly
leading to death, or marked by a progressive dementia
with predominantly frontal lobe signs (Moreaud et al.,
1996). Neuropathologically, the typical finding is destruction of myelinated fibers in the corpus callosum and
anterior commissure (Victor, 1994).
29.6. Adrenomyeloneuropathy,
adrenoleukodystrophy and hypothalamic-pituitary
dysfunction
Adrenomyeloneuropathy is a syndrome comprising spastic
paraparesis, polyneuropathy, primary adrenocortical
insufficiency and variable hypogonadism. It is characterized by a degeneration of the pyramidal tracts, posterior
funiculi and peripheral nerves, which follows a pattern
of retrograde axonopathy. Thick cuffs of perivascular
histiocytic cells are seen in all demyelinated tracts.
In addition, characteristic inclusion bodies are found:
these can take on an electron-lucent fusifor shape, an
electron-dense, boomerang-like one, or they can be triangular. Adrenomyeloneuropathy is an hereditary X-linked
disorder of peroxisomal metabolism, and is considered
to be an adult variant of adrenoleucodystrophy which
afflicts 5- to 15-year-old boys. The latter disorder
concerns children with primary adrenocortical insufficiency and diffuse demyelination in the central nervous
system, causing dementia and quadriparesis. Heterozygous carriers of adrenomyeloneuropathy may show
symptoms of spastic paresis and peripheral neuropathy.
Both adrenoleukodystrophy (ALD) and adrenomyeloneuropathy occur in members of the same family and are
biochemically characterized by an accumulation of very
long chain fatty acids in various tissues and body fluids
(Probst et al., 1980; Peckham et al., 1982; Simpson
et al., 1994; Van Geel et al., 1997). X-linked ALD is one
of the most frequent causes of Addisons disease in men.
It is based on impaired peroxisomal -oxidation of very
long chain fatty acids. Mutations have been found in the
ALD gene encoding a membrane transport protein, which
might be involved in the import of very long chain fatty
acid coenzyme A synthetase into the peroxisome. There
is a striking variability in neurological and endocrine
symptoms in ALD, even within the same kindred
(Korenke et al., 1997).
Fig. 29.16. Magnocellular neurons of a control (A, C, E) and an alcoholic (B, D, F). Sections are stained with cresyl violet (CV) (A, B, E,
F) or immunohistochemically for vasopressin (C, D). AD are photomicrographs of the paraventricular nucleus (PVN), while E and F are
photomicrographs of magnocellular neurons in islands within the hypothalamus. There are fewer neurons present in B and D than in A and
C. Note the presence of gliosis amongst the magnocellular neurons in
B and F when compared with A and E. A number of normal-appearing
neurons (open arrow) are present near to the pyknotic neurons (closed
arrow) in B. Scale in A is the same for BF. (From Harding et al.
1996, Fig. 1, with permission.)
develop the clinical symptoms of WernickeKorsakoff

(Blansjaar et al., 1992). It is interesting to note that the
neuropathological changes of Wernickes encephalopathy
and subacute necrotizing encephalopathy (Leighs
disease) are similar, except for the relative sparing of the
mamillary bodies in the latter (Charness and DeLaPaz,
1987). Normal-sized corpora mamillaria also distinguish
between Korsakoff (diencephalic) amnesia patients and
temporal lobe amnesia (Squire et al., 1990).
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Some cases of adrenomyeloneuropathy accompanied

by hypothalamic-pituitary dysfunction have been
described. A 32-year-old man suffered from contractures,
peripheral neuropathy, primary adrenocortical insufficiency and secundary hypogonadism. The low levels
of gonadotropins, the minimal response of testosterone
to LHRH and the diminished rise of testosterone levels
in response to chorionic gonadotropins indicated hypogonadism secondary to hypothalamic or pituitary
dysfunction. Other signs of this involvement were that
growth hormone levels repeatedly failed to rise in
response to hypoglycemia or levodopa. Prolactin levels
varied from normal to slightly elevated, and, although
they exhibited an exaggerated response to TRH, they
showed normal suppression after levodopa. The patients
basal TSH level was high, and there was an accentuated
response to TRH, as has also been described in cases of
primary adrenal cortical insufficiency (Peckham et al.,
1982). He showed impressive neurological improvement
after glucocorticoid replacement therapy. A 31-year-old
man with an Addisonian crisis and with fever of unknown
origin, followed by abrupt onset of spastic paraparesis,
had peripheral neuropathy and an increase in very long
chain fatty acid levels. Abnormal pituitary function, i.e.
the levels of LH and TSH that had increased, returned
to normal as a result of corticosteroid treatment of
Addisons disease. Two family members, who had been
diagnosed with multiple sclerosis, in retrospect probably
suffered from adrenomyeloneuropathy. A sibling died
with the diagnosis of Schilderss disease at the age of
8 years. It is also noteworthy that many of the family
members had psychiatric problems (Simpson et al., 1994).
In a series of 55 patients with ADL, adrenal insufficiency was found in 33 of them. Hypogonadism has been
observed in adult ADL patients and a reduced adrenal
androgen synthesis, reflected by low dehydroepiandrosterone sulfate (DHEAS) levels, is found in nearly all
ADL patients. As-yet-unknown hereditary factors seem
to interfere with the endocrine phenotype (Korenke et al.,
1997). In a group of 26 men with ADL, 21 already had
adrenoleukomyeloneuropathy. Clinical signs of gonadal
dysfunction were: diminished libido (58%), failure of
the testes to descend (15%), diminished body sexual
hair (50%), gynecomastia (35%) and small testes (12%),
low plasma testosterone (12%), insufficient increase after
human chorionic gonadotropin (HCG) stimulation (88%),
and increased LH (16%) and FSH (32%). The response
of LH to LHRH was abnormally high in 47% and that
of FSH was abnormally low in 16%. Concluding, in
20 out of 26 men, signs of hypogonadism were found.

Overt or subclinical testicular insufficiency may even be
the only manifestation of ADL.
Generally, the high ACTH levels found in adrenomyeloneuropathy and ADL are considered to be
secondary to a primary disorder in the adrenal glands
(De Weerd et al., 1982). It has, however, also been
proposed that ACTH with its high molecular weight
great quantities of which are present in plasma and
cerebrospinal CSF, does not seem to be the result of
adrenal hypofunction, but could stem from an extrapituitary source such as the brain (Saito et al., 1987).
Cerebral ADL and adrenomyeloneuropathy are frequently
associated with Addisons disease, but the adrenal
insufficiency may precede, coexist or develop after neurological dysfunction (Korenke et al., 1997).
A novel group of patients has recently been described.
What they have in common is an unclassified form of
leukodystrophy, progressive neurological deterioration,
primary ovarian dysfunction and diffuse white matter
disease, sometimes with frontal cortical atrophy. Some
have borderline IQ. Puberty does not develop in
some patients and is arrested in others, while one patient
had premature ovarian failure at the age of 13 years.
Pathological analysis showed streak ovaries in one
patient. The gonadal insufficiency in these patients is
considered to be primary, and the hypothalamohypophysial axis normal (Schiffman et al., 1997).
29.7. Other neurodegenerative disorders
(a) Frontotemporal dementia and parkinsonism linked
to chromosome 17
A family has been described that is clinically characterized by a Klver-Bucy-like desinhibition with hyper- and
hyposexuality. In addition, oral tendency, alcoholism
and aggressiveness, social withdrawal, depression and a
schizophrenia-like picture occurs in some patients.
Patients have been arrested and jailed or placed in
psychiatric hospitals. Moreover, dementia, Parkinsonism,
and, in one patient, amyotrophy are part of the complex.
Parkinsonism and cognitive deterioration lead to a rigid,
akinetic mute state; the mean duration of the disorder to
death is 14 years. Immunocytochemically, no proteaseresistant prion protein is found. The neuropathological
changes consist of circumscribed neuronal loss, gliosis,
and spongiosis of limbic neocortical areas and frontal
temporal and occipital association areas. Similar changes
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are present in the substantia nigra, ventral striatum and

amygdala. The hippocampus is spared, except for
degeneration of the afferent perforant tract, secondary
to entorhinal nerve cell loss. Argyrophilic neuronal
inclusions with a characteristic immunocytochemical
profile are found in brainstem nuclei, basal ganglia
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and hypothalamus. The inclusions stain intensely with

Bielchowskys silver impregnation and are composed of
haphazardly arranged spicules. The subcortical neuronal
inclusions and ballooned neurons stain positively for
phosphorylated neurofilaments, variable for ubiquitin and
negative for tau, -amyloid and -synuclein. In addition,
oligodendroglial argyrophilic tangle-like inclusions show
positive staining for ubiquitin and the microtubuleassociated protein tau. In the mamillary body, no neuronal
loss or spongiosis is found, but gliosis, non-Alzheimer
tangles, ballooned neurons and spheroids are present;
in the ventral hypothalamus, atrophy, neuronal loss,
gliosis and non-Alzheimer tangles are observed. Ultrastructurally, these inclusions have hitherto shown
undescribed abnormally assembled filaments of 1014
nm, with a lattice-like arrangement of variable periodicity.
Glial cytoplasmatic inclusions were widespread in
white-matter structures. These inclusions show parallel
tubural structures of 1417 nm in diameter. Linkage
analysis has localized the disease on 17q21-22 (Sima
et al., 1996; Spillantini et al., 1998a; Rosso et al.,
2001). A number of mutations in the tau gene have subsequently been reported in this disorder (Poorkaj et al.,
1998; Spillantini et al., 1998b; Rizzu et al., 1999;
Van Swieten et al., 1999; Rosso et al., 2002). The circadian restactivity rhythm of patients with frontotemporal
degeneration is highly fragmented and phase-advanced,
and apparently uncoupled from the rhythm of the core
body temperature (Harper et al., 2001). However, so far
no neuropathological information has become available
on the possible degenerative changes in the SCN. In 38%
of frontotemporal dementia cases, thyroid hormone abnormalities are found (Fldt et al., 1996; Smith et al., 2002),
but the TRH neurons have not been studied.
Fig. 29.17. (A) Correlation of paraventricular nucleus (PVN) (plus

signs) and supraoptic nucleus (SON) (crosses) volume with maximum
daily alcohol consumption. The slopes are similar, indicating that the
volume reduction of these nuclei with increasing alcohol consumption
is also similar. (B) The number of neurons in the PVN (squares) in
CV-stained sections correlated with the duration of alcohol consumption in years. The loss of neurons in the SON (circles) is not related
to duration of alcohol consumption. This implies that repeated high
levels of alcohol consumption are necessary for the loss of PVN neurons.
(C) The number of magnocellular hypothalamic neurons immunoreactive for vasopressin decreases with greater maximum daily alcohol
consumption, forming a significant regression (solid line). (From
Harding et al., 1996, Fig. 2, with permission.)
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Several multigeneration kindreds with an autosomal

dominant hereditary frontotemporal dementia have been
described in the Netherlands. There is also evidence of
linkage to chromosome 17q21-q22. Moderate to severe
atrophy of frontal and temporal cortex is found, with
neuronal gliosis and spongiosis, and Pick bodies are
absent. Unfortunately, the hypothalamus of these patients
has not been investigated (Heutink et al., 1997). Our own
observations on one subject of this family (94-003, male,
66 years of age) revealed a strong degeneration of
the corpora mamillaria and fornix, while an apparently
structurally intact SON, PVN, TMN, and nucleus tuberalis were found. Interestingly, the ApoE 4 genotype in
a Dutch study appears to be strongly increased. The
adjusted odds ratio is 5.2 (Stevens et al., 1998b).
Although, in a study of other families with frontotemporal dementia and defined tau mutations, no evidence
was found for an effect of ApoE genotype on the age of
onset of dementia (Houlden et al., 1999), a later study
of the Dutch group has shown that the ApoE 4 allele
frequency is increased in the temporal variant of this
disease (Rosso et al., 2002).
When 13 kindred that share clinical and neuropathological features were identified with sufficient linkage to
chromosome 17 and frontotemporal dementia, it was
agreed that the disorder should be named frontotemporal
dementia and parkinsonism linked to chromosome 17,
instead of the terms used earlier (dementia lacking distinctive histology, Picks disease without Pick bodies,
frontotemporal dementia, frontotemporal degeneration
without Pick bodies, frontal lobe degeneration of the
non-Alzheimer type, or asymetrical cortical syndrome)
(Spillantini et al., 1998a, b; Stevens et al., 1998b;
Wilhelmsen, 1998). The disease commonly begins insidiously, with behavioral or motor manifestations, typically
in the 5th decade. The duration of the disease is usually
10 years with a range of 330 years. The symptoms include
those described above, as well as impaired social conduct,
ranging from aggressiveness to apathy and obsessive
stereotyped behavior. No significant benefit is observed
with L-DOPA when tried against the motor abnormalities.
Changes in body weight, swallowing problems, and
changes in appetite, food preference and eating habits are
even more common than in Alzheimers disease (Ikeda et
al., 2002). Increases in body weight associated with hyperphagia also occur. Neuropathologically, frontotemporal
atrophy is a consistent feature, and substantia nigra depigmentation is found in most kindred (Foster et al., 1997).
The microscopic alterations are described above. The lack
of attention to the hypothalamus, and in particular the

pathology of the structures related to memory processes
such as the corpora mamillare and fornix is remarkable in
the consensus report on this disease.
Vincent van Goghs (18531890) major illness during the
last 2 years of his life was identified as temporal lobe
epilepsy, precipitated by the use of absinthe, in the presence
of an early limbic lesion, probably an injury sustained at
birth (Blumer, 2002).
(b) Hippocampal sclerosis

Hippocampal sclerosis is characterized by neuronal loss,
with gliosis involving the hippocampus, and is often associated with intractable temporal lobe epilepsy. Temporal
lobectomy is a widely accepted surgical treatment for
patients with hippocampal sclerosis. Hypothalamic
disorders have also been found in this disorder.
MRI detection of an asymmetrically small fornix or
mamillary body has been suggested as a useful presurgical, lateralizing sign of hippocampal sclerosis in
patients with temporal lobe epilepsy. However, it should
be noted that the majority of the fornical fibers originate
from the subiculum and not from the cornu ammonis and
project predominantly via the postcommissural fornix.
Moreover, the subiculum is not commonly affected in
hippocampal sclerosis. The remaining part of the fornical
fibers arise from the cornu Ammonis, and terminate exclusively in the septal nuclei via the precommissural fornix.
However, the low frequency of an asymmetrically small
fornix and its association with severe hippocampal
atrophy does not make the asymmetrically small fornix
a sensitive diagnostic sign of hippocampal sclerosis.
In addition, mamillary body asymmetry is not unique
to patients with mesial temporal sclerosis, as it is also
found after, e.g. a temporal infarct or a middle fossa
meningeoma. However, after temporal lobectomy, an
asymmetrically small fornix and mamillary body are
systematically found. Apparently temporal lobectomy
exaggerates the effect of neuronal degeneration as a result
of massive neuronal loss in the temporal region (Kim
et al., 1995; Mamourian et al., 1995). In the SCN of one
of the two patients with hippocampal sclerosis, Stopa
et al. (1999) found an increased astrocyte to neuron ratio.
The density of vasopressin and neurotensin neurons
seemed to be low in these patients, but more subjects
have to be studied. Moreover, there are more indications
that the seizures seen in hippocampal sclerosis will affect
circadian rhythms (Quigg et al., 1999).
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-tubulin, - and -crystallin and -synuclein (Lantos,

1998). In multisystem atrophy most patients have cerebellar and extrapyramidal features, while generalized
autonomic dysfunction such as orthostatic hypotension
and swings in blood pressure may not appear until later
in the disease process. Apart from orthostatic hypotension, urinary and rectal incontinence, loss of sweating,
iris atrophy, external ocular palsies, rigidity, tremor, loss
of associated movements, impotence, atonic bladder, loss
of rectal sphincter tone, fasciculations, wasting of distal
muscles, electromyographic evidence of involvement of
anterior horn cells and neuropathic lesions in muscular
biopsies are found. In contrast to Parkinson patients
and normal controls, no hypothalamic -adrenoceptor
response of growth hormone is present, as appears
following clonidine administration. Levodopa raised
growth hormone in the same way as in controls, which
suggests that the hypothalamic -adrenoceptor sites may
be specifically affected in multiple-system atrophy. And
indeed, there seems to be a loss of catecholaminergic
projections, i.e. from the locus coeruleus in the brainstem
to the hypothalamus (Shy and Drager, 1960; Spokes
et al., 1979; Benarroch et al., 1998; Mathias, 2002). An
impairment is observed of hypothalamic responses to
hemodynamic and other stresses, and baroreflex dysfunction, such as the lack of vasopressin increase in response
to tilt-induced hypotension. In patients with multisystem
atrophy, upright tilt elicits profound hypotension, whereas
circulating levels of vasopressin only increase a little
(Kaufman et al., 1992). Moreover, these patients have no
thirst during saline drinking (Bevilacqua et al., 1994).
Afferent and central baroreceptor and osmotic thirst
pathways involved in vasopressin release thus seem to be
impaired in patients with this disorder (Kaufman et al.,
1992; Bevilacqua et al., 1994). In addition, patients with
multisystem atrophy fail to excrete a water load while
standing up, suggesting abnormal postural regulation of
vasopressin release. The postural rise in vasopressin is
not inhibited by a dopamine agonist or opioid antagonist,
suggesting a loss of dopaminergic and opioid pathways
involved in vasopressin release in this disease (Puritz
et al., 1983). The patients do respond to vasopressin.
A patient that later appeared to have multisystem atrophy,
presented with signs of autonomic dysfunction during
an operation. The initial hypertension was treated with a
direct vasodilatator (hydralazine), which resulted in severe
hypotension that did not respond to adrenergic agonists.
The hypotension only responded to vasopressin (Vallejo
et al., 2002).
(c) Progressive supranuclear palsy (PSP)

Both disorders are clinically characterized by atypical
Parkinsonism and cognitive disorders. PSP, also known
as the SteeleRichardsonOlszewski syndrome, is a
neurodegenerative disease characterized by a loss of
voluntary control of vertical gaze, dysarthria, diffuse body
rigidity with dystonic extension of the neck, and dementia.
Histologically, the disease is characterized by extensive
lesions in the midbrain, specifically cell loss, gliosis and
neurofibrillary tangles. The substantia nigra, NBM, and
septum, may be strongly affected by neurofibrillary
tangles and neuronal loss in PSP, causing dopaminergic
and cholinergic defects (Tagliavini et al., 1983; Ruberg
et al., 1985). A substantial (4585%) neural reduction is
found in the subthalamic nucleus (Chapter 15a), both for
parvalbumin and calretinin-containing cells. Extracellular
neurofibrillary tangles and tau-positive glia cells were
observed in the subthalamic nucleus (Hardman et al.,
1997). In addition, there is an accumulation of hyperphosphorylated tau in this nucleus (Mattila et al., 2002).
(d) Multisystem atrophy (ShyDrager syndrome)
The term multisystem atrophy was originally introduced
to include striatonigral degeneration, olivopontocerebellar
atrophy and ShyDrager syndrome. Multisystem atrophy
is characterized by a combination of cerebellar signs,
parkinsonian features (see Fig. 29.12) and autonomic and
urinary dysfunction (Lantos, 1998). Degeneration of
the sacral horn cells (Onufs nucleus) in patients with
multisystem atrophy has been associated with urinary,
sexual and anorectal dysfunction (Vallejo et al., 2002).
Orthostatic hypotension, a loss of neurons in the substantia nigra, in the preganglionic nuclei in the medulla
oblongata and spinal cord, the basal ganglia, base of
the pons, cerebellar nuclei and cortex is found (Shy
and Drager, 1960; Saper, 1998; Mathias, 2002). Neuropathologically, multisystem atrophy is characterized
by cytoplasmic inclusions that contain -synuclein
(Wakabayashi et al., 1998). The definition given by
Lantos (1998) is: Multisystem atrophy is a sporadic,
progressive adult onset degenerative disease of the nervous
system of unknown cause, histologically characterized by
glial oligodendrocytic cytoplasmic inclusions. He goes
on to say that the term ShyDrager syndrome is no
longer useful. The oligodendrocytic cytoplasmic inclusions are positive for ubiquitin, tau protein, - and
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Involvement of the hypothalamus in multisystem

atrophy has been reported by several authors. In one
case, diabetes insipidus and mild gliosis in the SON have
been reported (Ozawa et al., 1993). In hypothalamic
areas such as the wall of the third ventricle, in the lateral
hypothalamic area, around the corpora mamillaria, and in
the infundibular nucleus, recent punctate hemorrhages
have been found (Schwartz, 1967). In addition, in one
patient with ShyDrager syndrome, a partial deficit in
vasopressin release and neuronal loss in the supraoptic
nucleus, and cluster breathing were found, an indication
of pontomedullary respiratory center damage, with a
normal CO2 response curve (Lockwood, 1976). Moreover,
hypothalamic norepinephrine, dopamine, glutamic acid
decarboxylase and choline acetyltransferase are markedly
reduced in patients with multiple-system atrophy (Spokes
et al., 1979). A patient with ShyDrager syndrome
exhibiting nocturnal polyuria and a reversed circadian
rhythm of vasopressin has been described (Ozawa et al.,
1993), suggesting that the SCN is affected in this disease.
Later, evidence was indeed provided for a disorder in the
SCN, the biological clock (see Chapter 4), in multisystem
atrophy. The patient who exhibited nocturnal polyuria
associated with decreased urinary specific gravity and
decrease of nocturnal vasopressin secretion had a
decreased number of vasopressin neurons and gliosis in
the SCN. Moreover, the vasopressin neurons in the SCN
of this patient were smaller than those of a series of
controls, and gliosis was present in the SCN. Also
the observation that patients with multisystem atrophy
have decreased early morning cortisol levels indicates a
functional alteration of the SCN (Ozawa et al., 2001).
A decrease in the nightly plasma vasopressin levels has
been confirmed in a sample of 13 patients with multisystem atrophy (Ozawa et al., 1998). The physiological
nocturnal fall of body core temperature is blunted in
multiple-system atrophy patients. The lack of decrease in
body temperature in these patients distinguishes them
from Parkinson patients (Pierangeli et al., 2001) and may
be caused by a defect in the SCN. The SON and PVN
seem to remain intact (Ozawa et al., 1998).
(e) Lewy body disease
Senile dementia of Lewy body type is characterized
clinically by fluctuating confusion and, in the majority of
cases, also by visual hallucinations (Perry et al., 1990).
Orthostatic hypotension is increasingly recognized as a
problem in diffuse Lewy body disease (Mathias, 2002).
Neuropathologically, Lewy bodies are especially found

in archicortical areas (Perry et al., 1990). However,
in the hypothalamus, including the subthalamic nucleus,
-synuclein-containing Lewy bodies are also detected
(Piao et al., 2000). Choline acetyltransferase activity is
significantly lower in the parietal and temporal cortex
of those patients with visual hallucinations (Perry et al.,
1990), indicating that the NBM is especially affected.
Indeed, reductions in nicotine-binding have been observed
in the substantia nigra, tegmentum and striatum in
demented patients with Lewy bodies (Court et al., 2000).
The loss of choline acetyltransferase in the neocortex
occurs much earlier in the Lewy body disease process,
and is much greater than observed in Alzheimers disease
(Tiraboschi et al., 2002). Moreover, the subthalamic
nucleus (Chapter 15a) is accumulating hyperphosphorylated tau (Mattila et al., 2002).
(f) Picks disease
In Picks disease, the NTL (see Chapter 12) shows severe
affliction, as indicated by strong staining for hyperphosphorylated tau-protein and argyrophylic Pick bodies,
which have an unusual, flat shape with peripheral indentations. Small, teardrop-shaped Pick neurites emerge in
varicose widenings of neuronal processes and display a
much weaker argyrophilia than the Pick bodies. The large
tuberomamillary neurons around the NTL usually remain
uninvolved in Picks disease (Braak and Braak, 1998a).
In the SCN of three Pick patients, Stopa et al. (1999)
have found a decreased density of vasopressin and
neurotensin neurons, changes that were similar to those
observed in AD (see Chapters 4.3 and 29.1).
(g) Miscellaneous
Sporadic amyotropic lateral sclerosis (ALS) is approximately twice as prevalent in men as in women, raising
the possibility of hormonal involvement. Indeed, serum
free testosterone is significantly decreased in both male
and female ALS patients, while no difference is found
for serum levels of DHEAS, 17- estradiol and total
testosterone. There is quite some experimental evidence
for a putative neuroprotective role for testosterone, in
particular in motorneurons (Militello et al., 2002).
In a rare neurodegenerative disease that is mainly
confined to Japanese patients, i.e. diffuse neurofibrillary
tangles with calcification or non-Alzheimer non-Pick
dementia with Fahrs syndrome, tangles are also found
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in the NBM and in the subthalamic nucleus (Tsuchiya

et al., 2002).
Variant CreutzfeldtJakob disease is a novel human
prion disease that appears to result from infection by the
bovine spongioform encephalopathy agent. All cases of
this disease are methionine homozygotes at codon 129
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of the protein phosphatase gene. The features comprise

spongiform change, neuronal loss, astrocytic and microglial proliferation, and accumulation of the abnormal
isoform of the prion protein. Spongiform changes are
most abundant in the hypothalamic supraoptic and paraventricular nuclei (Ironside, 2002).
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CHAPTER 30
Autonomic disorders
Finally, I want you to consider every function I attribute to

this machine (the brain), such as digestion, feeding,
breathing, waking and sleeping, the absorbing of light,
sound, smell, the impression of ideas in the organ of perception and imagination, the holding on to these ideas in the
memory, the lower movements of desires and passions, and
lastly the moving of all outer limbs, I tell you I want you
to consider these functions as taking place naturally in this
machine exclusively as a result of the nature of its organs,
in the manner of the movements of a clock.
Descartes, 15961650.
the ergotropic zone of the hypothalamus. In an area more

than 5 mm lateral from the wall of the third ventricle,
electrical stimulation often yields parasympathetic
responses such as a fall in blood pressure and bradycardia
(Sano et al., 1966, 1968). Various authors have described
the syndrome of autonomic storm (paroxysmal sympathetic storm or acute hypothalamic instability). This
is characterized by episodes of acute tachycardia,
hyperthermia, skin vasodilatation, shivering, tachypnea,
lacrimation and pupillary changes in patients with either
a tumor at the level of the foramen of Monro or lesions
near the third ventricle, which seem to be located in
the posterior subnucleus of the PVN (Koutcherov et al.,
2000) in cases of diencephalic syndrome (Connors and
Sheikholislam, 1977; Chapter 19.4), or associated with
closed head injury and hydrocephalus (Thorley et al.,
2001). The animal experiments of W. R. Hess (1969),
which have shown that cats enter a deep, normal sleep
when their anterior hypothalamic-preoptic regions are
stimulated, suggests the existence of a hypothalamic
sleep center in this area. Destruction of this area leads to
insomnia and destruction of the posterior hypothalamus
to hypersomnia (Carmel, 1985; Chapter 30.7). Disorders
of sleep and wakefulness are seen following hypothalamic
damage, e.g. in encephalitis lethargica (Chapter 20.2),
diencephalic idiopathic gliosis (Espiner et al., 1992;
Chapter 32.3) and Wernickes encephalopathy (Chapter
29.5). Animal experiments have indicated that the caudal
hypothalamus is involved in integration of respiratory
output. Neurons in this region are strongly sensitive
to perturbations in oxygen tension and hypercapnia
(Berquin et al., 2000). In cats, respiratory responses
to increases in PCO2 above the apneic threshold are
modulated by neurons in the posterior hypothalamus,
involving a GABAergic mechanism (Waldrop, 1991). In
Following hypothalamic lesions in patients, various vegetative or autonomic dysfunctions have been described
(Carmel, 1985), which illustrates the importance of this
brain structure in many autonomic processes. Moreover,
autonomic disturbances are part of the signs and symptoms of many hypothalamic disorders such as idiopathic
hypothalamic syndrome of childhood (Chapter 32.1),
hypothalamic atrophy (Chapter 32.2) and diencephalic
idiopathic gliosis (Chapter 32.3). Caloric balance may be
altered with ventromedial lesions, causing hyperphagia
(see Chapters 9 and 26.3) and the sympathetic nervous
system has been implicated in the development and
maintenance of obesity (Snitker et al., 2000). Temperature
regulation may be affected by lesions in various hypothalamic areas (Chapter 30.2). In Wernickes encephalopathy
a striking chronic hypothermia is seen that is thought to
be related to the periventricular and mamillary body
lesions (Chapter 29.5). Sweating may be disturbed by
hypothalamic multiple sclerosis (MS) lesions (Ueno et al.,
2000): a patient with a focal posterior hypothalamic stroke
developed episodes of exuberant sustained sweating of the
entire left side of the body (Smith, 2001). Stereotactic
electrical stimulation of the posteromedian hypothalamus
in patients causes a rise in blood pressure and pulse rate
(Sano et al., 1968; Ramamurthi, 1988). This area is called
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rats, moderate hypoxia or hypercapnia cause c-FOS activation in the posterior hypothalamic area, dorsomedial
hypothalamic nucleus (DMN), and ventral hypothalamic
area. In addition, hypoxia activates the supraoptic nucleus
(SON) whereas hypercapnia stimulates the paraventricular
nucleus (PVN). The PVN exerts a facilitatory effect on
ventilation, possibly mediated by direct projections to the
medullary respiratory neurons and to the phrenic nucleus
(Berquin et al., 2000). Oxytocin-containing projections of
the PVN to the brainstem are involved in the regulation
of breathing (Mack et al., 2002). In addition, the caudal
hypothalamus is a major site for central command or the
parallel activation of locomotion and respiration (Horn
and Waldrop, 1998). PET studies have shown that hypercapnia induces activation of a number of brain areas
in human, including the hypothalamus (Brannan et al.,
2001). Hypothalamic modulation of hypercapnic and
hypoxic ventilatory responses is presumed to be disturbed
in PraderWilli syndrome (Menendez, 1999; Chapter
23.1), in congenital central hypoventilation syndrome
and in late-onset central hypoventilation syndrome (Katz
et al., 2000; see the section Autonomic syndromes, and
Chapter 32.1).
A decrease in plasma glucose causes prompt release
of several counter-regulatory hormones, including
glucagon, catecholamines, cortisol and growth hormone,
which jointly act to correct hypoglycemia. The counterregulatory activation of the sympathetic nervous system
consists of adrenal secretion of adrenaline, cardiac stimulation with a rise in heart rate and the development of
hypoglycemic adrenergic symptoms. This reaction has its
source in the hypothalamic centers, since it is impaired
in patients who have undergone transcranial surgery for
a craniopharyngioma extending into the hypothalamic
region, and in a patient with neurosarcoidosis of the
hypothalamus (Fry et al., 1999; Schfl et al., 2002).
Cushing ulcers are peptic ulcers of the stomach or
pylorus that are found in association with intracranial
events. On the basis of a patient with a duodenal ulcer and
a tumor of the third ventricle, Harvey Cushing concluded
that there was a parasympathetic center in the hypothalamus that was connected to the vagal center (Carmel, 1985;
Dolenc, 1999). The PVN has indeed been implicated
in controlling the integrity of the gastric mucosa through
a combined modulation of pituitary hormones, acid
secretion and gastric motility. In accordance with such
observations, electrical stimulation of the PVN has been
shown to produce, within 1 h, gastric ulceration through
activation of cholinergic fibers of the vagus nerve (Smith
et al., 1998). In addition, oxytocin, when injected into the

dorsomedial nucleus of the vagus, increases gastric acid
secretion (Rogers and Hermann, 1985).
Orgasm causes elevations in blood pressure, heart rate
and levels of epinephrine and norepinephrine both in
women and in men (Bancroft, 1999; Exton et al., 1999), as
well as a release of neurohypophysial hormones (Chapter
8g), illustrating the concerted action of the hypothalamus
on neuroendocrine and autonomic mechanisms during
sexual behavior. Another, related example of such an
integrated response is the action of the vomeronasal
organ. Vomeropherins or pheromones not only stimulate
luteinizing hormone (LH) and follicle-stimulating hormone
(FSH) release in a sex-dependent manner, through the
vomeronasal organ, but also affect the autonomic system,
as appears from decreased respiratory frequency, increased
cardiac frequency, event-related EEG changes and
decreased skin temperature (Berliner et al., 1996; MontiBloch et al., 1994; Chapter 24.2b). Children with disruptive behavior disorders showed lower autonomic nervous
system activity and hypothalamopituitaryadrenal (HPA)
axis activity, although they have higher levels of emotional
arousal (Van Goozen et al., 2000a).
A large number of neurological and psychiatric diseases
may be accompanied by autonomic disturbances that are
attributed to hypothalamic disorders. Characteristic signs
and symptoms are found in McCuneAlbright syndrome
(Chapter 24.1b), fatal familial insomnia, a prion disease
(Lugaresi et al., 1998; Chapter 4), and Guamanian
neurodegenerative disease (Low et al., 1997). In MS
(Chapter 21.2), as well as disturbed function of the bowel,
bladder, of sexual behavior and sweating, and of cardiovascular regulation, disturbed temperature regulation such
as poikilothermia (Lammens et al., 1989; Kurz et al.,
1998) and hypothermia (Sullivan et al., 1987; White
et al., 1996) and sleep disturbances (Chapter 21.2) might
be present. Depression (for hypothalamic involvement,
see Chapter 26.4) is associated with altered autonomic
activity in patients with coronary heart disease, as reflected
by elevated resting heart rate and an exaggerated heartrate response to orthostatic challenge (Carney et al., 1999).
In Alzheimer patients, especially those with symptoms of
depression, an impaired response of the systolic blood
pressure on standing is observed (Vitiello et al., 1993).
In Parkinsons disease a series of autonomic disturbances
are found, e.g. sialorrhea, seborrhea, excessive sweating,
orthostatic hypotension, a change in the relationship
between blood pressure and pulse rate, and disruption of
circadian control of sleep (Awerbuch and Sandyk, 1992;
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Murata et al., 1997; Mathias, 2002; Chapter 29.3). In

addition, hypothalamic norepinephrine, dopamine,
glutamic acid decarboxylase, and choline acetyltransferase
are markedly reduced in patients with multiple-system
atrophy, who characteristically have autonomic failure
(Spokes et al., 1979; Mathias, 2002; Chapter 29.7d).
Orthostatic hypotension is frequently a problem in diffuse
Lewy body disease (Mathias, 2002; Chapter 29.7e).
Penfield (1929) first applied the term diencephalic
epilepsy to paroxysmal attacks of autonomic disturbances such as flushing, diaphoresis and temperature drop
in a patient with a cholesteatoma. This tumor, however,
was compressing the thalamus rather than the hypothalamus. Moreover, disorders of sweating mechanisms have
been reported, but the lesions are situated immediately
caudal of the hypothalamus (Carmel, 1985). Although
a 38-year-old man with autonomic seizures had a
hypothalamic astroblastoma, this tumor also invaded
the thalamus, and it is by no means certain that the
hypothalamic lesion was responsible for the symptoms
(McClean, 1934). On the other hand, diencephalic autonomic seizures of Penfields type have also been described
in patients with third-ventricle choroid plexus papillomas
(Jooma and Grant, 1983) and in a 20-month-old child with
an astrocytoma of the diencephalon (Solomon, 1973).
Brain death may coincide with autonomic storm,
which may affect donor-organ quality. The syndrome
includes rapid swings in blood pressure, with eventual
persistent hypotension, coagulopathies, pulmonary
changes, hypothermia and electrolyte aberrations
(Pratschke et al., 1999).
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PVN to the brainstem are involved in the regulation of

respiratory and cardiovascular activity (Mack et al., 2002).
The central actions of the stress hormone of the PVN,
corticotropin-releasing hormone (CRH), on visceral organ
activity are similar to those which are directly stressinduced. CRH administrated centrally elevates blood
pressure and increases heart rate; CRH also produces
metabolic, gastrointestinal and immune system responses.
It brings about an increase in plasma glucose levels and
a decrease in insulin levels (Dinan, 1994; Lehnert et al.,
1998). Intranasal administration of CRH initiates, probably via central nervous system mechanisms, inhibition
of gastric acid secretion and a change of mood (Kern
et al., 1997; Chapter 26.4). Studies in rat have, moreover,
indicated that PVN neurons participate in the regulation
of breathing activity and in the coordination of cardiovascular and respiratory functions. Tracing studies have
suggested the presence of a direct connection between
PVN and phrenic motorneurons (Yeh et al., 1997).
Thyrotropin-releasing hormone (TRH), which is produced
in the PVN and transported to many intra- and extrahypothalamic brain regions (Chapter 8.6), is presumed
to influence, e.g. thermoregulatory, gastrointestinal and
appetitive functions (Ciosek and Guzek, 1992), and
LH-releasing hormone (LHRH) neurons are involved in
temperature regulation (Chapter 30.1).
The human parabrachial nucleus, an important relay
center for the ascending visceral projections from the
nucleus tractus solitarius and area postrema, receives
afferents from the PVN. It thus reflects the chemical and
visceral profile of the organism. In addition, it receives
nociceptive information and information about the
internal milieu (Parvizi et al., 1998). This nucleus contains
a large number of peptidergic fibers, such as CRH,
somatostatin and vasoactive intestinal polypeptide (VIP).
These fibers may originate, at least partly, from the PVN
and other hypothalamic nuclei (Pammer et al., 1988;
Parvizi et al., 1998). Strong neuropathological Alzheimer
changes are observed in the parabrachial nucleus which
may lead to autonomic dysfunctions in this disorder
(Parvizi et al., 1998). On the other hand, no obvious
change in the density of the vasopressin and oxytocin
innervation, probably derived from the PVN, has been
observed in this nucleus in Alzheimer patients (Van
Zwieten et al., 1994).
Furthermore, animal experiments have shown that
also the suprachiasmatic nucleus (SCN) is involved
in the control of the autonomous nervous system, and
as such in circadian fluctuations in many functions,
Structures involved
The hypothalamus is the head ganglion of the autonomic
nervous system.
Hess, 1969.
The PVN is a crucial central structure for many

autonomous functions and disorders of the hypothalamus.
In the human brain, vasopressin and oxytocin fibers of
the PVN are presumed to project to, e.g. the nucleus
basalis of Meynert (NBM), diagonal band of Broca
(DBB), septum, bed nucleus of the stria terminalis, locus
coeruleus, parabrachial nucleus, the nucleus of the solitary
tract, the dorsal motor nucleus of the nervus vagus,
substantia nigra, dorsal raphe nucleus and spinal cord
(Sofroniew, 1980; Fliers et al., 1986; Unger and Lange,
1991; Fodor et al., 1992; Van Zwieten et al., 1994, 1996;
see Chapter 8). Oxytocinergic projections from the
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including temperature, heart rate, blood pressure, glucose

metabolism, and sleep (Nagai et al., 1996; Hall et al.,
1997; Buijs and Kalsbeek, 2001). Not only SCN changes
(Chapter 4), but also alterations in pineal calcification
during aging have been related to disturbed circadian
rhythmicity in the sleepwake cycle and daytime tiredness
in humans (Kunz et al., 1998), although the latter point
is controversial (Chapter 4.5). Animal experiments have
shown that brief, intermittent social stress may have a
long-term influence on autonomic circadian rhythms
(Tornatzky and Miczek, 1993). Similar data in humans
are not available. In humans, blood pressure generally
falls during the night (dippers), but in some essential
hypertensives this nocturnal fall in blood pressure does
not take place (nondippers) (Coca, 1994). This points
to a possible involvement of the SCN in this group of
hypertensives. Light influences the SCN and its output
instantaneously; it also influences resting heart rate,
depending on the phase of the day/night cycle and on the
intensity of light (Scheer et al., 1999). Multiple-system
atrophy, or ShyDrager syndrome, is characterized by
orthostatic hypotension and other autonomic disorders.
The SCN has indeed been found to be affected in this
disorder (Ozawa et al., 1998; Chapter 29.7). The SCN is
linked to a varied range of sympathetic and parasympathetic motor pathways, as well as being involved in setting
the sensitivity of endocrine organs by influencing their
autonomic innervation. A polysynaptic link has been
found in rat between the SCN and the intermediodorsolateral cell column in the spinal cord that may be involved
in transmission of the circadian nervous signals from the
SCN to the pineal gland. In a similar way, many other
organs, including the adrenal glands, receive autonomic
afferents that are influenced by the SCN. This concept
may be extended to the heart, intestines and thyroid gland,
and to other endocrine and nonendocrine organs (Vrang
et al., 1997; Buijs et al., 1999; Ueyama et al., 1999;
Gerendai and Halsz, 2000; Kalsbeek et al., 2000b;
La Fleur et al., 2000; Buijs and Kalsbeek, 2001; Scheer
et al., 2001). Lesion studies in rat have shown that the
SCN also controls basal glucose levels (La Fleur et al.,
1999) by means of the autonomic nervous system (Buijs
and Kalsbeek, 2001).
The posterior hypothalamic area controls many
autonomic activities such as respiration, cardiovascular
activity, locomotion, antinociception, arousal/wakefulness, sweating and eating behavior (see Chapter 13.3;
Smith, 2001).
Autonomic syndromes
Idiopathic hypothalamic syndrome of childhood is a
paraneoplastic syndrome based upon the production of
antiglial and antineuronal antibodies. Diffuse infiltrates
of small lymphocytes and single or paired histiocytes have
been found in the hypothalamus and in other brain regions
(see Chapter 32.1; Ouvrier et al., 1995).
Late-onset central hypoventilation with hypothalamic
dysfunction features hyperphagia with resultant obesity,
hypersomnia, thermal dysregulation, emotional instability
and highly variable endocrinopathies in addition to central
hypoventilation after infancy (see also Chapter 32.1).
The syndrome has been successfully treated by nasal,
intermittent positive-pressure ventilation. The link with
congenital central hypoventilation syndrome, which does
not feature symptoms of hypothalamic dysfunction and
which is characterized by an absent hypercapnic ventilatory response and often respiratory failure at birth, is
not clear. However, their association with disorders of
neural crest migration, such as Hirschsprungs disease,
and neural crest tumors, such as ganglioneuroblastoma
and ganglioneuroma, is well-documented. Although three
cases have revealed a histologically normal central
nervous system, one case has been reported with extensive
lymphocytic/histiocytic infiltrates of the hypothalamus,
which is consistent with a ganglioneuroblastomaassociated paraneoplastic syndrome.
A number of cases of acute pandysautonomia and acute
autonomic and sensory neuropathy have been described.
They originally presented as psychiatric disorders such as
hysterical neurosis, epilepsy, anorexia nervosa, emotional
instability and hypochondrial neurosis. However, psychiatric symptoms seem to arise from the autonomic nervous
dysfunction. In addition, headache, insomnia, constipation,
anhidrosis, fainting spells, vomiting, urinary incontinence,
impotence, or visual difficulties may be present (Okado,
1990). The degree of involvement of the hypothalamus is,
however, not clear.
Pure pandysautonomia is an immunological disorder
similar to the syndrome of GuillainBarr. The symptoms
comprise lethargy, decreased endurance, postural hypotension, fainting, difficulty with vision, decreased potency,
decrease of tears, saliva and sweat, absence of bowel
sounds and obstipation, and hypotonic bladder. There is
complete sympathetic and parasympathetic denervation
of the iris. In summary, there is unequivocal evidence
of postganglionic denervation of the pupil and the
peripheral vasculature. One patient who was treated with
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glucocorticoids indeed noted a dramatic increase in

salivation and a return of a general feeling of well-being
(Young et al., 1969). The site of the lesion is thought to be
the postganglionic fibers of both the sympathetic and the
parasympathetic nervous system, but central autonomous
mechanisms have also been considered (Okada, 1990).
Although some single postmortem studies have reported
Lewy bodies in the brainstem of such patients (Critchley
et al., 2003), no investigation of the hypothalamus seems
to have been performed.
RileyDay syndrome or familial dysautonomia has an
autosomal recessive means of transmission. It is characterized by pandysautonomia, including defective
lacrimation, orthostatic hypotension and vomiting crisis
(Kita, 1992). This disease occurs almost exclusively
in descendants of the Eastern European Ashkenazi
Jews (Mancini, 1990); an exception has been described
by rbeck and Oftedal (1977). The disorder is caused by
mutations of the IKBKAP gene on chromosome 9q31
(Anderson et al., 2001; Slaugenhaupt et al., 2001).
From the time of birth onwards there are difficulties
with feeding, episodes of unexplained fever and pneumonia, and a failure to thrive. Because of the defective
lacrimation there is cornea ulceration and absent corneal
reflexes. There are periods of unstable blood pressure
with episodes of hypertension, unstable body temperature,
profuse sweating, sialorrhea, an initial delay in mental
development followed by a subsequent achievement
of intellectual parity with ones peers, and an inability
to taste food. Strong emotions, whether pleasant
or distressing, frequently lead to episodes of loss of
consciousness. There is stunted growth and an inability
to feel pain, hot or cold. There is a loss of sympathetic
and parasympathetic ganglion cells and, to a lesser degree,
of the nerve cells in the sensory ganglia. There is also
an abnormally low concentration of serum dopamine
-hydroxylase, the enzyme that converts dopamine into
norepinephrine. About 25% of afflicted children are dead
by the age of 10 years. Approximately 50% survive until
the age of 20 years (Mancini, 1990). In the cytoplasm of
the neurons of the SON and PVN unusually large vacuoles
have been found (rbeck and Oftedal, 1977), which
encourage systematic hypothalamic investigations.
Congenital insensitivity to pain with anhidrosis is an
autosomal-recessive disorder characterized by recurrent
episodes of unexplained fever, absence of sweating and
of reaction to noxious stimuli, self mutilatory behavior
and mental retardation. Most probably this syndrome is
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based upon mutations in the tyrosine kinase (Trk)A

neurotrophin receptor (Indo et al., 1996). The hypothalamic involvement is not clear.
Autonomic failure with orthostatic hypotension and
nocturia has many possible causes (Mathias et al., 1986;
Chapter 22.4); but it has been successfully treated with
desmopressin (Kallas et al., 1999).
30.1. Temperature regulation
It has been known for a long time that hypothalamic
injury may cause disordered temperature regulation.
Cushing (1932, p. 37) stated that On experimental
grounds, a high and abrupt thermic reaction has been
occasionally seen after hypothalamic injuries of various
kinds, and such studies as have been made in this direction by associates have led some of them to believe that
a puncture in the region of the corpora mamillaria is more
likely than any other to produce them. The literature
shows that large lesions in the posterior hypothalamus
may impair heat production, which results in poikilothermia. In addition, hyperthermia, hypothermia or
poikilothermia may occur when the preoptic anterior
hypothalamic area (POAH) is damaged by infarction,
subarachnoid hemorrhage, trauma or surgery. The anterior hypothalamus seems to contain circuits for both heat
production (shivering) and heat dissipation (precapillary
vasodilatation, hyperpnoea) (Rudelli and Deck, 1979).
Animal experiments have shown warmth-sensitive and
cold-sensitive neurons in the POAH and the DBB and that
their discharge rate changes in non-REM sleep. In addition
to disorders of temperature regulation, POAH lesions
cause long-lasting insomnia (see Chapter 30.7a). The
POAH is involved in the regulation of non-REM sleep,
and the sleep regulatory and thermoregulatory mechanisms of the POAH are closely integrated. A number of
factors, including monoamines, steroid hormones, glucose
levels, osmotic pressure, prostoglandines, cytokines and
neuropeptides, can influence the discharge of POAH
temperature-sensitive neurons. The monoamines serotonin
and norepinephrine seem to act as antagonists on the
thermosensitive neurons (Brck and Zeisberger, 1987).
Thermosensitive neurons are found in experimental
animals, not only in the preoptic area, anterior hypothalamus and the DBB (Alam et al., 1995, 1996), but
also in the septum, cortex, midbrain, medulla and
spinal cord (Arancibia et al., 1996). LHRH can elicit
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thermoregulatory skin vasomotion by its action in the

septal area. The vasodilative effect of LHRH may be
related to the etiology of climacteric hot flushes (Hosono
et al., 1997; see also Chapter 11f). Histamine mainly
excites heat-sensitive neurons and causes hypothermia
(Brown et al., 2001). This way the tuberomamillary
nucleus (Chapter 13) is also involved in thermoregulation.
Localization of thermosensitive areas in the human
brain has only been possible by approximation. Because
PVN involvement is reported to be exclusively associated
with temperature elevations in bulbar poliomyelitis, the
PVN is proposed to be an essential structure for lowering
body temperature. In cases of hypothermia in this disease,
lateral and medial hypothalamic nuclei are involved
(Brown et al., 1953; Chapter 20.1). Subnormal temperature has also been reported in a sarcoidosis patient in
which the ventromedial nucleus (VMN) showed the
greatest involvement (Branch et al., 1971). The old
concept that the PVN is exclusively involved in lowering
body temperature does, however, no longer fit with the
knowledge from experimental animals on the autonomous
and endocrine response to a cold environment in which,
e.g. TRH neurons from the PVN are stimulated to activate
the thyroid axis. The old concept of a neural thermostat
located in the anterior and preoptic areas should thus
be replaced by one locating thermoregulation in a number
of integrated neuronal systems (Arancibia et al., 1996).
The PVN projections contain, moreover, e.g. oxytocin,
vasopressin, CRH, TRH and somatostatin. The experimental evidence that vasopressin is an antipyretic
neuropeptide involved in regulating febrile increases
in body temperature by its action on the ventral septal
area, the antipyretic sensitive area of the brain, has
been systematically described (Kasting et al., 1989).
Besides, there are direct projections from the PVN to
autonomic preganglionic neurons controlling the autonomic responses. These projections convey information
to peripheral targets involved in thermogenesis through
the dorsal vagal complex, the spinal cord, and the nucleus
tractus solitarius for parasympathetic and sympathetic
neurotransmissions and sensory transmission, respectively. The sympathetic branch releases norepinephrine,
which induces a rise in both metabolic rate and brown
fat tissue temperature. The parasympathetic vagal stimulation not only leads to temperature changes, but also to
gastric secretion and motor functions, as well as to the
formation of gastric lesions, probably by TRH-containing
fibers in the dorsovagal complex (Arancibia et al., 1996).
In fact, it was Cushing who pointed to the similar central
effects of vasopressin, oxytocin and pilocarpine (1932,

p. 7273), stating:
. . . with a sufficient dose, either of extract or drug, to give
a marked reaction the contrasting colour effect in the forehead is brought out by either intraventricular pilocarpine
or pituitrin (a posterior lobe extract) and also by an intramuscular injection of pilocarpine. On the other hand, the
intramuscular or intravenous injection of pituitrin, as
already pointed out, causes a generalized pallor which
affects the skin of both sides of the forehead alike. Since the
circulation of the bone flap remains intact (Fig. 30.1), this
would appear to indicate that the effects both of pituitrin
and pilocarpine introduced by way of the ventricle are not
exerted on the sweat glands through the medium of the circulating blood or of sympathetic fibres which accompany
arterial blood-vessels [sic], but must be produced by effector
impulses which travel from some higher center along fibers
which accompany the peripheral sensory nerves.
The SCN is responsible for the circadian fluctuations in

temperature (Nagai et al., 1996).
There have been a few reports regarding the thermoregulatory effects of acupuncture. It has been acknowledged
to induce either hyperthermia or hypothermia, depending
on the site of stimulation. Experiments in rat suggest that
the reduction of fever by acupuncture may be mediated by
an increased hypothalamic expression of interleukin-6 and
interleukin-1 (Son et al., 2002).
30.2. Disturbed thermoregulation (Table 30.1)
There are various neuropathological reports indicating
that hypothalamic pathology may lead to disorders of
thermoregulation. Dysthermia has been found as a result
of different hypothalamic disorders, i.e.: malformations;
tumors such as astrocytoma, pinealoma, craniopharyngioma, infundibuloma, angioma and plasmocytoma;
meningoencephalitis; Langerhans cell histiocytosis; and
arteriosclerotic degenerative changes (Bauer, 1954;
Klleffer and Stern, 1970; Haugh and Markesbery, 1983;
Kaltsas et al., 2000; Spiegel et al., 2002). Poikilothermia,
i.e. fluctuations of core temperature of more than 2C
due to changes in ambient temperature, may be present
in patients with hypothalamic strokes, tumors or MS
(MacKenzie et al., 1991; Kurz et al., 1998). In MS patients
who had chronic hypothermia and life-threatening
episodes of acute hypothermia or poikilothermia, a hypothalamic preoptic defect was presumed but not shown
(Sullivan et al., 1987; Kurz et al., 1998). Tourettes
syndrome patients have changes in their ambient thermal
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Fig. 30.1. Showing the vasodilator and suderific effects, sparing the bone flap of a recent operation, of 2.5 mg of pilocarpine injected into
the cerebral ventricles: an intraventricular injection of 1 ml of Pituitrin in susceptible persons gives an equally marked response. (From Cushing,
1932, Fig. 25, p. 58.)
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TABLE 30.1
Neuropathological abnormalities in chronic disorders of central thermoregulation.
Neoplasm
Astrocytoma
Craniopharyngioma
Infundibuloma
Glioblastoma multiforme
Neuroblastoma
Angioma, third ventricle
Facial hemangioma involving the hypothalamus
Pinealoma
Metabolic
Wernickes encephalopathy
Degenerative
Glial scarring, anterior hypothalamus

Parkinsons disease with reduction and shrinkage
of neurons in posterior hypothalamus
Diencephalic idiopathic gliosis
Poliomyelitis
Meningoencephalitis
Syphilitic endarteritis
Multiple sclerosis
Langerhans-cell histiocytosis
Developmental
Malformations
Shapiro syndrome
Hydrocephalus
Encephalocele
Vascular
Infarction
Hemorrhage
Miscellaneous
Granulomatosis
Sarcoidosis
Postneurosurgical
Head trauma
Iatrogenic neuroleptic malignant syndrome
Diazepam
Genetic malignant hypertension
Infections and neuroimmunological disorders
Based upon Martin et al. (1997).
perception and circadian dysregulation, interpreted as

being of hypothalamic origin (Kessler, 2002).
A number of case histories support the central role of
the hypothalamus in temperature regulation. One patient
with hypothermia had hypothalamic hemorrhage caused
by NasuHakola disease (Kobayashi et al., 2000) and
syphilitic endarteritis causing gliosis throughout the
hypothalamus (Fox et al., 1970). Hypothermia has also
been reported in a case of diencephalic idiopathic gliosis
(Espiner et al., 1992). The reason for the extensive gliosis
of the hypothalamus and other diencephalic structures
is not clear. Stress-induced malignant hypothermia
developed from physical and mental stress alone, e.g.
during preoperative excitement, is a seldom-recognized
disorder (Thorley et al., 2001). Periodic hypothermia in
combination with agenesis of the corpus callosum
(Shapiro syndrome) is considered to be based upon a
developmental arrest of the lamina terminalis (Chapter
28.2). In addition, spontaneous periodic hypothermia has
been described when hypothalamic lesions are present
(Nol et al., 1973; Rehman and Atkin, 1999; Chapter
28.2). Neuroleptic malignant syndrome (Chapter 25.2) is

found in psychiatric patients, possibly as a reaction to
neuroleptic drug administration. It is characterized by
disturbances in motor function, sometimes resulting in a
state of catatonic stupor followed by a complete breakdown of autonomic functions with fatal hyperpyrexia
(Kish et al., 1990). In the hypothalamus of one patient
with neuroleptic malignant syndrome a clear lesion was
observed (Horn et al., 1988). In addition, a decreased
hypothalamic norepinephrine content and a loss of
neurons in the NBM have been described in this disorder
(Kish et al., 1990). Malignant hyperthermia is a genetic
disease, mostly with an autosomal dominant pattern. The
incidence is estimated to be 1:50,000. The onset follows
exposure to inhalation anesthesia. The patient may present
with hypertonicity, hyperpyrexia, tachycardia and
tachypnea. The serum levels of creatine kinase are sharply
elevated during attacks, probably due to prolonged muscle
contraction (Guz and Baxter, 1985). Hyperthermia has
also been observed in paraneoplastic limbic encephalitis
(Gultekin et al., 2000). A loss of circadian temperature
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fluctuations may occur in the case of ventricular obstruction with consequent intracranial pressure rise and/or
hydrocephalus (Page et al., 1973). After administration
of diazepam to mothers in labor, thermogenesis of the
child is disturbed. An impaired metabolic response to cold
stress has been observed in these children (Cree et al.,
1973). In such cases a hypothalamic disorder may be
presumed, but has not been shown.
Various hypothalamic areas may be involved in
disturbed temperature regulation. A patient has been
described with selective infarction of the anterior hypothalamus involving the periventricular and medial zone
of the preoptic hypothalamic DBB, and extending into
the septum. In addition, the PVN and SON, infundibular,
dorsomedial and ventromedial nucleus (VMN) were
compromised. The lateral hypothalamic nuclei were
only partially affected, and the mamillary nuclei were
intact. The optic chiasm and tracts showed necrosis.
Hypothalamic infarction in this patient occurred as a result
of traumatic avulsion of part of the optic chiasm together
with the anterior perforating arteries. Symptoms of hypothalamic dysfunction included altered temperature
regulation, alternating diabetes insipidus and inappropriate antidiuretic hormone secretion (see Chapter 22.5),
altered patterns of arousal and changing cardiac arrhythmias, including severe atrial arrhythmias with ventricular
escape rhythms (Rudelli and Deck, 1979). In a young
man suffering from repeated episodes of hypothermia,
who revealed defects in the heat-conserving mechanisms
of peripheral vasoconstriction and shivering, necropsy
showed areas in the anterior hypothalamus of glial scarring with marked hypertrophy of astrocytes and fibrillary
gliosis. The cause of the gliosis was not apparent. An
infantry soldier who had been struck by a mortar shell
fragment and who had hyperthermia, appeared to have
a lesion in the preoptic region (Beaton and Herrman,
1945). In three other cases, widespread damage to the
periventricular gray matter of the third ventricle was
associated with persistent hypothermia. Also, lesions in
the tuberal/medial part of the hypothalamus may lead to
temperature disorders. In one patient there was scarring
of the infundibulum and necrosis of the anterior fornix,
in another, necrosis of the left side of the infundibulum
and purulant ventriculitis, in a third case there was
massive infarction involving the wall of the third ventricle
(Treip, 1970a, b).
The literature has also reported an infant with a benign
facial hemangioma, which developed into a malignant
hemangioendothelioma that spread rapidly into the
359
intracranial cavity by way of the auditory canal to the

hypothalamus and induced hypothermia. The tumor had
invaded and almost completely replaced the posterior and
lateral walls of the uppermost portion of the hypophysial
stalk, the median eminence and the adjacent retroinfundibular part of the hypothalamic VMN. Another
tumor nodule was found in the posterior part of the
hypothalamus, and the tumor had also invaded the lateral
hypothalamic area. The anterior part of the hypothalamus
was unaffected (Sunderman and Haymaker, 1947).
Familial dysautonomia, or the RileyDay syndrome, is
an autosomal hereditary disease with a dysfunction of the
sensory and autonomic system. Apart from impaired
temperature control, the symptoms include diminished
lacrimation, hyperhydrosis, transient skin blotching and
frequent vomiting. For example, in a postmortem study,
subependymal granulations in the walls of the posterior
hypothalamus have been found, indicating some damage
to the ependymal cells. In addition, slight gliosis in the
lateral parts of the hypothalamus have been observed, as
well as in the ventromedial thalamic nucleus, pointing
in the same direction. The striking vacuolation of the
neurons of the PVN and SON is regarded as an indication
of hyperactivity of these nuclei (rbeck and Oftedal,
1977). However, whether this is indeed the case should
be studied by parameters for activation of these neurons
such as vasopressin or oxytocin mRNA, the size of the
nucleoli or the Golgi apparatus (see Chapters 1.5, 8).
For other, related congenital dysautonomias (Alvarez
et al., 1996), no studies of the hypothalamus have been
performed. This also goes for congenital insensitivity to
pain with anhidrosis, an autosomal-recessive disorder
probably based on mutations in the TrkA receptor and
characterized by unexplained episodes of fever, due to
noninnervation of eccrine sweat glands (Indo et al., 1996).
An interesting observation has been made in patients
who, after severe traumatic brain injuries, always feel
cold, while sublingual temperature and thyroid function
are normal. After 4 weeks of lysine vasopressin nasal
spray (Syntopressin) administration, patients have declared
that they do not feel cold anymore. When administration
of the vasopressin spray is discontinued, temperature
perception remains normal (Eames, 1997). It is as yet
not clear how such a short-term treatment can produce a
lasting improvement. Although vasopressin innervation
of the hypothalamus is presumed to be involved in temperature regulation, no data are present on systems involved
in temperature perception. In any case, this effect should
first be repeated in a double-blind experiment.
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In conclusion, there are a number of case histories that

indicate hypothalamic pathology in disorders involving
temperature regulation, but the size of the lesions and
the nature of the disorders do not allow a more precise
indication of which nuclei and circuits of the human
hypothalamus are crucial for this function.
30.3. Cardiovascular regulation
Various hypothalamic nuclei are involved in cardiovascular regulation. The SCN controls the circadian
rhythm of heart rate via the sympathetic nervous system,
as seen in experiments in rats (Warren et al., 1994).
In addition, as shown in human subjects, light has an
instantaneous effect, increasing resting heart rate, most
probably via this hypothalamic structure (Scheer et al.,
1999). In rats it has indeed been shown that light affects
heart rate by means of the SCN, and that this effect
is mediated by a multisynaptic autonomic connection
from the SCN to the heart (Scheer et al., 2001). Animal
experiments have also implicated the DMN and PVN in
the cardiovascular response to stress. Chemical stimulation of the PVN has been reported to elicit tachycardia,
to increase blood pressure and to cause hemodynamic
changes resembling those observed in acute experimental
stress in rats. Furthermore, electrolytic lesions of this
region abolish the cardiovascular response to foot-shock
stress, while inhibition of neurons in the DMN but not
in the PVN suppresses the cardiovascular effects of
stress, suggesting that the DMN is a major site for the
neuronal control of the cardiovascular response to stress
(Stotz-Potter et al., 1996).
CRH is a crucial PVN neuropeptide involved in the
central cardiovascular regulation (Lehnert et al., 1998).
In rat, a decrease in mean arterial pressure activates PVN
neurons that project singly and through collaterals to
the nucleus tractus solitarius and caudal ventrolateral
medulla. This PVN response, as shown on the basis
of the expression of the immediate early gene c-FOS,
plays an important role in blood pressure regulation.
Neuronal nitric oxide may participate in this response
(Krukoff et al., 1997). A positive correlation has been
found between increased oxytocin plasma levels and
increased systolic blood pressure with orgasm in human.
Since oxytocin causes blood pressure rise following
intracisternal administration of oxytocin in dogs, this
observation supports the possibility that oxytocin from
the PVN is involved in the central control of blood
pressure (Carmichael et al., 1994). Moreover, oxytocin

has peripheral cardiorenal effects that are mediated by
oxytocin receptors in the heart and vasculature, and
by the release of atrial natriuretic peptide from the heart
(Gutkowska et al., 2000). Substance P in the hypothalamus generates a pressor response and tachycardia. Since
oxytocin-antisense oligonucleotide attenuated these
responses in rat, oxytocin from the PVN seems to mediate
the increase in blood pressure and heart rate induced by
substance P (Maier et al., 1998). This pathway is thought
to be part of an integrated response to nociceptive stimuli
and stress. In addition, the circumventricular organs
are involved in the maintenance of cardiovascular homeostasis and blood pressure (Chapter 30.5).
Patients with an autonomic failure have an intact
vasopressin response to osmotic stimuli, but a severely
blunted response to a cardiovascular stimulus such as
head-up tilt. This suggests that in man, as in rat, ascending
catecholaminergic pathways are important for the
mediation of the vasopressin response to cardiovascular
stimuli (Lightman and Williams, 1993). In the lateral
hypothalamus, cardiovascular pressor and depressor sites
have been identified that have descending projections
to the brain stem (Allen and Cechetto, 1992). Patients
whose posterior hypothalamus is electrically stimulated
show a rise in blood pressure, tachycardia and maximum
pupillary dilatation. The stimulated area starts in the
posterior medial hypothalamus and almost runs to
the posterior commissure. The area is localized 15 mm
lateral to the wall of the third ventricle, between the
anterior border of the mamillary nucleus and the nucleus
ruber. Stimulation studies in patients have delineated three
zones in the posterior hypothalamus: (i) the innermost,
which show parasympathetic responses; (ii) the medial
zone, 15 mm from the wall of the third ventricle, which
shows sympathetic responses; and (iii) a lateral zone,
which shows parasympathetic responses in the area more
than 5 mm lateral of the third ventricle, where stimulation often causes a fall in blood pressure and bradycardia
(Sano et al., 1966, 1968). The tuberomamillary nucleus
(Chapter 13) is also involved in cardiovascular regulation.
Histamine transiently increases blood pressure and
decreases heart rate (Brown et al., 2001).
30.4. Cardiovascular disturbances
Various cardiac arrhythmias have been described in
intracranial pathology, predominantly in subarachnoid
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hemorrhage, ischemic and hemorrhagic strokes, head

trauma, meningitis and brain tumors, for which hypothalamic lesions or stimulation are at least partly held
responsible (Treip, 1970a, b; Thorley et al., 2001). A
patient with a hypothalamic hamartoma had epilepsy and
ictal bradycardia. Monitoring with an intracranial depth
electrode showed that seizures arising from the tumor
were not associated with a slowing of the heart rate. It
was presumed that not the hypothalamic lesion per se,
but rather the fronto-orbital cortex or amygdalohippocampal complex could be responsible for the cardiac
variations (Kahane et al., 1999). A case of anterior hypothalamic infarction resulted temporarily in uncontrolled
triggering of vagal sinodepressive activity, which allowed
secondary ectopic rhythms (Doshi and Neil-Dwyer, 1977;
Rudelli and Deck, 1979). Hypertension, tachycardia and
mydriasis have been described as a result of stimulation
of the posterior hypothalamus, while destruction of this
region leads to a tendency to decrease sympathicotonia
or an increase in parasympathicotonia (Treip, 1970a, b).
Such mechanisms may be part of the acute hypothalamic
instability in traumatic brain injury (Thorley et al., 2001).
Activation of the sympathetic nervous system is supposed
to be peculiar to the essential hypertensive state (Grassi,
1998). Chronic or repetitive stressful stimuli are presumed
to lead to sustained sympathetic activation and hypertension in susceptible persons (Somers and Mark, 1992).
Paroxysmal hypertension with spontaneous periodic hypothermia has been described in Shapiro syndrome, in
which a developmental defect of the lamina terminalis
is presumed, together with an agenesis of the corpus
callosum (Chapter 28.2), and in diencephalic syndrome
(Chapter 19.4; Connors and Sheikholislam, 1977).
Necrosis of the anterior fornix and infundibular region
results in persistent bradycardia (Treip, 1970a, b),
and bradycardia has been found in a patient with a
hypothalamic lesion following excision of a craniopharyngioma (Rehman and Atkin, 1999). In a patient
with a hypothalamic viral encephalitis, bradycardia was
so severe, i.e. a heart rate of less than 30/min, that a
temporary pacemaker had to be implanted (Ishikawa
et al., 2001b).
In patients who have died of subarachnoid hemorrhage,
small, bilateral diffuse lesions are found in the hypothalamus (Doshi and Neil-Dwyer, 1977). It is proposed
that increased and prolonged sympathetic activity, as
appears from the high blood levels of catecholamines
following subarachnoid hemorrhage, cause spasms of
both blood vessels supplying the hypothalamus and the
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myocardium and thus cause lesions in these two organs.

The high levels of cortisol might have potentiating effects
on blood vessel constriction. Various hypothalamic nuclei
are affected in this disorder. Perivascular hemorrhages
and edema of the surrounding tissues have been observed
in the periventricular region, including the PVN and SON.
Some neurons in the PVN are shrunken and atrophic. In
some cases there is distension of perforating vessels and
vessels with small ball hemorrhages, similar to those
described by Crompton (1963). Some patients show
marked edema of the vessel wall, involving the endothelial cells, with perivascular cuffing by polymorphonuclear
leucocytes in the PVN. The occurrence of microinfarcts
is demonstrated by the presence of fat granule cells and
polymorphonuclear leukocytes. One of the cases with
severe ECG abnormalities showed almost complete
infarction of the hypothalamus. In patients with other
intracranial pathological changes, leading to raised
intracranial pressure, this hypothalamic pathology has not
been observed, so that increased intracranial pressure as
such does not seem to be the cause of this disorder (Doshi
and Neil-Dwyer, 1977).
In the case of orthostatic hypotension, pathological
changes were reported in the posterior hypothalamic area
and nucleus intercallatus of the mamillary body, but also
in many other brain regions (Shy and Drager, 1960).
The possible contribution of vasopressin, the SON and
the PVN in essential hypertension is discussed in Chapter
8.4. Whether the increased vasopressin plasma levels in
essential hypertension (Zhang et al., 1999) are an essential
part of the pathogenetic process or secondary to hypertension is still a matter of controversy (Padfield et al.,
1976). In essential hypertension, the normal circadian
rhythm, i.e. the nocturnal fall in blood pressure
(dippers) is not always found (nondippers) (Pedulla
et al., 1995). The period of circadian rhythmicity is
disturbed in about 30% of hypertensive subjects (Abitbol
et al., 1997; Chapter 8.5). The SCN of patients with
primary hypertension contains about half of the normal
number of vasopressin, VIP and neurotensin neurons
(Goncharuk et al., 2001). These observations indicate that
the SCN is seriously disturbed in its function in essential
hypertension, and the contribution of this structure to
the pathogenesis of hypertension is currently under investigation. The normal circadian rhythmicity of blood
pressure is disrupted in patients affected by Cushings
disease, indicating that glucocorticoids are involved in
the control of this circadian mechanism by the SCN
(Piovesan et al., 1990). In burn-out patients, heart rate is
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increased, and elevated early morning cortisol levels are

observed (De Vente et al., 2003), indicating an increased
amplitude of the circadian rhythm of this hormone.
30.5. Circumventricular organs: lamina terminalis,
subfornical organ and autonomic regulation
Brain tissue is separated from the circulating blood by
the bloodbrain barrier. The brain structures that are
outside the bloodbrain barrier because of the presence
of fenestrations in the capillary endothelium act as
windows through which the brain can receive information
about changes in humoral factors such as circulating
angiotensin II levels.
The organs that have fenestrated capillaries include the
median eminence (Chapter 11a), the neurohypophysis
(Chapters 8 and 22.1), organum vasculosum lamina terminalis (OVLT), subfornical organ (Chapters 30.5a, c) and
the area postrema. The area postrema in the brain stem
mediates actions of vasopressin, which causes sympathicoinhibition and a shift in baroreflex control to lower values.
These effects of vasopressin are mediated by -adrenoreceptor and glutamatergic mechanisms in the nucleus
tractus solitarius. In contrast, angiotensin-II acts on this
structure to blunt baroreflex control of heart rate and to
cause sympathicoexcitation (Hasser et al., 2000). Others
also include the pineal gland (Chapter 4.5) and choroid
plexus (Chapter 17.3) in the circumventricular organs
(Ganong, 2000).
(a) Organum vasculosum lamina terminalis:
experimental data.
The lamina terminalis is an unpaired, rostral midline
membrane that results from the closure of the anterior
neuropore and fusion of the massive lateral plates. This
area thus marks the rostral wall of the proencephalon
(Sarwar, 1989). The lamina terminalis can be subdivided
into a diencephalic (thin-walled) part and a telencephalic
(thickened) part, the boundary between these two being
the commissura anterior (Bruyn, 1977).
Animal experiments have shown that circumventricular
organs are essential for the normal control of hormone
release (e.g. of vasopressin, oxytocin and corticotropin
(ACTH)), sympathetic activation and behaviors (such as
thirst and salt appetite), which collectively contribute to
the maintenance of cardiovascular homeostasis, blood
pressure and body fluid homeostasis. The lamina terminalis is a layer of ependymal cells that forms the rostral
end of the neural tube early in development. Three midline

structures, i.e. the median preoptic nucleus (situated in
the midline between the commissura anterior and the top
of the third ventricle), the subfornical organ and the
OVLT are adjacent to the lamina terminalis. They are
implicated in fluid balance and cardiovascular functions,
and are strongly interconnected. Blood-born angiotensin
II acts on the subfornical organ, OVLT and periventricular
preoptic nuclei to induce water intake, to stimulate vasopressin release and to give a pressor action. Angiotensin
in descending projections from the lamina terminalis
interacts with extracellular norepinephrine to facilitate
vasopressin release from the hypothalamoneurohypophysial system (Johnson and Thurnhorst, 1996). In
addition, osmoreceptors are present in neurons of the
OVLT and subfornical organ that project to the SON and
subserve thirst and vasopressin secretion. The relevance
of these osmoreceptors, as compared to those in the SON
itself, is still in debate (McKinley et al., 1996).
Stimulation of central angiotensin-I receptors in the
OVLT and subfornical organs elicits systemic cardiovascular, neuroendocrine and behavioral actions. Furthermore,
angiotensin II may act as a neurotransmitter or neuromodulator responsible for an elevation in blood pressure
and dipsinogenic control, sodium appetite, natriuresis and
vasopressin release. High levels of circulating angiotensin
II may cause hypertension as a result of their action on
the area postrema and on the anterior portion of the ventral
third ventricle, and spontaneous hypertensive rats have
higher angiotensin II levels in the hypothalamus and
more angiotensin II receptors in the subfornical organ.
The action of angiotensin II on blood pressure may
be mediated by increased salt sensitivity (Muratani et al.,
1996).
. . . the slightly bulging lamina terminalis extends from the
divergent subcallosal gyri to the chiasm inferiorly and anteriorly. In its middle a rhomboid or better pentagonal darker
part is seen, which is surrounded by a delicate frame and
gives off a whitish rod projecting upward. This is the transparent part of the lamina terminalis, which I called fenestra
laminae terminalis. Like most other rudimentary parts,
the fenestral membrane is variably developed. It may be
quite large or of moderate size. In some cases it is, however,
indistinct and less transparent or reduced to a slender
midline gap of variable shape closed by the fenestral
membrane. Whatever its size and development, the lamina
terminalis cerebri is of considerable morphological interest.
Leaving aside the choroid plexus, it is one of the thinnest
structures of the brain wall, but with a reinforcement on its
outer aspect by the firmly attached pia mater (Retzius, 1896,
p. 56, cited by De Divitiis et al., 2002).
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(b) Human data
363
SON. These localizations agree with the effects of

angiotensin II observed in animal experiments on fluid
and electrolyte balance, cardiovascular regulation, and
release of vasopressin, oxytocin, and anterior pituitary
hormones (Allen et al., 1988b). Indeed, angiotensin II
infusion in humans induces increased plasma levels of
both vasopressin and oxytocin (Chiodera et al., 1998b).
Angiotensin-converting enzyme is a peptidyl carboxypeptidase that cleaves the histidyl dipeptide from angiotensin
I to form the vasoactive peptide angiotensin II. This
enzyme, which is capable of local conversion of bloodborne angiotensin I to angiotensin II, is present in
moderate amounts in the hypothalamus in the PVN and
SON. The OVLT, infundibulum and pineal gland display
the highest levels, while the choroid plexus contains only
moderate amounts (Chai et al., 1990).
In the neurons of the lamina terminalis of the fetus,
LHRH has been found from as early as 9 weeks of
gestation onwards (Bugnon et al., 1976; Paulin et al.,
1977; Rance et al., 1994; Duds et al., 2000). LHRH
neurons are already present in the human OVLT of 17
to 26-week-old fetuses (Bugnon et al., 1977; Leonardelli
and Tramu, 1979). Consistent with neurosecretion in the
bloodstream are reports that LHRH, angiotensin-II,
somatostatin and atrial natriuretic peptide-immunoreactive fibers terminate within the OVLT (McKinley and
Oldfield, 1990). The OVLT contains benzodiazepinebinding sites in the human newborn and infant, showing
GABA-mediated inhibitory neurotransmission (Najimi et
al., 2001a); and a dense fiber network containing delta
sleep-inducing peptide is found in the OVLT (Najimi
et al., 2001b). LHRH is colocalized with delta
sleep-inducing peptide (Vallet et al., 1990). In addition,
VIP-binding sites have been observed in this structure
that might well be related to innervation by the SCN.
No differences are found between VIP binding in male
and female individuals, nor between neonates/infants and
adults (Sarrieau et al., 1994), in spite of the fact that the
OVLT has been reported to play a role in the rat estrus
cycle. Sporadically, enlargement, vacuolation and multiplication of nucleoli, indicating increased neuronal
metabolic activity, have been observed in a man with
hypogonadotropic hypogonadism (Ule and Walter, 1983).
The OVLT is almost completely situated in the human

hypothalamus; it is, on average, 8.25 mm long, lying
between the upper edge of the optic chiasm and the lower
edge of the anterior commissure. The OVLT is a thin
sheet of gray matter covered by a pial layer, which is
attached as a wafer-thin membrane to the upper surface
of the optic chiasm and there gives rise to the optic recess
(De Divitiis et al., 2002). The ependymal cells are flattened. The OVLT contains a rich vascular plexus; it
receives its arterial supply from 4 sources: (1) a superior
median source branching from the anterior communicating artery, (2 and 3) two lateral sources from branches
of the anterior cerebral artery, and (4) an inferior median
source ascending from below the optic chiasm. These
sources anastomose, and branches twig off to enter the
pia mater and supply a dense, superficial capillary
network. From this superficial network, a secondary deep
capillary network extends into the body of the OVLT in
the form of sinusoidal capillary loops and coils. The
venous drainage is in a lateral direction to veins from the
adjacent hypothalamus and proceeding to the anterior
cerebral veins. Unlike in other species, fenestrations in
the capillary endothelial cells have not been observed in
the human OVLT. However, the selective entry into the
OVLT and other circumventricular organs of endogenous
iron deposits observed in cases of hemochromatosis and
entry of imbibed silver for cosmetic purposes into the
human OVLT suggest absence of the bloodbrain barrier
(McKinley and Oldfield, 1990). A large concentration of
estrogen receptor--containing astrocytes has been
observed in the OVLT and around the third ventricle
(Donahue et al., 2000). Many glial cells (spongioblasts)
can be seen in the deeper layer of the external zone, and
primitive neurons have been described. From animal
experiments it is concluded that the major input of the
OVLT comes from the subfornical organ, locus coeruleus,
central gray, preoptic area, lateral hypothalamic area
(LHA), DMN and VMN. There are strong projections
from the OVLT to the median preoptic nucleus and the
SON (McKinley and Oldfield, 1990). It has been found
that damage of the lamina terminalis in humans resulting
from tumors, trauma or surgery, has profound effects on
fluid balance (McKinley et al., 1996). In addition, autoradiographic data have shown that angiotensin II binding
is not only present in the human lamina terminalis structures, i.e. the OVLT, but also in the subfornical organ
and median preoptic nucleus, PVN, median eminence and
(c) Subfornical organ

The subfornical organ is situated in the dorsal aspect
of the midline anterior wall of the third ventricle.
Bulging into the third ventricle as a rounded, pearly gray
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translucent nodule of about 1 mm ventral to the junction

of the two fornical columns, this highly vascularized
structure is concealed with the overhanging choroid
plexus. It contains not only many glial cells, but also
neurons and a rich vascularization with fenestrated capillary endothelium. The ependyma of the human subfornical
organ is modified into flattened, squamous cells. Branches
of the anterior cerebral artery and posterior choroidal
artery anastomose to form the capillary network of the
subfornical organ. The capillaries exhibit extensive
perivascular spaces and drain laterally into a wide vein
on each side of the fornix, which eventually leads to
the great cerebral vein. The subfornical organ has
receptors for angiotensin II, which, when stimulated
induce water drinking and vasopressin secretion
(McKinley and Oldfield, 1990). Membrane-bound, waterselective channel aquaporin-4, which in rat is located in
astrocytes, may be involved in central osmoregulation
(Wells, 1998; Badaut et al., 2000). In the rat a large
majority of the subfornical organ neurons respond to
changes in osmolality (Anderson et al., 2000). Animal
experiments indicate, in addition, that there is release of
LHRH, somatostatin or angiotensin II by neurosecretion
into the bloodstream (McKinley and Oldfield, 1990). The
subfornical organ may be involved in the development
of hydrocephalus (Chapter 18.7). On the basis of observations in rats, it is assumed that a circuit involving V1
receptors in the subfornical organ, connecting fibers to
the SCN and vasopressinergic efferents of the SCN may
play a role in mediating the actions of vasopressin in the
maintenance of ethanol tolerance (Lanca et al., 1999).
For the subcommissural organ, see Chapter 18.7.
30.6. Micturition
In experimental animals, three brain areas are specifically
implicated in the control of micturition: the dorsomedial
pontine tegmentum (an area that controls the motor
neurons of the pelvic floor), the periaqueductal gray, and
the POAH. In the cat, stimulation of, e.g. the preoptic
area of the hypothalamus, bed nucleus of the stria terminalis and septal nuclei elicits bladder contractions.
Brouwer (1950) has described two cases of hypothalamic lesions, one in a case of chronic encephalitis,
and one in a circumscribed glioma in which involuntary
micturition was one of the first symptoms of the disease.
The human hypothalamus may indeed play a role in
initiating micturition. Using PET scanning in right-
handed male volunteers, micturition was associated with

increased blood flow in the hypothalamus, the right dorsomedial pontine tegmentum, the periaquaductal gray, and
the right inferior frontal gyrus (Blok et al., 1997).
30.7. Sleep (Figs. 30A and 30B)
O sleep, o gentle sleep/Natures soft nurse, how have
I frightened thee,/that thou no more wilt weigh my
eyelids down/And steep my senses in forgetfulness?. . .
Shakespeare, Part 2, Henry IV, Act III, scene 1,4.
(Fogan, 1989).
A person usually sleeps for approximately 6 h. Shorter

and longer sleep and sleeping pills are associated with
increased mortality. Prospective epidemiological data
have disclosed that men who usually sleep less than 4 h
are 2.8 times as likely to have died within 6 years of the
start of the investigation than men who report 7.07.9 h
of sleep. The ratio for women is 1.48. Men and women
who report more than 10 h of sleep had about 1.8 times
the mortality of those who reported 7.07.9 h of sleep.
For those using sleeping pills, the figure is a 1.5-timeslarger mortality than in people who have never used
sleeping pills (Kripke et al., 1979, 2002). Another study
could not confirm the relationship between sleep patterns
and survival in elderly subjects. There are, however,
significant correlations between polygraphic sleep criteria
and another operationalization of successful aging, i.e.
cognitive competence. In particular potential predictive
value of REM latency and REM density for cognitive
functioning are observed (Spiegel et al., 1999). Insomnia
is the most commonly encountered sleep disorder. It is
generally reported to be associated with an overall
increase in ACTH and cortisol secretion, which, however,
retain a normal circadian pattern (Vgontzas et al., 2001a).
In a recent study, however, cortisol secretion in primary
insomniacs did not differ from controls (Riemann et al.,
2002). The often-observed activation of the hypothalamopituitaryadrenal (HPA) axis is presumed to make
insomniacs at risk for anxiety and depression (Chapter
26.4), hypertension (Chapter 8.5) and obesity (Chapter
23). In contrast to short or long sleeping times, insomnia
is not found to be associated with an excess mortality
risk (Kripke et al., 2002).
(a) Hypothalamic structures involved in sleep
The SCN is responsible for the circadian aspects of sleep
and neuroendocrine circadian rhythms related to sleep
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Fig. 30A.
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Rustende slaapwandelaarster (resting sleepwalker) IV, 1971. Pyke Koch (19011991). Collectie Frisia Museum, Spanbroek.
penetrance or a multifactorial mode of inheritance

(Ancoli-Israel et al., 2001). A pathogenetic mechanism
of this syndrome may be the hypersensitivity of melatonin
suppression in response to light in the evening (Aoki et
al., 2001). A bright-light mask turned on 4 h before arising
advances the circadian phase and provides clinical benefit
in delayed sleep phase syndrome patients (Cole et al.,
2002a).
A flattening of circadian rhythms is also found in fatal
familial insomnia, a prion disease (Cortelli et al., 1999).
In infantile neuronal ceroid lipofuscinosis, a fragmented,
diurnal sleepwake pattern, with no distinct rhythm, is
found (Kirveskari et al., 2001), pointing to impairment
of the SCN.
Whipples disease is caused by infection with
Tropheryma whippelii, a gram-positive bacillus. A transient fetal abolition of the sleepwake cycle has been
found as a cerebral manifestation of this disease.
Endocrine tests have revealed hypothalamic dysfunction
with flattening of circadian rhythmicity of cortisol,
TSH, growth hormone and melatonin. Cerebrospinal fluid
(Van Cauter and Spiegel, 1997). Hereditary circadian

pacemaker properties are the biological basis for preferring morning or evening activity patterns and wake time
(Duffy et al., 2001; Vink et al., 2001a).
The difference between long sleepers (more than 9 h)
and short sleepers (less than 6 h) is retained under constant
environmental conditions and is thus a property of the
circadian pacemaker (Aeschbach et al., 2002).
A major sleep disorder, showing a phase advance, is
present in SmithMagenis syndrome, which is based on
interstitial deletions of chromosome 17p11.2 (De
Leersnyder et al., 2003; see Chapters 4, 4.5). A familial,
advanced sleep-phase syndrome, a short circadian rhythm
variant, has been described in humans (Jones et al., 1999)
which is due to a missense mutation of the human PER2
gene (Toh et al., 2001; Chapter 4b). In patients with a
delayed sleep phase syndrome, a polymorphism of the
human PER3 gene was found (Ebisawa et al., 2001). The
genetic transmission of this syndrome may take place
both via the paternal and maternal branch and may be
either of an autosomal dominant type with incomplete
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Fig. 30B.
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Zsuszi sleeping (Edma Balzs). Life and Work, published 1998, by Robert, Susan and John Bal*zs. (c) Robert, Susan and John Balzs,
ISBN: 0-9532750-1-9. (With permission.)
hypocretin is reduced, explaining the almost complete

loss of sleep (Voderholzer et al., 2002).
In retinitis pigmentosa patients, a decrease in sleep
quality takes place in an age-dependent manner, pointing
to the degeneration of photoreceptors mediating the photic
input to the SCN (Gordo et al., 2001). In addition, circadian and seasonal factors in sleep-related disorders may
be related to SCN function, such as the observation that
sudden infant death syndrome (SIDS) is more prevalent
in the winter months and typically occurs in the early
morning hours (Cornwell et al., 1998). Poor sleep is
reported in 1020% of the elderly (Asplund, 1999).
During aging the function of the SCN is affected (Chapter
4.3). Since bright light has proven to be effective in the
treatment of sleep maintenance insomnia in the elderly
(Asplund, 1999), the SCN seems to be an important structure in the pathogenesis of this disorder. Moreover,
cognitive processes are involved, since anticipation of an
early time of awakening goes together with an earlier

ACTH release that may facilitate spontaneous wakening
(Born et al., 1999).
The physiology and pathology of the circadian timing
system in relation to sleep and the effects of the pineal
gland hormone melatonin on sleep are discussed in
Chapter 4.5. The importance of endogenous melatonin
for sleep regulation is supported by case histories of
children with a pineal tumor and children that are blind
and have severe sleep disorders. Oral melatonin greatly
improves their sleep (Jan et al., 2001; Cavallo et al.,
2002). There is an association between melatonin levels
and sleep stages. Melatonin levels are at their lowest
during stages 3 and 4, higher in stage 2, and at their
highest in REM sleep. Modulation of melatonin secretion by increased sympathetic activity is suggested
(Luboshitzky et al., 1999). Melatonin does not produce
any sleep benefit in patients with primary insomnia
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(Almeida Montes et al., 2003). It has been proposed that

the onset of nocturnal melatonin secretion initiates the
chain of events that 2 h later leads to the opening of
the sleep gate. Once secretion into the bloodstream
commences, melatonin inhibits the SCN wakefulnessgenerating mechanism. This allows the somnogenic
structures to take over, unopposed by the wakefulness
mechanisms. Melatonin deficiency will thus interfere with
the smooth transition from wake to sleep (Lavie and
Luboshitzky, 1997), and altered circadian melatonin
secretion patterns are accompanied by sleep disorders
(Rodenbeck et al., 1998). In primary insomniacs, melatonin is reduced (Riemann et al., 2002). Changes in
melatonin levels occur in many conditions in which sleep
disorders have been reported. The effects of melatonin
on sleep disorders are discussed in Chapter 4.5c.
Melatonin did not produce any sleep benefit in patients
with primary insomnia (Almeida Montes et al., 2003). It
has been proposed that circadian sleeping disorders that
cannot be treated with bright light and melatonin should
be designated sleepwake schedule disorder disability
(Dagan and Abadi, 2001). The circadian temperature
rhythm provides an important signaling pathway for the
circadian modulation of sleep and wakefulness (Van
Someren, 2000b). In agreement with this idea are the
observations that increased nocturnal core temperature
due to sleeping under an electric blanket may disrupt
sleep (Fletcher et al., 1999), and that warm feet promote
the rapid onset of sleep. Dilatation of blood vessels in
the skin and feet, which increases heat loss at the extremities, is the best physiological predictor for the rapid onset
of sleep (Kruchi et al., 1999). The high nocturnal body
temperature and disturbed sleep in women with primary
dysmenorrhea (Baker et al., 1999) also support this
concept.
Ascending impulses from the brainstem reticular
formation that pass into the posterior hypothalamus are
important for the physiology of sleep. The serotonergic
and norepinephrinergic input to the hypothalamus are
important wake-promoting systems. The serotonergic
input is presumed to be disturbed in African trypanosomiasis, a syndrome accompanied by loss of 24-h
rhythmicity in sleep (Buguet, 1999). Lesions, such as
tumors (see Chapter 19.1) of the posterior hypothalamus,
produce hypersomnia, even up to severe coma. On the
basis of such observations, Wilder Penfield presumed
in the thirties that the indispensable substratum of
consciousness lies outside the cerebral cortex, . . .
probably in the diencephalon (Anderson and Haymaker,
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1974). Sleep-generating cells are presumed to be localized in the basal forebrain and anterior hypothalamus
(Culebras, 1992). Also the classic studies by Von
Economo (1930), about patients dying of encephalitis
lethargica (Chapter 20.2), suggest that lesions of the anterior hypothalamus and basal forebrain cause insomnia
and thus contain a sleep center; whereas lesions of the
posterior hypothalamus and mesencephalic tegmentum
provoke lethargy and hypersomnia and thus contain a
wake center. The 70-year-old hypothesis that a rostral
hypothalamic area is essential for maintaining sleep
has received support from the identification of a group
of sleep-active neurons in the ventrolateral preoptic
(VLPO) region of the rat hypothalamus, just lateral of
the optic chiasm, using c-FOS (Sherin et al., 1996).
The GABAergic and galanin-containing neurons of the
VLPO inhibit serotonergic and norepinephrinergic wakepromoting neurons and in this way facilitate the
sleep-onset process. The VLPO neurons also send
descending fibers to the histaminergic neurons in the
posterior hypothalamus (Salin-Pascual et al, 2001).
The histaminergic neurons of the tuberomamillary
nucleus promote arousal during wakefulness, become less
active during slow-wave sleep and cease firing during
REM sleep. The histaminergic neurons in rat are inhibited during sleep by GABAergic neurons that originate
in the VLPO (Sherin et al., 1996, 1998). Antihistamines
act as H1 receptor antagonists and may induce sleep and
cognitive deficits by their action on these receptors in the
cortex (Tashiro et al., 2002). However, the claim by Gaus
et al. (2002) that the human sexually dimorphic nucleus
of the preoptic area (SDN-POA) (Chapter 5) corresponds
to the VPLO in the rat is very unlikely, because of
its more lateral localization in the rat hypothalamus.
It is likely that sleep-promoting neurons extend beyond
the VLPO region in the preoptic area, and that warmthsensitive neurons in this region are essential in sleep
regulation (McGinty and Szymusiak, 2000). Hypersomnia
has been associated with a bilateral posterior hypothalamic lesion of unknown etiology in a 58-year-old
patient (Eisensehr et al., 2003). The identification of a
disorder of the orexin/hypocretin system in the lateral
hypothalamus/perifornical area as the basis for narcolepsia (Chapter 14a), and for primary hypersomnia
(Ebrahim et al., 2003) proves that Von Economo was
correct in concluding that the posterior hypothalamus
contains neurons that are important for wakefulness
(Aldrich and Naylor, 1989; Salin-Pascual et al., 2001;
Chapter 28.4). In contrast to the decreased CSF levels of
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hypocretin in narcolepsy, increased CSF hypocretin levels

are found in restless legs syndrome, especially in the
early-onset form of this sleep disorder (Allen et al., 2002).
One study indicates that plasma orexin-A levels are
decreased in sleep apnea syndrome (Nishijima et al.,
2003).
Animal experimental studies have confirmed that the
basal forebrain nuclei are important sites of sleepwake
regulation. Arousal-related functions are mediated by
this system of magnocellular cholinergic neurons, which
project monosynaptically to the entire neocortex and
participate not only in cognitive processes, but also in
the regulation of activated EEG patterns characteristic of
waking and REM sleep (see Chapter 2). Neurons that
display elevated discharge rates during transitions
from waking to sleep and during non-REM sleep have
been recorded in basal forebrain sites, where electrical
stimulation evokes sleep and experimental lesions cause
insomnia. Afferents to the basal forebrain from hypothalamic and brainstem regions are functionally important
for sleepwake regulation. Inputs from thermosensitive
neurons in the anterior hypothalamus modulate the
activity of the basal forebrain sleep- and arousal-related
cell types (Szymusiak, 1995). Slow-wave sleep requires
low acetylcholine concentrations in the brain, whereas
REM sleep is associated with high levels of acetylcholine
(DeLecea et al., 1996), and cholinergic compounds induce
REM sleep (Riemann et al., 1994).
(b) Neuroendocrine changes in sleep
Endocrine changes during sleep and the effects of
hormones on sleep indicate the involvement of the hypothalamus in sleep. TSH, melatonin (Chapter 4.5), ACTH
and cortisol (Chapter 4.1a), prolactin and growth hormone
all have their typical 24-h profiles (Van Cauter and
Spiegel, 1997), pointing to a role of the SCN in their
regulation. Growth hormone, prolactin, LH and FSH are
all secreted in large amounts during sleep, whereas TSH
and cortisol secretion are reduced during the first half of
the sleep period (Luboshitzky, 2000). Serum prolactin
levels exhibit an episodic release pattern with 515 secretory episodes per day. The amplitude of these pulses
increases within 6090 min after the onset of sleep,
occurring primarily during non-REM sleep periods, in
both men and women. The diurnal secretion of prolactin
seems to be sleep-induced, rather than induced by an
inherent diurnal rhythm (Ben-Jonathan and Hnasko,
2001). HPA activity is inhibited with the first nocturnal
periods of slow-wave (deep) sleep in humans, probably

under control of the SCN (Kalsbeek et al., 1992). Both
CRH and cortisol stimulate arousal/wakefulness and
inhibit slow-wave sleep (Vgontzas et al., 2001b). Cortisol
and ACTH levels have their nadir in the early hours of
nocturnal sleep. During late sleep, dominated by REM
sleep, HPA secretory activity reaches high levels. Salivary
free cortisol shows a marked increase following awakening, peaking at about 30 min, and subsequently declines
over the remainder of the day. Those subjects who awake
the earliest have higher levels of cortisol during the
45 min following awakening, as well as throughout
the rest of the day. They also show a more marked decline
(Edwards et al., 2001). This rhythm is supposed to
primarily reflect the activity of the SCN (Chapter 4)
but it is strengthened by sleep. The nocturnal inhibition
of the HPA axis disappears after blockade of mineralocorticoid receptors, which suggests that sleep exerts its
influence via the hippocampus or another structure that
has these receptors. The mineralocorticoid-expressing
cells seem to be simultaneously involved in the generation
of slow-wave sleep. Dysfunction of the described
neuroendocrine mode of regulation during early sleep is
present in patients with Cushings disease, in patients
with severe depression, in aged humans and in insomnia.
All of these groups show insufficient inhibition of HPA
secretory activity during early sleep and reduced slowwave sleep (Born et al., 1997; Born and Fehm, 1998;
Rodenbeck and Hajak, 2001). Elevated cortisol secretion
in the evening strongly and positively correlates with the
number of nocturnal awakenings, not only in insomniacs
but also in controls, indicating that elevated evening
cortisol levels may be crucial in inducing and maintaining
sleep disturbances (Rodenbeck and Hajak, 2001). Chronic
insomnia is associated with increased activation of ACTH
and cortisol secretion, which may be a risk factor
for anxiety and depression (Vgontzas et al., 2001a).
CRH receptor-1 antagonists have been proposed, therefore, as putative therapeutic drugs for sleep disorders
(Grammatopoulos and Chrousos, 2002). Growth hormonereleasing hormone (GHRH) promotes sleep in the elderly,
but, according to some studies, less efficiently so than in
young subjects (Guldner et al., 1997). The balance
between GHRH and CRH is said to play a key role in
normal and pathological sleep regulation. In young
subjects in that study, GHRH stimulates slow-wave sleep
and growth hormone secretion, and inhibits cortisol
release, whereas CRH has the opposite effect. The GHRH
to CRH ratio changes during aging and depression, which
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may result in sleep disturbances. In another study,

intranasal GHRH has had a coordinating function with
respect to the regulation of sleep processes and hormone
secretion, independent of the subjects age. GHRH
reduced the cortisol nadir in the beginning of sleep,
reduced sleep-induced elevations of GH during early sleep
and increased REM and slow wave sleep (Perras et al.,
1999b). Galanin, growth hormone-releasing peptide and
neuropeptide Y also promote sleep. In elderly subjects
sleep deteriorates after acute administration of somatostatin but improves after chronic treatment with
vasopressin (Steiger and Holsboer, 1997). Sustained
elevation of vasopressin levels are associated with a
reduction in REM sleep (Luboshitzky, 2000), but slowwave sleep increases following intranasal vasopressin
administration (Perras et al., 2003). VIP decelerates the
non-REM/REM cycle and advances the occurrence of
the cortisol nadir (Steiger and Holsboer, 1997). Growth
hormone secretion increases during the first two nonREM/REM sleep cycles. Sleep pathologies such as
obstructive sleep apnea syndrome, narcolepsia and
trypanosomiasis alter the 24-h growth hormone profiles.
Subjects with growth hormone disturbances due to
isolated growth hormone deficiency or acromegalics with
excess of growth hormone have abnormal REM and delta
sleep. Normalization of the growth hormone levels is
followed by correction of sleep stages, indicating that
there is not only an effect of sleep on growth hormone
release, but also an effect of growth hormone on sleep
(strm, 1995). In pubertal children the magnitude of the
nocturnal pulses of LH and FSH is increased during sleep.
As the child enters adulthood, the daytime pulse amplitude
increases also, eliminating the diurnal rhythm in LH and
FSH. In adult men, testosterone secretion reveals a
marked diurnal rhythm, with maximum levels during the
early morning and minimum levels in the late evening.
Testosterone levels rise approximately 90 min before the
first REM period, which supports the role of testosterone
in REM-associated penile tumescence. In elderly men the
diurnal testosterone rhythm disappears, although mean
levels and pulsatile secretory patterns are unchanged
(Luboshitzky, 2000). Two hormones that progressively
increase in pregnancy and affect sleep are progesterone
and estrogen. Progesterone has a sedative effect and
induces a shortening of the latency to sleep onset and
reduces wakefulness after sleep onset. Progesterone
primarily affects non-REM sleep. Estrogens suppress
REM sleep in rats, but enhance REM sleep in humans,
increase the amount of sleep and decrease the latency to
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REM sleep. The effects of sex hormones on sleep may

be responsible for at least some of the differences in sleep
between genders (Manber and Armitage, 1999; Santiago
et al., 2001).
One of the few compounds that has fulfilled every
proposed criterion as a sleep-regulatory substance is
interleukin-1 (IL-1). Administration of this compound
induces non-REM sleep. Interestingly, IL-1 induces a
release of growth hormone via a hypothalamic mechanism, and growth hormone release is coupled to non-REM
sleep (Krueger and Obl, 1997). In connection with these
observations one may wonder what IL-1 located in
the hypothalamoneurohypophysial system (Huitinga et al.,
2000a) may contribute to the physiology of sleep.
(c) Sleep and aging
As many as 40% of elderly people complain about sleep
disturbances. The relationship of these disorders to the
age-related changes in the SCN is discussed in Chapter
4.3. Because of the importance of the retinohypothalamic
tract for entrainment of circadian rhythms (Chapter 4b),
it is understandable that older adults reporting visual
impairment are also likely to report sleep complaints (Zizi
et al., 2002). Elderly people spend less time in slow-wave
and REM sleep (Vitiello, 1997). In elderly people a
decline in slow-wave and REM sleep and a decrease in
growth hormone secretion is found, while the cortisol
nadir increases as a function of age (Kern et al., 1996;
Cauter et al., 2000). Middle-aged men show increased
vulnerability of sleep to stress hormones such as CRH
and glucocorticoids, possibly resulting in impairments in
the quality of sleep during periods of emotional stress
(Vgontzas et al., 2001b). Age-related alterations in
nocturnal wake time and daytime sleepiness are associated
with elevations of both plasma interleukin-6 and cortisol
concentrations, but REM sleep decline is primarily associated with cortisol increases (Vgontzas et al., 2003).
Sleep-endocrine changes typically associated with major
depression, namely a reduction in sleep continuity and
slow-wave sleep, and an increase in REM density, are
most prominent in postmenopausal women (Antonijevic
et al., 2003). Although sleep disturbances in elderly
people are often multifactorial, melatonin may be useful
in the treatment of the circadian disturbances (Gentili and
Edinger, 1999) (see Chapter 4.5). Sleep may alter the
symptoms of a neurological disease. In Parkinsons
disease, for example, tremor and rigidity disappear during
sleep by sleep hypotonia or REM sleep atonia (Van
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Someren et al., 1993; Autret, 1997). Alleviation of symptoms during sleep also occurs in migraine (see Chapter
31.2), as well as many other neurological disorders
(Autret, 1997).
(d) Sleep in neurological and other disorders
After resection of hypothalamic/pituitary tumors, children
are at risk to develop hypersomnolence. The often-severe
daytime sleepiness is not the result of inappropriate
hormone replacement (Snow et al., 2002).
Many brain diseases are accompanied by sleep disturbances (Autret et al., 2001). Insomnia, a significant
reduction in sleep duration, may be found in, e.g. neurodegenerative diseases. Patients with Parkinsons disease
run a higher risk of insomnia, parasomnias, nightmares
and excessive daytime somnolence. The sleep disorders
correlate with increased severity of the disease (Chapter
29.3; Larsen and Tandberg, 2001; Kumar et al., 2002).
An MS patient with a hypothalamic plaque developed
acute hypersomnia, accompanied by indetectable CSF
hypocretin levels (Iseki et al., 2002). Patients with retinitis
pigmentosa have daytime sleepiness, reduced alertness
and more disturbed night-time sleep of poorer quality
than normally sighted counterparts, suggesting an influence of photoreceptor degeneration on the circadian cycle
(Ionescu et al., 2001). Sleep disturbances in Alzheimer
patients are discussed in Chapter 4.3c; symptomatic
narcolepsia is discussed in Chapter 28.4; and the
circadian disturbances in sleep patterns in Chapter 4.3.
Delayed-sleep disorder, which is considered to be due to
alterations in the function of the circadian system, has
been reported following traumatic brain injury. The sleep
delay of half a day was successfully treated with melatonin (Nagtegaal et al., 1997). In addition, a lack of REM
sleep has been reported in hypothalamic injury following
excision of a craniopharyngioma (Rehman and Atkin,
1999). Familial fatal insomnia is an autosomal-dominant
prion disease characterized by a prominent degeneration
of the thalamus and involving impaired control of
the sleepwake cycle and of autonomic and endocrine
function (see Chapter 4b; Autret, 1997; Parkes, 1999). A
SPECT study has provided the first in vivo evidence
that a reduction in serotonin transporter is present in
this disorder (Klppel et al., 2002). The claim that the
hypothalamic nuclei, including the supraoptic, paraventricular, suprachiasmatic and posterior nuclei were normal
(Lugaresi et al., 1986), should be investigated with
modern quantitative, functional anatomical techniques.
Chronic secondary hypertension and loss of the physiological nocturnal decrease in blood pressure are found,
together with hypercortisolism and abnormal secretory
patterns of growth hormone, prolactin and melatonin.
Advanced stages are invariably characterized by the
disappearance of any circadian autonomic and neuroendocrine rhythmicity (Avoni et al., 1991; Montagna et al.,
1995), indicating that the SCN is affected. One study
showed that the number of serotonin-producing neurons
in the medial raphe nucleus was increased, indicating
that the input to the SCN may have been altered in this
disorder (Wanschitz et al., 2000). The SCN appeared to
be affected in primary hypertension (Goncharuk et al.,
2001).
Sleep disorders have been reported in approximately
80% of Tourettes syndrome patients. Since these patients
also have abnormal growth hormone release following
administration of naxolone, it has been proposed that
abnormalities of the hypothalamic-mediated control
mechanism of sleep involving the intrinsic opioids
may account for the sleep disturbances (Sandyk et al.,
1987). SmithMajor syndrome is characterized by mental
retardation, aggression, tantrums and serious sleep disturbances. The circadian melatonin secretion is completely
inverted, showing a peak around mid-day (De Leersnyder
et al., 2001, 2003). Sleep apnea is more prevalent in
(neuro)endocrine diseases such as acromegaly, Cushings
disease and syndrome, hypothyroidism and diabetes
mellitus. The question whether changes in growth hormone
and IGF-I levels are involved in the pathogenetic
mechanism of sleep apne is unresolved. REM sleep abnormalities have been found in children at high risk for SIDS,
which may be indicative of a pervasive CNS immaturity
(Cornwell et al., 1998). Sleep problems are, moreover,
extremely common in children with mental handicaps or
learning disabilities (Quine, 1991; Wiggs and Stores,
1996; Hoban, 2000; Chapter 26.5). Some 51% of children
with a mental handicap have sleeping problems and 67%
have problems with waking up. These problems tend to
be very persistent (Quine, 1991). Sleeping problems
in children with developmental handicaps may react
favorably to melatonin treatment (Gordan, 2000; Dodge
and Wilson, 2001; see Chapter 4.5c). Children with
attention-deficit hyperactivity disorder (ADHD) have
greater difficulties with sleeping than children who
develop according to the norm (Ball, 1997).
Primary dysmenorrhea is characterized by painful
uterine cramps near and during menstruation. Women
suffering from primary dysmenorrhea have disturbed
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sleep patterns even before menstruation and in the absence

of pain. In addition, nocturnal body temperature and
estrogen levels are different compared with controls.
When the body temperature is high, less REM sleep
occurs, implying that REM sleep is sensitive to elevated
body temperatures (Baker et al., 1999).
Astronauts experience circadian alterations (Chapter 4)
and shorter, more disturbed sleep during space flights.
Also, the structure of their sleep is significantly different
in that a decreased amount of delta sleep is observed.
Also, the latency to the first REM period is shorter and
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slow-wave sleep redistributed from the first to the second

sleep cycle (Gundel et al., 1997; Monk et al., 1998).
Periodic insomnolence in KleineLevin syndrome
(Gadoth et al., 2001) is described in Chapter 28.1. For
sleep disturbances in PraderWilli syndrome, see Chapter
23.1. Interestingly, in contrast to all the disorders that
cause sleeping problems, patients with prolactinomas
sleep subjectively well. These patients spend more time
in slow-wave sleep (Frieboes et al., 1998). Hypersomnia
has been found in patients with paraneoplastic limbic
encephalitis (Gultekin et al., 2000; Chapter 32.1).
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CHAPTER 31
Pain and addiction
-endorphin and -lipotropic hormone (LPH) (Bloch

et al., 1978).
i(ii) The most recently discovered class of endogenous
opioid peptides consists of derivates of the 256-amino
acid precursor proenkephalin B (PENKB) or prodynorphin (PDYN) and coded for the pre-PDYN
gene. Cleavage of PDYN yields three main opioid
peptides, i.e. neoendorphin, dynorphin A, and
dynorphin B, all of which contain the sequence
leu-enkephalin (Sukhov et al., 1995). Leu-enkephalin
regulates the gonadal axis and, in the medial preoptic
area infundibular/median eminence region, leuenkephalin neurons and many leu-enkephalin fibers
seem to terminate on luteinizing hormone-releasing
hormone (LHRH) neurons (Duds and Merchenthaler,
2003). Neoendorphin can exhibit two different forms,
-neoendorphin and -neoendorphin, which differ
by only one amino acid (Sukhov et al., 1995; Hurd,
1996). The best-known cleavage products of dynorphin A are two smaller fragments, DYN A18, and
DYN A117. Processing of dynorphin B (DYNB)
can produce the 29-amino acid peptide leumorphin
or dymorphin B113 (Sukhov et al., 1995). Transcutaneous electrical nerve stimulation (TENS)
induces a release of dynorphin and is very effective
in ameliorating the withdrawal syndrome in heroin
addicts (Wu et al., 1999). Pre-PDYN gene expression
is found in neurons of the dorsomedial nucleus,
ventromedial nucleus (VMN), tuberomamillary
nucleus, caudal lateral hypothalamus, retrochiasmatic
area and in the bed nucleus of the stria terminalis
(Fig. 31.2AF; Sukhov et al., 1995). Abe et al.
(1988) have found dynorphin staining neurons
mainly in the supraoptic nucleus (SON), paraventricular nucleus (PVN), supramamillary nucleus and
31.1. Opioid peptides and other addictive

compounds
The opiate systems are a major factor in pain perception
and addiction. Moreover, these systems are involved in
a wide variety of neural functions, including eating,
drinking, reproduction, stress, emotions, learning and
homeostasis. The opiate systems are also supposed to be
involved in a number of placebo effects (Stefano et al.,
2001; Chapter 31.2b). Four different classes of opioid
peptides are distinguished: (i) -endorphins, (ii) dynorphins, (iii) enkephalins, and (iv) the orphanin peptide
system. They are synthesized by different genes, with
different precursor molecules:
ii(i) Pro-opiomelanocortin (POMC) is a 267-amino acid
peptide. It yields a group of opioid peptides, the
-endorphins, corticotropin (ACTH)- and MSHlike peptides (Fig. 23.21). The maturation and
cleavage into its various products are area-specific
and post-translational processing plays a crucial
role in determining the biological activity of the
POMC derivates. Patients with POMC mutations
leading to a lack of ACTH, -melanotropin (MSH)
and -endorphin show severe early-onset obesity
(Chapter 23.d), but no unusual pain sensation,
which points to only a minor role of -endorphin
in the modulation of pain (Krude and Grters,
2000). Of the three opioid systems, pre-POMC
neurons have the most restricted distribution and
are the most numerous in the infundibular nucleus
and retrochiasmatic area of the mediobasal hypothalamus (Sukhov et al., 1995; Fig. 31.1AC). In
the adult infundibular nucleus, the same neurons
stain for -endorphin ACTH, MSH, MSH,
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lateral hypothalamus, while a few positive cells have

been found in the arcuate nucleus.
(iii) Enkephalins are also produced by the 267-amino acid
precursor PENK. All cleavage products, including 4
metenkephalins, 2-carboxyl-extended metenkephalins
and one leu-enkephalin, exhibit opioid activity.
The opioid peptides are concentrated heavily in the
hypothalamus (Sukhov et al., 1995). Pre-PDYN
neurons are especially abundant in neurons of the
tuberal and mamillary regions, with a distinct
population of labeled cells in the premamillary
nucleus and dorsal posterior hypothalamus (Sukhov
et al., 1995). Pre-PENK neurons occur in varying
numbers in all hypothalamic nuclei except the mamillary bodies. The chiasmatic area is particularly rich
in pre-PENK neurons, with the highest packing
density in the sexually dimorphic nucleus of the preoptic area (SDN-POA). Simerly et al. (1988) found
more enkephalin neurons in the POA of the male rat.
Sexual dimorphism in the number of enkephalin
neurons in the human SDN-POA has yet to be
elucidated. In addition, pre-PENK neurons are
found in the dorsal suprachiasmatic nucleus, medial
preoptic area and rostral lateral hypothalamic area.
Pre-PENK neurons are numerous in the infundibular
nucleus, VMN, dorsomedial nucleus, caudal parvicellular neurons of the PVN, tuberomamillary
nucleus, lateral hypothalamus and retrochiasmatic
area, nucleus basalis of Meynert (NBM), and in the
bed nucleus of the stria terminalis (Fig. 31.3AF)
(Sukhov et al., 1995).
(iv) The orphanin peptides are structurally related to the
endogenous opioid family. The opioid receptor-like
receptor (ORL1) binds an endogenous ligand, a
heptadecapeptide, referred to as nociceptin or
orphanin. Orphanin has an amino acid sequence
strikingly similar to the endogenous opioid dynorphin, and may play a role in stress and pain systems.
Human ORL1 and orphanin expression are observed
in the hypothalamus from 16 weeks of gestation
Fig. 31.1. AC: Computer-assisted maps of the distribution of proopiomelanocortin (POMC) cells in coronal sections of human
hypothalamus arranged rostrocaudally from A to C. Each dot represents a single neuron. Numbers at the lower left correspond to sequential
locations of sections from anterior to posterior. Each section is 20 m
thick; hence, the distance between A and C is approx. 4.6 mm. Scale
bar 5 mm. (From Sukhov et al., 1995, Fig. 1, with permission.)
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Fig. 31.2. AF: Computer-assisted maps of the distribution of prodynorphin (PDYN) cells in coronal sections of human hypothalamus arranged
rostrocaudally from A to F. The most anterior section is A, and the most posterior section is F. Numbers at the lower left correspond to sequential
locations of sections from anterior to posterior. Each section is 20 m thick. Each dot represents a single neuron. Scale bar 5 mm. (From Sukhov
et al., 1995, Fig. 4, with permission.)
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Fig. 31.3. AF: Computer-assisted maps of the distribution of proenkephalin (PENK) cells in coronal sections of the human hypothalamus. The
most anterior section is A, and the most posterior section is F. Each dot represents a single neuron. Numbers at the lower left correspond to
sequential locations of sections from anterior to posterior. Each section is 20 m thick. Scale bar 5 mm. (From Sukhov et al., 1995, Fig. 7, with
permission.)
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onwards. Prepro-orphanin mRNA is present in this

fetal stage in the PVN and dorsal hypothalamic area.
By 2122 weeks it is present in the zona incerta,
mamillary bodies and subthalamic nucleus. At this
stage, expression of ORL1 messenger RNA (mRNA)
is found in the dorsomedial and ventromedial
hypothalamus, and in the PVN (Neal et al., 2001).
The human opioid receptor in present in the postmortem hypothalamus and a number of other brain
areas (Becker et al., 2003).
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numerous homeostatic functions and euphoria (Sukhov

et al., 1995). Endogenous opioid peptides inhibit the
hypothalamopituitaryadrenal (HPA) axis. This system is
hyperactive in depression (see Chapter 26.4). Using an
intravenous bolus injection of naloxone, a reduced
endogenous opioid tone is found that may explain why
some depressed patients self-medicate with opiates
(Burnett et al., 1999).
The hypothalamic opiate systems are presumed to play
a central role in addictive behavior (Sukhov et al., 1995;
Hurd, 1996). Studies on twins, adopted children and crossfostering also indicate that, apart from environmental
factors, there are also hereditary determinants for alcohol
dependency. The observation that individuals from
families with a high occurrence of alcohol dependency
are more sensitive to naloxone seems to imply that families with a history of alcohol dependency have diminished
endogenous hypothalamic opioid activity. In addition,
there are differences in the HPA axis dynamics as a
function of family history of alcoholism (Wand et al.,
1998). At first glance, the older observations of the influence of stereotactic hypothalamotomy on alcohol and drug
addiction (Dieckmann and Schneider, 1978) seem to be
of interest, in connection with the possible involvement
of hypothalamic systems in addiction. In a 2- to 3-year
follow-up of 13 patients addicted to alcohol and drugs,
the VMN was lesioned. The patients regained their selfcontrol and tended toward social stabilization. However,
this was an uncontrolled study. In the case of bilateral
hypothalamotomy (in 6 of 15 patients), the number of
side effects was considerable, including one patient who
died in a vegetative crisis. All patients experienced a
reduction of their sexual drive. The practical utility of
bilateral hypothalatomy is euphemistically judged to be
limited (Dieckmann and Schneider, 1977). In a totally
insufficiently documented study, Ndvornik et al. (1977)
have reported that bilateral anterior hypothalectomy is
quite effective in the treatment of hedonistic manifestations such as toxicomania and alcoholism. Little
attention was paid to the considerable risk of this operation (Sramka and Ndvornik, 1975), and even less to its
questionable ethical basis.
Analgesia by electrostimulation, using deep brain
electrodes, is presumed to act via the opioid system,
since it is associated with elevation of enkephalin and
-endorphin in the CSF of the third ventricle and because
the analgesic effect could be blocked by naloxone (see
Chapter 31.2). Transcutaneous cranial electric stimulation
has been used for the attenuation of drug and alcohol
The POMC neurons (Fig. 31.1), located in the mediobasal

hypothalamus, have an inhibitory influence on the regulation of gonadotropin secretion (Sukhov et al., 1995).
There is a cyclic -endorphin release into the portal
capillaries, and naloxan stimulates LHRH release. It has
therefore been postulated that -endorphin is an important determinant of the menstrual cycle (Ferin et al.,
1984; Gindoff and Ferin, 1987). The observation that in
postmenopausal women POMC mRNA decreases in the
infundibular nucleus (Abel and Rance, 1999) supports
such a tonic inhibitory function of -endorphin on LHRH
release. The effect of opiates on LHRH release from
the adult human hypothalamus has been confirmed
experimentally, using in vitro perfusion of postmortem
mediobasal hypothalamic tissue. Addition of morphine to
the medium reduced the frequency of LHRH pulses,
whereas subsequent addition of the opioid receptor antagonist naloxone restored the frequency. Furthermore,
fetal hypothalamic tissue responded to administration
of naloxone with increased release of LHRH and this
effect was inhibited by simultaneous administration of
-endorphin (Rasmussen, 1992). Leu-enkephalin neurons
are also involved in LHRH regulation, most probably by
directly synaptically contacting the latter neurons (Duds
and Merchenthaler, 2003). In addition, POMC-derived
peptides containing nerve fibers are found in the neural
lobe of the human pituitary. These peptides comprise
ACTH, -MSH, -endorphin and N-acetyl--endorphin,
and may be involved in the regulation of oxytocin and
vasopressin release (Manning et al., 1993; see Chapter
8d). A large number of neurons in the SON and PVN
coexpress dynorphin; these neurosecretory neurons
are probably the source of the dynorphin-containing
nerve fibers in the neurohypophysis (Abe et al., 1988).
The strikingly densely packed PDYN neurons of the
premamillary nucleus may be involved in hunger, thirst,
dysphoria and reproduction. PENK neurons are distributed throughout the hypothalamus and may participate in
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abstinence syndrome, the suppression of stress, the attenuation of postoperative pain, the potentiation of morphine
analgesia for patients with chronic pain, the regulation of
biorhythms disturbed by jet lag, and obstetric analgesia.
Since transcutaneous cranial electric stimulation increases
the level of endorphins in the CSF and plasma, while
naloxone antagonizes its effects, it also seems to act via
the opioid system (Limoge et al., 1999).
Neuropeptide FF (NPFF) and neuropeptide AF (NPAF)
are two amidated peptides, highly concentrated in the
posterior pituitary and hypothalamus, but also present in
other brain areas. They are derived from one precursor.
These peptides may be involved in pain modulation,
memory, autonomic and neuroendocrine regulation, i.e.
in water balance and prolactin release. In addition, NPFF
probably circulates as a hormone. The NPFF receptors
are coupled to a G protein. Intracerebroventricular injection of NPFF induces a vigorous abstinence syndrome in
morphine-tolerant rats (Boersma et al., 1993; Panula et
al., 1996, 1999; Laemmle et al., 2003).
A new hypothalamic peptide that may be involved in
drug abuse is cocaine- and amphetamine-regulated transcript (CART; Kuhar and Dall Vechia, 1999). For
distribution and its possible role in feeding behavior, see
Chapter 23c).
Marijuana (Cannabis sativa) has long been recognized
as a centrally acting cannabinoid with complex cognitive,
behavioral and endocrine effects. The cannabinoid
receptor is found in the hippocampal complex, in
the cortex of the frontal lobe, mediodorsal nucleus of the
thalamus, globus pallidus and substantia nigra. In
the hypothalamus the receptor has been observed in the
mamillary body (Glass et al., 1997). The enzyme that
degrades the endocannabinoids is an integral membrane
protein, fatty acid amidohydrolase. Its distribution resembles that of the central cannabinoid receptors. In the
hypothalamus it is present in the mamillary bodies, dorsomedial nucleus and posterior hypothalamic area (Romero
et al., 2002). Exposure of animals to 9-tetrahydrocannabinol (9-THC), which has effects that are similar
to those of the endogenous ligand anandamide, inhibits
gonadotropin, prolactin, growth hormone and thyroidstimulating hormone release, and stimulates the release
of ACTH. Therefore, hypothalamic mechanisms of action
are presumed (Murphy et al., 1998b). Marijuana and THC
affect multiple endocrine systems. A suppressive effect
is seen on the reproductive hormones, prolactin, growth
hormone and the thyroid axis, while the HPA axis is activated. These effects are mediated through CB1 receptor
activation in the hypothalamus. Many of these responses

are, however, lost with chronic administration (Brown
and Dobs, 2002).
Many epidemiological studies have shown that prenatal
exposure to tobacco increases the risk of cognitive
deficits, attention deficit disorder, conduct disorder and
criminal behavior in adulthood (see Chapter 26.9). In
addition, it has been shown that maternal smoking
during pregnancy or childhood increases the risk of the
children becoming smokers, possibly by a direct effect
of nicotine on the developing brain of the child
(Hellstrm-Lindahl and Nordberg, 2002). Polymorphism
in the MAO genes influences smoking habits and nicotine
dependency (Ito et al., 2002).
The effects of ethanol abuse on the hypothalamus are
described in Chapter 29.5. A functional NPY polymorphism (leu7Pro) is a risk factor for alcohol dependency
(Lappalainen et al., 2002).
MDMA (3,4-methylenedioxymethamphetamine, or
ecstasy) causes a release of vasopressin for at least 4 h
and may thus cause hyponatremia characteristic of
the syndrome of inappropriate vasopressin secretion
(Henry et al., 1998; Fallon et al., 2002; Chapter 22.6).
Hyperthermia, an acute and potentially life-threatening
complication associated with the use of ecstasy, results
from an interaction between the hypothalamopituitary
thyroid axis and the sympathetic nervous system (Sprague
et al., 2003).
31.2. Pain and the hypothalamus
Although pain is considered to be a necessary ingredient
for survival, life without any pain occurs in a few rare,
hereditary disorders, i.e. RileyDay syndrome or familial
dysautonomia (Chapter 30) and in a congenital indifference to pain (Mancini, 1990). Insensitivity to pain has
been reported in idiopathic hypothalamic syndrome of
childhood (Chapter 32.1), and as a congenital absence of
pain in a mentally retarded child. The total CSF opioid
activity was raised in this patient, but naloxone failed to
reverse the analgesia (Manfredi et al., 1981). Congenital
insensitivity to pain with anhydrosis is an autosomalrecessive disorder characterized by recurrent episodes of
unexplained fever, absence of sweating and of reaction
to noxious stimuli, and by self-mutilating behavior and
mental retardation. Most probably this syndrome is based
upon defects in the high-affinity neurotrophin receptor
tyrosine kinase A (TrkA) (Indo et al., 1996). Since
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patients affected by POMC mutations reveal no unusual

pain sensation, -endorphin seems to play only a minor
role in pain modulation (Krude and Grters, 2000).
Whether the elevated pain tolerance in patients with
anorexia nervosa, bulimia nervosa and binge-eating
(Raymond et al., 1999) has a hypothalamic basis should
be investigated. A core feature of fibromyalgia is pain, a
syndrome that has many neuroendocrine characteristics
(Chapter 26.8; Dessein et al., 2000).
379
the processing of nociceptive signals are the dorsal

noradrenergic bundle, originating in the locus coeruleus,
the serotonergic fibers that arise in the dorsal and median
raphe nuclei, the dopaminergic pathways of the ventral
tegmentum, and the cholinergic neurons of the NBM. The
dorsal noradrenergic bundle innervates the hypothalamus;
and neurons in the medullary reticular formation project
to the PVN of the hypothalamus via the ventral noradrenergic bundle. In the rat it has been shown that
nociceptive stimuli do not reach the hypothalamus by
indirect multisynaptic pathways only. Thousands of
neurons throughout the length of the spinal cord send
axons directly into the hypothalamus, and many of these
axons carry nociceptive information. Axon collaterals of
these fibers terminate in the lateral hypothalamus, VMN,
periventricular and posterior nuclei. Evidence for similar
connections is present in primates (Giesler et al., 1994).
The long-term antinociceptive effect of massage-like
stroking may be attributed, at least partly, to the oxytocinergic system, as shown in the rat; increased oxytocin
plasma levels and release of oxytocin in the periaqueductal gray matter takes place. Here, the oxytocinergic
fibers interact with the opiate system, where the - and
-receptors especially are involved (Lund et al., 2002).
The hypothalamus-mediated stress response plays a role
in pain chronicity. The PVN coordinates the neuroendocrine, autonomic, emotional and behavioral responses
to pain. The PVN activates the HPA axis and is responsible
for the stress-induced analgesia (Chapman, 1996).
Corticotropin-releasing hormone (CRH) may preferentially play a role in prolonged clinical pain (Lariviere
and Melzack, 2000). Fibromyalgia is characterized by
widespread muscle pain and a hypoactive CRH system
(Chapter 26.8b). CRH levels in CSF are increased in
chronic pain (Nemeroff, 1996), but the origin of CSF-CRH
may be extrahypothalamic (Chapter 26.4). CRH is the
central compound in the stress response and is also a
mediator in the stress-induced analgesia. It has been shown
to produce analgesia by all routes of administration,
including local, systemic and central routes. The majority
of the studies indicate that the pituitary or endogenous
opioids are not necessary for the analgesia that occurs
following intracranial or intravenous administration of
CRH. In the human fetus, a potentially painful procedure
such as prolonged intrauterine needling at 2934 weeks
of gestation is associated with an increase in plasma
cortisol and -endorphin. The hormonal stress response
to invasive procedures suggests (but does not prove)
that the human fetus may feel pain in utero and may
(a) The anatomy of pain; hypothalamic structures and

systems involved
Pain in the brain: are hormones to blame?
G. and R. Blackburn-Munro, 2003.
Pain is an unpleasant sensory and emotional experience

associated with actual or potential tissue damage
(Chapman, 1996). The distribution of the opiate systems
involved in pain regulation is discussed in Chapter 31.1.
The many brain structures and extensive pathways
involved in pain are discussed elsewhere (Ray, 1981; May
et al., 2000). Acute experimental, traumatic pain induction by intracutaneous injection of a minute amount
of ethanol prominently activates the hypothalamus, periaqueductal gray, amygdala and a number of other brain
areas as shown by PET studies. The circuits involving
these structures are responsible for integrating the
endocrine, autonomic, aggressive and defensive reactions
to pain. The metabolic activation of the hypothalamus by
traumatic pain implies that this structure may serve as a
bridge between higher cognitive states and physiological/
emotional responsivity (Hsieh et al., 1996). Also, in a
patient with chronic facial pain, the hypothalamic blood
flow was increased, as was the flow in other pain-related
brain structures (Kupers et al., 2000). Electrical stimulation, not only of the raphe nucleus and periaqueductal
gray, but also of the hypothalamus, produces analgesia
in experimental animals (Carstens, 1986), and medial
hypothalamic stimulation relieves pain also in humans
(see below).
Nociceptive transmission engages both spinoreticular
and spinothalamic pathways. A brainstem structure that
is important in nociception is the parabrachial nucleus.
This structure is seriously affected in Alzheimers disease
(AD) (Parvizi et al., 1998), a disorder in which the experience of affective components of pain in particular is
reduced (Scherder et al., 2003). Systems involved in
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benefit from analgesia or anesthesia (Giannakoulopoulos

et al., 1994).
Chronic pain disorder is characterized by the absence
of any relevant organic pathology, and psychologial
factors have consequently been suggested to have an
important role in the etiology of their disorder. There are
various peptides that have antinociceptive effects in
experimental animals, such as angiotensin II, vasopressin,
CRH, calcitonin, neurotensin, somatostatin, and some of
the opiomelanocortin family. Nociceptive peptides
include substance P and cholecystokinin (Carr and
Lipkowski, 1990; Wahlbeck et al., 1996). Substance P
effects on blood pressure and heart rate seem to be mediated by oxytocin. This is part of an integrated response
to nociceptive stimuli and stress (Maier et al., 1998). In
fibromyalgia, CSF levels of substance P are elevated,
while met-enkephalin levels are low (Pillemer et al., 1997;
see Chapter 26.8b). It has been hypothesized that incomplete degradation of nocipeptide peptides might produce
the pain experienced in chronic pain disorder. However,
so far only higher and not lower plasma vasopressin and
serum osmolality, and an increased CRH level in CSF
have been observed, possibly reflecting the chronic stress
condition of these patients (Nemeroff, 1996; Wahlbeck
et al., 1996). Others did not find alterations in plasma or
CSF vasopressin levels (Olsson et al., 1987). Patients in
a surgical emergency department complaining of pain
have increased plasma vasopressin levels (Kendler et al.,
1978). In addition, increased vasopressin levels are
observed in women with premenstrual pain or primary
dysmenorrhea (kerlund et al., 1979; Strmberg et al.,
1984). A therapeutic effect of an orally active vasopressin
V1a receptor antagonist in the prevention of dysmenorrhea has been published (Brouard et al., 2000; Paranjape
and Thibonnier, 2001). However, another study has failed
to show increased blood levels of vasopressin, finds no
effect of a vasopressin antagonist on menstrual pain, and
is thus unable to confirm the contention that vasopressin
is involved in the etiology of dysmenorrhea (Valentin
et al., 2000).
Sex steroids are thought to be involved in pain sensitivity. In general, women are more sensitive to pain than
men. Pain sensitivity peaks when estrogens are high
(Blackburn-Munro and Blackburn-Munro, 2003).
Melatonin has experimentally been shown to have
profound analgesic effects. Hypocretins (Chapter 28.4)
may also modulate nociception (Blackburn-Munro and
Blackburn-Munro, 2003).
Nerve growth factor causes hyperalgesia and pain

when administered either locally or systematically. In this
connection it may be highly relevant that high levels of
nerve growth factor are found in the CSF of patients with
chronic daily headache and a previous history of migraine
(Sarchielli et al., 2001). A pilot study on the treatment
of Alzheimer patients with nerve growth factor, intracerebroventricularly, had to be stopped because of weight
loss and pain as side effects (Chapter 2.5).
Alzheimer patients experience less-intense pain and
also suffer less from pain than nondemented elderly
people (Scherder and Bouma, 1997, 2001; Scherder
et al., 1999; Scherder, 2000; Scherder and Bouma, 2000a,
b). The primary sensory areas are relatively preserved in
AD (Braak and Braak, 1991). Consequently, AD patients
may still be able to perceive the nature of the pain
and differentiate between dull and sharp pricking pain
(the sensory-discriminative aspects of pain; Treede et al.,
2000). The pain threshold does not appear to be affected
by AD, a suggestion which is supported by a study in
which the pain threshold of AD patients was determined
by the application of peripheral electrical nociceptive
stimuli (Benedetti et al., 1999). Importantly, in contrast
to the pain threshold, Benedetti and co-workers (1999)
observed an increase in pain tolerance in the AD patients.
Pain tolerance concerns the processing of the affectivemotivational aspects of pain (Treede et al., 2000). One
can only speculate about the decrease in the processing
of the affective aspects of pain in AD. One explanation
might be the neuropathology that is present in the
hypothalamus, the medial temporal lobe, the anterior
cingulate gyrus and the prefrontal cortex (Chapter
29.1; Coleman and Flood, 1987; Braak and Braak,
1991). Interestingly, these areas are involved not only in
cognition but also in the processing of the emotional
components of pain (Scherder et al., 2003; Treede et al.,
2000). An affected functioning of these areas might thus
explain the increase in pain tolerance. Alternatively or
additionally, a decrease in experience of the affective
components of pain in AD patients may also be explained
by an increase in the amount of opioid peptides in the
CSF (Muhlbauer et al., 1986) and -endorphin in plasma
(Franceschi et al., 1988; Rolandi et al., 1992) of AD
patients. The influence of AD on -endorphin levels is,
however, equivocal, since Kaiya et al. (1983) and Heilig
et al. (1995) have observed a decreased CSF level of
-endorphin in AD patients.
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(b) Placebo analgesia and other placebo effects
381
that hypothalamic opiate and CCK systems are involved

in these analgesic effects still has to be studied.
It has been proposed that placebo effects can be elicited
by inducing a relaxation response. This is the opposite
of a stress response (see Chapter 8.5), resulting in
decreased metabolism, heart rate, blood pressure and rate
of breathing. Many different methods can be used to elicit
this acquired relaxation response, including progressive
muscle relaxation, meditation, autogenic training, yoga
and repeated physical exercise (Stefano et al., 2001). Yoga
exercise was shown to be accompanied by lower serum
cortisol levels (Kamei et al., 2000b); meditation is
followed by increased plasma melatonin levels during the
night (Tooley et al., 2000). In addition, many forms of
prayer can be used to elicit the relaxation response;
the method may be secular or religious, performed at
rest or during exercise. The opiates and nitric oxide are
hypothesized to be involved in this response. Relaxation
response-based approaches have been demonstrated to be
effective in chronic pain, hypertension, cardiac arrhythmias, insomnia, anxiety, depression, premenstrual
syndrome and infertility (Stefano et al., 2001).
It has been estimated that about 75% of the effectiveness of antidepressants derives from the placebo effect
(De la Fuente-Fernndez et al., 2002). In a PET study
in depressed patients, the clinical improvement was
comparable in both the placebo and the fluorexetine
responder groups. The regions of change in the placebo
group strongly overlapped with those seen in responders
who were administered fluoxetine, including the decrease
in metabolic activity in the hypothalamus and the increase
in activity in the prefrontal cortex. This is of considerable
interest in relation to the hyperactivity of a number of
hypothalamic systems in depression and the hypometabolism found in the prefrontal cortex in this disorder (see
Chapter 26.4). However, the fluoxetine response is
associated with additional changes, which are proposed
to explain the longer period of effectiveness of this
compound compared with placebo (Mayberg et al., 2002).
In a study using quantitative EEG, effective placebo
treatment has induced changes in brain function that
are distinct from those associated with antidepressant
medication (Leuchter et al., 2002). There thus appear to
be similarities as well as differences between placebo and
antidepressant treatment, as far as the mechanism of action
is concerned.
Placebo effects can thus be very specific, and the
specificity seems to depend on the information available
. . . we should learn to maximize the placebo effect inherent

in any active drug that we give to the patient . . .
De La Fuente-Fernndez et al., 2002.
The word placebo (Latin) means I shall please and is

the first word of the church vespers sung for those who
have died. In 12th century Europe the word placebo
was shorthand for those vespers. By 1300 the term had
been adapted in the secular vernacular to mean false
consolidation, since insincere mourners were paid to
sing these placebos. In 1811 placebo was defined as an
epithet given to any medicine meant to please rather than
benefit the patient. The term has kept this negative connotation in medicine as something inactive. Nevertheless,
a placebo response rate of on average 35% is found in
the treatment of conditions such as pain, hypertension,
migraine, seasickness and mood disturbances. Even
higher rates in effectiveness are found in angina pectoris,
asthma, herpes simplex and duodenal ulcers. The placebo
effect seems to represent an innate protective response,
tapping into positive expectations and beliefs of the
patient, and into the dopaminergic reward system. The
placebo effect has been defined as any effect attributable
to a pill, potion, or procedure, but not to its pharmacodynamic or specific properties. Whereas the ingredients
of a placebo preparation may be totally nonspecific, the
effects depend on the information given to the patient
and the expectations of the patient and can be very
specific. The power of placebos can thus be conceptualized as the minds healing power (Stefano et al., 2001;
De La Fuente-Fernndez et al., 2002).
Placebo analgesia represents a situation where the
administration of a substance known to be nonanalgesic
produces an analgesic response. When the subject is told
that the ineffective substance is a hyperalgesic drug, an
increase in pain may occur. Such a negative effect is
called a nacebo effect. The effect of a placebo on pain
is mediated by endogenous opioids, since naloxone can
reverse placebo analgesia. The blockade of cholecystokinin (CCK) receptors potentiate the placebo analgesic
response, suggesting an inhibitory role of CKK in placebo
analgesia. The sites of action of the endogenous opiates
and of interaction of the opiates and CCK are not exactly
clear, but naloxone antagonizes analgesia induced by
stimulation of the periaqueductal gray as it also antagonizes analgesia induced by TENS or acupuncture and by
a placebo (Benedetti and Amanzio, 1997). The possibility
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to the recipient. PET studies have indicated that the

placebo effect in Parkinsons disease is related to the
release of dopamine in the striatum, and to downregulation of the dopamine transporter. Since the nucleus
accumbens is susceptible to placebo-induced dopamine
release in Parkinsons disease, placebos may activate
reward mechanisms. Indeed, placebos can also be
addictive and can cause withdrawal symptoms when
treatment is discontinued (De la Fuente-Fernndez and
Stoessl, 2002).
(c) Analgesia by deep brain electrostimulation,
stereotactic lesions, acupuncture and TENS
Brief periods of stimulation aimed at the fibers of the
pro-opiomelanocortin system produces long-lasting analgesia in patients with chronic pain, e.g. from metastases,
low-back pain, paraplegia, spinal arachnoiditis, spinal
cord injury, thalamic pain, scoliosis, postherpetic
neuralgia, phantom limb pain, arthritis and atypical face
pain (Richardson and Akil. 1977; Akil et al., 1979;
Hosobuchi et al., 1979; Richardson, 1982; Pilcher et al.,
1988). In approximately 60% of patients who had deep
brain electrodes implanted for chronic self-stimulation,
this procedure caused significant relief from pain.
Analgesic brain stimulation has an opioid nature,
because it is associated with elevation of enkephalin and
-endorphin in the third-ventricular fluid, while the analgesic stimulation can be blocked by naloxone. However,
other neurotransmitter systems might also be involved in
this effect. The effects and side effects depend on the
stimulation site:
Stimulation of the basal hypothalamus produces pain
relief with side effects that occur at the level of effective
stimulation, such as flushing, smothering, dizziness
and diplopia. In addition, during stimulation, marked
elevation of blood pressure and pulse rate are obtained.
Endocrine side effects have not been studied.
Stimulation of the inferior septal area produces pain
relief with side effects obtained at hypalgesic stimulation levels, i.e. flushing, nystagmus and tingling
paresthesias.
Stimulation of the superior septal area produces pain
relief, while side effects, i.e. flushing, tingling, nausea
and warmth or heat sensation, occur only at levels well
above those producing pain reduction.
Periventricular gray stimulation in the third ventricle
produces significant pain relief with vertigo, tingling,
and elevation of pulse and blood pressure at levels of

stimulation above those producing pain reduction.
Superior periaqueductal gray stimulation induces pain
relief, while side effects are experienced just above the
level of analgesia. Side effects include oscillopsia,
warmth, flushing, tingling and strabismus.
Inferior periaqueductal gray stimulation causes pain
relief, with more side effects below pain-reduction
levels. The periaquaductal -endorphin-containing
fibers are thought to originate from the basal tuberal
hypothalamus. Stimulation proves most efficacious
with minimal side effects in the superior septal area
and periventricular gray, at the level of the posterior
third ventricle adjacent to the posterior commissure
(Akil et al., 1979; Richardson, 1982; Pilcher et al.,
1988). Others have reported that electrical stimulation
of the posteromedial hypothalamus produces relief of
pain, especially in the case of cancer. It also elevates
-endorphins in the third-ventricular CSF (Sano, 1987).
A thus-far underreported complication of deep brain
stimulation is the development of migraine-like
headaches in approximately 2050% of the patients
(Kumar et al., 1997).
Stereotactic lesions of the posterior hypothalamus relieve
intractable pain due to malignancies and are claimed to
be either not so effective for central pain (Sano, 1987)
or, on the contrary, to give a satisfactory relief of pain
(Fairman, 1973). A marked increase in appetite is noted
as a side effect of such operations (Fairman, 1973). Such
an operation was presumed to lesion not only one of the
main end-stations of the C-fibers and the slow delta-fibers,
but also the portions that exert influences on the specific
sensory system and thus decrease the intensity of volleys
of impulses and change the pattern of impulses which
can be interpreted as pain, especially pain in the case of
cancer, and elevate -endorphins in the third-ventricular
cerebrospinal fluid (Sano, 1987). On the other hand, the
same author had claimed earlier that stimulation of
the posteromedial hypothalamus produces an unpleasant
feeling of fear and horror. The hypothalamus is, therefore,
supposed to be important in the emotional coloring of
pain sensation (Sano et al., 1975).
Electroacupuncture and TENS both release dynorphin
and induce analgesia at 100 Hz, and even more efficiently
by alternating the stimulation between 2 Hz and 100 Hz.
Different kinds of opioid peptides and receptors are
implicated in these effects under different circumstances
(Wu et al., 1999; Han, 2003). A 2-Hz stimulation of a
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classical analgesic acupuncture point (LI4, Hegu) on the

back of the hand activated the hypothalamus as measured
by PET, suggesting that this brain structure may mediate
the analgesic efficacy of acupuncture (Hsieh et al.,
2001). It is interesting to note that in animal experiments
hypothalamic activity is enhanced by electroacupuncture
(Du and Chao, 1976). The positive effects of TENS a
technique frequently used to treat chronic pain and
tactile stimulation are hypothesized to result from
activation of brainstem areas such as the locus coeruleus
and nucleus raphe dorsalis, with subsequent activation
of the hypothalamus. In TENS, electrical pulses applied
to the skin are transmitted to spinal and supraspinal
areas through afferent nerve fibers of the peripheral
nervous system (A- and A- fibers) (Scherder et al.,
1995a, b, 1996). Histamine, produced in the tuberomamillary nucleus (Chapter 13) plays an important
role in antinociception, both by naloxone-sensitive and
naloxone-insensitive mechanisms. Histamine is a mediator of the stress-induced release of hormones such as
ACTH and -endorphin, and the release of noradrenaline
and serotonin (Brown et al., 2001).
383
systemic autonomic symptoms such as alteration in blood

pressure and heart rate are found. MR images show a
marked dilation of the ophthalmic artery, ipsilateral to
the pain (Dodick et al., 2000), while a localized narrowing
of the internal carotid artery is found (Goadsby, 2002).
Cluster headache has been differentiated into an upper
and a lower syndrome. It is proposed that changes in
hypothalamic activity may lead, posteroinferiorly, to
activation of the caudal part of the spinal trigeminal
nucleus by way of the hypothalamus, midbrain and
trigeminal nerve fibers, and consequently to activation of
the trigeminovascular system, with a different location
for the two syndromes. There would be a larger and more
extensive involvement of the subnucleus caudals in the
lower syndrome, compared with the upper syndrome,
where its ventrocaudal portions would be activated
(Cademartiri et al., 2002). Cluster headache has been
identified as a disorder that occurs mainly in men (maleto-female ratio of 67 : 1), but the clinical characteristics
are very similar in both sexes (Rozen et al., 2001). The
male-to-female ratio of both episodic and chronic cluster
headache depends strongly on age. The sex difference
is the largest between 30 and 49 years of age (7.2:1
and 11.0:1) and the lowest after 50 (2.3:1 and 0.6:1,
respectively) (Ekbom et al., 2002). In addition, it should
be noted that between 1960 and 1990 the male-to-female
ratio decreased from 6.2:1 to 2.1:1. These changes in sex
ratio are presumed to be related to changes in lifestyle
and smoking (Manzoni, 1998; Ekbom et al., 2002). In
4% of patients there is a family history (Dodick et al.,
2000). An autosomal dominant gene has a role in some
families with cluster headache (Ekbom and Hardebo,
2002).
It has been postulated that the cyclic phenomena
would originate from the hypothalamic clock, i.e. the
suprachiasmatic nucleus (SCN), with subsequent trigeminovascular reaction (Dodick et al., 2000; Goadsby,
2002), but there is only indirect evidence available for
this presumption. The most common episodic variety of
cluster headache is that 50% of the attacks occur during
the night and with a circannual pattern that is similar to
seasonal depression, because it increases in July and
January and decreases in April and October, suggesting
the involvement of the SCN in both disorders (see
Chapters 4.1 and 26.4). There are, moreover, various other
analogies between cluster headache, seasonal affective
disorder, and bipolar mood disorders in addition to
common seasonal patterns, i.e. the nature of predisposing
or precipitating factors, the peculiar relationship with
31.3. Headache
Various observations suggest an interplay of chronobiological, neuroendocrine and autonomic nervous systems
of the hypothalamus in these disorders. Headache can be
a symptom of many processes in the hypothalamic-pituitary region, including craniopharyngiomas and
sometimes even Rathkes cleft cysts (Chapter 19; Ward
et al., 2001).
Suicide headache (Dodick et al., 2000)
(a) Cluster headache

Cluster headache is characterized by stereotypic, shortlasting (several minutes to several hours), severe,
unilateral trigeminal pain attacks with a highly distinctive cyclic recurrence pattern, usually located in the
orbitotemporal region. An attack may be triggered by
an alcoholic beverage, by increased body heat from the
environment, a hot bath, central heating or from exercise
(including sexual intercourse) (Peres et al., 2000). The
pain is accompanied by homolateral autonomic signs,
which include local symptoms such as conjunctivatial
injection, lacrimation, rhinorrhea, erythema of the painful
area, and occasional miosis and ptosis. In addition,
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sleep, such as the temporal connection between attacks

and REM sleep, the neuroendocrine findings and clinical
response to current treatments such as lithium and flunarizine (Morales-Asin et al., 1997; Costa et al., 1998).
Some patients improve after melatonin or corticosteroid
administration (Pepping, 1999; Peres et al., 2000; Peres
and Rozen, 2001; Ekbom and Hardebo, 2002; Pringsheim
et al., 2002). Support for the idea that the hypothalamus
is the central site of origin of the pathogenesis of this
disorder has emerged from four other independent
observations. In the first place a significant structural
difference in gray matter density has been observed by
MRI. The difference consisted of an increase in gray
matter volume, bilateral in the inferior posterior hypothalamus. In the second place, PET scanning has shown
ipsilateral activation during cluster headache in the same
hypothalamic area (May et al., 1998, 1999; Goadsby
et al., 1999). The third relevant observation is that, in
patients with intractable cluster headache, who underwent
chronic high-frequency electric stimulation by means of
an electrode implanted in the posterior inferior ipsilateral
hypothalamic gray matter, the attacks were found to disappear after 48 h and to stay away during the follow-up of
233 months (Leone et al., 2001, 2003; Franzini et al.,
2003). Lastly, during nitroglycerin-induced cluster
headache attacks, the regional cerebral blood flow as
measured by PET was activated in the ipsilateral inferior
hypothalamic gray matter in the region of the SCN and
in a number of brain areas that are involved in pain.
Activation in the hypothalamus was seen solely while the
patients were still in a state of pain, and not in patients
who were recovering from the pain. The activation of the
hypothalamus is, therefore, proposed to be the primum
movens in the pathophysiology of cluster headache (May
et al., 1998, 2000). In addition to the episodic occurrence,
there are the neuroendocrine symptoms.
The possible involvement of the circadian timing
system (see Chapter 4) in this disorder is supported by
the observation that the acrophase of melatonin is moved
forward and the night-time peak is blunted and significantly reduced during cluster headache periods (Chazot
et al., 1984; Leone and Bussone, 1993; Dodick et al.,
2000). Also the growth hormone evening peak is
advanced in cluster headache (Chazot et al., 1984; Leone
and Bussoni, 1993), while there is an acrophase delay
in testosterone release (Facchinetti et al., 1986). Some
investigations have reported modifications in the diurnal
plasma levels of ACTH and cortisol, consisting of an
acrophase delay or advance, or an abnormal afternoon
peak of cortisol. Increased plasma levels of cortisol and

ACTH are especially found in the morning and in the
evening. Hypothalamic dysfunction in cluster headache
also appears from changes in hormone levels (Waldenlind
and Gustafson, 1987; Leone and Bussone, 1993). In
addition, 24-h cortisol production is increased in the
cluster period. The CRH test shows a downregulation
of adrenal function in cluster headache patients, as is
also found in patients receiving prolonged CRH administration. The dexamethasone suppression test results
are normal in cluster headache patients, showing that the
feedback control of CRH production is not altered. Factors
other than pain or sleep disturbances probably explain
hypercortisolemia in cluster headache, such as an alteration in the circadian rhythm of this hormone (Facchinetti
et al., 1986; Leone and Bussone, 1993; Strittmatter et al.,
1996b). The diurnal rhythm of prolactin has been reported
as normal or altered, as in cluster headache. Blunted
night peaks of prolactin are observed in men in clinical
remission, suggesting an impaired neuroendocrine regulation of prolactin, also during symptom-free intervals.
There are, however, great individual differences. In some
patients a loss of release rhythms is found, and attacks
of cluster headache are accompanied by prolactin
increases, especially when the attacks take place at night.
The persistence of hyperprolactinemia during cluster
headache remission indicates that these increases occur
independent of pain (Ferrari et al., 1983; Waldenlind and
Gustafsson, 1987; Leone and Bussone, 1993). Several
investigations have reported reduced thyrotropin (TSH)
responses to the TRH test during the cluster headache
period (Leone and Bussone, 1993). In addition, cluster
headache patients demonstrate significantly decreased
levels of norepinephrine, homovanillic acid (HVA) and
5-hydroxyindoleacetic acid (5-HIAA) in the CSF, which
concurs with a central genesis of this disorder (Strittmatter
et al., 1996b).
The prevalence of cluster headache in men, and the
fact that it is extremely rare in the preadolescent period,
indicates that sex hormones might also be involved in
the pathogenetic mechanism. Testosterone levels have
been reported to be normal or low during the cluster
headache period (Leone and Bussoni, 1993). Total, free
and carrier protein-bound testosterone levels are significantly diminished only in chronic cluster headache
patients whose basal and peak FSH levels are significantly
increased (Murialdo et al., 1989). In addition, a significant
reduction of the 24-h integrated mean testosterone level
(mesor) is found in cluster headache patients. It has been
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suggested that the stress of the attack causes elevated

cortisol levels and that this, in turn, reduces testosterone
levels (Facchinetti et al., 1986). Testosterone administration does not change the course of cluster headache,
whereas it does enhance sexual excitement (Nicolodi
et al., 1993).
A recognized treatment for intractable chronic cluster
headache is to section the trigeminal root proximal to the
ganglion. Oxygen and verapamil treatment also work
(Goadsby, 2002).
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events in the reproductive cycle. With puberty there is a

marked increase in the incidence of migraine headaches,
with a peak incidence occurring at menarche, and a
decrease at menopause. The majority of migrainous
women will have some of their attacks linked to the
menstrual cycle. Menstrual migraine seems to respond
very well to LHRH administration and to add-back
therapy, i.e. a combination with continuous, transdermal
estrogenprogesterone therapy (Murray and Muse, 1997).
Clear examples of the periodicity of headache are
weekend headaches, migraines that start during nocturnal
sleep, and (pre)menstrual migraine. The primary trigger
of menstrual migraine thus appears to be the withdrawal
of estrogen rather than the maintenance of sustained high
or low estrogen levels (Silberstein and Merriam, 1999).
In migraine patients, prolactin is excreted excessively in
response to stimulation (Dexter and Riley, 1975; Awaki
et al., 1989; Lance, 1992). Plasma levels of metenkephalin are higher in migrainous patients, both during
the attack and when there is no headache. However,
individual patients consistently present with lower metenkephalin levels during the pain-free period than during
the acute headache (Mosnaim et al., 1986).
Vasopressin plasma levels rise during migraine attacks
and are followed by a rise in endothelin-1, which exerts
vasoconstrictor and vasodilator actions on cerebral vessels
via endothelin A and B receptors. The elevated vasopressin levels may attribute in part to the nausea and
emesis that accompany the attack (Hasselblatt et al.,
1999). Another observation that connects migraine to
the hypothalamus is the increased digoxin synthesis
and upregulated isoprenoid pathway observed in these
patients. Digoxin is an inhibitor of membrane NaK
adenosine triphosphatase (ATP-ase); it is produced by the
hypothalamus and synthesized by the isoprenoid pathway
(Kumar and Kurup, 2001a). In patients with chronic daily
headaches, with a previous history of migraine, increased
nerve growth factor levels are found in the CSF. As
nerve growth factor is known for hyperalgesia when
administered either locally or systematically in many
species (Sarchielli et al., 2001), this observation may be
of therapeutic relevance.
(b) Migraine
Episodes of migraine may occur regularly, indicating the
involvement of some internal clock that probably involves
the hypothalamus, because premonitory symptoms such
as elation, a craving for sweet food, thirst or drowsiness
may precede headache by some 24 h. Hypothalamic
symptoms are reported by about 25% of patients (Lance,
1992). It has even been proposed that the SCN is the site
of initiation of a migraine attack (Zurak, 1997). Patients
with migraine are more likely to have headaches during
the bright arctic summer season. This distinguishes
migraine from other headaches and suggests a role of the
circadian/circannual system (Chapter 4) in the pathogenesis of this disorder (Salvesen et al., 2000). In this
connection it is also of interest that melatonin secretion
is reduced in patients with menstrual migraine (Dodick
et al., 1998) and that melatonin may relieve migraines
(Gagnier, 2001). Moreover, the circadian rhythmicity of
prolactin is often disturbed in migraine (Ferrari et al.,
1983). In chronic migraine, hypothalamic dysfunction
appears from: (i) a decreased nocturnal prolactin peak,
(ii) increased cortisol concentrations, (iii) a delayed
nocturnal melatonin peak, and (iv) lower melatonin
concentrations in patients with insomnia. On the basis
of these findings, a chronobiological dysregulation and
a possible hyperdopaminergic state are presumed to
be present in patients with chronic migraine (Peres
et al., 2001).
Migraine occurs more often in women than in men.
However, this sex difference is only present in the reproductive period of life. In children, migraine prevalence
is independent of sex. It is presumed that the basis of
the sexual dimorphism of migraine should be sought in
hypothalamic systems related to LHRH secretion, since
LHRH agonists may induce a complete relief of migraine
attacks (Facchinetti et al., 2000). The prevalence of
migraine headaches in women is influenced strongly by
(c) Hypnic headache syndrome

The hypnic headache syndrome (alarm clock syndrome)
is a rare, benign disorder of the elderly. It is characterized
by recurrent, nocturnal bilateral headaches that awaken
the patients from their sleep at a consistent time each
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night, usually between 1 and 3 a.m., more than 4 nights

a week. The pain is moderate to extremely severe and
lasts 20180 min. The mean age of onset is 61 years.
These headaches respond to treatment with lithium
carbonate and in some cases to caffeine in a tablet or
beverage (Newman et al., 1990; Dodick et al., 1998). One
case with a good response to indomethacin has been
described (Ivaez et al., 1998). The striking circadian
rhythmicity and the effectiveness of lithium carbonate
suggest the involvement of the SCN. The involvement of
the hypothalamus in the pathogenesis of cluster headache
is supported by the reduced 24-h plasma melatonin levels

during the cluster period, loss of circadian melatonin
secretion in remission and reduced urinary melatonin. In
addition, the levels of the melatonin metabolite 6-sulfatoxymelatonin do not differ during day and night in these
patients. The observation that altered excretion of 6-sulfatoxymelatonin is also present during remission indicates
that these anomalies are independent of the pain, and
provide further evidence of the involvement of hypothalamic, rhythm-regulating centers in cluster headache
(Leone et al., 1998).
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CHAPTER 32
Miscellaneous hypothalamic syndromes
32.1. Idiopathic hypothalamic syndrome of

childhood, a paraneoplastic syndrome
improves the vegetative disorders (Gurewitz et al., 1986;

Joseph et al., 1993), while naltrexone has little if any effect
(Loeuille et al., 1989).
Viral encephalitis cannot be excluded as a cause of
idiopathic hypothalamic syndrome, since in some patients
the attacks of hypothermia and somnolence follow a
respiratory illness (Gurewitz et al., 1986). Moreover, in
one case of a 2-year-old child who lacked thirst perception and who had inadequate temperature regulation,
hyperphagia and obesity, an autopsy revealed slight
dilations of the ventricles, while the floor of the third
ventricle consisted only of a very thin membrane. In the
hypothalamus small nests of chronic inflammatory cells
were scattered throughout the hypothalamic nuclei. The
white matter around the hypothalamic nuclei was not
affected. The cellular components were predominantly
lymphocytes, plasma cells and an occasional leukocyte.
Interspersed among the inflammatory cells, predominantly
degenerating neurons were seen that showed pycnosis,
cellular fragmentation and neuronophagia. Although
the paraventricular nucleus (PVN) exhibited the most
severe degree of degeneration, the supraoptic (SON) and
other hypothalamic nuclei displayed similar lesions.
The inflammatory foci were apparently confined to the
hypothalamus, and the neurohypophysis showed no
definite alterations (Travis et al., 1967). This observation
suggests that inflammation or an autoimmune process may
lie at the base of hypothalamic dysfunction in these
children and shows the need for the application of modern
neuropathological and neurobiological techniques on
postmortem tissue of such cases.
The association of this syndrome with disorders of
neural crest migration, such as Hirschsprungs disease and
neural crest tumors are well documented. Observations
by North et al. (1994) and Ouvrier et al. (1995) have
In the literature a number of children have been described

who have multiple neuroendocrine and behavioral problems due to idiopathic hypothalamic dysfunction. This
syndrome, of obscure origin, is also known as congenital
central hypoventilation syndrome (Katz et al., 2000). It is
not homogeneous, and the symptoms may include: apneic
spells; behavioral problems including hypersomnia;
developmental delay; hypodipsia with bouts of hypernatremia; episodes of inappropriate vasopressin excretion;
adipsia; life-threatening episodes of spontaneous hypothermia; lack of appetite control, i.e. polyphagia and
obesity, anorexia and emaciation; petit mal seizures;
precocious puberty that later fails to progress, probably
because of decreased luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) levels; hypercapnia
with absence of respiratory response to CO2 (oxygen
administration to these patients may, therefore, have
catastrophic consequences); insensitivity or hyposensitivity to pain; hyperprolactinemia and galactorrhea;
growth hormone deficiency; hypothyroidism; hypogonadotropism; hypocortisolism; and sleep disturbances.
In addition, behavioral disturbances have been found,
including personality changes, social and emotional
disinhibition, irascibility and impulsivity, aggressive
outbursts, impairment of concentration, outbursts of
euphoria and laughing, repetitive mannerisms, hyperactivity, psychomotor retardation, flat affect, social
withdrawal and lethargy (Nunn et al., 1997; Sirvent et al.,
2003). CT and MRI scans and autopsy generally do
not reveal any abnormality but in one case have shown a
structural lesion of the lateral part of the lentiform nucleus
(Joseph et al., 1993; Proulx et al., 1993). Clomipramine
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raised the possibility that a lymphocytic/histiocytic

infiltration in the hypothalamus of children with idiopathic
hypothalamic dysfunction is related to a ganglioneuroma
and might thus be considered as a paraneoplastic
syndrome. Seemingly idiopathic signs and symptoms
involving the nervous system sometimes precede the
diagnosis of a tumor outside the nervous system such
as a ganglioneuroma of the posterior abdominal wall,
or a neuroblastoma (Sirvent et al., 2003). Paraneoplastic
syndromes have been characterized in adults, but are
also thought to occur in children (North et al., 1994;
Ouvrier et al., 1995; Sirvent et al., 2003). This suggestion
is bolstered by the paper of Nunn et al. (1997) who
describes another patient with a ganglioneuroblastoma,
together with the histological picture of mild neuronal loss,
marked and widespread lymphocytic infiltration with
perivascular cuffing and brainstem, and thalamic and
hypothalamic aggregations. The demonstration of anti-Hu
antineuronal antibodies in the serum and cerebrospinal
fluid (CSF) has strongly supported the autoimmune
hypothesis. Hu-antigens are a class of neuron-specific,
RNA-binding proteins, expressed in most neuroblastomas
(Sirvent et al., 2003). On the basis of this autoimmune
concept, some have reported therapeutic success with
intravenous immunoglobulin, with corticosteroids, azothioprine and cyclosporine. Children presenting with
this syndrome should be extensively examined for neural
crest tumors. This includes MRI of the central nervous
system as well as the sympathetic chain. In addition there
should be a search for anti-neuronal antibodies (Nunn
et al., 1997). Support for the presence of hypothalamic
symptoms in paraneoplastic syndrome also comes from
the study of Gultekin et al. (2000). They have found that
all patients with anti-Ta (or anti-Ma-2) antibodies are
young men with testicular tumors, frequent hypothalamic
involvement and poor neurological outcome. In 30% of
patients, treatment of the tumor results in improvement.
The hypothalamic symptoms observed in that study
were: diabetes insipidus, loss of libido, hypothyroidism,
hypersomnia, hyperthermia and panhypopituitarism.
Removal of the tumor with intensive immunotherapy may
offer therapeutic hope.
32.2. Hypothalamic atrophy, Leighs disease and
Cornelia de Langes syndrome (Fig. 32A)
A 19-year-old female patient with progressive hypopituitarism and diabetes insipidus has been reported. She
had gross atrophy of the hypothalamus, demonstrated by

pneumencephalography. Basal pituitary (TSH), prolactin,
LH and FSH levels were consistently detectable and
responded briskly to thyrotropin-releasing hormone
(TRH) and LH-releasing hormone (LHRH) administration
(Hendricks et al., 1981). Hypothalamic atrophy in the
absence of systematic disease has also been described in
adults. A patient who was followed for 13 years developed
the first symptoms of progressive hypothalamic atrophy
at the age of 39 years. Hypothalamic dysfunction manifested itself by a loss of libido, by impotence, obesity,
polydipsia, somnolence and rage attacks, low serum levels
of testosterone, LH, FSH, decreased basal and stimulated
levels of growth hormone and progressively increasing
levels of serum prolactin, and a glucose tolerance test
revealed diabetes. A progressive enlargement of the
third ventricle was later associated with generalized but
proportionally less severe atrophy of the cerebellum and
cerebral hemispheres. Following levodopa therapy,
decreased somnolence and increased libido and potency
were found (Kelts and Hoehn, 1978). In neither patient
was any cause found for the hypothalamic atrophy.
Leighs disease was found in a 5-year-old child whose
condition had been deteriorating over a period of 6 months
before death. Postmortem investigation revealed cystic
and necrotic changes of the posterior hypothalamus,
subthalamic nuclei, midbrain, pons and medulla. Leighs
disease is a fatal encephalopathy that occurs in infancy
or childhood. It is inherited in an autosomal recessive
manner and is characterized by psychomotor regression,
brainstem dysfunction, respiratory abnormalities and
seizures. Neuropathology includes bilateral symmetrical
foci of necrosis, which are most prominent in the diencephalon and brainstem. The lesions are characterized by
necrosis, myelin destruction, astrocytosis and vascular
proliferation. Although lactic acidosis, pyruvate dehydrogenase complex deficiency and cytochrome-C-oxidase
deficiency have been found, they are not considered to
be a sufficient explanation of Leighs disease. The foci
of necrosis of the child with Leighs disease were
characterized by spongious changes around blood vessels,
capillary proliferation gliosis and macrophage infiltrates,
with relative preservation of neurons. These changes were
found in the posterior hypothalamus, while the mamillary
bodies were unaffected. There was optic atrophy with loss
of myelin (Heckmann et al., 1991).
Cornelia de Langes syndrome, first described in
Amsterdam in 1933 and called, by Cornelia de Lange (Fig.
32A) herself, Typus Degenerativus Amstelodamensis, is
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Fig. 32 A.
389
Portrait of Professor Cornelia de Lange (18711950). First female professor at the University of Amsterdam, painted by Lizzy Ansingh
(1957). Collection of University Museum De Agnietenkapel, Oudezijds Voorburgwal 231, 1012 EZ Amsterdam.
to the optic tract and the pituitary has also been described.
The patient was an 18-year-old girl with severe mental
retardation, polyuria, polydipsia, hypothyroidism, hypogonadotropism and limited response to growth hormone
and cortisol after insulin-induced hypoglycemia, while
the prolactin levels were normal. This case suggests a
possibly causal relationship between teratogenesis and
oncogenesis (Sato et al., 1986; Sugita et al., 1986;
Heckmann et al., 1991). Endocrine defects are often found
in Cornelia de Langes syndrome (Schlesinger et al., 1963;
France et al., 1969), indicating a defect in the vicinity
characterized by microcephaly, a simplified pattern of

cerebral convolutions, abnormal myelination and facial
dysmorphic features, including synophrys (eyebrows
growing together), a low-hair line on the neck and
forehead, long eyelashes and a depressed bridge of the
nose with upturned nostrils (Hayashi et al., 1996). Sleep
disturbances are correlated with severity of mental
retardation and the presence of autistic behavior (Hoban,
2000). Several studies have shown that this syndrome can
be associated with hypothalamic and hypophysial lesions.
A case complicated by a suprasellar germinoma extending
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of the median eminence (Abraham and Russell, 1968).

In a 5-year-old female child with Cornelia de Langes
syndrome, the optic systems, olfactory systems, hypothalamic nuclei, corpus callosum and cerebellar vermis were
hypoplastic. The septum pellucidum, fornix and anterior
commissure were present in rudimentary form. The SON
in particular were not recognized, and the posterior lobe
was hypoplastic. The brain had malformative features
of septo-optic dysplasia combined with commissural
dysplasia and cerebellar vermian hypoplasia, suggesting
a relationship between Cornelia de Langes syndrome
and midline development of the brain. Chromosomal
abnormalities have been pointed out in patients with
Cornelia de Langes syndrome, as well as in patients
with De Morsiers syndrome (Hayashi et al., 1996), and
Cornelia de Langes syndrome is considered to be an autosomal dominant disease, with most cases reflecting a fresh
mutation (Russell et al., 2001). In an adult case of Cornelia
de Langes syndrome, no neuropathology was observed in
the hypothalamus (Vuilleumier et al., 2002).
32.3. Diencephalic idiopathic gliosis
A 16-year-old girl with chronic diarrhea and dermopathy
had an unusual and widespread gliosis of hypothalamic
and other diencephalic structures with proportionally little
neural loss. The gliosis involved the hypothalamus from
the anterior commissure up to and including the mamillary
bodies, in particular in the medial portions of the arcuate,
ventromedial (VMN), and dorsomedial nucleus, and the
mamillary bodies. The lateral tuberal nucleus was also
moderately involved. Likewise, the SON and PVN
revealed mild gliosis and neuronal loss. The basal forebrain showed moderate gliosis, including the anterior
olfactory area, the nucleus basalis of Meynert and the
diagonal band of Broca. There was no sign of any
inflammatory reaction or vascular proliferation. Mild to
moderate gliosis was also present in the globus pallidus,
subthalamic nucleus, and anterior and mid-portions of the
thalamus as well as in the brainstem. The extrahypothalamic damage did not, however, cause recognized clinical
features. Hypothalamic disease was suggested during life
by sustained hypothermia, delayed sexual development,
altered sleepwake cycles, abnormal cortisol diurnal

rhythms and profound growth arrest from the age of 8
years onwards, despite normal growth hormone and
insulin-like growth factor (IGF)-I levels. The stimulus to
glial proliferation has not been identified (Espiner et al.,
1992). Fox et al. (1970) have reported a case of persistent and severe hypothermia (see Chapter 30.2) in a young
adult with marked gliosis, which was, however, confined
to the anterior hypothalamus, while pituitary functions
remained normal. The relationship of these cases of gliosis
to gliomatosis cerebri (Chapter 19.4c; Peretti-Viton et al.,
2002) is unknown.
32.4. Mitochondrial encephalomyopathy, lactic

acidosis and stroke-like episodes (MELAS)
syndrome
MELAS syndrome is due to the presence of a mixture

of mutated and wild-type mitochondrial DNA. Central
nervous system involvement may accompany mental
retardation, epilepsia partialis continua, stroke-like
episodes and neuroendocrine dysfunction, i.e. growth
hormone deficiency, hypothalamopituitary hypothyroidism, primary amenorrhea, prepubertal gonadotropin
levels, absence of any secondary sexual characteristics
and diabetes mellitus (insulin- and noninsulin-dependent)
(Balestri and Grosso, 2000).
32.5. Agenesis of the diencephalon
Agenesis of the diencephalon of the fetus and neuroepithelial folding of the diencephalon has been observed
following alcohol use by the mother during pregnancy
(Konovalov et al., 1997).
32.6. Tourettes syndrome
Changes of the ambient thermal perception and a
circadian dysregulation of the body temperature profile
are present in Tourettes syndrome probands. An
idiopathic hypothalamic disorder is presumed by the
authors (Kessler, 2002).
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CHAPTER 33
Brain death and dead neurons (Fig. 33A)
Die, my dear doctor thats the last thing I shall do!

Lord Palmerston, 17841865. British Prime Minister.
Some studies reported that hypothalamic and anterior

pituitary hormones are still detectable in peripheral
plasma after the diagnosis of brain death, suggesting that
hypothalamic function might, at least partly and for some
time, remain intact in this condition (Sugimoto et al.,
1992). In brain-dead patients, changes of the thyroid axis
have been described that were considered to be a variant
of euthyroid sick syndrome (= nonthyroidal sickness),
characterized by a reduction of serum total T3 and free
T3 levels, and a low or normal T4 (see Chapter 8.6).
Thyrotropin (TSH) may be normal, lower or, sometimes,
elevated, suggesting in that case the presence of intact
hypothalamic thyrotropin-releasing hormone (TRH)
neurons. As a result of these endocrine changes, tissue
T3 also lowers. Some authors suggest treating brain-dead
organ donors with T3 in order to improve the organs
condition for transplantation, but this is a controversial
subject (Keogh et al., 1988; Robertson et al., 1989;
Powner et al., 1990; Novitzky, 1991; Gramm et al., 1992;
Colpart et al., 1996). While the majority of brain-dead
people develop diabetes insipidus (see below), anterior
pituitary hormones do not decrease: corticotropin
(ACTH), follicle-stimulating hormone (FSH), luteinizing
hormone (LH), and prolactin levels remain within the
normal range. Not only TSH, but also growth hormone
levels may increase in brain death, suggesting some
residual hypothalamic functions and also some perfusion
of the hypothalamopituitary portal system (Howlett et al.,
1989; Harms et al., 1991; Gramm et al., 1992). As an
alternative explanation, one may propose that these
hormones are released into the circulation as a result of
necrosis of the anterior pituitary (Gramm et al., 1992).
On the other hand, the observation that 138 days after
brain death (Sugimoto et al., 1992) there was still a good
(a) The process of dying and brain death

The hypothalamic clock seems to play a crucial role
from the moment we are born (Chapter 4.2) to the moment
we die. To a certain degree the hypothalamus determines
the hour of the day at which we die, e.g. from ischemic
stroke or intracerebral hemorrhage and subarachnoid
hemorrhage in hypertensive patients, who show a
postawakening peak (see Chapter 4d). In addition, there
are circannual fluctuations in cerebral infarctions,
ischemic attacks, intracerebral hemorrhage and suicides
(Chapter 4.1b).
During the process of dying, various neuroendocrine
and autonomic changes may occur. The HPA system
is strongly activated, giving rise to extremely high
plasma and CSF levels of cortisol (Swaab et al., 1994c;
Lamberts et al., 1997a; Chapter 1.3.iib). In severely
demented patients we found even higher levels of CSF
cortisol than in patients with mild Alzheimers and
controls, while morphine in the last phase of life had no
effect on these high CSF cortisol levels. Physical stress
therefore seems to cause these high cortisol levels in the
moribund stage, rather than the psychological stress
of dying (Erkut et al., 2003). Prolactin in postmortem
venous blood samples correlates with stress. Markedly
higher blood levels of this hormone are found in postoperative deaths and in the chronically ill. However,
hyperprolactinemia in cases of suicide is likely to be the
result of the effects of the drugs used (Jones and
Hallworth, 1999).
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Fig. 33A.
The soul that tries to overcome the religious borders of the mind.
In 1882, J.W.C. van Gorkum, a colonel in the cavalry, died and was buried next to the wall of the Protestant part of the cemetery in Roermond,
the Netherlands. When his wife, Lady van Aefferden, a Roman Catholic, died six years later, she could not be buried on the Protestant side, next
to her husband. She chose to be buried as close as possible to the wall on the Catholic side. The tombstones were connected to symbolize their
alliance.
response to TRH in some patients favors the possibility

of residual hypothalamic and pituitary functions.
However, since another study showed a decrease in TSH,
T3 and T4 in 80% of the brain-dead potential donors, the
residual functions seem to be only partly intact (Colpart
et al., 1996).
In a study of 28 brain-dead patients, vasopressin plasma
levels dropped a short time after the diagnosis of brain
death. This manifested clinically as diabetes insipidus.
Anterior pituitary hormones were initially detected in all
patients, but they disappeared gradually. Morphological
studies showed a partial necrosis of the anterior lobe of
the pituitary, due to a lack of circulation in the portal

system that is probably caused by the rise of intracranial
pressure, while preservation of the posterior lobe lasted
1 week. The zona intermedia was preserved relatively
well. Some autopsy reports show that the hypothalamus
becomes extensively necrotic after 36 days of brain death
(Sugimoto et al., 1992), while a narrow outer shell of the
pars distalis is usually intact (McCormick et al., 1970).
On the other hand, it has also been reported that the diencephalon is less seriously affected than most other brain
areas (Walker et al., 1975). In general, the supraoptic
(SON) and paraventricular nuclei (PVN) are affected in
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Fig. 33B. Brain and Mind (detail) (c) Herms Romijn. Herms Romijn, who painted the water-color picture of which a detail is reproduced here,
has exhibited widely and was a neurobiologist at the Netherlands Institute for Brain Research. He has published many papers on the pineal gland,
neuron culture, epilepsy and the biological clock, and is the author of books (in Dutch) on sleep and mindbrain relationships. In this painting he
has tried to express the essence of his view on consciousness (Romijn 2002). He sees consciousness as a manifestation of complex patterns of
electric and/or magnetic fields in the brain, pointing out that virtual photons comprising these fields can therefore, in a sense, be regarded as
elementary carriers of consciousness. Because not only fields but neurons too are composed of elementary particles, he used the technique of
pointillism to emphasize this feature in the painting. (Cover illustration of Journal of Consciousness Studies 8 (910), Sept.Oct. 2002, with
permission.)
patients with coma dpass (irreversible coma or respirator brain), while the neural lobe shows a normal or
even an increased amount of neurosecretory material. The
mostly severe degeneration of the central portions of the
anterior lobe of the pituitary and the relative infrequency
of extensive necrosis of the pars nervosa in case of brain
death is explained by the difference in vascularization
(see Chapter 17.1). The blood supply of the pars nervosa
is predominantly arterial, derived from branches of the
internal carotid artery and almost completely extradural.
The anterior pituitary blood supply comes largely from
the low-pressure venous portal system from the pituitary
stalk and will thus be much more affected by the increased

arterial pressure generally seen in the respirator brain.
The outer rim of reasonably well preserved cells seen in
the anterior lobe of the pituitary is explained by their
blood supply from arterial twigs from the hypophyseal
arteries derived from the carotids (McCormick and Halmi,
1970; Gramm et al., 1992).
Some three-quarters of brain-dead patients develop
clinical diabetes insipidus (Keogh et al., 1988; Howlett
et al., 1989; Gramm et al., 1992). In about half of the
cases of diabetes insipidus, this disease had already developed before the onset of brain death (Gramm et al., 1992).
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Fig. 33.1. Histology and viability staining of motor cortex slices after long-term culturing. (A) Overview of the cortical layers in a slice at DIV
25 (NeuN: Alzheimer patient, 99-139). (B) Detail of layer III pyramidal neurons at DIV 38 (NeuN; control patient, 00-090). (C) Astrocytes in
layer III at DIV 78 (control, 00-090) stained with an antibody to GFAP (brown) and counterstained with NeuN (green). GFAP and NeuN were
visualized using peroxidase (DAB) and -galactosidase (X-gal), respectively. (D) Microglial cells (HLA, brown) and neurons (NeuN, green) in
layer III at DIV 78 (control, 00-090). (E) Dil tracing reveals the extensive dendritic arborizations of an upper layer III pyramidal neuron at DIV
50 (non-Alzheimer dementia patient, 99-142). Two optical CLSM sections, taken 20 m apart. (F) Electron micrograph showing axodendritic
synapses at DIV 25 (AD, 99-139). (G) Viability staining of a motor cortex slice (layer III) kept in basal medium (R16) for 48 days (AD, 99139). (H) Viability staining of a motor cortex slice (layer III) kept in basal medium (R16) supplemented with NGF, BDNF, and NT-3 for 48 days
(AD, 99-139). Arrows indicate viable neurons that have retained both esterase activity (green cytoplasm) and intact membranes (without red nuclei).
d, dendrite; s, synaptic terminal. Roman numerals indicate the cortical layers. Scale bar 400 m (A); 20 m (BD); 100 m (E); 35 m (G,H);
400 nm (F). (From Verwer et al., 2002, Fig. 1, with permission.)
In 76% of children with brain death, increased diuresis

is present, whereas genuine diabetes insipidus is found
in 38% of the patients (Fiser et al., 1987). These observations are in the first place of practical importance.
Brain-dead patients who are not given vasopressin, or

only in an antidiuretic dose, demonstrate circulatory
deterioration and cardiac arrest within a short time after
brain death, despite administration of a large dose of
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do not even want to lose myself, because I know that I cannot

come any further toward the truth and because one blunders
so easily on those subjects.
Eugene Dubois, cited by Pat Shipman in The Man who
Found the Missing Link.
epinephrine. All patients with a pressor dose of vasopressin, however, demonstrate stable circulation as long
as vasopressin and epinephrine are administered (Iwai
et al., 1989). Vasopressin substitution has therefore been
recommended for brain-dead donors (Howlett et al.,
1989). A more recent study on brain-dead organ donors
supports the protective action of vasopressin. Organ
donors often develop hypotension, due to vasodilation,
which adds to the scarcity of good organ donors for
transplantation. Hemodynamically unstable organ donors
without clinically apparent diabetes insipidus display
a defect in the baroreflex-mediated secretion of vasopressin. In these patients, a low dose of vasopressin
(0.040.1 U/min) administered as a continuous infusion
significantly increases blood pressure, with a pressor
response sufficient to reduce catecholamine administration. Nonetheless, vasopressin is not widely used to
improve donor stability. Instead 1-desamine-8-D-arginine
vasopressin (dDAVP) is used to treat diabetes insipidus
in organ donors. However, dDAVP acts selectively on
the V2 receptor subtype in the renal collecting tube
and has no vasopressor activity in humans, a type of
activity mediated by the V1 receptors on vascular smooth
muscle (Chen et al., 1999a). In addition, brain death may
go together with an autonomic storm (Chapter 30), characterized by rapid swings in blood pressure with eventual
persistent hypotension, coagulopathies, hypothermia and
electrolytic alterations. This syndrome may affect donor
organ quality (Pratschke et al., 1999).
Brain-dead patients who do not show diabetes insipidus have caused questions of a theoretical and ethical
nature to be raised. When enough vasopressin is still produced to prevent diabetes insipidus, the patient does not
fulfil the criterion of irreversible cessation of all functions
of the entire brain (Truog, 1997) and one may wonder
what other residual brain functions are still present in such
brain dead patients. The present monography will also
have made clear that the hypothalamus is involved in many
higher functions, so that it will be difficult to use the
higher brain criterion for death (Truog, 1997) if remnants
of the hypothalamus are still functioning.
Adult and fetal postmortem hypothalamic tissue has

been studied by in vitro perfusion chambers at 37C.
Oxygenated artificial CSF flowing through the chamber
bathes the tissue and is then collected in intervals into
sample tubes. Functional viability of fetal tissue of 2133
weeks of gestation obtained less than 6 h after delivery
and adult postmortem hypothalami within 12 h postmortem was assessed by the rapid release of LHRH
in response to a depolarizing dose of KCl. Dopamine
administration resulted in LHRH release in a dosedependent and dopamine-receptor-mediated fashion.
Increased release of LHRH was found in response to opiate
receptor blockade, supporting the inhibitory role of endogenous opioids in LHRH secretion (Chapters 24.1 and 31.1).
Fetal human medial basal hypothalamus tissue releases
LHRH in a pulsatile and calcium-dependent manner with
a periodicity of about 1 h, and adult tissue with a periodicity of 60100 min. These results indicate that the LHRH
pulse-generating mechanism is located entirely within this
brain area. Addition of morphine to the medium reduces
the frequency of LHRH pulses (Rasmussen, 1992).
Neurons from human fetal brain tissue of 1216 weeks
gestation have been isolated and cultured and induced to
undergo apoptosis by serum deprivation. Apoptosis can
be prevented by hormones such as 17--estradiol and
transcriptionally inactive 17--estradiol, while androgens
appear to induce neuroprotection directly through the
androgen receptor (Hammond et al., 2001). Human
neurons from craniotomies for intractable epilepsy or
tumor resection have also been cultured (Brewer et al.,
2001).
Our group has shown that it is possible to recover at
least some functions of human hypothalamic neurons up
to 8 h after death in postmortem cultured brain slices.
When brain slices are preincubated in modified artificial
CSF at 04C for 23 h, neuronal tracers, i.e. neurobiotin
or biotinylated dextran-amine are injected into the optic
nerve or hypothalamic nuclei. These tracers are taken up
and transported along the axon only by living neurons.
Following 618 h of incubation in artificial CSF at room
temperature, provided with 95% O2 and 5% CO2, the
tracer appears to be transported over 0.51.5 cm along
axons, e.g. from the optic nerve to the suprachiasmatic
(b) Postmortem perfusion of hypothalamic tissues and

neuronal cultures: life after death
I myself speak in publications about brains, exclusively
about brains never about the psyche, let alone about the
soul, Dubois declares defensively. In the latter subjects I
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Fig. 33.2. Transgene expression in adult human postmortem brain tissue. A) Overview of a motor cortex slice from a control patient showing
layers II and III with cells expressing -galactosidase (patient 99-044, infection at DIV 6; staining at DIV 13; rAAV titer; 8.3x108 tu/ml). B) Layer
III pyramidal neurons of an AD patient (99-001) expressing -galactosidase at DIV 24 after infection at DIV 14 (rAAV titer: 4.6x108 tu/ml). C)
-galactosidase-expressing layer III pyramidal cells in the motor cortex of a PD patient (99-069) (infection at DIV 34; staining at DIV 44l rAAV
titer 8.3x108 tu/ml. D) AT-8 staining at DIV 0 in layer III of a slice from the same tissue block as in B, showing plaques (asterisks), tangles
(arrows) and neuropil threads (arrowheads). D) Inset: a hyperphosphorylated tau (AT-8)-containing neuron (same patient) that also expressed
-galactosidase (infection at DIV 34; staining at DIV 44; rAAV titer 2x108 tu/ml). E) Overview of another slice stained at DIV 0 with an antibody against -amyloid showing the presence of many plaques (same patient as in B). F) Large pyramidal cells of layer V in a motor cortex slice
from the same experiment shown in C. Three adjacent cells suggesting that a high lipofuscin load is accompanied by low -galactosidase expression.
Inset: a higher magnification of the uppermost neuron. Arrowheads indicate the location of the lipofuscin accumulations. Scale bar 400 m (E);
200 m (A); 100 m (B, D); 50 m (C, F); 25 m (F, inset), and 6 m (D, inset). (From Verwer et al., 2002, Fig. 4, with permission.)
nucleus (SCN) and from the SCN to a number of mainly

hypothalamic sites of termination (Chapter 4). Axonal
transport under these conditions is an active, energydependent process, since no transport is visible when
oxygen, or oxygen and glucose are omitted during incu-
bation. Adding cortisol during incubation increases the

neurons ability to transport. Neurons of patients who
have been dead for 68 h thus appear to be capable
of recovering axonal transport with suitable in vitro
treatment (Dai et al., 1998a, b, c).
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Fig. 33.3. Culture for 21 days of a slice of postmortem human hypothalamus containing the supraoptic nucleus according to the procedure of
Verwer et al., 2002. The cells were stained for the Golgi apparatus with the antibody HG-130 (Ishunina et al., 2001). Patient: NHB 00-040, female,
95 years of age; postmortem delay, 4 h 45 min. Bar 100 m (preparation, T.A. Ishunina).
Subsequently, our group has shown that organotypic

human brain cultures obtained by autopsy within the
framework of the Netherlands Brain Bank at 28 h after
death can be maintained in vitro for extended periods and
can be manipulated experimentally. Slices in basal
medium supplemented with survival promoting neurotrophic factors retain more viable cells than slices in basal
medium alone. Cytochrome oxidase activity could be
enhanced by the addition of pyruvate as an extra energy
source to the medium. Also, we have reported for the
first time that neurons in these cultures (motor cortex,
hippocampus and cerebellum) can be transduced with
adenoassociated viral vectors, and were able to express
the reporter genes, enhanced green fluorescent protein

and LacZ, for as long as 44 days (Verwer et al., 2002;
Figs. 33.1 and 33.2). In this way, we have also successfully cultured nucleus basalis of Meynert neurons (E.J.G.
Dubelaar et al., unpublished observation), as well as of
the supraoptic nucleus (Ishunina et al., 2001; Fig. 17.13)
and other cortical areas, such as the parietal and visual
cortex.
These slice cultures offer new opportunities to study
the cellular and molecular mechanisms of aging and
neurodegenerative diseases. For instance, mutated genes
involved in Alzheimers disease may be expressed in
neurons of control patients to induce pathological alter-
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Fig. 33.4.
Het Literaire Leven. Peter van Straaten.
ations. Furthermore, putative therapeutic genes may be

applied to brain slices of Alzheimer patients to enhance
neuronal survival.
The examples mentioned above indicate that quite a
few neuronal functions may still be present when the
subject as an organism is already dead.
The idea that the building blocks of our personality, the
neurons, can live on after death is a curious one. It is even
more curious if one realizes that the building blocks of these

cells, molecules, are made of dead matter. When DNA, the
building block of life, is a dead molecule, then what is life?
(cf. Bert Keizer, Het Refrein is Hein. Uitgeverij SUN).
In a manual nothing remains of the effort, the doubt and
the despair that existed before a certain conclusion was
reached.
W.F. Hermans in Nooit meer slapen.
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References
Abas MA, Sahakian BJ, Levy R (1990). Neuropsychological

deficits and CT scan changes in elderly depressives. Psychol
Med 20: 507520.
Abayomi OK, Sadeghi-Nejad A (1986). The incidence of late
endocrine dysfunction following irradiation for childhood
medulloblastoma. Int J Radiat Oncol Biol Phys 12: 945948.
Abbattista AD, Vigevano F, Catena G, Parisi F (1997).
Anencephalic neonates and diagnosis of death. Transplant
Proc 29: 36343635.
Abbes AP, Bruggeman B, Van den Akker ELT, De Groot MR,
Franken AAM, Drexhage VR, Engel H (2000). Identification
of two distinct mutations at the same nucleotide position,
concomitantly with a novel polymorphism in the vasopressinneurophysin II gene (AVP-NP II) in two Dutch families with
familial neurohypophyseal diabetes insipidus. Clin Chem 46:
16991702.
Abdul Karim RW, Rizk PT (1970). The effect of oxytocin on
renal hemodynamics, water, and electrolyte excretion. Obstet
Gynecol Surv 25: 805813.
Abe J, Okamura H, Ibata Y, Kitamura T, Ibata Y, Minamino N,
Matsuo H, Paull WK (1988). Immunocytochemical demonstration of dynorphin (PH-8P)-like immunoreactive elements
in the human hypothalamus. J Comp Neurol 276: 508513.
Abe J, Okamuro H, Ibata Y, Motoyama A, Wakabayashi I, Ling
N, Paull WK (1990). Immunocytochemical demonstration of
GAP-like immunoreactive neuronal elements in the human
hypothalamus and pituitary. Histochemistry 94: 127133.
Abel TW, Rance NE (1999). Proopiomelanocortin gene
expression is decreased in the infundibular nucleus of postmenopausal women. Mol Brain Res 69: 202208.
Abel TW, Rance NE (2000). Stereologic study of the hypothalamic infundibular nucleus in young and older women. J
Comp Neurol 424: 679688.
Abelson JL, Curtis GC (1996a). Hypothalamic-pituitary-adrenal
axis activity in panic disorder: 24-hour secretion of corticotropin and cortisol. Arch Gen Psychiatry 53: 323331.
Abelson JL, Curtis GC (1996b). Hypothalamic-pituitary-adrenal
axis activity in panic disorder: prediction of long-term outcome
by pretreatment cortisol levels. Am J Psychiatry 153: 6973.
Abelson JL, Curtis GC, Cameron OG (1996). Hypothalamicpituitary-adrenal axis activity in panic disorder: effects of
alprazolam on 24 h secretion of adrenocorticotropin and
cortisol. J Psychiatr Res 30: 7993.
Abernethy WB, Bell MA, Morris M, Moody DM (1993). Microvascular density of the human paraventricular nucleus
decreases with aging but not hypertension. Exp Neurol 121:
270274.
Abitbol G, Reinberg A, Mechkouri M (1997). Variability in the
period of the blood pressure circadian rhythm in human
beings. Chronobiol Int 14: 307317.
Abraham JM, Russell A (1968). De Lange Syndrome. Acta
Paediatr Scand 57: 339353.
Absher JR, Vogt BA, Clark DG, Flowers DL, Gorman DG,
Keyes JW, Wood FB (2000). Hypersexuality and hemiballism
due to subthalamic infarction. Neuropsychiatry Neuropsychol
Behav Neurol 13: 220229.
Acers TE (1981). Optic nerve hypoplasia: septo-optic-pituitary
dysplasia syndrome. Trans Am Ophthalmol Soc 79: 425457.
Achermann JC, Silverman BL (2001). Dehydroepiandrosterone
replacement for patients with adrenal insufficiency. Lancet
357: 13811382.
Achermann JC, Gu W-X, Kotlar TJ, Meeks JJ, Sabacan LP,
Seminara SB, Habiby RL, Hindmarsh PC, Bick DP, Sherins
RJ, Crowley WF, Layman LC, Jameson JL (1999). Mutational
analysis of DAX1 in patients with hypogonadotropic
hypogonadism or pubertal delay. J Clin Endocrinol Metab
84: 44974500.
Achermann JC, Meeks JJ, Jameson JL (2001a). Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol
185: 1725.
Achermann JC, Weiss J, Lee E-J, Jameson JL (2001b). Inherited
disorders of the gonadotropin hormones. Mol Cell Endocrinol
179: 8996.
Ackerman AE, Lange GM, Clemens LG (1998). Effects of
Paraventricular lesions on sex behavior and seminal emission
in male rats. Physiol Behav 63(1): 4953.
Adams C, Fletcher WA, Myles ST (1997). Chiasmal glioma in
neurofibromatosis type 1 with severe visual loss regained with
radiation. Pediatr Neurol 17: 8082.
Adams CWM, Abdulla YH, Torres EM, Poston RN (1987).
Periventricular lesions in multiple sclerosis: their perivenous
origin and relationship to granular ependymitis. Neuropathol
Appl Neurobiol 13: 141152.
Adan A, Natale V (2002). Gender differences in morningness
eveningness preference. Chronobiol Int 19: 709790.
Adan L, Bussires L, Dinand V, Zerah M, Pierre-Kahn A,
Brauner R (2000). Growth, puberty and hypothalamic-
399
2014 Refs
400
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 400
D.F. SWAAB
pituitary function in children with suprasellar arachnoid cyst.

Eur J Pediatr 159: 348355.
Addonizio G, Susman VL, Roth SD (1987). Neuroleptic
malignant syndrome: review and analysis of 115 cases. Biol
Psychiatry 22: 10041020.
Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL
(1999). Reduced hypothalamic-pituitary and sympathoadrenal
responses to hypoglycemia in women with fibromyalgia
syndrome. Am J Med 106: 534543.
Adler GK, Manfredsdottir VF, Rackow RM (2002).
Hypothalamic-pituitary-adrenal axis function in fibromyalgia
and chronic fatigue syndrome. Endocrinologist 12: 513524.
Adolfsson R, Gottfries CG, Roos BE, Winblad B (1979).
Changes in the brain catecholamines in patients with dementia
of Alzheimer type. Br J Psychiatry 135: 216223.
Aeschbach D, Matthews JR, Postolache TT, Jackson MA,
Giesen HA, Wehr TA (1999). Two circadian rhythms in
the human electroencephalogram during wakefulness. Am J
Physiol 277: R1771R1779.
Aeschbach D, Sher L, Postolache TT, Matthews JR, Jackson
MA, Wehr TA (2002). A longer biological night in long
sleepers than in short sleepers. J Clin Endocrinol Metab 88:
2630.
Aguilar-Roblero R, Garcia-Hernandez F, Aguilar R,
Arankowsky-Sandoval G, Drucker-Colin R (1986).
Suprachiasmatic nucleus transplants function as an endogenous oscillator only in constant darkness. Neurosci Lett 69:
4752.
Aguilera G, Rabadan-Diehl C (2000). Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications
for stress adaptation. Regul Pept 96: 2329.
Aguil F, Vega LA, Haddock L, Rodrguez O (1969). Diabetes
insipidus syndrome in hypopituitarism of pregnancy. Acta
Endocrinol 60: 732.
Ahmed ABJ, George BC, Gonzalez-Auvert C, Dingman JF
(1967). Increased plasma arginine vasopressin in clinical
adrenocortical insufficiency and its inhibition by glucosteroids. J Clin Invest 46: 111123.
Ahmed ML, Foot ABM, Edge JA, Lamkin VA, Savage MO,
Dunger DB (1991). Noonans syndrome: abnormalities of the
growth hormone/IGF-I axis and the response to treatment
with human biosynthetic growth hormone. Acta Paediatr
Scand 80: 446450.
Ahmed SR, Aiello DP, Page R, Hopper K, Towfighi J, Santen
RJ (1993). Necrotizing infundibulo-hypophysitis: a unique
syndrome of diabetes insipidus and hypopituitarism. J Clin
Endocrinol Metab 76: 14991504.
Aimard G, Henry E, Devic M (1984). Maladie de Parkinson.
Presse Med 13: 919922.
Airaksinen MS, Partau A, Paljrvi L, Reinikainen K, Riekkinen
P, Suomalainen R, Panula P (1991a). Histamine neurons in
human hypothalamus: anatomy in normal and Alzheimer
diseased brains. Neuroscience 44: 465481.
Airaksinen MS, Reinikainen K, Riekkinen P, Panula P (1991b).

Neurofibrillary tangles and histamine-containing neurons in
Alzheimer hypothalamus. Agents Actions 33: 104107.
Aisen PS (1997). Inflammation and Alzheimers disease:
mechanisms and therapeutic strategies. Gerontology 43:
143149.
Aisen PS (2000). Anti-inflammatory therapy for Alzheimers
disease: implications of the prednisone trial. Acta Neurol
Scand 176: 8589.
Aisen PS, Pasinetti GM (1998). Glucocorticoids in Alzheimers
disease. The story so far. Drugs and Aging 12: 16.
Aizawa S, Tokura H (1999). The influence of the bright light
exposure during daytime on melatonin excreting rate in urine.
Biol Rhythm Res 30: 332338.
Ajlouni K, Kern MW, Tures JF, Theil GB, Hagen TC (1974).
Thiothixene-induced hyponatremia. Arch Intern Med 134:
11031105.
Ajlouni K, Jarrah N, El-Khateeb M, El-Zaheri M, El Shanti H,
Lidral A (2002). Wolfram syndrome: identification of a
phenotypic and genotypic variant from Jordan. Am J Med
Genet 115: 6165.
Akabayashi A, Koenig JI, Watanabe Y, Alexander JT, Leibowitz
SF (1994). Galanin-containing neurons in the paraventricular nucleus: a neurochemical marker for fat ingestion
and body weight gain. Proc Natl Acad Sci USA 91:
1037510379.
Akaboshi S, Inoue Y-I, Kubota N, Takeshita K (2000). Case
of a mentally retarded child with non-24 hour sleep-wake
syndrome caused by deficiency of melatonin secretion.
Psychiatry Clin Neurosci 54: 379380.
kefeldt A, Anvret M, Grandell U, Nordlinder R, Gillberg C
(1995). Dev Med Child Neurol 37: 11011109.
kefeldt A, Ekman R, Gillberg C, Mnsson J-E (1998).
Cerebrospinal fluid monoamines in PraderWilli syndrome.
Biol Psychiatry 44: 13211328.
kefeldt A, Trnhage C-J, Gillberg C (1999). A woman with
PraderWilli syndrome gives birth to a healthy baby girl. Dev
Med Child Neurol 41: 789790.
kefeldt A, Ekman R, Mnson J-E (2001). Cerebrospinal fluid
neuropeptide Y in PraderWilli syndrome. Dev Med Child
Neurol 43: 286288.
kerlund M, Strmberg P, Forsling ML (1979). Primary dysmenorrhea and vasopressin. Br J Obstet Gynaecol 86: 484487.
kerlund M, Strmberg P, Hauksson A, Franch Andersen L,
Lyndrup J, Trojnar J, Melin P (1987). Inhibition of uterine
contractions of premature labour with an oxytocin analogue.
Results from a pilot study. Br J Obstet Gynaecol 94:
10401044.
kerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski
T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M (1999).
Receptor binding of oxytocin and vasopressin antagonists and
inhibitory effects on isolated myometrium from preterm and
term pregnant women. Br J Obstet Gynaecol 106: 10471053.
2014 Refs
2/12/03
1:39 pm
Page 401
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
401
analysis of new AVPR2 mutations identified in Italian families. J Am Soc Nephrol 11: 10331043.
Albrecht U, Sun ZS, Eichele G, Lee CC (1997). A differential
response of two putative mammalian circadian regulators,
mper1 and mper2, to light. Cell 91: 10551064.
Albright AL, Lee PA (1992). Hypothalamic hamartomas and
sexual precocity. Pediatr Neurosurg 18: 315319.
Aldrich MS, Naylor MW (1989). Narcolepsy associated with
lesions of the diencephalon. Neurology 39: 15051508.
Alheid GF, Heimer L, Switzer RC (1990). Basal ganglia. In:
Paxinos G (Ed.) The Human Nervous System, pp. 508510.
Academic Press, San Diego.
Al-Herbish AS, Al-Jurayyan NA, Baabbad R, Jan M, Salih
MAM (1997). Epileptic laughter and precocious puberty due
to hypothalamic hamartoma: a case report with review of the
literature. Med Sci Res 25: 143144.
Al-Hussain S, Al-Jomard R (1996). Morphology of neurons in
the anterior hypothalamic area and supraoptic hypothalamic
nucleus of the adult human brain. Ital J Neurol Sci 17: 261266.
Alikchanov AA, Petrukhin AS, Mukhin KY, Nikanorov AY
(1998). Gelastic epilepsy, hypothalamic hamartoma, precocious puberty and agenesis of the corpus callosum: a new
association. Brain Dev 20: 239241.
Alkemade A, Unmehopa UA, Brouwer JP, Hoogendijk WJG,
Wiersinga WM, Swaab DF, Fliers E (2003). Decreased
thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus (PVN) of patients with major
depression. Mol Psychiatry 8: 838839.
Allen AJ, Leonard HL, Swedo SE (1995). Case study: a new
infection-triggered, autoimmune subtype of pediatric OCD
and Tourettes syndrome. J Am Acad Child Adolesc
Allen AM, McKinley MJ, Mendelsohn FAO (1988b).
Comparative neuroanatomy of angiotensin II receptor localization in the mammalian hypothalamus. Clin Exp Pharmacol
Physiol 15: 137145.
Allen GC, Armfield DR, Bontempo FA, Kingsley LA, Goldstein
NA, Post C (1999). Adenotonsillectomy in children with von
Willebrand disease. Arch Otolaryngol Head Neck Surg 125:
547551.
Allen GV, Cechetto DF (1992). Functional and anatomical organization of cardiovascular pressor and depressor sites in the
lateral hypothalamic area. I. Descending projections. J Comp
Neurol 315: 313332.
Allen LS, Hines M, Shryne JE, Gorski RA (1989a). Two sexually dimorphic cell groups in the human brain. J Neurosci 9:
497506.
Allen LS, Hines M, Shryne JE, Gorski RA (1990). Sex difference in the bed nucleus of the stria terminalis of the human
brain. J Comp Neurol 302: 697706.
Allen LS, Gorski RA (1991). Sexual dimorphism of the anterior commissure and massa intermedia of the human brain.
J Comp Neurol 312: 97104.
Akil H, Richardson DE, Barchas JD (1979). Pain control by

focal brain stimulation in man: relationship to enkephalins
and endorphins. In: Mechanisms of Pain and Analgesic
Compounds. Beers RF, Bassett EG (Eds.) Raven Press, NY,
pp. 239247.
Akins PT, Roberts R, Coxe WS, Kaufman BA (1996). Familial
colloid cyst of the third ventricle: case report and review of
associated conditions. Neurosurgery 38: 392395.
Akita S, Readhead C, Stefaneanu L, Fine J, TampanaruSarmesiu A, Kovacs K, Melmed S (1997). Pituitary-directed
leukemia inhibitory factor transgene forms Rathkes cleft
cysts and impairs adult pituitary function. J Clin Invest 99:
24622469.
Akman CI, Schubert R, Duran M, Loh J (2002). Gelastic seizure
with tectal tumor, lobar holoprosencephaly, and
subependymal nodules: clinical report. J Child Neurol 17:
152154.
Aksel S, Tyrey L (1977). Luteinizing hormone-releasing
hormone in the human fetal brain. Fertility Sterility 28:
10671071.
Ala Y, Morin D, Mouillac B, Sabatier N, Vargas R, Cotte N,
Dchaux M, Antignac C, Arthus M-F, Lonergan M, Turner
MS, Balestre M-N, Alonso G, Hibert M, Barberis C, Hendy
GN, Bichet D, Jard S (1998). Functional studies of twelve
mutant V2 vasopressin receptors related to nephrogenic
diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 9: 18611872.
Alaca R, Yilmaz B, Gunduz S (2002). Anterior hypopituitarism
with unusual delayed onset of diabetes insipidus after penetrating head injury. Am J Phys Med Rehabil 81: 788791.
Al-Attia HM (1996). Gender identity and role in a pedigree of
Arabs with intersex due to 5-alpha-reductase-2 deficiency.
Psychoneuroendocrinology 21: 651657.
Alam MN, McGinty D, Szymusiak R (1995). Neuronal
discharge of preoptic/anterior hypothalamic thermosensitive
neurons: relation to NREM sleep. Am J Physiol 269:
R1240R1249.
Alam MN, McGinty D, Szymusiak R (1996). Preoptic/anterior
hypothalamic neurons: thermosensitivity in wakefulness and
non rapid eye movement sleep. Brain Res 718: 7682.
Alamowitch S, Graus F, Uchuya M, Re R, Bescansa E,
Delattre JY (1997). Limbic encephalitis and small cell lung
cancer. Clinical and immunological features. Brain 120:
923928.
Albert DJ, Walsh ML, Jonk RH (1993). Aggression in humans:
What is its biological foundation? Neurosci Biobehav Rev
17: 405425.
Albert SG, Nakra BRS, Grossberg GT, Caminal ER (1994).
Drinking behavior and vasopressin responses to hyperosmolality in Alzheimers disease. Int Psychogeriatrics 6: 7986.
Albertazzi E, Zanchetta D, Barbier P, Faranda S, Frattini A,
Vezzoni P, Procaccio M, Bettinelli A, Guzzi F, Parenti M,
Chini B (2000). Nephrogenic diabetes insipidus: functional
401
2014 Refs
402
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 402
D.F. SWAAB
Allen LS, Gorski RA (1992). Sexual orientation and the size

of the anterior commissure in the human brain. Proc Natl
Acad Sci USA 89: 71997202.
Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ (2002).
Increased CSF hypocretin-1 (orexin-A) in restless legs
syndrome. Neurology 59: 639641.
Allen SJ, Dowbarn D, Wilcock GK (1988a). Morphometrical
immunochemical analysis of neurons in the nucleus basalis
of Meynert in Alzheimers disease. Brain Res 454: 275281.
Allen SJ, Dawbarn D, Spillantini MG, Goedert M, Wilcock GK,
Moss TH, Semenenko M (1989b). Distribution of -nerve
growth factor receptors in the human basal forebrain. J Comp
Neurol 289: 626640.
Allevard-Burguburu AM, Geelen G, Sempor B, Louis F, Legros
JJ, Gharib C (1981). Urinary excretion of immunoreactive
vasopressin in prepubertal children. Lack of correlation with
urinary excretion of immunoreactive neurophysins. Eur J
Pediatr 137: 291294.
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC,
Infante MC, Weiden PJ (1999). Antipsychotic-induced weight
gain: a comprehensive research synthesis. Am J Psychiatry
156: 16861696.
Almeida Montes LG, Ontiveros Uribe MP, Corts Sotres J,
Heinze Martin G (2003). Treatment of primary insomnia with
melatonin: a double-blind, placebo-controlled, crossover
study. J Psychiatry Neurosci 28: 191196.
Alonso G, Szafarczyk A, Assenmacher I (1986). Radioautographic evidence that axons from the area of supraoptic
nuclei in the rat project to extrahypothalamic brain regions.
Neurosci Lett 66: 251256.
Alpers BJ (1937). Relation of the hypothalamus to disorders of
personality. Arch Neurol Psychiatr 38: 291303.
Alpers BJ (1940). Personality and emotional disorders associated
with hypothalamic lesions. In: The Hypothalamus and Central
Levels of Autonomic Function. Fulton JF, Hanson SW, Frantz
AM (Eds.) pp. 725752. Williams & Wilkins Company,
Baltimore.
Alpers BJ, Berry RG, Paddison RM (1959). Anatomical studies
of the circle of Willis in normal brain. Arch Neurol Psychiatr
81: 409418.
Alshail E, Rutka JT, Becker LE, Hoffman HJ (1997). Optic
chiasmatic-hypothalamic glioma. Brain Pathol 7: 799806.
Altamura AC (1996). Hypothalamic-pituitaryadrenal axis in
schizophrenia. Biol Psychiatry 40: 560561.
Altamura C, VanGastel A, Piolo R, Mannu P, Maes M (1999).
Seasonal and circadian rhythms in suicide in Calgiari, Italy.
J Affect Disord 53: 7785.
Altemus M, Pigott T, Kalogeras KT, Demitrack M, Dubbert B,
Murphy DL, Gold, PW (1992). Abnormalities in the regulation
of vasopressin and corticotropin releasing factor secretion in
obsessive-compulsive disorder. Arch Gen Psychiatr 49: 920.
Altemus, M, Swedo, SE, Leonard, HL, Richter, D, Rubinow, DR,
Potter, WZ, Rapoport, JL (1994). Changes in cerebrospinal
fluid neurochemistry during treatment of obsessive-compulsive

disorder with clomipramine. Arch Gen Psychiatry 51: 794803.
Altemus, M, Jacobson, KR, Debellis, M, Kling, M, Pigott, T,
Murphy, DL, Gold PW (1999). Normal CSF oxytocin and
NPY levels in OCD. Biol Psychiatry 45: 931933.
Altemus M, Dale JK, Michelson D, Demitrack MA, Gold PW,
Straus SE (2001). Abnormalities in response to vasopressin
infusion in chronic fatigue syndrome. Psychoneuroendocrinology 26: 175188.
Altschuler LE, Wisdom S (1999). An old case of pathological
laughing and crying. Lancet 354: 1736.
Alvarez E, Ferrer T, Prez-Conde C, Lpez-Terradas JM,
Prez-Jimnez A, Ramos MJ (1996). Evaluation of congenital
dysautonomia other than RileyDay Syndrome. Neuropediatrics 27: 2631.
Amatruda TT, Hurst MM, DEsopo ND (1965). Certain
endocrine and metabolic facets of the steroid withdrawal
syndrome. J Clin Endocrinol Metabol 25: 12071217.
Ambrosi B, Colombo P, Re T, Passini E, Bochicchio D (1995).
Effects of vasoactive intestinal peptide (VIP) and peptide
histidine methionine (PHM) on basal and corticotropinreleasing hormone (CRH)-stimulated ACTH/cortisol
secretion in Cushings disease. Neuroendocrinol Lett 17:
313318.
American Society of Human Genetics/American College of
Medical Genetics Test and Technology Transfer Committee
(1996). ASHG/ACMG report diagnostic testing for Prader
Willi and Angelman syndromes: report of the ASHG/ACMG
test and technology transfer committee. Am J Hum Genet
58: 10851088.
Amico JA, Tenicela R, Johnston J, Robinson AG (1983). A
time-dependent peak of oxytocin exists in cerebrospinal fluid
but not in plasma of humans. J Clin Endocrinol Metab 57:
947951.
Amico JA, Ulbrecht JS, Robinson AG (1987). Clearance studies
of OT in humans using radioimmunoassay measurements of
the hormone in plasma and urine. J Clin Endocrinol Metab
64: 340345.
Amico JA, Levin SC, Cameron JL (1989). Circadian rhythm of
oxytocin in the cerebrospinal fluid of rhesus and cynomolgus
monkeys: effect of castration and adrenalectomy and presence of a caudal-rostral gradient. Neuroendocrinology 50:
624632.
Aminoff MJ, Gross M (1974). Vasoregulatory activity in
patients with Huntingtons chorea. J Neurol Sci 21: 3338.
Aminoff MJ, Simon RP, Wiedemann E (1984). The hormonal
responses to generalized tonicclonic seizures. Brain 107:
569578.
Amore M, Balista C, McCreadie RG, Cimmino C, Pisano F,
Bevilacqua G, Ferrari G (2003). Can breast-feeding protect
against schizophrenia? Biol Neonate 83: 97101.
Amory JK, Anawalt BD, Paulsen CA, Bremner WJ (2000).
Klinefelters syndrome. Lancet 356: 333335.
2014 Refs
2/12/03
1:39 pm
Page 403
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
403
Andersson A-M, Carlsen E, Petersen JH, Skakkebk NE (2003).

Variation in levels of serum inhibin B, testosterone, estradiol,
luteinizing hormone, follicle-stimulating hormone, and sex
hormone-binding globulin in monthly samples from healthy
men during a 17-month period: possible effects of seasons.
J Clin Endocrinol Metab 88: 932937.
Andersson P-B, Goodkin DE (1998). Glucocorticosteroid
therapy for multiple sclerosis: a critical review. J Neurol Sci
160: 1625.
Andrade C, Srihari BS, Reddy KP, Chandramma L (2001).
Melatonin in medically ill patients with insomnia: a double
blind, placebo-controlled study. J Clin Psychiatry 62: 4145.
Andres C (2002). Molecular genetics and animal models in
autistic disorder. Brain Res Bull 57: 109119.
Andrew DR (1991). Seizure and acute osmotic change: clinical
and neurophysiological aspects. J Neurol Sci 101: 718.
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann
J, Adam S, Starr E, Squitieri F, Lin B, Kalchman RK, Hayden
MR (1993). The relationship between trinucleotide (CAG)
repeat length and clinical features of Huntingtons disease.
Nat Genet 4: 398403.
Andrico S, Gambera A, Specchia C, Pellegrini C, Falsetti L,
Sartori E (2002). Leptin in functional hypothalamic amenorrheoa. Hum Reprod 17: 20432048.
Andy OJ, Stephan H (1968). The septum in the human brain.
Anema JR, Heijenbrok MW, Faes TJC, Heimans JJ, Lanting P,
Polman CH (1991). Cardiovascular autonomic function in
multiple sclerosis. J Neurol Sci 104: 129134.
Angulo M, Castro-Magana M, Uy J (1991). Pituitary evaluation and growth hormone treatment in PraderWilli syndrome.
J Pediatr Endocrinol 4: 167173.
Angulo M, Castro-Magana M, Mazur B, Canas JA, Vitollo PM,
Sarrantonio M (1996). Growth hormone secretion and effects
of growth hormone therapy on growth velocity and weight
gain in children with PraderWilli syndrome. J Pediatr
Anichtchik OV, Rinne JO, Kalimo H, Panula P (2000). An
altered histaminergic innervation of the substantia nigra in
Parkinsons disease. Exp Neurol 163: 2030.
Annern G, Gustavson K-H, Sara VR, Tuvemo T (1990).
Growth retardation in Down syndrome in relation to insulinlike growth factors and growth hormone. Am J Med Gen
Suppl 7: 5962.
Ansorge O, Daniel SE, Pearce RKB (1997). Neuronal loss and
plasticity in the supraoptic nucleus in Parkinsons disease.
Neurology 49: 610613.
Ansseau M, Legros JJ, Mormont C, Cerfontaine JL, Papart P,
Geenen V, Adam F, Franck G (1987). Intranasal oxytocin in
obsessive compulsive disorder. Psychoneuroendocrinology
12: 231236.
Anthony JC, Breitner JCS, Zandi PP, Meyer MR, Jurasova I,
Norton MC, Stone SV (2000). Reduced prevalence of AD in
Ananth J, Lin K-M (1987). SIADH: a serious side effect of

psychotropic drugs. Int J Psychiatry Med 16: 401407.
Ancoli-Israel S, Klauber MR, Gillin JC, Campbell SS, Hofstetter
CR (1994). Sleep in non-institutionalized Alzheimers disease
patients. Aging Clin Exp Res 6: 451458.
Ancoli-Israel S, Klauber MR, Williams Jones D, Kripke DF,
Martin J, Mason W, Pat-Horenczyk R, Fell R (1997).
Variations in circadian rhythms of activity, sleep, and light
exposure related to dementia in nursing-home patients. Sleep
20: 1823.
Ancoli-Israel S, Schnierow B, Kelsoe J, Fink R (2001). A
pedigree of one family with delayed sleep phase syndrome.
Chronobiol Int 18: 831840.
Ancoli-Israel S, Martin JL, Kripke DF, Marler M, Klauber MR
(2002). Effect of light treatment on sleep and circadian
rhythms in demented nursing home patients. J Am Geriatr
Soc 50: 282289.
Anderka M, Declercq R, Smith W (2000). A time to be born.
Am J Public Health 90: 124126.
Anderson B (1992). Relief of akinetic mutism from obstructive
hydrocephalus using bromocriptine and ephedrine. J
Neurosurg 76: 152155.
Anderson CH (1981). Nucleolus: changes at puberty in neurons
of the suprachiasmatic nucleus and the preoptic area. Exp
Neurol 74: 780786.
Anderson E, Haymaker W (1974). Breakthroughs in hypothalamic and pituitary research. Prog Brain Res 41: 160.
Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A,
Copeland JRM, Dartigues J-F, Kragh-Sorensen P, Baldereschi
M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman
A (1999). Gender differences in the incidence of AD and
vascular dementia. Neurology 53: 19921997.
Anderson JL, Vasile RG, Mooney JJ, Bloomingdale KL, Samson
JA, Schildkraut JJ (1992a). Changes in norepinephrine output
following light therapy for fall/winter seasonal depression.
Anderson JR, Antoun N, Burnet N, Chatterjee K, Edwards O,
Pickard JD, Sarkies N (1999). Neurology of the pituitary
gland. J Neurol Neurosurg Psychiatry 66: 703721.
Anderson JW, Washburn DLS, Ferguson AV (2000). Intrinsic
osmosensitivity of subfornical organ neurons. Neuroscience
100: 539547.
Anderson RA, Bancroft J, Wu FCW (1992b). The effects of
exogenous testosterone on sexuality and mood of normal men.
Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi
SA, Ekstein J, Rubin BY (2001). Familial dysautonomia is
caused by mutations of the IKAP gene. Am J Hum Genet
68: 753758.
Anderson-Hunt M (1994). Increased female sexual response
after oxytocin. Br Med J 309: 929.
Anderson-Hunt M, Dennerstein L (1995). Oxytocin and female
sexuality. Gynecol Obstet Invest 40: 217221.
403
2014 Refs
404
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 404
D.F. SWAAB
users of NSAIDs and H2 receptor antagonists. Neurology 54:

20662071.
Antoch MP, Song E-J, Chang A-M, Hotz Vitaterna M, Zhao
Y, Wilsbacher LD, Sangoram AM, King DP, Pinto LH,
Takahashi JS (1997). Functional identification of the mouse
circadian clock gene by transgenic BAC rescue. Cell 89:
655667.
Antonijevic IA, Murck H, Frieboes R-M, Holsboer F, Steiger
A (1999). On the gender differences in sleep-endocrine
regulation in young normal humans. Neuroendocrinology 70:
280287.
Antonijevic IA, Murck H, Frieboes R-M, Uhr M, Steiger A
(2003). On the role of menopause for sleep-endocrine
alterations associated with major depression. Psychoneuroendocrinology 28: 401418.
Antonini SRR, Jorge SM, Moreira AC (2000). The emergence
of salivary cortisol circadian rhythm and its relationship to
sleep activity in preterm infants. Clin Endocrinol 52: 423426.
Antonini SRR, Grecco Filho A, Elias LLL, Moreira AC, Castro
M (2002). Cerebral midline developmental anomalies:
endocrine, neuroradiographic and opthalmological features. J
Pediatr Endocrinol Metab 15: 15251530.
Anwar MM, Moustafa MA (2001). The effect of melatonin on
eye lens of rats exposed to ultraviolet radiation. Comp
Biochem Physiol C Toxicol Pharmacol 129: 5763.
Apkarian P, Reits D, Spekreijse H, Van Dorp D (1983). A
decisive electrophysiological test for human albinism.
Electroencephalogr Clin Neurophysiol 55: 513531.
Apkarian P, Spekreijse H, Van Swaay E, Van Schooneveld M
(1989). Visual evoked potentials in PraderWilli syndrome.
Doc Ophthalmol 71: 355367.
Apkarian P, Bour L, Barth PG (1994). A unique achiasmatic
anomaly detected in non-albinos with misrouted retinal-fugal
projections. Eur J Neurosci 6: 501507.
Appenzeller O, Gross JE (1971). Autonomic deficits in
Parkinsons syndrome. Arch Neurol 24: 5057.
Appignani B, Landy H, Barnes P (1993). MR in idiopathic
central diabetes insipidus of childhood. Am J Neuroradiol 14:
1407 1410.
Apple D, Keines K, Biehl JP (1978). The syndrome of
inappropriate antidiuretic hormone secretion in multiple
sclerosis. Arch Intern Med 138: 17131714.
Aoki H, Ozeki Y, Yamada N (2001). Hypersensitivity of
melatonin suppression in response to light in patients with
delayed sleep phase syndrome. Chronobiol Int 18: 263271.
Arai H, Moroji T, Kosaka K (1984a). Somatostatin and vasoactive intestinal polypeptide in postmortem brain from
patients with Alzheimer-type dementia. Neurosci Lett 52:
7378.
Arai H, Kosaka K, Iizuka R (1984b). Changes of biogenic
amines and their metabolites in postmortem brains from
patients with Alzheimer-type dementia. J Neurochem 43:
388393.
Arai H, Moroji T, Kosaka K, Iizuka R (1986). Extrahypophyseal

distribution of -melanocyte stimulating hormone (-MSH)like immunoreactivity in postmortem brains from normal
subjects and Alzheimer-type dementia patients. Brain Res
377: 305310.
Arancibia S, Rage F, Astier H, Tapia-Arancibia L (1996).
Neuroendocrine and autonomous mechanisms underlying
thermoregulation in cold environment. Neuroendocrinology
64: 257267.
Arango V, Underwood MD, Mann JJ (1996). Fewer pigmented
locus coeruleus neurons in suicide victims: preliminary
results. Biol Psychiatry 39: 112120.
Arat M, Bnki CM, Bissette G, Nemeroff CB (1989). Elevated
CSF CRF in suicide victims. Biol Psychiatry 25: 355359.
Araujo DM, Lapchak PA, Robitaille Y, Gauthier S, Quirion R
(1988). Differential alteration of various cholinergic markers
in cortical and subcortical regions of human brain in
Alzheimers disease. J Neurochem 50: 19141923.
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999).
The role of corticotropin-releasing factor in depression and
anxiety disorders. J Endocrinol 160: 112.
Arduini D, Rizzo G, Parlati E, Giorlandino C, Valensise H,
DellAcqua S, Romanini C (1986). Modifications of ultradian
and circadian rhythms of fetal heart rate after fetal-maternal
adrenal gland suppression: a double-blind study. Prenat Diagn
6: 409417.
Arduini D, Rizzo G, Parlati E, DellAcqua S, Romanini C,
Mancuso S (1987). Loss of circadian rhythms of fetal
behaviour in a totally adrenalectomized pregnant woman.
Gynecol Obstet Invest 23: 226229.
Ardura J, Gutierrez R, Andres J, Agapito T (2003). Emergence
and evolution of the circadian rhythm of melatonin in
children. Horm Res 59: 6672.
Arem R, Wiener GJ, Kaplan SG, Kim H-S, Reichlin S, Kaplan
M (1993). Reduced tissue thyroid hormone levels in fatal
illness. Metabolism 42: 11021108.
Arendt J (2000). In what circumstances is melatonin a useful
sleep therapy? WFSRS Focus Group, Dresden. J Sleep Res
9: 397398.
Arendt J, Bhanji S, Franey C, Mattingly D (1992). Plasma
melatonin levels in anorexia nervosa. Br J Psychiatry 161:
361364.
Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S
(1997). Efficacy of melatonin treatment in jet lag, shift work,
and blindness. J Biol Rhythms 12: 604617.
Arendt T, Bigl V, Arendt A, Tennstedt A (1983). Loss of
neurons in the nucleus basalis of Meynert in Alzheimers
disease, paralysis agitans and Korsakoffs disease. Acta
Neuropathol (Berl) 61: 101108.
Arendt T, Bigl V, Arendt A (1984). Neuron loss in the nucleus
basalis of Meynert in CreutzfeldtJakob Disease. Acta
Arendt T, Brckner MK, Bigl V, Marcova L (1995). Dendritic
reorganisation in the basal forebrain under degenerative
2014 Refs
2/12/03
1:39 pm
Page 405
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
405
Arita K, Ikawa F, Kurisu K, Sumida M, Harada K, Uozumi T,

Monden S, Yoshida J, Nishi Y (1999). The relationship
between magnetic resonance imaging findings and clinical
manifestations of hypothalamic hamartoma. J Neurosurg 91:
212220.
Ariznavarretta C, Cardinali DP, Villana MA, Granados B,
Martn M, Chiesa JJ, Golombek DA, Tresguerres JAF (2002).
Circadian rhythms in airline pilots submitted to long-haul
transmeridian flights. Aviat Space Environ Med 73: 445.
Arjona VE (1974). Stereotactic hypothalamotomy in erethic
children. Acta Neurochir Suppl 21: 185191.
Arletti R, Benelli A, Bertolini A (1989). Influence of oxytocin
on feeding behavior in the rat. Peptides 10: 8993.
Arletti R, Benelli A, Bertolini A (1992). Oxytocin involvement
in male and female sexual behavior. In: Pedersen CA,
Caldwell JD, Jirikowski GF, Insell TR (Eds.) Oxytocin in
maternal, sexual, and social behaviors, Vol. 652, pp. 180193.
NY Acad Sci, New York.
Arlt W, Hove U, Mller B, Reincke M, Berweiler U, Schwab
F, Allolio B (1997). Frequent and frequently overlooked:
treatment-induced endocrine dysfunction in adult longterm survivors of primary brain tumors. Neurology 49:
498506.
Armbruster-Moraes E, Schultz R, De Lourdes-Brizot M,
Miyadahira S, Zugaib M (1999). Holoprosencephaly in a
Klinefelter fetus. Am J Med Genet 85: 511512.
Armstrong DD (1997). Review of Rett syndrome. J Neuropathol
Exp Neurol 56: 843849.
Arnell H, Gustafsson J, Ivarsson SA, Annern G (1996). Growth
and pubertal development in Down syndrome. Acta Paediatr
85: 11021106.
Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW
(1991). The topographical and neuroanatomical distribution
of neurofibrillary tangles and neuritic plaques in the cerebral
cortex of patients with Alzheimers disease. Cereb Cortex 1:
103116.
Arnow BA, Desmond JE, Banner LL, Glover GH, Solomon A,
Lake Polan M, Lue TF, Atlas SW (2002). Brain activation
and sexual arousal in healthy, heterosexual males. Brain 125:
10141023.
Arnulf I, Konofal E, Merino-Andreu M, Houeto JL, Mesnage
V, Welter ML, Lacomblez L, Golmard JL, Derenne JP, Agid
Y (2002). Parkinsons disease and sleepiness. An integral part
of PD. Neurology 58: 10191024.
Aromki AS, Lindman RE, Eriksson CJP (1999). Testosterone,
aggressiveness, and antisocial personality. Aggress Behav 25:
113123.
Aronson R, Offman HJ, Joffe RT, Naylor D (1996). Triiodothyronine augmentation in the treatment of refractory
depression. Arch Gen Psychiatry 53: 842848.
Arosio M, Cortelazzi D, Persani L, Palmieri E, Casati G,
Baggiani AM, Gambino G, Beck-Peccoz P (1995).
Circulating levels of growth hormone, insulin-like growth
conditions and its defects in Alzheimers disease. II. Ageing,

Korsakoffs disease, Parkinsons disease, and Alzheimers
disease. J Comp Neurol 351: 189222.
Arendt T, Schindler C, Brckner MK, Eschrich K, Bigl V,
Zedlick D (1997). Plastic neuronal remodeling is impaired in
patients with Alzheimers disease carrying apolipoprotein 4
allele. J Neurosci 17: 516529.
Arginteanu MS, Hague K, Zimmerman R, Kupersmith MJ,
Shaiu JH, Schaeffer J, Post KD (1997). Craniopharyngioma
arising de novo in middle age. J Neurosurg 86: 10461048.
Argiolas A (1992). Oxytocin stimulation of penile erection:
pharmacology, site, and mechanism of action. In: Pedersen
CA, Caldwell JD, Jirikowski GF, Insell TR (Eds.) Oxytocin
in maternal, sexual, and social behaviors, Vol. 652,
pp. 194203. NY Acad Sci, New York.
Argiolas A (1999). Neuropeptides and sexual behaviour.
Neurosci Biobehav Rev 23: 11271142.
Argiolas A, Melis MR, Gessa GL (1986). Oxytocin: an
extremely potent inducer of penile erection and yawning in
male rats. Eur J Pharmacol 130: 265272.
Argyropoulou M, Perignon F, Brauner R, Brunelle F (1992).
Magnetic resonance imaging in the diagnosis of growth
hormone deficiency. J Pediatr 120: 886891.
Aric M, Egeler M (1998). Clinical aspects of Langerhans cell
histiocytosis. Hematol Oncol Clin North Am 12: 247258.
Arins-Kappers J (1955). The development of the paraphysis
cerebri in man with comments on its relationship to the intercolumnar tubercle and its significance for the origin of cystic
tumors in the third ventricle. J Comp Neurol 102: 425509.
Arins-Kappers J (1965). Survey of the innervation of the epiphysis cerebri and the accessory pineal gland organ of
vertebrates. Prog Brain Res 10: 87151.
Arieti S (1954). The pineal gland in old age. J Neuropathol Exp
Neurol 13: 482491.
Arii J, Kanbayashi T, Tanabe Y, Ono J, Nishino S, Kohno Y
(2001). A hypersomnolent girl with decreased CSF hypocretin
level after removal of a hypothalamic tumor. Neurology 56:
17751776.
Arimura A (1992). Pituitary adenylate cyclase activating
polypeptide (PACAP): discovery and current status of
research. Regul Pept 37: 287303.
Arisaka O, Arisaka M, Ikebe A, Niijima S, Shimura N, Hosaka
A, Yabuta K (1992). Central diabetes insipidus in hypoxic
brain damage. Childs Nerv Syst 8: 8182.
Arisaka O, Negishi M, Numata M, Hoshi M, Kanazawa S,
Oyama M, Nitta A, Suzumuara H, Kuribayashi T, Nakayama
Y (2001). Precocious puberty resulting from congenital hypothalamic hamartoma: persistent darkened areolae after birth
as the hallmark of estrogen excess. Clin Pediatr 40: 163167.
Arita K, Kurisu K, Iida K, Hanaya R, Akimitsu T, Hibino S,
Pant B, Hamasaki M, Shinagawa S (1998). Subsidence of
seizure induced by stereotactic radiation in a patient with
hypothalamic hamartoma. J Neurosurg 89: 645648.
405
2014 Refs
406
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 406
D.F. SWAAB
factor-1 and prolactin in normal, growth retarded and anencephalic human fetuses. J Endocrinol Invest 18: 346353.
Arranz B, Blennow K, Eriksson A, Mnsson J-E, Marcusson J
(1997). Serotonergic, noradrenergic, and dopaminergic
measures in suicide brains. Biol Psychiatry 41: 10001009.
Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL,
Housman DE, Evans RM (1987). Cloning of human mineralocorticoid receptor complementary DNA: structural and
functional kinship with the glucocorticoid receptor. Science
237: 268275.
Arroyo S, Lesser RP, Gordon B, Uematsu S, Hart J, Schwerdt
P, Andreasson K, Fisher RS (1993). Mirth, laughter and
gelastic seizures. Brain 116: 757780.
Arroyo S, Santamara J, Sanmart F, Lomea F, Catafau A,
Casamitjana R, Setoain J, Tolosa E (1997). Ictal laughter
associated with paroxysmal hypothalamopituitary dysfunction. Epilepsia 38: 114117.
Arslanian SA, Rothfus WE, Foley TP, Becker DJ (1984).
Hormonal, metabolic, and neuroradiologic abnormalities
associated with septo-optic dysplasia. Acta Endocrinol 107:
282288.
Arthus M-F, Lonergan M, Crumley MJ, Naumova AK, Morin
D, De Marco LA, Kaplan BS, Robertson GL, Sasaki S,
Morgan K, Bichet DG, Fujiwara TM (2000). Report of 33
novel AVPR2 mutations and analysis of 117 families with
X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol
11: 10441054.
Asa SL, Bilbao JM, Kovacs K, Linfoot JA (1980). Hypothalamic
neuronal hamartoma associated with pituitary growth
hormone cell adenoma and acromegaly. Acta Neuropathol
52: 231234.
Asa SL, Kovacs K, Bilbao JM, Penz G (1981). Immunohistochemical localization of keratin in craniopharyngiomas
and squamous cell nests of the human pituitary. Acta
Neuropathol 54: 257260.
Asa SL, Scheithauer BW, Bilbao JM, Horvath E, Ryan N,
Kovacs K, Randall RV, Laws ER, Singer W, Linfoot JA,
Thorner MO, Vale W (1984). A case for hypothalamic
acromegaly: a clinicopathological study of six patients with
hypothalamic gangliocytomas producing growth hormonereleasing factor. J Clin Endocrinol Metabol 58: 796803.
Asano E, Kuivaniemi H, Huq AHMM, Tromp G, Behen M,
Rothermel R, Herron J, Chugani DC (2001). A study of novel
polymorphisms in the upstream region of vasoactive intestinal
peptide receptor type 2 gene in autism. J Child Neurol 16:
357363.
Asfar P (2003). Terlipressin in chronic hyperdynamic endotoxic
shock: is it safe? Intensive Care Med 29: 154155.
Asher R (1949). Myxoedematous madness. Br Med J 2:
555562.
Asherson RA, Jackson WPU, Lewis B (1965). Abnormalities
of development associated with hypothalamic calcification
after tuberculous meningitis. Br Med J 2: 839843.
Ashkenazi IE, Reinberg A, Bicakova-Rocher A, Ticher A

(1993). The genetic background of individual variations of
circadian-rhythm periods in healthy human adults. Am J Hum
Genet 52: 12501259.
Askenasy JJM (1987). The functions and dysfunctions of
laughter. J Gen Psychol 114: 317334.
Askenasy JJM (1993). Sleep in Parkinsons disease. Acta Neurol
Scand 87: 167170.
Askenasy JJM, Yahr MD (1985). Reversal of sleep disturbance
in Parkinsons disease by antiparkinsonian therapy: a preliminary study. Neurology 35: 527532.
Askenasy JJM, Yahr MD (1990). Parkinsonian tremor loses its
alternating aspect during non-REM sleep and is inhibited by
REM sleep. J Neurol Neurosurg Psychiatry 53: 749753.
Asplund R (1999). Sleep disorders in the elderly. Drugs Aging
14: 91103.
Asplund R, berg H (1991). Diurnal variation in the levels of
antidiuretic hormone in the elderly. J Intern Med 229:
131134.
Asplund R, berg H, Wetterberg L (1998). The seasonal interrelationship between melatonin, vasopressin, and serum
osmolality in elderly subjects. J Pineal Res 25: 6772.
Assies J, Gooren LJG, Van Geel B, Barth PG (1997). Signs of
testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a
retrospective study. Int J Androl 20: 315321.
Assouline S, Shevell MI, Zatorre RJ, Jones-Gotman M, Schloss
MD, Oudjhane K (1998). Children who cant smell the coffee:
isolated congenital anosmia. J Child Neurol 13: 168172.
Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS,
Lofgreen CP, Veith RC, Plymate SR (1999). Cognitive and
neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimers disease: results of a
placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 24: 657677.
Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind
MA, Plymate SR (2001). High-dose estradiol improves cognition for women with AD. Neurology 57: 605612.
strm C (1995). Interaction between sleep and growth
hormone. Acta Neurol Scand 92: 281296.
Au Eong KG, Hariharan S, Chua EC, Leong S, Wong MC,
Tseng PSF, Yong VSH (1997). Idiopathic intracranial hypertension, empty sella turcica and polycystic ovary syndrome
a case report. Singapore Med J 38: 129130.
Austin CP, Lessell S (1991). Horners syndrome from hypothalamic infarction. Arch Neurol 48: 332334.
Autret A (1997). Sleep and neurological diseases. J Neurol
(Suppl 1) 244: S1S2.
Autret A, Lucas B, Hommet C, Corcia P, De Toffol B
(1997). Sleep and the epilepsies. J Neurol (Suppl 1) 244:
S10S17.
Autret A, Lucas B, Mondon K, Hommet C, Corcia P, Saudeau
D, De Toffol B (2001). Sleep and brain lesions: a critical
2014 Refs
2/12/03
1:39 pm
Page 407
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
407
Badino R, Caja A, Del Conte I, Guida C, Ivaldi M (1992).

KleineLevin syndrome in an 82-year-old man. Ital J Neurol
Sci 13: 355356.
Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver
DR (2001). Differential functions of mPer1, mPer2, and
mPer3 in the SCN circadian clock. Neuron 30: 525536.
Baehr EK, Revelle W, Eastman CI (2000). Individual differences in the phase and amplitude of the human circadian
temperature rhythm: with an emphasis on morningness
eveningness. J Sleep Res 9: 117127.
Baghai TC, Schule C, Zwanzger P, Minov C, Zill P,
Ella R, Eser D, Oezer S, Bondy B, Rupprecht R (2002).
Hypothalamic-pituitary-adrenocortical axis dysregulation in
patients with major depression is influenced by the insertion/deletion polymorphism in the angiotensin-I-converting
enzyme gene. Neurosci Lett 328: 299303.
Baghdoyan HA (1997). Cholinergic mechanisms regulating
REM sleep In: Schwarz WJ (Ed.) Sleep Science: Integrating
Basic Research and Clinical Practice (Monogr Clin Neurosci),
Vol. 15, pp. 88116. Basel, Karger.
Bagley, C. (1992) Maternal smoking and deviant-behavior in
16-year-olds a personal hypothesis. Pers Indiv Differences
13: 377378.
Bahn S, Augood SJ, Ryan M, Standaert DG, Starkey M, Emson
PC (2001). Gene expression profiling in the post-mortem human
brain no cause for dismay. J Chem Neuroanat 22: 7994.
Bahnsen U, Oosting P, Swaab DF, Nahke P, Richter D,
Schmale H (1992). A missense mutation in the vasopressinneurophysin precursor gene cosegregates with human autosomal dominant neurohypophyseal diabetes insipidus. EMBO
J 11: 1923.
Bailey JM, Bell AP (1993). Familiality of female and male
homosexuality. Behav Genet 23: 313322.
Bailey JM, Willerman L, Parks C (1991). A test of the maternal
stress theory of human male homosexuality. Arch Sex Behav
20: 277293.
Bailey JM, Pillard RC, Dawood K, Miller MB, Farrer LA,
Trivedi S, Murphy RL (1999). A family history study of male
sexual orientation using three independent samples. Behav
Genet 29: 7986.
Baischer W, Koinig G, Hartmann B, Huber J, Langer G (1995).
Hypothalamic-pituitary-gonadal axis in depressed premenopausal women: elevated blood testosterone concentrations
compared to normal controls. Psychoneuroendocrinology 20:
553559.
Baker AB, Cornwell S, Brown IA (1952). Poliomyelitis. VI.
The Hypothalamus. Arch Neurol Psychiatr 68: 1636.
Baker BL (1977). Cellular composition of the human pituitary
pars tuberalis as revealed by immunocytochemistry. Cell
Tissue Res 182: 151163.
Baker FC, Driver HS, Rogers GG, Paiker J, Mitchell D (1999).
High nocturnal body temperatures and disturbed sleep in women
with primary dysmenorrhea. Am J Physiol 277: E1013E1021.
review of the literature and additional new cases.

Neurophysiol Clin 31: 356375.
Avery D, Lenz M, Landis C (1998). Guidelines for prescribing
melatonin. Ann Med 30: 122130.
Avery DH, Eder DN, Bolte MA, Hellekson CJ, Dunner DL,
Vitiello MV, Prinz PN (2001). Dawn simulation and bright
light in the treatment of SAD: a controlled study. Biol
Avoni P, Cortelli P, Montagna P, Tinuper P, Sforza E, Contin
M, Parchi P, Pierangeli G, Maltoni P, Pavani A, Portaluppi
F, Baruzzi A, Cappelli M, Degli Uberti E, Gambetti P,
Lugaresi E (1991). Circadian hormonal rhythms in two
new cases of fatal familial insomnia. Acta Neurol 13:
574576.
Awaki E, Takeshima T, Takahashi K (1989). A neuroendocrinological study in female migraineurs: prolactin and
thyroid stimulating hormone responses. Cephalagia 9:
187193.
Awata T, Inoue K, Kurihara S, Ohkubo T, Inoue I, Abe T,
Takino H, Kanazawa Y, Katayama S (2000). Missense
variations of the gene responsible for Wolfram syndrome
(WFS1/wolframin) in Japanese: possible contribution of the
Arg456His mutation to type 1 diabetes as a nonautoimmune
genetic basis. Biochem Biophys Res Commun 268: 612616.
Awazu M, Matsuoka S, Kamimaki T, Watanabe H, Matsuo N
(2000). Absent circadian variation of blood pressure in
patients with anorexia nervosa. J Pediatr 136: 524527.
Awerbuch GI, Sandyk R (1992). Autonomic functions in the
early stages of Parkinsons disease. Intern J Neurosci 64:
714.
Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB,
Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH,
Krishnan KRR (1993). Hypercortisolemia and hippocampal
changes in depression. Psychiatry Res 47: 163173.
Aydan F, Ghatak NR (1994). Dystopic neurohypophysis. Endocr
Pathol 5: 7278.
Ayus JC, Wheeler JM, Arieff AI (1992). Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med
117: 891897.
Baccetti B, La Marca A, Piomboni P, Capitani S, Bruni E,
Petraglia F, De Leo V (2002). Insulin-dependent diabetes in
men is associated with hypothalamo-pituitary derangement
and with impairment in semen quality. Hum Reprod 17:
26732677.
Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger
A, DAgostino RB, White LR (1992). Prevalence of dementia
and probable senile dementia of the Alzheimer type in the
Framingham study. Neurology 42: 115119.
Badaut J, Nehlig A, Verbavatz J-M, Stoeckel M-E, FreundMercier M-J, Lasbennes F (2000). Hypervascularization in
the magnocellular nuclei of the rat hypothalamus: relationship
with the distribution of aquaporin-4 and markers of energy
metabolism. J Neuroendocrinol 12: 960969.
407
2014 Refs
408
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 408
D.F. SWAAB
Baker FC, Waner JI, V ieira EF, Taylor SR, Driver HS, Mitchell
D (2001). Sleep and 24-hour body temperatures: a comparison
in young men, naturally cycling women and women taking
hormonal contraceptives. J Physiol (Lond) 530: 565574.
Baker JW, Yerger S, Segar WE (1974). Elevated plasma
antidiuretic hormone levels in status asthmaticus. Mayo Clin
Proc 51: 3134.
Bakheit AMO, Behan PO, Dinan TG, Gray CE, OKeane V
(1992). Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue
syndrome. Br Med J 304: 10101012.
Bakheit AMO, Behan PO, Watson WS, Morton JJ (1993).
Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurol
Scand 87: 234238.
Bakker J, Van Ophemert J, Slob AK (1993). Organization
of partner preference and sexual behavior and its nocturnal rhythmicity in male rats. Behav Neuroscience 107: 10491058.
Balashov KE, Olek MJ, Smith DR, Khoury SJ, Weiner HL
(1998). Seasonal variation of interferon- production in
progressive multiple sclerosis. Ann Neurol 44: 824828.
Balasubramaniam A (1997). Neuropeptide Y family of hormones:
receptor subtypes and antagonists. Peptides 18: 445457.
Balasubramaniam V, Kanaka TS (1975). Amygdalotomy and
hypothalamotomy a comparative study. Confin Neurol 37:
195201.
Balcer LJ, Winterkorn JMS, Galetta SL (1997). Neuroophthalmic manifestations of Lyme disease. J Neuro
Ophthalmol 17: 108121.
Balestri P, Grosso S (2000). Endocrine disorders in two sisters
affected by MELAS syndrome. J Child Neurol 15: 755758.
Balkhoyor KB, Bernstein M (2000). Involution of diencephalic
pilocytic astrocytoma after partial resection. J Neurosurg 93:
484486.
Ball JD (1997). Sleep patterns among children with attentiondeficit hyperactivity disorder: a reexamination of parent
perceptions. J Pediatr Psychol 22: 389398.
Ball SG, Vaidja B, Baylis PH (1997). Hypothalamic adipsic
syndrome: diagnosis and management. Clin Endocrinol 47:
405409.
Ballering LAP, Steffens-Nakken HM, Esselink RAJ, De Vos
RAI, Jansen Steur ENH, Vermes I (1997). Apolipoprotein E
genotyping in patients with neurodegenerative diseases. Clin
Biochem 30: 405411.
Ballerini C, Campani D, Rombol G, Gran B, Nacmias B, Amato
MP, Siracusa G, Bartolozzi L, Sorbi S, Massacesi L (2000).
Association of apolipoprotein E polymorphism to clinical
heterogeneity of multiple sclerosis. Neurosci Lett 296:
174176.
Balligand JL, Brichard SM, Brichard V, Desager JP, Lambert
M (1998). Hypoleptinemia in patients with anorexia nervosa:
loss of circadian rhythm and unresponsiveness to short-term
refeeding. Eur J Endocrinol 138: 415420.
Ban Y, Shigeyoshi Y, Okamura H (1997). Development of

vasoactive intestinal peptide mRNA rhythm in the rat suprachiasmatic nucleus. J Neurosci 17: 39203931.
Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K,
Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K,
Wisniewski HM (1989). Accumulation of abnormally
phosphorylated tau precedes the formation of neurofibrillary
tangles in Alzheimers disease. Brain Res 477: 9099.
Bancroft J (1999). Cardiovascular and endocrine changes
during sexual arousal and orgasm. Psychosom Med 61:
290291.
Bandelow B, Wedekind D, Pauls J, Broocks A, Hajak G, Rther
E (2000a). Salivary cortisol in panic attacks. Am J Psychiatry
157: 454456.
Bandelow B, Wedekind D, Sandvoss V, Broocks A, Hajak G,
Pauls J, Peter H, Rther E (2000b). Diurnal variation of
cortisol in panic disorder. Psychiatry Res 95: 245250.
Banger M (2002). Affective syndrome during perimenopause.
Maturitas 41 (Suppl 1): S13S18.
Banki CM, Bissette G, Arato M, OConnor L, Nemeroff CB
(1987). CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry
144: 873877.
Banki CM, Karmacsi L, Bissette G, Nemeroff CB (1992).
Cerebrospinal fluid neuropeptides in mood disorder and
dementia. J Affect Disord 25: 3946.
Barajas MA, Ramrez-Guzmn G, Rodrguez-Vsquez C,
Toledo-Buenrostro V, Velsquez-Santana H, Del Valle
Robles R, Cuevas-Solrzano A, Rodrguez-Hernndez G
(2002). Multimodal management of craniopharyngiomas:
neuroendoscopy, microsurgery, and radiosurgery. J Neurosurg
(Suppl 5) 97: 607609.
Barak LS, Oakley RH, Laporta SA, Caron MG (2001).
Constitutive arrestin-mediated desensitization of a human
vasopressin receptor mutant associated with nephrogenic
diabetes insipidus. Proc Natl Acad Sci 98: 9398.
Baranowska B (1990). Are disturbances in opioid and adrenergic
systems involved in the hormonal dysfunction of anorexia
nervosa. Psychoneuroendocrinology 15: 371379.
Barberis C, Mouillac B, Durroux T (1998). Structural bases of
vasopressin/oxytocin receptor function. J Endocrinol 156:
223229.
Barden N, Reul JMHM, Holsboer F (1995). Do antidepressants
stabilize mood through actions on the hypothalamic-pituitaryadrenocortical system? Trends Neurosci 18: 611.
Bardoux P, Martin H, Ahloulay M, Schmitt F, Bouby N, TrinhTan M-M, Bankir L (1999). Vasopressin contributes to
hyperfiltration, albuminuria, and renal hypertrophy in diabetes
mellitus: study in vasopressin-deficient Brattleboro rats. Proc
Natl Acad Sci USA 96: 1039710402.
Bargmann W (1949). Uber die Neurosekretorische Verknpfung
von Hypothalamus und Neurohypophyse. Z Zellforsch 34:
610634.
2014 Refs
2/12/03
1:39 pm
Page 409
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
409
Barron WM, Cohen LH, Ulland LA, Lassiter WE, Fulghum

EM, Emmanouel D, Robertson G, Lindheimer MD (1984).
Transient vasopressin-resistant diabetes insipidus of pregnancy. N Engl J Med 310: 442444.
Barron WM, Durr JA, Stamoutsos BA, Lindheimer MD (1985).
Osmoregulation during pregnancy in homozygous and
heterozygous Brattleboro rats. Am J Physiol 248: R29R37.
Barry J (1954). Neurocrinie et synapses neuroscrtoires. Arch
Anat Microsc Morphol Exp 43: 310320.
Barry J (1977). Immunofluorescence study of LRF neurons in
man. Cell Tissue Res 181: 114.
Barry VC, Klawans HL (1976). On the role of dopamine in the
pathophysiology of anorexia nervosa. J Neural Transm 38:
107122.
Barsh G (1999). From agouti to pomc 100 years of fat blonde
mice. Nat Med 5: 984985.
Bartanusz V, Jezova D, Bertini LT, Tilders FJH, Aubry JM,
Kiss JZ (1993). Stress-induced increase in vasopressin and
corticotropin-releasing factor expression in hypophysiotrophic
paraventricular neurons. Endocrinology 132: 895902.
Bartels M, Van den Berg M, Sluyter F, Boomsma DI, De Geus
EJC (2003). Heritability of cortisol levels: review and simultaneous analysis of twin studies. Psychoneuroendocrinology
28: 121137.
Barthez M-A, Araujo E, Donadieu J (2000). Langerhans cell
histiocytosis and the central nervous system in childhood:
evolution and prognostic factors. Results of a collaborative
study. J Child Neurol 15: 150156.
Bartke A (1998). Growth hormone and aging. Endocrine 8:
103108.
Bartsch H, Buchberger A, Franz H, Bartsch C, Maidonis I,
Mecke D, Bayer E (2000). Effect of melatonin and pineal
extracts on human ovarian and mammary tumor cells in a
chemosensitivity assay. Life Sci 67: 29532960.
Bartus RT, Dean RL III Beer B, Lippa AS (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science
217: 408417.
Baruk MH (1936). Les hallucinations visuelles. Bull Soc
Ophtalmol Fr 2: 713739.
Barwick VS, Wooten MH, Bradfield JF, Myers RD (1994).
Fever of unknown origin: due to C albicans or other fungi
acting on the hypothalamus? Brain Res 635: 18.
Baskett JJ, Wood PC, Broad JB, Duncan JR, English J, Arendt
J (2001). Melatonin in older people with age-related sleep
maintenance problems: a comparison with age-matched
normal sleepers. Sleep 24: 418424.
Baskett JJ, Broad JB, Wood PC, Duncan JR, Pledger MJ,
English J, Arendt J (2003). Does melatonin improve sleep in
older people? A randomised crossover trial. Age Ageing 32:
164170.
Baskin DG, Breininger JF, Bonigut S, Miller MA (1999). Leptin
binding in the arcuate nucleus is increased during fasting.
Brain Res 828: 154158.
Bargmann W (1954). Das Zwischenhirn-hypophysensystem (p.

89). Springer, Berlin.
Barinaga M (1999). CRYs clock role differs in mice, flies.
Science 285: 506507.
Barinaga M (2002). How the brains clock gets daily enlightenment. Science 295: 955956.
Barkan AL, Clemmons DR, Molitch ME, Stewart PM, Young Jr
WF (2000). Growth hormone therapy for hypopituitary adults:
time for re-appraisal. Trends Endocrinol Metab 11: 238245.
Barkan AL, Dimaraki EV, Jessup SK, Symons KV, Ermolenko
M, Jaffe CA (2003). Ghrelin secretion in humans is sexually
dimorphic, suppressed by somatostatin, and not affected by
the ambient growth hormone levels. J Clin Endocrinol Metab
88: 21802184.
Barontini M, Garca-Rudaz MC, Veldhuis JD (2001).
Mechanisms of hypothalamic-pituitary-gonadal disruption in
polycystic ovarian syndrome. Arch Med Res 32: 544552.
Barrande G, Kujas M, Gancel A, Turpin G, Bruckert E, Kuhn
JM, Luton JP (1995). Les tumeurs a cellules granuleuses.
Presse Med 24: 13761380.
Barreca T, Francheschini R, Siani C, Messina V, Francaviglia
N, Perria C, Rolandi E (1988). Diurnal pattern of plasma and
cerebrospinal-fluid vasopressin levels in hydrocephalic
patients: absence of a circadian rhythm and of a correlation
between plasma and cerebrospinal-fluid variations. Horm Res
30: 2831.
Barreca T, Gandolfo C, Corsini G, Del Sette M, Cataldi A,
Rolandi E, Franceschini R (2001). Evaluation of the secretory
pattern of plasma arginine vasopressin in stroke patients.
Cerebrovasc Dis 11: 113118.
Barrett TG, Bundey SE, Macleod AF (1995). Neurodegeneration
and diabetes: UK nationwide study of Wolfram (DIDMOAD)
syndrome. Lancet 346: 14581463.
Barrett TG, Bundey SE (1997). Wolfram (DIDMOAD)
syndrome. J Med Genet 34: 838841.
Barrett-Connor E, Goodman-Gruen D, Patay B (1999a).
Endogenous sex hormones and cognitive function in older
men. J Clin Endocrinol Metabol 84: 36813685.
Barrett-Connor E, Von Mhlen DG, Kritz-Silverstein D (1999b).
Bioavailable testosterone and depressed mood in older men:
the Rancho Bernardo study. J Clin Endocrinol Metabol 84:
573577.
Barrientos A, Casademont J, Saiz A, Cardellach F, Volpini V,
Solans A, Tolosa E, Urbano-Mrquez A, Estivill X,
Nunes V (1996a). Autosomal recessive Wolfram syndrome
associated with an 85-kb mtDNA single deletion. Am J Hum
Genet 58: 963970.
Barrientos A, Volpini V, Casademont J, Genis D, Manzanares
J-M, Ferrer I, Corral J, Cardellach F, Urbano-Mrquez A,
Estivill X, Nunes V (1996b). A nuclear defect in the 4p16
region predisposes to multiple mitochondrial DNA deletions
in families with Wolfram syndrome. J Clin Invest 97:
15701576.
409
2014 Refs
410
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 410
D.F. SWAAB
Bassett AS, Bury A, Hodgkinson KA, Honer WG (1996).

Reproductive fitness in familial schizophrenia. Schizophrenia
Res 21: 151160.
Bassett JHD, OHalloran DJ, Williams GR, Beardwell CG,
Shalet SM, Thakker RV (1999). Novel DAX1 mutations in
X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism. Clin Endocrinol 50: 6975.
Bastrup-Madsen P, Greisen O (1963). Hypothalamic obesity in
acute leukaemia. Acta Haematol 29: 109116.
Batch JA, Williams DM, Davies HR, Brown BD, Evans BAJ,
Hughes IA, Patterson MN (1992). Role of the androgen
receptor in male sexual differentiation. Horm Res 38:
226229.
Bath LE, Anderson RA, Critchley HOD, Kelnar CJH, Wallace
WHB (2001). Hypothalamic-pituitaryovarian dysfunction
after prepubertal chemotherapy and cranial irradiation for
acute leukaemia. Hum Reprod 16: 18381844.
Battacharji SK, Hutchinson EC, McCall AJ (1967). The circle
of Willis the incidence of developmental abnormalities in
normal and infarcted brains. Brain 90: 747758.
Battaglia A (2003). Neuroimaging studies in the evaluation of
developmental delay/mental retardation. Am J Med Genet
117: 2530.
Battle YL, Martin BC, Dorfman JH, Miller LS (1999).
Seasonality and infectious disease in schizophrenia: the birth
hypothesis revisited. J Psychiatr Res 33: 501509.
Bauer HG (1954). Endocrine and other clinical manifestations
of hypothalamic disease. A survey of 60 cases, with autopsies.
J Clin Endocrinol 14: 1331.
Bauer HG (1959). Endocrine and metabolic conditions related
to pathology in the hypothalamus: a review. J Nerv Mental
Disease 128: 323338.
Bauer MS, Whybrow PC, Winokur A (1990). Rapid cycling
bipolar affective disorder. Arch Gen Psychiatry 47: 427432.
Baulieu E-E (1996). Dehydroepiandrosterone (DHEA): A
fountain of youth? J Clin Endocrinol Metab 81: 31473151.
Baulieu E-E (2002). Androgens and aging men. Mol Cell
Endocrinol 198: 4149.
Baulieu E-E, Robel P (1996). Dehydroepiandrosterone and
dehydroepiandrosterone sulfate as neuroactive neurosteroids.
J Endocrinol 150 (Suppl 1): S221S239.
Bauman ML (1991). Microscopic neuroanatomic abnormalities
in autism. Pediatrics 87: 791796.
Bauman ML, Kemper TL (1985). Histoanatomic observations
of the brain in early infantile autism. Neurology 35: 866874.
Baumann G, Maheswari HG (1999). Dwarfism GHRH resistance
In: Jameson JL (Ed.) Contemporary Endocrinology: Hormone
Resistance Syndromes. Humana Press, Totowa, NJ.
Baumgartner A, Riemann D, Berger M (1990a). Neuroendocrinological investigations during sleep deprivation in
depression. II. Longitudinal measurement of thyrotropin, TH,
cortisol, prolactin, LH, FSH, estradiol, and testosterone. Biol
Baumgartner A, Grf K-J, Krten I, Meinhold H, Scholz P

(1990b). Neuroendocrinological investigations during sleep
deprivation in depression. I. Early morning levels of
thyrotropin, TH, cortisol, prolactin, GH, and LH during sleep
and sleep deprivation. Biol Psychiatry 28: 556568.
Bayer AU, Keller ON, Ferrari F, Maag KP (2002a). Association
of glaucoma with neurodegenerative diseases with apoptotic
cell death: Alzheimers disease and Parkinsons disease. Am
J Ophthalmol 133: 135137.
Bayer AU, Ferrari F, Erb C (2002b). High occurrence rate of
glaucoma among patients with Alzheimers disease. Eur
Neurol 47: 165168.
Baylis PH, Cheetham T (1998). Diabetes insipidus. Arch Dis
Child 79: 8489.
Bayliss C, Munger K (1990). Persistence of maternal plasma
volume expansion in midterm pregnant rats maintained on a
zero sodium intake: evidence that early gestational volume
expansion does not require renal sodium retention. Clin Exp
Hypertens B Hypertens Pregnancy 9(3): 237.
Bayrakdar A, Gordon DL, Emanuele NV (1997). Primary hypothalamic lymphoma mimicking sarcoidosis. Endocrinologist
7: 6971.
Bazil CW, Short D, Crispin D, Zheng W (2000). Patients with
intractable epilepsy have low melatonin, which increases
following seizures. Neurology 55: 17461748.
Beach TG, Tago H, Nagai T, Kimura H, McGeer PL, McGeer
EG (1987a). Perfusion-fixation of the human brain for
immunohistochemistry: comparison with immersion-fixation.
J Neurosci Methods 19: 183192.
Beach TG, Tago H, McGeer EG (1987b). Light-microscopic
evidence for a substance P-containing innervation of
the human nucleus basalis of Meynert. Brain Res 408:
251257.
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA (1999).
New criteria for improved diagnosis of BardetBiedl
syndrome: results of a population survey. J Med Genet 36:
437446.
Bear D (1991). Neurological perspectives on aggressive
behavior. J Neuropsychiatr Clin Neurosci 3: S3S8.
Beaton LE, Herrmann JD (1945). Hyperthermia following
injury of the preoptic region. Arch Neurol Psychiatr 53:
150151.
Bebbington PE, Dunn G, Jenkins R, Lewis G, Brugha T, Farrell
M, Meltzer H (1998). The influence of age and sex on the
prevalence of depressive conditions: report from the National
Survey of Psychiatric Morbidity. Psychol Med 28: 919.
Beccaria L, Marziani E, Manzoni P, Arvat E, Valetto MR,
Gianotti L, Ghigo E, Chiumello G (1998). Further evidence
of cholinergic impairment of the neuroendocrine control of
the GH secretion in Downs syndrome. Dement Geriatr Cogn
Disord 9: 7881.
Beck B, Burlet A, Nicolas J-P, Burlet C (1993). Galanin in the
hypothalamus of fed and fasted lean and obese Zucker rats.
Brain Res 623: 124130.
2014 Refs
2/12/03
1:39 pm
Page 411
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
411
Bellastella A, Criscuolo T, Sinisi AA, Rinaldi A, Faggiano M

(1986b). Circannual variations of plasma thyrotropin in
Klinefelters syndrome. Neuroendocrinology 43: 132134.
Beller BM, Trevino A, Urban E (1971). Pitressin-induced
myocardial injury and depression in a young woman. Am J
Med 51: 675679.
Bellinger LL, Bernardis LL, Brooks S (1979). The effect of
dorsomedial hypothalamic nuclei lesions on body weight
regulation. Neuroscience 4: 659665.
Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia E (2001).
Effects of melatonin in perimenopausal and menopausal
women: a randomized and placebo controlled study. Exp
Gerontol 36: 297310.
Bemana I, Nagao S (1999). Treatment of brain edema with a
nonpeptide arginine vasopressin V1 receptor antagonist OPC21268 in rats. Neurosurgery 44: 148155.
Bemporad JR (1997). Cultural and historical aspects of eating
disorders. Theor Med 18: 401420.
Ben-Jonathan N, Hnasko R (2001). Dopamine as a prolactin
(PRL). inhibitor. Endocr Rev 22: 724763.
Benarroch EE, Smithson IL, Low PA, Parisi JE (1998).
Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic
failure. Ann Neurol 43: 156163.
Benedetti F, Amanzio M (1997). The neurobiology of placebo
analgesia: from endogenous opioids to cholecystokinin. Prog
Neurobiol 52: 109125.
Benedetti F Vighetti S, Ricco C, Lagna E, Bergamasco B,
Pinessi L, Rainero I (1999). Pain threshold and tolerance in
Alzheimers disease. Pain 80: 377382.
Benelli A, Bertolini A, Arletti R (1991). Oxytocin-induced inhibition of feeding and drinking: no sexual dimorphism in rats.
Neuropeptides 20: 5762.
Bennedsen BE, Mortensen PB, Olesen AV, Henriksen TB
(1999). Preterm birth and intra-uterine growth retardation
among children of women with schizophrenia. Br J Psychiatry
175: 239245.
Bennett-Clarke CA, Joseph SA (1986). Immunocytochemical
localization of somatostatin in human brain. Peptides 7:
877884.
Bentson J, Reza M, Winter J, Wilson G (1978). Steroids and
apparent cerebral atrophy on computed tomography scans. J
Comp Assisy Tomogr 2: 1623.
Benzing WC, Mufson EJ (1995). Increased number of NADPHd-positive neurons within the substantia innominata in
Alzheimers disease. Brain Res 670: 351355.
Bereket A, Lang CH, Geffner ME, Wilson TA (1998). Normal
growth in a patient with septo-optic dysplasia despite both
growth hormone and IGF-I deficiency. J Pediatr Endocrinol
Metab 11: 6975.
Berenbaum SA, Bailey JM (2003). Effects on gender identity
of prenatal androgens and genital appearance: evidence from
girls with congenital adrenal hyperplasia. J Clin Endocrinol
Metab 88: 11021106.
Beck E, Gajdusek DC (1966). Variable size of the septal nuclei

in man. Nature 210: 13381340.
Beck-Peccoz P, Cortelazzi D, Persani L, Papandreou MJ, Asteria
C, Borgato S, Preziati D, Tonachera M, Vitti P, Baggiani
AM, Marconi AM, Buscaglia M, Pardi G (1992). Maturation
of pituitarythyroid function in the anencephalic fetus. Acta
Med Austriaca 19 (Suppl 1): 7276.
Becker AE, Burwell RA, Gilman SE, Herzog DB, Hamburg P
(2002). Eating behaviours and attitudes following prolonged
exposure to television among ethnic Fijian adolescent girls.
Br J Psychiatry 180: 509514.
Becker J, Schmidt P, Fitzenreiter M, Musshoff F, Madea B
(2003). The regional pattern of -opioid receptor (MOR1).
mRNA in human brain: a real-time PCR assay. Int Congress
Ser 1239: 737739.
Beckmann H, Lang RE, Gattaz WF (1985). Vasopressinoxytocin in cerebrospinal fluid of schizophrenic patients and
normal controls. Psychoneuroendocrinology 10: 187191.
Beems T, Grotenhuis JA, Wesseling P (1999). Meningioma of
the pituitary stalk without dural attachment: case report and
review of the literature. Neurosurgery 45: 14741477.
Begega A, Cuesta M, Santn LJ, Rubio S, Astudillo A, Arias
JL (1999). Unbiased estimation of the total number of nervous
cells and volume of medial mamillary nucleus in humans.
Exp Gerontology 34: 771782.
Bgeot M, Dubois MP, Dubois PM (1978). Immunologic
localization of - and -endorphins and -lipotropin in
corticotropic cells of the normal and anencephalic fetal
pituitaries. Cell Tissue Res 193: 413422.
Begon S, Leyendecker G, Fahlbusch R, Buchfelder M, Wildt
L (1993). Pulsatile administration of gonadotrophin releasing
hormone as a diagnostic tool to distinguish hypothalamic from
pituitary hypogonadism following neurosurgery. Hum Reprod
8 (Suppl 2): 200203.
Behan DP, Khongsaly O, Owens MJ, Chung HD, Nemeroff
CB, De Souza EB (1997). Corticoptropin-releasing factor
(CRF), CRF-binding protein (CRF-BP), and CRF/CRF-BP
complex in Alzheimers disease and control postmortem
human brain. J Neurochem 68: 20532060.
Belanoff JK, Kalehzan M, Sund B, Fleming Ficek SK (2001).
Cortisol activity and cognitive changes in psychotic major
depression. Am J Psychiatry 158: 16121616.
Bell DS (1994). Chronic fatigue syndrome update Findings now
point to CNS involvement. Postgrad Med 96: 7381.
Bell GH, Robson JM (1938). The oxytocin content of the foetal
pituitary. Q J Exp Physiol 27: 205208.
Bell NH (1991). Endocrine complications of sarcoidosis. Endocr
Metab Clin North Am 20: 645654.
Bellastella A, Criscuolo T, Sinisi AA, Iorio S, Sinisi AM, Rinaldi
A,Faggiano M (1986a). Circannual variations of plasma
testosterone, luteinizing hormone, follicle-stimulating hormone
and prolactin in Klinefelters syndrome. Neuroendocrinology
42: 153157.
411
2014 Refs
412
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 412
D.F. SWAAB
Berg SJ, Wynne-Edwards KE (2001). Changes in testosterone,

cortisol, and estradiol levels in men becoming fathers. Mayo
Clin Proc 76: 582592.
Berga SL, Mortola JF, Yen SSC (1988). Amplification of
nocturnal melatonin secretion in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 66: 242244.
Berga SL, Daniels TL, Giles DE (1997). Women with functional hypothalamic amenorrhea but not other forms of
anovulation display amplified cortisol concentrations. Fertil
and Steril 67: 10241030.
Bergen AW, Van den Bree MBM, Yeager M, Welch R, Ganjei
JK, Haque K, Bacanu S, Berrettini W, Grice DE, Goldman
D, Bulik CM, Klump K, Fichter M, Halmi K, Kaplan A,
Strober M, Treasure J, Woodside B, Kaye WH (2003).
Candidate genes for anorexia nervosa in the 1p3336 linkage
region: serotonin 1D and delta opioid receptor loci exhibit
significant association to anorexia nervosa. Molec Psychiatry
8: 397406.
Berger B, Esclapez M, Alvarez C, Meyer G, Catala M (2001).
Human and monkey fetal brain development of the supramammillary-hippocampal projections: a system involved in
the regulation of theta activity. J Comp Neurol 429: 515529.
Berger L, Gauthier S, Leblanc R (1985). Akinetic mutism and
Parkinsonism associated with obstructive hydrocephalus. Can
J Neurol Sci 12: 255258.
Berger PA, Watson SJ, Akil H, Barchas JD (1981). Clinical
studies on the role of endorphins in schizophrenia. Mod Probl
Pharmacopsychiatry 17: 226235.
Bergeron C, Kovacs K, Ezrin C, Mizzen C (1991). Hereditary
diabetes insipidus: an immunohistochemical study of the
hypothalamus and pituitary gland. Acta Neuropathol 81:
345348.
Bergh C, Sdersten P (1996). Anorexia nervosa, self-starvation
and the reward of stress. Nat Med 2: 2122.
Bergh C, Brodin U, Lindberg G, Sdersten P (2002).
Randomized controlled trial of a treatment for anorexia and
bulimia nervosa. Proc Natl Acad Sci 99: 94869491.
Berginer VM (2000). Neurological aspects of the DavidGoliath
battle: restriction in the giants visual field. Isr Med Assoc J
2: 725727.
Bergland R, Bronson SR (1969). The arterial supply of the
human optic chiasm. J Neurosurg 31: 327334.
Berk C, Carr J, Sinden M, Martzke J, Honey CR (2002).
Thalamic deep brain stimulation for the treatment of tremor
due to multiple sclerosis: a prospective study of tremor and
quality of life. J Neurosurg 97: 815820.
Berk LS, Tan SA, Fry WF, Napier BJ, Lee JW, Hubbard RW,
Lewis JE, Eby WC (1989). Neuroendocrine and stress
hormone changes during mirthful laughter. Am J Med Sci
298: 390396.
Berkovic SF, Kuzniecky RI, Andermann F (1997). Human
epileptogenesis and hypothalamic hamartomas: new lessons
from an experiment of nature. Epilepsia 38: 13.
Berliner DL (1996). Steroidal substances active in the human

vomeronasal organ affect hypothalamic function. J Steroid
Biochem Mol Biol 58: 12.
Berliner DL, Monti-Bloch L, Jennings-White C, Diaz-Sanchez
V (1996). The functionality of the human vomeronasal organ
(VNO): evidence for steroid receptors. J Steroid Biochem
Mol Biol 58: 259265.
Berman RM, Narasimhan M, Sanacora G, Miano AP, Hoffman
RE, Hu XS, Charney DS, Boutros NN (2000). A randomized
clinical trial of repetitive transcranial magnetic stimulation in
the treatment of major depression. Biol Psychiatry 47:
332337.
Bernardis LL, Bellinger LL (1996). The lateral hypothalamic
area revisited: ingestive behavior. Neurosci Biobehav Rev 20:
189287.
Bernardis LL, Bellinger LL (1998). The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc Soc Exp Biol
Med 218: 284306.
Berner W, Brownstone G, Sluga W (1983). The cyproteronacetate treatment of sexual offenders. Neurosci Biobehav Rev
7: 441443.
Bernier PJ, Vinet J, Cossette M, Parent A (2000).
Characterization of the subventricular zone of the adult human
brain: evidence for the involvement of Bcl-2. Neurosci Res
37: 6778.
Bernstein H-G, Jrvinen M, Pllnen R, Schirpke H, Knfel B,
Rinne R (1988). Cyastatin C containing neurons in human
postmortem hypothalamus. Neurosci Lett 88: 131134.
Bernstein H-G, Stanarius A, Baumann B, Henning H, Krell D,
Danos P, Falkai P, Bogerts B (1998). Nitric oxide synthasecontaining neurons in the human hypothalamus: reduced
number of immunoreactive cells in the paraventricular nucleus
of depressive patients and schizophrenics. Neuroscience 83:
867875.
Bernstein H-G, Jirikowski GF, Heinemann A, Baumann B,
Hornstein C, Danos P, Diekmann S, Sauer H, Keilhoff G,
Bogerts B (2000). Low and infrequent expression of nitric
oxide synthase/NADPH-diaphorase in neurons of the human
supraoptic nucleus: a histochemical study. J Chem Neuroanat
20: 177183.
Bernstein H-G, Heinemann A, Krell D, Mawrin C, Bielau H,
Danos P, Diekmann S, Keilhoff G, Bogerts B, Baumann B
(2002a). Further immunohistochemical evidence for impaired
NO signaling in the hypothalamus of depressed patients. Ann
NY Acad Sci 973: 9193.
Bernstein H-G, Krell D, Emrich HM, Baumann B, Danos P,
Diekmann S, Bogerts B (2002b). Fewer beta-endorphin
expressing arcuate nucleus neurons and reduced beta-endorphinergic innervation of paraventricular neurons in
schizophrenics and patients with depression. Cell Mol Biol
(Online) 48: 259265.
Berquin P, Bodineau L, Gros F, Larnicol N (2000). Brainstem
and hypothalamic areas involved in respiratory chemoreflexes: a Fos study in adult rats. Brain Res 857: 3040.
2014 Refs
2/12/03
1:39 pm
Page 413
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
413
Biegon A, Fieldust S (1992). Reduced tyrosine hydroxylase

immunoreactivity in locus coeruleus of suicide victims.
Synapse 10: 7982.
Bierwolf C, Kern W, Mlle M, Born J, Fehm HL (2000).
Rhythms of pituitary-adrenal activity during sleep in patients
with Cushings disease. Exp Clin Endocrinol Diabetes 108:
470479.
Biesecker LG, Kletter G, Topf K (1994). Reply to the Editor.
J Pediatr 125: 177.
Bigl V, Arendt T, Fischer S, Fischer S, Werner M, Arendt A
(1987). The cholinergic system in aging. Gerontology 33:
172180.
Bignani A, Gherardi D, Gallo G (1961). Sclerosi a placche acuta
a localizzazione ipotalamica con sintomatologia psichica di
tipo malinconico. Riv Neurol 31: 240268.
Biller BMK (1994). Pathogenesis of pituitary Cushings
syndrome. Endocr Metab Clin N Am 23: 547554.
Billiard M, Guilleminault C, Dement WC (1975). A menstruation-linked periodic hypersomnia. Neurology 25: 436443.
Bilora F, Vigna GB, Manfredini R, Saccaro G, Rocco S, San
Lorenzo I (1997). Chronobiological analysis of sudden death
observed in an emergency department. Biol Rhythm Res 28:
404409.
Bin-Abbas B, Mawlawi H, Sakati N, Khafaja Y, Chaudhary
MA, Al-Ashwal A (2001). Endocrine sequelae of childhood
craniopharyngioma. J Pediatr Endocrinol Metab 14: 869874.
Binns W, James LF, Shupe JL (1964). The Human Brain in
Figures and Tables. A Quantitative Handbook. Basic Books,
Plenum Press, New York, p. 336, Table 115.
Bird ED, Chiappa SA, Fink G (1976). Brain immunoreactive
gonadotropin-releasing hormone in Huntingtons chorea and
in non-choreic subjects. Nature 260: 536538.
Birk K, Ford C, Smeltzer S, Ryan D, Miller R, Rudick RA
(1990). The clinical course of multiple sclerosis during pregnancy and the puerperium. Arch Neurol 47: 738742.
Birkenhger TK, Vegt M, Nolen WA (1997). An open study
of triiodothyronine augmentation of tricyclic antidepressants
in inpatients with refractory depression. Pharmacopsychiatry
30: 2326.
Birketvedt GS, Florholmen J, Sundsfjord J, sterud B, Dinges
D, Bilker W, Stunkard A (1999). Behavioral and neuroendocrine characteristics of the night-eating syndrome. JAMA
282: 657663.
Birketvedt GS, Sundsfjord J, Florholmen JR (2002). Hypothalamic-pituitary adrenal axis in the night eating syndrome.
Am J Physiol 282: E366E369.
Birkhuser M (2002). Depression, menopause and estrogens: is
there a correlation? Maturitas (Suppl 1) 41: S3S8.
Birnbacher R, Wandl-Vergesslich K, Frisch H (1994). Diagnosis
of X-recessive Kallmann syndrome in early infancy. Evidence
of hypoplastic rhinencephalon. Eur J Pediatr 153: 245247.
Birnbaumer M (1999). Vasopressin receptor mutations and
nephrogenic diabetes insipidus. Arch Med Res 30: 465474.
Bersanim G, Garavini A, Iannitelli A, Quartini A, Nordio M,

Di Biasi C, Pancheri P (2002). Reduced pineal volume in
male patients with schizophrenia: no relationship to clinical
features of the illness. Neurosci Lett 329: 246248.
Berson DM, Dunn FA, Takao M (2002). Phototransduction by
retinal ganglion cells that set the circadian clock. Science
295: 10701073.
Bertelloni S, Battini R, Baroncelli GI, Guerrini R, Viacava P,
Spinelli C, Simi P (1999). Central precocious puberty in
48,XXYY Klinefelter syndrome variant. J Pediatr Endocrinol
Metabol 12: 459465.
Bertherat J, Bluet-Pajot MT, Epelbaum J (1995). Neuroendocrine
regulation of growth hormone. Eur J Endocrinol 132: 1224.
Berthier ML, Santamaria J, Encabo H, Tolosa ES (1992).
Recurrent hypersomnia in two adolescent males with
Aspergers syndrome. J Am Acad Child Adolesc Psychiatry
31: 735738.
Berthier S, Gil H, Bonneville JF, Magy N, De Wazieres B,
Mallet H, Dupond JL (2000). Maladie de Wegener et diabte
insipide central. Ann Endocrinol 61: 531537.
Beswick SJ, Kirk JMW, Bradshaw K, Sanders DSA, Moss C
(2002). Progressive nodular histiocytosis in a child with a
hypothalamic tumour. Br J Dermatol 146: 138140.
Bettendorf M, Albers N, Bauer J, Heinrich UE, Linderkamp O,
Maser-Gluth C (1998). Longitudinal evaluation of salivary
cortisol levels in full-term and preterm neonates. Horm Res
50: 303308.
Bettinelli A, Rusconi R, Ciarmatori S, Righini V, Zammarchi
E, Donati MA, Isimbaldi C, Bevilaqua M, Cesareo L,
Tedeschi S, Garavaglia R, Casari G (1999). Gitelman disease
associated with growth hormone deficiency, disturbances in
vasopressin secretion and empty sella: a new hereditary renal
tubular-pituitary syndrome? Pediatr Res 46: 232238.
Bevilacqua M, Norbiato G, Righini V, Vago T, Castelli L,
Carella F, Caraceni T (1994). Loss of osmotic thirst in
multiple system atrophy: association with sinoaortic baroreceptor deafferentation. Am J Physiol 266: R1752R1758.
Bichet DG, Kortas C, Mettauer B, Manzini C, Marc-Aurele J,
Rouleau JL, Schrier RW (1986). Modulation of plasma and
platelet vasopressin by cardiac function in patients with heart
failure. Kidney Int 29: 11881196.
Bichet DG, Arthus MF, Barjon JN, Lonergan M, Kortas C
(1987). Human platelet fraction arginine-vasopressin.
Potential physiological role. J Clin Invest 79: 881887.
Bichet DG, Razi M, Lonergan M, Arthus M-F, Papukna V,
Kortas C, Barjon J-N (1988). Hemodynamic and coagulation
responses to 1-desamino[8-D-Arginine]vasopressin in patients
with congenital nephrogenic diabetes insipidus. N Engl J Med
318: 881887.
Bick D, Franco B, Sherins RJ, Heye B, Pike L, Crawford J,
Maddalena A, Incerti B, Pragliola A, Meitinger T, Ballabio
A (1992). Brief report: intragenic deletion of the Kalig-1 gene
in Kallmanns syndrome. N Engl J Med 326: 17521755.
413
2014 Refs
414
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 414
D.F. SWAAB
Birnbaumer M (2000). Vasopressin receptors. Trends Endocrinol

Metab 11: 406410.
Bisset GW, Black A, Hilton PJ, Jones NF, Montgomery M
(1976). Polyuria associated with an antibody to vasopressin.
Clin Sci Molec Med 50: 277283.
Bissette G, Reynolds GP, Kilts CD, Widerlv E, Nemeroff CB
(1985). Corticotropin-releasing factor-like immunoreactivity
in senile dementia of the Alzheimer type. JAMA 254:
30673069.
Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G (2003).
Elevated concentrations of CRF in the locus coeruleus of
depressed subjects. Neuropsychopharmacology 28: 13281335.
Biswas K, Kapoor A, Jain S, Ammini AC (2000). Hypothalamic
hamartoma as a cause of precocious puberty in neurofibromatosis type 1: patient report. J Pediatr Endocrinol Metab
13: 443444.
Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon
J-L, Vale W, Sawchenko PE (1992). The melaninconcentrating hormone system of the rat brain: an immunoand hybridization histochemical characterization. J Comp
Neurol 319: 218245.
Bittencourt JC, Elias CF (1998). Melanin-concentrating
hormone and neuropeptide EI projections from the lateral
hypothalamic area and zona incerta to the medial septal
nucleus and spinal cord: a study using multiple neuronal
tracers. Brain Res 805: 119.
Bixo M, Bckstrm T, Winblad B, Andersson A (1995).
Estradiol and testosterone in specific regions of the human
female brain in different endocrine states. J Steroid Biochem
Mol Biol 55: 297303.
Bjrkstrand E, Uvns-Moberg K (1996). Central oxytocin
increases food intake and daily weight gain in rats. Physiol
Behav 59: 947952.
Bjrklund A, Lindvall O (1984). Dopamine-containing systems
in the CNS. In: Bjrklund A, Hkfelt T (Eds.) Handbook of
Chemical Neuroanatomy. Classical Transmitters in the CNS,
part 1, volume 5, pp. 55122. Elsevier, Amsterdam.
Bjrn I, Sundstrm-Poromaa I, Bixo M, Nyberg S, Bckstrm
G, Bckstrm T (2003). Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal
therapy. J Clin Endocrinol Metab 88: 20262030.
Bjrntorp P, Rosmond R (1999). Hypothalamic origin of the
metabolic syndrome X. Ann NY Acad Sci 892: 297307.
Black DW (1982). Pathological laughter. A review of the
literature. J Nerv Ment Dis 170: 6771.
Blackburn-Munro G, Blackburn-Munro R (2003). Pain in the
brain: are hormones to blame? Trends Endocrinol Metab 14:
2027.
Blaicher W, Imhof MH, Gruber DM, Schneeberger C, Sator
MO, Huber JC (1999a). Endocrinological disorders. Gynecol
Obstet Invest 48: 179182.
Blaicher W, Gruber D, Bieglmayer C, Blaicher AM, Knogler
W, Huber JC (1999b). The role of oxytocin in relation to
female sexual arousal. Gynecol Obstet Invest 47: 125126.
Blair-Bell W (1909). The pituitary body and action of pituitary

extract in shock, uterine atony, and intestinal paresis. Br Med
J 2: 16091613.
Blanchet PJ, Fang J, Hyland K, Arnold LA, Mouradian MM,
Chase TN (1999). Short-term effects of high-dose 17estradiol in postmenopausal PD patients. Neurology 53: 9195.
Blanks JC, Hinton DR, Sadun AA, Miller CA (1989). Retinal
ganglion cell degeneration in Alzheimers disease. Brain Res
501: 364372.
Blanks JC, Torigoe Y, Hinton DR, Blanks RHI (1996a). Retinal
pathology in Alzheimers disease. I. Ganglion cell loss in
foveal/parafoveal retina Neurobiol Aging 17: 377384.
Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR,
Blanks RHI (1996b). Retinal pathology in Alzheimers
disease. II. Regional neuron loss and glial changes in GCL.
Neurobiol Aging 17: 385395.
Blansjaar BA, Vielvoye GJ, Van Dijk JG, Rijnders RJP (1992).
Similar brain lesions in alcoholics and Korsakoff patients:
MRI, psychometric and clinical findings. Clin Neurol
Blei AT, Zee P (1998). Abnormalities of circadian rhythmicity
in liver disease. J Hepatol 29: 832835.
Bleys RLAW, Cowen T, Groen GJ, Hillen B (1996).
Perivascular nerves of the human basal cerebral arteries: II.
Changes in aging and Alzheimers disease. J Cereb Blood
Flow Metab 16: 10481057.
Bleys RLAW, Cowen T (2001). Innervation of cerebral blood
vessels: morphology, plasticity, age-related, and Alzheimers
disease-related neurodegeneration. Microsc Res Tech 53:
106118.
Bliwise DL, Hughes M, McMahon PM, Kutner N (1995).
Observed sleep/wakefulness and severity of dementia in an
Alzheimers disease special care unit. J Gerontol Biol Sci
Med Sci A50: M303M306.
Bliwise DL, Rye DB, Dihenia B, Gurecki P (2002). Greater
daytime sleepiness in subcortical stroke relative to
Parkinsons disease and Alzheimers disease. J Geriatr
Psychiatry Neurol 15: 6167.
Bloch B, Bugnon C, Pellman D, Lenys D (1978). Immunocytochemical evidence that the same neurons in the human
infundibular nucleus are stained with anti-endorphins and
antisera of other related peptides. Neurosci Lett 10: 147152.
Bloch B, Baird A, Ling N, Guillemin R (1986). Immunohistochemical evidence that growth hormone-releasing factor
(GRF) neurons contain an amidated peptide derived from
cleavage of the carboxyl-terminal end of the GRF precursor.
Endocrinology 118: 156162.
Bloch B, Gaillard RC, Culler MD, Negro-Vilar A (1992).
Immunohistochemical detection of proluteinizing hormonereleasing hormone peptides in neurons in the human
hypothalamus. J Clin Endocrinol Metab 74: 135138.
Bloch GJ, Eckersell C, Mills R (1993). Distribution of galaninimmunoreactive cells within sexually dimorphic components
2014 Refs
2/12/03
1:39 pm
Page 415
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
of the medial preoptic area of the male and female rat. Brain
Res 620: 259268.
Bloch GJ, Butler PC, Kohlert JG (1996). Galanin microinjected
into the medial preoptic nucleus faciliates female- and maletypical sexual behaviors in the female rat. Physiol Behav 59:
11471154.
Bloch M, Schmidt PJ, Su T-P, Tobin MB, Rubinow DR (1998).
Pituitary-adrenal hormones and testosterone across the
menstrual cycle in women with premenstrual syndrome and
controls. Biol Psychiatr 43: 897903.
Block AJ, Boysen PG, Wynne JW, Hunt LA (1979). Sleep
apnea, hypopnea and oxygen desaturation in normal subjects.
New Engl J Med 300: 513517.
Blok BFM, Willemsen ATM, Holstege G (1997). A PET study
on brain control of micturition in humans. Brain 120: 111121.
Bloomgarden ZT, McLean GW, Rabin D (1981). Autonomous
hyperprolactinemia in tuberous sclerosis. Arch Intern Med
141: 15131515.
Blouin A, Blouin J, Aubin P, Carter J, Goldstein C, Boyer H,
Perez E (1992). Seasonal patterns of bulimia nervosa. Am J
Bluet-Pajot MT, Epelbaum J, Gourdji D, Hammond C, Kordon
C (1998). Hypothalamic and hypophyseal regulation of
growth hormone secretion. Cell Mol Neurobiol 18: 101123.
Blum A, Tempey FW, Lynch WJ (1983). Somatic findings in
patients with psychogenic polydipsia. J Clin Psychiatry 44:
5556.
Blumer D (2002). The illness of Vincent van Gogh. Am J
Blumstein A (2000). Violence: a new frontier for scientific
research. Science 289: 545.
Blunt SB, Lane RJM, Turjanski N, Perkin GD (1997). Clinical
features and management of two cases of encephalitis lethargica. Mov Disord 12: 354359.
Blusztajn JK, Berse B (2000). The cholinergic neuronal phenotype in Alzheimers disease. Metab Brain Dis 15: 4564.
Bobrow NA, Money J, Lewis VG (1971). Delayed puberty,
eroticism, and sense of smell: a psychological study of hypogonadotropinism, osmatic and anosmatic (Kallmanns
syndrome). Arch Sex Behav 1: 329344.
Boch A-L, Van Effenterre R, Kujas M (1997). Craniopharyngiomas in two consanguineous siblings: case report. Neurosurgery 41: 11851187.
Bodanszky M, Engel SL (1966). Oxytocin and the life-span of
male rats. Nature 210: 751.
Bodenheimer S, De Winter JSD, Faiman C (1973). Diurnal
rhythms of serum gonadotropins, testosterone, estradiol and
cortisol in blind men. J Clin Endocrinol Metab 37: 472475.
Bodensteiner JB, Schaefer GB (1997). Dementia pugilistica and
cavum septi pellucidi: born to box? Sports Med 24: 361365.
Bodensteiner JB, Pauling KJ (1999). The true prevalence of
cavum septi pellucidi. Pediatr Neurol 21: 506.
415
Bodensteiner JB, Schaefer GB, Craft JM (1998). Cavum septum

pellucidi and cavum vergae in normal and developmentally
delayed populations. J Child Neurol 13: 120121.
Boehm N, Gasser B (1993). Sensory receptor-like cells in the
human foetal vomeronasal organ. Neuroreport 4: 867870.
Boehm N, Roos J, Gasser B (1994). Luteinizing hormonereleasing hormone (LHRH)-expressing cells in the nasal
septum of human fetuses. Brain Res Dev Brain Res 82:
175180.
Boer K, Dogterom J, Pronker HF (1980). Pituitary content of
oxytocin, vasopressin and -melanocyte-stimulating hormone
in the fetus of the rat during labour. J Endocrinol 86: 221229.
Boer K, Boer GJ, Swaab DF (1981). Reproduction in Brattleboro
rats with diabetes insipidus. J Reprod Fertil 61: 273280.
Boer H, Holland A, Whittington J, Butler J, Webb T, Clarke
D (2002). Psychotic illness in people with PraderWilli
syndrome due to chromosome 15 maternal uniparental
disomy. Lancet 359: 135136.
Boersma CJC, Sonnemans MAF, Van Leeuwen FW (1993).
Immunocytochemical localization of neuropeptide FF (FMRF
amide-like peptide) in the hypothalamo-neurohypophyseal
system of Wistar and Brattleboro rats by light and electron
microscopy. J Comp Neurol 336: 555570.
Boersma CJC, Van Leeuwen FW (1994). Neuron-glia interactions in the release of oxytocin and vasopressin from the rat
neural lobe: the role of opioids, other neuropeptides and their
receptors. Neuroscience 62(4): 10031020.
Bogaert AF (2003). The interaction of fraternal birth order and
body size in male sexual orientation. Behav Neurosci 117:
381384.
Bogdan A, Bouchareb B, Touitou Y (2001). Ramadan fasting
alters endocrine and neuroendocrine circadian patterns. Mealtime as a synchronizer in humans? Life Sci 68: 16071615.
Boglioli LR, Taff ML (1990). Religious objection to autopsy.
An ethical dilemma for medical examiners. Am J Forensic
Med Pathol 11: 18.
Bohnen N, Twijnstra A, Terwel D, Jolles J (1992). Inverse relationship between plasma vasopressin and intracranial
pressure. Horm Metab Res 24: 141142.
Boissiere F, Faucheux B, Ruberg M, Agid Y, Hirsch EC (1997).
Decreased TrkA gene expression in cholinergic neurons of
the striatum and basal forebrain of patients with Alzheimers
disease. Exp Neurol 145: 245252.
Boivin DB, Czeisler CA, Dijk DJ, Duffy JF, Folkard S, Minors
DS, Totterdell P, Waterhouse JM (1997). Complex interaction of the sleepwake cycle and circadian phase modulates
mood in healthy subjects. Arch Gen Psychiatry 54: 145152.
Boivin DB, Czeisler CA (1998). Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light.
Neuroreport 9: 779782.
Bolt RJ, Van Weissenbruch MM, Cranendonk A, Lafeber HN,
Delemarre-van de Waal HA (2002a). The corticotrophinreleasing hormone test in preterm infants. Clin Endocrinol
56: 207213.
415
2014 Refs
416
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 416
D.F. SWAAB
Bolt RJ, Van Weissenbruch MM, Popp-Snijders C, Sweep CGJ,

Lafeber HN, Delemarre-van de Waal HA (2002b). Fetal
growth and the function of the adrenal cortex in preterm
infants. J Clin Endocrinol Metab 87: 11941199.
Bolt RJ, Van Weissenbruch MM, Lafeber HN, Delemarre-Van
de Waal HA (2002c). Development of the hypothalamic-pituitary-adrenal axis in the fetus and preterm infant. J Pediatr
Bolton C, Flower RJ (1989). The effects of the antiglucocorticoid RU 38486 on steroid-mediated suppression of
experimental allergic encephalomyelitis (EAE) in the Lewis
rat. Life Sci 45: 97104.
Bolton NJ, Tapanainen J, Koivisto M, Vihko R (1989).
Circulating sex hormone-binding globulin and testosterone in
newborns and infants. Clin Endocrinol 31: 201207.
Bona JR, Fackler SM, Fendley MJ, Nemeroff CB (1998).
Neurosarcoidosis as a cause of refractory psychosis: a complicated case report. Am J Psychiatry 155: 11061108.
Bonnefond C, Palacios JM, Probst A, Mengod G (1990).
Distribution of galanin mRNA containing cells and galanin
receptor binding sites in human and rat hypothalamus. Eur J
Neurosci 2: 629637.
Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa
C, Deste A (2003). Study of circadian melatonin secretion
pattern at different stages of Parkinsons disease. Clin
Neuropharmacol 26: 6572.
Born J, Fehm HL (1998). Hypothalamus-pituitary-adrenal
activity during human sleep: a coordinating role for the limbic
hippocampal system. Exp Clin Endocrinol Diabetes 106:
153163.
Born J, Kellner C, Uthgenannt D, Kern W, Fehm HL (1992).
Vasopressin regulates human sleep by reducing rapid-eyemovement. sleep Am J Physiol 262: E295E300.
Born J, Steinbach D, Dodt C, Fehm H-L (1997). Blocking of
central nervous mineralocorticoid receptors counteracts inhibition of pituitary-adrenal activity in human sleep. J Clin
Born J, Hansen K, Marshall L, Mlle M, Fehm HL (1999).
Timing the end of nocturnal sleep. Nature 397: 2930.
Borson-Chazot F, Jordan D, Fvre-Montange M, Kopp N,
Tourniaire J, Rouzioux JM, Veisseire M, Mornex R (1986).
TRH and LH-RH distribution in discrete nuclei of the human
hypothalamus: evidence for a left predominance of TRH.
Brain Res 382: 433436.
Bos NPA, Mirmiran M (1990). Circadian rhythm in neuronal
discharges of cultured suprachiasmatic nucleus. Brain Res
511: 158162.
Boson WL, Sarubi JC, dAlva CB, Friedman E, Faria D, De
Marco L, Wajchenberg B (2003). A signal peptide mutation
of the arginine vasopressin gene in monozygotic twins. Clin
Bossy J (1980). Development of olfactory and related structures
in staged human embryos. Anat Embryol 161: 225236.
Botez-Marquard T, Botez MI (1992). Visual memory deficits

after damage to the anterior commissure and right fornix.
Arch Neurol 49: 321324.
Boundy VA, Cincotta AH (2000). Hypothalamic adrenergic
receptor changes in the metabolic syndrome of genetically
obese (ob/ob) mice. Am J Physiol 279: R505R514.
Bouras C, Magistretti PJ, Morrison JH (1986). An immunohistochemical study of six biologically active peptides in the
human brain. Hum Neurobiol 5: 213226.
Bouras C, Magistretti PJ, Morrison JH, Constantinidis J (1987).
An immunohistochemical study of pro-somatostatin-derived
peptides in the human brain. Neuroscience 22: 781800.
Bourdeau I, Bard C, Nol B, Leclerc I, Cordeau M-P, Blair
M, Lesage J, Lafontaine L, Lacroix A (2002). Loss of brain
volume in endogenous Cushings syndrome and its
reversibility after correction of hypercortisolism. J Clin
Bourdette D, McClung M, Whitham R, Hatch T (1988). Hypothalamic hypogonadism may cause sexual dysfunction in some
males with multiple sclerosis. Neurology (Suppl) 38: 253.
Bourguignon J-P, Jaeken J, Gerard A, De Zegher F (1997).
Amino acid neurotransmission and initiation of puberty:
evidence from nonketotic hyperglycinemia in a female infant
and gonadotropin-releasing hormone secretion by rat hypothalamic explants. J Clin Endocrinol Metab 82: 18991903.
Bouvattier C, Carel JC, Lecointre C, David A, Sultan C,
Bertrand AM, Morel Y, Chaussain J-L (2002). Postnatal
changes of T, LH, and FSH in 46,XY infants with mutations
in the AR gene. J Clin Endocrinol Metab 87: 2932.
Bowen DM, Benton JS, Spillane JA, Smith CC, Allen SJ (1982).
Cholineacetyltransferase activity and histopathology of
frontal neocortex from biopsies of demented patients. J Neurol
Sci 57: 191202.
Bowen RL, Isley JP, Atkinson RL (2000). An association of
elevated serum gonadotropin concentrations and Alzheimer
disease? J Neuroendocrinol 12: 351354.
Bowen-Pidgeon D, Innamorati G, Sadeghi HM, Birnbaumer M
(2001). Arrestin effects on internalization of vasopressin
receptors. Mol Pharmacol 59: 13951401.
Boyar RM, Witkin M, Carruth A, Ramsey J (1979). Circadian
cortisol secretory rhythms in Cushings disease. J Clin
Boyer P (2000). Do anxiety and depression have a common
pathophysiological mechanism? Acta Psychiatr Scand Suppl
102: 2429.
Bozikas VP, Kvari E, Bouras C, Karavatos A (2002).
Neurofibrillary tangles in elderly patients with late onset
schizophrenia. Neurosci Lett 324: 109112.
Braak H, Braak E (1987a). The hypothalamus of the human
adult: chiasmatic region. Anat Embryol 176: 315330.
Braak H, Braak E (1987b). Argyrophilic grains: characteristic
pathology of cerebral cortex in cases of adult onset dementia
without Alzheimer changes. Neurosci Lett 76: 124127.
2014 Refs
2/12/03
1:39 pm
Page 417
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
417
Brambilla F (2001). Aetiopathogenesis and pathophysiology of

bulimia nervosa. CNS Drugs 15: 119136.
Brambilla F, Cazullo CL, Smeraldi E, Zibetti A (1974).
Endocrine function in multiple sclerosis: possible correlation
with immunitary phenomena. Acta Neurol 29: 618625.
Brambilla F, Ferrari E, Brunetta M, Peirone A, Draisci A,
Sacerdote P, Panerai A (1996). Immunoendocrine aspects of
anorexia nervosa. Psychiatry Res 62: 97104.
Brambilla F, Bellodi L, Arancio C, Ronchi P, Limonti D (2001).
Central dopaminergic function in anorexia and bulimia
nervosa: a psychoneuroendocrine approach. Psychoneuroendocrinology 26: 393409.
Brannan S, Liotti M, Egan G, Shade R, Madden L, Robillard
R, Abplanalp B, Stofer K, Denton D, Fox PT (2001).
Neuroimaging of cerebral activations and deactivations
associated with hypercapnia and hunger for air. PNAS 98:
20292034.
Branch EF, Burger PC, Brewer DL (1971). Hypothermia in a
case of hypothalamic infarction and sarcoidosis. Arch Neurol
25: 245255.
Brand M, Schoof E, Partsch C-J, Peter M, Hoepffner W, Drr
HG, Sippell WG (2000). Anorexia nervosa in congenital
adrenal hyperplasia: long-term follow-up of 4 cases. Exp Clin
Endocrinol Diabetes 108: 430435.
Brandi ML, Becherini L, Gennari L, Racchi M, Bianchetti A,
Nacmias B, Sorbi S, Mecocci P, Senin U, Govoni S (1999).
Association of the estrogen receptor gene polymorphisms
with sporadic Alzheimers disease. Biochem Biophys Res
Commun 265: 335338.
Brandon DH, Holditch-Davis D, Belyea M (2002). Preterm
infants born at less than 31 weeks gestation have improved
growth in cycled light compared with continuous near
darkness. J Pediatr 140: 192199.
Branson R, Potoczna N, Kral JG, Lentes K-U, Hoehe MR,
Horber FF (2003). Binge eating as a major phenotype of
melanocortin 4 receptor gene mutations. N Engl J Med 348:
10961103.
Brat DJ, Scheithauer BW, Staugaitis SM, Cortez SC, Brecher
K, Burger PC (1998). Third ventricular chordoid glioma: a
distinct clinicopathologic entity. J Neuropathol Exp Neurol
57: 283290.
Braun FC, Forney WR (1959). Diencephalic syndrome of
early infancy associated with brain tumor. Pediatrics 24:
609615.
Braverman LE, Mancini JP, McGoldrick DM (1965). Hereditary
idiopathic diabetes insipidus. A case report with autopsy
findings. Ann Intern Med 63: 503508.
Brayne C, Gill C, Paykel ES, Huppert F, OConnor DW (1995).
Cognitive decline in an elderly population a two wave study
change. Psychol Med 25: 673683.
Breder CD, Dinarello CA, Saper CB (1988). Interleukin-I
immunoreactive innervation of the human hypothalamus.
Science 240: 321324.
Braak H, Braak E (1989). Cortical and subcortical argyrophilic

grains characterize a disease associated with adult onset
dementia. Neuropathol Appl Neurobiol 15: 1326.
Braak H, Braak E (1991). Neuropathological stageing of
Alzheimer-related changes. Acta Neuropathol 82: 239259.
Braak H, Braak E (1992). Anatomy of the human hypothalamus
(chiasmatic and tuberal region). In: Swaab DF, Hofman MA,
Mirmiran M, Ravid R, Van Leeuwen FW (Eds.) The Human
Hypothalamus in Health and Disease. (Progress in Brain
Research, Vol. 93, pp. 316) Elsevier, Amsterdam.
Braak H, Braak E (1998a). Picks disease: cytoskeletal changes
in the hypothalamic lateral tuberal nucleus. Brain Res 802:
119124.
Braak H, Braak E (1998b). Argyrophilic grain disease:
frequency of occurrence in different age categories and
neuropathological diagnostic criteria. J Neural Transm 105:
801819.
Braak H, Braak E (2000). Pathoanatomy of Parkinsons disease.
J Neurol (Suppl 2) 247: II/3II/10.
Braak E, Braak H, Mandelkow E-M (1994). A sequence of
cytoskeletal changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol (Berl)
87: 554567.
Braak H, Braak E, Yilmazer D, De Vos RAI, Janssen ENH,
Bohl J (1996). Pattern of brain destruction in Parkinsons and
Alzheimers diseases. J Neural Transm 103: 455490.
Braak H, Del Tredici K, Rb U, De Vos RAI, Jansen Steur
ENH, Braak E (2003). Staging of brain pathology related to
sporadic Parkinsons disease. Neurobiol Aging 24: 197211.
Bradbury MJ, McBurnie MI, Denton DA, Lee KF, Vale WW
(2000). Modulation of urocortin-induced hypophagia and
weight loss by corticotropin-releasing factor receptor 1
deficiency in mice. Endocrinology 141: 27152724.
Bradford JMcDW, Pawlak A (1987). Sadistic homosexual
pedophilia: treatment with cyproterone acetate: a single case
study. Can J Psychiatry 32: 2230.
Brdvik L (2002). The occurrence of suicide in severe depression related to the months of the year and the days of the
week. Eur Arch Psychiatry Clin Neurosci 252: 2832.
Brady LS, Whitfield HJ, Jr, Fox RJ, Gold PW, Herkenham M
(1991). Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and
mineralcorticoid receptor gene expression in rat brain. J Clin
Invest 87: 831837.
Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ,
Jr (1992). The antidepressants fluoxetine, idazoxan and
phenylzine alter corticotropin-releasing hormone and tyrosine
hydroxylase mRNA levels in rat brain: therapeutic implication. Brain Res 572: 117125.
Brainard GC, Hanifin JP, Rollag MD, Greeson J, Byrne B,
Glickman G, Gerner E, Sanford B (2001). Human melatonin
regulation is not mediated by the three cone photopic visual
system. J Clin Endocrinol Metab 86: 433436.
417
2014 Refs
418
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 418
D.F. SWAAB
Breitner JCS (1996). Inflammatory processes and antiinflammatory drugs in Alzheimers disease: a current appraisal.
Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP,
Southwick SM, Delaney RC, McCarthy G, Charney DS, Innis
RB (1995). MRI-based measurement of hippocampal volume
in patients with combat-related posttraumatic stress disorder.
Am J Psychiatry 152: 973981.
Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ,
Southwick SM, Nemeroff CB, Charney DS (1997). Elevated
CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154: 624629.
Bremner JD (1999). Does stress damage the brain? Biol
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL,
Charney DS (2000). Hippocampal volume reduction in major
Bremner WJ, Vitiello MV, Prinz PN (1983). Loss of circadian
rhythmicity in blood testosterone levels with aging in normal
men. J Clin Endocrinol Metab 56: 12781281.
Brennan BMD, Rahim A, Blum WF, Adams JA, Eden OB, Shalet
SM (1999a). Hyperleptinaemia in young adults following
cranial irradiation in childhood: growth hormone deficiency
or leptin insensitivity? Clin Endocrinol 50: 163169.
Brennan PA, Grekin ER, Mednick SA (1999b). Maternal
smoking during pregnancy and adult male criminal outcomes.
Arch Gen Psychiatry 56: 215219.
Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR
(1997). Sex differences in posttraumatic stress disorder. Arch
Gen Psychiatry 54: 10441048.
Breslin NA, Suddath RL, Bissette G, Nemeroff CB, Lowrimore
P, Weinberger DR (1994). CSF concentrations of neurotensin
in schizophrenia: an investigation of clinical and biochemical correlates. Schizophr Res 12: 3541.
Bresson JL, Clavequin MC, Fellmann D, Bugnon C (1985).
Anatomical and ontogenetic studies of the human paraventriculoinfundibular corticoliberin system. Neuroscience 14: 10771090.
Human corticoliberin hypothalamic neuroglandular system:
comparative immunocytochemical study with anti-rat and
anti-ovine corticotropin-releasing factor sera in the early
stages of development. Brain Res Dev Brain Res 32: 241246.
Human hypothalamic neuronal system revealed with a
salmon-melanin-concentrating hormone (MCH) antiserum.
Brewer GJ, Espinosa J, McIlhaney MP, Pencek TP, Kesslak JP,
Cotman C, Viel J, McManus DC (2001). Culture and regeneration of human neurons after brain surgery. J Neurosci
Methods 107: 1523.
Brewerton TD (1995). Toward a unified theory of serotonin
dysregulation in eating and related disorders. Psychoneuroendocrinology 20: 561590.
Brewerton TD, Jimerson DC (1996). Studies of serotonin function in anorexia nervosa. Psychiatry Res 62: 3142.
Brzillon S, Detheux M, Parmentier M, Hkfelt T, Hurd
YL (2001). Distribution of an orphan G-protein coupled
receptor (JP05) mRNA in the human brain. Brain Res 921:
2130.
Bridges TE, Hillhouse EW, Jones MT (1976). The effect of
dopamine on neurohypophysial hormone release in vivo and
from the rat neural lobe and hypothalamus in vitro. J Physiol
(Lond) 260:647666.
Briess D, Cotter D, Doshi R, Everall I (1998). Mamillary body
abnormalities in schizophrenia. Lancet 352: 789790.
Brinch M, Isager T, Tolstrup K (1988). Anorexia nervosa and
motherhood: reproduction pattern and mothering behavior of
50 women. Acta Psychiatr Scand 77: 611617.
Brisman R, Chutorian AM (1970). Inappropriate antidiuretic
hormone secretion. Hypothalamic glioma in a child. Arch
Neurol 23: 6369.
Britton KT, Koob GF (1998). Premenstrual steroids? Nature
392: 869870.
Broberger C, Johansen J, Schalling M, Hkfelt T (1997).
Hypothalamic neurohistochemistry of the murine anorexia
(anx/anx) mutation: altered processing of neuropeptide Y in
the arcuate nucleus. J Comp Neurol 387: 124135.
Brockhaus H (1942). Beitrag zur normalen Anatomie des
Hypothalamus und der Zona incerta beim Menschen. J
Psychol Neurol 51: 96196.
Brodsky MC, Glasier CM (1993). Optic nerve hypoplasia: clinical significance of associated central nervous system
abnormalities on magnetic resonance imaging. Arch
Brodsky MC, Hoyt WF, Hoyt CS, Miller NR, Lam BL
(1995). Atypical retinochoroidal coloboma in patients with
dysplastic optic discs and transsphenoidal encephalocele.
Arch Ophthalmol 113: 624628.
Bromage TG, Dean MC (1985). Re-evaluation of the age at
death of immature fossil hominids. Nature 317: 525527.
Brndum-Nielsen K (1997). The genetic basis for PraderWilli
syndrome: the importance of imprinted genes. Acta Paediatr
Suppl 423: 5557.
Brnnegrd M, Stierna P, Marcus C (1996). Glucocorticoid
resistant syndromes molecular basis and clinical presentations. J Neuroendocrinol 8: 405415.
Brooks BS, El Gammal T, Allison JD, Hoffman WH (1989).
Frequency and variation of the posterior pituitary bright signal
on MR images. Ann J Neuroradiol 10: 943948.
Brooks CMcC (1988). The history of thought concerning the
hypothalamus and its functions. Brain Res Bull 20: 657667.
Brooksbank BWL, Balzs R (1988). Development and aging of
the brain in a common human aneuploidy Downs
syndrome. In: Meisami E, Timiras P (Eds.) CRC Handbook
of Human Growth and Developmental Biology, Vol. 1, Part
C. CRC Press, Boca Raton, p. 21.
2014 Refs
2/12/03
1:39 pm
Page 419
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
419
Brownell B, Hughes T (1962). The distribution of plaques in

the cerebrum in multiple sclerosis. J Neurol Neurosurg
Brownfield MS, Kozlowski GP (1977). The hypothalamochoroidal tract. I. Immunohistochemical demonstration of
neurophysin pathways to telencephalic choroid plexuses and
cerebrospinal fluid. Cell Tissue Res 178: 111127.
Bruce J, Tamarkin L, Riedel C, Markey S, Oldfield E (1991).
Sequential cerebrospinal fluid and plasma sampling in
humans: 24-hour melatonin measurements in normal subjects
and after peripheral sympathectomy. J Clin Endocrinol Metab
72: 819823.
Brck K, Zeisberger E (1987). Adaptive changes in thermoregulation and their neuropharmacological basis. Pharmacol
Ther 35: 163215.
Brugger P, Marktl W, Herold M (1995). Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 345: 1408.
Bruguerolle B, Simon N (2002). Biologic rhythms and
Parkinsons disease: a chronopharmacologic approach to
considering fluctuations in function. Clin Neuropharmacol 25:
194201.
Brunetti A, Fulham MJ, Aloj L, De Souza B, Nieman L, Oldfield
EH, Di Chiro G (1998). Decreased brain glucose utilization in patients with Cushings disease. J Nucl Med 39:
786790.
Brning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban
PC, Klein R, Krone W, Mller-Wieland D, Kahn CR (2000).
Role of brain insulin receptor in control of body weight and
reproduction. Science 289: 21222125.
Brunner HG, Nelen MR, Van Zandvoort P, Abeling NGGM,
Van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, Van
Oost BA (1993). X-linked borderline mental retardation with
prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.
Am J Hum Genet 52: 10321039.
Brunner J, Keck ME, Landgraf R, Uhr M, Namendorf C,
Bronisch T (2002). Vasopressin in CSF and plasma in
depressed suicide attempters: preliminary results. Eur
Neuropsychopharmacol 12: 489494.
Brusco LI, Mrquez M, Cardinali DP (1998). Monozygotic
twins with Alzheimers disease treated with melatonin: case
report. J Pineal Res 25: 260263.
Brusco LI, Mrquez M, Cardinali DP (2000). Melatonin treatment stabilizes chronobiologic and cognitive symptoms in
Alzheimers disease. Neuroendocrinol Lett 21: 3942.
Bruyn GW (1968). Huntingtons chorea. Historical, clinical and
laboratory synopsis. In: Vinken PJ, Bruyn GW (Eds.)
Diseases of the basal ganglia (Handbook of clinical
neurology, Vol. 6, pp. 298378). Elsevier, Amsterdam.
Bruyn GW (1977). Agenesis septi-pellucidi, cavum septi pellucidi, cavum vergae and cavum veli interpositi In: Vinken PJ,
Bruyn GW (Eds.) Handbook of Clinical Neurology, Vol. 30.
Elsevier, Amsterdam, pp. 299366.
Brouard R, Bossmar T, Fourni-Lloret D, Chassard D, kerlund M (2000). Effect of SR49059, an orally active V1a
vasopressin receptor antagonist, in the prevention of dysmenorrhoea. Br J Obstet Gynaecol 107: 614619.
Brouwer B (1950). Positive and negative aspects of hypothalamic disorders. J Neurol Neurosurg Psychiatr 13: 1623.
Brown AS, Hembree WC, Friedman JH, Kaufmann CA, Gorman
JM (1995a). The gonadal axis in men with schizophrenia.
Psychiatry Res 57: 231239.
Brown AS, Susser ES, Lin SP, Neugebauer R, Gorman JM
(1995b). Increased risk of affective disorders in males after
second trimester prenatal exposure to the Dutch Hunger
Winter of 19441945. Br J Psychiatry 166: 601606.
Brown AS, Van Os J, Driessens C, Hoek HW, Susser ES (2000).
Further evidence of relation between prenatal famine and
major affective disorder. Am J Psychiatry 157: 190195.
Brown DM (1977). Multiple hypothalamic-pituitary abnormalities in an adolescent girl with galactorrhea. J Pediatrics 91:
901903.
Brown GM (1992). Day-Night rhythm disturbance, pineal function and human disease. Horm Res (Suppl 3) 37: 105111.
Brown GM (1995). Melatonin in psychiatric and sleep disorders.
CNS Drugs 3: 209226.
Brown GM (1996). Pineal function in psychiatric disorders. In:
Tang PL, Pang SF, Reiter RJ (Eds.) Melatonin: a universal
photoperiodic signal with diverse actions. Front Horm Res
21: 174179.
Brown IA, Baker AB, Cornwell S (1953). Poliomyelitis. VIII. Studies
on temperature regulation. Arch Neurol Psychiatr 69: 332342.
Brown MA, Crawford GA, Horgan EA, Gallery EDM (1986).
Arginine vasopressin in hypertensive human pregnancy. Clin
Exp Hypertens B Hypertens Pregnancy 5: 253269.
Brown MA, Crawford GA, Horgan EA, Gallery EDM (1988).
Arginine vasopressin in primigravid human pregnancy. A
prospective study. J Reprod Med 33: 3540.
Brown NW, Ward A, Surwit R, Tiller J, Lightman S, Treasure
JL, Campbell IC (2003b). Evidence for metabolic and
endocrine abnormalities in subjects recovered from anorexia
nervosa. Metabolism 52: 296302.
Brown RC, Han Z, Cascio C, Papadoulos V (2003a). Oxidative
stress-mediated DHEA formation in Alzheimers disease
pathology. Neurobiol Aging 24: 5765.
Brown RE, Stevens DR, Haas HL (2001). The physiology of
brain histamine. Progr Neurobiol 63: 637672.
Brown TT, Dobs AS (2002). Endocrine effects of marijuana. J
Clin Pharmacol 42: 90S-96S.
Brown WA, Van Woert MH, Ambani LM (1973). Effect of
apomorphine on growth hormone release in human. J Clin
Endocrinol Metabol 37: 463465.
Brown-Grant K, Raisman G (1977). Abnormalities in reproductive function associated with the destruction of the
suprachiasmatic nuclei in female rats. Proc R Soc Lond B
Biol Sci 198: 279296.
419
2014 Refs
420
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 420
D.F. SWAAB
Bruyn GW, De Jong FH, Van der Molen JH (1972).

Huntingtons chorea and the adrenal. Br Med J 2: 506.
Bruyn GW (1973). Neuropathological changes in Huntingtons
chorea. In: Barbeau A, Chase TN, Paulson GW (Eds).
Huntingtons chorea 18721972. Adv Neurol 1: 399-403.
New York: Raven.
Brydon L, Roka F, Petit L, De Coppet P, Tissot M, Barrett P,
Morgan PJ, Nanoff C, Strosberg AD, Jockers R (1999). Dual
signalling of human mel1a melatonin receptors via Gi2, Gi3,
and Gq/11 proteins. Mol Endocrinol 13: 20252038.
Brzezinski A, Lynch HJ, Seibel MM, Deng MH, Nader TM,
Wurtman RJ (1988). The circadian rhythm of plasma melatonin during the normal menstrual cycle and in amenorrheic
women. J Clin Endocrinol Metab 66: 891895.
Brzezinski A (1997). Melatonin in humans. New Engl J Med
336:186195.
Bschor T, Baethge C, Adli M, Lewitzka U, Eichmann U,
Bauer M (2003). Hypothalamic-pituitary-thyroid system
activity during lithium augmentation therapy in patients with
unipolar major depression. Rev Psychiatr Neurosci 28:
210216.
Bchter D, Behre H, Kliesch S, Nieschlag E (1998). Pulsatile
GnRH or human chorionic gonadotropin/human menopausal
gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J
Buemi M, DAnna R, Di Pasquale G, Floccari F, Ruello A,
Aloisi C, Leonardi I, Frisina N, Corica F (2001). Urinary
excretion of aquaporin-2 water channel during pregnancy.
Cell Physiol Biochem 11: 203208.
Buguet A (1999). Is sleeping sickness a circadian disorder? The
serotonergic hypothesis. Chronobiol Int 16: 477489.
Bugnon C, Bloch B, Fellmann D (1976). Etude immunocytologique des cellules et des fibres a LH-RH chez le foetus
humain. Bull Assoc Anat 60: 269278.
Bugnon C, Fellmann D, Bloch B (1977). Immunocytochemical
study of the ontogenesis of the hypothalamic somatostatincontaining neurons in the human fetus. Cell Tissue Res 183:
319328.
Bugnon C, Bloch B, Lenys D, Fellmann D (1979). Infundibular
neurons of the human hypothalamus simultaneously reactive
with antisera against endorphins, ACTH, MSH and -LPH.
Cell Tissue Res 199: 177196.
Buijs RM, Swaab DF (1979). Immuno-electron microscopical
demonstration of vasopressin and oxytocin synapses in the
limbic system of the rat. Cell Tissue Res 204: 355365.
Buijs RM, Kalsbeek A (2001). Hypothalamic integration of
central and peripheral clocks. Nat Rev Neurosci 2: 521526.
Buijs RM, De Vries GJ, Van Leeuwen FW, Swaab DF (1983).
Vasopressin and oxytocin: distribution and putative functions
in the brain. In: Cross BA, Leng GA (Eds.) The neurohypophysis: structure, function and control. (Progress in Brain
Research, Vol. 60, pp. 115122) Elsevier, Amsterdam.
Buijs RM, Swaab DF, Dogterom J, Van Leeuwen FW (1978).

Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Cell Tissue Res 186: 423433.
Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MGP, Ter
Horst GJ, Romijn HJ, Kalsbeek A (1999). Anatomical and
functional demonstration of a multisynaptic suprachiasmatic
nucleus adrenal (cortex) pathway. Eur J Neurosci 11:
15351544.
Buijs RM, Chun SJ, Niijima A, Romijn HJ, Nagai K (2001).
Parasympathetic and sympathetic control of the pancreas: a
role for the suprachiasmatic nucleus and other hypothalamic
centers that are involved in the regulation of food intake. J
Bulik CM, Devlin B, Bacanu S-A, Thornton L, Klump KL,
Fichter MM, Halmi KA, Kaplan AS, Strober M, Woodside
DB, Bergen AW, Ganjei JK, Crow S, Mitchell J, Rotondo
A, Mauri M, Cassano G, Keel P, Berrettini WH, Kaye WH
(2003). Significant linkage on chromosome 10p in families
with bulimia nervosa. Am J Hum Genet 72: 200207.
Bullmann C, Faust M, Hoffmann A, Heppner C, Jockenhvel
F, Mller-Wieland D, Krone W (2000). Five cases with
central diabetes insipidus and hypogonadism as first presentation of neurosarcoidosis. Eur J Endocrinol 142: 365372.
Bullock TH (1984). Understanding brains by comparing taxa.
Perspect Biol Med 27: 510524.
Blow B, Hagmar L, rbk P, sterberg K, Erfurth EM (2002).
High incidence of mental disorders, reduced mental wellbeing and cognitive function in hypopituitary women with
GH deficiency treated for pituitary disease. Clin Endocrinol
56: 183193.
Bundey S, Poulton K, Whitwell H, Curtis E, Brown IAR, Fielder
AR (1992). Mitochondrial abnormalities in the DIDMOAD
syndrome. J Inherit Metab Dis 15: 315319.
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ
(1999). Effects of thyroxine as compared with thyroxine plus
triiodothyronine in patients with hypothyroidism. New Engl
J Med 340: 424429.
Bunnell DE, Treiber SP, Phillips NH, Berger RJ (1992). Effects
of evening bright light exposure on melatonin, body temperature and sleep. J Sleep Res 1: 1723.
Bunney WE, Bunney BG (2000). Molecular clock genes in
man and lower animals: possible implications for circadian
abnormalities in depression. Neuropsychopharmacology 22:
335345.
Burbach JPH, Luckman SM, Murphy D, Gainer H (2001). Gene
regulation in the magnocellular hypothalamo-neurohypophysial system. Physiol Rev 81: 11971267.
Burcar PJ, Norenberg MD, Yarnell PR (1977). Hyponatremia
and central pontine myelinolysis. Neurology 27: 223226.
Burch JB, Reif JS, Noonan CW, Ichinose T, Bachand AM,
Koleber TL, Yost MG (2002). Melatonin metabolite excretion among cellular telephone users. Int J Radiat Biol 78:
10291036.
2014 Refs
2/12/03
1:39 pm
Page 421
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
421
Bttner A, Winkler PA, Weis S (1997). Endodermal cyst of the

third ventricle: case report. Neurosurgery 40: 832835.
Bylesj I, Forsgren L, Wetterberg L (2000). Melatonin and
epileptic seizures in patients with acute intermittent porphyria.
Epileptic Disord 2: 203208.
Byne W (1998). The medial preoptic and anterior hypothalamic
regions of the rhesus monkey: cytoarchitectonic comparison
with the human and evidence for sexual dimorphism. Brain
Res 793: 346350.
Byne W, Parsons B (1993). Human sexual orientation: the
biological theories reappraised. Arch Gen Psychiatry 50:
228239.
Byne W, Mattiace L, Kress Y, Davies P (1991). Alz-50
immunoreactivity in the hypothalamus of the normal
and Alzheimer human and the rat. J Comp Neurol 306:
602612.
Byne W, Lasco MS, Kemether E, Shinwari A, Edgar MA,
Morgello S, Jones LB, Tobet S (2000). The interstitial nuclei
of the human anterior hypothalamus: an investigation of
sexual variation in volume and cell size, number and density.
Brain Res 856: 254258.
Byne W, Tobet S, Mattiace LA, Lasco MS, Kemether E, Edgar
MA, Morgello S, Buchsbaum MS, Jones LB (2001). The
interstitial nuclei of the human anterior hypothalamus: an
investigation of variation with sex, sexual orientation, and
HIV status. Horm Behav 40: 8692.
Cabanes J (1978). Asymptomatic persistence of infundibularis
recessus. J Neurosurg 49: 769772.
Cabbell KL, Ross DA (1996). Stereotactic microsurgical craniotomy for the treatment of third ventricular colloid cysts.
Neurosurgery 38: 301307.
Caberlotto L, Hurd YL, Murdock P, Wahlin JP, Melotto S,
Corsi M, Carletti R (2003). Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human
brain. Eur J Neurosci 17: 17361746.
Cacabelos R, Niigawa H, Ikemura Y (1986). Neuroendocrine
correlates in senile dementia of the Alzheimer type. Prog Clin
Neurosci 2: 231247.
Cacciari E, Zucchini S, Carla G, Pirazzoli P, Cicognani A,
Mandini M, Busacca M, Trevisan C (1990). Endocrine function and morphological findings in patients with disorders of
the hypothalamo-pituitary area: a study with magnetic resonance. Arch Dis Childhood 65: 11991202.
Cacciari E, Zucchini S, Ambrosetto P, Tani G, Carla G,
Cicognani A, Pirazzoli P, Sganga T, Balsamo A, Cassio A,
Zappulla F (1994). Empty sella in children and adolescents
with possible hypothalamic-pituitary disorders. J Clin
Endocrinol Metab 767771.
Cademartiri C, Torelli P, Cologno D, Manzoni GC (2002).
Upper and lower cluster headache: clinical and pathogenetic
observations in 608 patients. Headache 42: 630637.
Cadnapaphornchai MA, Schrier RW (2000). Pathogenesis and
management of hyponatremia. Am J Med 109: 688692.
Burd JM, Davison J, Weightman DR, Bayliss PH (1987).

Evaluation of enzyme inhibitors of pregnancy associated
oxytocinase: application to the measurement of plasma
immunoreactive oxytocin during human labour. Acta
Burford GD, Robinson ICAF (1982). Oxytocin, vasopressin and
neurophysins in the hypothalamo-neurohypophysial system
of the human fetus. J Endocrinol 95: 403408.
Burgess HJ, Sletten T, Savic N, Gilbert SS, Dawson D (2001).
Effects of bright light and melatonin on sleep propensity,
temperature, and cardiac activity at night. J Appl Physiol 91:
12141222.
Burguera B, Couce ME, Long J, Lamsam J, Laakso K, Jensen
MD, Parisi JE, Lloyd RV (2000). The long form of the leptin
receptor (OB-Rb) is widely expressed in the human brain.
Neuroendocrinology 71: 187195.
Burgus R, Dunn TF, Desiderio D, Guillemin R (1969). Structure
molculaire du facteur hypothalamique hypophysiotrope TRF
dorigine ovine: mise en vidence par spectromtrie de masse
de la squence PCA-His-Pro-NH2. CR Acad Sci Paris 269:
18701873.
Burkhoff AM, Linemeyer DL, Salon JA (1998). Distribution of
a novel hypothalamic neuropeptide Y receptor gene and its
absence in rat. Mol Brain Res 53: 311316.
Burman P, Ritzn EM, Lindgren AC (2001). Endocrine dysfunction in PraderWilli syndrome: a review with special
reference to GH. Endocr Rev 22: 787799.
Burnett FE, Scott LV, Weaver MG, Medbak SH, Dinan TG
(1999). The effect of naloxone on adrenocorticotropin and
cortisol release: evidence for a reduced response in depression. J Affect Disord 53:263268.
Burney-Puckett M (1996). Sundown syndrome: etiology and
management. J Psychosoc Nurs Ment Health Serv 34: 4043.
Burr IM, Slonim AE, Danish RK, Gadoth N, Butler IJ (1976).
Diencephalic syndrome revisited. J Pediatr 88: 439444.
Burt T, Lisanby SH, Sackeim HA (2002). Neuropsychiatric
applications of transcranial magnetic stimulation: a meta
analysis. Int J Neuropsychopharmacol 5: 73103.
Buruma OJS, Van der Kamp W, Barendswaard E et al (1987).
Which factors influence age at onset and rate of progression
in Huntingtons disease? J Neurol Sci 80: 299306.
Buskila D (2001). Fibromyalgia, chronic fatigue syndrome, and
myofascial pain syndrome. Curr Opin Rheumatol 13: 117127.
Butler MG, Moore J, Morawiecki A, Nicolson M (1998).
Comparison of leptin protein levels in PraderWilli syndrome
and control individuals. Am J Med Gen 75: 712.
Butler MG, Bittel D, Talebizadeh Z (2002). PraderWilli
syndrome and a deletion/duplication within the 15q11-q13
region. J Med Genet 39: 202204.
Butowt R, Von Bartheld CS (2003). Connecting the dots: trafficking of neurotrophins, lectins and diverse pathogens by
binding to the neurotrophin receptor p75NTR. Eur J Neurosci
17: 673680.
421
2014 Refs
422
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 422
D.F. SWAAB
Caff AR, Van Leeuwen FW (1983). Vasopressin-immunoreactive cells in the dorsomedial hypothalamic region, medial
amygdaloid nucleus and locus coeruleus of the rat. Cell Tissue
Res 233: 2333.
Cagampang FRA, Whatley SA, Mitchell AL, Powell JF,
Campbell IC, Coen CW (1999). Circadian regulation
of prion protein messenger RNA in the rat forebrain: a
widespread and synchronous rhythm. Neuroscience 91:
12011204.
Caglayan S, Ozata M, Ozisik G, Turan M, Bolu E, Oktenli C,
Arslan N, Erbil K, Gul D, Ozdemir IC (2001). Plasma
melatonin concentration before and during testosterone
replacement in Klinefelters syndrome: relation to hepatic
indolamine metabolism and sympathoadrenal activity. J Clin
Cagnacci A (1996). Melatonin in relation to physiology in adult
humans. J Pineal Res 21: 200213.
Cagnacci A, Volpe A (1996). Influence of melatonin and
photoperiod on animal and human reproduction. J Endocrinol
Invest 19: 382411.
Cagnacci A, Elliott JA, Yen SSC (1992). Melatonin: a major
regulator of the circadian rhythm of core temperature in
humans. J Clin Endocrinol Metab 75: 447452.
Cagnacci A, Arangino S, Malmusi S, Longo M, Volpe A (1997).
Melatonin in aged women. Possible modulation by estrogens.
Aging Clin Exp Res (Suppl 4) 9: 6263.
Cagnacci A, Soldani R, Yen SSC (1997). Melatonin enhances
cortisol levels in aged women: reversible by estrogens. J
Pineal Res 22: 8185.
Cagnacci A, Soldani R, Melis GB, Volpe A (1998a). Diurnal
rhythms of labor and delivery in women: modulation by parity
and seasons. Am J Obstet Gynecol 178: 140145.
Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB
(1998b). Influences of melatonin administration on the circulation of women. Am J Physiol 274: R335R338.
Cagnacci A, Arangino S, Angiolucci M, Melis GB, Facchinetti
F, Malmusi S, Volpe A (2001a). Effect of exogenous
melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy.
Clin Endocrinol 54: 261266.
Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB,
Cagnacci P, Volpe A (2001b). Influence of melatonin administration on glucose tolerance and insulin sensitivity of
postmenopausal women. Clin Endocrinol 54: 339346.
Caine ED, McBride MC, Chiverton P, Bamford KA, Rediess
S, Shiao J (1988). Tourettes syndrome in Monroe County
school children. Neurology 38: 472475.
Cairns H, Oldfield RC, Pennybacker JB, Whitteridge D (1941).
Akinetic mutism with an epidermoid cyst of the 3rd ventricle.
Brain 64: 273290.
Cairns H (1952). Disturbances of consciousness with lesions of
the brain-stem and diencephalon. Brain 75: 109146.
Cajal y Ramn S (1911). Histologie du systme nerveux de

lhomme et les vertbrs. T.2. Maloine, Paris, p. 466.
Callen DJA, Black SE, Gao F, Caldwell CB, Szalai JP (2001).
Beyond the hippocampus. MRI volumetry confirms widespread limbic atrophy in AD. Neurology 57: 16691674.
Calming U, Bemstrand C, Mosskin M, Stone Elander S, Ingvar M,
Henter J-I (2002). Brain 18-FDG PET scan in central nervous
system Langerhans cell histiocytosis. J Pediatr 141: 435440.
Calvo B, Bilbao JR, Rodrguez A, Rodrguez-Arnao MD, Castao
L (1999). Molecular analysis in familial neurohypophyseal
diabetes insipidus: early diagnosis of an asymptomatic carrier.
Cameron FJ, Khadilkar VV, Stanhope R (1999). Pituitary
dysfunction, morbidity and mortality with congenital midline
malformation of the cerebrum. Eur J Pediatr 158: 97102.
Campbell B, Petersen WE (1953). Milk let-down and the
orgasm in the human female. Hum Biol 25: 165168.
Campbell DA, Sundaramurthy D, Gordon D, Markham AF,
Pieri LF (1999). Association between a marker in the UCP2/UCP-3 gene cluster and genetic susceptibility to anorexia
nervosa. Mol Psychiatry 4: 6870.
Campbell SS, Kripke DF, Gillin JC, Hrubovcak JC (1988).
Exposure to light in healthy elderly subjects and Alzheimer
patients. Physiol Behav 42: 141144.
Campbell SS, Gillin JC, Kripke DF, Erikson P, Clopton P
(1989). Gender differences in the circadian temperature
rhythms of healthy elderly subjects: relationships to sleep
quality Sleep 12: 529536.
Campbell SS, Murphy PJ (1998). Extraocular circadian phototransduction in humans. Science 279: 396399.
Campbell WA, Lowther J, McKenzie I, Price WH (1982). Serum
gonadotrophins in Downs syndrome. J Med Genet 19: 9899.
Candy JM, Perry RH, Perry EK, Irving D, Blessed G, Fairbairn
AF, Tomlinson BE (1983). Pathological changes in the
nucleus of Meynert in Alzheimers and Parkinsons diseases.
J Neurol Sci 59: 277289.
Candy JM, Perry RH, Thompson JE, Johnson M, Oakley AE
(1985). Neuropeptide localisation in the substantia innominata
and adjacent regions of the human brain. J Anat 140: 309327.
Cannav S, Romano C, Buffa R, Faglia G (1997). Granulomatous
sarcoidotic lesion of hypothalamic-pituitary region associated
with Rathkes cleft cyst. J Endocrinol Invest 20: 7781.
Cannav S, Curt L, Venturino M, Squadrito S, Almoto B,
Narbone MC, Rao R, Trimarchi F (2002). Abnormalities of
hypothalamic-pituitary-thyroid axis in patients with primary
empty sella. J Endocrinol Invest 25: 236239.
Cannon M, Jones PB, Murray RM (2002). Obstetric complications and schizophrenia: historical and meta-analytic review.
Canteras NS, Swanson LW (1992). The dorsal premammillary
nucleus: an unusual component of the mammillary body. Proc
2014 Refs
2/12/03
1:39 pm
Page 423
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
423
Carlquist M, McDonald TJ, Go VLW, Bataille D, Johansson

C, Mutt V (1982). Isolation and amino acid composition of
human vasoactive intestinal polypeptide (VIP). Horm Metab
Res 14:2829.
Carlson DE, Dornhorst A, Seif SM, Robinson AG, Gann DS
(1982). Vasopressin-dependent and -independent control of
the release of adrenocorticotropin. Endocrinology 110:
680682.
Carlson LE, Sherwin BB, Chertkow HM (2000). Relationships
between mood and estradiol (E2) levels in Alzheimers disease
(AD) patients. J Gerontol B 55: P47P53.
Carlson M, Earls F (1997). Psychological and neuroendocrinological sequelae of early social deprivation in institutionalized
children in Romania. Ann NY Acad Sci 807: 419428.
Carlson MC, Zandi PP, Plassman BL, Tschanz JT, WelshBohmer KA, Steffens DC, Bastian LA, Mehta KM, Breitner
JCS (2001). Hormone replacement therapy and reduced
cognitive decline in older women. Neurology 57: 22102216.
Carlson MG, Snead WL, Oeser AM, Butler MG (1999). Plasma
leptin concentrations in lean and obese human subjects and
PraderWilli syndrome: comparison of RIA and ELISA
methods. J Lab Clin Med 133: 7580.
Carlsson A, Svennerholm L, Winblad B (1980a). Seasonal and
circadian monoamine variations in human brains examined
post mortem. Acta Psychiatr Scand (Suppl 280) 61: 7585.
Carlsson A, Adolfsson R, Aquilonius S-M, Gottfries C-G,
Oreland L, Svennerholm L, Winblad B (1980b). Biogenic
amines in human brain in normal aging, senile dementia, and
chronic alcoholism. In: Ergot Compounds and Brain Function.
Neuroendocrine and Neuropsychiatric Aspects. Raven Press,
New York, pp. 295304.
Carmel G, Mager EM, Binder LI, Kuret J (1996). The structural basis of monoclonal antibody Alz50s selectivity
for Alzheimers disease pathology. J Biol Chem 271:
3278932795.
Carmel PW (1980). Surgical syndromes of the hypothalamus.
Clin Neurosurg 27: 133159.
Carmel PW (1985). Vegetative dysfunctions of the hypothalamus. Acta Neurochir 75: 113121.
Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf
W, Davidson JM (1987). Plasma oxytocin increases in the
human sexual response. J Clin Endocrinol Metab 64: 2731.
Carmichael MS, Warburton VL, Dixen J, Davidson JM (1994).
Relationships among cardiovascular, muscular, and oxytocin
responses during human sexual activity. Arch Sex Behav 23:
5979.
Carney PA, Seggie J, Vojtechovsky M, Parker J, Grof E, Grof
P (1988). Bipolar patients taking lithium have increased
dark adaptation threshold compared with controls. Pharmacopsychiatry 21: 117120.
Carney RM, Freedland KE, Veith RC, Cryer PE, Skala JA,
Lynch T, Jaffe AS (1999). Major depression, heart rate, and
Canteras NS, Simerly RB, Swanson LW (1992). Projections of

the ventral premammillary nucleus. J Comp Neurol 324:
195212.
Cappa M, Grossi A, Borrelli P, Ghigo E, Bellone J, Benedetti
S, Carta D, Loche S (1993). Growth hormone (GH) response
to combined pyridostigmine and GH-releasing hormone
administration in patients with PraderLabhartWilli
syndrome. Horm Res 39: 5155.
Cappa M, Raguso G, Palmiotto T, Faedda A, Gurreri F, Neri
G, Deghenghi R, Loche S (1998). The growth hormone
response to hexarelin in patients with PraderWilli syndrome.
J Endocrinol Invest 21: 501505.
Cappelli C, Grill J, Raquin M, Pierre-Kahn A, Lellouch-Tubiana
A, Terrier-Lacombe M-J, Habrand J-L, Couanet D, Brauner
R, Rodriguez D, Hartmann O, Kalifa C (1998). Long
term follow up of 69 patients treated for optic pathway
tumours before the chemotherapy era. Arch Dis Child 79:
334338.
Cappiello A, Malison RT, McDougle CJ, Vegso SJ, Charney
DS, Heninger GR, Price LH (1996). Seasonal variation in
neuroendocrine and mood responses to IV L-tryptophan
in depressed patients and healthy subjects. Neuropsychopharmacology 15: 475483.
Capuron L, Ravaud A, Dantzer R (2000). Early depressive
symptoms in cancer patients receiving interleukin 2 and/or
interferon alpha-2b therapy. J Clin Oncol 18: 21432151.
Caraceni T, Panerai AE, Parati EA, Cocchi D, Mller EE (1977).
Altered growth hormone and prolactin responses to dopaminergic stimulation in Huntingtons chorea. J Clin Endocrinol
Metab 44: 870875.
Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S,
Boyd J, Korach KS, Simpson ER (1997). Effect of testosterone and estradiol in a man with aromatase deficiency. N
Engl J Med 337: 9195.
Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata
ARM (1999). Role of oestrogen in male sexual behaviour:
insights from the natural model of aromatase deficiency. Clin
Cardinali DP, Brusco LI, Liberczuk C, Furio AM (2002). The
use of melatonin in Alzheimers disease. Neuroendocrinol
Lett (Suppl 1) 23: 2023.
Carella C, Rotondi M, Del Buono A, Sinisi AM, Del Basso De
Caro ML, Mone CM, Vizioli L, Sorvillo F, Mazziotti G,
Bellastella A (1999). Diabetes insipidus and increased serum
levels of leptin and lactate-dehydrogenase (LDH) in an
adolescent boy with a primary intracranial germinoma. Case
Report and an endocrinological revaluation of literature. J
Endocrinol Invest 22: 558561.
Carey ML, Friedmann TB, Asher JH, Innis JW (1998). Septooptic dysplasia and WS1 in the proband of a WS1 family
segregating for a novel mutation in PAX3 exon 7. J Med
Genet 35: 248250.
423
2014 Refs
424
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 424
D.F. SWAAB
plasma norepinephrine in patients with coronary heart disease.

Caroff SN, Mann SC (1993). Neuroleptic malignant syndrome.
Med Clin North Am 77: 185202.
Caron P, Imbeaud S, Bennet A, Plantavid M, Camerino G,
Rochiccioli P (1999). Combined hypothalamic-pituitarygonadal defect in a hypogonadic man with a novel mutation
in the DAX-1 gene. J Clin Endocrinol Metab 84: 35633569.
Carpenter S, Yassa R, Ochs R (1982). A pathologic basis for
KleineLevin syndrome. Arch Neurol 39: 2528.
Carr D-B, Lipkowski A-W (1990). Neuropeptides and pain.
Agressologie 31: 173177.
Carrel AL, Myers SE, Whitman BY, Allen DB (2002). Benefits
of long-term GH therapy in PraderWilli syndrome: a 4-year
study. J Clin Endocrinol Metab 87: 15811585.
Carrier J, Paquet J, Morettini J, Touchette E (2002). Phase
advance of sleep and temperature circadian rhythms in the
middle years of life in humans. Neurosci Lett 320: 14.
Carrion VG, Weems CF, Ray RD, Glaser B, Hessl D, Reiss
AL (2002). Diurnal salivary cortisol in pediatric posttraumatic stress disorder. Biol Psychiatry 51: 575582.
Carroll N, Neal LA (1997). Diencephalic tumours presenting as
behavioural problems in the workplace. Occup Med 47: 5254.
Carson BS, Weingart JD, Guarnieri M, Fisher PG (1997). Third
ventricular choroid plexus papilloma with psychosis. J
Carson MJ, Slager UT, Steinberg RM (1977). Simultaneous occurrence of diabetes mellitus, diabetes insipidus, and optic atrophy
in a brother and sister. Am J Dis Child 131: 13821385.
Carstens E (1986). Hypothalamic inhibition of rat dorsal horn
neuronal responses to noxious skin heating. Pain 25: 95107.
Carter CS (1998). Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology 23: 779818.
Carter LS (1992). Oxytocin and sexual behavior. Neurosci
Biobehav Rev 16: 131144.
Casanova MF, Walker LC, Whitehouse PJ, Price DL (1985).
Abnormalities of the nucleus basalis in Downs syndrome.
Ann Neurol 18: 310313.
Casanova MF, Mannheim G, Kruesi M (2002). Hippocampal
pathology in two mentally ill paraphiliacs. Psychiatry Res
Neuroimaging 115: 7989.
Casanueva FF, Borras CG, Burguera B, Muruais C, Fernandez,
Devesa J (1987). Steroids and neuroendocrine function in
anorexia nervosa. J Steroid Biochem 27: 635640.
Cascino GD, Kelly PJ, Hirschorn KA, Scharbrough FW (1991).
Gelastic seizures with hypothalamic hamartoma: a depth electrode surgical series. Epilepsia 32: 9798.
Cascino GD, Andermann F, Berkovic SF, Kuzniecky RI,
Sharbrough FW, Keene DL, Bladin PF, Kelly PJ, Olivier A,
Feindel W (1993). Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial
EEG monitoring and outcome of surgical treatment.
Casiglia E, dEste D, Ginocchio G, Colangeli G, Onesto C,

Tramontin P, Ambrosio GB, Pessina AC (1996). Lack of
influence of menopause on blood pressure and cardiovascular
risk profile: a 16-year longitudinal study concerning a cohort
of 568 women. J Hypertens 14: 729736.
Casper RC (1998). Serotonin, a major player in the regulation
of feeding and affect. Biol Psychiatry 44: 795797.
Casper RF, Yen SSC, Wilkes MM (1979). Menopausal flushes:
a neuroendocrine link with pulsatile luteinizing hormone
secretion. Science 205: 823825.
Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW,
Taylor A, Poulton R (2002). Role of genotyoe in the cycle
of violence in maltreated children. Science 297: 851854.
Cassel CK (1998). Genetic testing and Alzheimers disease:
ethical issues for providers and families. Alz Dis Assoc Disord
(Suppl 3) 12: S16S20.
Cassidy EM, OKeane V (2000). Depression and interferonalpha therapy. Br J Psychiatry 176: 494.
Cassidy F, Carroll BJ (2002). Seasonal variation of mixed and
pure episodes of bipolar disorder. J Affect Disord 68: 2531.
Cassidy SB (1997). PraderWilli syndrome. J Med Genet 34:
917923.
Cassidy SB, Gainey AJ, Butler MG (1989). Occupational hydrocarbon exposure among fathers of PraderWilli syndrome
patients with and without deletions of 15q. Am J Hum Genet
44: 806810.
Casson IR, Siegel O, Sham R, Campbell EA, Tarlau M,
DiDomenico A (1984). Brain damage in modern boxers.
JAMA 251: 26632667.
Casson PR, Carson SA, Buster JE (1998). Replacement dehydroepiandrosterone in the elderly: rationale and prospects for
the future. Endocrinologist 8: 187194.
Cassoni P, Marrocco T, Deaglio S, Sapino A, Bussolati G
(2001). Biological relevance of oxytocin and oxytocin receptors in cancer cells and primary tumors. Ann Oncol (Suppl
2) 12: S37S39.
Cassoni P, Sapino A, Deaglio S, Bussolati B, Volante M,
Munaron M, Albini A, Torrisi A, Bussolati G (2002).
Oxytocin is a growth factor for Kaposis sarcoma cells:
evidence of endocrine-immunological cross-talk. Cancer Res
62: 24062413.
Castaeyra-Perdomo A, Meyer G, Carmona-Calero E, BauelosPineda J, Mndez-Medina R, Ormazabal-Ramos C,
Ferres-Torres R (1994). Alterations of the subcommissural
organ in the hydrocephalic human fetal brain. Brain Res Dev
Brain Res 79: 316320.
Castellano G, Solis-Herruzo J, Gonzalez A, Morillas JD, Moreno
D, Munoz T, Larrodera L (1994). Plasma arginine vasopressin
response to oral, gastric, and intravenous water load in
patients with cirrhosis. Gastroenterology 106: 678685.
Castells S, Torrado C, Bastian W, Wisniewski KE (1992).
Growth hormone deficiency in Downs syndrome children. J
Intellect Disabil Res 36: 2943.
2014 Refs
2/12/03
1:39 pm
Page 425
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
425
Chabbert Buffet N, Djakoure C, Christin Maitre S, Bouchard

P (1998). Regulation of the human menstrual cycle. Front
Neuroendocrinol 19: 151186.
Chai SY, McKenzie JS, McKinley MJ, Mendelsohn FAO
(1990). Angiotensin converting enzyme in the human basal
forebrain and midbrain visualized by in vitro autoradiography.
Chai SY, Bastias MA, Clune EF, Matsacos DJ, Mustafa T, Lee
JH, McDowall SG, Mendelsohn FAO, Albiston AL, Paxinos
G (2000). Distribution of angiotensin IV binding sites (AT4
receptor) in the human forebrain, midbrain and pons as visualised by in vitro receptor autoradiography. J Chem Neuroanat
20: 339348.
Challis JRG, Patrick JE, Campbell K, Natale R, Richardson B
(1980). Diurnal changes in maternal plasma oestrone and
oestradiol at 30 to 31, 34 to 35 and 38 to 39 weeks gestational
age. Br J Obstet Gynaecol 87: 983988.
Chalmers I, Campbell H, Turnbull AC (1975). Use of oxytocin
and incidence of neonatal jaundice. Br Med J (2), 5963:
116118.
Chamberlain RS, Herman BH (1990). A novel biochemical
model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biol
Chamberlain MC (1995). Recurrent chiasmatic-hypothalamic
glioma treated with oral etoposide. Arch Neurol 52: 509513.
Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR,
Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J,
Ellis C, Ganguly S, Konchar S, Cluderay J, Leslie R, Wilson
S, Sarau HM (1999). Melanin-concentrating hormone is the
cognate ligand for the orphan G-protein-coupled receptor
SLC-1. Nature 400: 261265.
Champier J, Jouvet A, Rey C, Guyotat J (2003). Differential
somatostatin receptor subtype expression in human normal
pineal gland and pineal parenchymal tumors. Cell Molec
Chan E-C, Falconer J, Madsen G, Rice KC, Webster EL,
Chrousos GP, Smith R (1998). A corticotropin-releasing
hormone type I receptor antagonist delays parturition in sheep.
Chan TYK (1997). Drug-induced syndrome of inappropriate
antidiuretic hormone secretion. Drugs Aging 11: 2744.
Chan-Palay VL (1988a). Galanin hyperinnervates surviving
neurons of the human basal nucleus of Meynert in dementias
of Alzheimers and Parkinsons disease: a hypothesis for the
role of galanin in accentuating cholinergic dysfunction in
dementia. J Comp Neurol 273: 543557.
Chan-Palay VL (1988b). Neurons with galanin innervate
cholinergic cells in the human basal forebrain and galanin
and acetylcholine coexist. Brain Res Bull 21: 465472.
Chan-Palay VL, Jentsch B (1992). Galanin tuberomamillary
neurons in the hypothalamus in Alzheimers and Parkinsons
disease. In: Swaab DF, Hofman MA, Mirmiran M, Ravid R,
Castells S, Beaulieu I, Torrado C, Wisniewski KE, Zarny S,

Gelato MC (1996). Hypothalamic versus pituitary dysfunction in Downs syndrome as cause of growth retardation. J
Castle DJ, Murray RM (1991). The neurodevelopmental basis
of sex differences in schizophrenia. Psychol Med 21:
565575.
Castro JR, Costoya JA, Gallego R, Prieto A, Arce VM, Sears
R (2000). Expression of growth hormone receptor in the
human brain. Neurosci Lett 281: 147150.
Castrogiovanni P, Iapichino S, Pacchierotti C, Pieraccini F
(1998). Season of birth in psychiatry. Neuropsychobiology
37: 175181.
Castrogiovanni P, Iapichino S, Pacchierotti C, Pieraccini F
(1999). Season of birth in panic disorder. Neuropsychobiology
40: 177182.
Catal MD, Caete-Nicols C, Iradi A, Tarazona FJ, Tormos
JM, Pascual-Leone A (1997). Melatonin levels in Parkinsons
disease: drug therapy versus electrical stimulation of the
internal globus pallidus. Exp Gerontol 32: 553558.
Cataln R, Gallart JM, Castellanos JM, Galard R (1998). Plasma
corticotropin-releasing factor in depressive disorders. Biol
Catalina PF, Rodriguez Garca M, De la Torre C, Pramo C,
Garca-Mayor RVG (1995). Diabetes insipidus for five years
preceding the diagnosis of hypothalamic Langerhans cell
histiocytosis. J Endocrinol Invest 18: 663666.
Catania A, Airaghi L, Colombo G, Lipton JM (2000).
-Melanocyte-stimulating hormone in normal human
physiology and disease states. Trends Endocrinol Metab 11:
304308.
Cavallini MC, Bertelli S, Chiapparino D, Riboldi S, Bellodi L
(2000). Complex segregation analysis of obsessive-compulsive disorder in 141 families of eating disorder probands,
with and without obsessive-compulsive disorder. Am J Med
Gen 96: 384391.
Cavallo A, Good WV, Ris MD, Succop P (2002). Dose response
to melatonin treatment for disordered sleep rhythm in a blind
child. Sleep Med 3: 159161.
Cavanagh JB (1999). Corpora-amylacea and the family of
polyglucosan diseases. Brain Res Rev 29: 265295.
avdar S, Onat F, Aker R, Sehirli
, San
T, Yananli HR (2001).
The afferent connections of the posterior hypothalamic
nucleus in the rat using horseradish peroxidase. J Anat 198:
463472.
Caviness VS (1992). Kallmanns syndrome beyond migration.
New Engl J Med 326: 17751777.
Cenacchi G, Giovenali P, Castrioto C, Giangaspero F (2001).
Pituicytoma: ultrastructural evidence of a possible origin from
folliculo-stellate cells of the adenohypophysis. Ultrastruct
Pathol 25: 309312.
Cerf ME, Raidoo DM (2000). Immunolocalization of plasma
kallikrein in human brain. Metab Brain Dis 15: 315323.
425
2014 Refs
426
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 426
D.F. SWAAB
Van Leeuwen FW (Eds.) The Human Hypothalamus in Health

and Disease. Progress in Brain Research Vol. 93, pp. 263270.
Elsevier, Amsterdam.
Chandler BJ, Brown S (1998). Sex and relationship dysfunction in neurological disability. J Neurol Neurosurg Psychiatry
65: 877880.
Chandrashekaran MK (1994). Circadian rhythms, menstrual
cycles and time sense in humans under social isolation. In:
Hirosige T, Honma K (Eds.) Evolution of Circadian Clock,
pp. 263274. Hokkaido University Press, Sapporo, Japan.
Chapman CR (1996). Limbic processes and the affective
dimension of pain. In: Carli G, Zimmermann M (Eds.)
Towards the neurobiology of chronic pain. Progress in Brain
Research, Vol. 110, pp. 6381. Elsevier, Amsterdam.
Chard T, Hudson CN, Edwards CRW, Boyd NRH (1971).
Release of oxytocin and vasopressin by the human foetus
during labour. Nature 234: 352354.
Chard T (1985). Fetal and maternal oxytocin in human
parturition. Am J Perinatol 6: 145152.
Charles G, Guillaume R, Schittecatte M, Pholien P, Van Wettere
JP, Wilmotte J (1989). Loxytocine dans le traitement du
trouble obsessionnel: un rapport ngatif propos de deux
cas. Psychiatr Psychobiol 4: 111115.
Charlett A, Dobbs RJ, Purkiss AG, Wright DJ, Peterson DW,
Weller C, Dobbs SM (1998). Cortisol is higher in parkisonism
and associated with gait deficit. Acta Neurol Scand 97: 7785.
Charness ME (1999). Intracranial voyeurism: revealing the
mammillary bodies in alcoholism. Alcohol Clin Exp Res 23:
19411944.
Charness ME, DeLaPaz RL (1987). Mamillary body atrophy in
Wernickes encephalopathy: antemortem identification using
magnetic resonance imaging. Ann Neurol 22: 595600.
Charnay Y, Perrin C, Vallet PG, Greggio B, Kovari E, Bouras
C (1999). Mapping of cocaine and amphetamine regulated
transcript (CART) mRNA expression in the hypothalamus of
elderly human. J Chem Neuroanat 17: 123128.
Chase TN (1997). A gene for Parkinson disease. Arch Neurol
54: 11561157.
Chau SS, Fitzpatrick RJ, Jamieson B (1969). Diabetes insipidus
and parturition. J Obstet Gynaecol Br Cwlth 76: 444450.
Chaudhuri A, Behan PO (1999). Chronic fatigue syndrome
is an acquired neurological channelopathy. Hum Psychopharmacol Clin Exp 14: 717.
Chaudhuri KR, Pal S, DiMarco A, Whately-Smith C, Bridgman
K, Mathew R, Pezzela FR, Forbes A, Hgl B, Trenkwalder
C (2002). The Parkinsons disease sleep scale: a new
instrument for assessing sleep and nocturnal disability in
Parkinsons disease. J Neurol Neurosurg Psychiatry 73:
629635.
Chawla MK, Gutierrez GM, Scott Young W III, McMullen NT,
Rance NE (1997). Localization of neurons expressing substance P and neurokinin B gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 384: 429442.
Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B

(1984). A chronobiological study of melatonin, cortisol
growth hormone and prolactin secretion in cluster headache.
Cephalalgia 4: 213220.
Checkley S (1996). The neuroendocrinology of depression and
chronic stress. Br Med Bull 52: 597617.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell
T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki
Y, Fitch TE, Nakazato M, Hammer RE, Saper CB,
Yanagisawa M (1999). Narcolepsy in orexin knockout mice:
molecular genetics of sleep regulation. Cell 98: 437451.
Chen A, Yahalom D, Ben-Aroya N, Kaganovsky E, Okon E,
Koch Y (1998). A second isoform of gonadotropin-releasing
hormone is present in the brain of human and rodents. FEBS
Lett 435: 199203.
Chen CH, Chen WY, Liu HL, Liu TT, Tsou AP, Lin CY, Chao
T, Qi Y, Hsiao KJ (2002). Identification of mutations in the
arginine vasopressin receptor 2 gene causing nephrogenic diabetes insipidus in Chinese patients. J Hum Genet 47: 6673.
Chen CJ (2001). Suprasellar and infrasellar craniopharyngioma
with a persistent craniopharyngeal canal: case report and
review of the literature. Neuroradiology 43: 760762.
Chen C-M, Huang C-C (1995). Gonadal dysfunction in mitochondrial encephalomyopathies. Eur Neurol 35: 281286.
Chen C-P, Chern S-R, Lee C-C, Chen W-L, Wang W (2001).
Prenatal diagnosis of mosaic ring chromosome 13 with anencephaly. Prenat Diagn 21: 102105.
Chen E-Y, Mufson EJ, Kordower JH (1996). Trk and p75
neurotrophin receptor systems in the developing human brain.
Chen G, Huo Y, Tan D-X, Liang Z, Zhang W, Zhang Y (2003).
Melatonin in Chinese medicinal herbs. Life Sci 73: 1926.
Chen JM, Cullinane S, Spanier TB, Artrip JH, John R, Edwards
NM, Landry DW (1999a). Vasopressin deficiency and pressor
hypersensitivity in hemodynamically unstable organ donors.
Circulation (Suppl 19) 100(II): 244246.
Chen K-K (2000). Paraventricular nucleus of hypothalamus
a brain locus in central neural regulation of penile erection
in the rat. Int J Androl (Suppl 2) 23: 81.
Chen S, Lger J, Garel C, Hassan M, Czernichow P (1999b).
Growth hormone deficiency with ectopic neurohypophysis:
anatomical variations and relationship between the visibility
of the pituitary stalk asserted by magnetic resonance imaging
and anterior pituitary function. J Clin Endocrinol Metab 84:
24082413.
Chesson AL, Levine SN, Kong L-S, Lee SC (1991). Neuroendocrine evaluation in KleineLevin syndrome: evidence
of reduced dopaminergic tone during periods of hypersomnolence. Sleep 14: 226232.
Chesson AL, Littner M, Davila D, Anderson WM, GriggDamberger M, Hartse K, Johnson S, Wise M (1999). Practice
parameters for the use of light therapy in the treatment of
sleep disorders. Sleep 22: 641660.
2014 Refs
2/12/03
1:39 pm
Page 427
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton

DK, Steiner RA (1997). Leptin is a metabolic gate for the
onset of puberty in the female rat. Endocrinology 138:
855858.
Cheung S, Ballew JR, Moore KE, Lookingland KJ (1998).
Contribution of dopamine neurons in the medial zona incerta
to the innervation of the central nucleus of the amygdala,
horizontal diagonal band of Broca and hypothalamic paraventricular nucleus. Brain Res 808: 174181.
Chevassus-au-Louis N, Cooper HM (1998). Is there a geniculohypothalamic tract in primates? A comparative immunohistochemical study in the circadian system of trepsirhine and
haplorhine species. Brain Res 805: 213219.
Cheyette SR, Cummings JL (1995). Encephalitis lethargica:
lessons for contemporary neuropsychiatry. J Neuropsychiatry
Clin Neurosci 7: 125134.
Chibbar R, Miller FD, Mitchell BF (1993). Synthesis of oxytocin
in amnion, chorion, and decidua may influence the timing of
human parturition. J Clin Invest 91: 185192.
Chico A, Puig-Domingo M, Martul P, De Juan M, Prats JM,
Mauricio D, Webb SM (1998). Reversible endocrine dysfunction and pituitary stalk enlargement. J Endocrinol Invest 21:
122127.
Chiesi M, Huppertz C, Hofbauer KG (2001). Pharmacotherapy
of obesity: targets and perspectives. Trends Pharmacol Sci
22: 247254.
Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi S
(1992). Defective hypothalamic response to immune and
inflammatory stimuli in patients with rheumatoid arthritis.
Arthritis Rheum 35: 12811288.
Chiodera P, Salvarinini C, Bacchi-Modena A, Spallanzani R,
Cigarini C, Alboni A, Gardini E (1991). Relationship between
plasma profiles of oxytocin and adrenocorticotropic hormone
during suckling or breast stimulation in women. Horm Res
35: 119123.
Chiodera P, Volpi R, Capretti L, Marchesi C, dAmato L,
DeFerri A, Bianconi L, Coiro V (1991). Effect of estrogen
or insulin-induced hypoglycemia on plasma oxytocin levels
in bulimia and anorexia nervosa. Metabolism 40: 12261230.
Chiodera P, Volpi R, Capretti L, Giuliani N, Maffei ML, Coiro
V (1998a). Effect of melatonin on arginine vasopressin secretion stimulated by physical exercise or angiotensin II in
normal men. Neuropeptides 32: 125129.
Chiodera P, Volpi R, Caiazza A, Giuliani N, Magotti MG, Coiro
V (1998b). Arginine vasopressin and oxytocin responses to
angiotensin II are mediated by AT1 receptor subtype in
normal men. Metab Clin Exp 47: 893896.
Chiodera P, Volpi R, Capretti L, Giuliani N, Caffarri G, Coiro
V (1998c). Melatonin inhibits oxytocin response to insulininduced hypoglycemia, but not to angiotensin II in normal
men. J Neural Transm 105: 173180.
Chiodera P, Volpi R, Capretti L, Coiro V (2001). Inhibitory
effect of oxytocin on plasma neuropeptide Y in humans. Clin
427
Chiodera P, Volpi R, Bianconcini M, Bortesi ML, Manfredi G,

Coiro V (2002). Desmopressin test in occult eutopic corticotropin microadenoma. Arch Intern Med 162: 840841.
Chipkevitch E, Fernandes ACL (1993). Hypothalamic tumor
associated with atypical forms of anorexia nervosa and
diencephalic syndrome. Arq Neuropsiquiatr 51: 270274.
Chiumello G, Di Natale B, Pellini C, Beneggi A, Scotti G,
Triulzi F (1989). Magnetic resonance imaging in diabetes
insipidus. Lancet (1) 8643(22): 901.
Cho K (2001). Chronic jet lag produces temporal lobe atrophy
and spatial cognitive deficits. Nat Neurosci 4: 567568.
Chong BW, Newton TH (1993). Hypothalamic and pituitary
pathology. Radiol Clin North Am 31: 11471183.
Choudhury RP (1969). Effects of cholera on the human hypothalamus and hypophysis part II. J Trop Med Hyg 72:
185192.
Chow EWC, Zipursky RB, Mikulis DJ, Bassett AS (2002).
Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol Psychiatry 51:
208215.
Christeff N, Gherbi N, Mammes O, Dalle M-T, Gharakhanian
S, Lortholary O, Melchior J-C, Nunez EA (1997). Serum
cortisol and DHEA concentrations during HIV infection.
Psychoneuroendocrinology (Suppl 1) 22: S11S18.
Christensen B, Blaas HG, Vogt Isaksen C, Roald B, rstavik
KH (2000). Sibs with anencephaly, anophthalmia, clefts,
omphalocele, and polydactyly: hydrolethalus or acrocallosal
syndrome? Am J Med Genet 91: 231234.
Christie JE, Whalley LJ, Bennie J, Dick H, Blackburn IM,
Blackwood DHR, Fink G (1987). Characteristic plasma
hormone changes in Alzheimers disease. Br J Psychiatry
150: 674681.
Christophe J (1993). Type I receptors for PACAP (a neuropeptide even more important than VIP?). Biochim Biophys Acta
1154:183199.
Chui HC, Bondareff W, Zarow C, Slager U (1984). Stability
of neuronal number in the human nucleus basalis of Meynert
with aging. Neurobiol Aging 5: 8388.
Chung WCJ, De Vries GJ, Swaab DF (2002). Sexual differentiation of the bed nucleus of the stria terminalis in humans
may extend into adulthood. J Neurosci 22: 10271033.
Ciampelli M, Guido M, Cucinelli F, Cinque B, Barini A,
Lanzone A (2000). Hypothalamic-pituitary-adrenal axis sensitivity to opioids in women with polycystic ovary syndrome.
Fertil Steril 73: 712 717.
Cianfarani S, Nicholl RM, Medbach S, Charlesworth MC,
Savage MO (1993). Idiopathic hypothalamus-pituitary
dysfunction: review of five cases. Horm Res 39: 4750.
Cicconetti P, Cacciafesta M, Migliori M, Di Gioacchino CF,
Vetta F, Chiarotti F, Marigliano V (2000). Influence of sex
and age on blood pressure variability. Arch Gerontol Geriatr
30: 225236.
Ciesielski KT, Yanofsky R, Ludwig RN, Hill DE, Hart DE,
Astur RS, Snyder T (1994). Hypoplasia of the cerebellar
427
2014 Refs
428
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 428
D.F. SWAAB
vermis and cognitive deficits in survivors of childhood

leukemia. Arch Neurol 51: 985993.
Ciofi P, Croix D, Tramu G (1988). Colocalization of GHRF
and NPY immunoreactivities in neurons of the infundibular
area of the human brain. Neuroendocrinology 47: 469472.
Ciofi P, Tramu G, Bloch B (1990). Comparative immunohistochemical study of the distribution of neuropeptide Y, growth
hormone-releasing factor and the carboxy-terminus of
precursor protein GHRF in the human hypothalamic
infundibular area. Neuroendocrinology 51: 429436.
Ciosek J, Guzek JW (1992). Thyrotropin-releasing hormone
(TRH) and vasopressin and oxytocin release: in vitro as well
as in vivo studies. Exp Clin Endocrinol 100: 152159.
Ciosek J, Stempniak B (1997). The influence of vasopressin or
oxytocin on thyroid-stimulating hormone and thyroid
hormones concentrations in blood plasma of euthyroid rats.
J Physiol Pharmacol 48: 813823.
Ciriello J (1998). Afferent renal inputs to paraventricular nucleus
vasopressin and oxytocin neurosecretory neurons. Am J
Physiol 275: R1745R1754.
Citron JT, Ettinger B, Rubinoff H, Ettinger V, Minkoff J, Hom
F, Kan P, Alloo R (1996). Prevalence of hypothalamicpituitary imaging abnormalities in impotent men with
secondary hypogonadism. J Urol 155: 529533.
Clapham JC, Arch JRS, Tadayyon M (2001). Anti-obesity drugs:
a critical review of current therapies and future opportunities.
Pharmacol Ther 89: 81121.
Clark AW, Parhad IM, Folstein SE, Whitehouse PJ, Hedreen
JC, Price DL, Chase GA (1983). The nucleus basalis in
Huntingtons disease. Neurology 33: 12611267.
Clark CM, Fleming JA, Li D, Oger J, Klonoff H, Paty D (1992).
Sleep disturbance, depression and lesion site in patients with
multiple sclerosis. Arch Neurol 49: 641643.
Clark PM (1998). Programming of the hypothalamopituitaryadrenal axis and the fetal origins of adult disease
hypothesis. Eur J Pediatr (Suppl 1) 157: S7S10.
Clark PM, Hindmarsh PC, Shiell AW, Law CM, Honour JW,
Barker DJP (1996). Size at birth and adrenocortical function
in childhood. Clin Endocrinol 45: 721726.
Clarke DJ (1993). PraderWilli syndrome and psychoses. Br J
Clarke DJ, Boer H, Whittington J, Holland A, Butler J, Webb
T (2002). PraderWilli syndrome, compulsive and ritualistic
behaviours: the first population-based survey. Br J Psychiatry
180362.
Clarke DJ, Webb T, Bachmann-Clarke JP (1995). PraderWilli
syndrome and psychotic symptoms: report of a further case.
Ir J Psychol Med 12: 2729.
Clarke G, Lincoln DW, Merrick LP (1979). Dopaminergic
control of oxytocin release in lactating rats. J Endocrinol 83:
409420.
Clarren SK, Alvord EC, Hall JG (1980). Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate
anus, and postaxial polydactyl a new syndrome? Part

II: Neuropathological considerations. Am J Med Genet 7:
7583.
Clattenburg RE, Singh RP, Montemurro DG (1972). Postcoital
ultrastructural changes in neurons of the suprachiasmatic
nucleus of the rabbit. Z Zellforsch 125: 448459.
Clavelou P, Tournilhac M, Vidal C, Georget AM, Picard L,
Merienne L (1995). Narcolepsy associated with arteriovenous
malformation of the diencephalon. Sleep 18: 202205.
Claybaugh JR, Sato AK, Crosswhite LK, Hassell LH (2000).
Effects of time of day, gender, and menstrual cycle phase on
the human response to a water load. Am J Physiol 279:
R966R973.
Cleare AJ (2003). The neuroendocrinology of chronic fatigue
syndrome. Endocr Rev 24: 236252.
Cleare AJ, Heap E, Malhi GS, Wessely S, OKeane V, Miell
J (1999). Low-dose hydrocortisone in chronic fatigue
syndrome: a randomised crossover trial. Lancet 353: 455458.
Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS,
OKeane V (2001). Hypothalamo-pituitaryadrenal axis
dysfunction in chronic fatigue syndrome, and the effects of
low-dose hydrocortisone therapy. J Clin Endocrinol Metab
86: 35453554.
Clment K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto
D, Gourmelen M, Dina C, Chambaz J, Lacorte J-M,
Basdevant A, Bougnres P, Lebouc Y, Froguel P, Guy-Grand
B (1998). A mutation in the human leptin receptor gene causes
obesity and pituitary dysfunction. Nature 392: 398401.
Clerici M, Trabattoni D, Piconi S, Fusi ML, Ruzzante S,
Clerici C, Villa ML (1997). A possible role for the cortisol/
anticortisols imbalance in the progression of human immunodeficiency virus. Psychoneuroendocrinology (Suppl 1) 22:
S27S31.
Cliffer KD, Burstein R, Giesler GJ Jr (1991). Distributions of
spinothalamic, spinohypothalamic, and spinotelencephalic
fibers revealed by anterograde transport of PHA-L in rats. J
Neurosci 11: 852868.
Clift S, Dahlitz M, Parkes JD (1994). Sleep apnoea in the
PraderWilli syndrome. J Sleep Res 3: 121126.
Clifton VL, Challis JRG (1997). Placental corticotropin
releasing hormone function during human pregnancy.
Endocrinologist 7: 448458.
Climo LH (1982). Anorexia nervosa associated with hypothalamic tumor: the search for clinicalpathological correlations.
Psychiatr J Univ Ottawa 7: 2025.
Clinicopathological conference (1973). A case of anorexia. Br
Med J 2 (3859): 158163.
Clyde BL, Stechison MT (1995). Repair of temporosphenoidal
encephalocele with a vascularized split calvarial cranioplasty:
technical case report. Neurosurgery 36: 202206.
Cnattingius S, Hultman CM, Dahl M, Sparn P (1999). Very
preterm birth, birth trauma, and the risk of anorexia nervosa
among girls. Arch Gen Psychiatry 56: 634638.
2014 Refs
2/12/03
1:39 pm
Page 429
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
429
Coleman PD, Flood D (1987). Neuron numbers and dendritic

extent in normal aging and Alzheimers disease. Neurobiol
Aging 8: 521545.
Collado P, Beyer C, Hutchison JB, Holman SD (1995).
Hypothalamic distribution of astrocytes is gender-related in
Mongolian gerbils. Neurosci Lett 184: 8689.
Collerton D (1986). Cholinergic function and intellectual decline
in Alzheimers disease. Neuroscience 19: 128.
Collett-Solberg PF, Sernyak H, Satin-Smith M, Katz LL, Sutton
L, Molloy P, Moshang Jr, T (1997). Endocrine outcome in
long-term survivors of low-grade hypothalamic/chiasmatic
glioma. Clin Endocrinol 47: 7985.
Collier DA, Barrett TG, Curtis D, MacLeod A, Arranz MJ,
Maassen JA, Bundey S (1996). Linkage of Wolfram syndrome
to chromosome 4p161 and evidence for heterogeneity. Am J
Hum Genet 59: 855863.
Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I,
Maffei P, Beck S, Boerkoel CF, Sicolo N, Martin M, Nishina
PM, Naggert JK (2002). Mutations in ALMS1 cause obesity,
type 2 diabetes and neurosensory degeneration in Alstrm
syndrome. Nat Genet 31: 7478.
Collin R (1928). La neurocrinie hypophysaire Etude histophysiologique du complexe tuberoinfundibulo-pituitaire. Arch
Morphol Gen Exp Paris 28: 1102.
Collins E, Turner G (1973). The Noonan syndrome a review
of the clinical and genetic features of 27 cases. J Pediatrics
83: 941950.
Collins GB, Marzewski DJ, Rollins MB (1981). Paranoid
psychosis after DDAVP therapy for Alzheimers dementia.
Lancet (8250) 2: 808.
Collu R, Tang J, Castagn J, Lagac G, Masson N, Huot C, Deal
C, Delvin E, Faccenda E, Eidne KA, Van Vliet G
(1997). A novel mechanism for isolated central hypothyroidism:
inactivating mutations in the thyrotropin-releasing hormone
receptor gene. J Clin Endocrinol Metab 82: 15611565.
Colombo N, Berry I, Kucharczyk J, Kucharczyk W, De Groot
J, Larson T, Norman D, Newton TH (1987). Posterior pituitary gland: appearance on MR images in normal and
pathologic states. Radiology 165: 481485.
Colover J (2000). Pathological laughter and crying. Lancet 355:
238.
Colpart JJ, Ramella S, Bret M, Coronel B, Dorez D, Mercatello
A, Hadj Aissa A, Moskovtchenko JF (1996). Hypophysisthyroid axis disturbances in human brain-dead donors. Transpl
Proc 28: 171172.
Comings DE, Chen C, Wu S, Muhleman D (1999). Association
of the androgen receptor gene (AR) with ADHD and conduct
disorder. Neuroreport 10: 15891592.
Commentz JC, Helmke K (1995). Precocious puberty and
decreased melatonin secretion due to a hypothalamic hamartoma. Horm Res 44: 271275.
Commins D, Baran GA, Molleston M, Vollmer D (1994).
Hypothalamic chordoma. J Neurosurg 81: 130132.
Coca A (1994). Circadian rhythm and blood pressure control:

physiological and pathophysiological factors. J Hypertens 12:
S13S21.
Coca S, Vaquero J, Escandon J, Moreno M, Peralba J, Rodriguez
J (1992). Immunohistochemical characterization of pineocytomas. Clin Neuropathol 11: 298303.
Coccaro EF (1992). Impulsive aggression and central serotonergic system function in humans: an example of a dimensional
brainbehavior relationship. Int Clin Psychopharmacol 7: 312.
Coccaro EF, Kavoussi RJ, Hauger RL, Cooper TB, Ferris CF
(1998). Cerebrospinal fluid vasopressin levels. Arch Gen
Cocco E, Marrosu MG (2000). Is multiple sclerosis severity a
genetically influenced trait? Neurol Sci (4 Suppl 2) 21:
S843S847.
Coffey RJ (1989). Hypothalamic and basal forebrain germinoma
presenting with amnesia and hyperphagia. Surg Neurol 31:
228233.
Cohen MM (2001). Problems in the definition of holoprosencephaly. Am J Med Genet 103: 183187.
Cohen RA, Albers HE (1991). Disruption of human circadian
and cognitive regulation following a discrete hypothalamic
lesion: a case study. Neurology 41: 726729.
Cohen RA, Barnes J, Jenkins M, Albers HE (1997). Disruption
of short-duration timing associated with damage to the
suprachiasmatic region of the hypothalamus. Neurology 48:
15331539.
Cohen-Kettenis PT, Gooren LJG (1998). Transsexualism: a
review of etiology, diagnosis and treatment. J Psychosom Res
46: 315333.
Cohen-Mansfield J, Garfinkel D, Lipson S (2000). Melatonin
for treatment of sundowning in elderly persons with dementia
a preliminary study. Arch Gerontol Geriatr 31: 6576.
Coiro V, dAmato L, Marchesi C, Capretti L, Volpi R, Roberti
G, Cerri L, Chiodera P (1990). Luteinizing hormone and
cortisol responses to naloxone in normal weight women with
bulimia. Psychoneuroendocrinology 15: 463470.
Coiro V, Volpi R, Marchesi C, De Ferri A, dAmato L, Caffari
G, Davolio M, Rossi E, Caffarra P, Chiodera P (1994).
Lack of seasonal variation in abnormal TSH secretion in patients
with seasonal affective disorder. Biol Psychiatry 35: 3641.
olak A (1998). Hypothalamic Langerhans cell histiocytosis.
J Neurosurg 89: 344345.
Cole RJ, Smith JS, Alcal YC, Elliott JA, Kripke DF (2002a).
Bright-light mask treatment of delayed sleep phase syndrome.
J Biol Rhythms 17: 89101.
Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF,
Kupfer DJ, Frank E (2002b). Slower treatment response in
bipolar depression predicted by lower pretreatment thyroid
function. Am J Psychiatry 159: 116121.
Coleman M (1979). Studies of the autistic syndromes. In:
Katzman R (Ed.) Congenital and Acquired Cognitive
Disorders. Raven Press, NY, pp. 265275.
429
2014 Refs
430
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 430
D.F. SWAAB
Concha S, Hamilton BPM, Millan JC, Donald McQueen J

(1975). Symptomatic Rathkes cleft cyst with amyloid stroma.
J Neurol Neurosurg Psychiatry 8: 782786.
Condren RM, ONeill A, Ryan MCM, Barrett P, Thakore JH
(2002). HPA axis response to a psychological stressor in
generalised social phobia. Psychoneuroendocrinology 27:
693703.
Cone RD (1999). The central melanocortin system and energy
homeostasis. Trends Endocrinol Metab 10: 211216.
Connors MH, Sheikholislam BM (1977). Hypothalamic symptomatology and its relationship to diencephalic tumor in
childhood. Childs Brain 3: 3136.
Conroy JM, Grebe TA, Becker LA, Tsuchiya K, Nicholls RD,
Buiting K, Horsthemke B, Cassidy SB, Schwartz S (1997).
Balanced translocation 46,XY,t(2;15) (q372;q112) associated
with atypical PraderWilli syndrome. Am J Hum Genet 61:
388394.
Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF
(1996). The hypothalamic leptin receptor in humans.
Identification of incidental sequence polymorphisms and
absence of the db/db mouse and fa/fa rat mutations. Diabetes
45: 992994.
Constine LS, Woolf PD, Cann D, Mick G, McCormick K,
Raubertas RF, Rubin P (1993). Hypothalamic-pituitary
dysfunction after radiation for brain tumors. N Engl J Med
328: 8794.
Contarino A, Dellu F, Koob GF, Smith GW, Lee K-F, Vale W,
Gold LH (1999). Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor
receptor 1. Brain Res 835: 19.
Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER
(1994). A syndrome of female pseudohermaphrodism,
hypergonadotropic hypogonadism, and multicystic ovaries
associated with missense mutations in the gene encoding
aromatase (P450arom). J Clin Endocrinol Metab 78:
12871292.
Conte-Devolx B, Grino M, Nieoullon A, Javoy-Agid F, Castanas
E, Guillaume V, Tonon MC, Vaudry H, Oliver C (1985).
Corticoliberin, somatocrinin and amine contents in normal
and Parkinsonian human hypothalamus. Neurosci Lett 56:
217222.
Coogan AN, Rawlings N, Luckman SM, Piggins HD (2001).
Effects of neurotensin on discharge rates of rat suprachiasmatic nucleus neurons in vitro. Neuroscience 103: 663672.
Coolidge FL, Thede LL, Young SE (2002). The heritability of
gender identity disorder in a child and adolescent twin sample.
Behav Genet 32: 251257.
Cooper ERA (1945). The development of the human lateral
geniculate body. Brain 68: 222239.
Cooper PE, Fernstrom MH, Borstad OP, Leeman SE, Martin
JB (1981). The regional distribution of somatostatin,
substance P and neurotensin in human brain. Brain Res 218:
219232.
Cooperstock M (1998). Are there seasonal effects on obstetric

circadian rhythms? Am J Obstet Gynecol 179: 563564.
Coplan JD, Lydiard RB (1998). Brain circuits in panic disorder.
Coppola G, Spagnoli D, Sciscio N, Russo F, Villani RM (2002).
Gelastic seizures and low-grade hypothalamic astrocytoma:
a case report. Brain Dev 24: 183186.
Corcos M, Taeb O, Benoit-Lamy S, Paterniti S, Jeammet P,
Flament MF (2002). Suicide attempts in women with bulimia
nervosa: frequency and characteristics. Acta Psychiatr Scand
106: 381386.
Corder R, Pralong FP, Muller AF, Gaillard RC (1990). Regional
distribution of neuropeptide Y-like immunoreactivity in
human hypothalamus measured by immunoradiometric assay:
possible influence of chronic respiratory failure on tissue
levels. Neuroendocrinology 51: 2330.
Cordero ME, Valenzuela CY, Torres R, Rodriguez A (2000).
Sexual dimorphism in number and proportion of neurons in
the human median raphe nucleus. Brain Res Dev Brain Res
124: 4352.
Cordido F, Casanueva FF, Dieguez C (1989). Cholinergic
receptor activation by pyridostigmine restores growth
hormone (GH) responsiveness to GH-releasing hormone
administration in obese subjects: evidence for hypothalamic
somatostatinergic participation in the blunted GH release of
obesity. J Clin Endocrinol Metab 68: 290293.
Corneli G, Baldelli R, Di Somma C, Grottoli S, Durante C,
Gasco V, Ferretti E, Colao A, Tamburrano G, Lombardi G,
Aimaretti G, Ghigo E (2002). Evaluation of GH deficiency
by GHRH+arginine test and IGF-I levels in a large population
of young, middle-aged and elderly patients who had
undergone neurosurgery for tumor masses in the hypothalamus-pituitary area. J Endocrinol Invest (Suppl 10) 25: 3839.
Corneli G, Baldelli R, Di Somma C, Rovere S, Gaia D, Pellegrino
M, Gasco V, Durante C, Grottoli S, Colao A, Tamburrano G,
Lombardi G, Ghigo E, Aimaretti G (2003). Occurrence of GH
deficiency in adult patients who underwent neurosurgery in
the hypothalamus-pituitary area for non-functioning tumour
masses. Growth Horm IGF Res 13: 104108.
Cornlissen G, Halberg F, Burioka N, Perfetto F, Tarquini R,
Bakken EE (2000). Do plasma melatonin concentrations
decline with age? Am J Med 109: 343345.
Cornwell AC, Feigenbaum P, Kim A (1998). SIDS, abnormal
nighttime REM sleep and CNS immaturity. Neuropediatrics
29: 7279.
Corral M, Kuan A, Kostaras D (2000). Bright light therapys
effect on postpartum depression. Am J Psychiatry 157:
303304.
Corsellis JAN, Bruton CJ, Freeman-Browne D (1973). The aftermath of boxing. Psychol Med 3: 270303.
Cortelli P, Gambetti P, Montagna P, Lugaresi E (1999). Fatal
familial insomnia: clinical features and molecular genetics. J
Sleep Res (Suppl 1) 8: 2329.
2014 Refs
2/12/03
1:39 pm
Page 431
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Corts R, Probst A, Palacios JM (1987). Quantitative light

microscopic autoradiographic localization of cholinergic
muscarinic receptors in the human brain: forebrain.
Neuroscience 20: 65107.
Corts R, Soriano E, Pazos A, Probst A, Palacios JM (1988).
Autoradiography of antidepressant binding sites in the human
brain: localization using [3H]imipramine and [3H]paroxetine.
Coryell W, Tsuang D (1992). Hypothalamic-pituitary-adrenal
axis hyperactivity and psychosis: recovery during an 8-year
follow-up. Am J Psychiatry 149: 10331039.
Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A
(1997b). Stimulation of corticotrophin-releasing hormone
release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroreport 8: 11311134.
Costa A, Leston JA, Cavallini A, Nappi G (1998). Cluster
headache and periodic affective illness: common chronobiological features. Funct Neurol 13: 263272.
Costa DC, Brostoff J, Douli V, Ell PJ (1992). Postviral fatigue
syndrome. Br Med J 304: 1567.
Costa JM, Ley L, Claramunt E, Lafuente J (1997a). Choroid
plexus papillomas of the III ventricle in infants. Childs Nerv
Syst 13: 244249.
Costa MM, Reus VI, Wolkowitz OM, Manfredi F, Lieberman
M (1999). Estrogen replacement therapy and cognitive
decline in memory-impaired post-menopausal women. Biol
Costeff H, Holm VA, Ruvalcaba R, Shaver J (1990). Growth
hormone secretion in PraderWilli syndrome. Acta Paediatr
Scand 79: 10591062.
Costin G (1979). Endocrine disorders associated with tumors of
the pituitary and hypothalamus. Pediatr Clin North Am 26:
1531.
Costin G, Murphree AL (1985). Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child
139: 249254.
Cotrufo P, Monteleone P, dIstria M, Fuschino A, Serino I,
Maj M (2000). Aggressive behavioral characteristics and
endogenous hormones in women with bulimia nervosa.
Neuropsychobiology 42: 5861.
Cottrell SS, Wilson SAK (1926). The affective symptomatology
of disseminated sclerosis: a study of 100 cases. J Neurol
Psychopathol 7: 130.
Couce ME, Burguera B, Parisi JE, Jensen MD, Lloyd RV (1997).
Localization of leptin receptor in the human brain.
Coulter CL, Leech RW, Schaefer GB, Scheithauer BW,
Brumback RA (1993). Midline cerebral dysgenesis, dysfunction of the hypothalamic-pituitary axis, and fetal alcohol
effects. Arch Neurol 50: 771775.
Counts SE, Perez SE, Kahl U, Bartfai T, Bowser RP, Deecher
DC, Mash DC, Crawley JN, Mufson EJ (2001). Galanin:
neurobiologic mechanisms and therapeutic potential for
Alzheimers disease. CNS Drug Rev 7: 445470.
431
Court J, Martin-Ruiz C, Graham A, Perry E (2000). Nicotinic

receptors in human brain: topography and pathology. J Chem
Neuroanat 20: 281298.
Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M,
Perry E (2001). Nicotinic receptor abnormalities in
Alzheimers disease. Biol Psychiatry 49: 175184.
Couzinet B, Young J, Brailly S, Le Bouc Y, Chanson P,
Schaison G (1999). Functional hypothalamic amenorrhea: a
partial and reversible gonadotrophin deficiency of nutritional
origin. Clin Endocrinol 50: 229235.
Cowdry RW, Wehr TA, Athanasios PZ, Goodwin FK (1983).
Thyroid abnormalities associated with rapid-cycling bipolar
illness. Arch Gen Psychiatry 40: 414420.
Cowley A, Liard JF (1987). Cardiovascular actions of vasopressin. In: Boer G, Cash D (Eds.) Vasopressin. Plenum Press,
pp. 389422.
Cowley AW, Cushman WC, Quillen EW, Skelton MM,
Langford HG (1981). Vasopressin elevation in essential
hypertension and increased responsiveness to sodium intake.
Hypertension 3: 93100.
Cowley MA, Smart JL, Rubinstein M, Cerdn MG, Diano S,
Horvath TL, Cone RD, Low MJ (2001). Leptin activates
anorexigenic POMC neurons through a neural network in the
arcuate nucleus. Nature 411: 480484.
Cox AW, Brown MH (1977). Results of multi-target limbic
surgery in the treatment of schizophrenia and aggressive
states. In: Sweet WH et al. (Eds.) Neurosurgical Treatment
in Psychiatry, Pain, and Epilepsy. University Park Press,
Baltimore, pp. 469479.
Coyle JT, Price DL, DeLong MR (1983). Alzheimers disease:
a disorder of cortical cholinergic innervation. Science 219:
11841190.
Cree JE, Meyer J, Hailey DM (1973). Diazepam in labour: its
metabolism and effect on the clinical condition and thermogenesis of the newborn. Br Med J 4 (5887) 3: 251255.
Creel DJ, Bendel CM, Wiesner GL, Wirtschafter JD, Arthur
DC, King RA (1986). Abnormalities of the central visual
pathways in PraderWilli syndrome associated with hypopigmentation. N Engl J Med 314: 16061609.
Cremers CWRJ, Wijdeveld PGAB, Pinckers AJLG (1977).
Juvenile diabetes mellitus, optic atrophy, hearing loss,
diabetes insipidus, atonia of the urinary tract and bladder,
and other abnormalities (Wolfram syndrome). Acta Paediatr
Scand Suppl 264: 316.
Cresswell JL, Barker DJP, Osmond C, Egger P, Phillips DIW,
Fraser RB (1997). Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet 350: 11311135.
Crick F (1995). The Astonishing Hypothesis. Touchstone Books,
London, 300 pp.
Crino PB, Petri-Henske E (1999). New developments in the
neurobiology of the tuberous sclerosis complex. Neurology
53: 13841390.
431
2014 Refs
432
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 432
D.F. SWAAB
Critchley HD, Good CD, Ashburner J, Frackowiak RS, Mathias

CJ, Dolan RJ (2003). Changes in cerebral morphology
consequent to peripheral autonomic denervation. Neuroimage
18: 908916.
Critchley M (1962). Periodic hypersomnia and megaphagia in
adolescent males. Brain 85: 627657.
Critchley PHS, Malcolm GP, Malcolm PN, Gibb WR, Arendt
J, Parkes JD (1991). Fatigue and melatonin in Parkinsons
disease. J Neurol Neurosurg Psychiatry 54: 9192.
Crofford LJ, Kalogeras KT, Mastorakos G, Magiakou M-A,
Wells J, Kanik KS, Gold PW, Chrousos GP, Wilder RL
(1997). Circadian relationships between interleukin (IL)-6 and
hypothalamic-pituitary-adrenal axis hormones: failure of
IL-6 to cause sustained hypercortisolism in patients with early
untreated rheumatoid arthritis. J Clin Endocrinol Metab 82:
12791283.
Crompton MR (1963). Hypothalamic lesions following the
rupture of cerebral berry aneurysms. Brain 86: 301314.
Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO (2000).
Melatonin secretion after surgery. Lancet 356: 1244 1245.
Crosby EC, Humphrey T, Lauer EW (1962). Correlative
Anatomy of the Nervous System. MacMillan, NY, 310.
Cross BA, TD Glover (1958). The hypothalamus and seminal
emission. J Endocrinol 16: 385395.
Crotty TB, Scheithauer BW, Young WF, Davis DH, Shaw EG,
Miller GM, Burger PC (1995). Papillary craniopharyngioma:
a clinicopathological study of 48 cases. J Neurosurg 83:
206214.
Croxson TS, Chapman WE, Miller LK, Levit CD, Senie R,
Zumoff B (1989). Changes in the hypothalamic-pituitarygonadal axis in human immunodeficiency virus-infected
homosexual men. J Clin Endocrinol Metab 68: 317321.
Crozier S, Lehricy S, Verstichel P, Masson C, Masson M
(1996). Transient hemiballism/hemichorea due to an ipsilateral subthalamic nucleus infarction. Neurology 46: 267268.
Cruz-Snchez FF, Mordini E, Ravid R (1997). Ethical aspects
to be considered in brain banking. Ann 1st Super Sanita 33:
477482.
Cryns K, Pfister M, Pennings RJE, Bom SJH, Flothmann K,
Caethoven G, Kremer H, Schatteman I, Kln KA, Tth T,
Kupka S, Blin N, Nrnberg P, Thiele H, Van de Heyning
PH, Reardon W, Stephens D, Cremers CWRJ, Smith RJH,
Van Camp G (2002). Mutations in the WFS1 gene that cause
low-frequency sensorineural hearing loss are small noninactivating mutations. Hum Genet 110: 389394.
Cugini P, Gori MC, Petrangeli CM, Tisei P, Giubilei F (1999).
Preserved blood pressure and heart rate circadian rhythm in
early stage Alzheimers disease. J Gerontol: A Biol Sci Med
Sci 54: M304M308.
Cui L-N, Saeb-Parsy K, Dyball REJ (1997). Neurones in the
supraoptic nucleus of the rat are regulated by a projection
from the suprachiasmatic nucleus. J Physiol (Lond) 502:
149159.
Cullberg J, Nyback H (1992). Persistent auditory hallucinations

correlate with the size of the third ventricle in schizophrenic
patients. Acta Psychiatr Scand 86: 469472.
Culebras A (1992). Neuroanatomic and neurologic correlates of
sleep disturbances. Neurology (Suppl 6) 42(7): 1927.
Cullen KM, Halliday GM (1995). Mechanisms of cell death in
cholinergic basal forebrain neurons in chronic alcoholics.
Metab Brain Dis 10: 8191.
Cullen KM, Halliday GM, Double KL, Brooks WS, Creasey
H, Broe GA (1997). Cell loss in the nucleus basalis is related
to regional cortical atrophy in Alzheimers disease. Neuroscience 78: 641652.
Cummings JL (1986). Organic psychosis. Delusional disorders
and secondary mania. Psychiatr Clin North Am 9: 293311.
Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE,
Frayo RS, Schwartz MW, Basdevant A, Weigle DS (2002).
Elevated plasma ghrelin levels in PraderWilli syndrome. Nat
Med 8: 643644.
Cummings DR (2002). The seasonality of human births,
melatonin and cloud cover. Biol Rhythm Res 33: 521559.
Cummings JL (1992). Depression and Parkinsons disease. Am
J Psychiatry 149: 443454.
Cummings TJ, Provenzale JM, Hunter SB, Friedman AH,
Klintworth GK, Bigner SH, McLendon RE (2000). Gliomas
of the optic nerve: histological, immunohistochemical (MIB1 and p53), and MRI analysis. Acta Neuropathol 99: 563570.
Cuneo RC, Judd S, Wallace JD, Perry-Keene D, Burger H, LimTio S, Strauss B, Stockigt J, Topliss D, Alford F, Hew L,
Bode H, Conway A, Handelsman D, Dunn S, Boyages S,
Cheung NW, Hurley D (1998). The Australian multicenter
trial of growth hormone (GH) treatment in GH-deficient
adults. J Clin Endocrinol Metab 83: 107116.
Cunningham CJ, Sinnott M, Denihan A, Rowan M, Walsh JB,
OMoore R, Coakley D, Coen RF, Lawler BA, ONeill DD
(2001). Endogenous sex hormone levels in postmenopausal
women with Alzheimers disease. J Clin Endocrinol Metab
86: 10991103.
Curcio CA, Drucker DN (1993). Retinal ganglion cells in
Alzheimers disease and aging. Ann Neurol 33: 248257.
Curfs LMG, Verhulst FC, Fryns JP (1991). Behavioral and
emotional problems in youngsters with PraderWilli
syndrome. Genet Couns 2: 3341.
Curtis GC, Abelson JL, Gold PW (1997). Adrenocorticotropic
hormone and cortisol responses to corticotropin-releasing
hormone: changes in panic disorder and effects of alprazolam
treatment. Biol Psychiatry 41: 7685.
Cushing H (1932). Papers relating to the pituitary body, hypothalamus and parasympathetic nervous system. Charles C
Thomas, Springfield, Ill.
Cusimano G, Capriani C, Bonifati V, Meco G (1991).
Hypothalamo-pituitary function and dopamine dependence in
untreated parkinsonian patients. Acta Neurol Scand 83:
145150.
2014 Refs
2/12/03
1:39 pm
Page 433
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
433
Dai JP, Swaab DF, Buijs RM (1997). Distribution of vasopressin

and vasoactive intestinal polypeptide (VIP) fibers in the human
hypothalamus with special emphasis on suprachiasmatic
nucleus efferent projections. J Comp Neurol 383: 397414.
Dai JP, Van der Vliet J, Swaab DF, Buijs RM (1998a). Human
retinohypothalamic tract as revealed by in vitro postmortem
tracing. J Comp Neurol 397: 357370.
Dai JP, Swaab DF, Van der Vliet J, Buijs RM (1998b).
Postmortem tracing reveals the organization of the hypothalamic projections to the suprachiasmatic nucleus in the
human brain. J Comp Neurol 400: 87102.
Dai JP, Swaab DF, Buijs RM (1998c). Recovery of axonal
transport in dead neurons. Lancet 351: 499500.
Dai JP, Van der Vliet J, Swaab DF, Buijs RM (1998d).
Postmortem anterograde tracing of intrahypothalamic projections of the human dorsomedial nucleus of the hypothalamus.
Dal Canto MC (1996). The Golgi apparatus and the pathogenesis of Alzheimers disease. Am J Pathol 148: 355360.
Dal Forno G, Carson KA, Brookmeyer R, Troncoso J, Kawas
CH, Brandt J (2002). APOE genotype and survival in men
and women with Alzheimers disease. Neurology 58:
10451050.
Dall Vechia S, Lambert PD, Couceyro PC, Kuhar MJ, Smith
Y (2000). CART peptide immunoreactivity in the hypothalamus and pituitary in monkeys: analysis of ultrastructural
features and synaptic connections in the paraventricular
nucleus. J Comp Neurol 416: 291308.
Dalman C, Allebeck P (2002). Paternal age and schizophrenia:
further support for an association. Am J Psychiatry 159:
15911592.
Dalos NP, Rabins PV, Brooks BR, ODonnell P (1983). Disease
activity and emotional state in multiple sclerosis. Ann Neurol
13: 573577.
Dalton LD, Carpenter RG, Grossman SP (1981). Ingestive
behavior in adult rats with dorsomedial hypothalamic lesions.
Physiol Behav 26: 117123.
Daly RC, Schmidt PJ, Roca CA, Rubinow DR (2001).
Testosterones effects not limited to mood. Arch Gen
Dana-Haeri J, Trimble MR, Oxley J (1983). Prolactin and
gonadotrophin changes following generalised and partial
seizures. J Neurol Neurosurg Psychiatry 46: 331335.
Daniel PM, Prichard MML (1972). The human hypothalamus
and pituitary stalk after hypophysectomy or pituitary stalk
section. Brain 95: 813824.
Daniel PM, Prichard MML (1975). Studies of the hypothalamus
and the pituitary gland with special reference to the effects
of transection of the pituitary stalk. Acta Endocrinol (Suppl
201): 1216.
Daniel SS, Stark RI, Zubrow AB, Fox HE, Husain MK, James
LS (1983). Factors in the release of vasopressin by the
hypoxic fetus. Endocrinology 113: 16231628.
Cussen LJ (1964). Diencephalic syndrome of early infancy. Case

report. Med J Aust 1: 881882.
Cutolo M, Straub RH (2000). Polymyalgia rheumatica: evidence
for a hypothalamic-pituitaryadrenal axis-driven disease. Clin
Exp Rheumatol 18: 655658.
Cutolo M, Foppiani L, Prete C, Ballarino P, Sulli A, Villaggio
B, Seriolo B, Giusti M, Accardo S (1999). Hypothalamopituitary-adrenocortical axis function in premenopausal
women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol 26: 282288.
Czh B, Michaelis T, Watanabe T, Frahm J, De Biurrun G, Van
Kampen M, Bartolomucci A, Fuchs E (2001). Stress-induced
changes in cerebral metabolites, hippocampal volume, and cell
proliferation are prevented by antidepressant treatment with
tianeptine. Proc Nat Acad Sci USA 98: 1279612801.
Czeisler CA, Allan JS, Strogatz SH, Ronda JM, Snchez R, Ros
CD, Freitag WO, Richardson GS, Kronauer RE (1986). Bright
light resets the human circadian pacemaker independent of the
timing of the sleep-wake cycle. Science 233: 667671.
Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman
DJ, Emens JS, Klein T, Rizzo JF (1995). Suppression of
melatonin secretion in some blind patients by exposure to
bright light. New Engl J Med 332: 611.
Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF,
Rimmer DW, Ronda JM, Silva EJ, Allan JS, Emens JS, Dijk
D-J, Kronauer RE (1999). Stability, precision, and near-24hour period of the human circadian pacemaker. Science 284:
21772181.
Czernichow P (1998). Traitement du diabte insipide par le
Minirin(r) comprim. Ann Endocrinol 59: 407409.
Czernichow P, Garel C, Lger J (2000). Thickened pituitary
stalk on magnetic resonance imaging in children with central
diabetes insipidus. Horm Res (Suppl 3) 53: 6164.
Dabbs JM, Mohammed S (1992). Male and female salivary
testosterone concentrations before and after sexual activity.
Dabbs JM, Frady RL, Carr TS, Besch NF (1987). Saliva testosterone and criminal violence in young adult prison inmates.
Psychosom Med 49: 174182.
Dagan Y, Abadi J (2001). Sleep-wake schedule disorder
disability: a lifelong untreatable pathology of the circadian
time structure. Chronobiol Int 18: 10191027.
Dahl RE, Ryan ND, Puig-Antich J, Nguyen NA, Al-Shabbout
M, Meyer VA, Perel J (1991). 24-Hour cortisol measures in
adolescents with major depression: a controlled study. Biol
Dahlstrm A, Fuxe K (1964). Evidence for the existence of
monoamine-containing neurons in the central nervous system.
I. Demonstration of monoamines in the cell bodies of brain
stem neurons. Acta Physiol Scand 62: 155.
Dahmen N, Bierbrauer J, Kasten M (2001). Increased prevalence
of obesity in narcoleptic patients and relatives. Eur Arch
433
2014 Refs
434
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 434
D.F. SWAAB
Daniell HW (2002). Hypothyroidism: a frequent event after

radiotherapy for patients with head and neck carcinoma.
Cancer 95: 673674.
Danilenko KV, Wirz-Justice A, Kruchi K, Weber JM, Terman
M (2000). The human circadian pacemaker can see by the
dawns early light. J Biol Rhythms 15: 437446.
Dare C, Eisler I, Russell G, Treasure J, Dodge L (2001).
Psychological therapies for adults with anorexia nervosa. Br
Das UN (2002). Is type 2 diabetes mellitus a disorder of the
brain? Nutrition 18: 667672.
Dattani MT, Robinson IC (2000). The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet
57: 337346.
Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM,
Gupta R, Wales JKH, Hindmarsh PC, Beddington RSP,
Robinson ICAF (1999). HESX1: a novel gene implicated in
a familial form of septo-optic dysplasia. Acta Paediatr (Suppl
88) (433): 4954.
Dattani MT, Martinez-Barbera J-P, Thomas PQ, Brickman JM,
Gupta R, Wales JKH, Hindmarsh PC, Beddington RSP,
Robinson ICAF (2000). Molecular genetics of septo-optic
dysplasia. Horm Res (Suppl 1) 53: 2633.
Dauvilliers Y, Mayer G, Lecendreux M, Neidhart E, PeraitaAdrados R, Sonka K, Billiard M, Tafti M (2002).
KleineLevin syndrome. An autoimmune hypothesis based
on clinical and genetic analyses. Neurology 59: 17391745.
DAvella D, Giusa M, Blandino A, Angilero FF, La Rosa G,
Tomasello F (1997). Microsurgical excision of a primary
isolated hypothalamic eosinophilic granuloma. J Neurosurg
87: 768772.
Davidson JM, Kwan M, Greenleaf WJ (1982). Hormonal
replacement and sexuality in men. Clin Endocrinol Metab 11:
599623.
Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ,
Catania JA (1983). Hormonal changes and sexual function
in aging men. J Clin Endocrinol Metab 57: 7177.
Davidson M, Bastiaens L, Davis BM, Shah MB, Davis KL
(1988). Endocrine changes in Alzheimers disease. Endocrinol
Davidson RJ, Abercrombie H, Nitschke JB, Putnam K (1999).
Regional brain function, emotion and disorders of emotion.
Curr Opin Neurobiol 9: 228234.
Davis C, Katzman DK, Kirsh C (1999b). Compulsive physical
activity in adolescents with anorexia nervosa. J Nerv Ment
Dis 187: 336342.
Davies DC, McCoubrie P, McDonald B, Jobst KA (1995).
Myelinated axon number in the optic nerve is unaffected by
Alzheimers disease. Br J Ophthalmol 79: 596600.
Davies J, Murphy D (2002). Autophagy in hypothalamic
neurones of rats expressing a familial neurohypophysial diabetes insipidus transgene. J Neuroendocrinol 14:
629637.
Davis KL, Davis BM, Greenwald BS, Mohs RC, Math AA,
Johns CA, Horvath TB (1986). Cortisol and Alzheimers
disease. I: Basal studies. Am J Psychiatry 143: 3.
Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M,
Austin G, Haroutunian V (1999a). Cholinergic markers in
elderly patients with early signs of Alzheimer disease. JAMA
281: 14011406.
Davies MJ, King TT, Metcalfe KA, Monson JP (1997).
Intraventricular craniopharyngioma: a long-term follow-up of
six cases. Br J Neurosurg 11: 533541.
Davis RC, Morris DS, Briggs JE (1992). Nocturnal enuresis.
Lancet 340: 1550.
Davis SR, Tran J (2001). Testosterone influences libido and
well being in women. Trends Endocrinol Metab 12: 3337.
Davis TME, Thu LTA, Binh TQ, Robertson K, Dyer JR, Danh
PT, Meyer D, Beaman MH, Anh TK (1997). The hypothalamic-pituitary-adrenocortical axis in severe falciparum malaria:
effects of cytokines. J Clin Endocrinol Metab 82: 30293033.
Davison C, Demuth EL (1946). Disturbances in sleep mechanism: a clinicopathologic study. Arch Neurol Psychiatry 55:
111125.
Davison JM, Vallotton MB, Lindheimer MD (1981). Plasma
osmolality and urinary concentration and dilution during and
after pregnancy: evidence that lateral recumbancy inhibits
maximal urinary concentrating ability. Br J Obstet Gynaecol
88: 472479.
Davison JM, Gilmore EA, Durr J, Robertson GL, Lindheimer
MD (1984). Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol 246:
F105F109.
Davison JM, Shiells EA, Philips PR, Lindheimer MD (1988).
Serial evaluation of vasopressin release and thirst in human
pregnancy. Role of human chorionic gonadotropin in the osmoregulatory changes of gestation. J Clin Invest 81: 798806.
Davison JM, Sheills EA, Barron WM, Robinson AG,
Lindheimer MD (1989). Changes in metabolic clearance of
vasopressin and in plasma vasopressinase throughout human
pregnancy. J Clin Invest 83: 13131318.
Dawson BH (1958). The blood vessels of the human optic
chiasma and their relation to those of the hypophysis and
hypothalamus. Brain 81: 207217.
Dean AF, Gabrels BAThF, Morley S, Bingham J, Khanim F,
Barrett TG, Watkins PJ, Swaab DF (2003). Wolfram
(DIDMOAD) syndrome: clinical, pathological and genetic
findings in 3 patients (in prep.).
De Becker P, De Meirleir K, Joos E, Campine I, Van Steenberge
E, Smitz J, Velkeniers B (1999). Dehydroepiandrosterone
(DHEA) response to iv ACTH in patients with chronic fatigue
syndrome. Horm Metab Res 31: 1821.
De Bellis A, Bizzarro A, Amoressano Paglionico S, Di Martino
S, Criscuolo T, Sinisi A, Lombardi G, Bellastella A (1994).
Detection of vasopressin cell antibodies in some patients with
autoimmune endocrine diseases without overt diabetes
insipidus. Clin Endocrinol 40: 173177.
2014 Refs
2/12/03
1:39 pm
Page 435
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
435
De Goeij DCE, Dijkstra H, Tilders FJH (1992a). Chronic

psychosocial stress enhances vasopressin but not corticotropin-releasing factor in the external zone of the median
eminence of male rats: relationship to subordinate status.
De Goeij DCE, Binnekade E, Tilders FJH (1992b). Chronic
intermittent stress enhances vasopressin but not corticotropinreleasing factor secretion during hypoglycemia. Am J Physiol
263: E394399.
De Groot CJA, Bergers E, Kamphorst W, Ravid R, Polman CH,
Barkhof F, Van der Valk P (2001). Post-mortem MRI-guided
sampling of multiple sclerosis brain lesions. Brain 124:
16351645.
De Groot LJ (1999). Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 84:
151164.
De Jong TPMV, Van der Heyden AJ (1991). Desmopressine
en enuresis nocturna. Ned Tijdschr Geneesk 135: 1762.
De Jonge FH, Louwerse AL, Ooms MP, Evers P, Endert E,
Van de Poll NE (1989). Lesions of the SDN-POA inhibit
sexual behaviour of male Wistar rats. Brain Res Bull 23:
483492.
De Jongh FE, Jbsis AC, Elte JWF (2001). Thyroid morphology
in lethal non-thyroidal illness: a post-mortem study. Eur J
De Keyzer Y, Ren P, Lenne P, Auzan C, Clauser E, Bertagna
X (1997). V3 vasopressin receptor and corticotrophic phenotype in pituitary and nonpituitary tumors. Horm Res 47:
259262.
De Kloet ER, Vreugdenhil E, Oitzl MS, Jols M (1997).
Glucocorticoid feedback resistance. Trends Endocrinol Metab
8: 2633.
DeKosky ST, Ikonomovic MD, Styren SD, Beckett L,
Wisniewski S, Bennett DA, Cochran EJ, Kordower JH,
Mufson EJ (2002). Upregulation of choline acetyltransferase
activity in hippocampus and frontal cortex of elderly subjects
with mild cognitive impairment. Ann Neurol 51: 145155.
De la Fuente-Fernndez R, Stoessl AJ (2002). The placebo effect
in Parkinsons disease. Trends Neurosci 25: 302306.
De la Fuente-Fernndez R, Schulzer M, Stoessl AJ (2002). The
placebo effect in neurological disorders. Lancet Neurol 1:
8591.
De la Fuente Bobes J, Vizuete C, Mendlewicz J (2002).
Biological nature of depressive symptoms in borderline
personality disorder: endocrine comparison to recurrent brief
and major depression. J Psychiatr Res 36: 137145.
De Lecea L, Criado JR, Prospero-Garcia O, Gautvik KM,
Schweitzer P, Danielson PE, Dunlop CLM, Siggins GR,
Henriksen SJ, Sutcliffe JG (1996). A cortical neuropeptide
with neuronal depressant and sleep-modulating properties.
Nature 381: 242245.
De Lecea L, Kilduff TS, Peyron C, Gao XB, Foye PE, Danielson
PE, Fukuhara C, Battenberg ELF, Gautvik VT, Bartlett FS
De Bellis A, Colao A, Di Salle F, Muccitelli VI, Iorio S, Perrino

S, Pivonello R, Coronella C, Bizzarro A, Lombardi G,
Bellastella A (1999). A longitudinal study of vasopressin cell
antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central
diabetes insipidus. J Clin Endocrinol Metab 84: 30473051.
De Bellis A, Colao A, Bizzarro A, Di Salle F, Coronella C,
Solimeno S, Vetrano A, Pivonello R, Pisano G, Lombardi G,
Bellastella A (2002). Longitudinal study of vasopressin-cell
antibodies and of hypothalamic-pituitary region on magnetic
resonance imaging in patients with autoimmune and idiopathic complete central diabetes insipidus. J Clin Endocrinol
Metabol 87: 38253829.
De Bellis MD, Gold PW, Geracioti TD, Listwak SJ, Kling MA
(1993). Association of fluoxetine treatment with reductions
in CSF concentrations of corticotropin-releasing hormone and
arginine vasopressin in patients with major depression. Am
De Bellis MD, Baum AS, Birmaher B, Keshavan MS, Eccard
CH, Boring AM, Jenkins FJ, Ryan ND (1999). Developmental
traumatology part I: biological stress systems. Biol Psychiatry
45: 12591270.
Debeneix C, Bourgeois M, Trivin C, Sainte-Rose C, Brauner
R (2001). Hypothalamic hamartoma: comparison of clinical
presentation and magnetic resonance images. Horm Res 56:
1218.
De Bruin VMS, Vieira MCM, Rocha MNM, Viana GSB (2002).
Cortisol and dehydroepiandosterone sulfate plasma levels and
their relationship to aging, cognitive function, and dementia.
Brain Cogn 50: 316323.
De Bustros A, Hatipoglu B (2001). Testosterone storm during
pregnancy. Endocrinologist 11: 5760.
De Cornulier M, David A, Cohen JY (1993). Pubert prcoce
centrale rvlatrice dune sclrose tubreuse de Bourneville.
Arch Pediatr 50: 421 423.
De Coursey PJ, Buggy J (1989). Circadian rhythmicity after
neural transplant to hamster third ventricle: specificity of
suprachiasmatic nuclei. Brain Res 500: 263275.
De Divitiis O, Angileri FF, dAvella D, Tschabitscher M,
Tomasello F (2002). Microsurgical anatomic features of the
lamina terminalis. Neurosurgery 50: 563570.
De Geest K, Thiery M, Piron Possuyt G, Vanden Driesche R
(1985). Plasma oxytocin in human pregnancy and parturition.
J Perinat Med 13: 313.
De Goeij DCE, Jezova D, Tilders FJH (1992c). Repeated stress
enhances vasopressin synthesis in corticotropin releasing
factor neurons in the paraventricular nucleus. Brain Res 577:
165168.
De Goeij DCE, Kvetnansky R, Whitnall MH, Jezova D,
Berkenbosch F, Tilders FJH (1991). Repeated stress induced
activation of corticotropin-releasing factor (CRF) neurons
enhances vasopressin stores and colocalization with CRF in the
median eminence of rats. Neuroendocrinology 53: 150159.
435
2014 Refs
436
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 436
D.F. SWAAB
III, Frankel WN, Van den Pol AN, Bloom FE, Gautvik KM,
Sutcliffe JG (1998). The hypocretins: hypothalamus-specific
peptides with neuroexcitatory activity. Proc Natl Acad Sci
USA 95: 322327.
De Leersnyder H, De Blois M-C, Claustrat B, Romana S,
Albrecht U, Van Kleist-Retzow J-C, Delobel B, Viot G,
Lyonnet S, Vekemans M, Munnich A (2001). Inversion of
the circadian rhythm of melatonin in the SmithMagenis
syndrome. J Pediatr 139: 111116.
De Leersnyder H, Bresson JL, De Blois M-C, Souberbielle JC, Mogenet A, Delhotol-Landes B, Salefranque Munnich A
(2003). -Adrenergic antagonists and melatonin reset the
clock and restore sleep in a circadian disorder,
SmithMagenis syndrome. J Med Genet 40: 7478.
De Leo V, La Marca A, Talluri B, DAntona D, Morgante G
(1998). Hypothalamo-pituitaryadrenal axis and adrenal function before and after ovariectomy in premenopausal women.
Eur J Endocrinol 138: 430435.
De Leon J (2003). Polydipsia A study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci 253: 3739.
De Leon MJ, McRae T, Tsai JR, George AE, Marcus DL,
Freedman M, Wolf AP, McEwen B (1988). Abnormal cortisol
response in Alzheimers disease linked to hippocampal
atrophy. Lancet 2 (8607) 13: 391392.
De Leon MJ, McRae T, Rusinek H, Convit A, De Santi S,
Tarshish C, Golomb J, Volkow N, Daisley K, Orentreich N,
McEwen B (1997). Cortisol reduces hippocampal glucose
metabolism in normal elderly, but not in Alzheimers disease.
De los Santos T, Schweizer J, Rees CA, Francke U (2000).
Small evolutionary conserved RNA, resembling C/D box
small nucleolar RNA, is transcribed for PWCR1, a novel
imprinted gene in the PraderWilli deletion region, which is
highly expressed in brain. Am J Hum Genet 67: 10671082.
Del Parigi A, Gautier J-F, Chen K, Salbe AD, Ravussin E,
Reiman E, Tataranni PA (2002). Neuroimaging and obesity.
Ann NY Acad Sci 967: 389397.
De Marinis L, Mancini A, Valle D, Bianchi A, Gentilella R,
Liberale I, Mignani V, Pennis M, Della Corte F (1999). Hypothalamic derangement in traumatized patients: growth hormone
(GH) and prolactin response to thyrotropin-releasing hormone
and GH-releasing hormone. Clin Endocrinol 50: 741747.
De Morsier G (1956). Etudes sur les dysraphies cranioencephaliques. Schweiz Arch Neurol Psych 77: 267292.
Densmore VS, Urbanski HF (2003). Relative effect of
gonadotropin-releasing hormone (GnRH)-I and GnRH-II on
gonadotropin release. J Clin Endocrinol Metab 88:
21262134.
De Reuck J, Decoo D, Van Aken J, Strijckmans K, Lemahieu
I, Vermeulen A (1992). Positron emission tomography study
of the human hypothalamus during normal ageing in in
ischemic and degenerative disorders. Clin Neurol Neurosurg
94: 113118.
De Rijk RH, Schaaf M, De Kloet ER (2002). Glucocorticoid

receptor variants: clinical implications. J Steroid Biochem
Mol Biol 81: 103122.
De Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison
G, Milgrom E (1997). A family with hypogonadotropic
hypogonadism and mutations in the gonadotropin-releasing
hormone receptor. New Engl J Med 337: 15971601.
De Sanctis C, Lala P, Matarazzo P, Balsamo A, Bergamaschi
R, Cappa M, Cisternino M, De Sanctis V, Lucci M, Franzese
A, Ghizzoni L, Pasquino AM, Segni M, Rigon F, Saggese
G, Bertelloni S, Buzi F (1999). McCuneAlbright syndrome:
a longitudinal clinical study of 32 patients. J Pediatr
De Vente W, Olff M, Van Amsterdam JGC, Kamphuis JH,
Emmelkamp PMG (2003). Physiological differences between
burnout patients and healthy controls: blood pressure, heart
rate, and cortisol responses. Occup Environ Med 60: i54i61.
Devi BI, Shukla D, Bhat D, Santosh V (2001). Hypothalamic
tumour with haemorrhage. Childs Nerv Syst 17: 567569.
De Vile CJ, Grant DB, Hayward RD, Kendall BE, Neville BGR,
Stanhope R (1996). Obesity in childhood craniopharyngioma:
relation to post-operative hypothalamic damage shown by
magnetic resonance imaging. J Clin Endocrinol Metab 81:
27342737.
De Vos RAI, Jansen ENH, Stam FC, Ravid R, Swaab DF (1995).
Lewy body disease: clinico-pathological correlations in 18
consecutive cases of Parkinsons disease with and without
dementia. Clin Neurol Neurosurg 97: 1322.
De Vries GJ, Buijs RM (1983). The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum. Brain Res 273: 307317.
De Vries GJ, Buijs RM, Swaab DF (1981). Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their
extrahypothalamic projections in the rat brain presence of a
sex difference in the lateral septum. Brain Res 218: 6778.
De Vries MW, Peeters FPML (1997). Melatonin as a therapeutic agent in the treatment of sleep disturbance in
depression. J Nerv Ment Dis 185: 201202.
De Weerd AW, Van Huffelen AC, Reeser HM (1982).
Progression of endocrinological and neurological dysfunction
in adrenoleukodystrophy. Eur Neurol 21: 117123.
De Wied D (1965). The influence of the posterior and intermediate lobe of the pituitary and pituitary peptides on the
maintenance of a conditioned avoidance response in rats. Int
J Neuropharmacol 4: 157.
De Wied D, Bohus B (1966). Long term and short term effects
on retention of a conditioned avoidance response of a conditioned avoidance response in rats by treatment with long
acting pitressin and -MSH. Nature (Lond), 212: 14841486.
De Wied D, Van Ree JM (1982). Neuropeptides, mental performance and aging. Life Sci 31: 709719.
De Zegher F, Devlieger H, Veldhuis JD (1992). Pulsatile and
sexually dimorphic secretion of luteinizing hormone in the
human infant on the day of birth. Pediatr Res 32: 605607.
2014 Refs
2/12/03
1:39 pm
Page 437
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
437
Del Cerro MCR (1998). Role of the vomeronasal input in

maternal behavior. Psychoneuroendocrinology 23: 905926.
Del Tredici K, Rb U, De Vos RAI, Bohl JRE, Braak H (2002).
Where does Parkinson disease pathology begin in the brain.
J Neuropathol Exp Neurol 61: 413426.
Delville Y, De Vries GJ, Ferris CF (2000). Neural connections
of the anterior hypothalamus and agonistic behavior in golden
hamsters. Brain Behav Evol 55: 5376.
Demeter S, Ringo JL, Doty RW (1988). Morphometric analysis
of the human corpus callosum and anterior commissure. Hum
Demitrack MA (1994). Chronic fatigue syndrome: a disease of
the hypothalamic-pituitary-adrenal axis? Ann Med 26: 15.
Demitrack MA (1997). Neuroendocrine correlates of chronic
fatigue syndrome: a brief review. J Psychiatr Res 31: 6982.
Demitrack MA, Lesem MD, Brandt HA, Pigott TA, Jimerson
DC, Altemus M, Gold PW (1989). Neurohypophyseal
dysfunction: implications for the pathophysiology of eating
disorders. Psychopharmacol Bull 25: 439443.
Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi
MJP, Chrousos GP, Gold PW (1991). Evidence for impaired
activation of the hypothalamic-pituitary-adrenal axis in
patients with chronic fatigue syndrome. J Clin Endocrinol
Metab 73: 12241234.
Den Boer JA, Westenberg HGM (1992). Oxytocin in obsessive
compulsive disorder. Peptides 13: 10831085.
Den Hartog Jager WA, Bethlem J (1960). The distribution of
Lewy bodies in the central and autonomic nervous systems
in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry
23: 283290.
Denis D, Chateil J-F, Brun M, Brissaud O, Lacombe D, Fontan
D, Flurin V, Pedespan J-M (2000). Schizenphaly: clinical and
imaging features in 30 infantile cases. Brain Dev 22: 475483.
Den Heijer JC, Bollen WLEM, Reulen JPH et al (1988).
Autonomic nervous function in Huntingtons disease. Arch
Neurol 45: 309312.
Den Ouden DT, Kroon M, Hoogland PH, Geelhoed-Duijvestijn
PHLM, Wit JM (2002). A 43-year-old male with untreated
panhypopituitarism due to absence of the pituitary stalk: from
dwarf to giant. J Clin Endocrinol Metab 87: 54305434.
DeRijk RH, Schaaf M, De Kloet ER (2002). Glucocorticoid
receptor variants: clinical implications. J Steroid Biochem
Mol Biol 81L 103122.
Desan PH, Oren DA, Malison R, Price LH, Rosenbaum J,
Smoller J, Charney DS, Gelernter J (2000). Genetic polymorphism at the CLOCK gene locus and major depression.
Am J Med Gen 96: 418421.
Descartes R (1662). De homine, figuris at latinate donatus a
Schhuyl (Batavorum: F Lugduni).
Descheemaeker MJ, Vogels A, Govers V, Borghgraef M,
Willekens D, Swillen A, Verhoeven W, Fryns JP (2002).
PraderWilli syndrome: new insights in the behavioural and
psychiatric spectrum. J Intellect Disabil Res 46: 4150.
DeBattista C, Posener JA, Kalehzan BM, Schatzberg AF (2000).

Acute antidepressant effects of intravenous hydrocortisone
and CRH in depressed patients: a double-blind, placebocontrolled study. Am J Psychiatry 157: 13341337.
Decaux G (2001). Long-term treatment of patients with
inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide.
Am J Med 110: 582584.
Deen PMT, Knoers NVAM (1998). Vasopressin type-2 receptor
and aquaporin-2 water channel mutants in nephrogenic
diabetes insipidus. Am J Med Sci 316: 300309.
Deen PMT, Van Balkom BWM, Kamsteeg E-J (2000). Routing
of the aquaporin-2 water channel in health and disease. Eur
J Cell Biol 79: 523530.
Deen PMT, Dahl N, Caplan MJ (2002). The aquaporin-2 water
channel in autosomal dominant primary nocturnal enuresis.
J Urol 167: 14471450.
DeFazio J, Meldrum DR, Laufer L, Vale W, Rivier J, Lu JKH,
Judd HL (1983). Induction of hot flashes in premenopausal
women treated with a long-acting GnRH agonist. J Clin
Degli Uberti EC, Ambrosio MR, Cella SG, Margutti
AR, Trasforini G, Rigamonti AE, Petrone E, Mller EE
(1997). Defective hypothalamic growth hormone (GH)releasing hormone activity may contribute to declining GH
secretion with age in man. J Clin Endocrinol Metab 82:
28852888.
Deijen JB, De Boer H, Blok GJ, Van der Veen EA (1996).
Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21: 313322.
Dekkers JC, Geenen R, Godaert GLR, Glaudemans KAFM,
Lafeber FPJG, Van Doornen LJP, Bijlsma JWJ (2001).
Experimentally challenged reactivity of the hypothalamic
pituitary adrenal axis in patients with recently diagnosed
rheumatoid arthritis. J Rheumatol 28: 14961506.
Delalande O, Rodriguez D, Chiron C, Fohlen M (2001).
Successful surgical relief of seizures associated with hamartoma of the floor of the fourth ventricle in children: report
of two cases. Neurosurgery 49: 726730.
De la Torre JC (2002). Alzheimer disease as a vascular disorder.
Nosological evidence. Stroke 33: 11521162.
Delattre JY, Poisson M, Pertuiset BF, Touati M, Duyckaerts C,
Hauw JJ (1986). Ncrose des voies optiques, de lhypothalamus
et du tronc crbral aprs irradiation dun adnome hypophysaire a doses conventionelles. Rev Neurol 142: 232237.
Delay J, Deniker P (1968). Drug-induced extrapyramidal
syndromes. In: Vinken PJ, Bruyn GW (Eds.) Handbook of
Clinical Neurology: Diseases of the Basal Ganglia. Elsevier,
Amsterdam, Vol. 6, pp. 248266.
Delbende C, Contesse V, Mocar E, Kamoun A, Vaudry H
(1991): The novel antidepressant tianeptine reduces stressevoked stimulation of the hypothalamo-pituitary-adrenal axis.
Eur J Pharmacol 202: 391396.
437
2014 Refs
438
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 438
D.F. SWAAB
Dessein PH, Shipton EA, Stanwix AE, Joffe BI (2000).

Neuroendocrine deficiency-mediated development and persistence of pain in fibromyalgia: a promising paradigm? Pain
86: 213215.
Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Van de Poll
NE, Koppe JG, Boer K (1999). Prenatal exposure to anticonvulsants and psychosexual development. Arch Sex Behav
28: 3144.
DeSesso JM, Scialli AR, Holson JF (1999). Apparent lability
of neural tube closure in laboratory animals and humans. Am
J Med Gen 87: 143162.
Dsy L, Pelletier G (1978). Immunohistochemical localization
of alpha-melanocyte stimulating hormone (-MSH) in the
human hypothalamus. Brain Res 154: 377381.
Deuschle M, Gotthardt U, Schweiger U, Weber B, Krner A,
Schmider J, Standhardt H, Lammers C-H, Heuser I (1997).
With aging in humans the activity of the hypothalamus-pituitaryadrenal system increases and its diurnal amplitude
flattens. Life Sci 61: 22392246.
Deuschle M, Schweiger U, Weber B, Gotthardt U, Krner A,
Schmider J, Standhardt H, Lammers C-H, Heuser I (1997a).
Diurnal activity and pulsatility of the hypothalamus-pituitary
adrenal system in male depressed patients and healthy
controls. J Clin Endocrinol Metab 82: 234238.
Deutsch SI, Rosse RB, Schwartz BL (1997). Histamine
H2 receptor antagonists in schizophrenia. CNS Drugs 8:
276284.
Devanand DP, Lisanby S, Lo E-S, Fitzsimons L, Cooper TB,
Halbreich U, Sackeim HA (1998). Effects of electroconvulsive therapy on plasma vasopressin and oxytocin. Biol
Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla
M, Marder K, Bell K, Stern Y, Mayeux R (2000). Olfactory
deficits in patients with mild cognitive impairment predict
Alzheimers disease at follow-up. Am J Psychiatry 157:
13991405.
DeVane GW (1985). Vasopressin levels during pregnancy and
labor. J Reprod Med 30: 324327.
DeVile CJ, Sufraz R, Lask BD, Stanhope R (1995). Occult
intracranial tumours masquerading as early onset anorexia
nervosa. Br Med J 311: 13591360.
Devitt H, Holland P, Butler R, Redfern E, Hiley E, Roberts G
(1999). Plasma vasopressin and response to treatment in
primary nocturnal enuresis. Arch Dis Child 80: 448451.
De Winter RFP, Van Hemert AM, DeRijk RH, Zwinderman KH,
Frankhuijzen-Sierevogel AC, Wiegant VM, Goekoop JG
(2003). Anxious-retarded depression: relation with plasma vasopressin and cortisol. Neuropsychopharmacology 28: 140147.
Dexter JD, Riley TL (1975). Studies in nocturnal migraine.
Headache 15: 5162.
Dhurandhar NV, Israel BA, Kolesar JM, Mayhew GF, Cook
ME, Atkinson RL (2000). Increased adiposity in animals due
to a human virus. Int J Obesity 24: 989996.
Dimaraki EV, Jaffe CA, Demott-Friberg R, Russell-Aulet M,

Bowers CY, Marbach P, Barkan AL (2001). Generation of
growth hormone pulsatility in women: evidence against
somatostatin withdrawal as pulse initiator. Am J Physiol 280:
E489E495.
Di Prospero NA, Tagle DA (2000). Normal and mutant huntingtin: partners in crime? Nat Med 6: 12081209.
Di Virgilio G, Clarke S, Pizzolato G, Schaffner T (1999).
Cortical regions contributing to the anterior commissure in
man. Exp Brain Res 124: 17.
Diamond M, Sigmundson K (1997). Sex reassignment at birth.
Long-term review and clinical implications. Arch Pediatr
Adolesc Med 151: 298304.
Diamond SG, Markham CH, Hoehn MM, McDowell FH,
Muenter MD (1990). An examination of malefemale differences in progression and mortality of Parkinsons disease.
Dickerman RD, McCobathy WJ (1997). Testosterone, vasopressin and depression. Prog Neuro-Psychopharmacol Biol
Dickerman RD, Jaikumar S (2001). Secondary partial empty
sella syndrome in an elite bodybuilder. Neurol Res 23:
336338.
Dieckmann G, Hassler R (1977). Treatment of sexual violence
by stereotactic hypothalamotomy. In: Sweet WH, Obrador S,
Martin-Rodriguez JG (Eds.) Neurosurgical Treatment in
Psychiatry, Pain, and Epilepsy. Univ Park Press, Baltimore,
pp. 451462.
Dieckmann G, Schneider H (1978). Influence of stereotactic
hypothalamotomy on alcohol and drug addiction. Appl
Neurophysiol 41: 9398.
Dieckmann G, Schneider-Jonietz B, Schneider H (1988).
Psychiatric and neuropsychological findings after stereotactic
hypothalamotomy, in cases of extreme sexual aggressivity.
Acta Neurochir Suppl 44: 163166.
Diederich S, Eckmanns T, Exner P, Al-Saadi N, Bhr V, Oelkers
W (2001). Differential diagnosis of polyuric/polydipsic
syndromes with the aid of urinary vasopressin measurement
in adults. Clin Endocrinol 54: 665671.
Diepen R (1962). Der Hypothalamus. In: Bargmann W (Ed.),
Handbuch der mikroskopische Anatomie des Menschen IV/7,
pp. 1181. Springer, Berlin.
Dierickx K, Vandesande F (1977). Immunocytochemical localization of the vasopressinergic and the oxytocinergic neurons
in the human hypothalamus. Cell Tissue Res 184: 1527.
Dierickx K, Vandesande F (1979). Immunocytochemical
demonstration of separate vasopressin-neurophysin and
oxytocin-neurophysin neurons in the human hypothalamus.
Dieterich KD, Lehnert H, De Souza EB (1997). Corticotropinreleasing factor receptors: an overview. Exp Clin Endocrinol
Diabetes 105: 6582.
2014 Refs
2/12/03
1:39 pm
Page 439
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
439
Doblhammer G, Vaupel, JW (2001). Lifespan depends on month

of birth. Proc Natl Acad Sci 98: 29342939.
Dodge NN, Wilson GA (2001). Melatonin for treatment of sleep
disorders in children with developmental disabilities. J Child
Neurol 16: 581584.
Dodick DW, Mosek AC, Campbell JK (1998). The hypnic
(alarm clock) headache syndrome. Cephalalgia 18:
152156.
Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD (2000).
Cluster headache. Cephalalgia 20: 787803.
Dolberg OT, Hirschmann S, Grunhaus L (1998). Melatonin for
the treatment of sleep disturbances in major depressive
disorder. Am J Psychiatry 155: 11191121.
Dolenc VV (1999). Hypothalamic gliomas. Adv Techn Stand
Domnech E, Gmez-Zaera M, Nunes V (2002). WFS1 mutations in Spanish patients with diabetes mellitus and deafness.
Eur J Hum Genet 10: 421426.
Domes G, Heinrichs M, Reichwald U, Hautzinger M (2002).
Hypothalamic-pituitary-adrenal axis reactivity to psychological stress and memory in middle-aged women: high
responders exhibit enhanced declarative memory performance. Psychoneuroendocrinology 27: 843853.
Dominguez CE, Laughlin GA, Nelson JC, Yen SSC (1997).
Altered binding of serum thyroid hormone to thyroxinebinding globulin in women with functional hypothalamic
amenorrhea. Fertil Steril 68: 992996.
Domnguez-Rodrguez A, Abreu-Gonzlez P, Garca MJ,
Sanchez J, Marrero F, De Armas-Trujillo D (2002). Decreased
nocturnal melatonin levels during acute myocardial infarction.
J Pineal Res 33: 248252.
Donahue JE, Stopa EG, Chorsky RL, King JC, Schipper HM,
Tobet SA, Blaustein JD, Reichlin S (2000). Cells containing
immunoreactive estrogen receptor- in the human basal
forebrain. Brain Res 856: 142151.
Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis
KA, Rivier JE, Vaughan JM, Vale WW (1996). Cloning and
characterization of human urocortin. Endocrinology 137:
21672170.
Donoghue MB, Latimer E, Pillsbury HL, Hertzog JH
(1998). Hyponatremic seizure in a child using desmopressin
for nocturnal enuresis. Arch Pediatr Adolesc Med 152:
290292.
Doppman JL (1997). Petrosal sinus sampling and corticotropinreleasing hormone in Cushings syndrome. Endocrinologist
7: 24S-29S.
Dring WKH, Herzenstiel M-N, Krampe H, Jahn H, Pralle L,
Sieg S, Wegerle E, Poser W, Ehrenreich H (2003). Persistent
alterations of vasopressin and N-terminal proatrial natriuretic
peptide plasma levels in long-term abstinent alcoholics.
Alcohol Clin Exp Res.
Dorn LD, Burgess ES, Dubbert B, Simpson S-E, Friedman T,
Kling M, Gold PW, Chrousos GP (1995). Psychopathology
DiFazio MP, Davis RG (2000). Utility of early single photon

emission computed tomography (SPECT) in neonatal gelastic
epilepsy associated with hypothalamic hamartoma. J Child
Neurol 15: 414417.
DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel
JP, Aronin N (1997). Aggregation of huntingtin in neuronal
intranuclear inclusions and dystrophic neurites in brain.
Science 277: 19901993.
Dijk D-J, Neri DF, Wyatt JK, Ronda JM, Riel E, Ritz-De Cecco
A, Hughes RJ, Elliott AR, Prisk GK, West JB, Czeisler CA
(2001). Sleep, performance, circadian rhythms, and lightdark
cycles during two space shuttle flights. Am J Physiol 281:
R1647R1664.
Dill JE, Wells RF (1971). Use of vasopressin in the
MalloryWeiss syndrome. N Engl J Med 284: 852853.
DiMeglio LA, Gagliardi PC, Browning JE, Quigley CA,
Repaske DR (2001). A missense mutation encoding
Cys67 Gly in neurophysin II is associated with early onset
autosomal dominant neurohypophyseal diabetes insipidus.
Mol Gen Metab 72: 3944.
Dinan TG (1994). Glucocorticoids and the genesis of depressive
illness. A psychobiological model. Br J Psychiatry 164:
365371.
Dinan TG, Lavelle E, Cooney J, Burnett F, Scott L, Dash A,
Thakore J, Berti C (1997). Dexamethasone augmentation in
treatment-resistant depression. Acta Psychiatr Scand 95: 5861.
Dinan TG, Lavelle E, Scott LV, Newell-Price J, Medbak S,
Grossman AB (1999). Desmopressin normalizes the blunted
adrenocorticotropin response to corticotropin-releasing
hormone in melancholic depression: evidence of enhanced
vasopressinergic responsivity. J Clin Endocrinol Metab 84:
22382240.
Dingemans AE, Bruna MJ, Van Furth EF (2002). Binge eating
disorder: a review. Int J Obesity 26: 299307.
Dinser R, Halama T, Hoffmann A (2000). Stringent endocrinological testing reveals subnormal growth hormone secretion
in some patients with fibromyalgia syndrome but rarely severe
growth hormone deficiency. J Rheumatol 27: 24822488.
Discussion between Daly JJ, Nabarro JDN (1973). A case of
anorexia. Br Med J 2: 156161.
Dissaneevate P, Warne GL, Zacharin MR (1998). Clinical
evaluation in isolated hypogonadotrophic hypogonadism
(Kallmann syndrome). J Pediatr Endocrinol Metab 11:
631638.
Dittmann RW, Kappes ME, Kappes MH (1992). Sexual
behavior in adolescent and adult females with congenital
adrenal hyperplasia. Psychoneuroendocrinology 17: 153170.
Dittmann V, Elster K, Graw P, Wirz-Justice A (1994). Seasonal
affective disorder: are the DSM-III-R criteria valid? Psychopathology 27: 291297.
Dluhy RG (1990). Editorial The growing spectrum of HIVrelated endocrine abnormalities. J Clin Endocrinol Metabol
70: 563565.
439
2014 Refs
440
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 440
D.F. SWAAB
in patients with endogenous Cushings syndrome: atypical

or melancholic features. Clin Endocrinol 43: 433442.
Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW,
Chrousos GP (1997a). The longitudinal course of
psychopathology in Cushings syndrome after correction of
hypercortisolism. J Clin Endocrinol Metab 82: 912919.
Dorn LD, Dahl RE, Birmaher B, Williamson DE, Kaufman J,
Frisch L, Perel JM, Ryan ND (1997b). Baseline thyroid
hormones in depressed and non-depressed pre- and earlypubertal boys and girls. J Psychiatr Res 31: 555567.
Drner G (1988). Neuroendocrine response to estrogen and
brain differentiation in heterosexuals, homosexuals, and transsexuals. Arch Sexual Behav 17: 5775.
Drner G, Staudt J (1972). Vergleichende morphologische
Untersuchungen der Hypothalamusdifferenzierung bei Ratte
und Mensch. Endokrinologie 59: 152155.
Drner G, Gtz F, Rohde W, Plagemann A, Lindner R, Peters
H, Ghanaati Z (2001). Genetic and epigenetic effects on
sexual brain organization mediated by sex hormones.
Neuroendocrinol Lett 22: 403409.
Dorries KM, Schmidt HJ, Beauchamp GK, Wysocki CJ (1989).
Changes in sensitivity to the odor of androstenone during
adolescence. Dev Psychobiol 22: 423435.
Doshi PK, Chhaya N, Bhatt MH (2002). Depression leading to
attempted suicide after bilateral subthalamic nucleus stimulation for Parkinsons disease. Mov Disord 17: 10841100.
Doshi R, Neil-Dwyer G (1977). Hypothalamic and myocordial
lesions after subarachnoid haemorrhage. J Neurol Neurosurg
Dtsch J, Kiess W, Hnze J, Repp R, Ldeke D, Blum WF, Rascher
W (1996). Gs mutation at Codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCuneAlbright syndrome. J Clin Endocr Metab 81: 38393842.
Douglas AJ, Scullion S, Antonijevic IA, Brown D, Russell JA,
Leng G (2001). Uterine contractile activity stimulates
supraoptic neurons in term pregnant rats via a noradrenergic
pathway. Endocrinology 142: 633644.
Douglas CP (1965). Oxytocin and antidiuresis in pregnancy at
term. Clin Sci 28: 3942.
Douglas S, Rawles J (1999). Latitude-related changes in the
amplitude of annual mortality rhythm. The biological equator
in man. Chronobiol Int 16: 199212.
Dowling GA (1996). Behavioral intervention strategies for
sleep-activity disruption. Int Psychogeriatr (Suppl 1) 8: 7786.
Draganski B, Geisler P, Hajak G, Schuierer G, Bogdahn U,
Winkler J, May A (2002). Hypothalamic gray matter changes
in narcoleptic patients. Nat Med 8: 11861188.
Drent ML, Wever LDV, Adr HJ, Van der Veen EA (1995).
Growth hormone administration in addition to a very low
calorie diet and an exercise program in obese studies. Eur J
Drenth JPH, Van der Meer JWM (2001). Hereditary periodic
fever. New Engl J Med 345: 17481757.
Driggs M, Spatz M (1939). Pubertas praecox bei einer hyperplastischen Mibildung des Tuber cinereum. Virchows Archiv
305: 567592.
Drost M, Holm LW (1968). Prolonged gestation in ewes after
foetal adrenalectomy. J Endocrinol 40: 293296.
Drucker-Colin R, Aguilar-Roblero R, Garcia-Hernandez F,
Fernandez-Cancino F, Bermudez Rattoni F (1984). Fetal
suprachiasmatic nucleus transplants: diurnal rhythm recovery
of lesioned rats. Brain Res 311: 353357.
Drukker J (1967). Het syndroom van Frhlich, dystrophia
adiposo-genitalis en pseudo-Frhlich. Ned T Geneesk 111:
405407.
Drummer C, Valenti G, Cirillo M, Perna A, Bellini L, Nenov
V, De Santo NG (2002). Vasopressin, hypercalciuria and
aquaporin the key elements for impaired renal water
handling in astronauts? Nephron 92: 503514.
Du HJ, Chao YF (1976). Localization of central structures
involved in descending inhibitory effect of acupuncture on
viscerosomatic reflex discharges. Sci Sin 19: 137148.
Duchen LW (1966). Metastatic carcinoma in the pituitary gland
and hypothalamus. J Pathol Bacteriol 91: 347355.
Duckmann R, Chao D (1957). Laughter in epilepsy. Neurology
7: 2636.
Duclos M, Gatta B, Corcuff J-B, Rashedi M, Pehourcq F, Roger
P (2001). Fat distribution in obese women is associated with
subtle alterations of the hypothalamic-pituitary-adrenal axis
activity and sensitivity to glucocorticoids. Clin Endocrinol
55: 447454.
Ducsay CA (1996). Rhythms and parturition. Endocrinologist
6: 3743.
Duds B, Merchenthaler I (2001). Catecholaminergic axons
innervate LH-releasing hormone immunoreactive neurons of
the human diencephalon. J Clin Endocrinol Metab 86:
56205626.
Duds B, Merchenthaler I (2002a). Close juxtapositions between
LHRH immunoreactive neurons and substance P immunoreactive axons in the human diencephalon. J Clin Endocrinol
Metabol 87: 29462953.
Duds B, Merchenthaler I (2002b). Topography and associations of leu-encephalin and luteinizing hormone-releasing
hormone neuronal systems in the human diencephalon. J Clin
Dudas B, Merchenthaler I (2002c). Close juxtapositions between
luteinizing hormone-releasing hormone-immunoreactive
neurons and corticotropin-releasing factor-immunoreactive
axons in the human diencephalon. J Clin Endocrinol Metab
87: 57785784.
Dudas B, Merchenthaler I (2003). Topography and associations
of leu-enkephalin and luteinizing hormone-releasing hormone
neuronal systems in the human diencephalon. J Clin
Duds B, Mihly A, Merchenthaler I (2000). Topography and
associations of luteinizing hormone-releasing hormone and
2014 Refs
2/12/03
1:39 pm
Page 441
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
441
DuRivage SK, Winter RJ, Brouillette RT, Hunt CE, Noah Z

(1985). Idiopathic hypothalamic dysfunction and impaired
control of breathing. Pediatrics 75: 896898.
Durr JA, Hoggard JG, Hunt JM, Schrier RW (1987). Diabetes
insipidus in pregnancies associated with abnormally high
circulating vasopressinase activity. N Engl J Med 316:
10701074.
Durso R, Ruggeri SA, Denaro A, Tamminga CA (1984).
Neuroendocrine studies in Huntingtons disease. In: Shah NS,
Donald AG (Eds.) Psychoneuroendocrine dysfunction. New
York, pp. 209230.
Durso R, Tamminga CA, Denaro A, Ruggeri S, Denaro A, Kuo
S, Chase TN (1983b). Twenty-four hour plasma levels of
growth hormone and prolactin in Huntingtons disease. J
Neurol Neurosurg Psychiatry 46: 11341137.
Dusoir H, Kapur N, Byrnes DP, McKinstry S, Hoare RD (1990).
The role of diencephalic pathology in human memory
disorder. Brain 113: 16951706.
Durso R, Tamminga CA, Denaro A, Ruggeri S, Chase TN
(1983a). Plasma growth hormone and prolactin response to
dopaminergic, GABA mimetic and cholinergic stimulation in
Huntingtons disease. Neurology 33: 12291232.
Dutta JK (1996). Excessive libido in a woman with rabies.
Postgrad Med J 72: 554555.
Duval F, Mokrani M-C, Crocq M-A, Jautz M, Bailey P,
Diep T-S, Macher J-P (1996). Effect of antidepressant
medication on morning and evening thyroid function tests
during a major depressive episode. Arch Gen Psychiatry 53:
833840.
Duvernoy H (1972). The vascular architecture of the median
eminence. In: BrainEndocrine Interaction. Median Eminence:
Structure and Function. Karger, Basel, pp. 79108.
Duvernoy HM, Parratte B, Tatu L, Vuillier F (2000). The human
pineal gland: relationships with surrounding structures and
blood supply. Neurol Res 22: 747790.
Eames P. (1997). Feeling cold: an unusual brain injury symptom
and its treatment with vasopressin. J Neurol Neurosurg
Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM (1998).
Bright light treatment of winter depression. A placebocontrolled trial. Arch Gen Psychiatry 55: 883889.
Eastman CI, Martin SK, Hebert M (2000). Failure of extraocular light to facilitate circadian rhythm reentrainment in
humans. Chronobiol Int 17: 807826.
Eastwood H, Brown KMO, Markovic D, Pieri LF (2002).
Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Mol Psychiatry 7: 8689.
Eaton SJ, Cote NK, Harrington ME (1995). Histamine synthesis
inhibition reduces light-induced phase shifts of circadian
rhythms. Brain Res 695: 227230.
Ebisawa T, Kajimura N, Uchiyama M, Katoh M, Sekimoto M,
Watanabe T, Ozeki Y, Ikeda M, Jodoi T, Sugishata M, Iwase
T, Kamei Y, Kim K, Shibui K, Kudo Y, Yamada N,
neuropeptide Y-immunoreactive neuronal systems in the

human diencephalon. J Comp Neurol 427: 593603.
Duff JM, Meyer FB, Ilstrup DM, Laws ER, Schleck CD,
Scheithauer BW (2000). Long-term outcomes for surgically
resected craniopharyngiomas. Neurosurgery 46: 291305.
Duffy JF, Czeisler CA (2002). Age-related change in the
relationship between circadian period, circadian phase,
and diurnal preference in humans. Neurosci Lett 318:
117120.
Duffy JF, Rimmer DW, Czeisler CA (2001). Association of
intrinsic circadian period with morningnesseveningness,
usual wake time, and circadian phase. Behav Neurosci 115:
895899.
Duffy JF, Zeitzer JM, Rimmer DW, Klerman EB, Dijk D-J,
Czeisler CA (2002). Peak of circadian melatonin rhythm
occurs later within the sleep of older subjects. Am J Physiol
282: E297E303.
Duffy JP, Davison K (1968). A female case of the KleineLevin
syndrome. Br J Psychiatry 114: 7784.
Duggan J, Kilfeather S, Lightman SL, OMalley K (1993). The
association of age with plasma arginine vasopressin and
plasma osmolality. Age Ageing 22: 332336.
Dumont Y, Jacques D, Bouchard P, Quirion R (1998). Species
differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4 and Y5 receptors in rodents, guinea pig
and primates brains. J Comp Neurol 402: 372384.
Dumont Y, Jacques D, St-Pierre JA, Tong Y, Parker R, Herzog
H, Quirion R (2000). Distribution of NPY-like immunoreactivity and NPY receptor subtypes in the human brain. In:
Quirion R, Bjorklund A, Hkfelt T (Eds.) Handbook of
Chemical Neuroanatomy, Part II, Vol. 16, pp. 431475.
Dunger DB, Lightman S, Williams M, Preece MA, Grant DB
(1985). Lack of thirst, osmoreceptor dysfunction, early
puberty and abnormally aggressive behaviour in two boys.
Dunn HG, MacLeod PM (2001). Rett syndrome: review of
biological abnormalities. Can J Neurol Sci 28: 1629.
Dunoyer C, Ragheb J, Resnick T, Alvarez L, Jayakar P, Altman
N, Wolf A, Duchowny M (2002). The use of stereotactic
radiosurgery to treat intractable childhood partial epilepsy.
Epilepsia 43: 292300.
Dnser MW, Mayr AJ, Ulmer H, Ritsch N, Knotzer H, Pajk
W, Luckner G, Mutz NJ, Hasibeder WR (2001). The effects
of vasopressin on systemic hemodynamics in catecholamineresistant septic and postcardiotomy shock: a retrospective
analysis. Anesth Analg 93: 713.
Dnser MW, Mayr AJ, Ulmer H, Knotzer H, Sumann G, Pajk
W, Friesenecker B, Hasibeder WR (2003). Arginine vasopressin in advanced vasodilatory shock. Circulation 107:
23132319.
Duquette P, Girard M (1993). Hormonal factors in susceptibility
to multiple sclerosis. Curr Opin Neurol Neurosurg 6: 195201.
441
2014 Refs
442
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 442
D.F. SWAAB
Toyoshima R, Okawa M, Takahashi K, Yamauchi T (1999).

Alleic variants of human melatonin 1a receptor: function and
prevalence in subjects with circadian sleep disorder. Biochem
Biophys Res Commun 262: 832837.
Ebisawa T, Uchiyama M, Kajimura N, Kamei Y, Shibui K,
Kim K, Kudo Y, Iwase T, Sugishita M, Jodoi T, Ikeda M,
Ozeki Y, Watanabe T, Sekimoto M, Katoh M, Yamada N,
Toyoshima R, Okawa M, Takahashi K, Yamauchi T (2000).
Genetic polymorphisms of human melatonin 1b receptor gene
in circadian rhythm sleep disorders and controls. Neurosci
Lett 280: 2932.
Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y,
Katoh M, Watanabe T, Sekimoto M, Shibui K, Kim K, Kudo
Y, Ozeki Y, Sugishita M, Toyoshima R, Inoue Y, Yamada
N, Nagase T, Ozaki N, Ohara O, Ishida N, Okawa M,
Takahashi K, Yamauchi T (2001). Association of structural
polymorphisms in the human period3 gene with delayed sleep
phase syndrome. EMBO Rep 2: 342346.
Ebling FJP, Cronin AS (2000). The neurobiology of reproductive development. Neuroreport 11: R23R33.
Ebrahim IO, Sharief MK, De Lacy S, Semra YK, Howard RS,
Kopelman MD, Williams AJ (2003). Hypocretin (orexin).
deficiency in narcolepsy and primary hypersomnia. J Neurol
Neurosurg Psychiatry 74: 127130.
Eda M, Saeki N, Fujimoto N, Sunami K (2002). Demonstration
of the optic pathway in large pituitary adenoma on heavily
T2 weighted MR images. Br J Neurosurgery 16: 2129.
Editorial (1986). DIDMOAD (Wolfram syndrome). Lancet 1
(8489). 10: 10751076.
Edwards DA, Walter B, Liang P (1996b). Hypothalamic and
olfactory control of sexual behavior and partner preference
in male rats. Physiol Behav 60: 13471354.
Edwards S, Lennox G, Robson K, Whiteley A (1996a).
Hypothermia due to hypothalamic involvement in multiple
sclerosis. J Neurol Neurosurg Psychiatry 61: 419420.
Edwards S, Evans P, Hucklebridge F, Clow A (2001).
Association between time of awakening and diurnal cortisol
secretory activity. Psychoneuroendocrinology 26: 613622.
Eggert P, Mller-Schltert K, Mller D (1999). Regulation
of arginine vasopressin in enuretic children under fluid
restriction. Pediatrics 103: 452455.
Eguchi K, Uozumi T, Arita K, Kurisu K, Yano T, Sumida M,
Takechi A, Pant B (1994). Pituitary function in patients with
Rathkes cleft cyst: significance of surgical management.
Endocr J 41: 535540.
Ehl S, Severin T, Sutor AH (2000). DDAVP (desmopressin;
1-deamino-cys8-D-arginine-vasopressin).
treatment
in
children with haemophilia B. Br J Haematology 111:
12601262.
Ehrhardt AA, Meyer-Bahlburg HFL, Rosen LR, Feldman JF,
Veridiano NP, Zimmerman I, McEwen BS (1985). Sexual
orientation after prenatal exposure to exogenous estrogen.
Arch Sex Behav 14: 5775.
Ehrhardt DA, Tang X, Yoshiuchi I, Cox NJ, Bell GI (2002).

Relationship of insulin receptor substrate1 and 2 genotypes
to phenotypic features of polycystic ovary syndrome. J Clin
Eiholzer U, Weber R, Stutz K, Steinert H (1997). Effect of 6
months of growth hormone treatment in young children with
PraderWilli syndrome. Acta Paediatr Suppl 423: 6668.
Eiholzer U, Stutz K, Weinmann C, Torresani T, Molinari L,
Prader A (1998). Low insulin, IGF-I and IGFBP3 levels in
children with PraderLabhartWilli syndrome. Eur J Pediatr
157: 890893.
Eiholzer U, Bachmann S, lAllemand D (2000). Is there growth
hormone deficiency in PraderWilli syndrome? Horm Res 53
(Suppl. 3): 4452.
Einspieler C, Kenner T (1985). A possible relation between
oxytocin for induction of labor and sudden infant death
syndrome. N Engl J Med 313: 1660.
Eisenberg HM, Sarwar M, Schochet S (1976). Symptomatic
Rathkes cleft cyst. J Neurosurg 45: 585588.
Eisenman A, Armali Z, Enat R, Bankir L, Baruch Y (1999).
Low-dose vasopressin restores diuresis both in patients with
hepatorenal syndrome and in anuric patients with end-stage
heart failure. J Intern Med 246: 183190.
Eisensehr I, Noachtar S, Von Schlippenbach C, Uttner I, Kleine
J, Seelos K, Helmchen C (2003). Hypersomnia associated
with bilateral posterior hypothalamic lesion. Eur Neurol 49:
169172.
Eisenstat DD (2001). Craniopharyngioma. Curr Treat Options
Neurol 3: 7787.
Eisler T, Thorner MO, MacLeod RM, Kaiser DL, Calne DB
(1981). Prolactin secretion in Parkinson disease. Neurology
31: 13561359.
Ekbom K, Hardebo JE (2002). Cluster headache: aetiology,
diagnosis and management. Drugs 62: 6169.
Ekbom K, Svensson DA, Trff H, Waldenlind E (2002). Age
at onset and sex ratio in cluster headache: observations over
three decades. Cephalalgia 22: 94100.
Ekinci G, Kili T, Baltacioglu F, Elmaci I, Altun E, Pamir
MN, Erzen C (2003). Transsphenoidal (large craniopharyngeal). canal associated with a normally functioning
pituitary gland and nasopharyngeal extension, hyperprolactinemia, and hypothalamic hamartoma. Am J Roentgenol
180: 7677.
Ekman R, Gobom J, Persson R, Mecocci P, Nilsson CL (2001).
Arginine vasopressin in the cytoplasm and nuclear fraction
of lymphocytes from healthy donors and patients with depression or schizophrenia. Peptides 22: 6772.
Ekmekcioglu C, Haslmayer P, Philipp C, Mehrabi MR, Glogar
HD, Grimm M, Thalhammer T, Marktl W (2001). 24H variation in the expression of the mt1 melatonin receptor subtype
in coronary arteries derived from patients with coronary heart
disease. Chronobiol Int 18: 973985.
2014 Refs
2/12/03
1:39 pm
Page 443
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
El-Badri SM, Lewis MA (1991). Anorexia nervosa associated

with Klinefelters syndrome. Compr Psychiatry 32: 317319.
Elias CF, Lee C, Kelly J, Aschkenas C, Ahima RS, Couceyro
PR, Kuhar MJ, Saper CB, Elmquist JK (1998). Leptin
activates hypothalamic CART neurons projecting to the spinal
cord. Neuron 21: 13751385.
Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M, Saper CB,
Elmquist JK (2001). Characterization of CART neurons
in the rat and human hypothalamus. J Comp Neurol 432: 119.
Ellenberger C, Runyan TE (1970). Holoprosencephaly with
hypoplasia of the optic nerves, dwarfism, and agenesis of the
septum pellucidum. Am J Ophthalmol 70: 960967.
Ellenbogen RG, Moores LE (1997). Endoscopic management
of a pineal and suprasellar germinoma with associated hydrocephalus: technical case report. Minim Invasive Neurosurg
40: 1316.
Elliott WJ (2001). Cyclic and circadian variations in cardiovascular events. Am J Hypertens 14: 291S295S.
Ellis CR (1992). Chronobiological aspects of epileptic
phenomena: a literature review, implications for nursing and
suggestions for research. J Neurosci Nurs, 24: 335339.
Ellis L (1996). Theories of homosexuality. In: Savin-Williams
RC, Cohen KM (Eds). The lives of lesbians, gays, and
bisexuals. Children to adults. Harcourt Brace College
Publishers, Fort Worth, pp. 1170.
Ellis L, Ames MA, Peckham W, Burke D (1988). Sexual orientation of human offspring may be altered by severe maternal
stress during pregnancy. J Sex Res 25: 152157.
Ellis L, Cole-Harding S (2001). The effects of prenatal stress,
and of prenatal alcohol and nicotine exposure, on human
sexual orientation. Physiol Behav 74: 213226.
El-Majdoubi M, Sahu A, Ramaswamy S, Plant TM (2000).
Neuropeptide Y: a hypothalamic brake restraining the onset
of puberty in primates. Proc Natl Acad Sci USA 97:
61796184.
Elman I, Adler CM, Malhotra AK, Bir C, Pickar D, Breier A
(1998). Effect of acute metabolic stress on pituitary-adrenal
axis activation in patients with schizophrenia. Am J
Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB
(1997). Leptin activates neurons in ventrobasal hypothalamus
and brainstem. Endocrinology 138: 839842.
El-Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K (2000).
Homozygosity mapping identifies an additional locus for
Wolfram syndrome on chromosome 4q. Am J Hum Genet
66: 12291236.
Emre M (2003). Dementia associated with Parkinsons disease.
Lancet Neurol 2: 229237.
Endo T (1993). Morning bright light effects on circadian rhythms
and sleep structure of SAD. Jikeikai Med J 40: 295307.
Engel GL, Aring CD (1945). Hypothalamic attacks with thalamic lesion. I. Physiologic and psychologic considerations.
Arch Neurol Psychiatry 54: 3743.
443
England MA (2001). Anatomical development of the CNS. In:

Levene M, Chervenak FA, Whittle MJ, Bennett MJ, Punt J
(Eds). Fetal and Neonatal Neurology and Neurosurgery.
Churchill Livingstone, London, pp. 2138.
Engum A, Bjro T, Mykletun A, Dahl AA (2002). An association between depression, anxiety and thyroid function a clinical fact or an artefact? Acta Psychiatr Scand 106:
2734.
Eogan MA, Geary MP, OConnell MP, Keane DP (2003). Effect
of fetal sex on labour and delivery: retrospective review. Brit
Med J 326: 137.
Epperson CN, McDougle CJ, Price LH (1996). Intranasal
oxytocin in obsessive-compulsive disorder. Biol Psychiatry
40: 547549.
Erb JL, Kadane JB, Tourney G (1981). Discrimination between
schizophrenic and control subjects by means of plasma dehydroepiandrosterone measurements. J Clin Endocrinol Metab
52: 181186.
Erickson JC, Clegg KE, Palmiter RD (1996). Sensitivity to
leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381: 415418.
Ericson H, Blomqvist A, Khler C (1991). Origin of neuronal
inputs to the region of the tuberomammillary nucleus of the
rat brain. J Comp Neurol 311: 4564.
Eriksdotter Jnhagen M, Nordberg A, Amberla K, Bckman L,
Ebendal T, Meyerson B, Olson L, Seiger , Shigeta M,
Theodorsson E, Viitanen M, Winblad B, Wahlund L-O
(1998). Intracerebroventricular infusion of nerve growth
factor in three patients with Alzheimers disease. Dement
Geriatr Cogn Disord 9: 246257.
Eriksson KS, Sergeeva O, Brown RE, Haas HL (2001).
Orexin/hypocretin excites the histaminergic neurons of the
tuberomammillary nucleus. J Neurosci 21: 92739279.
Erkal SH, Serin M, akmak A (1997). Management of optic
pathway and chiasmatic-hypothalamic gliomas in children
with radiation therapy. Radiother Oncol 45: 1115.
Erkut ZA, Hofman MA, Ravid R, Swaab DF (1995). Increased
activity of hypothalamic corticotropin-releasing hormone
neurons in multiple sclerosis. J Neuroimmunol 62: 2733.
Erkut ZA, Pool CW, Swaab DF (1998). Glucocorticoids
suppress corticotropin-releasing hormone and vasopressin
expression in human hypothalamic neurons. J Clin Endocrinol
Metab 83: 20662073.
Erkut ZA, Gabrels BATF, Eikelenboom J, Van Leeuwen FW,
Swaab DF (2002a). Glucocorticoid treatment is associated
with decreased expression of processed AVP but not of
proAVP, neurophysin or oxytocin in the human hypothalamus: Are PC1 and PC2 involved? Neuroendocrinol Lett 23:
3344.
Erkut ZA, Endert B, Huitinga I, Swaab DF (2002b). Cortisol
is increased in postmortem cerebrospinal fluid of multiple
sclerosis patients: relationship with cytokines and sepsis. Mult
Scler 8: 229236.
443
2014 Refs
444
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 444
D.F. SWAAB
Erkut ZA, Klooker T, Endert E, Huitinga I, Swaab DF (2003).

Stress of dying is not suppressed by high-dose morphine or
dementia. Neuropsychopharmacology (in press).
Erlich SS, Itabashi HH (1986). Narcolepsy: a neuropathologic
study. Sleep 9: 126132.
Errico AL, King AC, Lovallo WR, Parsons OA (2002). Cortisol
dysregulation and cognitive impairment in abstinent male
alcoholics. Alcohol Clin Exp Res 26: 11981204.
Eschweiler GW, Wegerer C, Schlotter W, Spandl C, Stevens
A, Bartels M, Buchkremer G (2000). Left prefrontal activation predicts therapeutic effects of repetitive transcranial
magnetic stimulation (rTMS). in major depression. Psychiatry
Res 99: 161172.
Escobar-Morreale HF, Obregn MJ, Escobar del Rey F,
Morreale de Escobar G (1995). Replacement therapy for
hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J
Clin Invest 96: 28282838.
Espiner E, Donaldson I, Chapman B, Bergeron C (1992).
Diencephalic idiopathic gliosis: an unusual hypothalamic
syndrome of dermopathy, diarrhea and growth arrest. J
Essex MJ, Klein MH, Cho E, Kalin NH (2002). Maternal stress
beginning in infancy may sensitize children to later stress
exposure: effects on cortisol and behavior. Biol Psychiatry
52: 776784.
Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NPV, Quirion
R (1986). Nucleus basalis neuronal loss, neuritic plaque and
choline acetyltransferase activity in advanced Alzheimers
disease. Neuroscience 19: 12791291.
Etzioni A, Luboshitzky R, Tiosano D, Ben-Harush M, Goldsher
D, Lavie P (1996). Melatonin replacement corrects sleep
disturbances in a child with pineal tumor. Neurology 46:
261263.
Eubanks S, Nguyen TL, Deeb R, Villafania A, Alfadhli A,
Breslow E (2001). Effects of diabetes insipidus mutations on
neurophysin folding and function. J Biol Chem 276:
2967129680.
Eugster EA, Shankar R, Feezle LK, Pescovitz OH (1999).
Tamoxifen treatment of progressive precocious puberty in a
patient with McCuneAlbright syndrome. J Pediatr
Evans C, Chalmers J, Capewell S, Redpath A, Finlayson A,
Boyd J, Pell J, McMurray J, Macintyre K, Graham L (2000a).
I dont like Mondays day of the week of coronary heart
disease deaths in Scotland: study of routinely collected data.
Br Med J 320: 218219.
Evans DAP, Van der Kleij AAM, Sonnemans MAF, Burbach
JPH, Van Leeuwen FW (1994). Frameshift mutations at two
hotspots in vasopressin transcripts in post-mitotic neurons.
Proc Natl Acad Sci USA 91: 60596063.
Evans DAP, Burbach JPH, Swaab DF, Van Leeuwen FW
(1996). Mutant vasopressin precursors in the human hypo-
thalamus: evidence for neuronal somatic mutations in man.

Evans JJ (1997). Oxytocin in the human regulation of derivations and destinations. Eur J Endocrinol 137: 559571.
Evans KL, Lawson D, Meitinger T, Blackwood DHR, Porteous
DJ (2000b). Mutational analysis of the Wolfram syndrome
gene in two families with chromosome 4p-linked bipolar
affective disorder. Am J Med Gen 96: 158160.
Evers S, Hengst K, Pecuch PW (2001). The impact of repetitive
transcranial magnetic stimulation on pituitary hormone levels
and cortisol in healthy subjects. J Affect Disord 66: 8388.
Everson SA, Kaplan GA, Goldberg DE, Salonen JT (2000).
Hypertension incidence is predicted by high levels of hopelessness in Finnish men. Hypertension 35: 561567.
Exton MS, Bindert A, Krger T, Scheller F, Hartmann U,
Schedlowski M (1999). Cardiovascular and endocrine alterations after masturbation-induced orgasm in women.
Psychosom Med 61: 280289.
Fabian VA, Nelson J, Smith NM, Urich H (2001). Lethal Xlinked microcephaly with dysmorphic features, bilateral optic
pathway asplasia and normal eyes. Acta Neuropathol 102:
393397.
Facchinetti F, Nappi G, Cicoli C, Micieli G, Ruspa M, Bono
G, Genazzani AR (1986). Reduced testosterone levels in
cluster headache: a stress-related phenomenon? Cephalalgia
6: 2934.
Facchinetti F, Sgarbi L, Piccinini F (2000). Hypothalamic resetting at puberty and the sexual dimorphism of migraine. Funct
Neurol 15 (Suppl. 3): 137142.
Fadda F, Rossetti ZI (1998). Chronic ethanol consumption: from
neuroadaptation to neurodegeneration. Progr Neurobiol 56:
385431.
Fahlbusch R, Honegger J, Paulus W, Huk W, Buchfelder M
(1999). Surgical treatment of craniopharyngiomas: experience
with 168 patients. J Neurosurg 90: 237250.
Fain JS, Tomlinson FH, Scheithauer BW, Parisi JE, Fletcher
GP, Kelly PJ, Miller GM (1994). Symptomatic glial cysts of
the pineal gland. J Neurosurg 80: 454460.
Fairburn CG, Cooper Z, Doll HA, Norman P, OConnor M (2000).
The natural course of bulimia nervosa and binge eating disorder in young women. Arch Gen Psychiatry 57: 659665.
Fairman D (1973). Stereotactic hypothalamotomy for the alleviation of pain in malignant tumors. J Surg Oncol 5: 7984.
Fajardo B, Browning M, Fisher D, Paton J (1990). Effect of
nursery environment of state regulation in very-low-birthweight premature infants. Infant Behav Dev 13: 287303.
Fldt R, Passant U, Nilsson K, Wattmo C, Gustafson L (1996).
Prevalence of thyroid hormone abnormalities in elderly
patients with symptoms of organic brain disease. Aging. Clin
Exp Res 8: 347353.
Fallon JH, Loughlin SE, Ribak CE (1983). The islands of Calleja
complex of rat basal forebrain. III. Histochemical evidence
for a striatopallidal system. J Comp Neurol 218: 91120.
2014 Refs
2/12/03
1:39 pm
Page 445
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
445
Favaro A, Rodella FC, Santonastaso P (2000). Binge eating and

eating attitudes among Nazi concentration camp survivors.
Psychol Med 30: 463466.
Fazekas F, Strasser-Fuchs S, Schmidt H, Enzinger C, Ropele
S, Lechner A, Flooh E, Schmidt R, Hartung H-P (2000).
Apolipoprotein E genotype related differences in brain lesions
of multiple sclerosis. J Neurol Neurosurg Psychiatry 69:
2528.
Fehm HL, Smolnik R, Kern W, McGregor GP, Bickel U, Born
J (2001). The melanocortin melanocyte-stimulating
hormone/adrenocorticotropin410 decreases body fat in
humans. J Clin Endocrinol Metab 86: 11441148.
Fehn M, Lohman F, Ldecke DK, Rudorff K-H, Saeger W
(1998). Ganglioglioma of the neurohypophysis with secretion
of vasopressin. Exp Clin Endocrinol Diabetes 106: 425430.
Feibel JH, Schiffer RB (1981). Sympathoadrenomedullary
hyperactivity in the neuroleptic malignant syndrome: a case
report. Am J Psychiatry 138: 11151116.
Feinstein A, Feinstein K, Gray T, OConnor P (1997).
Prevalence and neurobehavioral correlates of pathological
laughing and crying in multiple sclerosis. Arch Neurol, 54:
11161121.
Feinstein U, Sheiner E, Levy A, Hallak M, Mazor M (2002).
Risk factors for arrest of descent during the second stage of
labor. Int J Gynecol Obstet 77: 714.
Fekete CS, Strutton PH, Cagampang FRA, Hrabovszky E, Kall
I, Shughrue PJ, Dob E, Mihly E, Baranyi L, Okada H,
Panula P, Merchenthaler I, Coen CW, Liposits ZS
(1999). Estrogen receptor immunoreactivity is present in the
majority of central histaminergic neurons: evidence for a new
neuroendocrine pathway associated with luteinizing hormonereleasing hormone-synthesizing neurons in rats and humans.
Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB,
Coviello AD, Bremner WJ, McKinlay J (2002). Age trends in
the level of serum testosterone and other hormones in middleaged men: longitudinal results from the Massachusetts male
aging study. J Clin Endocrinol Metab 87: 589598.
Fellmann D, Bloch B, Bugnon C, Lenys D (1979). Etude
immunocytologique de la maturation des axes neuroglandulaires hypothalamo-neurohypophysaires chez le foetus
humain. J Physiol (Paris). 75: 3743.
Fenzi F, Simonati A, Crosato F, Ghersini L, Rizzuto N (1993).
Clinical features of KleineLevin syndrome with localized
encephalitis. Neuropediatrics 24: 292295.
Feremutsch K (1948). Die Variabilitt der cytoarchitektonischen
struktur des menschlichen Hypothalamus. Monatschr
Psychiatr Neurol 116: 257283.
Feremutsch K (1955). Strukturanalyse des menschlichen
Hypothalamus. Monatschr Psychiatr Neurol 130: 185.
Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997). Axonal
damage in acute multiple sclerosis lesions. Brain 120:
393399.
Fallon JK, Shah D, Kicman AT, Hutt AJ, Henry JA, Cowan
DA, Forsling M (2002). Action of MDMA (ecstacy). and its
metabolites on arginine vasopressin release. Ann NY Acad
Sci 965: 399409.
Falsetti L, Gambera A, Barbetti L, Specchia C (2002). Longterm follow-up of functional hypothalamic amenorrhea and
prognostic factors. J Clin Endocrinol Metab 87: 500505.
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997).
Role of melanocortinergic neurons in feeding and the agouti
obesity syndrome. Nature 385: 165168.
Fang J, Fishbein W (1996). Sex differences in paradoxical sleep:
influences of estrus cycle and ovariectomy. Brain Res 734:
275285.
Farhy LS, Straume M, Johnson ML, Kovatchev B, Veldhuis JD
(2001). A construct of interactive feedback control of the GH
axis in the male. Am J Physiol 281: R38R51.
Farini A (1913). Diabete insipide ed opoterapia ipofisaria.
Gazetta Ospedali Clin 34: 11351139.
Farley IJ, Price KS, McCullough E, Deck JHN, Hordynski W,
Hornykiewicz O (1978). Norepinephrine in chronic paranoid
schizophrenia: above-normal levels in limbic forebrain.
Science 200: 456458
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH,
Prentice AM, Hughes IA, McCamish MA, ORahilly S
(1999). Effects of recombinant leptin therapy in a child with
congenital leptin deficiency. New Engl J Med 341: 879884.
Farooqi IS, Jones MK, Evans M, ORahilly S, Hodges JR (2000).
Triple H syndrome: a novel autoimmune endocrinopathy
characterized by dysfunction of the hippocampus, hair follicle,
and hypothalamic-pituitaryadrenal axis. J Clin Endocrinol
Metab 85: 26442648.
Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T,
ORahilly S (2003). Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:
10851095.
Farrag A, Khedr EM, Abdel-Aleem H, Rageh TA (2002). Effect
of surgical menopause on cognitive functions. Dement Geriatr
Cogn Disord 13: 193198.
Farrer LA, Yu P-I (1985). Anthropometric discrimination among
affected, at-risk, and not at-risk individuals in families with
Huntington disease. Am J Med Genet 21: 307316.
Fassbender K, Schmidt R, Mssner R, Daffertshofer M,
Hennerici M (1994). Pattern of activity of the hypothalamicpituitary-adrenal axis in acute stroke. Stroke 25: 11051108.
Faull CM, Holmes C, Baylis PH (1993). Water balance in elderly
people: is there a deficiency of vasopressin? Age Ageing 22:
114120.
Faustini-Fustini M, Rochira V, Carani C (1999). Oestrogen deficiency in men: where are we today? Eur J Endocrinol 140:
111129.
Fava GA (1994). Affective disorders and endocrine disease.
New insights from psychosomatic studies. Psychosomatics
35: 341353.
445
2014 Refs
446
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 446
D.F. SWAAB
Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR,
Winslow JT (2000). Social amnesia in mice lacking the
oxytocin gene. Nat Genet 25: 284288.
Fergusson DM, Woodward LJ, Horwood LJ (1998). Maternal
smoking during pregnancy and psychiatic adjustment in late
adolescence. Arch Gen Psychiatry 55: 721727.
Ferin M, Van Vugt D, Wardlaw S (1984). The hypothalamic
control of the menstrual cycle and the role of the endogenous opioid peptides. Recent Progr Horm Res 40: 441485.
Ferini-Strambi L, Filippi M, Martinelli V, Oldani A, Rovaris
M, Zucconi M, Comi G, Smirne S (1994). Nocturnal sleep
study in multiple sclerosis: correlations with clinical and brain
magnetic resonance imaging findings. J Neurol Sci 125:
194197.
Ferlito A, Rinaldo A, Devaney KO (1997). Syndrome of inappropriate antidiuretic hormone secretion associated with head
and neck cancers: review of the literature. Ann Otol Rhinol
Laryngol 106: 878883.
Fernandez JK, Klein MJ, Ater JL, Kuttesch JF, VassilopoulouSellin R (2002). Triiodothyronine supplementation for
hypothalamic obesity. Metabolism 51: 13811383.
Fernndez JM, Lara I, Gila L, ONeill of Tyrone A, Tovar J,
Gimeno A (1990). Disturbed hypothalamic-pituitary axis in
idiopathic recurring hypersomnia syndrome. Acta Neurol
Scand 82: 361363.
Fernndez-Guasti A, Kruijver FPM, Fodor M, Swaab DF (2000).
Sex differences in the distribution of androgen receptors in
the human hypothalamus. J Comp Neurol 425: 422435.
Ferrari E, Canepari C, Bossolo PA, Vailati A, Martignoni E,
Micieli G, Nappi G (1983). Changes of biological rhythms
in primary headache syndromes. Cephalalgia 1: 5868.
Ferrari E, Fraschini F, Brambilla F (1990). Hormonal circadian rhythms in eating disorders. Biol Psychiatry 27:
10071020.
Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L,
Fioravanti M, Solerte SB, Magri F (2000). Pineal and
pituitary-adrenocortical function in physiological aging and
in senile dementia. Exp Gerontol 35: 12391250.
Ferrari E, Cravello L, Muzzoni B, Casarotti D, Paltro M, Solerte
SB, Fioravanti M, Cuzzoni G, Pontiggia B, Magri F (2001).
Age-related changes of the hypothalamic-pituitary-adrenal
axis: pathophysiological correlates. Eur J Endocrinol 144:
319329.
Ferrera PC, Kass LE (1997). Third ventricle colloid cyst. Am
J Emerg Med 15: 145147.
Ferrier BM, Kennett DJ, Devlin MC (1980). Influence of
oxytocin on human memory processes. Life Sci 27:
23112317.
Ferrier IN, Cross AJ, Johnson JA, Roberts GW, Crow TJ,
Corsellis JAN, Lee YC, OShaugnessy D, Adrian TE,
McGregor GP, Baracese-Hamilton AJ, Bloom SR (1983).
Neuropeptides in Alzheimer type dementia. J Neurol Sci 62:
159170.
Ferrier N, Pascual J, Charlton BG, Wright C, Leake A, Griffiths

HW, Fairbairn AF, Edwardson JA (1988). Cortisol, ACTH,
and dexamethasone concentrations in a psychogeriatric population. Biol Psychiatry 23: 252260.
Fertl E, Auff E, Doppelbauer A, Waldhauser F (1991). Circadian
secretion pattern of melatonin in Parkinsons disease. J Neural
Transm 3: 4147.
Fry F, Plat L, Van de Borne P, Cogan E, Mockel J (1999).
Impaired counterregulation of glucose in a patient with hypothalamic sarcoidosis. New Engl J Med 340: 852856.
Fetell MR, Stein BM (1986). Neuroendocrine aspects of pineal
tumors. Neurol Clin 4: 877905.
Fetissov S, Marsais F, Nicoladis S, Calas A (1997). Expression
of tyrosine hydroxylase in magnocellular hypothalamic
neurons of obese (fa/fa). and lean heterozygous (Fa/fa).
Zucker rats. Mol Brain Res 50: 314318.
Fetissov SO, Hallman J, Oreland L, Af Klinteberg B, Grenbck
E, Hulting A-L, Hkfelt T (2002). Autoantibodies against MSH, ACTH, and LHRH in anorexia and bulimia nervosa
patients. Proc Natl Acad Sci USA 99: 1715517160.
Feuillan PP, Jones J, Ross JL (1995). Growth hormone hypersecretion in a girl with McCuneAlbright syndrome: comparison with controls and response to a dose of long-acting
somatostatin analog. J Clin Endocrinol Metab 80: 13571360.
Feuillan PP, Jones JV, Barnes K, Oerter-Klein K, Cutler GB
(1999). Reproductive axis after discontinuation of
gonadotropin-releasing hormone analog treatment of girls
with precocious puberty: long-term follow-up comparing girls
with hypothalamic hamartoma to those with idiopathic precocious puberty. J Clin Endocrinol Metab 84: 4449.
Feuillan PP, Jones JV, Barnes K, Oerter-Klein K, Cutler GB
(2000). Boys with precocious puberty due to hypothalamic
hamartoma: reproductive axis after discontinuation of
gonadotropin-releasing hormone analog therapy. J Clin
Feuillan P, Peters KF, Cutler GB, Biesecker LG (2001).
Evidence for decreased growth hormone in patients with
hypothalamic hamartoma due to PallisterHall syndrome. J
Pediatr Endocrinol Metab 14: 141149.
Fife MS, Fisher SA, John S, Worthington J, Shah CJ, Ollier
WER, Panayi GS, Lewis CM, Lanchbury JS (2000).
Multipoint linkage analysis of a candidate gene locus in
rheumatoid arthritis demonstrates significant evidence of
linkage and association with the corticotropin-releasing
hormone genomic region. Arthritis Rheum 43: 16731678.
Filkins JA, Cohle S, Levy BK, Graham M (1996). Unexpected
deaths due to colloid cysts of the third ventricle. J Forensic
Sci 41: 521523.
Finer NN, Craft A, Vaucher YE, Clark RH, Sola A (2000).
Postnatal steroids: short-term gain, long-term pain? J Pediatr
137: 913.
Finkelstein JW, Rusovic DE, Green E, Foreman S, Kulin HE,
DArcangelo MR, Kemezys R (2001). Children with organic
2014 Refs
2/12/03
1:39 pm
Page 447
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
447
Fluteau-Nadler S, Bremont C, Billaud L, Thomopoulos P, Luton

JP (1998). Diabte insipide avec anomalie morphologique
hypothalamo-hypophysaire au cours dune grossesse. Presse
Med 27: 10951098.
Flynn FG, Cummings JL, Tomiyasu U (1988). Altered behavior
associated with damage to the ventromedial hypothalamus: a
distinctive syndrome. Behav Neurol 1: 4958.
Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, Allen
S, Krause G (1999). Dehydroepiandrosterone replacement
in aging humans. J Clin Endocrinol Metab 84: 15271533.
Fodor M, Grcs TJ, Palkovits M (1992). Immunohistochemical study on the distribution of neuropeptides within the pontine
tegmentum particularly the parabrachial nuclei and the locus
coeruleus of the human brain. Neuroscience 46: 891908.
Fodor M, Van Leeuwen FW, Swaab DF (2002). Differences in
post mortem stability of sex steroid receptor immunoreactivity
in rat brain. J Histochem Cytochem 50: 641650.
Fogan L (1989). The neurology in Shakespeare. Arch Neurol
46: 922924.
Foltynie T, Sawcer S, Brayne C, Barker RA (2002). The genetic
basis of Parkinsons disease. J Neurol Neurosurg Psychiatry
73: 363370.
Fombonne E (1995). Anorexia nervosa: no evidence of an
increase. Br J Psychiatry 166: 462471.
Ford SM, Lumpkin HL (1986). Transient vasopressinresistant diabetes insipidus of pregnancy. Obstet Gynecol
68:726728.
Forest MG, Lecoq A, Salle B, Bertrand J (1981). Does neonatal
phenobarbital treatment affect testicular and adrenal functions
and steroid binding in plasma in infancy? J Clin Endocrinol
Metab 52: 103110.
Forest MG (1989). Physiological changes in circulating androgens. Pediatr Adolesc Endocrinol 19: 104129.
Forsling ML, Williams AJ (2002). The effect of exogenous
melatonin on stimulated neurohypophysial hormone release
in man. Clin Endocrinol 57: 615620.
Forsling ML, kerlund M, Strmberg P (1981). Variations in
plasma concentrations of vasopressin during the menstrual
cycle. J Endocrinol 89: 263266.
Forsling ML, Montgomery H, Halpin D, Windle RJ, Treacher
DF (1998). Daily patterns of secretion of neurohypophysial hormones in man: effect of age. Exp Physiol 83:
409418.
Forsling M, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Henry
JA (2001). Arginine vasopressin release in response to the
administration of 3,4-methylenedioxymethamphetamine
(ecstasy): is metabolism a contributory factor? J Pharm
Pharmacol 53: 13571363.
Frstl H, Burns A, Luthert P, Cairns N, Lantos P, Levy R
(1992). Clinical and neuropathological correlates of depression in Alzheimers disease. Psychol Med 22: 877884.
Fortuna A, Celli P, Ferrante L, Turano C (1979). A review of
papillomas of the third ventricle. J Neurosurg Sci 23: 6176.
growth hormone deficiency have elevated cortisol responses

to stimuli. J Clin Endocrinol Metab 86: 28542856.
Finlay GD, Whitsett TL, Cucinell EA, Goldberg LI (1971).
Augmentation of sodium and potassium excretion, glomerular
filtration rate and renal plasma flow by levodopa. N Engl J
Med 284: 865870.
Fischer P, Simanyi M, Danielczyk W (1990). Depression in
dementia of the Alzheimer type and in multi-infarct dementia.
Fiser DH, Jimenez JF, Wrape V, Woody R (1987). Diabetes
insipidus in children with brain death. Crit Care Med 15:
551553.
Flannery MT, Pattani S, Wallach PM, Warner E (1993). Case
report: hypothalamic tuberculoma associated with secondary
panhypopituitarism. Am J Med Sci 306: 101103.
Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora
A (2003). Head injury as a risk factor for Alzheimers disease:
the evidence 10 years on; a partial replication. J Neurol
Fletcher A, Van den Heuvel C, Dawson D (1999). Sleeping
with an electric blanket: effect on core temperature, sleep,
and melatonin in young adults. Sleep 22: 313318.
Fliers E, Swaab DF (1983). Activation of vasopressinergic and
oxytocinergic neurons during aging in the Wistar rat. Peptides
4: 165170.
Fliers E, Swaab DF, Pool CW, Verwer RWH (1985). The vasopressin and oxytocin neurons in the human supraoptic and
paraventricular nucleus: changes with aging and in senile
dementia. Brain Res 342: 4553.
Fliers E, Guldenaar SEF, Van de Wal N, Swaab DF (1986).
Extrahypothalamic vasopressin and oxytocin in the human
brain; presence of vasopressin cells in the bed nucleus of the
stria terminalis. Brain Res 375: 363367.
Fliers E, Noppen NWAM, Wiersinga WM, Visser TJ, Swaab
DF (1994). Distribution of thyrotropin-releasing hormone
(TRH)-containing cells and fibers in the human hypothalamus.
Fliers E, Guldenaar SEF, Wiersinga WM, Swaab DF (1997).
Decreased hypothalamic thyrotropin-releasing hormone
(TRH). gene expression in patients with nonthyroidal illness.
Fliers E, Unmehopa U, Manniesing S, Vuijst CL, Wiersinga
WM, Swaab DF (2001a). Decreased neuropeptide Y (NPY).
expression in the infundibular nucleus of patients with nonthyroidal illness. Peptides 22: 459465.
Fliers E, Alkemade A, Wiersinga WM (2001b). The hypothalamus-pituitary-thyroid axis in critical illness. Best Pract Res
Clin Endocrinol Metab 15: 453464.
Flck CE, Deladoy J, Nayak S, Zeller O, Kopp P, Mullis PE
(2001). Autosomal dominant neurohypophyseal diabetes
insipidus in a Swiss family, caused by a novel mutation
(C59/A60W). in the neurophysin moiety of preprovasopressinneurophysin II (AVP-NP II). Eur J Endocrinol 145: 439444.
447
2014 Refs
448
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 448
D.F. SWAAB
Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G,

Nemeroff CB (1996). Cerebrospinal fluid corticotropinreleasing factor concentrations in patients with anxiety
disorders and normal comparison subjects. Biol Psychiatry
39: 703707.
Foster NL, Wilhelmsen K, Sima AAF, Jones WZ, DAmato CJ,
Gilman S, Conference Participants (1997). Frontotemporal
dementia and Parkinsonism linked to chromosome 17: a
consensus conference. Ann Neurol 41: 706715.
Fountoulakis KN, Karamouzis M, Iacovides A, Nimatoudis J,
Diakogiannis J, Kaprinis G, Demitriadou A, Bech P (2001).
Morning and evening plasma melatonin and dexamethasone
suppression test in patients with nonseasonal major depressive disorder from Northern Greece (latitude 4041.5).
Fourtillan JB, Brisson AM, Fourtillan M, Ingrand I, Decourt
JP, Girault J (2001). Melatonin secretion occurs at a constant
rate in both young and older men and women. Am J Physiol
280: E11E22.
Fowler CJ, Van Kerrebroeck PhEV, Nordenbo A, Van Poppel,
H (1992). Treatment of lower urinary tract dysfunction in
patients with multiple sclerosis. J Neurol Neurosurg
Fox MW, Anderson RE, Meyer FB (1993). Neuroprotection by
corticotropinreleasing factor during hypoxia in rat brain.
Stroke 24: 10721076.
Fox RH, Davies TW, Marsh FP, Urich H (1970). Hypothermia
in a young man with an anterior hypothalamic lesion. Lancet
2 (7665): 185188.
France NE, Crome L, Abraham JM (1969). Pathological features
in the De Lange Syndrome. Acta Paediatr Scand 58:
470480.
Franceschi, M, Perego L, Ferini-Strambi L, Smirne S, Canal N
(1988). Neuroendocrinological function in Alzheimers
disease. Neuroendocrinology 48: 367370.
Franceschi M, Airhaghi L, Gramigna C, Truci G, Manfredi MG,
Canal N, Catania A (1991). ACTH and cortisol secretion
in patients with Alzheimers disease. J Neurol Neurosurg
Franceschini R, Tenconi GL, Zoppoli F, Barreca T (2001).
Endocrine abnormalities and outcome of ischaemic stroke.
Biomed Pharmacother 55: 458465.
Frank GK, Kaye WH, Altemus M, Greeno CG (2000). CSF
oxytocin and vasopressin levels after recovery from bulimia
nervosa and anorexia nervosa, bulimic subtype. Biol
Frank GK, Kaye WH, Sahu A, Fernstrom J, McConaha C
(2001). Could reduced cerebrospinal fluid (CSF). galanin
contribute to restricted eating in anorexia nervosa?
Neuropsychopharmacology 24: 706709.
Franks S, Gharani N, Waterworth D, Batty S, White D,
Williamson R, McCarthy M (1997). The genetic basis of
polycystic ovary syndrome. Hum Reprod 12: 26412648.
Franzini A, Ferroli P, Leone M, Broggi G (2003). Stimulation

of the posterior hypothalamus for treatment of chronic
intractable cluster headaches: first reported series. Neurosurgery 52: 10951101.
Fratiglioni L, Viitanen M, Von Strauss E, Tontodonati V, Herlitz
A, Winblad B (1997). Very old women at highest risk of
dementia and Alzheimers disease: incidence data from the
Kungsholmen Project Stockholm. Neurology 48: 132138.
Frattali CM, Liow K, Craig GH, Korenman LM, Makhlouf F,
Sato S, Biesecker LG, Theodore WH (2001). Cognitive
deficits in children with gelastic seizures and hypothalamic
hamartoma. Neurology 57: 4346.
Frayne J, Nicholson, HD (1998). Localization of oxytocin receptors in the human and macaque monkey male reproductive
tracts: evidence for a physiological role of oxytocin in the
male. Mol Hum Reprod 4: 527532.
Freda PU, Bilezikian JP (1999). The hypothalamus-pituitaryadrenal axis in HIV disease. AIDS Read 9: 4350.
Frederiksen SO, Ekman R, Gottfries C-G, Widerlv E, Jnsson
S (1991). Reduced concentrations of galanin, arginine vasopressin, neuropeptide Y and peptide YY in the temporal cortex
but not in the hypothalamus of brains from schizophrenics.
Acta Psychiatr Scand 83: 273277.
Freed CR, Greene PE, Breeze RE, Tsai W-Y, DuMouchel W,
Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ,
Eidelberg D, Fahn S (2001). Transplantation of embyronic
dopamine neurons for severe Parkinsons disease. N Engl J
Med 344: 710719.
Freeman JL, Harvey AS, Rosenfeld JV, Wrennall JA, Bailey
CA, Berkovic SF (2003). Generalized epilepsy in hypothalamic hamartoma. Neurology 60: 762767.
Freiesleben W, Sylemezoglu F, Lowe J, Janzer RC, Kleihues
P (1997). Wernickes encephalopathy with ballooned neurons
in the mamillary bodies: an immunohistochemical study.
Neuropathol Appl Neurobiol 23: 3642.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP
(1999). Repeated antenatal corticosteroids: size at birth
and subsequent development. Am J Obstet Gynecol 180:
114121.
Frequin STFM, Lamers KJB, Barkhof F, Borm GF, Hommes
OR (1994). Follow-up study of MS patients treated with highdose intravenous methylprednisolone. Acta Neurol Scand 90:
105110.
Freud S (1959). The Origins of Psychoanalysis: Letters to
Wilhelm Fleiss. Drafts and Notes: 18871902. New York:
Basic Books.
Frieboes R-M, Murck H, Stalla GK, Antonijevic IA, Steiger A
(1998). Enhanced slow wave sleep in patients with
prolactinoma. J Clin Endocrinol Metab 83: 27062710
Friedman DI, Johnson JK, Chorsky RL, Stopa EG (1991).
Labeling of human retinohypothalamic tract with the carbocyanine dye, DiI. Brain Res 560: 297302.
2014 Refs
2/12/03
1:39 pm
Page 449
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
449
Fujii H, Iida S, Moriwaki K (2000). Familial neurohypophyseal

diabetes insipidus associated with a novel mutation in
the vasopressin-neurophysin II gene. Int J Mol Med 5:
229234.
Fujioka T, Sakata Y, Yamaguchi K, Shibasaki T, Kato H,
Nakamura S (1999). The effects of prenatal stress on the
development of hypothalamic paraventricular neurons in fetal
rats. Neuroscience 92: 10791088.
Fujisawa I, Kikuchi L, Nishimura K, Togashi K, Itoh K, Noma
S, Minami S, Sagoh T, Hiraoka T, Momoi T, Mikawa H,
Nakano Y, Itoh H, Konishi J (1987a). Transection of the pituitary stalk: development of an ectopic posterior lobe assessed
with MR imaging. Radiology 165: 487489.
Fujisawa I, Nishimura K, Asato R, Togashi K, Itoh K, Noma S,
Kawamura Y, Sago T, Minami S, Nakano Y, Itoh H, Torizuka
K (1987b). Posterior lobe of the pituitary in diabetes insipidus:
MR findings. J Comput Assist Tomogr 11: 221225.
Fujisawa I, Asato R, Kawata M, Sano Y, Nakao K, Yamada
T, Imura H, Naito Y, Hoshino K, Noma S, Nakano Y, Konishi
J (1989). Hyperintense signal of the posterior pituitary on
T1-weighted MR images: an experimental study. J Comp
Assist Tomogr 13: 371377.
Fujisawa I, Asato R, Okumura R, Nakano Y, Shibata T,
Hamanake D, Hashimoto T, Konishi J (1991). Magnetic resonance imaging of neurohypophyseal germinomas. Cancer 68:
10091014.
Fujisawa I, Murakami N, Furuto-Kato S, Araki N, Konishi J
(1996). Plasma and neurohypophyseal content of vasopressin
in diabetes mellitus. J Clin Endocrinol Metab 81: 28052809.
Fujiwara I, Kondo Y, Iinuma K (1999). Oral-facial-digital
syndrome with hypothalamic hamartoma, postaxial ray
hypoplasia of the limbs, and vagino-cystic communication: a
new variant? Am J Med Genet 83: 7781.
Fujiwara T, Ota K, Kakudo N, Rikimaru S, Sugawara T, Yamada
K, Satoh T, Yano M, Tamate E, Miura M, Ikeda H, Kimura
T (2001). Idiopathic giant cell granulomatous hypophysitis
with hypopituitarism, right abducens nerve paresis and
masked diabetes insipidus. Intern Med 40: 915919.
Fujiyoshi K, Suga H, Okamoto K, Nakamura S, Kameyama M
(1987). Reduction of arginine-vasopressin in the cerebral
cortex in Alzheimer type senile dementia. J Neurol Neurosurg
Fukagawa A, Ishikawa S-E, Saito T, Kusaka I, Nakamura T,
Higashiyama M, Nagasaka S, Kusaka G, Masuzawa T, Saito
T (2001). Chronic hypernatremia derived from hypothalamic
dysfunction: impaired secretion of arginine vasopressin and
enhanced renal water handling. Endocr J 48: 233239.
Fukuda K, Ishihara K (1997). Development of human sleep and
wakefulness rhythm during the first six months of life: discontinuous changes at the 7th and 12th week after birth. Biol
Rhythm Res 28: 94103.
Fukuzako H, Kodama S (1998). Cavum septum pellucidum in
Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M,

Tsenter J, Babaey S, Ben Yehuda A, Grosswasser Z (1999).
Apolipoprotein E-4 genotype predicts a poor outcome in
survivors of traumatic brain injury. Neurology 52: 244248.
Friedman S, Even C, Dardennes R, Guelfi JD (2002). Light
therapy, obesity, and night-eating syndrome. Am J Psychiatry
159: 875876.
Friedman SM, Friedman CL (1963). Effect of posterior pituitary extracts on the life-span of old rats. Nature 200: 237238
Friedman TC, Yanovski JA, Nieman LK, Doppman JL, Cutler
GB, Oldfield EH, Gold PM, Chrousos GP, Kalogeras KT
(1996). Inferior petrosal sinus arginine vasopressin concentrations in normal volunteers and patients with Cushings
disease. J Clin Endocrinol Metab 81: 30683072.
Friedmann AS, Malott KA, Memoli VA, Pai SI, Yu X-M, North
WG (1994). Products of vasopressin gene expression in smallcell carcinoma of the lung. Br J Cancer 69: 260263.
Frisch A, Laufer N, Danziger Y, Michaelovsky E, Leor S, Carel
C, Stein D, Fenig S, Mimouni M, Apter A, Weizman A
(2001). Association of anorexia nervosa with the high activity
allele of the COMT gene: a family-based study in Israeli
patients. Mol Psychiatry 6: 243245.
Frisch C, Hasenhrl RU, Haas HL, Weiler HT, Steinbusch
HWM, Huston JP (1998). Facilitation of learning after lesions
of the tuberomammillary nucleus region in adult and aged
rats. Exp Brain Res 118: 447456.
Fritzsche M, Heller R, Hill H, Kick H (2001). Sleep deprivation
as a predictor of response to light therapy in major depression.
J Affect Disord 62: 207215.
Frohman EM, Frohman TC, Moreault AM (2002). Acquired
sexual paraphilia in patients with multiple sclerosis. Arch
Neurol 59: 10061010.
Frolkis VV, Golovchenko SF, Medved VI, Frolkis RA (1982).
Vasopressin and cardiovascular system in aging. Gerontology
28: 290302.
Frolkis VV, Kvitnitskaya-Ryzhova TY, Dubiley TA (1999).
Vasopressin, hypothalamo-neurohypophyseal system and
aging. Arch Gerontol Geriatr 29: 193214.
Fuchs A, Romero R, Keefe D, Parra M, Oyarzun E, Behnke E
(1991). Oxytocin secretion and human parturition: Pulse
frequency and duration increase during spontaneous labor in
women. Am J Obstet Gynecol 165: 15151523.
Fuchs A, Behrens O, Liu H (1992). Correlation of nocturnal
increase in plasma oxytocin with a decrease in plasma estradiol/progesterone ratio in late pregnancy. Am J Obstet
Gynecol 167: 15591563.
Fuchs E, Flgge G, Ohl F, Lucassen P, Vollmann-Honsdorf
GK, Michaelis T (2001). Psychosocial stress, glucocorticoids,
and structural alterations in the tree shrew hippocampus.
Fuchs F, Fuchs AR, Poblete VF, Risk A (1967). Effect of alcohol
on threatened premature labor. Am J Obstet Gynecol 99:
627637.
449
2014 Refs
450
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 450
D.F. SWAAB
Fulham MJ, Brunetti A, Aloj L, Raman R, Dwyer AJ, Di Chiro

G (1995). Decreased brain glucose metabolism in patients
with brain tumors: an effect of cortico-steroids. J Neurosurg
83: 657664.
Fuqua JS (2000). Wolfram syndrome: clinical and genetic
aspects. Endocrinologist 10: 5159.
Furlan R, Guzzetti S, Crivellaro W, Dassi S, Tinelli M, Baselli
G, Cerutti S, Lombardi F, Pagani M, Malliani A (1990).
Continuous 24-hour assessment of the neural regulation of
systemic arterial pressure and RR variabilities in ambulant
subjects. Circulation 81: 537547.
Furujo M, Ichiba Y (1998). Two cases of septo-optic dysplasia
(SOD). Endocr J (Suppl. 1) 45: S175-S177.
Fuse I, Higuchi W, Mito M, Aizawa Y (2003) DDAVP normalized the bleeding time in patients with congenital platelet
TxA2 receptor abnormality. Transfusion 43: 563567.
Futterweit W, Weiss RA, Fagerstrom RM (1986). Endocrine
evaluation of forty female-to-male transsexuals: increased
frequency of polycystic ovarian disease in female transsexualism. Arch Sex Behav 15: 6977.
Gaab J, Hster D, Peisen R, Engert V, Heitz V, Schad T,
Schrmeyer Ehlert, U (2002). Hypothalamic-pituitary-adrenal
axis reactivity in chronic fatigue syndrome and health under
psychological, physiological, and pharmacological stimulation. Psychosom Med 64: 951962.
Gabrels BAThF, Swaab DF, Seidah NG, Van Duijnhoven HLP,
Martens GJM, Van Leeuwen FW (1994). Differential expression of the neuroendocrine polypeptide 7B2 in hypothalami
of Prader (Labhart)Willi syndrome patients. Brain Res 657:
281293.
Gabrels B, Swaab D, De Kleijn D, Dean A, Seidah N,
Van de Loo J-W, Van de Ven W, Martens G, Van
Leeuwen F (1998a). The vasopressin precursor is not
processed in the hypothalamus of Wolfram syndrome
patients with diabetes insipidus: evidence for the
involvement of PC2 and 7B2. J Clin Endocrinol Metab
83: 40264033.
Gabrels B, Swaab D, De Kleijn D, Seidah N, Van de Loo, JW, Van de Ven W, Martens G, Van Leeuwen F (1998b).
Attenuation of the polypeptide 7B2 prohormone convertase
PC2 and vasopressin in the hypothalamus of some
PraderWilli patients: indications for a processing defect. J
Clin Endocrinol Metab 83: 591599
Gabrielsen A, Videbaek R, Johansen LB, Warberg J, Christensen
NJ, Pump B, Norsk P (2000a). Forearm vascular and neuroendocrine responses to graded water immersion in humans.
Acta Physiol Scand 169: 8794.
Gabrielsen A, Warberg J, Christensen NJ, Bie P, Stadeager C,
Pump B, Norsk P (2000b). Arterial pulse pressure and vasopressin release during graded water immersion in humans.
Am J Physiol 278: R1583-R1588.
Gadoth N, Dickerman Z, Bechar M, Laron Z, Lavie P (1987).
Episodic hormone secretion during sleep in Kleine-Levin
syndrome: evidence for hypothalamic dysfunction. Brain Dev

9: 309315.
Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P (2001).
Clinical and polysomnographic characteristics of 34 patients
with KleineLevin syndrome. J Sleep Res 10: 337341.
Gaffori O, Geffard M, Van Ree JM (1983). des-Tyr1--endorphin and haloperidol increase pineal gland melatonin levels
in rats. Peptides 4: 393395.
Gagel O (1941). Eine Granulationsgeschwulst im Gebiete des
Hypothalamus. Z Ges Neurol Psychiatry 172: 710722.
Gagnier JJ (2001). The therapeutic potential of melatonin in
migraines and other headache types. Altern Med Rev 4:
383389.
Gahr M (1997). How should brain nuclei be delineated?
Consequences for developmental mechanisms and for correlations of area size, neuron numbers and functions of brain
nuclei. Trends Neurosci 20: 5862.
Gai WP, Geffen LB, Blessing WW (1990). Galanin immunoreactive neurons in the human hypothalamus: colocalization
with vasopressin-containing neurons. J Comp Neurol 298:
265280.
Gajjar A, Bhargava R, Jenkins JJ, Heideman R, Sanford RA,
Langston JW, Walter AW, Kuttesch JF, Muhlbauer M, Kun
LE (1995). Low-grade astrocytoma with neuraxis dissemination at diagnosis. J Neurosurg 83: 6771.
Galard R, Cataln R, Castellanos JM, Gallart JM (2002). Plasma
corticotropin-releasing factor in depressed patients before and
after the dexamethasone suppression test. Biol Psychiatry 51:
463468.
Galasso C, Scir G, Fabbri F, Spadoni GL, Killoran CE,
Biesecker, LG, Boscherini, B (2001). Long-term treatment
with growth hormone improves final height in a patient with
PallisterHall syndrome. Am J Med Genet 99: 128131.
Galderisi S, Mucci A, Monteleone P, Sorrentino D, Piegari G,
Maj M (2003). Neurocognitive functioning in subjects with
eating disorders: the influence of neuroactive steroids. Biol
Gallerani M, Manfredini R, Cocurullo A, Goldoni C, Bigoni
M, Fersini C (1993). Chronobiological aspects of acute cerebrovascular diseases. Acta Neurol Scand 87: 482487.
Gallinelli A, Matteo ML, Volpe A, Facchinetti F (2000).
Autonomic and neuroendocrine responses to stress in patients
with functional hypothalamic secondary amenorrhea. Fertil
Steril 73: 812816.
Galluzzi P, Filosomi G, Vallone IM, Bardelli AM, Venturi C
(1999). MRI of Wolfram syndrome (DIDMOAD).
Neuroradiology 41: 729731.
Galynker II, Cai J, Ongseng F, Finestone H, Dutta E, Serseni
D (1998). Hypofrontality and negative symptoms in major
depressive disorder. J Nucl Med 39: 608612.
Gandolfo RE, Franceschini R, Cataldi A, Garibaldi A, Barreca
T (1992). Twenty-four-hour beta-endorphin secretory pattern
in Alzheimers disease. Neuropsychobiology 25: 188192.
2014 Refs
2/12/03
1:39 pm
Page 451
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
451
Gebarski SS (1993). Pituitary gland imaging: the last bottle of

iodinated contrast material. Radiology 189: 2930.
Geddes JR, Lawrie SM (1995). Obstetric complications and
schizophrenia: a meta analysis. Br J Psychiatry 167: 786793.
Geddes JF, Jansen GH, Robinson SFD, Gmri E, Holton JL,
Monson JP, Besser GM, Rvsz T (2000). Gangliocytomas
of the pituitary. Am J Surg Pathol 24: 607613.
Geenen R, Jacobs JWG, Bijlsma JWJ (2002). Evaluation and
management of endocrine dysfunction in fibromyalgia.
Rheum Dis Clin N Am 28: 389404.
Geerlings MI, Launer LJ, De Jong FH, Ruitenberg A, Stijnen
T, Van Swieten JC, Hofman A, Witteman JCM, Pols HAP,
Breteler MMB (2003). Endogenous estradiol and risk of
dementia in women and men: the Rotterdam study. Ann
Neurol 53: 607615.
Geffroy S, Evrard V, Taufour D, Vanderbecken S, De
Martinville B (1998). Further example of a patient with
PraderWilli and Klinefelter syndromes of different parental
origins. Am J Med Genet 80: 286287.
Gehlert DR, Heiman M (1997). Obesity: leptin neuropeptide
Y interactions in the control of body weight. Annual Reports
in Medicinal Chemistry, Vol. 32, Chap. 3. Academic Press,
Inc, pp. 2130.
Gehm BD, McAndrews JM, Chien P-Y, Jameson JL (1997).
Resveratrol, a polyphenolic compound found in grapes and
wine, is an agonist for the estrogen receptor. Proc Natl Acad
Sci USA 94: 1413814143.
Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD,
King DP, Takahashi JS, Weitz CJ (1998). Role of the Clock
protein in the mammalian circadian mechanism. Science, 280:
15641569.
Geller, DS, Farhi A, Pinkerton, N, Fradley, M, Moritz, M,
Spitzer A, Meinke, G, Tsai, FTF, Sigler, PB, Lifton, RP
(2000). Activating mineralocorticoid receptor mutation in
hypertension exacerbated by pregnancy. Science 289:
119123.
Genazzani AD, Petraglia, F, Gastaldi, M, Gamba, O, Corazza,
F, DAmbrogio, G, Genazzani AR (1996). Growth-hormone
(GH)-releasing hormone induced GH response in hypothalamic amenorrhea: evidence of altered central neuromodulation.
Fertil Steril 65: 935938.
Genazzani AD, Bersi, C, Luisi, S, Fruzzetti, F, Malavasi, B,
Luisi, M, Petraglia, F, Genazzani AR (2001). Increased
adrenal steroid secretion in response to CRF in women with
hypothalamic amenorrhea. J Steroid Biochem Mol Biol 78:
247252.
Gencik M, Dahmen N, Wieczorek S, Kasten M, Bierbrauer J,
Anghelescu I, Szegedi A, Saecker M, Epplen JT (2001). A
prepro-orexin gene polymorphism is associated with
narcolepsy. Neurology 56: 115117.
Gens D, Dvalos A, Molins A, Ferrer I (1997). Wolfram
syndrome: a neuropathological study. Acta Neuropathol 93:
426429.
Ganong WF (2000). Circumventricular organs: definition and

role in the regulation of endocrine and autonomic function.
Clin Exp Pharmacol Physiol 27: 422427.
Gao B, Moore RY (1996a). Glutamic acid decarboxylase
message isoforms in human suprachiasmatic nucleus. J Biol
Rhythms 11: 172179.
Gao B, Moore RY (1996b). The sexually dimorphic nucleus of
the hypothalamus contains GABA neurons in rat and man.
Brain Res 742: 163171.
Garcia H, Kaplan SL, Feigin RD (1981). Cerebrospinal fluid
concentration of arginine vasopressin in children with bacterial meningitis. J Pediatr 98: 6770.
Garcia-Velasco J, Mondragon M (1991). The incidence of the
vomeronasal organ in 1000 human subjects and its possible
clinical significance. J Steroid Biochem Mol Biol 39:
561564.
Garrels L, Kockott G, Michael N, Preuss W, Renter K, Schmidt
G, Sigusch V, Windgassen K (2000). Sex ratio of transsexuals
in Germany: the development over three decades. Acta
Psychiatr Scand 102: 445448.
Garty BZ, Dinari G, Gellvan A, Kauli R (1999). Cirrhosis in
a child with hypothalamic syndrome and central precocious
puberty treated with cyproterone acetate. Eur J Pediatr 158:
367370.
Garver DL (1988). Neuroendocrine findings in the schizophrenias. Endocrinol Metab Clin North Am 17: 103109.
Gasparini M, Spinnler H (1975). Fattening of Parkinsonians: a
hypothalamic side effect of L-dopa? Med J Austr 2 (Oct. 11):
617.
Gasser T (1998). Genetics of Parkinsons disease. Ann Neurol
44 (Suppl. 1): S53S57.
Gastel JA, Roseboom PH, Rinaldi PA, Weller JL, Klein DC
(1998). Melatonin production: proteasomal proteolysis in
serotonin N-acetyltransferase regulation. Science 279:
13581360.
Gatz M, Fiske A, Reynolds CA, Loebach Wetherell J, Johansson
B, Pedersen NL (2003). Sex differences in genetic risk for
dementia. Behav Gen 33: 95105.
Gau S-F, Soong W-T, Liu H-M, Hou J-W, Tsai W-Y, Chiu
Y-N, Yeh Y-C, Wang P-J, Wang T-R (1996). KleineLevin
syndrome in a boy with PraderWilli syndrome. Sleep 19:
1317.
Gaudino EA, Coyle PK, Krupp LB (1997) Post-Lyme syndrome
and chronic fatigue syndrome. Neuropsychiatric similarities
and differences. Arch Neurol 54: 13721376.
Gaus SE, Strecker RE, Tate BA, Parker RA, Saper CB (2002).
Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience
115: 285294.
Gautier J-F, Del Parigi A, Chen K, Salbe AD, Bandy D, Pratley
RE, Ravussin E, Reiman EM, Tataranni PA (2001). Effect
of satiation on brain activity in obese and lean women.
Obesity Res 9: 676684.
451
2014 Refs
452
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 452
D.F. SWAAB
Gentili A, Edinger JD (1999). Sleep disorders in older people.

Aging Clin Exp Res 11: 137141.
George DT, Umhau JC, Phillips MJ, Emmela D, Ragan PW,
Shoaf SE, Rawlings RR (2001). Serotonin, testosterone and
alcohol in the etiology of domestic violence. Psychiatry Res
104: 2737.
George MS, Ketter TA, Post RM (1993). SPECT and PET
imaging in mood disorders. J Clin Psychiatry (Suppl.) 54:
613.
George MS, Wassermann EM, Post RM (1996). Transcranial
magnetic stimulation; a neuropsychiatric tool for the 21st
century. J Neuropsychiatry Clin Neurosci 8: 373382.
George MS, Nahas Z, Molloy M, Speer AM, Oliver NC, Li XB Arana GW, Risch SC, Ballenger JC (2000). A controlled
trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry 48: 962970.
Geracioti TD, Loosen PT, Orth DN (1997). Low cerebrospinal
fluid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biol Psychiat 42: 165174.
Geriacioti TD, Orth DN, Ekhator NN, Blumenkopf B, Loosen
PT (1992). Serial cerebrospinal fluid corticotropin-releasing
hormone concentrations in healthy and depressed humans. J
Gerald C, Walker MW, Criscione L, Gustafson EL, BatzlHartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM,
Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer
KG, Taber RI, Branchek TA, Weinshank RL (1996). A
receptor subtype involved in neuropeptide-Y-induced food
intake. Nature 382: 168171.
Gerbitz K-D (1999). Reflexions on a newly discovered diabetogenic gene, wolframin (WFS1). Diabetologia 42: 627630.
Gerendai I, Halsz B (1997). Neuroendocrine asymmetry. Front
Gerendai I, Halsz B (2000). Central nervous system structures
connected with the endocrine glands. Findings obtained with
the viral transneuronal tracing technique. Exp Clin Endocrinol
Diabetes 108: 389395.
German DC, Bruce G, Hersh LB (1985). Immunohistochemical
staining of cholinergic neurons in the human brain using a
polyclonal antibody to human choline acetyltransferase.
Geula C, Bu J, Nagykery N, Scinto LFM, Chan J, Joseph J,
Parker R, Wu C-K (2003). Loss of calbindin-D28K from aging
human cholinergic basal forebrain: relation to neuronal loss.
Ghebremedhin E, Braak H, Braak E, Sahm J (1998a). Improved
method facilitates reliable APOE genotyping of genomic
DNA extracted from formaldehyde-fixed pathology specimens. J Neurosci Methods 79: 229231.
Ghebremedhin E, Schultz C, Botez G, Rb U, Sassin I, Braak
E, Braak H (1998b). Argyrophilic grain disease is associated
with apolipoprotein E2 allele. Acta Neuropathol 96:
222224.
Ghigo E, Arvat E, Gianotti L, Lanfranco F, Broglio F, Aimaretti

G, Maccario M, Camanni F (2000). Hypothalamic growth hormone-insulin-like growth factor-I axis across the human life
span. J Pediatr Endocrinol Metab (Suppl. 6) 13: 14931502.
Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk
NM (1994). Fetal plasma cortisol and -endorphin response
to intrauterine needling. Lancet 344: 7781.
Gibb WRG (1986). Idiopathic Parkinsons disease and the Lewy
body disorders. Neuropathol Appl Neurobiol 12: 223234.
Gibb WRG (1988). Neuroleptic malignant syndrome in striatonigral degeneration. Br J Psychiatry 153: 254255.
Giesler GJ, Katter JT, Dado RJ (1994). Direct spinal pathways
to the limbic system for nociceptive information. Trends
Gilbert JD, Scott G, Byard RW (2001). Septo-optic dysplasia
and unexpected adult death. An autopsy approach. J Forensic
Sci 46: 913915.
Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko
NB, Orr SP, Pitman RK (2002). Smaller hippocampal volume
predicts pathologic vulnerability to psychological trauma. Nat
Neurosci 5: 12421247.
Giles DE, Berga SL (1993). Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled
comparison. Fertil Steril 60: 486492.
Gillam MP, Kopp P (2001). Genetic defects in thyroid hormone
synthesis. Curr Opin Pediatr 13: 364372.
Gillberg C, Coleman M (1992). The biology of the autistic
syndromes, 2nd edn. Clinics in Developmental Medicine, 126.
London, MacKeith Press.
Gillessen-Kaesbach G, Demuth S, Thiele H, Theile U, Lich C,
Horsthemke B (1999). A previously unrecognised phenotype
characterised by obesity, muscular hypotonia, and ability to
speak in patients with Angelman syndrome caused by an
imprinting defect. Eur J Hum Genet 7: 638644.
Gillies GE, Lowry PJ (1979). Corticotropin releasing factor may
be modulated by vasopressin. Nature 278: 463464.
Gillies GE, Linton EA, Lowry PJ (1982). Corticotropin releasing
activity of the new CRF is potentiated several times by vasopressin. Nature 299: 355357.
Gilligan BS (1973). Periodic megaphagia and hypersomnia. An
example of the Kleine-Levin syndrome in an adolescent girl.
Proc Austral Assoc Neurol 9: 6772.
Gilmor ML, Erickson JD, Varoqui H, Hersh LB, Bennett DA,
Cochran EJ, Mufson EJ, Levey AI (1999). Preservation of
nucleus basalis neurons containing choline acetyltransferase
and the vesicular acetylcholine transporter in the elderly with
mild cognitive impairment and early Alzheimers disease. J
Gindoff PR, Ferin M (1987). Brain opioid peptides and
menstrual cyclicity. Semin Reprod Endocrinol 5(2): 125133.
Gingell K, Parmar R, Sungum-Paliwal S (1996). Autism and
multiple pituitary deficiency. Dev Med Child Neurol 38:
545549.
2014 Refs
2/12/03
1:39 pm
Page 453
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
453
Go T (1999). ACTH treatment for gelastic seizures. Arch Dis

Child 81: 278285.
Goadsby PJ (2002). Pathophysiology of cluster headache: a
trigeminal autonomic cephalgia. Lancet Neurol 1: 251257.
Goadsby PJ, Bahra A, May A (1999). Mechanisms of cluster
headache. Cephalalgia 19 (Suppl. 23): 1923.
Goekoop JG, Knoppert-Van der Klein EAM (1990). Recente
ontwikkelingen met betrekking tot het neuroleptisch maligne
syndroom. Ned Tijdschr Geneesk 134: 370374.
Goh VHH, Lee KO (1998). Does a positive oestrogen feedback
on the hypothalamic-pituitary axis exist concurrently with a
defective testosterone feedback in Klinefelters syndrome.
Horm Res 50: 160165.
Gkalp HZ, Yceer N, Arasil E, Erdogan A, Dincer C, Baskaya
M (1996). Colloid cyst of the third ventricle. Acta Neurochir
138: 4549.
Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI,
Tropper PJ (1993). Elevated levels of umbilical cord plasma
corticotropin-releasing hormone in growth-retarded fetuses. J
Gold MS, Pottash ALC, Extein I (1981). Hypothyroidism and
depression: evidence from complete thyroid function evaluation. JAMA 245: 19191922.
Gold PW, Chrousos GP (1999). The endocrinology of melancholic and atypical depression: relation to neurocircuitry and
somatic consequences. Proc Assoc Am Phys 111: 2234.
Gold PW, Chrousos GP (2002). Organization of the stress
system and its dysregulation in melancholic and atypical
depression: high vs. low CRH/NE states. Mol Psychiatry 7:
254275
Gold PW, Kaye W, Robertson GL, Ebert M (1983).
Abnormalities in plasma and cerebrospinal-fluid arginine
vasopressin in patients with anorexia nervosa. N Engl J Med
308: 11171123.
Gold PW, Gwirtsman H, Avgerinos PC, Nieman LK, Gallucci
WT, Kaye W, Jimerson D, Ebert M, Rittmaster R, Loriaux
DL, Chrousos GP (1986). Abnormal hypothalamic-pituitaryadrenal function in anorexia nervosa. New Engl J Med 314:
13351342.
Gold PW, Licinio J, Wong ML, Chrousos GP (1995). Corticotropin releasing hormone in the pathophysiology of melancholic and atypical depression and in the mechanism of action
of antidepressant drugs. Ann NY Acad Sci 771: 716729.
Gold PW, Drevets WC, Charney DS (2002). New insights into
the role of cortisol and the glucocorticoid receptor in severe
depression. Biol Psychiatry 52: 381385.
Gold RM (1973). Hypothalamic obesity: the myth of the ventromedial nucleus. Science 182: 488490.
Goldberg AE, Newlin DB (2000). Season of birth and substance
abuse: findings from a large national sample. Alcohol Clin
Exp Res 24: 774780.
Golden JA (1998). Holoprosencephaly: a defect in brain
patterning. J Neuropathol Exp Neurol 57: 991999.
Gioia L, Vogt LJ, Freeman WM, Flood A, Vogt BA, Vrana

KE (1998). PCR-based apolipoprotein E genotype analysis
from archival fixed brain. J Neurosci Methods 80: 209214.
Gionis D, Iliasm I, Moustaki M, Mantzos E, Papadatos I,
Koutras DA, Mastorakos G (2003). Hypothalamic-pituitaryadrenal axis and interleukin6 activity in children with head
trauma and syndrome of inappropriate secretion of antidiuretic hormone. J Pediatr Endocrinol Metab 16: 4954.
Giovenardi M, Padoin MJ, Cadore LP, Lucion AB (1998).
Hypothalamic paraventricular nucleus modulates maternal
aggression in rats: effects of ibotenic acid lesion and oxytocin
antisense. Physiol Behav 63: 351359.
Giraudo SQ, Billington CJ, Levine AS (1998). Feeding effects
of hypothalamic injection of melanocortin 4 receptor ligands.
Brain Res 809: 302306.
Gispen-De Wied CC (2000). Stress in schizophrenia: an integrative view. Eur J Pharmacol 405: 375384.
Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S,
Chiurazzi P, Cordaro S, Corona G, Trimarchi G, Barberi I
(2001). Effects of melatonin treatment in septic newborns.
Pediatr Res 50: 756760.
Giuliano F, Rampin O, Brown K, Courtois F, Benoit G, Jardin
A (1996): Stimulation of the medial preoptic area of the hypothalamus in the rat elicits increases in intracavernous pressure.
Giubilei F, Patacchioli FR, Antonini G, Sepe Monti M, Tisei
P, Bastianello S, Monnazzi P, Angelucci L (2001). Altered
circadian cortisol secretion in Alzheimers disease: clinical
and neuroradiological aspects. J Neurosci Res 66: 262265.
Gizewski ER, Forsting M (2001). Histiocytosis mimicking a
pineal gland tumour. Neuroradiol 43: 644646.
Gjerris A, Rafaelsen OJ, Vendsborg P, Fahrenkrug J, Rehfeld
JF (1984). Vasoactive intestinal polypeptide decreased in
cerebrospinal fluid (CSF). in atypical depression. J Affect
Disord 7: 325337.
Gjerris AG, Hammer M, Vendsborg P, Christensen NJ,
Rafaelsen OJ (1985). Cerebrospinal fluid vasopressin
changes in depression. Br J Psychiatry 147: 696701.
Gladue BA, Green R, Helleman RE (1984). Neuroendocrine
response to estrogen and sexual orientation. Science 225:
14961499.
Glass M, Dragunow M, Faull RLM (1997). Cannabinoid receptors in the human brain: a detailed anatomical and quantitative
autoradiographic study in the fetal, neonatal and adult human
brain. Neuroscience 77: 299318.
Gleckman AM, Patalas ED, Joseph JT (2002). Sudden unexpected death resulting from hypothalamic sarcoidosis. Am J
Forensic Med Pathol 23: 4851.
Glovinsky D, Kalogeras KT, Kirch DG, Suddath R, Wyatt RJ
(1994). Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and
is not changed by neuroleptic medication. Schizophr Res 11:
273276.
453
2014 Refs
454
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 454
D.F. SWAAB
Golden NH, Ashtari M, Kohn MR, Patel M, Jacobson MS,

Fletcher A, Shenker IR (1996). Reversibility of cerebral
ventricular enlargement in anorexia nervosa, demonstrated by
quantitative magnetic resonance imaging. J Pediatr 128:
296301.
Golden WL, Sudduth KW, Burnett SH, Kelly TH (1999).
Mosaicism in PraderWilli syndrome: detection using fluorescent in situ hybridization. Am J Med Gen 85: 424425.
Goldman MB (1999). Syndrome of inappropriate antidiuretic
hormone. Biol Psychiat 45: 515.
Goldman MB, Luchins DJ, Robertson GL (1988). Mechanisms
of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 318: 397403.
Goldman MB, Robertson GL, Luchins DJ, Hedeker D, Pandey
GN (1997). Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia
and polydipsia. Arch Gen Psychiatry 54: 443449
Goldsmith SR (1987). Vasopressin as vasopressor. Am J Med
82: 12131219.
Goldsmith SR (1989). The effect of moderate hypotension on
vasopressin levels in normal humans. Am J Med Sci 298:
295298.
Goldstein CS, Braunstein S, Goldfarb S (1983). Idiopathic
syndrome of inappropriate antidiuretic hormone secretion
possibly related to advanced age. Ann Intern Med 99:
185188.
Goldstein JL, Fialkow PJ (1973). The Alstrm syndrome.
Medicine 52: 5371.
Goldstein JM, Seidman LJ, OBrien LM, Horton NJ, Kennedy
DN, Makris N, Caviness VS, Faraone SV, Tsuang MT (2002).
Impact of normal sexual dimorphisms on sex differences in
structural brain abnormalities in schizophrenia assessed by
magnetic resonance imaging. Arch Gen Psychiatry 59:
154164
Goldstein M (1974). Brain research and violent behavior. Arch
Neurol 30: 2635.
Goldstone AP, Unmehopa UA, Bloom SR, Swaab DF (2002).
Hypothalamic neuropeptide Y and agouti-related protein are
increased in human illness but not in PraderWilli syndrome
and other obese subjects. J Clin Endocrinol Metab 87:
927937.
Goldstone AP, Unmehopa U, Swaab DF (2003). Hypothalamic
growth hormone-releasing hormone (GHRH). cell number in
human illness, PraderWilli syndrome and obesity. Clin
Golombok S, Spencer A, Rutter M (1983). Children in lesbian
and single-parent households: psychosexual and psychiatric
appraisal. J Child Psychol Psychiatry 4: 551572.
Gomez F, Chapleur M, Fernette B, Burlet C, Nicolas J-P, Burlet
A (1997). Arginine vasopressin (AVP) depletion in neurons
of the suprachiasmatic nuclei affects the AVP content of the
paraventricular neurons and stimulates adrenocorticotrophic
hormone release. J Neurosci Res 50: 565574.
Gmez-Alonso J (1998). Rabies. A possible explanation for the

vampire legend. Neurology 51: 856859.
Gomez-Daspet J, Elko L, Grebenev D, Vesely DL (2002).
Survival with serum sodium level of 180 mEq/l: permanent
disorientation to place and time. Am J Med Sci 324: 321325.
Gonatas NK, Gonatas JO, Stieber A (1998). The involvement
of the Golgi apparatus in the pathogenesis of amyotrophic
lateral sclerosis, Alzheimers disease, and ricin intoxication.
Histochem Cell Biol 109: 591600.
Goncharuk VD, Van Heerikhuize JJ, Dai JP, Swaab DF, Buijs
RM (2001). Neuropeptide changes in the suprachiasmatic
nucleus in primary hypertension indicate functional impairment of the biological clock. J Comp Neurol 431: 320330.
Goncharuk VD, Van Heerikhuize JJ, Swaab DF, Buijs RM
(2002). Paraventricular nucleus of the human hypothalamus
in primary hypertension: activation of corticotropin-releasing
hormone neurons. J Comp Neurol 443: 321331.
Gonzales-Portillo G, Tomita T (1998). The syndrome of inappropriate secretion of antidiuretic hormone: an unusual
presentation for childhood craniopharyngioma: report of three
cases. Neurosurgery 42: 917922.
Goodfellow CF, Hull MGR, Swaab DF, Dogterom J, Buijs RM
(1983). Oxytocin deficiency at delivery with epidural analgesia. Br J Obstet Gynaecol 90: 214219.
Goodin DS, Ebers GC, Johnson KP, Rodriguez M, Sibley WA,
Wolinsky JS (1999). The relationship of MS to physical
trauma and psychological stress. Neurology 52: 17371745.
Goodwin GM, Shapiro CM, Dick H, Carroll S, Fink G (1989).
The neuroendocrine responses and psychological effects of
infusion of L-tryptophan in anorexia nervosa. Psychol Med
19: 857864.
Goodyer I, Herbert J, Moor S, Altham P (1991). Cortisol hypersecretion in depressed school-aged children and adolescents.
Goodyer IM, Herbert J, Altham PME, Pearson J, Secher SM,
Shiers HM (1996). Adrenal secretion during major depression in 8- to 16-year-olds. I. Altered diurnal rhythms in
salivary cortisol and dehydroepiandrosterone (DHEA). at
presentation. Psychol Med 26: 245256.
Goodyer IM, Herbert J, Altham PME (1998). Adrenal steroid
secretion and major depression in 8- to 16-year-olds, III.
Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major
depression. Psychol Med 28: 265273.
Goodyer IM, Herbert J, Tamplin A, Altham PME (2000). Recent
life events, cortisol, dehydroepiandrosterone and the onset of
major depression in high-risk adolescents. Br J Psychiatry
177: 499504.
Gooley JJ, Lu J, Chou TC, Scammell TE, Saper CB (2001).
Melanopsin in cells of origin of the retinohypothalamic tract.
Nat Neurosci 4: 1165.
Gooren LJG, Fliers E, Courtney K (1990). Biological determinants of sexual orientation. Ann Rev Sex Res 1: 175196.
2014 Refs
2/12/03
1:39 pm
Page 455
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
455
dementia disorders of Alzheimer type (AD/SDAT). Neurobiol

Aging 4: 261271.
Gottfries CG, Frederiksen SO, Heilig M (1995). Neuropeptides
and Alzheimers disease. Eur Neuropsychopharmacol 5:
491500.
Gottschalk S, Tavakolian R, Buske A, Tinschert S, Lehmann
R (1999). Spontaneous remission of chiasmatic/hypothalamic
masses in neurofibromatosis type 1: report of two cases.
Neuroradiology 41: 199201.
Goudsmit E, Fliers E, Swaab DF (1988). Vasopressin and
oxytocin excretion in the brown Norway rat in relation to
aging, water metabolism and testosterone. Mech Ageing Dev
44: 241252.
Goudsmit E, Hofman MA, Fliers E, Swaab DF (1990). The
supraoptic and paraventricular nuclei of the human hypothalamus in relation to sex, age and Alzheimers disease.
Neurobiol Aging, 11, 529536.
Goudsmit E, Neijmeijer-Leloux A, Swaab DF (1992). The
human hypothalamo-neurohypophyseal system in relation to
development, aging and Alzheimers disease. In: Swaab, DF,
Hofman, MA, Mirmiran, M, Ravid, R and Van Leeuwen, FW
(eds) The Human Hypothalamus in Health and Disease
(Progress in Brain Research, vol. 93, pp. 237248). Elsevier,
Amsterdam.
Gould EL, Loesch DZ, Martin MJ, Jenssen Hagerman R,
Armstrong SM, Huggins RM (2000). Melatonin profiles and
sleep characteristics in boys with fragile X syndrome: a
preliminary study. Am J Med Genet 95: 307315.
Gouras GK, Rance NE, Young III WS, Koliatsos VE (1992).
Tyrosine-hydroxylase-containing neurons in the primate basal
forebrain magnocellular complex. Brain Res 584: 287293.
Grabenbauer GG, Schuchardt U, Buchfelder M, Rdel CM,
Gusek G, Marx M, Doerr HG, Fahlbusch R, Huk WJ, Wenzel
D, Sauer R (2000). Radiation therapy of optico-hypothalamic
gliomas (OHG) radiographic response, vision and late toxicity. Radiother Oncol 54: 239245.
Graeber MB, Bise K, Mehraein P (1994). CR3/43, a marker for
activated human microglia: application to diagnostic
neuropathology. Neuropathol Appl Neurobiol 20: 406408.
Graeber MB, Ksel S, Egensperger R, Schnopp NM, Bise K,
Mehraein P (1995). Strategies for using archival brain tissue
in neurogenetic research. J Neuropathol Exp Neurol (Suppl)
27S28S.
Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor
E (2002). Effect of postmenopausal hormone therapy on
cognitive function: the heart and estrogen/progestin replacement study. Am J Med 113: 543548.
Graf A, Wallner C, Schubert V, Willeit M, Wik W, Fischer P,
Kasper S, Neumeister A (2001). The effects of light therapy
on mini-mental state examination scores in demented patients.
Biol Psychiatry 50: 725727
Graham E, James DG (1988). Neurosarcoidosis. Sarcoidosis 5:
125131.
Gordo MA, Recio J, Snchez-Barcel J (2001). Decreased sleep

quality in patients suffering from retinitis pigmentosa. J Sleep
Res 10: 159164.
Gordon N (1992). The more unusual sleep disturbances of childhood. Brain Dev 14: 182184.
Gordon N (2000). The therapeutics of melatonin: a paediatric
perspective. Brain Dev 22: 213217.
Gordijn MCM, Beersma DGM, Korte HJ, Van den Hoofdakker
RH (1998). Testing the hypothesis of a circadian phase disturbance underlying depressive mood in nonseasonal depression.
J Biol Rhythm 13: 132147.
Gorman DG, Cummings JL (1992). Hypersexuality following
septal injury. Arch Neurol 49: 308310.
Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000).
Neuroanatomical hypothesis of panic disorder, revised. Am
Gorski RA (2002). Hypothalamic imprinting by gonadal steroid
hormones. In: Zderic SA et al. (eds) Pediatric Gender
Assignment: A critical reappraisal. Kluwer Academic/Plenum
Publishers, pp. 5773.
Gorski RA, Gordon JH, Shryne JE, Southam AM (1978).
Evidence for a morphological sex difference within the medial
preoptic area of the rat brain. Brain Res 148: 333346.
Gorwood P, Ads J, Bellodi L, Cellini E, Collier DA, Di Bella
D, Di Bernardo M, Estivill X, Fernandez-Aranda F, Gratacos
M, Hebebrand J, Hinney A, Hu X, Karwautz A, Kipman A,
Mouren-Simoni M-C, Nacmias B, Ribass M, Remschmidt
H, Ricca V, Rotella CM, Sorbi S, Treasure J (2002). The 5HT2A1438G/A polymorphism in anorexia nervosa: a
combined analysis of 316 trios from six European centres.
Mol Psychiatry 7: 9094.
Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL,
Strosberg AD, McKeigue PM, Scott J, Aitman TJ (1997).
Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 6:
869876.
Gotoh M, Nakano J, Midorikawa S, Nimura S, Ono Y, Mizuno
K (2002). Multiple endocrine disorders and Rathkes cleft
cyst with Klinefelters syndrome: a case report. Endocr J 49:
523529.
Gotter AL, Reppert SM (2001). Analysis of human Per4. Brain
Res Mol 92: 1926.
Gottfries CG, Roos BE, Winblad B (1974). Determination of
5-hydroxytryptamine, 5-hydroxyindoleacetic acid and
homovanillic acid in brain tissue from an autopsy material.
Acta Psychiat Scand 50: 496507.
Gottfries CG, Adolfsson R, Winblad B (1980). Transmitter of
biochemistry of human brain tissue. In: Riederer P, Usdin E
(eds) Proceedings of the Symposium Held at the 12th CINP
Congress, Gteborg, Sweden, pp. 4754.
Gottfries CG, Adolfson R, Aquilonius S-M, Carlsson A,
Eckerns S-, Nordberg A, Oreland L, Svennerholm L,
Wiberg , Winblad B (1983). Biochemical changes in
455
2014 Refs
456
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 456
D.F. SWAAB
Gramm H-J, Meinhold H, Bickel U, Zimmermann J, Von

Hammerstein B, Keller F, Dennhardt R, Voigt K (1992).
Acute endocrine failure after brain death. Transplantation 54:
851857.
Grammatopoulos DK, Chrousos GP (2002). Functional characteristics of CRH receptors and potential clinical applications
of CRH-receptor antagonists. Trends Endocrinol Metab 13:
436444.
Grand S, Hoffmann D, Bost F, Francois-Joubert A, Pasquier B,
Le Bas JF (1996). Case report: pseudotumoral brain lesion as
the presenting feature of sarcoidosis. Br J Radiol 69: 272275.
Granerus A-K, Jagenburg R, Svanborg A (1977). Kaliuretic
effect of L-dopa treatment in Parkinsonian patients. Acta Med
Scand 201: 291297.
Grant FD, Ahmadi A, Hosley CM, Majzoub JA (1998).
Two novel mutations of the vasopressin gene associated
with familial diabetes insipidus and identification of an
asymptomatic carrier infant. J Clin Endocrinol Metab 83:
39583964.
Grasser A, Mller A, Backmund H, Yassouridis A, Holsboer F
(1996). Heterogeneity of hypothalamic-pituitary-adrenal
system response to a combined dexamethasone-CRH test in
multiple sclerosis. Exp Clin Endocrinol Diabetes 104: 3137.
Grassi G (1998). Role of the sympathetic nervous system in
human hypertension. J Hypertens 16: 19791987.
Gratacs M, Nadal M, Martn-Santos R, Pujana MA, Gago J,
Peral B, Armengol L, Ponsa I, Mir R, Bulbena A, Estivill
X (2001). A polymorphic genomic duplication on human
chromosome 15 is a susceptibility factor for panic and phobic
disorders. Cell 106: 367379.
Gravestock S (2000). Eating disorders in adults with intellectual disability. J Intellect Disabil Res 44: 625637.
Gravett MG, Hitti J, Hess DL, Eschenbach DA (2000).
Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. Am J
Obstet Gynecol 182: 14041413.
Gray JB, Martinovic AM (1994). Eicosanoids and essential fatty
acid modulation in chronic disease and the chronic fatigue
syndrome. Med Hypotheses 43: 3142
Greco A, Tannock C, Brostoff J, Costa DC (1997). Brain MR
in chronic fatigue syndrome. Am J Neuroradiol 18:
12651269.
Green JD (1946). The histology of the hypophysial stalk and
median eminence in man with special reference to blood
vessels, nerve fibers and a peculiar neurovascular zone in this
region. Anat Rec 100: 273295.
Green H (1995). Borderline personality disorder: history, theory,
and nursing intervention. J Psychiatr Nursing 33: 2630.
Green R (1978). Sexual identity of 37 children raised by
homosexual or transsexual parents. Am J Psychiatry 135:
692697.
Green R (2000). Family cooccurrence of gender dysphoria:
ten sibling or parent-child pairs. Arch Sex Behav 29: 499507.
Green JD, Harris GW (1947). The neurovascular link between

the neurohypophysis and the adenohypophysis. J Endocrinol
5: 136146.
Green JD, Harris GW (1949). Observations of the hypophysioportal vessles of the living rat. J Physiol 108: 359361.
Green JR, Buchan GC, Alvord EC, Swanson AG (1967).
Hereditary and idiopathic types of diabetes insipidus. Brain
90: 707714.
Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris
M (2001). Oxytocin and autistic disorder: alterations in
peptide forms. Biol Psychiatry 50: 609613.
Green R, Keverne EB (2000). The disparate maternal aunt-uncle
ratio in male-transsexuals: an explanation invoking genomic
imprinting. J Theor Biol 202: 5563.
Green R, Young R (2001). Hand preference, sexual preference,
and transsexualism. Arch Sex Behav 30: 565574.
Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick
D, Duara R, Kukull WA, Chui H, Edeki T, Griffith PA,
Friedland RP, Bachman D, Farrer L (2003). Depression as a
risk factor for Alzheimers disease. Arch Neurol 60: 753759.
Greenes D, Woods M (1996). Case report: a 4-month-old boy
with severe emaciation, normal linear growth, and a happy
affect. Curr Opin Pediatr 8: 5057.
Greenspan SL, Rowe JW, Maitland LA, McAloon-Dyke M,
Elahi D (1993). The pituitary-adrenal glucocorticoid
response is altered by gender and disease. J Gerontol 48:
M72-M77.
Gregg TR, Siegel, A (2001). Brain structures and neurotransmitters regulating aggression in cats: implications for human
aggression. Prog Neuropsychopharmacol Biol Psychiat 25:
91140.
Grice DE, Halmi KA, Fichter MM, Strober M, Woodside DB,
Treasure JT, Kaplan AS, Magistretti PJ, Goldman D, Bulik
CM, Kaye WH, Berrettini WH (2002). Evidence for a susceptibility gene for anorexia nervosa on chromosome 1. Am J
Hum Genet 70: 787792.
Griep EN, Boersma JW, De Kloet ER (1993). Altered reactivity
of the hypothalamic-pituitary-adrenal axis in the primary
fibromyalgia syndrome. J Rheumatol 20: 469474.
Griep EN, Boersma JW, Lentjes EGWM, Prins PA, Van der
Korst JK, De Kloet ER (1998). Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and
low back pain. J Rheumatol 25: 13741381.
Griepentrog T, Bauer M, Hornstein C, Sauer H, Jirikowski GF
(2000). Coexistence of intestinal trefoil factor (hITF) and
oxytocin in magnocellular neurons in the human hypothalamus. Horm Metab Res 32: 121124.
Griffin WST, Mrak RE (2002). Interleukin1 in the genesis
and progression of and risk for development of neuronal
degeneration in Alzheimers disease. J Leukocyte Biol 72:
233238.
Griffioen HA, Duindam H, Van der Woude TP, Rietveld WJ,
Boer GJ (1993). Functional development of fetal suprachi-
2014 Refs
2/12/03
1:39 pm
Page 457
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
457
Grosso S, Cioni M, Buoni S, Peruzzi L, Pucci L, Berardi R

(1998). Growth hormone secretion in PraderWilli syndrome.
J Endocrinol Invest 21: 418422.
Grosso S, Anichini C, Berardi R, Balestri P, Pucci L, Morgese
G (2000). Central precocious puberty and abnormal chromosomal patterns. Endocr Pathol 11: 6975.
Grosso S, Berardi R, Farnetani MA, Margollicci M, Mancini
MG,Morgese G, Balestri P (2001). Multiple neuroendocrine
disorder in salla disease. J Child Neurol 16: 775777.
Grumbach MM (2002). The neuroendocrinology of human
puberty revisited. Horm Res (Suppl. 2) 57: 214.
Grumbach Y, Audebert M, Remond A, Braibant JM, Risbourg
B, Piussan Ch (1977). La sclrose tubreuse de Bourneville.
Med Infant 84: 271284.
Grundy PL, Harbuz MS, Jessop DS, Lightman SL, Sharples
PM (2001). The hypothalamo-pituitary-adrenal axis response
to experimental traumatic brain injury. J Neurotrauma 18:
13731381.
Grnthal E (1950). In: Hess WR (Ed.). Symposion ber das
Zwischenhirn. Helv Physiol Pharm Acta, Suppl VI: 180.
Gu GB, Simerly RB (1997). Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat.
Gu H, Wang S, Messam CA, Yao Z (2002). Distribution of
nestin immunoreactivity in the normal adult human forebrain.
Brain Res 943: 174180.
Gu J, Huang WM, Polak JM (1985). Stability of immunocytochemical reactivity of neuronal substances following delayed
fixation. J Neurosci Methods 12: 297302.
Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J, Chin
W, Maruti S, Deng N, Fisher SL, Franco LS, Burn P, Yagaloff
KA, Nathan J, Heymsfield S, Albu J, Pi-Sunyer FX, Allison
DB (1999). Identification and functional analysis of novel
human melanocortin4 receptor variants. Diabetes 48:
635639.
Gu W-X, Colquhoum-Kerr JS, Kopp P, Bode HH, Jameson JL
(1998). A novel aminoterminal mutation in the KAL1 gene
in a large pedigree with X-linked Kallman syndrome. Mol
Genet Metab 65: 5961.
Guagnano MT, Del Ponte A, Manigrasso MR, Merlitti D, PacePalitti V, Sensi S (2001). Age-related circadian rhythm of
DHEAS plasma levels in male subjects. Biol Rhythm Res
32: 323331.
Guazzo EP, Kirkpatrick PJ, Goodyer IM, Shiers HM, Herbert
J (1996). Cortisol, dehydroepiandrosterone (DHEA), and
DHEA sulfate in the cerebrospinal fluid of man: relation to
blood levels and the effects of age. J Clin Endocrinol Metab
81: 39513960.
Guibaud L, Rode V, Saint-Pierre G, Pracros J-P, Foray P, TranMinh VA (1995). Giant hypothalamic hamartoma: an unusual
neonatal tumor. Pediatr Radiol 25: 1718.
Guihard J, Velot-Lerou A, Poitrat C, Laloum D, lHirondel J
(1971). Hypothermie spontane rcidivante avec agnsie du
asmatic nucleus grafts in suprachiasmatic nucleus-lesioned

rats. Brain Res Bull 31: 145160.
Griffiths PA, Folkard S, Bojkowski C, English J, Arendt J
(1986). Persistent 24-h variations of urinary 6-hydroxy
melatonin sulphate and cortisol in Antarctica. Experientia 42:
430432.
Griffond B, Baker BI (2002). Cell and molecular cell biology of
melanin-concentrating hormone. Int Rev Cytol 213: 233277.
Grimoldi N, Tomei G, Stankov B, Lucini V, Masini B, Caputo
V, Repetti ML, Lazzarini G, Gaini SM, Lucarini C, Fraschini
F, Villani R (1998). Neuroendocrine, immunohistochemical,
and ultrastructural study of pineal region tumors. J Pineal
Res 25: 147158.
Grindstaff RJ, Grindstaff RR, Cunningham JT (2000).
Baroreceptor sensitivity of rat supraoptic vasopressin neurons
involves noncholinergic neurons in the DBB. Am J Physiol
279: R1934-R1943.
Grilo CM, Masheb RM (2002). Childhood maltreatment and
personality disorders in adult patients with binge eating
disorder. Acta Psychiatr Scand 106: 183188.
Grinspoon SK, Bilezikian JP (1992). HIV disease and the
endocrine system. New Engl J Med 327: 13601365.
Grinspoon SK, Donovan Jr, DS, Bilezikian JP (1994). Aetiology
and pathogenesis of hormonal and metabolic disorders in HIV
infection. Baillires Clin Endocrinol Metab 8: 735755.
Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson
E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A
(1996). Serum leptin levels in women with anorexia nervosa.
Grinsted L, Heltberg A, Hagen C, Djursing H (1989). Serum
sex hormone and gonadotropin concentration in menstruating
women with multiple sclerosis. J Intern Med 226: 241244.
Groenveld M, Pohl KRE, Espezel H, Jan JE (1994). The septum
pellucidum and spatial ability of children with optic nerve
hypoplasia. Dev Med Child Neurol 36: 191197.
Gropman AL, Packer RJ, Nicholson HS, Vezina LG, Jakacki
R, Geyer R, Olson JM, Phillips P, Needle M, Broxson EH,
Reaman G, Finlay J (1998). Treatment of diencephalic
syndrome with chemotherapy. Cancer 83: 166172.
Gross M, Bannister R, Godwin-Austen R (1972). Orthostatic
hypotension in Parkinsons disease. Lancet 1: 174176.
Gross-Isseroff R, Biegon A (1988). Autoradiographic analysis
of [3H]imipramine binding in the human brain postmortem:
effects of age and alcohol. J Neurochem 51: 528534.
Gross-Isseroff R, Israeli M, Biegon A (1988). Autoradiographic
analysis of [3H]desmethylimipramine binding in the human
brain post-mortem. Brain Res 456: 120126.
Grossi D, Lopez OL, Martinez AJ (1989). Mamillary bodies in
Alzheimers disease. Acta Neurol Scand 80: 4145.
Grossman A (1992). What is the cause of Cushings disease?
Grossman WF, Sanfield JA (1994). Hypothalamic atrophy
presenting as amenorrhea and sexual infantilism in a female
adolescent. J Reprod Med 39: 738740.
457
2014 Refs
458
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 458
D.F. SWAAB
corps calleux. Sem Hp, Paris (Ann Pediatr) 47: 2307/P. 6452318/P. 656.
Guillemette J, Hbert M, Paquet J, Dumont M (1998). Natural
bright light exposure in the summer and winter in subjects
with and without complaints of seasonal mood variations.
Guillery RW, Okoro AN, Witkop CJ (1975). Abnormal visual
pathways in the brain of the human albino. Brain Res 96:
373377.
Guillon G, Balestre MN, Roberts JM, Bottari SP (1987).
Oxytocin and vasopressin: distinct receptors in myometrium.
Gulati S, Gera S, Menon PSN, Kabra M, Kalra V (2002). Hypothalamic hamartoma, gelastic epilepsy, precocious puberty a
diffuse cerebral dysgenesis. Brain Devel 24: 784786.
Guldenaar SEF, Swaab DF (1995). Estimation of oxytocin
mRNA in the human paraventricular nucleus in AIDS by
means of quantitative in situ hybridization. Brain Res 700:
107114.
Guldenaar SEF, Veldkamp B, Bakker O, Wiersinga WM, Swaab
DF, Fliers E (1996). Thyrotropin-releasing hormone gene
expression in the human hypothalamus. Brain Res 743: 93101.
Gldner F-H (1982). Sexual dimorphisms of axo-spine synapses
and postsynaptic density material in the suprachiasmatic
nucleus of the rat. Neurosci Lett 28: 145150.
Gldner F-H (1983). Numbers of neurons and astroglial cells
in the suprachiasmatic nucleus of male and female rats. Exp
Brain Res 50: 373376.
Guldner J, Schier T, Friess E, Colla M, Holsboer F, Steiger A
(1997). Reduced efficacy of growth hormone-releasing
hormone in modulating sleep endocrine activity in the elderly.
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB,
Dalmau J (2000). Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour
association in 50 patients. Brain 123: 14811494.
Gulyas AI, Seress L, Tth K, Acsdy L, Antal M, Freund TF
(1991). Septal gabaergic neurons innervate inhibitory
interneurons in the hippocampus of the macaque monkey.
Gunatilake S, Harendra De Silva DG (1995). Laughing seizures
due to a midline intraventricular neoplasm in tuberous sclerosis. Arch Dis Child 72: 443444.
Gundel A, Plyakov VV, Zulley J (1997). The alteration of human
sleep and circadian rhythms during spaceflight. J Sleep Res
6: 18.
Gunn T, Bortolussi R, Little JM, Andermann F, Fraser FC,
Belmonte MM (1976). Juvenile diabetes mellitus, optic
atrophy, sensory nerve deafness, and diabetes insipidus a
syndrome. J Pediatr 89: 565570.
Gunn TM, Miller KA, He L, Hyman RW, Davis RW, Azarani
A, Schlossman SF, Duke-Cohan JS, Barsh GS (1999). The
mouse mahogany locus encodes a transmembrane form of
human attractin. Nature 398: 152156.
Guo X, Kuzumi E, Charman SC, Vuylsteke A (2002). Perioperative melatonin secretion in patients undergoing coronary
artery bypass grafting. Anesth Analg 94: 10851091.
Guoth MS, Kim J Lotbiniere, ACJ, Brines ML (1998).
Neurosarcoidosis presenting as hypopituitarism and a cystic
pituitary mass. Am J Med Sci 315: 220224.
Gupta DR, Cohen NH (1972). Oxytocin, salting out, and water
intoxication. JAMA 220: 681683.
Gupta P, Mick G, Fong C-T, Jospe N, McCormick K
(2000). Hyponatremia secondary to reset osmostat in a child
with a central nervous system midline defect and a chromosomal
abnormality. J Pediatr Endocrinol Metab 13: 16371641.
Gurdjian ES (1927). The diencephalon of the albino rat. J Comp
Neurol 43: 1114.
Gurevich D, Siegel B, Dumlao M, Perl E, Chaitin P, Bagne C,
Oxenkrug G (1990). HPA-axis responsivity to dexamethasone
and cognitive impairment in dementia. Prog Neuropsychopharmacol Biol Psychiatry 14: 297308.
Gurewitz R, Blum I, Lavie P, Pertzelan A, Stivel M, Weinstein
R, Galatzer A, Laron Z (1986). Recurrent hypothermia, hypersomnolence, central sleep apnea, hypodipsia, hypernatremia,
hypothyroidism, hyperprolactinemia, and growth hormone
deficiency in a boy treatment with clomopramine. Acta
Endocrinol Suppl. 279: 468471.
Guridi J, Obeso JA (2001). The subthalamic nucleus, hemiballismus and Parkinsons disease: reappraisal of a neurosurgical
dogma. Brain 124: 519.
Gustafson Y, Olsson T, Asplund K, Hgg E (1993). Acute
confusional state (delirium). soon after stroke is associated
with hypercortisolism. Cerebrovasc Dis 3: 3338.
Gutkowska J, Jankowski M, Mukaddam-Daher S, McCann SM
(2000). Oxytocin is a cardiovascular hormone. Braz J Med
Biol Res 33: 625633.
Guz BH, Baxter LR (1985). Neuroleptic malignant syndrome.
NEngl J Med 313: 163166.
Haak HR, Van Hilten JJ, Roos RAC, Meinders AE (1990).
Functional hypothalamic derangement in a case of Wernickes
encephalopathy. Neth J Med 36: 291296.
Habener JF, Dashe AM (1966). Hypothalamic change and water
metabolism following Yttrium Y 90: hypophysectomy in man.
Hagino H, Suzuki M, Kurokawa K, Mori K, Nohara S,
Takahashi T, Yamashita I, Yotsutsuji T, Kurachi M, Seto H
(2001). Magnetic resonance imaging study of the cavum
septum pellucidi in patients with schizophrenia. Am J
Hahn JS, Berquist W, Alcorn DM, Chamberlain L, Bass D
(1998b). Wernicke encephalopathy and beriberi during total
parenteral nutrition attributable to multivitamin infusion
shortage. Pediatrics 101: 10.
Hahn TM, Breininger JF, Baskin DG, Schwartz MW (1998a).
Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1: 271272.
2014 Refs
2/12/03
1:39 pm
Page 459
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
459
Hamilos DL, Nutter D, Gershtenson J, Ikle D, Hamilos SS,

Redmond DP, Di Clementi JD, Schmaling KB, Jones JF
(2001). Circadian rhythm of core body temperature in
subjects with chronic fatigue syndrome. Clin Physiol 21:
184195.
Hamilton CR, Scully RE, Kliman B (1972). Hypogonadotropinism in PraderWilli syndrome. Am J Med 52:
322329.
Hamilton DV (1978). Inappropriate secretion of antidiuretic
hormone associated with cerebellar and cerebral atrophy.
Postgrad Med J 54: 427428
Hammerum MS, Bie P, Pump B, Johansen LB, Christensen NJ,
Norsk P (1998). Vasopressin, angiotensin II and renal
responses during water immersion in hydrated humans. J
Physiol 511: 323330.
Hammond DN, Moll GW, Robertson GL, Chelmicka-Schorr E
(1986). Hypodipsic hypernatremia with normal osmoregulation of vasopressin. New Engl J Med 315: 433436.
Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc
A (2001). Testosterone-mediated neuroprotection through the
androgen receptor in human primary neurons. J Neurochem
77: 13191326.
Han L,Wang K, Du Z, Cheng Y, Simons JS, Rosenthal NE
(2000). Seasonal variations in mood and behavior among
Chinese medical students. Am J Psychiatry 157: 133135.
Han J-S (2003). Acupuncture: neuropeptide release produced
by electrical stimulation of different frequencies. Trends
Neurosci 26: 1722.
Hanania M, Kitain E (2002). Melatonin for treatment and
prevention of postoperative delirium. Anesth Analg 94:
338339.
Hanhart E (1940). Erbpathologie des Stoffwechsels. In: Bauer
KH, Hanhart E, Lange J (eds) Handbuch der Erbbiologie des
Menschen. Julius Springer-Verlag, Berlin, pp. 798823.
Hankins MW, Lucas RJ (2002). The primary visual pathway in
humans is regulated according to long-term light exposure
through the action of a nonclassical photopigment. Current
Biol 12: 191198.
Hanna FWF, Scanlon MF (1997). Hyponatraemia, hypothyroidism, and role of arginine-vasopressin. Lancet 350: 755756.
Hannibal J (2002). Neurotransmitters of the retino-hypothalamic
tract. Cell Tiss Res 309: 7388.
Hannibal J, Hindersson P, Knudsen SM, Georg B, Fahrenkrug
J (2002). The photopigment melanopsin is exclusively present
in pituitary adenylate cyclase-activating polypeptidecontaining retinal ganglion cells of the retinohypothalamic
tract. J Neurosci 22: RC191 (17).
Hansen LK, Rittig S, Robertson GL (1997). Genetic basis of
familial neurohypophyseal diabetes insipidus. Trends
Hao, H, Rivkees SA (1999). The biological clock of very premature primate infants is responsive to light. Proc Natl Acad
Sci USA 96: 24262429.
Haider NB, Searby C, Galperin E, Mintz L, Horowitz M, Stone

EM, Sheffield, VC. (1999). Evaluation and molecular characterization of EHD1, a candidate gene for Bardet-Biedl
syndrome 1 (BBS1). Gene 240: 227232.
Haimov I, Shochat T, Lavie P (1997). Melatonin a possible
link between sleep and the immune system. Isr J Med Sci
33: 246250.
Haines DE, Dietrichs E, Mihailoff GA, McDonald EF (1997).
The cerebellar-hypothalamic axis: basic circuits and clinical
observations. Int Rev Neurobiol 41: 83107.
Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT,
Rabinowitz D, Lallone RL, Burley SK, Friedmann JM (1995).
Weight-reducing effects of the plasma protein encoded by
the obese gene. Science 269:543546.
Halberg F (1995). The week in phylogeny and ontogeny: opportunities for oncology. In Vivo 9: 269278.
Halbreich U (2000). Gonadal hormones, reproductive age, and
women with depression. Arch Gen Psychiatry 57: 11631164.
Hald JK, Eldevik OP, Skalpe IO (1995). Craniopharyngioma
identification by CT and MR imaging at 1.5 T. Acta Radiol
36: 142147.
Hall AC, Hoffmaster RM, Stern EL, Harrington ME, Bickar D
(1997). Suprachiasmatic nucleus neurons are glucose sensitive. J Biol Rhythms 12: 388400.
Hall JE, Gill S (2001). Neuroendocrine aspects of aging in
women. Endocrinol Metab Clin N Am 30: 631646.
Hall JE, Taylor AE, Hayes FJ, Crowley jr WF (1998). Insights
into hypothalamic-pituitary dysfunction in polycystic ovary
syndrome. J Endocrinol Invest 21: 602611.
Hall JE, Hildebrandt DA, Kuo J (2001). Obesity hypertension:
role of leptin and sympathetic nervous system Am J
Hypertension 14 (Suppl. 1): 103S115S.
Halmi KA (2002). Eating disorders in females: genetics, pathophysiology, and treatment. J Pediatr Endocrinol Metab 15:
13791386.
Halpern CT, Udry JR, Suchindran C (1998). Monthly measures
of salivary testosterone predict sexual activity in adolescent
males. Arch Sex Behav 27: 445465.
Hamada J, Seto H, Miura M, Kuratsu J, Ushio Y (1990).
Suprasellar pituitary adenoma arising from the pars tuberalis:
case report. Neurosurgery 27: 647649.
Hamamoto Y, Niino K, Adachi M, Hosoya T (2002). MR and
CT findings of craniopharyngioma during and after radiation
therapy. Neuroradiology 44: 118122.
Hamer DH (1999). Genetics and male sexual orientation.
Science 285: 803.
Hamer DH, Hu S, Magnuson VL, Hu N, Pattatucci AML (1993).
A linkage between DNA markers on the X chromosome and
male sexual orientation. Science 261: 321327.
Hamilos DL, Nutter D, Gershtenson J, Redmond DP, Di
Clementi JD, Schmaling KB, Make BJ, Jones JF (1998). Core
body temperature is normal in chronic fatigue syndrome. Biol
459
2014 Refs
460
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 460
D.F. SWAAB
Happe S, Schrdl B, Faltl M, Mller C, Auff E, Zeitlhofer J

(2001). Sleep disorders and depression in patients with
Parkinsons disease. Acta Neurol Scand 104: 275280.
Haqq AM, Farooqi S, ORahilly S, Stadler DD, Rosenfeld RG,
Pratt KL, LaFranchi SH, Purnell JQ. (2003). Serum ghrelin
levels are inversely correlated with body mass index, age,
and insulin concentrations in normal children and are
markedly increased in PraderWilli syndrome. J Clin
Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG, Purnell JQ,
LaFranchi SH (2003). Effects of growth hormone on
pulmonary function, sleep quality, behavior, cognition,
growth velocity, body composition, and resting energy expenditure in PraderWilli syndrome. J Clin Endocrinol Metab
88: 22062212.
Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM,
Sinton CM, Sugiyama F, Yagami K-i, Goto K, Yanagisawa
M, Sakurai T (2001). Genetic ablation of orexin neurons in
mice results in narcolepsy, hypophagia, and obesity. Neuron
30: 345354.
Harada MY, Harada T, Ishizaki F, Izumi Y, Nakamura S (1997).
Autonomic dysfunction in Parkinsons disease and vascular
parkinsonism. Acta Neurol Scand 96: 359365.
Harada K, Yoshida J, Wakabayashi T, Okabe H, Sugita K
(1995). A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious
puberty. Acta Neurochir 137: 102105.
Hardelin, JP, Levilliers J, Young J, Pholsena M, Legouis R,
Kirk J, Bouloux P, Petit C, Schaison G (1993). Xp22.3 deletions in isolated familial Kallmanns syndrome. J Clin
Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N,
Verney C, Schwanzel-Fukuda M, Ayer-le-Lievre C, Petit C
(1999). Anosmin1 is a regionally restricted component of
basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X
chromosome-linked Kallmann syndrome. Dev Dynamics 215:
2644.
Hardelin JP (2001). Kallmann syndrome: towards molecular
pathogenesis. Mol Cell Endocrinol 179: 7581.
Harding AJ, Ng JLF, Halliday GM, Oliver J (1995). Comparison
of the number of vasopressin-producing hypothalamic
neurons in rats and humans. J Neuroendocrinol 7: 629636.
Harding AJ, Halliday GM, Ng JLF, Harper CG, Kril, JJ (1996).
Loss of vasopressin-immunoreactive neurons in alcoholics is
dose-related and time-dependent. Neuroscience 72: 699708.
Hardman CD, Halliday GM, McRitchie DA, Morris JGL (1997).
The subthalamic nucleus in Parkinsons disease and progressive supranuclear palsy. J Neuropathol Exp Neurol 56:
132142.
Hardy C, Khanim F, Torres R, Scott-Brown M, Seller A, Poulton
J, Collier D, Kirk J, Polymeropoulos M, Latif F, Barrett T
(1999). Clinical and molecular genetic analysis of 19 Wolfram
syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet 65: 12791290.
Hardy JA, Dodd PR, Oakley AE, Perry RH, Edwardson JA, Kidd
AM (1983). Metabolically active synaptosomes can be prepared
from frozen rat and human brain. J Neurochem 40: 608614.
Hardy JA, Wester P, Winblad B, Gezelius C, Bring G, Eriksson
A (1985). The patients dying after long terminal phase have
acidotic brains: implications for biochemical measurements
on autopsy tissue. J Neural Transm 61: 253264.
Harhangi BS, De Rijk MC, Van Duijn CM, Van Broeckhoven
C, Hofman A, Breteler MMB (2000). APOE and the risk of
PD with or without dementia in a population-based study.
Neurology 54: 12721276.
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR
(2001). Longitudinal effects of aging on serum total and free
testosterone levels in healthy men. J Clin Endocrinol Metab
86: 724731.
Harmatz MG, Well AD, Overtree CE, Kawamura KY, Rosal
M, Ockene IS (2000). Seasonal variation of depression and
other moods: a longitudinal approach. J Biol Rhythms 15:
344350.
Harms J, Isemer F-E, Kolenda H (1991). Hormonal alteration
and pituitary function during course of brain-stem death in
potential organ donors. Transplant Proc 23: 26142616.
Harper C (1983). The incidence of Wernickes encephalopathy
in Australia a neuropathological study of 131 cases. J Neurol
Harper C (1998). The neuropathology of alcohol-specific brain
damage, or Does alcohol damage the brain? J Neuropath Exp
Neurol 57: 101110.
Harper DG (2001). Differential circadian rhythm disturbances
in men with Alzheimer disease and frontotemporal degeneration. Arch Gen Psychiatry 58: 353360.
Harris BT, Horoupian DS, Tse V, Herrick MK (1999). Melanotic
craniopharyngioma: a report of two cases. Acta Neuropathol
98: 433436.
Harris GW, Campbell HJ (1966). The regulation of the secretion
of luteinizing hormone and ovulation. In: Harris GW,
Campbell HJ (eds) The Pituitary Gland. Butterworths,
London, pp. 99165.
Harris RBS (2000). Leptin much more than a satiety signal.
Annu Rev Nutr 20: 4575.
Harris TO, Borsanyi S, Messari S, Stanford K, Cleary SE, Shiers
HM, Brown GW, Herbert J (2000). Morning cortisol as a
risk factor for subsequent major depressive disorder in adult
women. Br J Psychiatry 177: 505510.
Harrison PJH (2000). Dopamine and schizophrenia proof at
last? Lancet 356: 958959.
Hart MAJMN (1971). Hypertrophy of human subventricular hypothalamic nucleus in starvation. Arch Pathol 91:
493496.
Hartmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser
I (1997). Twenty-four hour cortisol release profiles in patients
2014 Refs
2/12/03
1:39 pm
Page 461
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
461
Hattori M, Kunugi H, Akahane A, Tanaka H, Ishida S,

Hirose T, Morita R, Yamakawa K, Nanko S (2002). Novel
polymorphisms in the promoter region of the neurotrophin3
gene and their associations with schizophrenia. Am J Med
Genet 114: 304309.
Hauffa BP (1997). One-year results of growth hormone treatment of short stature in PraderWilli syndrome. Acta Paediatr
Suppl 423: 6365.
Haugh RM, Markesbery, WR (1983). Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of
behavior and endocrine and autonomic function. Arch Neurol
40: 560563.
Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA,
Mixson AJ, Weintraub BD (1993). Attention deficit-hyperactivity disorder in people with generalized resistance to
thyroid hormone. N Engl J Med 328: 9971001.
Hayashi E (2000). Effect of melatonin on sleep-wake rhythm:
the sleep diary of an autistic male. Psychiat Clin Neurosci
54: 383384.
Hayashi M, Sakamoto K, Kurata K, Nagata J, Satoh J,
Morimatsu Y (1996). Septo-optic dysplasia with cerebellar
hypoplasia in Cornelia de Lange syndrome. Acta Neuropathol
92: 625630.
Hayashi Y, Hamada Y, Oki H, Yamashita J (1997). Pituitary
stalk meningioma: case report. Neuroradiology 39: 351353.
Hayashi Y, Tachibana O, Muramatsu N, Tsuchiya H, Tada M,
Arakawa Y, Suzuki M, Yamashita J (1999). Rathke cleft cyst:
MR and biomedical analysis of cyst content. J Comp Assist
Tomogr 23: 3438.
Hayek A, Driscoll SG, Warshaw JB (1973). Endocrine studies
in anencephaly. J Clin Invest 52: 16361641.
Hayek A, Peake GT (1982). Hypothalamic adipsia without
demonstrable structural lesion. Pediatrics 70: 275278.
Hayes FJ, Seminara SB, Crowley WF (1998). Hypogonadotropic
hypogonadism. Endocrinol Metab Clin North Am 27:
739763.
Hayes FJ, Decruz S, Seminara SB, Boepple PA, Crowley WF
(2001). Differential regulation of gonadotropin secretion by
testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone
secretion. J Clin Endocrinol Metab 86: 5358.
Haymaker W, Anderson E, Nauta WJH (Eds) (1969). The hypothalamus. Charles C. Thomas Publisher, Springfield, Ill.,
USA, 805 pp.
Hazebroek EJ, De Vos tot Nederveen Cappel R, Gommers D,
Van Gelder T, Weimar W, Steyerberg EW, Bonjer HJ,
IJzermans JNM (2002). Antidiuretic hormone release during
laparoscopic donor nephrectomy. Arch Surg 137: 600604.
Hazell AS, Todd KG, Butterworth RF (1998). Mechanisms of
neuronal cell death in Wernickes encephalopathy. Metab
Brain Dis 13: 97122.
Healy D (1987). Rhythm and blues. Neurochemical, neuropharmacological and neuropsychological implications of a
with Alzheimers and Parkinsons disease compared to normal

controls: ultradian secretory pulsatility and diurnal variation.
Harvey JN, Nagi DK, Bayliss PH, Wilkinson R, Belchetz PE
(1991). Disturbance of osmoregulated thirst and vasopressin
secretion in thyrotoxicosis. Clin Endocrinol 35: 2933.
Harwood-Nash DC (1994). Neuroimaging of childhood craniopharyngioma. Pediatr Neurosurg (Suppl. 1) 21: 210.
Hasegawa A, Ohtsubo K, Mori W (1987). Pineal gland in old
age: quantitative and qualitative morphological study of 168
human autopsy cases. Brain Res 409: 343349.
Hasegawa H, Bitoh S, Koshino K, Obashi J, Kobayashi Y,
Kobayashi M, Wakasugi C (1995). Mixed cavernous angioma
and glioma (angioglioma) in the hypothalamus. Neurol Med
Chir (Tokyo) 35: 238242.
Hashimoto T, Aihara R, Tayama M, Miyazaki M, Shirakawa
Y, Kuroda Y (1991). Reduced thyroid-stimulating hormone
response to thyrotropin-releasing hormone in autistic boys.
Dev Med Child Neurol 33: 313319.
Haskell SG, Richardson ED, Horwitz RI (1997). The effect of estrogen replacement therapy on cognitive function in women: a critical review of the literature. J Clin Epidemiol 50: 12491264.
Haslam RHA, Winternitz WW, Howieson J (1969). Selective
hypopituitarism following tuberculous meningitis. Am J Dis
Child 118: 903908.
Hasselblatt M, Khler, J, Volles, E, Ehrenreich, H (1999).
Simultaneous monitoring of endothelin1 and vasopressin
plasma levels in migraine. Neuroreport 10: 423425.
Hasselblatt M, Krieg-Hartig C, Hfner M, Halaris A, Ehrenreich
H (2003). Persistent disturbance of the hypothalamicpituitary-gonadal axis in abstinent alcoholic men. Alc
Alcoholism 38: 239242.
Hasser EM, Cunningham JT, Sullivan MJ, Curtis KS, Blaine
EH, Hay M (2000). Area postrema and sympathetic nervous
system effects of vasopressin and angiotensin II. Clin Exp
Pharmacol Physiol 27: 432436.
Htnen T, Laakso M-L, Heiskala H, Alila-Johansson A, Sainio
K, Santavuori P (1998). Bright light suppresses melatonin in
blind patients with neuronal ceroid-lipofuscinoses. Neurology
50: 14451450.
Htnen T, Kirveskari E, Heiskala H, Sainio K, Laakso M-L,
Santavuori P (1999). Melatonin ineffective in neuronal ceroid
lipofuscinosis patients with fragmented or normal motor
activity rhythms recorded by wrist actigraphy. Mol Genet
Metab 66: 401406.
Hattar S, Liao HW, Takao M, Berson DM, Yau K-W (2002).
Melanopsin-containing retinal ganglion cells: architecture,
projections, and intrinsic photosensitivity. Science 295:
10651069.
Hatton GI (1976). Nucleus circularis: is it an osmoreceptor in
the brain. Brain Res Bull 1: 123131.
Hatton GI (1997). Function-related plasticity in hypothalamus.
Annu Rev Neurosci 20: 375397.
461
2014 Refs
462
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 462
D.F. SWAAB
hypothesis of circadian rhythm dysfunction in the affective

disorders. Psychopharmacology 93: 271285.
Healy D, Waterhouse JM (1995). The circadian system and the
therapeutics of the affective disorders. In: Redfern PH,
Waterhouse J (Eds) Pharmacological Therapy, vol. 65.
Heaney RP, Eliel LP, Joel W, Stout H (1954). Hyperphagia,
obesity and duodenal ulcer associated with hypothalamic
leukemic infiltration. J Clin Endocrinol 14: 829830.
Heath RG (Ed) The Role of Pleasure in Behavior. Hoeber
Medical Division, Harper and Row, New York, 1964.
Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul
A, Ziegler A, Warnke A, Rascher W, Remschmidt H (1997).
Leptin levels in patients with anorexia nervosa are reduced
in the acute stage and elevated upon short-term weight restoration. Mol Psychiatry 2: 330334.
Hebebrand J, Fichter M, Gerber G, Grg T, Hermann H, Geller
F, Schfer H, Remschmidt H, Hinney A (2002). Genetic
predisposition to obesity in bulimia nervosa: a mutation screen
of the melanocortin4 receptor gene. Mol Psychiatry 7:
647651.
Hebert, LE Scherr PA, McCann JJ, Beckett LA, Evans DA
(2001). Is the risk of developing Alzheimers disease greater
for women than for men? Am J Epidemiology 153: 132136.
Hbert M, Martin SK, Eastman CI (1999). Nocturnal melatonin
secretion is not suppressed by light exposure behind the knee
in humans. Neurosci Letts 274: 127130.
Heckmann, H, Ang LC, Casey R, George DH, Lowry N, Shokeir
MHK (1991). Leighs disease with clinical manifestations of
Cornelia de Lange Syndrome. Pediatr Neurosurg 17: 192195.
Hedera P, Gorski JL (2001). Retinitis pigmentosa, growth
hormone deficiency, and acromelic skeletal dysplasia in two
brothers: possible familial RHYNS syndrome. Am J Med
Genet 101: 142145.
Hedges III TR, Perez Galves R, Speigelman D, Barbas NR,
Peli E, Yardley CJ (1996). Retinal nerve fiber layer abnormalities in Alzheimers disease. Acta Ophthalmol Scand 74:
271275.
Hedreen J, Struble RG, Whitehouse PJ, Price DL (1984).
Topography of the magnocellular basal forebrain system in
human brain. J Neuropath exp Neurol 43: 121.
Heerssen HM, Segal RA (2002). Location, location, location:
a spatial view of neurotrophin signal transduction. Trends
Heesen C, Gold SM, Raji A, Wiedemann K, Schulz K-H (2002).
Cognitive impairment correlates with hypothalamo-pituitaryadrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology 27: 505517.
Hefti F, Hartikka J, Salvatierra A, Weiner WJ, Mash DC (1986).
Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain. Neurosci Lett 69: 3741.
Hefti F, Mash DC (1989). Localization of nerve growth factor
receptors in the normal human brain and in Alzheimers
disease. Neurobiol Aging 10: 7587.
Heijligenberg R, Sauerwein HP, Brabant G, Endert E, Hommes

MJ, Romijn JA (1996). Circadian growth hormone secretion
in asymptomatic human immune deficiency virus infection
and acquired immunodeficiency syndrome. J Clin Endocrinol
Metab 81: 40284032.
Heikens J, Michiels EMC, Behrendt H, Endert E, Bakker PJM,
Fliers E (1998). Long-term neuroendocrine sequelae after
treatment for childhood medulloblastoma. Eur J Cancer 34:
15921597.
Heilig M, Sjgren M, Blennow K, Ekman R, Wallin A (1995).
Cerebrospinal fluid neuropeptides in Alzheimers disease and
vascular dementia. Biol Psychiatry 38: 210216.
Heim C, Nemeroff CB (2001). The role of childhood trauma
in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49: 10231039.
Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall
R, Miller AH, Nemeroff CB (2000). Pituitary-adrenal and
autonomic responses to stress in women after sexual and
physical abuse in childhood. JAMA 284: 592597.
Heimann H (1979). Psychiatrische, psychologische, soziologische und ethische implikationen psychochirurgischer
Massnahmen unter besonderer Bercksichtigung der
Hypothalamotomie bei Sexualdeviationen. Nervenartz 50:
682688.
Heimer L (2000). Basal forebrain in the context of schizophrenia. Brain Res Rev 31: 205235.
Heimer L, Harlan RE, Alheid GF, Garcia MM, De Olmos JS
(1997). Substantia innominata: a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders.
Heimer L, De Olmos JS, Alheid GF, Pearson J, Sahamoto N,
Shinoda K, Marksteiner J, Switzer III RC (1999). The human
basal forebrain. Part II. In: Bloom FE, Bjrklund A, Hkfelt
T (eds) The Primate Nervous System, part III (Handbook of
Chemical Neuroanatomy, vol. 15). Elsevier Science B.V,
Amsterdam, pp. 57226.
Heinbecker P (1944). The pathogenesis of Cushings syndrome.
Medicine 23: 225247.
Helderman JH, Vestal RE, Rowe JW, Tobin JD, Andres R,
Robertson GL (1978). The response of arginine vasopressin
to intravenous ethanol and hypertonic saline in man: the
impact of aging. J Gerontol 33: 3947.
Heleniak E, ODesky, I (1999). Histamine and prostaglandins
in schizophrenia: revisited. Med Hypotheses 52: 3742.
Hellerstein MK, Kahn J, Mudie H, Viteri F (1990). Current
approach to the treatment of human immunodeficiency virusassociated weight loss: pathophysiologic considerations and
emerging management strategies. Semin Oncol 17 (Suppl. 9):
1733.
Hellstrm A, Wiklund L-M, Svensson E, Strmland K,
Albertsson-Wikland K. (1998). Midline brain lesions in children with hormone insufficiency indicate early prenatal
damage. Acta Paediatr 87: 528536.
2014 Refs
2/12/03
1:39 pm
Page 463
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
463
Herholz K (1996). Neuroimaging in anorexia nervosa.

Herlitz J, Eek M, Holmberg M, Holmberg S (2002). Diurnal,
weekly and seasonal rhythm of out of hospital cardiac arrest
in Sweden. Resuscitation 54: 133138.
Hermann D, Heinz A, Mann K (2002). Dysregulation of the
hypothalamic-pituitary-thyroid axis in alcoholism. Addiction
97: 13691381.
Hernndez I, Parra A, Mndez I, Cabrera V, Del Carmen
Cravioto M, Mercado M, Daz-Snchez V, Larrea F (2000)
Hypothalamic dopaminergic tone and prolactin bioactivity in
women with polycystic ovary syndrome. Arch Med Res 31:
216222.
Herpertz S, Wagner R, Albers N, Blum WF, Pelz B, Langkafel
M, Kpp W, Henning A, Oberste-Berghaus C, Mann K, Senf
W, Hebebrand J (1998). Circadian plasma leptin levels in
patients with anorexia nervosa: relation to insulin and cortisol.
Horm Res 50: 197204.
Herpertz, S Albers, N, Wagner R, Pelz B, Kpp W, Mann K,
Blum WF, Senf W, Hebebrand J (2000). Longitudinal changes
of circadian leptin, insulin and cortisol plasma levels and
their correlation during refeeding in patients with anorexia
nervosa. Eur J Endocrinol 142: 373379.
Herrmann, BL Saller B, Janssen OE, Gocke P, Bockisch A,
Sperling H, Mann K, Broecker M (2002). Impact of estrogen
replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin
Hertz G, Cataletto M, Feinsilver SH, Angulo M (1993). Sleep
and breathing patterns in patients with PraderWilli syndrome
(PWS): effects of age and gender. Sleep 16: 366371.
Herv C, Fellmann D (1997). Changes in rat melanin-concentrating hormone and dynorphin messenger ribonucleic acids
induced by food deprivation. Neuropeptides 31: 237242.
Herzberg NH, Goudsmit E, Kruisbrink J, Boer GJ (1989).
Testosterone treatment restores reduced vasopressin-binding
sites in the kidney of the ageing rat. J Endocrinol 123: 5963.
Herzog AG, Edelheit PB, Jacobs AR (2001). Low salivary
cortisol levels and aggressive behavior. Arch Gen Psychiatry
58: 513514.
Hess WR (1969). Hypothalamus and thalamus. Georg Thieme
Verlag, Stuttgart.
Hessl D, Glaser B, Dyer-Friedman J, Blasey C, Hastie T, Gunnar
M, Reiss AL (2002). Cortisol and behavior in fragile-X
syndrome. Psychoneuroendocrinology 27: 855872.
Hestnes A, Stovner LJ, Husy , Flling I, Fougner KJ, Sjaastad
O (1991). Hormonal and biochemical disturbances in Downs
syndrome. J Ment Defic Res 35: 179193.
Heuser I (2002). Depression, endocrinologically a syndrome of
premature aging? Maturitas 41 (Suppl. 1): S19-S23.
Heuser I, Chase JN, Mouradian MM (1991). The limbic-hypothalamic-pituitary-adrenal axis in Huntingtons disease. Biol
Psychiatry 30: 943952
Hellstrm A, Aronsson M, Axelson C, Kyllerman M, Kopp S,

Steffenburg S, Strmland K, Westphal O, Wiklund L-M,
Albertsson Wikland K (2000). Children with septo-optic
dysplasia - how to improve and sharpen the diagnosis. Horm
Res 53 (Suppl. 1): 1925.
Hellstrm-Lindahl E, Nordberg A (2002). Smoking during pregnancy: a way to transfer the addiction to the next generation.
Respiration 69: 289293.
Henderson VW, Wooten GF (1981). Neuroleptic malignant
syndrome: a pathogenetic role for dopamine receptor
blockade? Neurology 31: 132137.
Henderson VW, Watt L, Buckwalter JG (1996). Cognitive
skills associated with estrogen replacement in women
with Alzheimers disease. Psychoneuroendocrinology 21:
421430.
Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes
PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow
MR (2000). Estrogen for Alzheimers disease in women:
randomized, double-blind, placebo-controlled trial. Neurology
54: 295301.
Hendricks SA, Lippe BM, Kaplan SA, Bentson JR (1981).
Hypothalamic atrophy with progressive hypopituitarism in an
adolescent girl. J Clin Endocrinol Metab 52: 562564.
Hengstschlger M, Van Trotsenburg M, Repa C, Marton E,
Huber JC, Bernaschek G (2003). Sex chromosome aberrations and transsexualism. Fertil Steril 79: 639640.
Henke H, Lang W (1983). Cholinergic enzymes in neocortex,
hippocampus and basal forebrain of non-neurological and
senile dementia of Alzheimer-type patients. Brain Res 267:
281291.
Henley WN, Koehnle TJ (1997). Thyroid hormones and the
treatment of depression: an examination of basic hormonal
actions in the mature mammalian brain. Synapse 27:
3644.
Henneberry HP, Slater JDH, Eisen V, Fhr S (1992). Arginine
vasopressin response to hypertonicity in hypertension studied
by arginine vasopressin assay in unextracted plasma. J
Hypertens 10: 221228.
Hennig J, Friebe J, Ryl I, Krmer B, Bttcher J, Netter P (2000).
Upright posture influences salivary cortisol. Psychoneuroendocrinology 25: 6983.
Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling
M (1998). Low-dose MDMA (ecstasy). induces vasopressin
secretion. Lancet 351: 1784.
Heppner C, Kotzka J, Bullmann C, Krone W, Mller-Wieland
D (1998). Identification of mutations of the arginine vasopressin-neurophysin II gene in two kindreds with familial
central diabetes insipidus. J Clin Endocrinol Metab 83:
693696.
Herbert J, Goodyer IM, Altham PME, Pearson J, Secher SM,
Shiers HM (1996). Adrenal secretion and major depression
in 8- to 16-year-olds, II. Influence of co-morbidity at presentation. Psychol Med 26: 257263.
463
2014 Refs
464
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 464
D.F. SWAAB
Heuser I, Gotthardt U, Schweiger U, Schmider J, Lammers CH, Dettling M, Holsboer F (1994a). Age-associated changes
of pituitary-adrenocortical hormone regulation in humans:
importance of gender. Neurobiol Aging 15: 227231.
Heuser I, Yasssouridis A, Holsboer F (1994b). The combined
dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 28: 341356.
Heuser I, Deuschle M, Luppa P, Schweiger U, Standhardt H,
Weber B (1998). Increased diurnal plasma concentrations of
dehydroepiandrosterone in depressed patients. J Clin
Heutink P, Stevens M, Rizzu P, Bakker E, Kros JM, Tibben
A, Niermeijer MF, Van Duijn CM, Oostra BA, Van Swieten
JC (1997). Hereditary frontotemporal dementia is linked to
chromosome 17q21-q22: a genetic and clinicopathological
study of three Dutch families. Ann Neurol 41: 150159.
Highley JR, Esiri MM, McDonald B, Roberts HC, Walker MA,
Crow TJ (1999). The size and fiber composition of the anterior commissure with respect to gender and schizophrenia.
Higuchi M, Yanai K, Okamura N, Meguro K, Arai H, Itoh M,
Iwata R, Ido T, Watanabe T, Sasaki H (2000). Histamine H1
receptors in patients with Alzheimers disease assessed by
positron emission tomography. Neuroscience 99: 721729.
Higuchi S, Arai H, Matsushita S, Matsui T, Kimpara T, Takeda
A, Shirakura K (1998). Mutation in the -synuclein gene and
sporadic Parkinsons disease, Alzheimers disease, and
dementia with Lewy bodies. Exp Neurol 153: 164166.
Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N,
Yoshino A, Matsui T, Muraoka H, Ishizuka Y, Kanba S,
Sakurai T (2002). Plasma orexin-A is lower in patients with
narcolepsy. Neurosci Lett 318: 6164.
Hilker R, Voges J, Ghaemi M, Lehrke R, Rudolf J, Koulousakis
A, Herholz K, Wienhard K, Sturm V, Heiss W-D (2003).
Deep brain stimulation of the subthalamic nucleus does not
increase the striatal dopamine concentration in Parkinsonian
humans. Mov Disord 18: 4148.
Hillen T, Lun A, Reischies FM, Borchelt M, SteinhagenThiessen E, Schaub RT (2000). DHEA-S plasma levels and
incidence of Alzheimers disease. Biol Psychiatry 47:
161163.
Hineno T, Mizobuchi M, Hiratani K, Inami Y, Kakimoto Y
(1992). Disappearance of circadian rhythms in Parkinsons
disease model induced by 1-methyl4-phenyl1,2,3,6-tetrahydropyridine in dogs. Brain Res 580: 9299.
Hines M, Johnston KJ, Golombok S, Rust J, Stevens M, Golding
J, ALSPAC Study Team (2002). Prenatal stress and gender
role behavior in girls and boys: a longitudinal, population
study. Horm Behav 42: 126134.
Hinney A, Schmidt A, Nottebom K, Heiblt O, Becker I, Ziegler
A, Gerber G, Sina M, Grg T, Mayer H, Siegfried W, Fichter
M, Remschmidt H, Hebebrand J (1999). Several mutations
in the melanocortin4 receptor gene including a nonsense and
a frameshift mutation associated with dominantly inherited

obesity in humans. J Clin Endocrinol Metab 84: 14831486.
Hinney A, Hoch A, Geller F, Schfer H, Siegfried W,
Goldschmidt H, Remschmidt H, Hebebrand J (2002). Ghrelin
gene: identification of missense variants and a frameshift
mutation in extremely obese children and adolescents and
healthy normal weight students. J Clin Endocrinol Metab 87:
27162719.
Hinton DR, Sadun AA, Blanks JC, Miller CA (1986). Optic
nerve degeneration in Alzheimers disease. N Engl J Med
315: 485487.
Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M,
Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H,
Sekiguchi M, Kurokawa T, Nishimura O, Onda H, Fujino M
(1998). A prolactin-releasing peptide in the brain. Nature 393:
272276.
Hiort O (2000). Neonatal endocrinology of abnormal male
sexual differentiation: molecular aspects. Horm Res 53
(Suppl. 1): 3841.
Hirabayashi K, Shimokawa K, Ikeda K, Orthner H (1979). ber
Kernkugeln
in
Nervenzellen
des
menschlichen
Hypothalamus. J Hirnforsch 20: 455465.
Hirano A, Zimmerman HM (1962). Alzheimers neurofibrillary
changes. Arch Neurol 7: 227242.
Hirshberg B, Ben-Yehuda A (1997). The syndrome of inappropriate antidiuretic hormone secretion in the elderly. Am
J Med 103: 270273.
His W (1893). Vorschlge zur Einteilung des Gehirns. Arch
Anat Entwicklungsgesch (Leipzig) 17: 172179.
Hoban TF (2000). Sleeplessness in children with neurodevelopmental disorders. CNS Drugs 14: 1122.
Hochberg Z Moses AM, Miller M, Benderli A, Richman RA
(1982). Altered osmotic threshold for vasopressin release and
impaired thirst sensation: additional abnormalities in
Kallmanns syndrome. J Clin Endocrinol Metab 55: 779782.
Hock CH, Heese K, Olivieri G, Hulette CH, Rosenberg C,
Nitsch RM, Otten U (2000). Alterations in neurotrophins and
neurotrophin receptors in Alzheimers disease. J Neural
Transm Suppl. 59: 171174.
Hodgins S, Kratzer L, McNeil TF (2001). Obstetric complications, parenting, and risk of criminal behavior. Arch Gen
Hoek HW, Bartelds AIM, Bosveld JJF, Van der Graaf Y,
Limpens VEL, Maiwald M, Spaaij CJK (1995). Impact of
urbanization on detection rates of eating disorders. Am J
Psychiat 152: 12721278.
Hoek HW, Brown AS, Susser E (1998). The Dutch famine and
schizophrenia spectrum disorders. Soc Psychiatry Psychiatr
Epidemiol 33: 373379.
Hoffman DM, Ho KKY (1997). Growth hormone deficiency in
adults. Endocrinologist 7: 233237.
Hofman MA (2001). Seasonal rhythms of neuronal activity in
the human biological clock: a mathematical model. Biol
Rhythm Res 32: 1734.
2014 Refs
2/12/03
1:39 pm
Page 465
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
465
Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria C,

Aronowitz BR, Mosovich S (2003). Oxytocin infusion
reduces repetitive behaviors in adults with autistic and
Aspergers disorders. Neuropsychopharmacology 28:
193198.
Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo
R, Thompson EB, Rosenfeld MG, Evans RM (1985). Primary
structure and expression of a functional human glucocorticoid
receptor cDNA. Nature 318: 635641.
Holm VA, Cassidy SB, Butler MC, Hanchett JM, Greenswag
LR, Whitman BY, Greenberg F (1993). PraderWilli
syndrome: consensus diagnostic criteria. Pediatrics 91:
398402.
Holman SD, Hutchison JB (1991). Differential effects of
neonatal castration on the development of sexually dimorphic brain areas in the gerbil. Brain Res Dev 61: 147150.
Holmes C, Arranz M, Collier D, Powell J, Lovestone S (2003).
Depression in Alzheimers disease: the effect of serotonin
receptor gene variation. Am J Med Genet Part B: 119B:
4043.
Holmes C, Levy R, McLoughlin DM, Powell JF, Lovestone S
(1997). Apolipoprotein E: non-cognitive symptoms and
cognitive decline in late onset Alzheimers disease. J Neurol
Holmes CL, Patel BM, Russell JA, Walley KR (2001).
Physiology of vasopressin relevant to management of septic
shock. Chest 120: 9891002.
Holmes GL, Dardick KR, Russman BS (1980). Laughing
seizures (gelastic seizures) in childhood. Clin Pediatr 19:
295296.
Holsboer F (2000). The corticosteroid receptor hypothesis of
depression. Neuropsychopharmacology 23: 477501.
Holsboer F (2001). Stress, hypercortisolism and corticosteroid
receptors in depression: implications for therapy. J Affect
Disord 62: 7791.
Holsboer F, Barden N (1996). Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 17: 187.
Holsboer F, Gerken A, Van Bardeleben U, Grimm W, Beyer
H, Mller OA, Stalla GK (1986). Human corticotropinreleasing hormone in depression correlation with thyrotropin
secretion following thyrotropin-releasing hormone. Biol
Psychiatr 21: 601611.
Holsboer F, Spengler D, Heuser I (1992). The role of corticotropin-releasing hormone in the pathogenesis of Cushings
disease, anorexia nervosa, alcoholism, affective disorders and
dementia. In: Swaab DF, Hofman MA, Mirmiran M, Ravid
R, Van Leeuwen FW (Eds) The human hypothalamus in
health and disease (Progress in Brain Research, vol. 93), pp.
385417. Elsevier, Amsterdam.
Holsboer F, Lauer CJ, Schreiber W, Krieg J-C (1995). Altered
hypothalamic-pituitary-adrenocortical regulation in healthy
subjects at high familial risk for affective disorders.
Hofman MA, Swaab DF (1989). The sexually dimorphic nucleus

of the preoptic area in the human brain: a comparative
morphometric study. J Anat 164: 5572.
Hofman MA, Swaab DF (1992a). The human hypothalamus:
comparative morphometry and photoperiodic influences. In:
Swaab DF, Hofman MA, Mirmiran M, Ravid R, Van
Leeuwen FW (Eds) The Human Hypothalamus in Health and
Disease. Progress in Brain Research vol. 93, pp. 133149.
Hofman MA, Swaab DF (1992b). Seasonal changes in the
suprachiasmatic nucleus of man. Neurosci Lett 139: 257260.
Hofman MA, Swaab DF (1993). Diurnal and seasonal rhythms
of neuronal activity in the suprachiasmatic nucleus of humans.
J Biol Rhythms 8: 283295.
Hofman MA, Swaab, DF (1994). Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human
suprachiasmatic nucleus with aging. Brain Res 651: 134142.
Hofman MA, Swaab DF (1995). Influence of aging on the
seasonal rhythm of the human suprachiasmatic nucleus
(SCN). Neurobiol Aging 16: 965971.
Hofman MA, Purba JS, Swaab DF (1993). Annual variations
in the vasopressin neuron population of the human suprachiasmatic nucleus. Neuroscience 53: 11031112.
Hofman MA, Skene DJ, Swaab DF (1995). Effect of photoperiod on the diurnal melatonin and 5-methoxytryptophol
rhythms in the human pineal gland. Brain Res 671: 254260.
Hofman MA, Zhou JN, Swaab DF (1996). Suprachiasmatic
nucleus of the human brain: an immunocytochemical and
morphometric analysis. Anat Rec 244: 552562.
Hofmann PJ, Nutzinger DO, Kotter MR, Herzog G (2001). The
hypothalamic-pituitary-thyroid axis in agoraphobia, panic
disorder, major depression and normal controls. J Affect
Disord 66: 7577.
Hofmann S, Bezold R, Jaksch M, Obermaier-Kusser B, Mertens
S, Kaufhold P, Rabl W, Hecker W, Gerbitz K-D (1997).
Wolfram (DIDMOAD) syndrome and leber hereditary optic
neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 39: 818.
Hogenesch JB, Gu Y-Z, Jain S, Bradfield CA (1998). The basichelix-loop-helix-PAS orphan MOP3 forms transcriptionally
active complexes with circadian and hypoxia factors. Proc
Hogervorst E, Williams J, Budge M, Riedel W, Jolles J (2000).
The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal
women: a meta-analysis. Neuroscience 101: 485512.
Holden RJ, Pakula IS (1996). The role of tumor necrosis factor in the pathogenesis of anorexia and bulimia nervosa, cancer
cachexia and obesity. Med Hypotheses 47: 423438.
Holland AJ, Whittington JE, Butler J, Webb T, Boer H, Clarke D
(2003). Behavioural phenotypes associated with specific genetic
disorders: evidence from a population-based study of people
with PraderWilli syndrome. Psychol Med 33: 141153.
465
2014 Refs
466
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 466
D.F. SWAAB
Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ,

Breitner JCS, Guralnik JM, Plassman BL (2002). Head injury
in early adulthood and the lifetime risk of depression. Arch
Holtzman A, Simon EW (2000). Body temperature as a risk
factor for Alzheimers disease. Med Hypotheses 55: 440444
Holtzman EJ, Harris HW, Kolakowski LF, Guay-Woodford LM,
Botelho B, Ausiello DA (1993). A molecular defect in the
vasopressin V2-receptor gene causing nephrogenic diabetes
insipidus. N Engl J Med 328:15341537.
Holzbauer M, Muscholl E, Rack K, Sharman DF (1983).
Evidence that dopamine is a neurotransmitter in the neurointermediate lobe of the hypophysis. In: Cross BA, Leng G
(Eds) The Neurohypophysis (Progress in Brain Research vol.
60). Elsevier, Amsterdam, pp. 357364.
Honda K, Yanagimoto M, Negoro H, Narita K, Murata T,
Higuchi T (1999). Excitation of oxytocin cells in the hypothalamic supraoptic nucleus by electrical stimulation of the
dorsal penile nerve and tactile stimulation of the penis in the
rat. Brain Res Bull 48: 309313.
Honegger J, Renner C, Fahlbusch R, Adams EF (1997).
Progesterone receptor gene expression in craniopharyngiomas
and evidence for biological activity. Neurosurgery 41:
13591364.
Honegger J, Buchfelder M, Fahlbusch R (1999). Surgical treatment of craniopharyngiomas: endocrinological results. J
Honma A, Ishii R, Ito A, Kato M, Saitoh S, Hayasaka K (1999).
PraderWilli syndrome in a child with XYY. J Hum Genet
44: 412413.
Honma K, Honma S, Kohsaka M, Fukuda N (1992). Seasonality
in human circadian rhythms: sleep, body temperature and
plasma melatonin rhythms. In: Hiroshige, T Honma K(Eds),
Circadian Clocks from Cell to Human, pp. 97116. Hokkaido
University Press, Sapporo.
Honnebier WJ, Swaab DF (1973). The influence of anencephaly
upon intrauterine growth of fetus and placenta and upon gestation length. J Obstet Gynaecol Br Cmwlth 80: 577588.
Honnebier MBOM, Swaab DF, Mirmiran M (1989a). Diurnal
rhythmicity during early human development. In: Reppert SM
(Ed) Development of Circadian Rhythmicity and photoperiodism in Mammals, pp. 83103, Perinatology Press, Ithaca, NY.
Honnebier MBOM, Figueroa JP, Rivier J, Vale W, Nathanielsz
PW (1989b). Studies on the role of oxytocin in late pregnancy in the pregnant rhesus monkey: plasma concentrations
of oxytocin in the maternal circulation throughout the 24-h
day and the effect of the synthetic oxytocin antagonist [1-Mpa(-CH2)5)1,(Me(Tyr2,Orn8] oxytocin on spontaneous
nocturnal myometrial contractions. J Dev Physiol 12:
225232.
Honnebier WJ, Jbsis AC, Swaab DF (1974). The effect of
hypohysial hormones and human chorionic gonadotrophin
(HCG) on the anencephalic fetal adrenal cortex and on partu-
rition in the human. J Obstet Gynaecol Br Cmwlth 81:

423438.
Hoogendijk JE, Fliers E, Swaab DF, Verwer RWH (1985).
Activation of vasopressin neurons in the human supraoptic
and paraventricular nucleus in senescence and senile
dementia. J Neurol Sci 69: 291299.
Hoogendijk WJG, Pool CW, Troost D, Van Zwieten EJ, Swaab
DF (1995). Image-analyser-assisted morphometry of the locus
coeruleus in Alzheimers disease, Parkinsons disease and
amyotrophic lateral sclerosis. Brain 118: 131143.
Hoogendijk WJG, Purba JS, Hofman MA, De Vos RAI, Jansen
ENH, Swaab DF (1998). Depression in Parkinsons disease
is not accompanied by more corticotropin-releasing hormone
expressing neurons in the hypothalamic paraventricular
nucleus. Biol Psychiatry 43: 913917
Hoogendijk WJG, Sommer IEC, Pool CW, Kamphorst W,
Hofman MA, Eikelenboom P, Swaab DF (1999a). Lack of
association between depression and loss of neurons in the
locus coeruleus in Alzheimer disease. Arch Gen Psychiatry
56: 4551.
Hoogendijk WJG, Feenstra MGP, Botterblom MHA, Gilhuis
MHA, Sommer IEC, Kamphorst W, Eikelenboom P, Swaab DF
(1999b). Increased activity of surviving locus coeruleus neurons in Alzheimers disease. Ann Neurol 45: 8291.
Hoogervorst ELJ, Polman CH, Barkhoff F (2002). Cerebral
volume changes in multiple sclerosis patients treated with
high-dose intravenous methylprednisolone. Mult Scler 8:
415419.
Hoorneman EMD, Buijs RM (1982). Vasopressin fiber pathways in the rat brain following suprachiasmatic nucleus
lesioning. Brain Res 243: 235241.
Hopkins DFC, Williams G (1997). Insulin receptors are widely
distributed in human brain and bind human and porcine
insulin with equal affinity. Diabet Med 14: 10441050.
Hori A (1983). A brain with two hypophyses in median cleft
face syndrome. Acta Neuropathol 59: 150154.
Hori A (1997). Anatomical variants of brain structure: confused
spatial relationship of the fornix to the corpus callosum and
anterior commissure. Anat Anz 179: 545547.
Hori A, Schmidt D, Rickels E (1999). Pharyngeal pituitary:
development, malformation, and tumorigenesis. Acta
Horn E, Lach B, Lapierre Y, Hrdina P (1988). Hypothalamic
pathology in the neuroleptic malignant syndrome. Am J
Horn EM, Waldorp, TG (1998). Suprapontine control of respiration. Respir Physiol 114: 201211.
Horrobin DF, Manku MS, Hillman H, Iain A, Glen M (1991).
Fatty acid levels in the brains of schizophrenics and normal
controls. Biol Psychiatry 30: 795805.
Horvath S, Palkovits M (1987). Morphology of the human
septal area: a topographic atlas. Acta Morphol Hung 35:
157174.
2014 Refs
2/12/03
1:39 pm
Page 467
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
467
Howard G, Peng L, Hyde JF (1997). An estrogen receptor

binding site within the human galanin gene. Endocrinology
138: 46494656.
Howard RS, Wiles CM, Hirsch NP, Loh L, Spencer GT,
Newson-Davis J (1992). Respiratory involvement in multiple
sclerosis. Brain 115: 479494.
Howland RH (1997). Sleep-onset rapid eye movement periods
in neuropsychiatric disorders: implications for the pathophysiology of psychosis. J Nerv Ment Dis 185: 730738.
Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH (1989).
Anterior and posterior pituitary function in brain-stem-dead
donors. Transplantation 47: 828834.
Hoyaux D, Decaestecker C, Heizmann CW, Vogl T, Schfer BW,
Salmon I, Kiss R, Pochet R (2000). S100 proteins in corpora
amylacea from normal human brain. Brain Res 867: 280288.
Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS (1970). Septooptic dysplasia and pituitary dwarfism. Lancet 1 (7652):
893894.
Hozumi, S, Okawa M, Mishima K, Hishikawa Y, Hori H,
Takahashi K (1990): Phototherapy for elderly patients with
dementia and sleep-wake rhythm disorders a comparison
between morning and evening light exposure. Jpn J Psychiatry
Neurol, 44, 813814.
Hsieh J-C, Sthle-Bckdahl M, Hgermark , Stone-Elander
S, Rosenquist G, Ingvar M (1996). Traumatic nociceptive
pain activates the hypothalamus and the periaqueductal
gray: a positron emission tomography study. Pain 64:
303314.
Hsieh J-C, Tu C-H, Chen F-P, Chen M-C, Yeh T-C, Cheng HC, Wu Y-T, Liu R-S, Ho L-T (2001) Activation of the
hypothalamus characterizes the acupuncture stimulation at the
analgesic point in human: a positron emission tomography
study. Neurosci Lett 307: 105108.
Hsu SY and Hsueh AJW (2001). Human stresscopin and stresscopin-related peptide are selective ligands for the type 2
corticotropin-releasing hormone receptor. Nat Med 7:
605611.
Hsu LKG, Mulliken B, McDonagh B, Krupa Das S, Rand W,
Fairburn CG, Rolls B, McCrory MA, Saltzman E, Shikora
S, Dwyer J, Roberts S (2002). Binge eating disorder in
extreme obesity. Int J Obesity 26: 13981403.
Hsueh WA, Hsu TH, Federman DD (1978). Endocrine features
of Klinefelters syndrome. Medicine 57: 447461.
Hu S, Pattatucci AML, Patterson C, Li L, Fulker DW, Cherny
SS, Kruglyak L, Hamer DH, (1995). Linkage between sexual
orientation and chromosome Xq28 in males but not in
females. Nat Genet 11: 248256.
Huang YL, Liu RY, Wang Q-S, Van Someren EJW, Xu H,
Zhou JN (2002). Age-associated difference in circadian sleepwake and rest-activity rhythms. Physiol Behav 76: 597603.
Huang ZJ, Edery I, Rosbash M (1993). PAS is a dimerization
domain common to Drosophila period and several transcription factors. Nature 364: 259262.
Horvath E, Scheithauer BW, Kovacs K, Lloyd RV (1997).

Regional neuropathology: hypothalamus and pituitary. In:
Graham DI, Lantos PL (eds) Greenfields Neuropathology.
Arnold, London, pp. 10071094.
Horvath E, Kovacs K, Lloyd RV (1999). Pars intermedia of the
human pituitary revisited: morphologic aspects and frequency
of hyperplasia of POMC-peptide immunoreactive cells.
Endocr Pathol 10: 5564.
Horvath TL, Naftolin F, Leranth C, Sahu A, Kalra SP (1996).
Morphological and pharmacological evidence for neuropeptide Y-galanin interaction in the rat hypothalamus.
Hoshino Y, Yokoyama P, Watanabe M, Murata S, Kaneko M,
Kumashiro H (1987). The diurnal variation and response to
dexamethasone suppression test of saliva cortisol level in
autistic children. Jpn J Psychiatry Neurol 41: 227235.
Hosobuchi Y, Rossier J, Bloom FE, Guillemin R (1979).
Stimulation of human periaqueductal gray for pain relief
increases immunoreactive -endorphin in ventricular fluid.
Science 203: 279281.
Hosono T, Yanase-Fujiwara M, Zhang YH, Xiao-Ming C, Fukuda
Y, Asaki Y, Yamaji K, Kanosue K (1997). Effect of gonadotropin releasing hormone on thermoregulatory vasomotor
activity in ovariectomized female rats. Brain Res 754: 8894.
Hotta M, Shibasaki T, Masuda A, Imaki T, Demura H, Ling N,
Shizume K (1986). The responses of plasma adrenocorticotropin
and cortisol to corticotropin-releasing hormone (CRH) and cerebrospinal fluid immunoreactive CRH in anorexia nervosa
patients. J Clin Endocrinol Metab 62: 319324.
Hotta M, Sato K, Shibasaki T, Demura H (1998). Hypercalcemia
in an euthyroid patient with secondary hypoadrenalism and
diabetes insipidus due to hypothalamic tumor. Endocr J 45:
773778.
Houang M, Gourmelen M, Moatti L, Le Bouc Y, Garabdian
EN, Denoyelle F (2002). Hypogonadotrophic hypogonadism
associated with prelingual deafness due to a connexin 26 gene
mutation. J Pediatr Endocrinol Metab 15: 219223.
Houlden H, Rizzu P, Stevens M, De Knijff P, Van Duijn CM,
Van Swieten JC, Heutink P, Perez-Tur J, Thomas V, Baker
M et al. (1999). Apolipoprotein E genotype does not affect
the age of onset of dementia in families with defined tau
mutations. Neurosci Lett 260: 193195.
Hoverd PA, Fowler CJ (1998). Desmopressin in the treatment
of daytime urinary frequency in patients with multiple
sclerosis. J Neurol Neurosurg Psychiatry 65: 778780.
467
2014 Refs
468
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 468
D.F. SWAAB
Huber SJ, Freidenberg DL, Paulson GW, Shuttleworth EC,

Christy JC (1990). The pattern of depressive symptoms varies
with progression of Parkinsons disease. J Neurol Neurosurg
Huber TJ, Rollnik J, Wilhelms J, Von zur Mhlen A, Emrich
HM, Schneider U (2001). Estradiol levels in psychotic disorders. Psychoneuroendocrinology 26: 2735.
Huch KM, Wall BM, Mangold TA, Bobal MA, Cooke CR
(1998). Hemodynamic response to vasopressin in dehydrated
human subjects. J Investig Med 46: 312318.
Hucks D, Lowther S, Crompton MR, Katona CLE, Horton RW
(1997). Corticotropin-releasing factor binding sites in cortex
of depressed suicides. Psychopharmacology 134: 174178.
Hudson JI, Pliner LF, Hudson MS, Goldenberg DL, Melby JC
(1984). The dexamethasone suppression test in fibrositis. Biol
Hughes AM, Everitt BJ, Lightman SL, Todd K (1987). Oxytocin
in the central nervous system and sexual behavior in male
rats. Brain Res 414: 133137.
Hughes RJ, Badia, P (1997). Sleep-promoting and hypothermic
effects of daytime melatonin administration in humans. Sleep
20: 124131.
Huitinga I, Erkut ZA, Van Beurden D, Swaab DF (2003).
Impaired HPA-axis activation and more severe MS with
active hypothalamic lesions. Ann Neurol (in press).
Huitinga I, Van der Cammen MJF, Salm L, Erkut Z, Van Dam
A-M, Tilders FJH, Swaab DF (2000a). IL1 immunoreactive neurons in the human hypothalamus: reduced numbers
in multiple sclerosis. J Neuroimmunology 107: 820.
Huitinga I, Schmidt ED, Van der Cammen MJF, Binnekade R,
Tilders FJH (2000b). Priming with interleukin1 suppresses
experimental allergic encephalomyelitis in the Lewis rat. J
Huitinga I, De Groot CJA, Van der Valk P, Kamphorst
W, Tilders FJH, Swaab DF (2001). Hypothalamic lesions
in multiple sclerosis. J Neuropathol Exp Neurol 60:
12081218.
Hulshoff Poll HE, Hoek HW, Susser E, Brown AS, Dingemans
A, Schnack HG, Van Haren NEM, Pereira Ramos LM,
Gispen-De Wied CC, Kahn RS (2000). Prenatal exposure to
famine and brain morphology in schizophrenia. Am J
Hulter BM, Lundberg PO (1995). Sexual function in women
with advanced multiple sclerosis. J Neurol Neurosurg
Hummer M, Kemmler G, Kurz M, Kurzthaler I, Oberbauer H,
Fleischhacker WW (1999). Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J
Hung S-C, Wen Y-K, Ng Y-Y, Yang W-C (2000). Inappropriate
antidiuresis associated with pituitary adenoma mechanisms
not involving inappropriate secretion of vasopressin. Clin
Nephrol 54: 157160.
Hunsballe JM, Hansen TK, Rittig S, Pedersen EB, Djurhuus JC

(1998). The efficacy of DDAVP is related to the circadian
rhythm of urine output in patients with persisting nocturnal
enuresis. Clin Endocrinol 49: 793801.
Huntingtons Disease Collaborative Research Group (1993). A
novel gene containing a trinucleotide repeat that is expanded
and unstable on Huntingtons disease chromosomes. Cell 72:
971983.
Hupf H, Grimm D, Riegger GAJ, Schunkert H (1999). Evidence
for a vasopressin system in the rat heart. Circ Res 84: 365370.
Hurd YL (1996). Differential messenger RNA expression of
prodynorphin and proenkephalin in the human brain.
Hurd YL, Fagergren, P (2000). Human cocaine- and amphetamine-regulated transcript (CART). mRNA is highly expressed
in limbic- and sensory-related brain regions J Comp Neurol
425: 583598.
Hurley TR, DAngelo CM, Clasen RA, Wilkinson SB, Passavoy
RD (1994). Magnetic resonance imaging and pathological analysis of a pituicytoma: case report. Neurosurgery 35: 314317.
Husain MK, Fernando N, Shapiro M, Kagan A, Glick SM
(1973). Radioimmunoassay of arginine vasopressin in human
plasma. J Clin Endocrinol Metab 37: 616625.
Huston JP, Wagner U, Hasenhrl RU (1997). The tuberomammillary nucleus projections in the control of learning, memory
and reinforcement processes: evidence for an inhibitory role.
Behav. Brain Res 83: 97105.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang
Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone
RD, Smith FJ, Campfield LA, Burn P, Lee F (1997). Targeted
disruption of the melanocortin4 receptor results in obesity
in mice. Cell 88: 131141.
Hwang DH, Townsend JC, Ilsen PF, Bright DC (1996). Colloid
cyst of the third ventricle. J Am Optom Assoc 67: 227234.
Hwang DH, Froehlich JC, Hwang WS, Lumeng L, Li T-K
(1998). More vasopressin mRNA in the paraventricular hypothalamic nucleus of alcohol-preferring rats and high alcohol
drinking rats selectively bred for high alcohol preference.
Alcohol Clin Exp Res 22: 664669.
Hynd MR, Lewohl JM, Scott HL, Dodd PR (2003). Biochemical
and molecular studies using human autopsy brain tissue. J
Neurochem 85: 543562.
Hyypp M (1972). Hypothalamic monoamines in human fetuses.
Iacoboni M, Padovani A, Di Piero V, Lenzi GL (1995). Poststroke depression: relationships with morphological damage
and cognition over time. Ital J Neurol Sci 16: 209216.
Iannetti P, Chessa L, Raucci U, Basile LA, Fantozzi LM, Bozzao
L (1992). Gelastic epilepsy. A clinical contribution. Clin
Pediatr 31: 467470.
Ibez L, Potau N, De Zegher F (1999). Endocrinology and
metabolism after premature pubarche in girls. Acta Paediatr
(Suppl. 433) 88: 7377.
2014 Refs
2/12/03
1:39 pm
Page 469
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
469
Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa

I, Yamabe H (1993). Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J
Med 329: 683689.
Inder WJ, Donald RA, Prickett TCR, Frampton CM, Sullivan
PF, Mulder RT, Joyce PR (1997). Arginine vasopressin is
associated with hypercortisolemia and suicide attempts in
depression. Biol Psychiatry 42: 744747.
Indira B, Panigrahi MK, Vajramani G, Shankar SK, Santosh V,
Das BS (1996). Tuberculoma of the hypothalamic region as
a rare case of hypopituitarism: a case report. Surg Neurol 45:
347350.
Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano
T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I (1996).
Mutations in the TRKA/NGF receptor gene in patients with
congenital insensitivity to pain with anhidrosis. Nat Genet
13: 485488.
Inestrosa NC, Marzolo MP, Bonnefont AB (1998). Cellular and
molecular basis of estrogens neuroprotection. Potential relevance for Alzheimers disease. Mol Neurobiol 17: 7386.
Ingram CD, Snowball RK, Mihai R (1996). Circadian rhythm of
neuronal activity in suprachiasmatic nucleus slices from the vasopressin-deficient Brattleboro rat. Neuroscience 75: 635641.
Inoue T, Ohnishi A, Matsuo A, Kawai B, Kunihiro N, Tada Y,
Koizumi F, Chau T, Okada K, Yamamura Y, Tanaka T
(1998a). Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis.
Clin Pharmacol Ther 63: 561570.
Inoue Y, Nemoto Y, Murata R, Tashiro T, Shakudo M, Kohno
K, Matsuoka O, Mochizuki K (1998b). CT and MR imaging
of cerebral tuberous sclerosis. Brain Dev 20: 209221.
Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, BernalMizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock
P et al. (1998c). A gene encoding a transmembrane protein
is mutated in patients with diabetes mellitus and optic atrophy
(Wolfram syndrome). Nat Genet 20: 143148.
Insel TR (1992). Oxytocin a neuropeptide for affiliation:
evidence from behavioral, receptor autoradiographic, and
comparative studies. Psychoneuroendocrinology 17: 335.
Insel TR (1997). A neurobiological basis of social attachment.
Insel TR, OBrien DJ, Leckman JF (1999). Oxytocin, vasopressin
and autism: is there a connection? Biol Psychiatry 45: 145157.
Inui A (1999). Cancer anorexia-cachexia syndrome: are
neuropeptides the key? Cancer Res 59: 44934501.
Invited Report of a Workshop (1998). Consensus guidelines for
the diagnosis and treatment of adults with growth hormone
deficiency: summary statement of the growth hormone
research society workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 83: 379381.
Ionescu D, Driver HS, Heon E, Flanagan J, Shapiro CM (2001).
Sleep and daytime sleepiness in retinitis pigmentosa patients.
J Sleep Res 10: 329335.
Ichinose H, Ohye T, Shinotoh H, Arai K, Yamazaki S, Mizuta

E, Kuno S, Nagatsu T (2003). Biopterin metabolism in
patients with malignant syndrome. Parkinsonism Relat Disord
9: S11S14.
Ichise M, Salit IE, Abbey SE, Chung D-G, Gray B, Kirsh JC,
Freedman M (1992). Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.
Nuclear Med Commun 13: 767772.
IGF-1, and leptin, but not with measures of obesity. Horm Res
58: 215222.
Iglesias P, Dez JJ (2000). Diabetes insipidus as a primary clinical manifestation of lymphocytic hypophysitis in a
postmenopausal woman. Endocrinologist 10: 127130.
Iino K, Sasano H, Oki Y, Andoh N, Shin R-W, Kitamoto T,
Takahashi K, Suzuki H, Tezuka F, Yoshimi T, Nagura H
(1999). Urocortin expression in the human central nervous
system. Clin Endocrinol 50: 107114.
Ikeda M, Nomura M (1997). cDNA cloning and tissue-specific
expression of a novel basic helix-loop-helix/PAS protein
(BMAL1). and identification of alternatively spliced variants
with alternative translation initiation site usage. Biochem.
Biophys. Res. Commun. 233: 258264.
Ikeda M, Brown J, Holland AJ, Fukuhara R, Hodges JR (2002).
Changes in appetite, food preference, and eating habits in
frontotemporal dementia and Alzheimers disease. J Neurol
Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL (1995). The
nuclear receptor steroidogenic factor 1 is essential for the
formation of the ventromedial hypothalamic nucleus. Mol
Ikemoto K, Suzuki T, Ichinose H, Ohye T, Nishimura A, Nishi
K, Nagatsu I, Nagatsu T (2002). Localization of sepiapterin
reductase in the human brain. Brain Res 954: 237246.
Ikonomov OC, Stoynev AG, Shisheva AC (1998). Integrative
coordination of circadian mammalian diversity: neuronal
networks and peripheral clocks. Progr Neurobiol 54: 8797.
Ikonomovic MD, Nocera R, Mizukami K, Armstrong DM
(2000). Age-related loss of the AMPA receptor subunits
GluR2/3 in the human nucleus basalis of Meynert. Exp Neurol
166: 363375.
Illnerova H, Buresov M, Presl J (1993). Melatonin rhythm in
human milk. J Clin Endocrinol Metab 77: 838841.
Imperato-McGinley J, Miller M, Wilson JD, Peterson RE,
Shackleton C, Gajdusek DC (1991). A cluster of male pseudohermaphrodites with 5-reductase deficiency in Papua New
Guinea. Clin Endocrinol 34: 293298.
Imperato-McGinley J, Peterson RE, Gautier T, Sturla, E (1979).
Androgens and the evolution of male-gender identity among
male pseudohermaphrodites with 5-reductase deficiency. N
Engl J Med 300: 12331237.
Imperato-McGinley J, Zhu Y-S (2002). Androgens and male
physiology the syndrome of 5-reductase-2 deficiency. Mol
Cell Endocrinol 198: 5159.
469
2014 Refs
470
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 470
D.F. SWAAB
Iraizoz I, De Lacalle S, Gonzalo M (1991). Cell loss and nuclear

hypertrophy in topographical subdivisions of the nucleus
basalis of Meynert. Neuroscience 41: 3340.
Ireland WP, Connell BJ (1990). Correlation between cellular
changes in supraoptic and paraventricular nuclei and waterdrinking in neuroleptic-treated rats. Behav Brain Res 41:
111116.
Irle E, Markowitsch HJ (1986). Afferent connections of the
substantia innominata/basal nucleus of Meynert in carnivores
and primates. J Hirnforsch 27: 343367.
Ironside JW (2002). Neuropathology of variant Creutzfeldt
Jakob disease. CR Acad Sci III Biologies 325: 2731.
Ironside JW, Bell JE (1996). The high-risk neuropathological
autopsy in AIDS and CreutzfeldtJakob disease: principles
and practice. Neuropathol Appl Neurobiol 22: 388393.
Isaac MA, Hahn SS, Kim J-AC, Bogart JA, Chung CT (2001).
Management of craniopharyngioma. Cancer J 7: 516520.
Iseki K, Mezaki T, Oka Y, Terada K, Tomimoto H, Miki
Y, Shibasaki H (2002). Hypersomnia in MS. Neurology 59:
2006.
Ishiguro H, Arinami T, Saito T, Akazawa S, Enomoto M,
Mitushio H, Fujishiro H, Tada K, Akimoto Y, Mifune H,
Shiozuka S, Hamaguchi H, Toru M, Shibuya H (1998).
Systematic search for variations in the tyrosine hydroxylase
gene and their associations with schizophrenia, affective
disorders, and alcoholism. Am J Med Genet 81: 388396.
Ishii T (1966). Distribution of Alzheimers neurofibrillary
changes in the brain stem and hypothalamus of senile
dementia. Acta Neuropathol 6: 181187.
Ishikawa SE, Saito T, Okada K, Nagasaka S, Kuzuya T
(1990). Prompt recovery of plasma arginine vasopressin in
diabetic coma after intravenous infusion of a small dose of
insulin and a large amount of fluid. Acta Endocrinol 122:
455461.
Ishikawa S-E, Fujita N, Fujisawa G, Tsuboi Y, Sakuma N,
Okada K, Saito T (1996). Involvement of arginine vasopressin
and renal sodium handling in pathogenesis of hyponatremia
in elderly patients. Endocr J 43: 101108.
Ishikawa SE (2000). Urinary excretion of aquaporin2 in pathological states of water metabolism. Ann Med 32: 9093.
Ishikawa SE, Saito T, Fukagawa A, Higashiyama M, Nakamura
T, Kusaka I, Nagasaka S, Honda K, Saito T (2001a). Close
association of urinary excretion of aquaporin-2 with appropriate and inappropriate arginine vasopressin-dependent
antidiuresis in hyponatremia in elderly subjects. J Clin
Ishikawa S, Aoki H, Akahane C, Shimada H, Takei Y, Ichinose
Y, Ikeda S (2001b). Hypothalamic encephalitis with bradycardia. Intern Med 40: 805807.
Ishunina TA, Swaab DF (1999). Vasopressin and oxytocin
neurons of the human supraoptic and paraventricular nucleus;
size changes in relation to age and sex. J Clin Endocrinol
Metab 84: 46374644.
Ishunina TA, Swaab DF (2001). Increased expression of

estrogen receptor and in the nucleus basalis of Meynert
in Alzheimers disease. Neurobiol Aging 22: 417426.
Ishunina TA, Swaab DF (2002). Neurohypophyseal peptides in
aging and Alzheimers disease. Ageing Res Rev 1: 537558.
Ishunina TA, Salehi A, Hofman MA, Swaab DF (1999). Activity
of vasopressinergic neurons of the human supraoptic nucleus
is age and sex dependent. J Neuroendocr 11: 251258.
Ishunina TA, Unmehopa UA, Dolzhikov AA, Swaab DF
(2000a). Multinucleated arginine-vasopressin neurons in the
human supraoptic nucleus: a hallmark of pulmonary
pathology. Neuroendocrinology 72: 318326.
Ishunina TA, Kruijver FP, Balesar R, Swaab DF (2000b).
Differential expression of estrogen receptor alpha and
beta immunoreactivity in the human supraoptic nucleus in
relation to sex and aging. J Clin Endocrinol Metab 85:
32833291.
Ishunina TA, Salehi A, Swaab DF (2000c). Sex- and age-related
p75 neurotrophin receptor expression in the human supraoptic
nucleus. Neuroendocrinology 71: 243251.
Ishunina TA, Unmehopa UA, Van Heerikhuize JJ, Pool CW,
Swaab DF (2001). Metabolic activity of the human ventromedial nucleus neurons in relation to sex and aging. Brain
Res 893: 7076.
Ishunina TA, Swaab DF (2003). Increased neuronal metabolic
activity and estrogen receptors in the vertical limb of the
diagonal band of Broca in Alzheimers disease: relation to
sex and aging. Exp Neurol 183: 159172.
Ismail K, Murray RM, Wheeler MJ, OKeane V (1998). The
dexamethasone suppression test in schizophrenia. Psychol
Med 28: 311317.
Itagaki S, McGeer PL, Akiyama H, Beattie BL, Walker DG,
Moore GR, McGeer EG (1989). A case of adultonset dementia with argyrophilic grains. Ann Neurol 26:
685689.
Ito H, Hamajima N, Matsuo K, Okuma K, Sato S, Ueda R,
Tajima K (2002). Monoamine oxidase polymorphisms and
smoking behaviour in Japanese. Pharmacogenetics 13: 7379.
Ito M, Mori Y, Oiso Y, Saito H (1991). A single base substitution in the coding region for neurophysin II associated
with familial central diabetes insipidus. J Clin Invest 87:
725728.
Ito M, Jameson L, Ito M (1997). Molecular basis of autosomal
dominant neurohypophyseal diabetes insipidus. J Clin Invest
99: 18971905.
Ito M, Yu RN, Jameson JL (1999). Mutant vasopressin precursors that cause autosomal dominant neurohypophyseal
diabetes insipidus retain dimerization and impair the secretion
of wild-type proteins. J Biol Chem 274: 90299037.
Ito Y, Fisher CR, Conte FA, Grumbach MM, Simpson ER.
(1993). Molecular basis of aromatase deficiency in an adult
female with sexual infantilism and polycystic ovaries. Proc
2014 Refs
2/12/03
1:39 pm
Page 471
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
471
Izumi Y, Tatsumi K, Okamoto S, Ogawa T, Hosokawa A,

Matsuo T, Kato Y, Fukui H, Amino N (2001). Analysis of
the KAL1 gene in 19 Japanese patients with Kallmann
syndrome. Endocr J 48: 143149.
Jackson IMD (1998). The thyroid axis and depression. Thyroid
8: 951956.
Jackson MJ, Bindoff LA, Weber K, Wilson JN, Ince P, Alberti
KGMM, Turnbull DM (1994). Biochemical and molecular
studies of mitochondrial function in diabetes insipidus,
diabetes mellitus, optic atrophy, and deafness. Diabetes Care
17: 728733.
Jackson RS, Creemers JWM, Ohagi S, Raffin-Sanson
M-L, Sanders L, Mantague C, Hutton JC, ORahilly S
(1997). Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase
1 ((PC1) gene. Nat Genet 16: 303306.
Jacobs EH, Yamatodani A, Timmerman H (2000). Is histamine
the final neurotransmitter in the entrainment of circadian
rhythms in mammals? Trends Pharmacol Sci 21: 293298.
Jacobson CD, Shryne JE, Shapiro F, Gorski RA (1980).
Ontogeny of the sexually dimorphic nucleus of the preoptic
area. J Comp Neurol 193: 541548.
Jacobson P, Ukkola O, Rankinen T, Snyder EE, Leon AS, Rao
DC, Skinner JS, Wilmore JH, Lnn L, Cowan GS, Sjstrom
L, Bouchard C (2002). Melanocortin 4 receptor sequence
variations are seldom a cause of human obesity: the Swedish
obese subjects, the HERITAGE family study, and a Memphis
cohort. J Clin Endocrinol Metab 87: 44424446.
Jacobson RR, Lishman WA. (1990). Cortical and diencephalic
lesions in Korsakoffs syndrome: a clinical and CT scan study.
Jacome EG, McLain LW, Fitzgerald R (1980). Postural reflex
gelastic seizures. Arch Neurol 37: 249251.
Jacques D, Tong Y, Dumont Y, Shen SH, Quirion R (1996).
Expression of the neuropeptide Y Y1 receptor mRNA in the human
brain: an in situ hybridization study. Neuroreport 7: 10531056.
Jacques D, Dumont Y, Fournier A, Quirion R (1997).
Characterization of neuropeptide Y receptor subtypes in the
normal human brain, including the hypothalamus. Neuroscience 79: 129148.
Jacques D, Tong, Y, Shen, SH, Quirion, R (1998). Discrete
distribution of the neuropeptide Y Y5 receptor gene in the
human brain: an in situ hybridization study. Mol Brain Res
61: 100107.
Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I,
DeMott-Friberg R, Bermann M Barkan AL (1998).
Regulatory mechanisms of growth hormone secretion are
sexually dimorphic. J Clin Invest 102: 153164.
Jger B, Liedtke R, Knsebeck H-W, Lempa W, Kersting
A, Seide L (1996). Psychotherapy and bulimia nervosa:
evaluation and long-term follow-up of two conflictorientated treatment conditions. Acta Psychiatr Scand 93:
268278.
Itoh M, Nakano E, Ieshima A, Takeshita K (1995). Neuroleptic

malignant syndrome in striatonigral degeneration. Pediatr
Neurol 13: 255256.
Itoh M, Ishizuka B, Kuribayashi Y, Amemiya A, Sumi Y (1999).
Melatonin, its precursors, and synthesizing enzyme activities
in the human ovary. Mol Hum Reprod 5: 402408.
Itoh N, Obata K, Yanaihara N, Okamoto H (1983). Human
preprovasoactive intestinal polypeptide contains a novel PHI27-like peptide, PHM-27. Nature 304: 547549.
Itoi K, Helmreich DL, Lopez-Figueroa, MO, Watson, SJ (1999).
Differential regulation of corticotropin-releasing hormone and
vasopressin gene transcription in the hypothalamus by norepinephrine. J Neurosci 19: 54645472.
Ivaez V, Soler R, Barreiro P (1998). Hypnic headache
syndrome: a case with good response to indomethacin.
Ivanisevic M, Behrens O, Helmer H, Demarest K, Fuchs A-R
(1989). Vasopressin receptors in human pregnant
myometrium and decidua: interactions with oxytocin and
vasopressin agonists and antagonists. Am J Obstet Gynecol
161: 16371643.
Iwai A, Sakano T, Uenishi M, Sugimoto H, Yoshioka T,
Sugimoto T (1989). Effects of vasopressin and catecholamines on the maintenance of circulatory stability in
brain-dead patients. Transplantation 48: 613617.
Iwai H, Ohno Y, Hoshiro M, Fujimoto M, Nishimura A,
Kishitani Y, Aoki N (2000). Syndrome of inappropriate
secretion of antidiuretic hormone (SIADH). and adrenal insufficiency induced by Rathkes cleft cyst: a case report. Endocr
J 47: 393399.
Iwaki T (2001). Hypothalamic mass in a 28-year-old man with
diabetes insipidus ataxia, nystagmus and dysarthria.
Neuropathology 21: 99100.
Iwamoto HS, Rudolph AM, Keil LC, Heymann MA (1979).
Hemodynamic responses of the sheep fetus to vasopressin
infusion. Circ Res 44: 430436.
Iwasaki Y, Oiso Y, Kondo K, Takagi S, Takatsuki K, Hasegawa
H, Ishikawa K, Fujimura Y, Kazeto S, Tomita A (1991).
Aggravation of subclinical diabetes insipidus during pregnancy. N Eng J Med 324: 522526.
Iwasaki Y, Kondo K, Hasegawa H, Oiso Y (1997). Osmoregulation of plasma vasopressin in three cases with adrenal
insufficiency of diverse etiologies. Horm Res 47: 3844.
Iwasaki Y, Oiso Y, Saito H, Majzoub JA (2000). Effects of
various mutations in the neurophysin/glycopeptide portion of
the vasopressin gene on vasopressin expression in vitro.
Tohoku J Exp Med 191: 187202.
Izenberg N, Rosenblum M, Parks JS (1984). The endocrine spectrum of septo-optic dysplasia. Clin Pediatr 23:
632636.
Izumi Y, Tatsumi K, Okamoto S, Hosokawa A, Ueno S, Fukui
H, Amino N (1999). A novel mutation of the KAL1 gene in
Kallmann syndrome. Endocr J 46: 651658.
471
2014 Refs
472
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 472
D.F. SWAAB
Jagla W, Wiede A, Dietzmann K, Rutkowski K, Hoffman W

(2000). Co-localization of TFF3-peptide and oxytocin in the
human hypothalamus. FASEB J 14: 11261131.
Jakacki RI, Cohen BH, Jamison C, Mathews VP, Arenson E,
Longee DC, Hilden J, Cornelius A, Needle M, Heilman D,
Boaz JC, Luerssen TG (2000). Phase II evaluation of interferon--2a for progressive or recurrent craniopharyngiomas.
Jan JE, Espezel H, Freeman RD, Fast DK (1998). Melatonin
treatment of chronic sleep disorders. J Child Neurol 13: 98.
Jan JE, Freeman RD, Fast DK (1999). Melatonin treatment of
sleep-wake cycle disorders in children and adolescents. Dev
Jan JE, Tai J, Hahn G, Rothstein RR (2001). Melatonin replacement therapy in a child with a pineal tumor. J Child Neurol
16: 139140.
Janknegt, RA, Smans AJ (1990). Treatment with desmopressin in
severe nocturnal enuresis in childhood. Br J Urol 66: 535537.
Jankowski M, Wang D, Hajjar F, Mukaddam-Daher S, McCann
SM, Gutkowska J (2000). Oxytocin and its receptors are
synthetized in the rat vasculature. Proc Natl Acad Sci USA
97: 62076211.
Janowsky JS, Oviatt SK, Orwoll ES (1994). Testosterone influences spatial cognition in older men. Behav Neurosci 108:
325332.
Jansen C, Hendriks-Stegeman BI, Jansen M (2000). A novel
nonsense mutation of the KAL gene in two brothers with
Kallmann syndrome. Horm Res 53: 207212.
Jansen LMC, Gispen-De Wied CC, Gademan PJ, De Jonge RCJ,
Van der Linden JA, Kahn RS (1998). Blunted cortisol
response to a psychosocial stressor in schizophrenia.
Schizophrenia Res 33: 8794.
Janss AJ, Grundy R, Cnaan A, Savino PJ, Packer RJ, Zackai
EH, Goldwein JW, Sutton LN, Radcliffe J, Molloy PT,
Phillips PC, Lange BJ (1995). Optic pathway and hypothalamic chiasmatic gliomas in children younger than age 5 years
with a 6-year follow-up. Cancer 75: 10511059.
Janz D (1962). The grand mal epilepsies and the sleepingwaking cycle. Epilepsia 3: 69109.
Jaruratanasirikul S, Patarakijvanich N, Patanapisarnsak C
(1998). The association of congenital hypothyroidism and
congenital gastrointestinal anomalies in Downs syndrome
infants. J Ped Endocrinol Metab 11: 241246.
Jay P, Rougeulle C, Massacrier A, Moncla A, Mattei M-G,
Malzac P, Rockel N, Taviaux S, Berg Lefranc J-L, Cau P,
Berta P, Lalande M, Muscatelli F (1997). The human necdin
gene, NDN, is maternally imprinted and located in the
PraderWilli syndrome chromosomal region. Nat Genet 17:
357361.
Jean-Louis G, Von Gizycki H, Zizi F (1998). Melatonin effects
on sleep, mood, and cognition in elderly with mild cognitive
impairment. J Pineal Res 25: 177183.
Jeffcoate WJ (1999). Chronic fatigue syndrome and functional hypoadrenia - fighting vainly the old ennui. Lancet 353: 424425.
Jelliffe SE, White, WA (1935). Multiple sclerosis syndromes.
In: Jelliffe SE, White WA (Eds.) Disease of the
Nervous System, 6th Edn. Philadelphia; Lae & Febiger,
pp. 590609.
Jenevein EP (1964). A neurohypophyseal tumor originating
from pituicytes. Am J Clin Pathol 41: 522526.
Jengeleski CA, Powers RE, OConnor DT, Price DL (1989).
Noradrenergic innervation of human pineal gland: abnormalities in aging and Alzheimers disease. Brain Res 481:
378382.
Jenkins JS (1991). Thirst and vasopressin. Clin Endocrinol 35:
219220.
Jensen JB, Garfinkel BD (1988). Neuroendocrine aspects of attention deficit hyperactivity disorder. Neurol Clin 6: 111129.
Jensen-Jazbutis, GT (1970). Clinical-anatomical study of
microcephalia vera (a microcephalic brother and sister with
atrophy of the left mamillary body). J Hirnforsch, 12,
287305.
Ji CH, Teng MMH, Chang I (1995). Granular cell tumour of
the neurohypophysis. Neuroradiology 37: 451452.
Jiao Y, Medina L, Veenman CL, Toledo C, Puelles L, Reiner
A (2000). Identification of the anterior nucleus of the ansa
lenticularis in birds as the homolog of the mammalian subthalamic nucleus. J Neurosci 20: 69987010.
Jin CY, Kalimo H, Panula P (2002). The histaminergic system
in human thalamus: correlation of innervation to receptor
expression. Eur J Neurosci 15: 11251138.
Jin Y-P, De Pedro-Cuesta J, Sderstrm M, Stawiarz L, Link
H (2000). Seasonal patterns in optic neuritis and multiple
sclerosis: a meta-analysis. J Neurol Sci 181: 5664.
Jin-No Y, Kamiya Y, Okada M, Watanabe O, Ogasawara M,
Fujinami T (1998). Pregnant woman with transient diabetes
insipidus resistant to 1-desamino8-D-arginine vasopressin.
Endocr J 45: 693696.
Jiroutek MR, Chen M-H, Johnston CC, Longcope C (1998).
Changes in reproductive hormones and sex hormone-binding
globulin in a group of postmenopausal women measured over
10 years. Menopause 5: 9094.
Joel D, Weiner I (1997). The connections of the primate subthalamic nucleus: indirect pathways and the open-interconnected
scheme of basal ganglia-thalamocortical circuitry. Brain Res
Rev 23: 6278.
Joffe RS, Lippert GP, Tray TA, Sawa G, Hovath Z (1987).
Mood disorder and multiple sclerosis. Arch Neurol 44:
376378.
Joffe RT, Sokolov STH, Singer W (1995). Thyroid hormone
treatment of depression. Thyroid 5: 235239.
Johanson CE, Preston JE, Chodobski A, Stopa EG, SzmydyngerChodobska J, McMillan PN (1999). AVP V1 receptormediated decrease in C1- efflux and increase in dark cell
number in choroid plexus epithelium. Am J Physiol 276:
C82C90.
2014 Refs
2/12/03
1:39 pm
Page 473
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
473
in Brain Research vol. 60). Elsevier Science Publishers,

pp. 169182.
Jonat S, Santer R, Schneppenheim R, Obser T, Eggert P (1999).
Effect of DDAVP on nocturnal enuresis in a patient with
nephrogenic diabetes insipidus. Arch Dis Child 81: 5759.
Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy
PJ, Jones B, Czajkowski L, Ptcek LJ (1999). Familial
advanced sleep-phase syndrome: a short-period circadian
rhythm variant in humans. Nat Med 5: 10621065.
Jones EM, Dawson A (1989). Neuroleptic malignant syndrome:
a case report with post-mortem brain and muscle pathology.
Jones E, Burton H, Saper CB, Swanson LW (1976). Midbrain,
diencephalic and cortical relationships of the basal nucleus
of Meynert and associated structures in primates. J Comp
Neurol 167: 385420.
Jones HE, Ruscio MA, Keyser LA, Gonzalez C, Billack B,
Rowe R, Hancock C, Lambert KG, Kinsley CH (1997).
Prenatal stress alters the size of the rostral anterior commissure in rats. Brain Res Bull 42: 341346.
Jones JE, Pick RR, Davenport MD, Keene AC, Corp ES, Wade
GN (2002). Disinhibition of female sexual behavior by a
CRH receptor antagonist in Syrian hamsters. Am J Physiol
283: R591R597.
Jones PB, Harvey I, Lewis SW, Toone BK, Van Os J, Williams
M, Murray RM (1994). Cerebral ventricle dimensions as risk
factors for schizophrenia and affective psychosis: an epidemiological approach to analysis. Psychol Med 24: 9951011.
Jones TJ, Hallworth MJ (1999). Postmortem prolactin as a
marker of antemortem stress. J Clin Pathol 52: 749751.
Jong MTC, Gray TA, Ji Y, Glenn CC, Saitoh S, Driscoll DJ,
Nicholls RD (1999). A novel imprinted gene, encoding a
RING zinc-finger protein, and overlapping antisense transcript
in the PraderWilli syndrome critical region. Hum Mol Genet
8: 783793.
Jongkind JF, Swaab DF (1967). The distribution of thiamine
diphosphate-phosphohydrose in the neurosecretory nuclei
of the rat following osmotic stress. Histochemie 11: 319324.
Jooma R, Grant DN (1983). Third ventricle choroid plexus papillomas. Childs Brain 10: 242250.
Jordan D, Borson-Chazot F, Veisseire M, Deluermoz S, Malicier
D, Dalery J, Kopp N (1992). Disappearance of hypothalamic
TRH asymmetry in suicide patients. J Neural Transm 89:
103110.
Jordan J, Tank J, Diedrich A, Robertson D, Shannon JR (2000).
Vasopressin and blood pressure in humans. Hypertension 36:
E3E4.
Joseph MG, Jouanny AC, Chomienne F, Champion G, Ginis
JL, Limal JM (1993). Hypothalamic dysfunction. Review of
clinical and endocrinological disorders (in French). Ann
Pdiatr 40: 475479.
Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, Wehr TA,
Skwerer R, Kasper S, Gold PW (1991). Abnormal pituitary-
Johansson , Olsson T, Carlberg B, Karlsson K, Fagerlund M

(1997). Hypercortisolism after stroke partly cytokine-mediated? J Neurol Sci 147: 4347.
Johansson C, Smedh C, Partonen T, Pekkarinen P, Paunio T,
Ekholm J, Peltonen L, Lichtermann D, Palmgren J, Adolfsson
R, Schalling M (2001). Seasonal affective disorder and serotonin-related polymorphisms. Neurobiol Dis 8: 351357.
Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kiesepp
T, Lichtermann D, Praschak-Rieder N, Neumeister A, Nilsson
L-G, Kasper S, Peltonen L, Adolfsson R, Schalling M,
Partonen T (2003). Circadian clock-related polymorph-isms in
seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28: 734739.
Johnson A, Josephson R, Hawke M (1985). Clinical and
histological evidence for the presence of the vomeronasal
(Jacobsons) organ in adult humans. J Otolaryngol 14:
7179.
Johnson AE, Coirini H, Insel T, McEwen BS (1991). The
regulation of oxytocin receptor binding in the ventromedial
hypothalamic nucleus by testosterone and its metabolites.
Johnson AG, Crawford GA, Kelly D, Nguyen TV, Gyory AZ
(1994). Arginine vasopressin and osmolality in the elderly. J
Am Geriatr Soc 42: 399404.
Johnson AK, Cunningham JT, Thunhorst RL (1996). Integrative
role of the lamina terminalis in the regulation of cardiovascular and body fluid homeostasis. Clin Exp Pharmacol
Physiol 23: 183191.
Johnson HR, Myhre SA, Ruvalcaba RHA, Thuline HC, Kelley
VC (1970). Effects of testosterone on body image and
behavior in Klinefelters syndrome: a pilot study. Dev Med
Child Neurol 12: 454460.
Johnson JG, Cohen P, Kasen S, Brook JS (2002a). Childhood
adversities associated with risk for eating disorders or weight
problems during adolescence or early adulthood. Am J
Johnson JG, Cohen P, Kasen S, Brook JS (2002b). Eating
disorders during adolescence and the risk for physical and
mental disorders during early adulthood. Arch Gen Psychiatry
59: 545552.
Johnston CI (1985). Vasopressin in circulatory control and
hypertension. J. Hypertension 3: 557569.
Joiner TE, Pfaff JJ, Acres JG, Johnson F (2002). Birth month
and suicidal and depressive symptoms in Australians born in
the Southern vs. the Northern hemisphere. Psychiatry Res
112: 8992.
Jolkkonen J, Helkala E-L, Kutvonen R, Lehtinen M, Riekkinen PJ
(1989). Vasopressin levels in CSF of Alzheimer patients: correlations with monoamine metabolites and neuropsychological test
performance. Psychoneuroendocrinology 14: 8995.
Jolles J (1983). Vasopressin-like peptides and the treatment of
memory disorders in man. In: Cross BA, Leng G (Eds.) The
Neurohypophysis: Structure, Function and Control (Progress
473
2014 Refs
474
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 474
D.F. SWAAB
adrenal responses to corticotropin-releasing hormone in

patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab 72:
13821387.
Jouvet A, Fvre-Montange M, Besanon R, Derrington E, SaintPierre G, Belin MF, Pialat J, Lapras C (1994). Structural and
ultrastructural characteristics of human pineal gland, and
pineal parenchymal tumors. Acta Neuropathol 88: 334348.
Judge DM, Kulin HE, Page R, Santen R, Trapukdi S (1977).
Hypothalamic hamartoma: a source of luteinizing-hormonereleasing factor in precocious puberty. New Eng J Med 296:
710.
Jung H, Carmel P, Schwarz MS, Witkin JW, Bentele KHP,
Westphal M, Piatt JH, Costa ME, Cornea A, Ma YJ, Ojeda
SR (1999). Some hypothalamic hamartomas contain transforming growth factor , a puberty-inducing growth factor,
but not luteinizing hormone-releasing hormone neurons. J
Jung H, Ojeda SR (2002). Pathogenesis of precocious puberty
in hypothalamic hamartoma. Horm Res 57 (Suppl. 2):
3134.
Jungheim K, Badenhoop K, Ottmann OG, Usadel KH (1999).
KleineLevin and Munchausen syndromes in a patient with
recurrent acromegaly. Eur J Endocrinol 140: 140142.
Justino L, Kergoat M-J, Bergman H, Chertkow H, Robillard A,
Kergoat H (2001). Neuroretinal function is normal in early
dementia of the Alzheimer type. Neurobiol Aging 22:
691695.
Kadotani H, Faraco J, Mignot E (1998). Genetic studies in the
sleep disorder narcolepsy. Genome Res 8: 427434.
Kadva A, Djahanbakch O, Monson J, Di WL, Silman R (1998).
Elevated nocturnal melatonin is a consequence of
gonadotropin-releasing hormone deficiency in women with
hypothalamic amenorrhea. J Clin Endocrinol Metab 83:
36533662.
Kagan H (1958). Anorexia and severe inanition associated with
a tumour involving the hypothalamus. Arch Dis Child 33:
257260.
Kageji T, Nagahiro S, Horiguchi H, Watanabe T, Suzuya H,
Okamoto Y, Kuroda Y (2003). Successful high-dose
chemotherapy for widespread neuroaxis dissemination of an
optico-hypothalamic juvenile pilocytic astrocytoma in an
infant: a case report. J Neuro-Oncol 62: 281287.
Kahane P, Tassi L, Hoffmann D, Francione S, Gratadou-Juery
G, Pasquier B, Munari C (1994). Crises dacrystiques et hamartome hypothalamique: propos dune observation
vido-stro-EEG. Epilepsies 6: 259279.
Kahane P, Di Leo M, Hoffmann D, Munari C (1999). Ictal
bradycardia in a patient with a hypothalamic hamartoma: a
stereo-EEG study. Epilepsia 40: 522527.
Kahn EA, Crosby EC (1972). Korsakoffs syndrome associated
with surgical lesions involving the mamillary bodies.
Khan MH, Johnson FC (1987). Kleine-Levin syndrome: a

review. SDJ Med 40: 710.
Kaiya H, Tanaka T, Takeuchi K, Morita K, Adachi S, Shirakawa
H, Ueki H, Namba M (1983). Decreased level of -endorphin-like immunoreactivity in cerebrospinal fluid of patients
with senile dementia of Alzheimer type. Life Sciences 33:
10391043.
Kajantie E, Phillips DIW, Andersson S, Barker DJP, Dunkel L,
Forsn T, Osmond C, Tuominen J, Wood PJ, Eriksson J
(2002). Size at birth, gestational age and cortisol secretion in
adult life: foetal programming of both hyper- and hypocortisolism? Clin Endocrinol 57: 635641.
Kakiya S, Arima H, Yokoi H, Murase T, Yambe Y, Oiso Y
(2000). Effects of acute hypotensive stimuli on arginine vasopressin gene transcription in the rat hypothalamus. Am J
Physiol 279: E886-E892.
Kalimo H, Garcia JH, Kamijyo Y, Tanaka J, Viloria JE,
Valigorsky JM, Jones RT, Kim KM, Mergner WJ,
Pendergrass RE, Trump BF (1974). Cellular and subcellular
alterations of human CNS. Arch Pathol 97: 352359.
Kallas HE, Chintanadilok J, Maruenda J, Donahue JL,
Lowenthal DT (1999). Treatment of nocturia in the elderly.
Drugs Aging 15: 429437.
Kallmann FJ (1952). Comparative twin study on the genetic aspects
of male homosexuality. J Nerv Mental Dis 115: 283298.
Kallmann F, Schoenfeld WA, Barrera SE (1944). The genetic
aspects of primary eunuchoidism. Am J Ment Defic 48:
203236.
Kalmijn S, Launer LJ, Stolk RP, De Jong FH, Pols HAP,
Hofman A, Breteler MMB, Lamberts SWJ (1998). A prospective study on cortisol, dehydroepiandrosterone sulfate, and
cognitive function in the elderly. J Clin Endocrinol Metab
83: 34873492.
Kalmijn S, Mehta KM, Pols HAP, Hofman A, Drexhage HA,
Breteler MMB (2000). Subclinical hyperthyroidism and the
risk of dementia. The Rotterdam study. Clin Endocrinol 53:
733737.
Kalra SP and Kalra PS (1996). Nutritional infertility: the role
of the interconnected hypothalamic neuropeptide-Ygalaninopioid network. Front Neuroendocrinol 17: 371401.
Kalra SP, Horvath T, Naftolin F, Xu B, Pu S, Kalra PS
(1997). The interactive language of the hypothalamus for
the gonadotropin releasing hormone (GNRH) system. J
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS (1999).
Interacting appetite-regulating pathways in the hypothalamic
regulation of body weight. Endocr Rev 20: 68100.
Kalsbeek A, Buijs RM, Van Heerikhuize JJ, Arts M, Van der
Woude TP (1992). Vasopressin-containing neurons of the
suprachiasmatic nuclei inhibit corticosterone release. Brain
Res 580: 6267.
Kalsbeek A, Teclemariam-Mesbah R, Pvet P (1993). Efferent
projections of the suprachiasmatic nucleus in the golden
2014 Refs
2/12/03
1:39 pm
Page 475
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
475
Kanbayashi T, Yano T, Ishiguro H, Kawanishi K, Chiba S,

Aizawa R, Sawaishi Y, Hirota K, Nishino S, Shimizu T
(2002b). Hypocretin1 (orexin-A) levels in human lumbar
CSF in different age groups: infants to elderly persons. Sleep
25: 337339.
Kanbayashi T, Abe M, Fujimoto S, Miyachi T, Takahashi T,
Yano T, Sawaishi Y, Arii J, Szilagyi G, Shimizu T (2003).
Hypocretin deficiency in NiemannPick type C with cataplexy. Neuropediatrics 34: 5253.
Kandel E, Brennan PA, Mednick SA, Michelson NM (1989).
Minor physical anomalies and recidivistic adult violent criminal behavior. Acta Psychiatr Scand 79: 103107.
Kandel E, Mednick, SA (1991). Perinatal complications predict
violent offending. Criminology 29: 519529.
Kaneda Y, Fujii A (2000). Effects of chronic neuroleptic administration on the hypothalamo-pituitary-gonadal axis of male
schizophrenics. Prog Neuropsychopharmacol Biol Psychiatry
24: 251258.
Kaneda Y, Fujii A, Ohmori T (2002). The hypothalamic-pituitary-adrenal axis in chronic schizophrenic patients long-term
treated with neuroleptics. Prog Neuropsychopharmacol Biol
Kaneko M, Yokoyama F, Hoshino Y, Takahagi K, Murata S,
Watanabe M, Kumashiro H (1992). Hypothalamic-pituitaryadrenal axis function in chronic schizophrenia: association
with clinical features. Neuropsychobiology 25: 17.
Kaneko M, Hoshino Y, Hashimoto S, Okano T, Kumashiro H
(1993). Hypothalamic-pituitary-adrenal axis function in children with attention-deficit hyperactivity disorder. J Autism
Dev Disord 23: 5965.
Kang S, Graham JM, Olney AH, Biesecker LG (1997). GL13
frameshift mutations cause autosomal dominant PallisterHall
syndrome. Nat Genet 15: 266268.
Kaplan AS, Garfinkel PE (1988). The neuroendocrinology of
anorexia nervosa. In: Collu R, Brown GM, Van Loon GR
(Eds.) Clinical Neuroendocrinology, pp. 105122, Blackwell
Scientific Publications, Boston, USA.
Kaplan J, Fredrickson PA, Richardson JW (1991). Sleep and
breathing in patients with the PraderWilli syndrome. Mayo
Clin Proc 66: 11241126.
Kaplan SL, Grumbach MM, Hoyt WF (1970). A syndrome of
hypopituitary dwarfism, hypoplasia of optic nerves, and
malformation of prosencephalon: report of 6 patients. Pediatr
Res 4: 480481.
Kapur N (1997). (Ed.) Injured Brains of Medical Minds. Views
from Within. Oxford University Press, Oxford. 426 pp.
Kapur N, Barker S, Burrows EH, Ellison D, Brice J, Illis LS,
Scholey K, Colbourn C, Wilson B, Loates M (1994). Herpes
simplex encephalitis: long-term magnetic resonance imaging
and neuropsychological profile. J Neurol Neurosurg
Kapur N, Thompson S, Cook P, Lang D, Brice J (1996).
Anterograde but not retrograde memory loss following
hamster (Mesocricetus auratus). J Comp Neurol 332:

293314.
Kalsbeek A, Garidou M-L, Palm IF, Van der Vliet J,
Simonneaux V, Pvet P, Buijs RM (2000a). Melatonin sees
the light: blocking GABA-ergic transmission in the paraventricular nucleus induces daytime sectretion of melatonin. Eur
J Neurosci 12: 31463154.
Kalsbeek A, Fliers E, Franke AN, Wortel J, Buijs RM
(2000b). Functional connections between the suprachiasmatic
nucleus and the thyroid gland as revealed by lesioning and
viral tracing techniques in the rat. Endocrinology 141:
38323841.
Kaltsas GA, Powles TB, Evanson J, Plowman PN, Drinkwater
JE, Jenkins PJ, Monson JP, Besser GM, Grossman AB (2000).
Hypothalamo-pituitary abnormalities in adult patients with
Langerhans cell histiocytosis: clinical, endocrinological, and
radiological features and response to treatment. J Clin
Kamalian N, Keesey RE, ZuRhein GM (1975). Lateral hypothalamic demyelination and cachexia in a case of malignant
multiple sclerosis. Neurology 25: 2530.
Kamei Y, Hayakawa T, Urata J, Uchiyama M, Shibui K, Kim
K, Kudo Y, Okawa M (2000a). Melatonin treatment for
circadian rhythm sleep disorders. Psychiatry Clin Neurosci
54: 381382.
Kamei T, Toriumi Y, Kimura H, Ohno S, Kumano H, Kimura
K (2000b). Decrease in serum cortisol during yoga exercise
is correlated with alpha wave activation. Percept Mot Skills
90: 10271032.
Kamel N, Ilgin SD,
orapioglu D, Deda H, Gll S (1998).
Lymphocytic infundibuloneurohypophysitis presenting as
diabetes insipidus in a man. J Endocrinol Invest 21: 537540.
Kaminsky R, Moriarty TM, Bodine J, Wolf DE, Davidson M
(1990). Effect of famotidine on deficit symptoms of schizophrenia. Lancet 335: 13511352.
Kammerer-Doak DN, Rogers RG, Johnson Maybach J, Traynor
Mickelson M (2001). Vasopressin as an etiologic factor for
infection in gynecologic surgery: a randomized double-blind
placebo-controlled trial. Am J Obstet Gynecol 185:
13441348.
Kamoi K, Toyama M, Takagi M, Koizumi T, Nishiyama K-I,
Takahashi K, Sasaki H, Muto T (1999). Osmoregulation
of vasopressin secretion in patients with the syndrome of
inappropriate antidiuresis associated with central nervous
system disorders. Endocr J 46: 269277.
Kamsteeg EJ, Deen PMT, Van Os CH (2000). Defective
processing and trafficking of water channels in nephrogenic
diabetes insipidus. Exp Nephrol 8: 326331.
Kanbayashi T, Inoue Y, Chiba S, Aizawa R, Saito Y, Tsukamoto
H, Fujii Y, Nishino S, Shimizu T (2002a). CSF hypocretin1
(orexin-A) concentrations in narcolepsy with and without
cataplexy and idiopathic hypersomnia. J Sleep Res 11:
9193.
475
2014 Refs
476
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 476
D.F. SWAAB
combined mammillary body and medial thalamic lesions.

Neuropsychologia 34: 18.
Karalis K, Muglia LJ, Bae D, Hilderbrand H, Majzoub JA (1997).
CRH and the immune system. J Immunol 72: 131136.
Karama S, Roch Lecours A, Leroux J-M, Bourgouin P,
Beaudoin G, Joubert S, Beauregard M (2002). Areas of brain
activation in males and females during viewing of erotic film
excerpts. Hum Brain Mapp 16: 113.
Karasek M (1999). Melatonin in humans where we are 40
years after its discovery. Neuroendocrinol Lett 20: 179188.
Karasek M, Pawlikowski M (1999). Pineal gland, melatonin
and cancer. Neuroendocrinol Lett 20: 139144.
Karasek M, Stankiewicz A, Bandurska-Stankiewicz E, Zylinska
K, Pawlikowski M, Kuzdak K (2000). Melatonin concentrations in patients with large goiter before and after surgery.
Karasek M, Szuflet A, Chrzanowski W, Zylinska K,
Swietoslawski J (2002). Circadian serum melatonin profiles
in patients suffering from chronic renal failure.
Neuroendocrinol Lett 23 (Suppl. 1): 97102.
Kariyawasam SH, Zaw F, Handley SL (2002). Reduced salivary cortisol in children with comorbid attention deficit
hyperactivity disorder and oppositional defiant disorder.
Krkel J, Vakkuri O, Kaukinen S, Huang W-Q, Pasanen M
(2002). The influence of anaesthesia and surgery on the circadian rhythm of melatonin. Acta Anaesthesiol Scand 46:
3036.
Karlsborg M, Smed A, Jespersen H, Stephensen S, Cortsen M,
Jennum P, Herning M, Korfitsen E, Werdelin L (1997). A
prospective study of 39 patients with whiplash injury. Acta
Neurol Scand 95: 6572.
Karlsson B, Gustafsson J, Hedov G, Ivarsson S-A, Annern G
(1998). Thyroid dysfunction in Downs syndrome: relation to
age and thyroid autoimmunity. Arch Dis Child 79: 242245.
Karp M, Laron Z, Sandbank U (1978). Wolfram syndrome. Am
J Dis Child 132: 818819.
Kartha KNB, Ramakrishna T (1996). The role of sexually dimorphic medial preoptic area of the hypothalamus in the sexual behaviour of male and female rats. Physiol Res 45:
459466.
Kasashima S, Oda Y (2003). Cholinergic neuronal loss in the
basal forebrain and mesopontine tegmentum of progressive
supranuclear palsy and corticobasal degeneration. Acta
Kasckow JW, Hagan M, Mulchahey JJ, Baker DG, Ekhator NN,
Strawn JR, Nicholson W, Orth DN, Loosen PT, Geracioti Jr
TD (2001a). The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in human. Brain Res 904:
218224.
Kasckow JW, Baker D, Geriacioti TD (2001b). Corticotropinreleasing hormone in depression and post-traumatic stress
disorder. Peptides 22: 845851.
Kashani AH, Hutchins GM (2001). Meningeal-cutaneous relationships in anencephaly: evidence for a primary
mesenchymal abnormality. Hum Pathol 32: 553558.
Kasting NW (1989). Criteria for establishing a physiological
role for brain peptides. A case in point: the role of vasopressin in thermoregulation during fever and antipyresis.
Brain Res Rev 14: 143153.
Katayama Y, Tsubokawa T, Maeda T, Yamamoto T (1994).
Surgical management of cavernous malformations of the third
ventricle. J Neurosurg 80: 6472.
Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS,
Parfrey PS, Ansley SJ, Davidson WS, Lupski JR (2000).
Mutations in MKKS cause obesity, retinal dystrophy and renal
malformations associated with BardetBiedl syndrome. Nat
Genet 26: 6770.
Katz B, Rimmer S, Iragui V, Katzman R (1989). Abnormal pattern electroretinogram in Alzheimers disease: evidence for
retinal ganglion cell degeneration? Ann Neurol 26: 221225.
Katz ES, McGrath S, Marcus CL (2000). Late-onset central
hypoventilation with hypothalamic dysfunction: a distinct
clinical syndrome. Pediatr Pulmonol 29: 6268.
Katz G, Durst R, Zislin Y, Barel Y, Knobler HY (2001).
Psychiatric aspects of jet lag: review and hypothesis. Med
Hypotheses 56: 2023.
Katz JD, Ropper AH (2002). Familial KleineLevin syndrome.
Katz JM, Bruno KM, Winterkorn JMS, Nealon N (2003). The
pathogenesis and treatment of optic disc swelling in neurosarcoidosis. Arch Neurol 60: 426430.
Kaufman J, Birmaher B, Perel J, Dahl RE, Moreci P, Nelson
B, Wells W, Ryan ND (1997). The corticotropin-releasing
hormone challenge in depressed abused, depressed
nonabused, and normal control children. Biol Psychiat 42:
669679.
Kaufman LM, Miller MT, Mafee MF (1989). Magnetic resonance imaging of pituitary stalk hypoplasia. Arch Ophthalmol
107: 14851489.
Kaufmann H, Oribe E, Miller M, Knott P, Wiltshire-Clement
M, Yahr, MD (1992). Hypotension-induced vasopressin
release distinguishes between pure autonomic failure and
multiple system atrophy with autonomic failure. Neurology
42: 590593.
Kaufmann WA, Barnas U, Mayer J, Saria A, Alheid GF,
Marksteiner J (1997). Neurochemical compartments in the
human forebrain: evidence for a high density of secretoneuron-like immunoreactivity in the extended amygdala.
Synapse 26: 114130.
Kaufmann H, Bhattacharya KF, Voustianiouk A, Gracies JM
(2002). Stimulation of the subthalamic nucleus increases heart
rate in patients with Parkinsons disease. Neurology 59:
16571658.
Kauppila A, Kivel A, Pakarinen A, Vakkuri O (1987a). Inverse
seasonal relationship between melatonin and ovarian activity
2014 Refs
2/12/03
1:39 pm
Page 477
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
477
Keil LC, Ellis S (1976). Plasma vasopressin and renin activity

in women exposed to bed rest and Gz acceleration. J Appl
Physiol 40: 911914.
Kelemen J, Becus T (1977). Histopathologic changes of the
human hypothalamus in systemic atherosclerosis (a clinicopathological study). Neurol Psychiat 15: 6572.
Kelley S, Robertson L, Amico J (1992). Antidiuretic action of
oxytocin in humans. Clin Res 40: 711A.
Kellner M, Wiedemann K, Holsboer F (1992). Atrial natriuretic
factor inhibits the CRH-stimulated secretion of ACTH and
cortisol in man. Life Sci 50: 18351842.
Kellner M, Yassouridis A, Manz B, Steiger A, Holsboer F,
Wiedemann K (1997). Corticotropin-releasing hormone
inhibits melatonin secretion in healthy volunteers a potential
link to low-melatonin syndrome in depression? Neuroendocrinology 65: 284290.
Kelly JJ, Williamson PM, Whitworth JA (1998). Cortisol and
hypertension. Clin Exp Pharmacol Physiol suppl. 25:
S51S56.
Kelly TM, Mann JJ (1996). Validity of DSM-III-R diagnosis
by psychological autopsy: a comparison with clinician antemortem diagnosis. Acta Psychol Scand 94: 337343.
Kelly WM, Kucharczyk W, Kucharczyk J, Kjos B, Peck WW,
Norman D, Newton TH (1988). Posterior pituitary ectopia: an
MR feature of pituitary dwarfism. Am J Neuroradiol 9: 453460.
Kelts KA, Hoehn MM (1978). Hypothalamic atrophy. J Clin
Kemper TL, Bauman, M (1998). Neuropathology of infantile
autism. J Neuropathol Exp Neurol 57: 645652.
Kendall AR, Lewy AJ, Sack RL (2001). Effects of aging on
the intrinsic circadian period of totally blind humans. J Biol
Rhythms 16: 8795.
Kendler KS, Weitzman RE, Fisher DA (1978). The effect of
pain on plasma arginine vasopressin concentrations in man.
Kennaway DJ, Royles P (1986). Circadian rhythms of 6-sulphatoxy melatonin, cortisol and electrolyte excretion at the
summer and winter solstices in normal men and women. Acta
Kennaway DJ, Van Dorp CF (1991). Free-running rhythms of
melatonin, cortisol, electrolytes, and sleep in humans in
Antarctica. Am J Physiol 260: R11371144.
Kennaway DJ, Voultsios A (1998). Circadian rhythm of free
melatonin in human plasma. J Clin Endocrinol Metab 83:
10131015.
Kennaway DJ, Lushington, K, Dawson D, Lack, L, Van den
Heuvel C, Rogers, N (1999). Urinary 6-sulfatoxymelatonin
excretion and aging: new results and a critical review of the
literature. J Pineal Res 27: 210220.
Kennaway DJ, Flanagan DE, Moore VM, Cockington RA,
Robinson JS, Phillips DIW (2001). The impact of fetal size
and length of gestation on 6-sulphatoxymelatonin excretion
in adult life. J Pineal Res 30: 188192.
in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metabol 65: 823828.
Kauppila A, Pakarinen A, Kirkinen P, Mkil U (1987b). The
effect of season on the circulating concentrations of anterior
pituitary, ovarian and adrenal cortex hormones and hormone
binding proteins in the subarctic area; evidence of increased
activity of the pituitary-ovarian axis in spring. Gynecol
Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ (2000).
Disturbed neuroendocrine-immune interactions in chronic
fatigue syndrome. J Clin Endocrinol Metabol 85: 692696.
Kavvadia V, Greenough A, Dimitriou G, Forsling ML (2000).
A comparison of arginine vasopressin levels and fluid balance
in the perinatal period in infants who did and did not develop
chronic oxygen dependency. Biol Neonate 78: 8691.
Kawachi T, Ishii K, Sakamoto S, Matsui M, Mori T, Sasaki M
(2002). Gender differences in cerebral glucose metabolism:
a PET study. J Neurol Sci 199: 7983.
Kaye WH, George DT, Gwirtsman HE, Jimerson DC, Goldstein
DS, Ebert MH, Lake CR (1990). Isoproterenol infusion test in
anorexia nervosa: assessment of pre- and post-beta-noradrenergic receptor activity. Psychopharmacol Bull 26:
355359.Kaye WH (1996). Neuropeptide abnormalities in
anorexia nervosa. Psychiatry Res 62: 6574.
Kaye WH (1997). Anorexia nervosa, obsessional behavior, and
serotonin. Psychopharmacol Bull 33: 335344.
Kaye W, Gendall K, Strober M (1998). Serotonin neuronal
function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa. Biol Psychiatry 44:
825838.
Kaye W, Strober M, Stein D, Gendall K (1999). New directions in treatment research of anorexia and bulimia nervosa.
Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM (2001).
A randomized, double-blind, placebo-controlled crossover
study of the effect of exogenous melatonin on delayed sleep
phase syndrome. Psychosom Med 63: 4048.
Keck ME, Sillaber I, Ebner K, Welt T, Toschi N, Kaehler ST,
Singewald N, Phillippu A, Eibel GK, Wotjak CT, Holsboer
F, Landgraf R, Engelmann M (2000). Acute transcranial
magnetic stimulation of frontal brain regions selectively
modulates the release of vasopressin, biogenic amines and
amino acids in the rat brain. Eur J Neurosci 12: 37133720.
Keck ME, Holsboer F (2001). Hyperactivity of CRH neuronal
circuits as a target for therapeutic interventions in affective
disorders. Peptides 22: 835844.
Keenan DM, Veldhuis JD (2001). Disruption of the hypothalamic luteinizing hormone pulsing mechanism in aging men.
Am J Physiol 281: R1917-R1924.
Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress
ME, Yaldoo DT (1996). The effect on memory of chronic
prednisone treatment in patients with systemic disease.
Neurology 47: 13961402.
477
2014 Refs
478
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 478
D.F. SWAAB
Kennedy KA, Fielder AR, Hardy RJ, Tung B, Gordon DC,

Reynolds JD (2001). Reduced lighting does not improve
medical outcomes in very low birth weight infants. J Pediatr
139: 527531.
Kennedy P, Kendrick JW, Stormont C (1957). Adenohypophyseal aplasia, an inherited defect associated with abnormal
gestation in Guernsey cattle. Cornell Vet 47: 160178.
Kennedy SH, Brown GM, Garfinkel PE, McVey G, Costa D,
Parienti V (1990). Sulphatoxy melatonin: an index of depression in anorexia nervosa and bulimia nervosa. Psychiatry Res
32: 221227.
Kennett DJ, Devlin MC, Ferrier BM (1982). Influence of
oxytocin on human memory processes: validation by a control
study. Life Sci 31: 273275.
Keogh HJ, Johnson RH, Nanda RN, Sulaiman WR (1976).
Altered growth hormone release in Huntingtons chorea. J
Keogh, AM, Howlett, TA, Perry, L, Rees, LH (1988). Pituitary
function in brain-stem dead organ donors: a prospective
survey. Transplant Proc 20: 729730.
Kepes JJ, Kepes M (1969). Predominantly cerebral forms of
Histiocytosis-X. Acta Neuropathol 14: 7798.
Kergoat H, Kergoat M-J, Justino L, Chertkow H, Robillard A,
Bergman H (2001). An evaluation of the retinal nerve fiber
layer thickness by scanning laser polarimetry in individuals
with dementia of the Alzheimer type. Acta Ophthalmol Scand
79: 187191.
Kern W, Dodt C, Born J, Fehm HL (1996). Changes in cortisol
and growth hormone secretion during nocturnal sleep in the
course of aging. J Gerontol 51A: M3M9.
Kern W, Schiefer B, Schwarzenburg J, Stange EF, Born J, Fehm
HL (1997). Evidence for central nervous effects of corticotropin-releasing hormone on gastric acid secretion in
humans. Neuroendocrinology 65: 291298.
Kerr GD (1973). Acute intermittent porphyria and inappropriate
secretion of antidiuretic hormone in pregnancy. Proc Royal
Soc Med 66: 763764.
Kertzner RM, Goetz R, Todak G, Cooper T, Lin S-H, Reddy
MM, Novacenko H, Williams JBW, Ehrhardt AA, Gorman
JM (1993). Cortisol levels, immune status, and mood in homosexual men with and without HIV infection. Am J Psychiatry
150: 16741678.
Kesler A, Gadoth N, Vainstein G, Peled R, Lavie P (2000).
KleineLevin syndrome (KLS). in young females. Sleep 23:
563567.
Kessler AR (2002). Tourette syndrome associated with body
temperature dysregulation: possible involvement of an idiopathic hypothalamic disorder. J Child Neurol 17: 738744.
Kessler, RC, McGonagle, KA, Zhao, S, Nelson CB, Hughes,
M, Eshleman, S, Wittchen, H-U, Kendler, KS (1994).
Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psych 51:
819.
Keverne EB (1999). The vomeronasal organ. Science 286:

716720.
Keverne EB, Fundele R, Narasimha M, Barton SC, Surani MA
(1996). Genomic imprinting and the differential roles of
parental genomes in brain development. Brain Res Dev 92:
91100.
Khafaga Y, Jenkin D, Kanaan I, Hassounah M, Shabanah MA,
Gray A (1998). Craniopharyngioma in children. Int J Radiat
Oncol Biol Phys 42: 601606.
Khafaga Y, Hassounah M, Kandil A, Kanaan I, Allam A, El
Husseiny G, Kofide A, Belal A, Al Shabanah M, Schultz H,
Jenkin D (2003). Optic gliomas: a retrospective analysis of
50 cases. Int J Radiat Oncol Biol Phys 56: 807812.
Khan MH, Johnson FC (1987). KleineLevin syndrome: a
review. S D J Med 40: 710.
Khan SG, Levy, HL, Legerski, R, Quackenbush E, Reardon,
JT, Emmert, S, Sancar, A, Li, L, Schneider, TD, Cleaver, JE,
Kraemer, KH (1998). Xeroderma pigmentosum group C
splice mutation associated with autism and hypoglycinemia.
J Invest Dermatol 111: 791796.
Khan-Dawood FS, Dawood MY (1984). Oxytocin content of
human fetal pituitary glands. Am J Obstet Gynecol 148:
420422.
Khanim F, Kirk J, Latif F, Barrett TG (2001). WFS1/Wolframin
mutations, Wolfram syndrome, and associated diseases. Hum
Mutat 17: 357367.
Khardori R, Stephens JW, Page OC, Dow RS (1983). Diabetes
mellitus and optic atrophy in two siblings: a report on a new
association and a review of the literature. Diabetes Care 6:
6770.
Kida Y, Kobayashi T, Mori Y (2000). Gamma knife radiosurgery for low-grade astrocytomas: results of long-term
follow up. J Neurosurg 93 (Suppl. 3): 4246.
Kieff DA, Boey H, Schaeffer PW, Goodman M, Joseph MP
(1997). Isolated neurosarcoidosis presenting as anosmia
and visual changes. Otolaryngol Head Neck Surg 117: S183S186.
Kihara T, Miyata M (2002). Brain abscess formed in the cavum
septi pellucidi. J Neurol Neurosurg Psychiatry 72: 411.
Kikuchi, S, Fukazawa, T, Niino, M, Yabe, I, Miyagishi, R,
Hamada, T, Tashiro, K (2002). Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients:
interaction with HLA-DRB1*1501 and disease modulation.
J Neuroimmunol 128: 7781.
Killeffer FA, Stern WE (1970). Chronic effects of hypothalamic injury. Arch Neurol 22: 419429.
Kim JH, Tien RD, Felsberg GJ, Osumi AK, Lee N (1995).
Clinical significance of asymmetry of the fornix and mamillary body on MR in hippocampal sclerosis. Am J Neuroradiol
16: 509515.
Kim JK, Summer SN, Wood WM, Schrier RW (2001b).
Role of glucocorticoid hormones in arginine vasopressin gene
regulation. Biochem Biophys Res Comm 289: 12521256.
2014 Refs
2/12/03
1:39 pm
Page 479
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
479
Kirkland JL, Lye M, Godddard C, Vargas E, Davies I (1984).

Plasma arginine vasopressin in dehydrated elderly patients.
Kirkpatrick B, Litman D, Kim JW, Vladar K, Breier A,
Buchanan RW (1997). Failure of fusion of the septum pellucidum and the heterogeneity of schizophrenia. J Nerv Ment
Dis 185: 639641.
Kirkpatrick M, Smith C, Roy R (1981). Lesbian mothers and
their children: a comparative survey. Am J Orthopsychiatry
51: 545551.
Kirschbaum C, Kudielka BM, Gaab J, Schommer NC,
Hellhammer DH (1999). Impact of gender, menstrual
cycle phase, and oral contraceptives on the activity of the
hypothalamus-pituitary-adrenal axis. Psychosom Med 61:
154162.
Kirveskari E, Partinen M, Santavuori P (2001). Sleep and its
disturbance in a variant form of late infantile neuronal ceroid
lipofuscinosis (CLN5). J Child Neurol 16: 707713.
Kish S, Karlinsky H, Becker L, Gilbert J, Rebbetoy M, Chang
L-J, DiStefano L, Hornykiewicz O (1989). Downs syndrome
individuals begin life with normal levels of brain cholinergic
markers. J Neurochem 52: 11831187.
Kish SJ, Kleinert R, Minauf M, Gilbert J, Walter GF, Slimovitch
C, Maurer E, Rezvani Y, Myers R, Hornykiewicz O (1990).
Brain neurotransmitter changes in three patients who had a
fatal hyperthermia syndrome. Am J Psychiatry 147:
13581363.
Kish SJ, Mamelak M, Slimovitch C, Dixon LM, Lewis A,
Shannak K, DiStefano L, Chang LJ, Hornykiewicz O (1992).
Brain neurotransmitter changes in human narcolepsy.
Kish SJ, Kalasinsky KS, Furukawa Y, Guttman M, Ang L, Li
L, Adams V, Reiber G, Anthony RA, Anderson W, Smialek
J, DiStefano L (1999). Brain choline acetyltransferase activity
in chronic, human users of cocaine, methamphetamine, and
heroin. Mol Psychiatry 4: 2632.
Kiss JZ, Mezey E (1986). Tyrosine hydroxylase in magnocellular neurosecretory neurons; response to physiological
manipulations. Neuroendocrinology 43: 519525.
Kita K (1992). RileyDay syndrome (familial dysautonomia).
Nippon Rinsho 50: 846851.
Kitahama K, Ikemoto K, Jouvet A, Nagatsu I, Sakamoto N,
Pearson J (1998a). Aromatic L-amino acid decarboxylaseand tyrosine hydroxylase-immunohistochemistry in the adult
human hypothalamus. J Chem Neuroanat 16: 4355.
Kitahama K, Ikemoto K, Jouvet A, Nagatsu I, Geffard M,
Okamura H, Pearson J (1998b). Dopamine synthesizing
enzymes in paraventricular hypothalamic neurons of the
human and monkey (Macaca fuscata). Neurosci Lett 243: 14.
Kitajima T, Kanbayashi T, Saitoh Y, Ogawa Y, Sugiyama T,
Kaneko Y, Sasaki Y, Aizawa R, Shimisu T (2001). The effects
of oral melatonin on the autonomic function in healthy
subjects. Psychiatry Clin Neurosci 55: 299300.
Kim SH, Cairns N, Fountoulakisc M, Lubec G (2001a).

Decreased brain histamine-releasing factor protein in patients
with Down syndrome and Alzheimers disease. Neurosci Lett
300: 4144.
Kim S-J, Young LJ, Gonen D, Veenstra-VanderWeele J,
Courchesne R, Courchesne E, Lord C, Leventhal BL, Cook
EH, Insel TR (2002). Transmission disequilibrium testing of
arginine vasopressin receptor 1A (AVPR1A) polymorphisms
in autism. Mol Psychiatry 7: 503507.
Kimber JR, Watson L, Mathias CJ (1997). Distinction of
idiopathic Parkinsons disease from multiple-system atrophy
by stimulation of growth-hormone release with clonidine.
Lancet 349: 18771881.
Kimmel DW, ONeill BP (1983). Systemic cancer presenting
as diabetes insipidus. Cancer 52: 23552358.
Kimura D, Harshman, RA (1984). Sex differences in brain organization for verbal and non-verbal functions. Prog Brain Res
61: 423441.
Kindon HA, Baum MJ, Paredes RJ (1996). Medial preoptic/anterior hypothalamic lesions induce a female-typical profile of
sexual partner preference in male ferrets. Horm Behav 30:
514527.
King ML (1958). In: The Words of Martin Luther King, Jr,
selected by Coretta Scott King. Newmarket Press, New York,
1958.
King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M,
Antoch MP, Steeves TDL, Hotz Vitaterna M, Kornhauser
JM, Lowrey PL, Turek FW, Takahashi JS (1997). Positional
cloning of the mouse circadian clock gene. Cell 89: 641653.
King LS, Yasui M (2002). Aquaporins and disease: lessons from
mice to humans. Trends Endocrinol Metab 13: 355360.
King LS, Choi M, Fernandez PC, Cartron J-P, Agre P (2001).
Defective urinary concentrating ability due to a complete
deficiency of aquaporin1. N Engl J Med 345: 175179.
Kingsbury AE, Foster OJF, Nisbet AP, Cairns N, Bray L, Eve
DJ, Lees AJ, Marsden CD (1995). Tissue pH as an indicator
of mRNA preservation in human post-mortem brain. Mol
Brain Res 28: 311318.
Kinsley BT, Swift M, Dumont RH, Swift RG (1995). Morbidity
and mortality in the Wolfram syndrome. Diabetes Care 18:
15661570.
Kira J, Harada M, Yamaguchi Y, Shida N, Goto I (1991).
Hyperprolactinemia in multiple sclerosis. J Neurol Sci 102:
6166.
Kirchlechner V, Hoffmann-Ehrhart B, Kovacs J, Waldhauser F
(2001). Melatonin production is similar in children with
monosymptomatic nocturnal enuresis or other forms of
enuresis/incontinence and in controls. J Urol 166: 24072410.
Kirkegaard C, Faber J (1998). The role of thyroid hormones in
depression. Eur J Endocrinol 138: 19.
Kirkland JL, Pearson DJ, Goddard C, Davies I (1983). Polyuria
and inappropriate secretion of arginine vasopressin in hypothalamic sarcoidosis. J Clin Endocrinol Metab 56: 269272.
479
2014 Refs
480
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 480
D.F. SWAAB
Kito M, Yabuta K, Kato S, Osawa M, Okuda H (2001). Gelastic

seizures in clusters in a case of West syndrome after perinatal hypothalamic hemorrhage. J Perinat Med 29: 357359.
Kivipelto M, Helkala E-L, Laakso MP, Hnninen T, Hallikainen
M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J,
Nissinen A, Soininen H (2002). Apolipoprotein E4 allele,
elevated midlife total cholesterol level, and high midlife
systolic blood pressure are independent risk factors for latelife Alzheimer disease. Ann Intern Med 137: 149155.
Kiyohara K, Tamai H, Karibe C, Kobayashi N, Fujii S, Fukino
O, Nakagawa T, Kumagai L, Nagataki S (1987). Serum
thyrotropin (TSH) responses to thyrotropin-releasing hormone
(TRH) in patients with anorexia nervosa and bulimia: influence of changes in body weight and eating disorders.
Kiyohara K, Tamai H, Kobayashi N, Nakagawa T (1988).
Hypothalamic-pituitary-thyroidal axis alterations in bulimic
patients. Am J Clin Nutr 47: 805809.
Kjaer I, Fischer-Hansen B (1995). Human fetal pituitary gland
in holoprosencephaly and anencephaly. J Craniofac Genet
Dev Biol 15: 222229.
Kjaer I, Fischer-Hansen B (1996). The human vomeronasal organ:
prenatal developmental stages and distribution of luteinizing
hormone-releasing hormone. Eur J Oral Sci 104: 3440.
Kjaer A, Knigge U, Jrgensen H, Warberg J (2000).
Dehydration-induced vasopressin secretion in humans:
involvement of the histaminergic system. Am J Physiol 279:
E1305-E1310.
Klapps P, Seyfert S, Fischer T, Scherbaum WA (1992).
Endocrine function in multiple sclerosis. Acta Neurol Scand
85: 352357.
Klauber GT (1989). Clinical efficacy and safety of desmopressin in the treatment of nocturnal enuresis. J Pediatr 114:
719722.
Klaver CCW, Ott A, Hofman A, Assink JJM, Breteler MMB,
De Jong PTVM (1999). Is age-related maculopathy associated
with Alzheimers disease? Am J Epidemiol 150: 963968.
Klein CJ, Silber MH, Halliwill JR, Schreiner SA, Suarez GA,
Low PA (2001). Basal forebrain malformation with hyperhidrosis and hypothermia: variant of Shapiros syndrome.
Kleine W (1925). Periodische Schlafsucht. Mschr Psychiatr
Neurol 57: 285320.
Kleinpeter G, Schatzer R, Bck F (1995). Is blood pressure
really a trigger for the circadian rhythm of subarachnoid
hemorrhage? Stroke 26: 18051810.
Klerman EB, Zeitzer JM, Duffy JF, Khalsa SBS, Czeisler CA
(2001a). Absence of an increase in the duration of the
circadian melatonin secretory episode in totally blind human
subjects. J Clin Endocrinol Metab 86: 31663170.
Klerman EB, Duffy JF, Dijk D-J, Czeisler CA (2001b).
Circadian phase resetting in older people by ocular bright
light exposure. J Invest Med 49: 3040.
Klinefelter HF Jr, Reifenstein EC Jr, Albright F (1942).

Syndrome characterized by gynecomastia, aspermatogenesis
with a-Leydigism and increased secretion of folliclestimulating hormone. J Clin Endocrinol Metab 2: 615622.
Kling MA, Demitrack MA, Whitfield HJ, Kalogeras KT,
Listwak SJ, De Bellis MD, Chrousos GP, Gold PW, Brandt
HA (1993). Effects of glucocorticoid antagonist RU 486 on
pituitary-adrenal function in patients with anorexia nervosa
and healthy volunteers: Enhancement of plasma ACTH
and cortisol secretion in underweight patients. Neuroendocrinology 57: 10821091.
Kloeden PE, Rssler R, Rssler OE (1990). Does a centralized
clock for ageing exist? Gerontology 36: 314322.
Kloos RT (1995). Spontaneous periodic hypothermia. Medicine
74: 268280.
Kloosterman, GJ (1968). The obstetrician and dysmaturity. In:
Jonxis JHP, Visser HKA, Troelstra JA (Eds.) Nutricia
Symposium Aspects of Praematurity and Dysmaturity.
Stenfert Kroese N.V, Leiden, pp. 263280.
Kloosterman GJ (1970). On intrauterine growth. Int J Gynaecol
Obstet 8: 895912.
Klppel S, Pirker W, Brcke T, Kovcs GG, Almer G (2002).
-CIT SPECT demonstrates reduced availability of serotonin
transporters in patients with fatal familial insomnia. J Neural
Transm 109: 11051110.
Kloss B, Price JL, Saez L, Blau J, Rothenflu A, Wesley CS,
Young MW (1998). The Drosophila clock gene double-time
encodes a protein closely related to human casein kinase I.
Cell 94: 97107.
Knepper MA (1994). The aquaporin family of molecular water
channels. Proc Natl Acad Sci 91: 62556258.
Knoepfelmacher M, Pradal MJ, Di Dio R, Salgado LR, Semer
M, Wajchenberg BL, Liberman B (1997). Resistance to vasopressin action on the kidney in patients with Cushings
disease. Eur J Endocrinol 137: 162166.
Knollema S, Brown ER, Vale W, Sawchenko PE (1992).
Novel hypothalamic and preoptic sites of prepro-melaninconcentrating hormone messenger ribonucleic acid and peptide expression in lactating rats. J Neuroendocrinol 4:
709717.
Knook L, Kavelaars A, Sinnema G, Kuis W, Heijnen CJ (2000).
High nocturnal melatonin in adolescents with chronic fatigue
syndrome. J Clin Endocrinol Metab 85: 36903692.
Kobayashi H, Ogawa Y, Shintani M, Ebihara K, Shimodahira
M, Iwakura T, Hino M, Ishihara T, Ikekubo K, Kurahachi
H, Nakao K (2002). A novel homozygous missense mutation of melanocortin4 receptor (MC4R) in a Japanese woman
with severe obesity. Diabetes 51: 243246.
Kobayashi K, Kobayashi E, Miyazu K, Muramori F, Hiramatsu
S, Aoki T, Nakamura I, Koshino Y (2000). Hypothalamic
haemorrhage and thalamus degeneration in a case of NasuHakola disease with hallucinatory symptoms and central
hypothermia. Neuropathol Appl Neurobiol 26: 98101.
2014 Refs
2/12/03
1:39 pm
Page 481
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
481
Kopelman PG (1999). Is the hypothalamic-pituitary-adrenal axis

really hyperactivated in visceral obesity? J Endocrinol Invest
22: 7680.
Kopp N, Najimi M, Champier J, Chigr F, Charnay Y, Epelbaum
J, Jordan D (1992). Ontogeny of peptides in human hypothalamus in relation to sudden infant death syndrome (SIDS).
Prog Brain Res 93: 167188, Elsevier, Amsterdam.
Kpp W, Blum WF, Von Prittwitz S, Ziegler A, Lbbert H,
Emons G, Herzog W, Herpertz S, Deter H-C, Remschmidt
H, Hebebrand J (1997). Low leptin levels predict amenorrhea in underweight and eating disordered females. Mol
Korbonits M, Kaltsas G, Perry LA, Putignano P, Grossman
AB, Besser GM, Trainer PJ (1999). The growth hormone
secretagogue hexarelin stimulates the hypothalamo-pituitaryadrenal axis via arginine vasopressin. J Clin Endocrinol Metab
84: 24892495.
Kordower JH, Gash DM, Bothwell M, Hersh L, Mufson EJ
(1989). Nerve growth factor receptor and choline acetyltransferase remain colocalized in the nucleus basalis (CH4)
of Alzheimers patients. Neurobiol Aging 10: 6774.
Korebrits C, Ramirez MM, Watson L, Brinkman E, Bocking
AD, Challis JRG (1998). Maternal corticotropin-releasing
hormone is increased with impending preterm birth. J Clin
Korenke GC, Roth C, Krasemann E, Hfner M, Hunneman DH,
Hanefeld F (1997). Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy:
clinical, laboratory and genetic findings. Eur J Endocrinol
137: 4047.
Korndrfer SR, Lucas AR, Suman VJ, Crowson CS, Krahn LE,
Melton LJ (2003). Long-term survival of patients with
anorexia nervosa: a population-based study in Rochester,
Minn. Mayo Clin Proc 78: 278284.
Kornreich L, Blaser S, Schwarz M, Shuper A, Vishne TH,
Cohen IJ, Faingold R, Michovitz S, Koplewitz B, Horev G
(2001). Optic pathway glioma: correlation of imaging findings with the presence of neurofibromatosis. Am J
Neuroradiol 22: 19631969.
Korpi ER, Goodman SI, Kleinman JE, Wyatt RJ. (1987a).
Relationship between tryptophan and serotonin concentrations
in postmortem human brain. Med Biol 65: 217220.
Korpi ER, Kleinman JE, Goodman SI, Wyatt RJ (1987b).
Neurotransmitter amino acids in post-mortem brains of
chronic schizophrenic patients. Psychiatric Res 22: 291301.
Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C,
Masterson L, Engelberg NC, Haus E, Demitrack MA,
Crofford L (1999). Melatonin levels in women with
fibromyalgia and chronic fatigue syndrome. J Rheumatol 26:
26752680.
Korszun A, Young EA, Engleberg NC, Masterson L, Dawson
EC, Spindler K, McClure LA, Brown MB, Crofford LJ
(2000). Follicular phase hypothalamic-pituitary-gonadal axis
Kobayashi S, Otsuka A, Tsunoda T (1996). Herniation of the

third ventricle into empty sella caused by surgery for pituitary apoplexy. Neurol Med Chir 36: 451454.
Kobayashi T, Okuno H, Nishiyama H, Nakamura E, Ogawa O,
Kawahara M, Shimatsu A (2002). Adult-onset idiopathic
hypogonadotropic hypogonadism presented with erectile and
ejaculatory disorder. Int J Urol 9: 604606.
Koeppen AH, Daniels JC, Barron KD (1969). Subnormal body
temperatures in Wernickes encephalopathy. Arch Neurol 21:
493498.
Kogan AO, Guilford PM (1998). Side effects of short-term
10,000 lux light therapy. Am J Psychiatry 155: 293294.
Koh J-Y, Gwag BJ, Lobner D, Choi DW (1995). Potentiated
necrosis of cultured cortical neurons by neurotrophins.
Science 268: 573575.
Khler C, Swanson LW, Haglund L, Wu J-Y (1985). The
cytoarchitecture, histochemistry and projections of the tuberomammillary nucleus in the rat. Neuroscience 16: 85110.
Koike Y, Takahashi A (1997). Autonomic dysfunction in
Parkinsons disease. Eur Neurol 38 (Suppl. 2): 812.
Kojima M, Hosoda H, Matsuo H, Kangawa K (2001). Ghrelin: discovery of the natural endogenous ligand for the growth hormone
secretagogue receptor. Trends Endocrinol Metab 12: 118121.
Kok SW, Meinders AE, Overeem S, Lammers GJ, Roelfsema
F, Frolich M, Pijl H (2002). Reduction of plasma leptin levels
and loss of its circadian rhythmicity in hypocretin (orexin)deficient narcoleptic humans. J Clin Endocrinol Metab 87:
805809.
Kolmac C, Power BD, Mitrofanis J (1998). Patterns of connections between zon incerta and brainstem in rats. J Comp
Neurol 396: 544555.
Konovalov A, Gorelyshev S, Serova N (1994). Surgery of giant
gliomas and chiasma and IIIrd ventricle. Acta Neurochir
(Wien) 130: 7179.
Konovalov HV, Kovetsky NS, Bobryshev YV, Ashwell KWS
(1997). Disorders of brain development in the progeny of
mothers who used alcohol during pregnancy. Early Hum Dev
48: 153166.
Konrad D, Gartenmann M, Martin E, Schoenle EJ (2000).
Central diabetes insipidus as the first manifestation of
neurosarcoidosis in a 10-year-old girl. Horm Res 54: 98100.
Koorengevel KM, Gordijn MCM, Beersma DGM, Meesters
Y, Den Boer JA, Van den Hoofdakker RH, Daan S
(2001). Extraocular light therapy in winter depression: a
double-blind placebo-controlled study. Biol Psychiatry 50:
691698.
Koorengevel KM, Beersma DGM, Den Boer JA, Van den
Hoofdakker RH (2003). Mood regulation in seasonal affective disorder patients and healthy controls studied in forced
desynchrony. Psychiatry Res 117: 5774.
Kopala LC, Good KP, Koczapski AB, Honer WG (1998).
Olfactory deficits in patients with schizophrenia and severe
polydipsia. Biol Psychiatry 43: 497502.
481
2014 Refs
482
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 482
D.F. SWAAB
function in women with fibromyalgia and chronic fatigue

syndrome. J Rheumatol 27: 15261530.
Korting C, Van Zwieten EJ, Boer GJ, Ravid R, Swaab DF (1996).
Increase in vasopressin binding sites in the human choroid
plexus in Alzheimers disease. Brain Res 706: 151154.
Korvatska E, Van de Water J, Anders TF, Gershwin ME (2002).
Genetic and immunologic considerations in autism. Neurobiol
Disease 9: 107125.
Ksel S, Graeber MB (1994). Use of neuropathological tissue
for molecular genetic studies: parameters affecting DNA
extraction and polymerase chain reaction. Acta Neuropathol
88: 1925.
Koshiyama H, Sato H, Yorita S, Koh T, Kanatsuna T, Nishimura
K, Hayakawa K, Takahashi J, Hashimoto H (1994).
Lymphocytic hypophysitis presenting with diabetes insipidus:
case report and literature review. Endocr J 41: 9397.
Koss E, Weiffenbach JM, Haxby JV, Friedland RP (1987).
Olfactory detection and recognition in Alzheimers disease.
Lancet (8533) 622.
ckovic-Sterni
Kostic VS, Covi

c N, Beslac-Bumbasirevic L, Ocic,
G, Pavlovic D, Nicolic M (1990). Dexamethasone suppression
test in patients with Parkinsons disease. Mov Disord 5: 2326.
Kostoglou-Athanassiou I, Treacher DF, Wheeler MJ, Forsling
ML (1998a). Bright light exposure and pituitary hormone
secretion. Clin Endocrinol 48: 7379.
Kostoglou-Athanassiou I, Athanassiou K, Treacher DF, Wheeler
MJ, Forsling ML (1998b). Neurohypophysial hormone
and melatonin secretion over the natural and suppressed
menstrual cycle in premenopausal women. Clin Endocrinol
49: 209216.
Kostovic I (1986). Prenatal development of nucleus basalis
complex and related fiber systems in man: a histochemical
study. Neuroscience 17: 10471077.
Koutcherov Y, Mai JK, Ashwell KWS, Paxinos G (2000).
Organization of the human paraventricular hypothalamic
Koutcherov Y, Mai JK, Ashwell KWS, Paxinos G (2002).
Organization of human hypothalamus in fetal development.
Kovacs K (1984). Pathology of the neurohypophysis. In:
Reichlin S (Ed.) The Neurohypophysis. Physiological and
clinical aspects. Plenum, New York, pp. 95111.
Kovacs K, Sheehan HL (1982): Pituitary changes in Kallmans
syndrome. A histologic, immunocytologic, ultrastructural, and
immunoelectron microscopic study. Fert Steril 37: 8389.
Kovacs L, Robertson GL (1992). Syndrome of inappropriate
antidiuresis. Endocrinol Metab Clin N Am 21: 854875.
Kozicz T, Vigh S, Arimura A (1998). The source of origin of
PACAP- and VIP-immunoreactive fibers in the laterodorsal
division of the bed nucleus of the stria terminalis in the rat.
Brain Res 810: 211219.
Krack P, Poepping M, Weinert D, Schrader B, Deuschl G
(2000). Thalamic, pallidal, or subthalamic surgery for
Parkinsons disease? J Neurol 247: II/122-II/134.
Krack P, Kumar R, Ardouin C, Limousin-Dowsey P, McVicker

JM, Benabid A-L, Pollak P (2001). Mirthful laughter induced
by subthalamic nucleus stimulation. Move Disord 16:
867875.
Kraemer GW (1997). Psychobiology of early social attachment
in rhesus monkey. Ann NY Acad Sci: 401418.
Kraft W, Greenberg HE, Waldman SA (1998). Paradoxical
hypotension and bradycardia after intravenous arginine vasopressin. J Clin Pharmacol 38: 283286.
Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH (2002).
Hypocretin (orexin) levels in cerebrospinal fluid of patients
with narcolepsy: relationship to cataplexy and HLA
DQB*0602 status. Sleep 25: 733736
Krajnak K, Kashon ML, Rosewell KL, Wise PM (1998). Sex
differences in the daily rhythm of vasoactive intestinal
polypeptide but not arginine vasopressin messenger ribonucleic acid in the suprachiasmatic nuclei. Endocrinology 139:
41894196.
Kramer U, Spector S, Nasser W, Siomin V, Fried I, Constantini
S (2001). Surgical treatment of hypothalamic hamartoma and
refractory seizures. Pediatr Neurosurg 34:4042.
Kruchi K, Cajochen C, Danilenko KV, Wirz-Justice A (1997).
The hypothermic effect of late evening melatonin does not
block the phase delay induced by concurrent bright light in
human subjects. Neurosci Lett 232: 5761.
Kruchi K, Cajochen C, Werth E, Wirz-Justice A (1999).
Warm feet promote the rapid onset of sleep. Nature 401:
3637.
Kraus T, Haack M, Schuld A, Hinze-Selch D, Pollmcher T
(2001). Low leptin levels but normal body mass indices in
patients with depression or schizophrenia. Neuroendocrinology 73: 243247.
Kreier F, Fliers E, Voshol PJ, Van Eden CG, Havekes LM,
Kalsbeek A, Van Heijningen CL, Sluiter AA, Mettenleiter
TC, Romijn JA, Sauerwein HP, Buijs RM (2002). Selective
parasympathetic innervation of subcutaneous and intraabdominal fat functional implications. J Clin Invest 110:
12431250.
Kremer HPH (1992a). The lateral hypothalamus in
Huntingtons, Alzheimers and Parkinsons disease. Thesis,
University of Leiden.
Kremer HPH (1992b). The hypothalamic lateral tuberal nucleus:
normal anatomy and changes in neurological diseases. Prog
Brain Res 93: 249261.
Kremer HPH, Bots GTAM (1993). Lewy bodies in the lateral
hypothalamus; do they imply neuronal loss? Mov Disord 8:
315320.
Kremer HPH, Roos RAC, Frlich M, Radder JK, Nieuwenhuijzen
Kruseman AC, Van der Velde A, Buruma OJS (1989).
Endocrine functions in Huntingtons disease. A two-and-a-half
years follow-up study. J Neurol Sci 90: 335344.
Kremer HPH, Roos RAC, Dingjan G, Marani E, Bots GTAM
(1990). Atrophy of the hypothalamic lateral tuberal nucleus
2014 Refs
2/12/03
1:39 pm
Page 483
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
483
Kroboth PD, Salek FS, Pittenger AL, Fabian TK, Frye RF

(1999). DHEA and DHEA-S: a review. J Clin Pharmacol 39:
327348.
Kroisel PM, Peter E, Wagner K, Kurnik P (2000). Complex
chromosomal translocation in a patient with Kallmann
syndrome. Am J Med Gen 91: 240.
Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grters
A (1998). Severe early-onset obesity, adrenal insufficiency
and red hair pigmentation caused by POMC mutations in
humans. Nat Genet 19: 155157.
Krude H, Grters A (2000). Implications of proopiomelanocortin
(POMC). mutations in humans: the POMC deficiency
syndrome. Trends Endocrinol Metabol 11: 1522.
Krueger JM, Obl F (1997). Sleep regulatory substances. In:
Schwartz, WJ (Ed.) Sleep Science. Integrating basic research
and clinical practice. Karger, Basel, pp. 175194.
Krger THC, Haake P, Chereath D, Knapp W, Janssen OE,
Exton MS, Schedlowski M, Hartmann U (2003). Specificity
of the neuroendocrine response to orgasm during sexual
arousal in men. J Endocrinol 177: 5764.
Krugers HJ, Maslam S, Van Vuuren SM, Korf J, Jols M (1999).
Postischemic steroid modulation: effects on hippocampal
neuronal integrity and synaptic plasticity. J Cereb Blood Flow
Metab 19: 10721082.
Krugers HJ, Maslam S, Korf J, Jols M, Holsboer F (2000).
The corticosterone synthesis inhibitor metyrapone prevents
hypoxia/ischemia-induced loss of synaptic function in the rat
hippocampus. Stroke 31: 11621172.
Kruijver FPM, Zhou JN, Pool CW, Hofman MA, Gooren LJG,
Swaab DF (2000). Male-to-female transsexuals have female
neuron numbers in a limbic nucleus. J Clin Endocrinol Metab
85: 20342041.
Kruijver FPM and Swaab DF (2002). Sex hormone receptors
are present in the human suprachiasmatic nucleus.
Kruijver FPM, Fernndez-Guasti A, Fodor M, Kraan E, Swaab
DF (2001). Sex differences in androgen receptors of the
human mamillary bodies are related to endocrine status rather
than to sexual orientation or transsexuality. J Clin Endocrinol
Metab 86: 818827.
Kruijver FPM, Balesar R, Espila A, Unmehopa UA, Swaab DF
(2002). Estrogen receptor- distribution in the human hypothalamus in relation to sex and endocrine status. J Comp
Neurol 454: 115139.
Kruisbrink J, Mirmiran M, Van der Woude TP, Boer GJ (1987).
Effect of enhanced cerebrospinal fluid levels of vasopressin,
vasopressin antagonist or vasopressin intestinal polypeptide,
on circadian sleep-wake rhythm in rat. Brain Res 419: 7686.
Kruk MR, Westphal KGC, Van Erp AMM, Van Asperen J, Cave
BK, Slater E, De Koning J, Haller J (1998). The hypothalamus:
cross-roads of endocrine and behavioural regulation in
grooming and aggression. Neurosci Biobehav Rev 23:
163177.
in Huntingtons disease. J Neuropathol Exp Neurol 49:

371382.
Kremer HPH, Roos RAC Dingjan GM, Bots GTAM, Bruyn GW,
Hofman MA (1991a). The hypothalamic lateral tuberal nucleus
and the characteristics of neuronal loss in Huntingtons disease.
Kremer HPH, Swaab DF, Bots GThAM, Fisser B, Ravid R,
Roos RAC (1991b). The hypothalamic lateral tuberal nucleus
in Alzheimers disease. Ann Neurol 29: 279284.
Kremer HPH, Squitieri F, Telenius H, Andrew SE, Theilmann
J, Spence N, Goldberg YP, Hayden MR (1993a). Molecular
analysis of late onset Huntingtons disease. J Med Genet 30:
991995.
Kremer HPH, Tallaksen-Greene SJ, Albin RL (1993b). AMPA
and NMDA binding sites in the hypothalamic lateral tuberal
nucleus: implications for Huntingtons disease. Neurology 43:
15931595.
Kremer HPH, Goldberg P, Andrew SE, Theilmann J, Telenius
H, Zeisler J, Squittieri F, Lin B, Bassett A, Almqvist E,
Bird TD, Hayden MR (1994). A worldwide study of
the Huntingtons disease mutation. The sensitivity and
specificity of measuring CAG repeats. N Engl J Med 330:
14011406.
Krieg J-C, Lauer CJ, Schreiber W, Modell S, Holsboer F (2001).
Neuroendocrine, polysomnographic and psychometric observations in healthy subjects at high familial risk for affective
disorders: the current state of the Munich vulnerability
study. J Affect Disord 62: 3337.
Krieger DT, Krieger HP (1966). Circadian variation of the
plasma 17-hydroxycorticosteroids in central nervous system
disease. J Clin Endocr Metab 26: 929940.
Kripke DF (1985). Therapeutic effects of bright light in
depressed patients. Ann NY Acad Sci 453: 270281.
Kripke DF (1998). Light treatment for nonseasonal depression:
speed, efficacy, and combined treatment. J Affect Disord 49:
109117.
Kripke DF, Simons RN, Garfinkel L, Hammond EC (1979).
Short and long sleep and sleeping pills. Arch Gen Psychiatry
36: 103116.
Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR
(2002). Mortality associated with sleep duration and insomnia.
Kripke DF, Youngstedt SD, Rex KM, Klauber MR, Elliott JA
(2003). Melatonin excretion with affect disorders over age
60. Psychiatry Res 118: 4754.
Krishnan KRR, Doraiswamy PM, Lurie SN, Figiel GS, Husain
MM, Boyko OB, Ellinwood EH, Nemeroff CB (1991a).
Pituitary size in depression. J Clin Endocrinol Metab 72:
256259.
Krishnan KRR, Doraiswamy PM, Figiel GS, Husain MM, Shah
SA, Na C, Boyko OB, McDonald WM, Nemeroff CB,
Ellinwood EH (1991b). Hippocampal abnormalities in depression. J Neuropsychiatry Clin Neurosci 3: 387391.
483
2014 Refs
484
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 484
D.F. SWAAB
Krukoff TL, Mactavish D, Jhamandas JH (1997). Activation by

hypotension of neurons in the hypothalamic paraventricular
nucleus that project to the brainstem. J Comp Neurol 385:
285296.
Krupp LB, Pollina D (1996). Neuroimmune and neuropsychiatric aspects of chronic fatigue syndrome. Adv Neuroimmunol
6: 155167.
Krysiak R, Obuchowicz E, Herman ZS (1999). Interactions
between the neuropeptide Y system and the hypothalamicpituitary-adrenal axis. Eur J Endocrinol 140: 130136.
Kubek MJ, Garg BP (2002). Thyrotropin-releasing hormone in
the treatment of intractable epilepsy. Pediatr Neurol 26: 917.
Kubota H, Kabayashi, T (2002). A case of acute disseminated
encephalomyelitis presenting hypersomnia with decreased
hypocretin level in cerebrospinal fluid. J Child Neurol 17:
537539.
Kubota T, Uchiyama M, Suzuki H, Shibui K, Kim K, Tan X,
Tagaya H, Okawa M, Inou S (2002). Effects of nocturnal
bright light on saliva melatonin, core body temperature and
sleep propensity rhythms in human subjects. Neurosci Res
42: 115122.
Kudesia S, Das S, Shankar S.K, Santosh V, Reddy AK (1996).
Colloid cyst xanthogranuloma of the third ventricle a case
report. Indian J Pathol Microbiol 39: 221223.
Kudoh A, Kudo M, Ishihara H, Matsuki A (1998). Increased
plasma vasopressin and atrial natriuretic peptide in chronic
schizophrenic patients during abdominal surgery. Neuropsychobiology 37: 169174.
Kuebber S, Ropte S, Hori A (1990). Proliferation of adenohypophyseal cells into posterior lobe. Acta Neurochir 104:
2126.
Kuhar MJ, Dall Vechia SE (1999). CART peptides: novel
addiction- and feeding-related neuropeptides. Trends
Kulkarni J, Riedel A, DeCastella RA, Fitzgerald PB, Rolfe TJ,
Taffe J, Burger H (2000). Have some treatments been overlooked? Schizophrenia Res 41: 8.
Kulman G, Lissoni P, Rovelli F, Roselli MG, Brivio F, Sequeri
P (2000). Evidence of pineal endocrine hypofunction in
autistic children. Neuroendocrinol Lett 21: 3134.
Kumar K, Toth C, Nath RK (1997). Deep brain stimulation for
intractable pain: a 15-year experience. Neurosurgery 40:
736747.
Kumar M, Kumarm AM, Waldrop D, Antoni MH,
Schneiderman N, Eisdorfer C (2002). The HPA axis in HIV1
infection. J Acquir Immune Defic Syndr 31: S89-S93.
Kumar AR, Kurup PA (2001a). Membrane Na+ K+ ATPase
inhibition related dyslipidemia and insulin resistance in
neuropsychiatric disorders. Indian J Physiol Pharmacol 45:
296304.
Kumar AR, Kurup PA (2001b). A hypothalamic digoxin mediated model for conscious and subliminal perception. J Neural
Transm 198: 855868.
Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket

E, Lang AE (1998). Double-blind evaluation of subthalamic
nucleus deep brain stimulation in advanced Parkinsons
disease. Neurology 51: 850855.
Kumar S, Bhatia M, Behari M (2002). Sleep disorders in
Parkinsons disease. Mov Disord 17: 775781.
Kumaresan P, Anandarangam PB, Dianzon W, Vasicka A
(1974). Plasma oxytocin levels during pregnancy and labor
as determined by radioimmunoassay. Am J Obstet Gynecol
119: 215223.
Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR,
Jin X, Maywood ES, Hastings MH, Reppert SM (1999).
mCRY1 and mCRY2 are essential components of the
negative limb of the circadian clock feedback loop. Cell 98:
193205.
Kmpfel T, Then Bergh F, Friess E, Uhr M, Yassouridis A,
Trenkwalder C, Holsboer F (1999). Dehydroepiandrosterone
response to the adrenocorticotropin test and the combined dexamethasone and corticotropin-releasing hormone test in patients
with multiple sclerosis. Neuroendocrinology 70: 431438.
Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai
T (1999). Orexins/hypocretins regulate drinking behaviour.
Brain Res 842: 256261.
Kunz D, Bes F (1997). Melatonin effects in a patient with severe
REM sleep behavior disorder: case report and theoretical
considerations. Neuropsychobiology 36: 211214.
Kunz D, Bes F, Schlattmann P, Herrmann WM (1998).
On pineal calcification and its relation to subjective sleep
perception: a hypothesis-driven pilot study. Psychiatry Res
82: 187191.
Kunz D, Bes F (1999). Melatonin as a therapy in REM sleep
behavior disorder patients: an open-labeled pilot study on the
possible influence of melatonin on REM-sleep regulation.
Mov Disord, 14: 507511.
Kunz D, Bes F (2001). Exogenous melatonin in periodic limb
movement disorder: an open clinical trial and a hypothesis.
Sleep 24: 183187.
Kunz D, Schmitz S, Mahlberg R, Mohr A, Stter C, Wolf KJ, Herrmann WM (1999). A new concept for melatonin deficit:
on pineal calcification and melatonin excretion. Neuropsychopharmacology 21: 765772.
Kuo JS, Casey SO, Thompson L, Truwit CL (1999). PallisterHall syndrome: clinical and MR features. Am J Neuroradiol
20: 18391841.
Kupari M, Pelkonen R, Valtonen V (1980). Post-encephalitic
hypothalamic-pituitary insufficiency. Acta Endocrinol 94:
433438.
Kupers RC, Gybels JM, Gjedde A (2000). Positron emission
tomography study of a chronic pain patient successfully
treated with somatosensory thalamic stimulation. Pain 87:
295302.
Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T,
Kanakura Y, Kitani T (1998). Dehydroepiandrosterone sulfate
2014 Refs
2/12/03
1:39 pm
Page 485
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
485
Labudova O, Fang-Kircher S, Cairns M, Moenkemann H,

Yeghiazaryan K, Lubec G (1998). Brain vasopressin levels
in Down syndrome and Alzheimers disease. Brain Res 806:
5559.
Lack LC, Mercer JD, Wright H (1996). Circadian rhythms of
early morning awakening insomniacs. J Sleep Res 5: 211219.
Lckgren G, Hjlms K, Van Gool J, Von Gontard A, de
Gennaro M, Lottmann H, Terho P (1999). Nocturnal enuresis:
a suggestion for a European treatment strategy. Acta Paediatr
88: 679690.
Laemmle B, Schindler M, Beilmann M, Hamilton BS, Doods
HN, Wieland HA (2003). Characterization of the NPGP
receptor and identification of a novel short mRNA isoform
in human hypothalamus. Regul Pept 111: 2129.
Laemle LK (1988). Vasoactive intestinal polypeptide (VIP)-like
immunoreactivity in the suprachiasmatic nucleus of the perinatal rat. Brain Res Dev Brain Res 41: 308312.
Lafitte C, Bedat A-L, Jan M, Fetissof F (1994). Etude immunohistochimique et ultrastructurale dune tumeur cellules
granuleuses de la neurohypophyse. Ann Pathol 14: 398402.
La Fleur SE, Kalsbeek A, Wortel J, Buijs RM (1999). A
suprachiasmatic nucleus generated rhythm in basal glucose
concentrations. J Neuroendocrinol 11: 643652.
La Fleur SE, Kalsbeek A, Wortel J, Buijs RM (2000).
Polysynaptic neural pathways between the hypothalamus,
including the suprachiasmatic nucleus, and the liver. Brain
Res 871: 5056.
Lafreniere R, McGrath MH (1998). End-of-life issues: anencephalic infants as organ donors. J Am Coll Surg 187:
443447.
Lahiri DK (1999). Melatonin affects the metabolism of the amyloid precursor protein in different cell types. J Pineal Res
26: 137146.
Laing RBS, Dean JCS, Pearson DWM, Johnston AW (1991).
Facial dysmorphism: a marker of autosomal dominant cranial
diabetes insipidus. J Med Genet 28: 544546.
Laitinen LV (1988). Psychosurgery today. Acta Neurochir
(Suppl) 44: 158162.
Lakhdar-Ghazal N, Kalsbeek A, Pvet P (1992). Sexual dimorphism and seasonal variations in vasoactive intestinal peptide
immunoreactivity in the suprachiasmatic nucleus of jerboa
(Jaculus orientalis). Neurosci Lett 144: 2933.
lAllemand D, Eiholzer U, Rousson V, Girard J, Blum W,
Torresani T, Gasser T (2002). Increased adrenal androgen
levels in patients with PraderWilli syndrome are associated
with insulin,
Lam RW, Goldner EM, Solyom L, Remick RA (1994). A
controlled study of light therapy for bulimia nervosa. Am J
Lam RW, Goldner EM, Grewal A (1996a). Seasonality of
symptoms in anorexia and bulimia nervosa. Int J Eat Disord 19:
3544.
deficiency in chronic fatigue syndrome. Int J Mol Med 1:

143146.
Kurian KM, Statham PFX, Smith C, Bell JE, Ironside JW (2002).
Third ventricular chordoid glioma: clinicopathological features of two cases. Neuropathol Appl Neurobiol 28. p. 165.
Kuroda Y, Mori T, Hori, T (1994). Restrained stress suppresses
experimental allergic encephalomyelitis in Lewis rats. Brain
Res Bull 34: 1517.
Kurokawa Y, Abiko S, Ikeda N, Ideguchi M, Okamura T (2001).
Surgical strategy for cavernous angioma in hypothalamus. J
Kurt G, Dogulu F, Kaymaz M, Emmez H, nk A, Baykaner
MK (2002). Hypothalamic lipoma adjacent to mamillary
bodies. Childs Nerv Syst 18: 732734.
Kurtzke JF, Beebe GW, Norman JE (1979). Epidemiology of
multiple sclerosis in US veterans: 1. Race, sex, and geographic
distribution. Neurology 29: 12281235.
Kurup RK, Kurup PA (2002). Hypothalamic digoxin, cerebral
dominance, and sexual orientation. Arch Androl 48: 359367.
Kurz A, Sessler DI, Tayefeh F, Goldberger R (1998).
Poikilothermia syndrome. J Intern Med 244: 431436.
Kusaka I, Saito T, Nakamura T, Nagasaka S, Ishibashi S,
Ishikawa S-E (2002). Urinary excretion of aquaporin2 water
channel in diabetic ketoacidosis. Nephron 91: 167169.
Kuslich CD, Kobori JA, Mohapatra G, Gregorio-King C, Donlon
TA (1999). Prader-Willi syndrome is caused by disruption of
the SNRPN gene. Am J Genet, 64: 7076.
Kusumi I, Ohmori T, Kohsaka M, Ito M, Honma H, Koyama
T (1995). Chronobiological approach for treatment-resistant
rapid cycling affective disorders. Soc Biol Psychol 37:
553559.
Kuwabara Y, Takeda S, Mizuno M, Sakamoto S. (1987).
Oxytocin levels in maternal and fetal plasma, amniotic fluid,
and neonatal plasma and urine. Arch Gynecol Obstet 241:
1323.
Kuzeyli K, akir E, Baykal S, Karaarslan G (2001). Diabetes
insipidus secondary to penetrating spinal cord trauma. Spine
26: E510-E511.
Kuzniecky R, Guthrie B, Mountz J, Bebin M, Faught E, Gilliam
F, Liu HG (1997). Intrinsic epileptogenesis of hypothalamic
hamartomas in gelastic epilepsy. Ann Neurol 42: 6067.
Kvetnoy I, Sandvik AK, Waldum HL (1997). The diffuse
neuroendocrine system and extrapineal melatonin. J Mol
Endocrinol 18: 13.
Kwon JS, Shenton ME, Hirayasu Y, Salisbury DF, Fischer IA,
Dickey CC, Yurgelun-Todd D, Tohen M, Kikinis R, Jolesz
FA, McCarley RW (1998). MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and schizotypal
personality disorder. Am J Psychiatry 155: 509515.
Kyomen HH, Hennen J, Gottlieb GL, Wei JY (2002). Estrogen
therapy and noncognitive psychiatric signs and symptoms in
elderly patients with dementia. Am J Psychiatry 159:
12251227.
485
2014 Refs
486
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 486
D.F. SWAAB
Lam RW, Zis AP, Grewal A, Delgado PL, Charney DS, Krystal
JH (1996b). Effects of rapid tryptophan depletion in patients
with seasonal affective disorder in remission after light
therapy. Arch Gen Psychiatry 53: 4144.
Lambert G, Johansson M, gren H, Friberg P (2000). Reduced
brain norepinephrine and dopamine release in treatmentrefractory depressive illness. Arch Gen Psychiatry 57: 787793.
Lambert G, Reid C, Kaye D, Jennings G, Esler M (2002). Effect
of sunlight and season on serotonin turnover in the brain.
Lancet 360: 18401842.
Lambert G, Reid C, Kaye D, Jennings G, Esler M (2003).
Increased suicide rate in the middle-aged and its association
with hours of sunlight. Am J Psychiatry 160: 793795.
Lambert JC, Harris JM, Mann D, Lemmon H, Coates J,
Cumming A, St-Clair D, Lendon C (2001). Are the estrogen
receptors involved in Alzheimers disease? Neurosci Lett 306:
193197.
Lamberts SWJ, Bruining HA, De Jong FH (1997a).
Corticosteroid therapy in severe illness. N Engl J Med 337:
12851292.
Lamberts SWJ, Van den Beld AW, Van der Lely A-J (1997b).
The endocrinology of aging. Science 278: 419424.
Lamberts SWJ, De Herder WW, Van der Lely AJ (1998).
Pituitary insufficiency. Lancet 352: 127134.
Lamberts SWJ (2001). Hereditary glucocorticoid resistance. Ann
Lammens M, Lissoir F, Carton H (1989). Hypothermia in three
patients with multiple sclerosis. Clin Neurol Neurosurg 91:
117121.
Lampl Y, Eshel Y, Kessler A, Fux A, Gilad R, Boaz M, Matas
Z, Sadeh M (2002). Serum leptin level in women with idiopathic intracranial hypertension. J Neurol Neurosurg
Lana AJ, Wu PH, Jung B, Liu J-F, Ng V, Kalant H (1999).
Differential increase in Fos immunoreactivity in hypothalamic and septal nuclei by arginine 8-vasopressin and
desglycinamide9-arginine 8-vasopressin. Neuroscience 91:
13311341.
Lance JW (1992). The pathophysiology of migraine: a tentative synthesis. Pathol Biol 40: 355360.
Lancon JA, Haines DE, Raila FA, Parent AD, Vedanarayanan
VV (1996). Expanding cyst of the septum pellucidum. J
Neurosurg 85: 11271134.
Landn M, Wlinder J, Lundstrm B (1996). Incidence and sex
ration of transsexualism in Sweden. Acta Psychiatr Scand 93:
261263.
Landfield PW, Baskin RK, Pitler TA (1981). Brain aging correlates: retardation by hormonal-pharmacological treatments.
Science 214: 581584.
Landry DW, Levin HR, Gallant EM, Ashton RC, Seo S,
DAllesandro D, Oz MC, Oliver JA (1997). Vasopressin deficiency contributes to the vasodilation of septic shock.
Circulation 95: 11221125.
Landry DW, Oliver JA (2001). The pathogenesis of vasodilatory shock. New Engl J Med 345: 588595.
Landt M, Parvin CA, Wong M (2000). Leptin in cerebrospinal
fluid from children: correlation with plasma leptin, sexual
dimorphism, and lack of protein binding. Clin Chem 46:
854858.
Landtblom A-M, Dige N, Schwerdt K, Sfstrm P, Granrus
G (2002). A case of KleineLevin syndrome examined with
SPECT and neuropsychological testing. Acta Neurol Scand
105: 318321.
Lang RE, Heil J, Ganten D, Hermann K, Rascher W, Unger T
(1983). Effects of lesions in the paraventricular nucleus of
the hypothalamus on vasopressin and oxytocin contents in
brainstem and spinal cord of rat. Brain Res 260: 326329.
Langdon-Down M, Brain WR (1929). Time of day in relation
to convulsions in epilepsy. Lancet 2: 10291032.
Lange G, De Luca J, Maldjian JA, Lee H-J, Tiersky LA,
Natelson BH (1999). Brain MRI abnormalities exist in a
subset of patients with chronic fatigue syndrome. J Neurol
Sci 171: 37.
Langer SZ, Javoy-Agid F, Raisman R, Briley M, Agid Y
(1981). Distribution of specific high-affinity binding sites
for [3H]imipramine in human brain. J Neurochem 37:
267271.
Langston JW, Forno LS (1978). The hypothalamus in
Parkinsons disease. Ann Neurol 3: 129133.
Lanotte MM, Rizzone M, Bergamasco B, Faccani G, Melcarne
A, Lopiano L (2002). Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome
correlations with the effects of stimulation. J Neurol
Lantos PL (1998). The definition of multiple system atrophy:
a review of recent developments. J Neuropathol Exp Neurol
57: 10991111.
Lantos TA, Grcs TJ, Palkovits M (1995). Immunohistochemical mapping of neuropeptides in the premamillary
region of the hypothalamus in rats. Brain Res Brain Res Rev
20: 209249.
Lantos TA, Grcs TJ, Palkovits M (1996). Immunohistochemical localization of calcitonin gene-related peptide in the
terete nucleus of the rat hypothalamus. Neurobiology 4:
7384.
Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck
C, Rosenheck RA, Cramer J, Southwick S, Charney D,
Krystal J, Gelernter J (2002). A functional neuropeptide Y
leu7pro polymorphism associated with alcohol dependence in
a large population sample from the united states. Arch Gen
Lariviere WR, Melzack R (2000). The role of corticotropinreleasing factor in pain and analgesia. Pain 84: 112.
Laron Z, Roitman A, Kauli R (1979). Effect of human growth
hormone therapy on head circumference in children with
hypopituitarism. Clin Endocrinol 10: 393399.
2014 Refs
2/12/03
1:39 pm
Page 487
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
487
Lawson WB, Karson CN, Bigelow LB (1985). Increased urine

volume in chronic schizophrenic patients. Psychiatry Res 14:
323331.
Laxer KD, Mullooly JP, Howell B (1985). Prolactin changes
after seizures classified by EEG monitoring. Neurology 35:
3135.
Layman LC (1999a). Mutations in human gonadotropin genes
and their physiologic significance in puberty and reproduction. Fertil Steril 71: 201218.
Layman LC (1999b). Genetics of human hypogonadotropic
hypogonadism. Am J Med Gen 89: 240248.
Le Dafniet M, Lefebvre P, Barret A, Mechain C, Feinstein MC,
Brandi AM, Peillon F (1990). Normal and adenomatous
human pituitaries secrete thyrotropin-releasing hormone in
vitro: modulation by dopamine, haloperidol, and somatostatin.
Le Gros Clark WE (1938). Morphological aspects of the hypothalamus. In: Le Gros Clark WE, Beattie J, Riddoch G, Dott
NM (Eds.) The Hypothalamus. Morphological, Functional,
Clinical and Surgical Aspects, pp. 168. Oliver and Boyd,
Edinburgh.
Leadbetter RA, Shutty MS, Elkashef AM, Kirch DG, Spraggins
T, Cail WS, Wu Houwei Bilder RM, Lieberman JA, Wyatt
RJ (1999). MRI changes during water loading in patients with
polydipsia and intermittent hyponatremia. Am J Psychiatry
156: 958960.
Leaf AA, Ross RJM, Jones RB, Besser GM, Savage MO (1989).
Response to growth hormone releasing hormone as evidence
of hypothalamic defect in optic nerve hypoplasia. Acta
Paediatr Scand 78: 436439.
Leake A, Perry EK, Perry RH, Jabeen S, Fairbairn AF, McKeith
IG, Ferrier IN (1991). Neocortical concentrations of
neuropeptides in senile dementia of the Alzheimer and Lewy
body type: comparison with Parkinsons disease and severity
correlations. Biol Psychiatry 29: 357364.
Leake RD, Fisher DA (1985). Ontogeny of vasopressin in man.
Front Horm Res 13: 4251.
Leake RD, Weitzman RE, Glatz TH, Fisher DA (1981a). Plasma
oxytocin concentrations in men, nonpregnant women, and
pregnant women before and during spontaneous labor. J Clin
Leake RD, Weitzman RE, Fisher DA (1981b). Oxytocin concentrations during the neonatal period. Biol Neonate 39: 127131.
Leal AJR, Passo V, Calado E, Vieira J, Silva Cunha JP (2002).
Interictal spike EEG source analysis in hypothalamic hamartoma epilepsy. Clin Neurophysiol 113: 19611969.
Lebert F, Pasquier F, Petit H (1996). Sundowning syndrome in
demented patients without neuroleptic therapy. Arch Gerontol
Geriatr 22: 4954.
Lebl J, Snajderov
M, Kolouskov S (1999). Severe hypoglycemia and reduction of insulin requirement in a girl with
insulin-dependent diabetes mellitus: first sign of a craniopharyngioma. J Pediatr Endocrinol Metab 12: 695697.
Larriva-Sahd J, Orozco-Estvez H, Conds-Lara M (1998).

Perinatal administration of testosterone induces hypertrophy
of the anterior commissure in adult male and female rats.
Larsen JP, Tandberg E (2001). Sleep disorders in patients with
Parkinsons disease. CNS Drugs 15: 267275.
Larsen PJ (1999). Tracing autonomic innervation of the rat
pineal gland using viral transneuronal tracing. Microsc Res
Techn 46: 296304.
Laruelle M, Abi-Dargham A (1999). Dopamine as the wind of
the psychotic fire: new evidence from brain imaging studies.
J Psychopharmacol 13: 358371.
Lary JM, Paulozzi LJ (2001). Sex differences in the prevalence
of human birth defects: a population-based study. Teratology
64: 237251.
Lasco MS, Jordan TJ, Edgar TJ, Edgar MA, Petito CK,
Byne W (2002). A lack of dimorphism of sex or sexual orientation
in the human anterior commissure. Brain Res 936: 9598.
Lau KY, Fung WT, Chan PO, Sze WM, Lee AWM, Yau
TK (2001). MRI of the hypothalamus and pituitary gland
in patients with hyperprolactinaemia following radiotherapy for nasopharyngeal carcinoma. Singapore Med J 42:
406409.
Laubichler W, Ruby M (1986). Tageszeitliche Bindungen delinquenten Verhaltens. Arch Kriminol 177: 176184.
Laughlin GA, Barrett-Connor E (2000). Sexual dimorphism in
the influence of advanced aging on adrenal hormone levels:
the Rancho Bernardo study. J Clin Endocrinol Metab 85:
35613568.
Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A,
Amaducci LA, Brayne C, Copeland JRM, Dartigues J-F,
Kragh-Sorensen P et al. Euroderm Incidence Research Group
and Work Groups (1999). Rates and risk factors for dementia
and Alzheimers disease. Neurology 52: 7884.
Lauritsen MB, Ewald H (2001). The genetics of autism. Acta
Lauson HD (1974). Metabolism of the neurohypophysial
hormones. In: Sawyer WH, Knobil E (Eds.) Handbook of
Physiology, section 7, Endocrinology, Vol. IV. American
Physiological Society, Washington, DC, pp. 311.
Laviano A, Russo M, Freda F, Rossi-Fanelli F (2002).
Neurochemical mechanisms for cancer anorexia. Nutrition 18:
100105.
Lavie P, Luboshitzky R (1997). Melatonin: possible role in
human sleep and reproduction. In: Hayashi O, Inoue S (Eds.)
Sleep and sleep disorders: from molecule to behavior. Takeda
Science Foundation, pp. 209222.
Lavin PJM, Bone I, Sheridan P (1981). Studies of hypothalamic function in Huntingtons chorea. J Neurol Neurosurg
Law SP (1986). The regulation of menstrual cycle and its
relationship to the moon. Acta Obstet Gynaecol Scand 65:
4548.
487
2014 Refs
488
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 488
D.F. SWAAB
LeBlanc ES, Janowsky J, Chan BKS, Nelson HD (2001).

Hormone replacement therapy and cognition. Systematic
review and meta-analysis. JAMA 285: 14891499.
Le Blond CB, Morris S, Karakiulakis G, Powell R, Thomas PJ
(1982). Development of sexual dimorphism in the suprachiasmatic nucleus of the rat. J Endocrinol 95: 137145.
Leboyer M, Bouvard MP, Launay J-M, Tabuteau F, Waller D,
Dugas M, Kerdelhue B, Lensing P, Panksepp J (1992). A
double-blind study of naltrexone in infantile autism. J Autism
Dev Disord 22: 309319.
Leckman JF, Goodman WK, North WG, Chappell PB, Price
LH, Pauls DL, Anderson GM, Riddle MA, McSwigganHardin M, McDougle CJ, Barr LC, Cohen DJ (1994).
Elevated cerebrospinal fluid levels of oxytocin in obsessivecompulsive disorder. Arch Gen Psychiatry 51: 782792.
Ledingham JGG, Crowe MJ, Forsling ML, Phillips PA,
Rolls BJ (1987). Effects of aging on vasopressin secretion,
water excretion, and thirst in man. Kidney Int (Suppl) 32:
S90S92.
Lee AG, Tang RA, Roberts D, Schiffman JS, Osborne A
(2001b). Primary central nervous system lymphoma involving
the optic chiasm in AIDS. J Neuroophthalmol 21: 9598.
Lee GP, Loring DW, Meader KJ, Brooks BB (1990).
Hemispheric specialization for emotional expression: a reexamination of results from intracarotid administration of
sodium amobarbital. Brain Cogn 12: 267280.
Lee Harris N, McNeely WF, Shepard JO, Ebeling SH, Ellender
SM, Peters CC (Eds.) (2002). Case records of the
Massachusetts General Hospital. N Engl J Med 346: 513520.
Lee PA (1999). Central precocios puberty. An overview of diagnosis, treatment, and outcome. Endocrinol Metab Clin North
Am 28: 901918.
Lee PDK, Wilson DM, Hintz RL, Rosenfeld RG (1987). Growth
hormone treatment of short stature in PraderWilli syndrome.
J Pediatr Endocrinol 2: 3134.
Lee M-C, Chung Y-T, Lee J-H, Jung J-J, Kim H-S, Kim SU
(2001a). Antioxidant effect of melatonin in human retinol
neuron cultures. Exp Neurol 172: 407415.
Lee PDK (2000). Effects of growth hormone treatment in
children with PraderWilli syndrome. Growth Horm IGF Res
(Suppl B), S75S79.
Lee S, Chow CC (1995). Thyroid abnormalities in chronic
schizophrenia. Aust NZ J Psychiatry 29: 157159.
Lee S, Merriam A, Kim TS, Liebling M, Dickson DW, Moore
GRW (1989). Cerebellar degeneration in neuroleptic malignant syndrome: neuropathologic findings and review of the
literature concerning heat-related nervous system injury. J
Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991). A68:
a major subunit of paired helical filaments and forms of
normal Tau. Science 251: 675678.
Lee Y-L, Lin JCT, Shen E-Y, Liang D-C, Wong T-T, Huang
F-Y (1996). Loss of visibility of the neurohypophysis as
a sign of central diabetes insipidus. Eur J Radiol 21:

233235.
Lee Y-S, Kok-Seng Poh L, Loke K-Y (2002). A novel
melanocortin 3 receptor gene (MC3R) mutation associated
with severe obesity. J Clin Endocrinol Metab 87: 14231426.
Leger J, Velasquez A, Garel C, Hassan M, Czernichow P (1999).
Thickened pituitary stalk on magnetic resonance imaging in
children with central diabetes insipidus. J Clin Endocrinol
Metab 84: 19541960.
Legouis R, Cohen-Salmon M, Del Castillo I, Petit C (1994).
Isolation and characterization of the gene responsible for the
X chromosome-linked Kallmann syndrome. Biomed
Pharmacother 48: 241246.
Lgrdi G, Emerson CH, Ahima RS, Flier JS, Lechan RM
(1997). Leptin prevents fasting-induced suppression of
prothyrotropin-releasing hormone messenger ribonucleic acid
in neurons of the hypothalamic paraventricular nucleus.
Legro RS, Driscoll D, Strauss JF III Fox J, Dunaif A (1998).
Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 95:
1495614960.
Legros JJ (2001). Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin
ying-yang neurohormones. Psychoneuroendocrinology 26:
649655.
Legros JJ, Ansseau M (1992). Neurohypophyseal peptides and
psychopathology. Prog Brain Res 93: 455461.
Legros JJ, Franchimont P (1972). Human neurophysine blood
levels under normal, experimental and pathological conditions. Clin Endocrinol 1: 99113.
Legros JJ, Geenen V (1996). Neurophysins in central diabetes
insipidus. Horm Res 45: 182186.
Legros JJ, Gilot P, Schmitz S, Bruwier M, Mantanus H, TimsitBerthier M (1980). Neurohypophyseal peptides and cognitive
function: a clinical approach. In: Brambilla F, Racagni G, De
Wied D (Eds.) Progress in Psychoneuroendocrinology.
Elsevier, Amsterdam, p. 325.
Legros JJ, Deconinck I, Willems D, Roth B, Pelc I, Brauman
J, Verbanck M (1983). Increase of neurophysin II serum
levels in chronic alcoholic patients: relationship with
alcohol consumption and alcoholism blood markers during withdrawal therapy. J Clin Endocrinol Metab 56:
871875.
Legros JJ, Gazzotti C, Carvelli T, Franchimont P, TimsitBerthier M, Von Frenckell R, Ansseau M (1992).
Apomorphine stimulation of vasopressin- and oxytocinneurophysin. Evidence for increased oxytocinergic and
decreased vasopressinergic function in schizophrenics.
Lehman MN, Silver R, Gladstone WR, Kahn RM, Gibson M,
Bittman EL (1987). Circadian rhythmicity restored by neural
transplant. Immunocytochemical characterization of the graft
2014 Refs
2/12/03
1:39 pm
Page 489
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
489
cluster headache: a 3-year follow-up. Neurol Sci 24:

S143S145.
Leopold NA, Podolsky S (1975). Exaggerated growth hormone
response to arginine infusion in Huntingtons disease. J Clin
Leppmki S, Partonen T, Lnnqvist J (2002). Bright-light exposure combined with physical exercise elevates mood. J Affect
Disord 72: 139144.
Leppmki S, Partonen T, Vakkuri O, Lnnqvist J, Partinen M,
Laudon M (2003). Effect of controlled-release melatonin on
sleep quality, mood, and quality of life in subjects with
seasonal or weather-associated changes in mood and behaviour. Eur Neuropsychopharmacol 13: 137145.
Lerner AJ, Hedera P, Koss E, Stuckey J, Friedland RP (1997).
Delirium in Alzheimer disease. Alzheimer Dis Assoc Disord
11: 1620.
Lerner V, Bergman J, Greenberg D, Bar-El Y (1995).
LaurenceMoonBardetBiedl syndrome in combination with
Cotards syndrome. Case report. Isr J Psychiatry Relat Sci
32: 291294.
Lesch A, Bogerts B (1984). The diencephalon in Schizophrenia:
evidence for reduced thickness of the periventricular grey
matter. Eur Arch Psychiatry Neurol Sci 234: 212219.
Leslie W (1940). Cyst of the cavum vergae. Can Med Assoc J
43: 433435.
Leslie RDG, Isaacs AJ, Gomez J, Raggatt PR, Bayliss R (1978).
Hypothalamo-pituitary-thyroid function in anorexia nervosa:
influence of weight gain. Br Med J 2 (6136): 526528.
Lesperance MM, Hall III JW, San Agustin TB, Leal SM (2003).
Mutations in the Wolfram syndrome type 1 gene (WFS1).
define a clinical entity of dominant low-frequency sensorineural hearing loss. Arch Otolaryngeal Head Neck Surg 129:
411420.
Lester NA, Keel PK, Lipson SF (2003). Symptom fluctuation
in bulimia nervosa: relation to menstrual-cycle phase and
cortisol levels. Psychol Med 33: 5160.
Lesur A, Gaspar P, Alvarez C, Berger B (1989). Chemoanatomic
compartments in the human bed nucleus of the stria terminalis. Neuroscience 32: 181194.
Letenneur L, Gilleron V, Commenges D, Helmer C, Orgogozo
JM, Dartigues JF (1999). Are sex and educational level
independent predictors of dementia and Alzheimers disease?
Incidence data from the PAQUID project. J Neurol Neurosurg
Letenneur L, Launer LJ, Andersen K, Dewey ME, Ott A,
Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi
M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman
A (2000). Education and the risk for Alzheimers disease:
sex makes a difference. EURODEM pooled analyses.
EURODEM Incidence Research Group. Am J Epidemiol 151:
10641071.
Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M (2002).
Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 159: 122129.
and its integration with the host brain. J Neurosci 7:

16261638.
Lehmann DJ, Butler HT, Warden DR, Combrinck M, King E,
Nicoll JAR, Budge MM, De Jager CA, Hogervorst E, Esiri
MM, Ragoussis J, Smith AD (2003). Association of the
androgen receptor CAG repeat polymorphism with
Alzheimers disease in men. Neurosci Lett 340: 8790.
Lehnert H, Schulz C, Dieterich K (1998). Physiological and
neurochemical aspects of corticotropin-releasing factor
actions in the brain: the role of the locus coeruleus.
Neurochem Res 23: 10391052.
Leibenluft E, Albert PS, Rosenthal NE, Wehr TA (1996).
Relationship between sleep and mood in patients with rapidcycling bipolar disorder. Psychiatry Res 63: 161168.
Leibenluft E, Schmidt PJ, Turner EH, Danaceau MA, Ashman
SB, Wehr TA, Rubinow DR (1997). Effects of leuprolideinduced hypogonadism and testosterone replacement on sleep,
melatonin, and prolactin secretion in men. J Clin Endocrinol
Metab 82: 32033207.
Leibowitz SF, Hammer NJ, Chang K (1981). Hypothalamic
paraventricular nucleus lesions produce overeating and
obesity in the rat. Physiol Behav 27: 10311040.
Leibowitz SF (1992). Neurochemical-neuroendocrine systems
in the brain controlling macronutrient intake and metabolism.
Trends Neurosci 15: 491497.
Lemire I (1993). Revue du syndrome de KleineLevin: vers
une approche intgre. Can J Psychiatry 38: 277284.
Lemmer B, Hauptfleisch S, Witte K (2000). Loss of 24 h rhythm
and light-induced c-fos mRNA expression in the suprachiasmatic
nucleus of the transgenic hypertensive TGR(mRen2). 27 rat and
effects on cardiovascular rhythms. Brain Res 883: 250257.
Leng G, Mason WT, Dyer RG (1982). The supraoptic nucleus
as an osmoreceptor. Neuroendocrinology 34: 7582.
Lentjes EG, Griep EN, Boersma JW, Romijn FP, De Kloet ER
(1997). Glucocorticoid receptors, fibromyalgia and low back
pain. Psychoneuroendocrinology 22: 603614.
Leonard H, Bower C (1998). Is the girl with Rett syndrome
normal at birth? Dev Med Child Neurol 40: 115121.
Leonardelli J, Tramu G (1979). Immunoreactivity for -endorphin in LH-RH neurons of the fetal human hypothalamus.
Leone M, Bussone G (1993). A review of hormonal findings
in cluster headache. Evidence for hypothalamic involvement.
Leone M, Lucini V, DAmico D, Grazzi L, Moschiano F,
Fraschini F, Bussone G (1998). Abnormal 24-hour urinary
excretory pattern of 6-sulphatoxymelatonin in both phases of
cluster headache. Cephalalgia 18: 664667.
Leone M, Franzini A, Bussone G (2001). Stereotactic stimulation
of posterior hypothalamic gray matter in a patient with intractable cluster headache. New Engl J Med 345: 14281429.
Leone M, Franzini A, Broggi G, Bussone G (2003).
Hypothalamic deep brain stimulation for intractable chronic
489
2014 Refs
490
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 490
D.F. SWAAB
Leung A, Chue P (2000). Sex differences in schizophrenia, a

review of the literature. Acta Psychiatr Scand (Suppl) 401: 338.
Leung AKC, MacArthur RG, McMillan DD, Ko D, Deacon JS,
Parboosingh JT, Lederis KP (1980). Circulating antidiuretic
hormone during labor and in the newborn. Acta Paediatr
Scand 69: 505510.
LeVay S (1991). A difference in hypothalamic structure between
heterosexual and homosexual men. Science 253: 10341037.
Levene MI (1995). The spectrum of neural tube defects. In:
Levene MI, Lilford RJ, Bennett MJ, Punt J (Eds.) Fetal and
Neonatal Neurology and Neurosurgery, pp. 281286.
Churchill Livingstone, Edinburgh.
Levi F (2001). Circadian chronotherapy for human cancers.
Lancet Oncol 2: 307315.
Levi F, Halberg F (1982). Circaseptan (about-7-day) bioperiodicity spontaneous and reactive and the search for
pacemakers. Ricerca Clin Lab 12: 323369.
Levin M (1929). Narcolepsy and other varieties of morbid
somnolence. Arch Neurol Psychiatry 22: 1172.
Levine LS, Boston BA (2000). Effect of inhaled corticosteroids
on the hypothalamic-pituitary-adrenal axis and growth in children. J Pediatr 137: 450454.
Levine ME, Milliron AN, Duffy LK (1994). Diurnal and
seasonal rhythms of melatonin, cortisol and testosterone in
interior Alaska. Arctic Med Res 53: 2534.
Levitan RD, Kaplan AS, Brown GM, Joffe RT, Levitt AJ,
Vaccarino FJ, Kennedy SH (1997). Low plasma cortisol in
bulimia nervosa patients with reversed neurovegetative symptoms of depression. Biol Psychiatry 41: 366368.
Lewin K, Mattingly D, Millis RR (1972). Anorexia nervosa
associated with hypothalamic tumor. Br Med J 2 (814):
629630.
Lewis AI, Crone KR, Taha J, Van Loveren HR, Yeh H-S, Tew
JM (1994). Surgical resection of third ventricle colloid cysts.
Lewis DO, Shanok SS, Balla DA (1979). Perinatal difficulties,
head and face trauma, and child abuse in the medical histories of seriously delinquent children. Am J Psychiatry 136:
419423.
Lewis LK, Hinshaw DB, Will AD, Hasso AN, Thompson JR
(1988). CT and angiographic correlation of severe neurological
disease of toxemia of pregnancy. Neuroradiology 30: 5964.
Lewis WH, Alving AS (1938). Changes with age in the renal
function in adult men. Am J Physiol 123: 500515.
Lewy AJ, Sack RL (1996). The role of melatonin and light
in the human circadian system. Prog Brain Res 111:
205216.
Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP
(1980). Light suppresses melatonin secretion in humans.
Science 210: 12671269.
Lewy AJ, Bauer VK, Cutler NL, Sack RL (1998a). Melatonin
treatment of winter depression: a pilot study. Psychiatry Res
77: 5761.
Lewy AJ, Bauer VK, Cutler NL, Sack RL, Ahmed S, Thomas
KH, Blood ML, Jackson JM (1998b). Morning vs evening
light treatment of patients with winter depression. Arch Gen
Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires MLN, Sack
RL (2001). Capturing the circadian rhythms of free-running
blind people with 05 mg melatonin. Brain Res 918: 96100.
Leyton M, Blanger C, Martial J, Beaulieu S, Corin E, Pecknold
J, Kin NMK, Meaney M, Thavundayil J, Larue S, Nair NP
(1996). Cardiovascular, neuroendocrine, and monoaminergic
responses to psychological stressors: possible differences
between remitted panic disorder patients and healthy controls.
Li C, Chen P, Smith MS (2000). Corticotropin releasing
hormone neurons in the paraventricular neurons are direct
targets for neuropeptide Y neurons in the arcuate nucleus: an
anterograde tracing study. Brain Res 854: 122129.
Li G, Aryan M, Silverman JM, Haroutunian V, Perl DP, Birstein
S, Lantz M, Marin DB, Mohs RC, Davis KL (1997). The
validity of the family history method for identifying
Alzheimer disease. Arch Neurol 54: 634640.
Li Y-J, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance
MA, Watts RL, Hubble JP, Koller WC, Pahwa R et al. (2002).
Age at onset in two common neurodegenerative diseases is
genetically controlled. Am J Hum Genet 70: 985993.
Li YW, Halliday GM, Joh TH, Geffen LB, Blessing WW (1988).
Tyrosine-hydroxylase-containing neurons in the supraoptic
and paraventricular nuclei of the adult human. Brain Res 461:
7586.
Liang Y-Q, Akishita M, Kim S, Ako J, Hashimoto M, Iijima
K, Ohike Y, Watanabe T, Sudoh N, Toba K, Yoshizumi M,
Ouchi Y (2002). Estrogen receptor is involved in the
anorectic action of estrogen. Int J Obesity 26: 11031109.
Lichtenstein MJ, Tilley WS, Sandler MP (1982). The syndrome
of hypothalamic hypopituitarism complicating viral meningoencephalitis. J Endocrinol Invest 5: 111.
Licinio J, Wong M-L, Gold PW (1996). The hypothalamicpituitary-adrenal axis in anorexia nervosa. Psychiatry Res 62:
7583.
Liggins GC (1962). The treatment of missed abortion by high
dosage syntocinon intravenous infusion. J Obstet Gynaecol
Br Commun 69: 277281.
Liggins GC (1969). Premature delivery of foetal lambs infused
with glucocorticoids. J Endocrinol 45: 515523.
Liggins GC (2000). The role of the hypothalamic-pituitaryadrenal axis in preparing the fetus for birth. Am J Obstet
Gynecol 182: 475477.
Liggins GC, Kennedy PC (1968). Effects of electrocoagulation
of the foetal lamb hypophysis on growth and development.
J Endocrinol 40: 371381.
Liggins GC, Kennedy PC, Holm LW (1967). Failure of imitation of parturition after electrocoagulation of the pituitary of
the fetal lamb. Am J Obstet Gynecol 98: 10801086.
2014 Refs
2/12/03
1:39 pm
Page 491
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
491
large skin area does not affect melatonin or bilirubin levels

in human. Biol Psychiatry 48: 10981104.
Lindblom N, Heiskala H, Kaski M, Leinonen L, Laakso M-L
(2002). Sleep fragmentation in mentally retarded people
decreases with increasing day length in spring. Chronobiol
Int 19: 441459.
Linder N, Matoth I, Ohel G, Yourish D, Tamir I (1986). LDeamino-8-D-arginine vasopressin treatment in pregnancy
and neonatal outcome. Am J Perinatol 3: 165166.
Lindgren AC, Ritzn EM (1999). Five years of growth hormone
treatment in children with PraderWilli syndrome. Acta
Paediatr (Suppl) 433: 109111.
Lindgren AC, Marcus C, Skwirut C, Elimam A, Hagens L,
Schalling M, Anvret M, Lnnqvist F (1997a). Increased leptin
messenger RNA and serum leptin levels in children with
PraderWilli syndrome and nonsyndromal obesity. Pediatr
Res 42: 593596.
Lindgren AC, Hagens L, Mller J, Blichfeldt S, Rosenborg M,
Brismar T, Ritzn EM (1997b). Effects of growth hormone
treatment on growth and body composition in PraderWilli
syndrome: a preliminary report. Acta Paediatr (Suppl) 423:
6062.
Lindgren AC, Hagens L, Mller J, Blichfeldt S, Rosenborg M,
Brismar T, Ritzn EM (1998). Growth hormone treatment of
children with PraderWilli syndrome affects linear growth
and body composition favourably. Acta Paediatr 87: 2831.
Lindgren AC, Hagens L, Ritzn EM (1999). Growth hormone
treatment of children with PraderWilli syndrome: effects on
glucose and insulin homeostasis. Horm Res 51: 157161.
Lindheimer MD, Davison JM (1995). Osmoregulation, the
secretion of arginine vasopressin and its metabolism during
pregnancy. Eur J Endocrinol 132: 133143.
Lindheimer MD, Barron WM, Davison JM (1985). Water
metabolism and vasopressin secretion in pregnancy. In:
Schrier RW (Ed.) Vasopressin. Raven Press, New York, pp.
229240.
Lindow SW, Van der Spuy ZM, Hendricks M S, Rosselli
AP, Lombard C, Leng G (1992). The effect of morphine
and naloxone administration on plasma oxytocin concentrations in the first stage of labour. Clin Endocrinol 37:
349353.
Lindow SW, Newham A, Hendricks MS, Thompson JW, Van
der Spuy ZM (1996). The 24-hour rhythm of oxytocin and
-endorphin secretion in human pregnancy. Clin Endocrinol
45: 443446.
Lindow SW, Hendricks MS, Nugent FA, Dunne TT, Van
der Spuy ZM (1999). Morphine suppresses the oxytocin
response in breast-feeding women. Gynecol Obstet Invest 48:
3337.
Lindsay J, Laurin D, Verreault R, Hbert R, Helliwell B, Hill
GB, McDowell I (2002). Risk factors for Alzheimers disease:
a prospective analysis from the Canadian study of health and
aging. Am J Epidemiol 156: 445453.
Lightman SL, Forsling ML (1980). Evidence for dopamine as

an inhibitor of vasoprotein release in man. Clin Endocrinol
12: 3946.
Lightman SL, Williams TDM (1993). Hypothalamic and
pituitary function in autonomic failure. In: Bannister Sir R,,
Mathias CJ (Eds.) Autonomic Failure. A Textbook of Clinical
Disorders of the Autonomic Nervous System. Oxford
University Press, Oxford.
Lightman SL, Iversen LL, Forsling ML (1982). Dopamine
and [D-Ala2, D-Leu5]enkephalin inhibit the electrically stimulated
neurohypophyseal release of vasopressin in vitro; evidence for
calcium-dependent opiate action. J Neurosci 2: 7881.
Lilien AA (1968). Oxytocin-induced water intoxication. Obstet
Gynecol 32: 171173.
Lilly R, Cummings JL, Benson DF, Frankel M (1983). The
human KlverBucy syndrome. Neurology 33: 11411145.
Limburg CC (1950). In: Multiple Sclerosis and the Demyelinating Disease. Williams and Wilkins, Baltimore, pp. 1524.
Limoge A, Robert C, Stanley TH (1999). Transcutaneous cranial
electrical stimulation (TCES): a review 1998. Neurosci
Biobehav Rev 23: 529538.
Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C,
Hoffmann D, Benabid A-L (1998). Electrical stimulation of
the subthalamic nucleus in advanced Parkinsons disease. N
Engl J Med 339: 11051111.
Lin K-D, Lin J-D, Hsu H-H, Juang J-H, Huang M-J, Huang
H-S (1998). Endocrinological aspects of Langerhans cell
histiocystosis complicated with diabetes insipidus. J
Lin K-L, Wang H-S, Chou M-L, Rui T-N (1997). Role of cavum
septum pellucidum in akinetic mutism of hydrocephalic children. Pediatr Neurol 16: 156159.
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X,
De Jong PJ, Nishino S, Mignot E (1999). The sleep disorder
canine narcolepsy is caused by a mutation in the hypocretin
(orexin) receptor 2 gene. Cell 98: 365376.
Lin L, Hungs M, Mignot E (2001). Narcolepsy and the HLA
region. J Neuroimmunol 117: 920.
Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF (2002b).
High aggregate burden of somatic mtDNA point mutations
in aging and Alzheimers disease brain. Hum Mol Genet 11:
133145
Lin S-H, Bichet DG, Sasaki S, Kuwahara M, Arthus M-F,
Lonergan M, Lin Y-F (2002a). Two novel aquaporin-2
mutations responsible for congenital nephrogenic diabetes
insipidus in Chinese families. J Clin Endocrinol Metab 87:
26942700.
Lindamer LA, Buse DC, Lohr JB, Jeste DV (2001). Hormone
replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms? Biol
Lindblom N, Htnen T, Laakso M-L, Alila-Johansson A,
Laipio ML, Turpeinen U (2000). Bright light exposure of a
491
2014 Refs
492
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 492
D.F. SWAAB
Lingjaerde O, Reichborn-Kjennerud T, Haggag A, Grtner I,

Berg EM, Narud K (1993). Treatment of winter depression
in Norway. I. Short- and long-term effects of 1500-lux white
light for 6 days. Acta Psychiatr Scand 88: 292299.
Lingjaerde O, Reichborn-Kjennerud T, Haug E (1995). Thyroid
function in seasonal affective disorder. J Affect Disord 33:
3945.
Lingjaerde O, Freland AR, Dankertsen J (1998). Dawn simulation vs. lightbox treatment in winter depression: a
comparative study. Acta Psychiatr Scand 98: 7380.
Linkowski P, Mendlewicz J, Kerkhofs M, Leclercq R, Golstein
J, Brasseur M, Copinschi G, Van Cauter E (1987). 24-hour
profiles of adrenocorticotropin, cortisol, and growth hormone
in major depressive illness: effect of antidepressant treatment.
J Clin Endocrinol Metabol 65: 141152.
Linnemann HK, Schrder C, Mix M, Krger G, Fusch C (1999).
PraderLabhartWilli syndrome with central precocious
puberty and empty sella syndrome. Acta Paediatr 88:
12951297.
Lino RS, Reis LC, Reis MA, Gobbi H, Teixeira VPA (2000).
Hypothalamic neurocysticerosis as a possible cause of
obesity. Trans R Soc Trop Med Hyg 94: 294.
Lipani JD, Bhattacharjee MB, Corey DM, Lee DA (2000).
Reduced nerve growth factor in Rett syndrome postmortem
brain tissue. J Neuropathol Exp Neurol 59: 889895.
Lipnick RN, Hung W, Pandian MR (1993). Neurosarcoidosis
presenting as secondary amenorrhea in a teenager. J Adolesc
Health 14: 464467.
Lippa CF, Fujiwara H, Mann DMA, Giasson B, Baba M,
Schmidt ML, Nee LE, OConnell B, Pollen DA, St GeorgeHyslop P et al. (1998). Lewy bodies contain altered
-synuclein in brains of many familial Alzheimers disease
patients with mutations in presenilin and amyloid precursor
protein genes. Am J Pathol 153: 13651370.
Lippa RA (2001). Gender-related traits in transsexuals and
nontranssexuals. Arch Sex Behav 30: 603614.
Lipponi G, Cadeddu G, Antonicelli R, Compagnucci M,
Spazzafumo L, Foschi F, Gaetti R (1990). Vasopressin,
prolactin and growth hormone in Alzheimers disease: their
evaluation after metaclopramide stimulation. Arch Gerontol
Geriatr 10: 269278.
Lipsett MB, MacClean JP, West CD, Li MC, Pearson OH
(1956). An analysis of the polyuria induced by hypophysectomy in man. J Clin Endocrinol Metab 16: 183195.
Lipsett MB, Dreifuss FE, Thomas LB (1962). Hypothalamic
syndrome following varicella. Am J Med 32: 471475.
Liu GT (2001). Visual loss in childhood. Survey Ophthalmol
46: 3542.
Liu RY, Unmehopa UA, Zhou JN, Swaab DF (2003).
Glucocorticoids suppress vasopressin gene expression in the
human biological clock (submitted).
Liu RY, Zhou JN, Van Heerikhuize JJ, Hofman MA, Swaab
DF (1999). Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimers disease, and
apolipoprotein E-4/4 genotype. J Clin Endocrinol Metab 84:

323327.
Liu RY, Zhou J-N, Hoogendijk WJG, Van Heerikhuize J,
Kamphorst W, Unmehopa UA, Hofman MA, Swaab DF
(2000b). Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without
depression. J Neuropathol Exp Neurol 59: 314322
Liu Y, Gao J-H, Liu H-L, Fox PT (2000a). The temporal
response of the brain after eating revealed by functional MRI.
Nature 405: 10581062.
Liu Y-C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff
VK, Reppert SM (1997a). Molecular dissection of two distinct
actions of melatonin on the suprachiasmatic circadian clock.
Neuron 19: 91102.
Liu Y-C, Salamone JD, Sachs BD (1997b). Impaired sexual
response after lesions of the paraventricular nucleus of the
hypothalamus in male rats. Behav Neurosci 111: 13611367.
Lobosky JM, Vangilder JC, Damasio AR (1984). Behavioural
manifestations of third ventricular colloid cysts. J Neurol
Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R,
Arendt J (1997). Relationship between napping and melatonin in the blind. J Biol Rhythms 12: 1625.
Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt
J (2000). Melatonin administration can entrain the freerunning circadian system of blind subjects. J Endocrinol 164:
R1R6.
Lockwood AH (1976). ShyDrager syndrome with abnormal
respirations and antidiuretic hormone release. Arch Neurol
33: 292295.
Loesch DV, Gilman S, Del Dotto J, Rosenblum ML (1995).
Cavernous malformation of the mamillary bodies: neuropsychological implications. J Neurosurg 83: 354358.
Loeuille GA, De Parscau L, Ythier H, Beaufrere B, Chatelain
P, Franois R (1989). Dysfonctionnement hypothalamique.
Etude de deux cas: apport de limagerie par rsonance magntique, essai thrapeutique de la naltrexone. Pdiatrie 44:
203212.
Loftus M, Knight RT, Amaral DG (2000). An analysis of
atrophy in the medial mammillary nucleus following
hippocampal and fornix lesions in humans and nonhuman
primates. Exp Neurol 163: 180190.
Loh K-C, Green A, Dillon Jr, WP, Fitzgerald PA, Weidner N,
Tyrrell JB (1997). Diabetes insipidus from sarcoidosis confined to the posterior pituitary. Eur J Endocrinol 137: 514519.
Lkkegaard E, Pedersen AT, Laursen P, Loft IP, Larsen S,
Jrgensen T (2002). The influence of hormone replacement
therapy on the aging-related change in cognitive performance.
Analysis based on a Danish cohort study. Maturitas 42:
209218.
Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G,
Gandevia S (1999). Double-blind controlled investigation of
transcranial magnetic stimulation for the treatment of resistant major depression. Am J Psychiatry 156: 946948.
2014 Refs
2/12/03
1:39 pm
Page 493
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Loosen PT (1992). Effects of thyroid hormones on central

nervous system in aging. Psychoneuroendocrinology 17:
355374.
Loosen PT, Prange AJ (1982). Serum thyrotropin response to
thyrotropin-releasing hormone in psychiatric patients: a
review. Am J Psychiatry 139: 405416.
Lopiano L, Rizzone M, Bergamasco B, Tavella A, Torre E,
Perozzo P, Valentini MC, Lanotte M (2001). Deep brain stimulation of the subthalamic nucleus: clinical effectiveness and
safety. Neurology 56: 552554.
Lorber J (1958). Diabetes insipidus following tuberculous
meningitis. Arch Dis Child 33: 315319.
Lortholary O, Christeff N, Casassus P, Thobie N, Veyssier P,
Trogoff B, Torri O, Brauner M, Nunez EA, Guillevin L
(1996). Hypothalamo-pituitary-adrenal function in human
immunodeficiency virus-infected men. J Clin Endocrinol
Metab 81: 791796.
Losa M, Saeger W, Mortini P, Pandolfi C, Terreni MR, Taccagni
G, Giovanelli M (2000). Acromegaly associated with a granular cell tumor of the neurohypophysis: a clinical and
histological study. J Neurosurg 93: 121126.
Losa M, Mortini P, Dylgjeri S, Barzaghi R, Franzin A, Mandelli
C, Giovanelli M (2001). Desmopressin stimulation test before
and after pituitary surgery in patients with Cushings disease.
Loup F, Tribollet E, Dubois-Dauphin M, Pizzolato G, Dreifuss
JJ (1989). Localization of oxytocin binding sites in the human
brainstem and upper spinal cord: an autoradiographic study.
Brain Res 500: 223230.
Loup F, Tribollet E, Dubois-Dauphin M, Dreifuss JJ (1991).
Localization of high-affinity binding sites for oxytocin and
vasopressin in the human brain. An autoradiographic study.
Brain Res 555: 220232.
Lvs K, Husebye ES, Holsten F, Bjorvatn B (2003). Sleep
disturbances in patients with Addisons disease. Eur J
Low PA, Ahlskog JE, Petersen RC, Waring SC, Esteban-Santillan
C, Kurland LT (1997). Autonomic failure in Guamanian neurodegenerative disease. Neurology 49: 10311034.
Lowes-Hommel P, Gertz JZ, Ferszt R, Cerros-Navarro J (1989).
The basal nucleus of Meynert revised, the nerve cell number
decreases with age. Arch Geront Geriatr 8: 2127.
Lu S, Guan J-L, Wang Q-P, Uehara K, Yamada S, Goto N,
Date Y, Nakazato M, Kojima M, Kangawa K, Shioda S
(2002). Immunocytochemical observation of ghrelincontaining neurons in the rat arcuate nucleus. Neurosci Lett
321: 157160.
Lubkin V, Beizai P, Sadun AA (2002). The eye as metronome
for the body. Surv Ophthalmol 47: 1726.
Luboshitzky R (2000). Endocrine activity during sleep. J Pediatr
Luboshitzky R, Lavie P (1999). Melatonin and sex hormone
interrelationships a review. J Pediatr Endocrinol Metab 12:
355362.
493
Luboshitzky R, Lavi S, Thuma I, Lavie P (1995). Increased

nocturnal melatonin secretion in male patients with hypogonadotropic hypogonadism and delayed puberty. J Clin
Luboshitzky R, Lavi S, Thuma I, Lavie P (1996). Testosterone
treatment alters melatonin concentrations in male patients
with gonadotropin-releasing hormone deficiency. J Clin
Endocrinol Metabol 81: 770774.
Luboshitzky R, Herer P, Lavie P (1997a). Pulsatile patterns of
melatonin secretion in patients with gonadotropin-releasing
hormone deficiency: effects of testosterone treatment. J Pineal
Res 22: 95101.
Luboshitzky R, Wagner O, Lavi S, Herer P, Lavie P
(1997b). Abnormal melatonin secretion in hypogonadal
men: the effect of testosterone treatment. Clin Endocrinol 47:
463469.
Luboshitzky R, Dharan M, Goldman D, Herer P, Hiss Y, Lavie
P (1997c). Seasonal variation of gonadotropins and gonadal
steroids receptors in the human pineal gland. Brain Res Bull
44: 665670.
Luboshitzky R, Dharan M, Goldman D, Hiss Y, Herer P, Lavie
P (1997d) Immunohistochemical localization of gonadotropin
and gonadal steroid receptors in human pineal glands. J Clin
Luboshitzky R, Yanai D, Shen-Orr Z, Israeli E, Herer P, Lavie
P (1998). Daily and seasonal variations in the concentration
of melatonin in the human pineal gland. Brain Res Bull 47:
271276.
Luboshitzky R, Lavi S, Lavie P (1999). The association between
melatonin and sleep stages in normal adults and hypogonadal
men. Sleep 22: 867874.
Luboshitzky R, Qupti G, Ishay A, Shen-Orr Z, Futerman B,
Linn S (2001). Increased 6-sulfatoxymelatonin excretion in
women with polycystic ovary syndrome. Fertil Steril 76:
506510.
Lucas RJ, Douglas RH, Foster RG (2001). Characterization of
an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 4: 621626
Lucassen PJ, De Kloet ER (2001). Glucocorticoids and the aging
brain: cause of consequence? In: Hof PR, Mobbs CV (Eds.)
Functional Neurobiology of Aging. Academic Press, San
Diego, pp. 883905.
Lucassen PJ, Ravid R, Gonatas NK, Swaab DF (1993).
Activation of the human supraoptic and paraventricular
neurons with aging and in Alzheimers disease as judged
from increasing size of the Golgi apparatus. Brain Res 632:
105113.
Lucassen PJ, Salehi A, Pool CW, Gonatas NK, Swaab DF
(1994). Activation of vasopressin neurons in aging and
Alzheimers disease. J Neuroendocrinol 6: 673679.
Lucassen PJ, Goudsmit E, Pool CW, Mengod G, Palacios JM,
Raadsheer FC, Guldenaar SEF, Swaab DF (1995). In situ
hybridization for vasopressin mRNA in the human supraoptic
493
2014 Refs
494
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 494
D.F. SWAAB
and paraventricular nucleus; quantitative aspects of formalinfixed, paraffin-embedded tissue section as compared to
cryostat sections. J Neurosci Methods 57: 221230.
Lucassen PJ, Van Heerikhuize JJ, Guldenaar SEF, Pool CW,
Hofman MA, Swaab DF (1997). Unchanged amounts of vasopressin mRNA in the supraoptic and paraventricular nucleus
during aging and in Alzheimers disease. J Neuroendocrinol
9: 297305.
Lucassen PJ, Mller MB, Holsboer F, Bauer J, Holtrop A,
Wouda J, Hoogendijk WJG, De Kloet ER, Swaab DF (2001a).
Hippocampal apoptosis in major depression is a minor event
and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 158: 453468.
Lucassen PJ, Vollmann-Honsdorf GK, Gleisberg M, Czh B,
De Kloet ER, Fuchs E (2001b). Chronic psychosocial stress
differentially affects apoptosis in hippocampal subregions and
cortex of the adult tree shrew. Eur J Neurosci 14: 161166.
Lugaresi A, Baruzzi A, Cacciari E, Cortelli P, Medori R,
Montagna P, Tinuper P, Zucconi M, Roiter I, Lugaresi E
(1987). Lack of vegetative and endocrine circadian rhythms
in fatal familial thalamic degeneration. Clin Endocrinol 26:
573580.
Lugaresi E, Medori R, Montagna P, Baruzzi A, Cortelli P,
Lugaresi A, Tinuper P, Zucconi M, Gambetti P (1986). Fatal
familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315: 9971003.
Lugaresi E, Tobler I, Gambetti P, Montagna P (1998). The
pathophysiology of fatal familial insomnia. Brain Pathol 8:
521526.
Lund I, Yu L-C, Uvnas-Moberg K, Wang J, Yu C, Kurosawa
M, Agren G, Rosn A, Lekman M, Lundeberg T (2002).
Repeated massage-like stimulation induces long-term effects
on nociception: contribution of oxytocinergic mechanisms.
Eur J Neurosci 16: 330338.
Lundberg PO, Brattberg A (1992). Sexual dysfunction in
selected neurologic disorders: hypothalamopituitary disorders,
epilepsy, myelopathies, polyneuropathies, and sacral nerve
lesions. Semin Neurol 12: 115119.
Lundberg PO, Hulter B (1991). Sexual dysfunction in patients
with hypothalamo-pituitary disorders. Exp Clin Endocrinol
98: 8188.
Lunshof MS (2000). Circadian rhythms in the normal and
growth-retarded fetus and infant. (PhD thesis) University of
Amsterdam.
Lunshof MS, Boer K, Van Hoffen G, Wolf H, Mirmiran M
(1997). The diurnal rhythm in fetal heart rate in a twin pregnancy with discordant anencephaly: comparison with three
normal twin pregnancies. Early Hum Dev 48: 4757.
Lunshof MS, Boer K, Wolf H, Van Hoffen G, Bayram N,
Mirmiran M (1998). Fetal and maternal diurnal rhythms
during the third trimester of normal pregnancy: outcomes of
computerized analysis of continuous twenty-four-hour fetal
heart rate recordings. Am J Obstet Gynecol 178: 247254.
Lunshof S, Van Someren EJW, Kortes-Van Hoffen G, Wolf H,

Boer K (2000). Lack of relationship between diurnal rhythms
in fetal heart rate and maternal cortisol concentration. Am J
Luo S, Li C, Ma Z, Zhang Y, Jia G, Cheng Y (2002a).
Microsurgical treatment for hypothalamic hamartoma in children with precocious puberty. Surg Neurol 57: 356362.
Luo LG, Yano N, Mao QF, Jackson IMD, Stopa EG (2002b).
Thyrotropin releasing hormone (TRH) in the hippocampus of
Alzheimer patients. J Alzheimers Dis 4: 97103.
Lupien SJ, McEwen BS (1997). The acute effects of corticosteroids on cognition: integration of animal and human model
studies. Brain Res Brain Res Rev 24: 127.
Lupien SJ, De Leon M, De Santi S, Convit A, Tarshish C,
Nair NPV, Thakur M, McEwen BS, Hauger RL, Meaney
MJ (1998). Cortisol levels during human aging predict
hippocampal atrophy and memory deficits. Nat Neurosci 1:
6973.
Luse SA, Kernohan JW (1955). Granular cell tumors of the
stalk and posterior lobe of the pituitary gland. Cancer 8:
616622.
Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P,
Broome DC, Smith K, Li H, Hudson MM, Heideman RL,
Kun LE (1999). Hypothalamic obesity caused by cranial insult
in children: altered glucose and insulin dynamics and reversal
by a somatostatin agonist. J Pediatr 135: 162168.
Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK,
Burghen GA, Xiong X, Wu S, Merchant TE (2003). Risk
factors for the development of obesity in children surviving
brain tumors. J Clin Endocrinol Metab 88: 611616.
Lutz B, Kuratani S, Rugarli EI, Wawersik S, Wong C, Bieber
FR, Ballabio A, Eichele G (1994). Expression of the Kallmann
syndrome gene in human fetal brain and in the manipulated
chick embryo. Hum Mol Genet 3: 17171723.
Lvovich AI (2001). Descending pathways of the frontal lobe
cortex to nuclei of the hypothalamic mamillary bodies in
craniocerebral trauma in humans. Neurosci Behav Physiol 31:
371374.
Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ,
Handelsman DJ (2001). A double-blind, placebo-controlled,
randomized clinical trial of transdermal dihydrotestosterone
gel on muscular strength, mobility, and quality of life in older
men with partial androgen deficiency. J Clin Endocrinol
Metab 86: 40784088.
Lyness SA, Zarow C, Chui HC (2003). Neuron loss in key
cholinergic and aminergic nuclei in Alzheimer disease: a
meta-analysis. Neurobiol Aging 24: 123
Ma TP, Johnson JC, Hoskins GA (1997). Organization of the
zona incerta in the macaque: an electron microscopic study.
Anat Rec 249: 259275.
MacAdams MR, White RH, Chipps BE (1986). Reduction of
serum testosterone levels during chronic glucocorticoid
therapy. Ann Intern Med 104: 648651.
2014 Refs
2/12/03
1:39 pm
Page 495
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
495
circadian rhythm of temperature, pulse and blood pressure in

depressed patients with good and disturbed sleep. Int J
Psychophysiol 20: 145154.
Maeda K, Tanimoto K, Terada T, Shintani T, Kakigi T (1991).
Elevated urinary free cortisol in patients with dementia.
Maes M, Cosyns P, Meltzer HY, De Meyer F, Peeters D (1993a).
Seasonality in violent suicide but not in nonviolent suicide
or homicide. Am J Psychiatry 150: 13801385.
Maes M, Meltzer HY, Cosyns P, Suy E, Schotte C (1993b).
An evaluation of basal hypothalamic-pituitary-thyroid axis
function in depression: results of a large-scaled and controlled
study. Psychoneuroendocrinology 18: 607620.
Maes M, Meltzer HY, Suy E, De Meyer F (1993c). Seasonality
in severity of depression: relationships to suicide and homicide occurrence. Acta Psychiatr Scand 88: 156161.
Maes M, Mommen K, Hendrickx D, Peeters D, DHondt P,
Ranjan R, De Meyer F, Scharp S (1997). Components of
biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in
healthy volunteers. Clin Endocrinol 46: 587598.
Maes M, Lin A, Bonaccorso S, Van Hunsel F, Van Gastel A,
Delmeire L, Biondi M, Bosmans E, Kenis G, Scharpe S
(1998). Increased 24-hour urinary cortisol excretion in
patients with post-traumatic stress disorder and patients with
major depression, but not in patients with fibromyalgia. Acta
Maes M, Van West D, De Vos N, Westenberg H, Van Hunsel
F, Hendriks D, Cosyns P, Scharp S (2001). Lower baseline
plasma cortisol and prolactin together with increased body
temperature and higher mCPP-induced cortisol responses in
men with pedophilia. Neuropsychopharmacology 24: 3746.
Maestroni GJM, Conti A, Pierpaoli W (1988). Role of the pineal
gland in immunity III. Melatonin antagonizes the immunosuppressive effect of acute stress via an opiatergic mechanism.
Immunology 63: 465469.
Mafee MF, Dorodi S, Pai E (1999). Sarcoidosis of the eye,
orbit, and central nervous system. Radiol Clin North Am 37:
7387.
Maffei M, Stoffel M, Barone M, Moon B, Dammerman M,
Ravussin E, Bogardus C, Ludwig DS, Flier DS, Talley M,
Auerbach S, Friedman JM (1996). Absence of mutations in
the human OB gene in obese/diabetic subjects. Diabetes 45:
679682.
Maggi M, Del Carlo P, Fantoni G, Giannini S, Torrisi C,
Casparis D, Massi G, Serio M (1990). Human myometrium
during pregnancy contains and responds to V1 vasopressin
receptors as well as oxytocin receptors. J Clin Endocrinol
Metab 70: 11421154.
Maghnie M, Triulzi F, Larizza D, Preti P, Priora C, Scotti G,
Severi F (1991). Hypothalamic-pituitary dysfunction in
growth hormone-deficient patients with pituitary abnormalities. J Clin Endocrinol Metab 73: 7983.
Macafee CAJ, Beischer NA, McBride F (1973). Subnormal

maternal urinary oestriol excretion when the fetus has diabetes
insipidus, optic atrophy, and absence of the septum pellucidum. Aust NZ J Obstet Gynaecol 13: 105106.
Macchi G (1951). The ontogenetic development of the olfactory telencephalon in man. J Comp Neurol 95: 245305.
MacColl G, Quinton R, Bouloux PMG (2002). GnRH neuronal
development: insights into hypogonadotrophic hypogonadism. Trends Endocrinol Metab 13: 112118.
MacDonald HR, Wevrick R (1997). The necdin gene is deleted
in PraderWilli syndrome and is imprinted in human and
mouse. Hum Mol Genet 6: 18731878.
MacGowan SH, Wilcock GK, Scott M (1998). Effect of gender
and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimers disease. Int J Geriat
MacHale SM, Cavanagh JTO, Bennie J, Carroll S, Goodwin
GM, Lawrie SM (1998). Diurnal variation of adrenocortical
activity in chronic fatigue syndrome. Neuropsychobiology 38:
213217.
Mack SO, Kc P, Wu M, Coleman BR, Tolentino-Silva FP,
Haxhiu MA (2002). Paraventricular oxytocin neurons are
involved in neural modulation of breathing. J Appl Physiol
92: 826834.
Macke JP, Hu N, Hu S, Bailey M, King VL, Brown T, Hamer
D, Nathans J (1993). Sequence variation in the androgen
receptor gene is not a common determinant of male sexual
orientation. Am J Hum Genet 53: 844852.
MacKenzie MA, Hermus ARMM, Wollersheim HCH, Pieters
GFFM, Smals AGH, Binkhorst RA, Thien T, Kloppenborg
PWC (1991). Poikilothermia in man: pathophysiology and
clinical implications. Medicine 70: 257268.
MacLean HE, Warne GL, Zajac JD (1995). Defects of androgen
receptor function: from sex reversal to motor neurone disease.
Mol Cell Endocrinol 112: 133141.
MacLean HE, Warne GL Zajac JD (1996). Spinal and bulbar
muscular atrophy: androgen receptor dysfunction caused by
a trinucleotide repeat expansion. J Neurol Sci 135: 149157.
MacLean PD, Ploog DW (1962). Cerebral representation of
penile erection. J Neurophysiol 25: 2955.
MacNeil DJ, Howard AD, Guan X, Fong TM, Nargund RP,
Bednarek MA, Goulet MT, Weinberg DH, Strack AM, Marsh
DJ et al. (2002). The role of melanocortins in body weight
regulation: opportunities for the treatment of obesity. Eur J
Pharmacol 440: 141157.
MacPhee IAM, Antoni FA, Mason DW (1989). Spontaneous
recovery of rats from experimental allergic encephalomyelitis
is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 169: 431445.
Madden PAF, Heath AC, Rosenthal NE, Martin NG (1996).
Seasonal changes in mood and behavior: the role of genetic
factors. Arch Gen Psychiatry 53: 4755.
Madjirova NP, Tashev TG, Delchev NN, Bakalova RG (1995).
Interrelationship between cortisol levels in plasma and the
495
2014 Refs
496
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 496
D.F. SWAAB
Maghnie M, Villa A, Arico M, Larizza D, Pezzotta S, Beluffi

G, Genovese E, Severi F (1992). Correlation between
magnetic resonance imaging of posterior pituitary and neurohypophyseal function in children with diabetes insipidus. J
Maghnie M, Genovese E, Bernasconi S, Binda S, Aric M
(1997). Persistent high MR signal of the posterior pituitary
gland in central diabetes insipidus. Am J Neuroradiol 18:
17491752.
Maghnie M, Genovese E, Sommaruga Aric M, Locatelli D,
Arbustini E, Pezzotta S, Severi F (1998a). Evolution of childhood central diabetes insipidus into panhypopituitarism with
a large hypothalamic mass: is lymphocytic infundibuloneurohypophysitis in children a different entity? Eur J
Maghnie M, Bossi G, Klersy C, Cosi G, Genovese E, Aric M
(1998b). Dynamic endocrine testing and magnetic resonance
imaging in the long-term follow-up of childhood Langerhans
cell histiocytosis. J Clin Endocrinol Metab 83: 30893094.
Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A,
Zecca S, Tinelli C, Gallucci M, Bernasconi S, Boscherini B,
Severi F, Arico M (2000). Central diabetes insipidus in children and young adults. N Engl J Med 343: 9981007.
Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW,
Chrousos GP (1996). Hypothalamic corticotropin-releasing
hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this
time. J Clin Endocrinol Metab 81: 19121917.
Magiakou MA, Mastorakos G, Chrousos GP (1997). Cushing
syndrome. Differential diagnosis and treatment. In: Wierman
ME (Ed.) Diseases of the Pituitary: Diagnosis and Treatment.
Contemporary Endocrinology, Vol. 3. Humana Press Inc,
Totowa, NJ, pp. 179202.
Magoon EH, Robb RM (1981). Development of myelin in
human optic nerve and tract. A light- and electron-microscopic study. Arch Ophthalmol 99: 655659.
Magri F, Locatelli M, Balza G, Molla G, Cuzzoni G, Fioravanti
M, Solerte SB, Ferrari E (1997). Changes in endocrine circadian rhythms as markers of physiological and pathological
brain aging. Chronobiol Int 14: 385396.
Mahachoklertwattana P, Kaplan SL, Grumbach MM (1993). The
luteinizing hormone-releasing hormone secreting hypothalamic hamartoma is a congenital malformation: natural history.
Mahoney CP, Weinberger E, Bryant C, Ito M, Jameson JL, Ito
M (2002). Effects of aging on vasopressin production in a
kindred with autosomal dominant neurohypophyseal diabetes
insipidus due to the E47 neurophysin mutation. J Clin
Mai JK, Stephens PH, Hopf A, Cuello AC (1986). Substance
P in the human brain. Neuroscience 17: 709739.
Mai JK, Kedziora O, Teckhaus L, Sofroniew MV (1991).
Evidence for subdivisions in the human suprachiasmatic
Mai JK, Berger K, Sofroniew MV (1993). Morphometric evaluation of neurophysin immunoreactivity in the human brain:
pronounced inter-individual variability and evidence for
altered staining patterns in schizophrenia. J Hirnforsch 34:
133154.
Mai JK, Lensing-Hhn S, Ende AA, Sofroniew MV (1997).
Developmental organization of neurophysin neurons in the
human brain. J Comp Neurol 385: 477489.
Maier T, Dai WJ, Csiks T, Jirikowski GF, Unger T, Culman
J (1998). Oxytocin pathways mediate the cardiovascular and
behavioral responses to substance P in the rat brain.
Hypertension 31: 480486.
Mainieri AS, Viera JGH, Elnecave RH (1998). Response of the
free alpha-subunit to GnRH distinguishes individuals with
functional from those with permanent hypogonadotropic
hypogonadism. Horm Res 50: 212216.
Maira G, Anile C, Colosimo C, Cabezas D (2000). Craniopharyngiomas of the third ventricle: trans-lamina terminalis
approach. Neurosurgery 47: 857865.
Majzoub JA, McGregor JA, Lockwood CJ, Smith R, Snyder
Taggart M, Schulkin J (1999). A central theory of preterm
and term labor: putative role for corticotropin-releasing
hormone. Am J Obstet Gynecol 180: S232241.
Makara GB (1992). The relative importance of hypothalamic neurons containing corticotrophin-releasing factor or vasopressin in
the regulation of adrenocorticotropic, hormone secretion. In:
Functional Anatomy of the Neuroendocrine Hypothalamus, pp.
4353. John Wiley & Sons Inc, New York.
Malamud N (1967). Psychiatric disorder with intracranial tumors
of limbic system. Arch Neurol 17: 113123.
Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman
D, Susser ES (2001). Advancing paternal age and the risk of
schizophrenia. Arch Gen Psychiatry 58: 361367.
Malaspina D, Coleman E, Goetz RR, Harkavy-Friedman J,
Corcoran S, Amador X, Yale S, Gorman JM (2002a). Odor
identification, eye tracking and deficit syndrome schizophrenia. Biol Psychiatry 51: 809815.
Malaspina D, Corcoran C, Fahim C, Berman A, HarkavyFriedmann J, Yale S, Goetz D, Goetz R, Harlap S, Gorman
J (2002b). Paternal age and sporadic schizophrenia: evidence
for de novo mutations. Am J Med Genet 114: 299303.
Malhotra S, Das MK, Gupta N, Muralidharan R (1997). A clinical
study of Kleine-Levin syndrome with evidence for hypothalamicpituitary axis dysfunction. Biol Psychiatry 42: 299301.
Malik S, Boeve BF, Krahn LE, Silber MH (2001). Narcolepsy
associated with other central nervous system disorders.
Malinovskaya NK, Komarov FI, Rapoport SI, Voznesenskaya
LA, Wetterberg L (2001). Melatonin production in patients
with duodenal ulcer. Neuroendocrinol Lett 22: 109117.
Malko N, Topaloglu R, zn A, Turanli G, Bilginturan N
(2000). Langerhans cell histiocytosis: report of an atypical
case. J Pediatr Endocrinol Metab 13: 565566.
2014 Refs
2/12/03
1:39 pm
Page 497
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
497
in presenile Alzheimers disease, senile dementia of

Alzheimer type and Downs syndrome in middle age. J Neurol
Sci 69: 139159.
Mann DMA, Yates PO, Marcyniuk B (1986). The nucleus
basalis of Meynert in multi-infarct (vascular) dementia. Acta
Mann NP, Haddow R, Stokes L, Goodley S, Rutter N (1986).
Effect of night and day on preterm infants in a newborn
nursery: randomised trial. Br Med J 293: 12651267.
Manni R, Martinetti M, Ratti MT, Tartara A (1993).
Electrophysiological and immunogenetic findings in recurrent
monosymptomatic-type hypersomnia: a study of two unrelated Italian cases. Acta Neurol Scand 88: 293295.
Manni R, Politini L, Nobili L, Ferrillo F, Livieri C, Veneselli
E, Biancheri R, Martinetti M, Tartara A (2001). Hypersomnia
in the PraderWilli syndrome: clinical-electrophysiological
features and underlying factors. Clin Neurophysiol 112:
800805.
Manning AB, Chronwall BM, Millington WR (1993). POMCderived peptide immunoreactivity in neural lobe axons of the
human pituitary. Peptides 14: 857860.
Mannucci PM (2001). How I treat patients with von Willebrand
disease. Blood 97: 19151919.
Manski TJ, Haworth CS, Duval-Arnould BJ, Rushing EJ (1994).
Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. J Neurosurg 81:
595600.
Mantzoros CS (2000). Role of leptin in reproduction. Ann NY
Acad Sci 900: 174183.
Mantzoros CS, Flier JS, Rogol AD (1997). A longitudinal
assessment of hormonal and physical alterations during
normal puberty in boys. V. Rising leptin levels may
signal the onset of puberty. J Clin Endocrinol Metab 82:
10661070.
Manuck SB, Flory JD, Ferrell RE, Dent KM, Mann JJ, Muldoon
MF (1999). Aggression and anger-related traits associated
with a polymorphism of the tryptophan hydroxylase gene.
Manz B, Alexander H, Wagner B, Pollow K (1990). 24-Hr
pattern of serum melatonin in patients with anorexia nervosadetermined by a novel 125I-radioimmunoassay without
extraction. In: Gupta, Wollmann, Ranke (Eds.) Neuroendocrinology: New Frontiers. Tbingen, 1990.
Manzoni GC (1998). Gender ratio of cluster headache over the
years: a possible role of changes in lifestyle. Cephalalgia 18:
138142.
Marangell LB, Ketter TA, George MS, Pazzaglia PJ Callahan
AM, Parekh P, Andreason PJ, Horwitz B, Herscovitch P, Post
RM (1997a). Inverse relationship of peripheral thyrotropinstimulating hormone levels to brain activity in mood
disorders. Am J Psychiatry 154: 224230.
Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia
PJ, LHerrou TA, Leverich GS, Post RM (1997b). Effects
Mamourian AC, Rodichok L, Towfighi J (1995). The asymmetric mamillary body: association with medial temporal lobe disease demonstrated with MR. Am J Neuroradiol 16: 517522.
Mamourian AC, Cromwell LD, Harbaugh RE (1998). Colloid
cyst of the third ventricle: sometimes more conspicuous on
CT than MR. Am J Neuroradiol 19: 875878.
Manber R, Armitage R (1999). Sex, steroids, and sleep: a review.
Sleep 22: 540555.
Mancini LS (1990). RileyDay syndrome, brain stimulation and
the genetic engineering of a world without pain. Med
Hypotheses 31: 201207.
Mandera M, Bazowski P, Wencel T, Dec R (1999). Melatonin
secretion in patients with pineal region tumors preliminary
report. Neuroendocrinol Lett 20: 167170.
Mandoki MW, Sumner GS, Hoffman RP, Riconda DL (1991).
A review of Klinefelters syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry 30: 167172.
Manfredi M, Bini G, Cruccu G, Accornero N, Berardelli A,
Medolago L (1981). Congenital absence of pain. Arch Neurol
38: 507511.
Mangin P, Lugnier AA, Chaumont AJ, Offner M, Grucker M
(1983). Forensic significance of postmortem estimation of the
blood cerebrospinal fluid barrier permeability. Forensic Sci
Int 22: 143149.
Manji HK, Moore GJ, Rajkowska G, Chen G (2000).
Neuroplasticity and cellular resilience in mood disorders. Mol
Manji HK, Drevets WC, Charney DS (2001). The cellular neurobiology of depression. Nat Med 7: 541547.
Manly JJ, Merchant CA, Jabobs DM, Small SA, Bell K, Ferin
M, Mayeux R (2000). Endogenous estrogen levels and
Alzheimers disease among postmenopausal women.
Mann CLA, Davies MB, Stevenson VL, Leary SM, Boggild
MD, Ko Ko C, Jones PW, Fryer AA, Strange RC, Thompson
AJ, Hawkins CP (2002). Interleukin 1 genotypes in multiple
sclerosis and relationship to disease severity. J Neuroimmunol
129: 197204.
Mann DR, Fraser HM (1996). The neonatal period: a critical
interval in male primate development. J Endocrinol 149:
191197.
Mann DMA, Yates PO, Marcyniuk B (1984). Alzheimers presenile dementia, senile dementia of the Alzheimer type and
Downs syndrome in middle age from an age related
continuum of pathological changes. Neuropathol Appl
Mann DMA, Yates PO, Marcyniuk B (1985a). Changes in
Alzheimers disease in the magnocellular neurones of the
supraoptic and paraventricular nuclei of the hypothalamus
and their relationship to the noradrenergic deficit. Clin
Mann DMA, Yates PO, Marcyniuk B (1985b). Some morphometric observations in the cerebral cortex and hippocampus
497
2014 Refs
498
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 498
D.F. SWAAB
of intrathecal thyrotropin-releasing hormone (protirelin) in

refractory depressed patients. Arch Gen Psychiatry 54:
214222.
Maran G (1947). Diabetes insipidus and uterine atony. Br
Med J 2: 769771.
Marcos A, Varela P, Toro O, Lpez-Vidriero I, Nova E,
Madruga D, Casas J, Morand G (1997). Interactions between
nutrition and immunity in anorexia nervosa: a 1-y follow-up
study. Am J Clin Nutr 66: 485S490S.
Marcus CL, Trescher WH, Halbower AC, Lutz J (2002).
Secondary narcolepsy in children with brain tumors. Sleep
25: 435439.
Marcus R (1996). Should all older people be treated with growth
hormone? Drugs Aging 8: 14
Marn O, Baker J, Puelles L, Rubenstein JLR (2002). Patterning
of the basal telencephalon and hypothalamus is essential for
guidance of cortical projections. Development 129: 761773.
Marinella MA, Chey W (1997). The syndrome of inappropriate
antidiuretic hormone secretion in a patient with Whipples
disease. Am J Med Sci 313: 247248.
Marin-Padilla M (1965). Morphogenesis of anencephaly and
related malformations. Curr Top Pathol 51: 145174.
Markianos M, Sfagos C (1989). Plasma testosterone, prolactin,
luteinizing hormone, and disease activity in male multiple
sclerosis patients. Neuroendocrinol Lett 11: 5358.
Marks DL, Ling N, Cone RD (2001). Role of the central melanocortin system in cachexia. Cancer Res 61:
14321438.
Marksteiner J, Saria A, Kirchmair R, Pycha R, Benesch H,
Fischer-Colbrie R, Haring C, Maier H, Ransmayer G (1993).
Distribution of secretoneuron-like immunoreactivity in
comparison with substance P- and enkephalin-like immunoreactivities in various human forebrain regions. Eur J
Neurosci 5: 15731585.
Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN,
Johnston DG (1992). Detection of premature atherosclerosis
by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 340: 11881192.
Marlowe WB, Mancall EL, Thomas JJ (1975). Complete
KlverBucy syndrome in man. Cortex 11: 5359.
Marquardt JL, Loriaux DL (1974). Diabetes mellitus and optic
atrophy with associated findings of diabetes insipidus and
neurosensory hearing loss in two siblings. Arch Intern Med
134: 3237.
Marr N, Bichet DG, Lonergan M, Arthus M-F, Jeck N, Seyberth
HW, Rosenthal W, Van Os CH, Oksche A, Deen PMT (2002).
Heteroligomerization of an aquaporin-2 mutant with wildtype aquaporin-2 and their misrouting to late endosomes/
lysosomes explains dominant nephrogenic diabetes insipidus.
Hum Mol Genet 11: 779789.
Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD (1998). Role
of the Y5 neuropeptide Y receptor in feeding and obesity.
Nature Med 4: 718721.
Marshall JC, Eagleson CA, McCartney CR (2001).

Hypothalamic dysfunction. Mol Cell Endocrinol 183: 2932.
Martignoni E, Petraglia F, Costa A, Bono G, Genazzani
AR, Nappi G (1990). Dementia of the Alzheimer type and
hypothalamus-pituitary-adrenocortical axis: changes in cerebrospinal fluid corticotropin releasing factor and plasma
cortisol levels. Acta Neurol Scand 81: 452456.
Martin A (1985). A qualitative limitation on visula transfer via
the anterior commissure. Evidence from a case of callosal
agenesis. Brain 108: 4363.
Martin A, State M, Anderson GM, Kaye WM, Hanchett JM,
McConaha CW, North WG, Leckman JF (1998b).
Cerebrospinal fluid levels of oxytocin in PraderWilli
syndrome: a preliminary report. Biol Psychiatry 44:
13491352.
Martin A, State M, Koenig K, Schultz R, Dykens EM, Cassidy
SB, Leckman JF (1998a). PraderWilli syndrome. Am J
Martin D, Camper SA (2001). Genetic regulation of forebrain
and pituitary development. In: Rappaport R, Amselem S (Eds.)
Hypothalamic-Pituitary Development. Genetic and Clinical
Aspects. Endocr Dev. Basel, Karger, Vol. 4, pp. 112.
Martin F (1958). Pathologie des aspects neurologiques et
psychiatriques de quelques manifestations carentielles avec
troubles digestifs et neuro-endocriniens. Acta Neurol Belg
58: 816830.
Martin J, Jeste DV, Caliguiri MP, Patterson T, Heaton R, AncoliIsrael S (2001). Actigraphic estimates of circadian rhythms
and sleep/wake in older schizophrenia patients. Schizophr Res
47: 7786.
Martin JB, Riskind PN (1992). Neurologic manifestations of
hypothalamic disease. Prog Brain Res 93: 3144.
Martin JB, Reichlin S, Brown GM (Eds.) (1997). Clinical
Neuroendocrinology. FA Davis Company, PA, USA.
Martin JP (1950). Fits of laughter (sham mirth) in organic
cerebral disease. Brain 73: 453464.
Martin LJ, Powers RE, Dellovade TL, Price DL (1991). The
bed nucleus-amygdala continuum in human and monkey. J
Martin M, Jones G (1999). Handedness and season of birth: a
gender-invariant relation. Cortex 35: 123128.
Martin WJ, McGowan E, Cashen DE, Gantert LT, Drisko JE,
Hom GJ, Nargund R, Sebhat I, Howard AD, Van der Ploeg
LHT, MacIntyre DE (2002). Activation of melanocortin MC4
receptors increases erectile activity in rats ex copula. Eur J
Pharmacol 454: 7179.
Martinelli V (2000). Trauma, stress and multiple sclerosis.
Neurol Sci (4 Suppl 2) 21: S849S852.
Martnez-Mir MI, Pollard H, Moreau J, Traiffort E, Ruat M,
Schwartz JC, Palacios JM (1993). Loss of striatal histamine
H2 receptors in Huntingtons chorea but not in Parkinsons
disease: comparison with animal models. Synapse 15:
209220.
2014 Refs
2/12/03
1:39 pm
Page 499
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
499
Masugi F, Ogihara T, Sakaguchi K, Otsuka A, Tsuchiya Y,

Morimoto S, Kumahara Y, Saeki S, Nishide M (1989). High
plasma levels of cortisol in patients with senile dementia of
the Alzheimers type. Methods Find Exp Clin Pharmacol 11:
707710.
Mather HM, Ang V, Jenkins JS (1981). Vasopressin in plasma
and CSF of patients with subarachnoid haemorrhage. J Neurol
Mathew SJ, Coplan JD, Gorman JM (2001). Neurobiological
mechanisms of social anxiety disorder. Am J Psychiatry 158:
15581567.
Mathew SJ, Coplan JD, Goetz RR, Feder A, Greenwald S, Dahl
RE, Ryan ND, Mann JJ, Weissman MM (2003).
Differentiating depressed adolescent 24 h cortisol secretion
in light of their adult clinical outcome. Neuropsychopharmacology 28: 13361343.
Mathias CJ (2002). Neurodegeneration, parkinsonian syndromes
and autonomic failure. Auton Neurosci 96: 5058.
Mathias CJ, Fosbraey P, Da Costa DF, Thornley A, Bannister
R (1986). The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension
in patients with autonomic failure. Br Med J 293:
353354.
Mathiesen T, Grane P, Lindquist C, Von Holst H (1993). High
recurrence rate following aspiration of colloid cysts in the
third ventricle. J Neurosurg 78: 748752.
Mathiesen T, Grane P, Lindgren L, Lindquist C (1997). Third
ventricle colloid cysts: a consecutive 12-year series. J
Neurosurg 86: 512.
Mathieu J, Barth A, Rosa FM, Wilson SW, Peyriras N (2002).
Distinct and cooperative roles for Nodal and Hedgehog
signals during hypothalamic development. Development 129:
30553065.
Matsuda M, Liu Y, Mahankali S, Pu Y, Mahankali A,
Wang J, DeFronzo RA, Fox PT, Gao J-H (1999). Altered
hypothalamic function in response to glucose ingestion in
obese humans. Diabetes 48: 18011806.
Matsuda S, Sone T, Doi T, Kahyo H (1993). Seasonality of
mean birth weight and mean gestational period in Japan. Hum
Biol 65: 481501.
Matsumoto A, Arai Y (1983). Sex difference in volume of the
ventromedial nucleus of the hypothalamus in the rat.
Endocrinol Jpn 30: 277280.
Matsumoto A, Arai Y (1986). Male-female difference in
synaptic organization of the ventromedial nucleus of the
hypothalamus in the rat. Neuroendocrinology 42: 232236.
Matsumoto H, Koya G, Takeuchi T (1965). Fetal Minamata
disease. A neuropathological study of two cases of
intrauterine intoxication by a methyl mercury compound. J
Neuropathol Exp Neurol 24: 563574.
Matsumoto M, Sack RL, Blood ML, Lewy AJ (1997).
The amplitude of endogenous melatonin production is not
affected by melatonin treatment in humans. J Pineal Res 22:
4244.
Martzke JS, Kopala LC, Good KP (1997). Olfactory dysfunction in neuropsychiatric disorders: review and methodological
considerations. Biol Psychiatry 42: 721732.
Masliah E, Hansen LA, Quijada S, DeTeresa R, Alford M,
Kauss J, Terry R (1991). Late onset dementia with argyrophilic grains and subcortical tangles or atypical progressive
supranuclear palsy. Ann Neurol 29: 389396.
Masliah E, Alford M, Galasko D, Salmon D, Hansen LA, Good
PF, Perl DP, Thal L (2001). Cholinergic deficits in the brains
of patients with parkinsonism-dementia complex of Guam.
Mason D, MacPhee I, Antoni FA (1990). The role of neuroendocrine system in determining genetic susceptibility to
experimental allergic encephalomyelitis in the rats.
Immunology 70: 15.
Mason JW, Wang S, Yehuda R, Bremner JD, Riney SJ, Lubin
H, Johnson DR, Southwick SM, Charney DS (1995). Some
approaches to the study of the clinical implications of thyroid
alterations in post-traumatic stress disorder. In: Friedman MJ,
Charney DS, Deutch AY (Eds.) Neurobiological and Clinical
Consequences of Stress: From Normal Adaptation to PTSD.
Lippincott-Raven, Philadelphia, pp. 367379.
Mason R, Biello SM (1992). A neurophysiological study of a
lithium-sensitive phosphoinositide system in the hamster
suprachiasmatic (SCN) biological clock in vitro. Neurosci
Lett 144: 135138.
Mason WT, Ho YW, Hatton GI (1984). Axon collaterals of
supraoptic neurones: anatomical and electrophysiological
evidence for their existence in the lateral hypothalamus.
Massie AP (1979). A granular-cell pituicytoma of the neurohypophysis. J Pathol 129: 5358.
Massie RJ, Shaw PJ, Burgess M (1993). Intracranial choriocarcinoma causing precocious puberty and cured with combined
modality therapy. J Paediatr Child Health 29: 464467.
Massimino M, Spreafico F, Cefalo G, Riccardi R, Tesoro-Tess
JD, Gandola L, Riva D, Ruggiero A, Valentini L, Mazza E
et al. (2002). High response rate to cisplatin/etoposide
regimen in childhood low-grade glioma. J Clin Oncol 20:
42094216.
Massin N, Pcheux C, Eloit C, Bensimon J-L, Galey J, Kuttenn
F, Hardelin J-P, Dod C, Touraine P (2003). X-Chromosomelinked Kallmann syndrome: clinical heterogeneity in three
siblings carrying an intragenic deletion of the KAL-1 gene. J
Masterman T, Zhang Z, Hellgren D, Salter H, Anvret M, Lilius
L, Lannfelt L, Hillert J (2002). APOE genotypes and disease
severity in multiple sclerosis. Mult Scler 8: 98103.
Mastorakos G, Weber JS, Magiakou M-A, Gunn H, Chrousos
GP (1994). Hypothalamic-pituitary-adrenal axis activation
and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the
syndrome of inappropriate vasopressin secretion. J Clin
499
2014 Refs
500
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 500
D.F. SWAAB
Matsuno A, Nagashima, T, Teramoto A, Kirino T (2001).

Endocrinologic aspects of twenty-three patients with Rathkes
cleft cyst. Endocrinologist 11: 245246.
Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H,
Miyawaki T, Azuma N, Natsui K, Nishimura H, Yoshimasa
Y, Nishi S, Thompson DB, Nakao K (1997). Human leptin
receptor gene in obese Japanese subjects: evidence against
either obesity-causing mutations or association of sequence
variants with obesity. Diabetologia 40: 12041210.
Matsuoka K, Orikasa H, Eyden B, Yamazaki K (2002).
Postmortem diagnosis of occult Klinefelter syndrome in a
patient with chronic renal disease and liver cirrhosis. Arch
Pathol Lab Med 126: 359361.
Matsuzaki M, Izumi T, Shishikura K, Suzuki H, Hirayama Y
(2002). Hypothalamic growth hormone deficiency and supplementary GH therapy in two patients with mitochondrial
myopathy, encephalopathy, lactic acidosis and stroke-like
episodes. Neuropediatrics 33: 271273.
Matthew E, Woods JF (1993). Growth hormone and prolactin
in temporal lobe epilepsy. Epilepsy Res 16: 215222.
Matthews WB (1991). Symptoms and signs: the anatomic
nervous system. In: Matthews WB, Compston A, Allen N,
Martyn CN (Eds.) McAlpins Multiple Sclerosis, 2nd edn.
Edinburgh, Churchill Livingstone, pp. 97100.
Mattila P, Togo T, Dickson DW (2002). The subthalamic
nucleus has neurofibrillary tangles in argyrophilic grain
disease and advanced Alzheimers disease. Neurosci Lett 320:
8185.
Mattson D, Petrie M, Srivastava DK, McDermott M (1995).
Multiple sclerosis. Sexual dysfunction and its response to
medications. Arch Neurol 52: 862868.
Matzuk MM, Saper CB (1985). Preservation of hypothalamic
dopaminergic neurons in Parkinsons disease. Ann Neurol 18:
552555.
May A, Bahra A, Bchel C, Frackowiak RSJ, Goadsby PJ
(1998). Hypothalamic activation in cluster headache attacks.
Lancet 352: 275278.
May A, Ashburner J, Bchel C, McGonigle DJ, Friston KJ,
Frackowiak RSJ, Goadsby PJ (1999). Correlation between
structural and functional changes in brain in an idiopathic
headache syndrome. Nat Med 5: 836838.
May A, Bahra A, Bchel C, Frackowiak RSJ, Goadsby PJ
(2000). PET and MRA findings in cluster headache and MRA
in experimental pain. Neurology 55: 13281335.
Maya-Nuez G, Zenteno JC, Ullua-Aguirre A, Kofman-Alfaro
S Mendez JP (1998). A recurrent missense mutation in the
KAL gene in patients with X-linked Kallmanns syndrome. J
Mayberg HS (1994). Frontal lobe dysfunction in secondary
depression. J Neuropsychiatry Clin Neurosci 6: 428442.
Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin
RK, McGinnis S, Jerabek PA (2002). The functional
neuroanatomy of the placebo effect. Am J Psychiatry 159:
728737.
Mayeda A, Mannon S, Hofstetter J, Adkins M, Baker R, Hu

K, Nurnberger J (1998). Effects of indirect light and propranolol on melatonin levels in normal human subjects.
Mayer A, Lahr G, Swaab DF, Pilgrim C, Reisert I (1998a). The
Y-chromosomal genes SRY and ZFY are transcribed in adult
human brain. Neurogenetics 1: 281288.
Mayer G, Leonhard E, Krieg J, Meier-Ewert K (1998b).
Endocrinological and polysomnographic findings in Kleine
Levin syndrome: no evidence for hypothalamic and circadian
dysfunction. Sleep 21: 278284.
Mayeux T, Williams JBW, Stern Y, Ct L (1984). Depression and
Parkinsons disease. In: Hassler RG, Christ JF (Eds.) Advances
in Neurology 40. Raven Press, New York, pp. 241250.
Mayinger B, Hensen J (1999). Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene.
Exp Clin Endocrinol Diabetes 107: 157165.
Mazur A, Booth A (1998). Testosterone and dominance in men.
Behav Brain Sci 21: 35397.
Mazurek MF, Growdon JH, Beal MF, Martin JB (1986). CSF
vasopressin concentration is reduced in Alzheimers disease.
Neurology 36: 11331137.
Mazurek MF, Beal MF, Bird ED, Martin JB (1987). Oxytocin
in Alzheimers disease: postmortem brain levels. Neurology
37: 10011003.
Mazurkiewicz-Kwilecki IM, Nsonwah S (1989). Changes in the
regional brain histamine and histidine levels in postmortem brains
of Alzheimer patients. Can J Physiol Pharmacol 67: 7578.
Mazzitelli N, Vauthay L, Grandi C, Fuksman R, Rittler M (2002).
Reviewing old concepts at the start of a new millennium:
growth restriction, adrenal hypoplasia, and thymomegaly in
human anencephaly. Teratology 66: 105114.
McAbee GN, Chan A, Erde EL (2000). prolonged survival with
hydranencephaly: report of two patients and literature review.
Pediatr Neurol 23: 8084.
McArthur AJ, Budden SS (1998). Sleep dysfunction in Rett
syndrome: a trial of exogenous melatonin treatment. Dev Med
McArthur AJ, Lewy AJ, Sack RL (1996). Non-24-hour
sleep-wake syndrome in a sighted man: circadian rhythm
studies and efficacy of melatonin treatment. Sleep 19:
544553.
McBride G (1999). Melatonin disrupts sleep in SmithMagenis
McBride PA, Anderson GM, Shapiro T (1996). Autism research.
Bringing together approaches to pull apart the disorder. Arch
McBurnett K, Lahey BB, Rathouz PJ, Loeber R (2000). Low
salivary cortisol and persistent aggression in boys referred
for disruptive behavior. Arch Gen Psychiatry 57: 3843.
McCain GA, Tilbe KS (1989). Diurnal hormone variation in
fibromyalgia syndrome: a comparison with rheumatoid
arthritis. J Rheumatol (Suppl) 16: 154157.
2014 Refs
2/12/03
1:39 pm
Page 501
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
501
McKenzie JC, Berman NEJ, Thomas CR, Young JK, Compton

LY, Cothran LN, Liu W-L, Klein RM (1994). Atrial natriuretic peptide-like (ANP-LIR) and ANP prohormone
immunoreactive astrocytes and neurons of human cerebral
cortex. Glia 12: 228243.
McKenzie R, OFallon A, Dale J, Demitrack M, Sharma G,
Deloria M, Garcia-Borreguero D, Blackwelder W, Straus SE
(1998). Low-dose hydrocortisone for treatment of chronic
fatigue syndrome. JAMA 280: 10611066.
McKinley MJ, Oldfield BJ (1990). Circumventricular Organs.
In: G Paxinos (Ed.) The Human Nervous System. Academic
Press, Harcourt Brace Jovanovich, Publishers, Chapter 16,
pp. 415438.
McKinley MJ, Allen AM, Clevers J, Paxinos G, Mendelsohn
FAO (1987). Angiotensin receptor binding in human hypothalamus: autoradiographic localization. Brain Res 420: 375379.
McKinley MJ, Pennington GL, Oldfield BJ (1996).
Anteroventral wall of the third ventricle and dorsal lamina
terminalis: headquarters for control of body fluid homeostasis? Clin Exp Pharmacol Physiol 23: 271281.
McLean M, Smith R (1999). Corticotropin-releasing hormone
in human pregnancy and parturition. Trends Endocrinol
Metab 10: 174178.
McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R
(1995). A placental clock controlling the length of human
pregnancy. Nat Med 1: 460463.
McLeod JF, Kovcs L, Gaskill MB, Rittig S, Bradley GS,
Robertson GL (1993). Familial neurohypophyseal diabetes
insipidus associated with a signal peptide mutation. J Clin
Endocrinol Metab 77: 599A599G.
McLoughlin TG, Shanklin DR (1967). Pathology of Laurence
MoonBardetBiedl syndrome. J Pathol Bacteriol 93: 6579.
McMillen IC, Kok JSM, Adamson M, Deayton JM, Nowak R
(1991). Development of circadian sleep-wake rhythms in
preterm and full-term infants. Pediatr Res 29: 381384.
McMillen IC, Phillips ID, Ross JT, Robinson JS, Owens JA
(1995). Chronic stress the key to parturition? Reprod Fertil
Dev 7: 499507.
McNeil TF, Cantor-Graae E, Weinberger DR (2000).
Relationship of obstetric complications and differences in size
of brain structures in monozygotic twin pairs discordant for
schizophrenia. Am J Psychiatry 157: 203212.
McNeilly AS, Gilmore D, Dobbie G, Chard T (1977). Prolactin
releasing activity in the early human foetal hypothalamus. J
McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sullivan
N, Smith AD (2001). Anosmia in dementia is associated with
Lewy bodies rather than Alzheimers pathology. J Neurol
Meana JJ, Barturen F, Garca-Sevilla JA (1992). 2Adrenoceptors in the brain of suicide victims: increased
receptor density associated with major depression. Biol
McCann UD, Kimbrell TA, Morgan CM, Anderson T,

Geraci M, Benson BE, Wassermann EM, Willis MW, Post
RM (1998). Repetitive transcranial magnetic stimulation for
posttraumatic stress disorder. Arch Gen Psychiatry 55:
276279.
McClean AJ (1934). Autonomic epilepsy. Arch Neurol
McClintock MK (1971). Menstrual synchrony and suppression.
Nature 229: 244245.
McCormick WF, Halmi NS (1970). The hypophysis in patients
with Coma Dpass (Respirator Brain). Am J Clin Pathol
54: 374383.
McCowen KC, Glickman JN, Black PMcL, Zervas NT, Lidov
HGW, Garber JR (1999). Gangliocytoma masquerading as a
prolactinoma. J Neurosurg 91: 490495.
McDonald TJ, Nathanielsz PW (1991). Bilateral destruction of
the fetal paraventricular nuclei prolongs gestation in sheep.
Am J Obstet Gynecol 165: 764770.
McDonald WI (1994). The pathological and clinical dynamics
of multiple sclerosis. J Neuropathol Exp Neurol 53: 338343.
McDonald WI, Barnes D (1992). The ocular manifestations of
multiple sclerosis. 1. Abnormalities of the afferent visual
system. J Neurol Neurosurg Psychiatry 55: 747752.
McDougle CJ, Barr LC, Goodman WK, Price LH (1999).
Possible role of neuropeptides in obsessive compulsive
disorder. Psychoneuroendocrinology 24: 124.
McDuff T, Sumi SM (1985). Subcortical degeneration in
Alzheimers disease. Neurology 35: 123126.
McEntagart ME, Webb T, Hardy C, King MD (2000). Familial
PraderWilli syndrome: case report and a literature review.
Clin Genet 58: 216223.
McEwen BS (1997). Possible mechanisms for atrophy of the
human hippocampus. Mol Psychiatry 2: 255262.
McGeer PL, McGeer EG, Suzuki J, Dolman CE, Nagai T (1984).
Aging, Alzheimers disease and the cholinergic system of the
basal forebrain. Neurology 34: 741745.
McGinty D, Szymusiak R (2000). The sleep-wake switch: a
neuronal alarm clock. Nat Med 6: 510511.
McGrath P (1978). Aspects of the human pharyngeal hypophysis
in normal and anencephalic fetuses and neonates and their
possible significance in the mechanism of its control. J Anat
127: 6581.
McGraw K, Hoffmann R, Harker C, Herman JH (1999). The
development of circadian rhythms in a human infant. Sleep
22: 303310.
McKenna KE (1998). Central control of penile erection. Int J
Impot Res (Suppl 1) 10: S25S34.
McKenna K, Thompson C (1998). Osmoregulation in clinical
disorders of thirst appreciation. Clin Endocrinol 49: 139152.
McKenna K, Morris AD, Azam H, Newton RW, Baylis PH,
Thompson CJ (1999). Exaggerated vasopressin secretion and
attenuated osmoregulated thirst in human survivors of hyperosmolar coma. Diabetologia 42: 534538.
501
2014 Refs
502
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 502
D.F. SWAAB
Meco G, Vanacore N, Bellatreccia A, Bonifati V (1991).

Depression, cognitive impairment and dexamethasone
suppression test in Parkinsons disease. Neuroendocrinol Lett
13: 315323.
Meesters Y, Lambers PA (1990). Light therapy in patient with
seasonal fatigue. Lancet 336: 745.
Meesters Y, Letsch MC (1998). The dark side of light treatment
for seasonal affective disorder. Int J Risk Safety Med 11:
115120.
Meesters Y, Beersma DGM, Bouhuys AL, Van den Hoofdakker
RH (1999). Prophylactic treatment of seasonal affective
disorder (SAD) by using light visors: bright white or infrared
light? Biol Psychiatry 46: 239246.
Meierkord H, Shorvon S, Lightman S, Trimble M
(1992). Comparison of the effects of frontal and temporal
lobe partial seizures on prolactin levels. Arch Neurol 49:
225230.
Meierkord H, Shorvon S, Lightman SL (1994). Plasma
concentrations of prolactin, noradrenaline, vasopressin and
oxytocin during and after a prolonged epileptic seizure. Acta
Meisami E (1988). Aging of the nervous system: sensory
changes. In: Timiras PS (Ed.) Physiological Basis of
Geriatrics. MacMillan, New York, pp. 156178.
Meisel RL, Sachs BD (1994). The physiology of male sexual
behavior. In: Knobil E, Neill JD (Eds.) The Physiology of
Reproduction, 2nd edn. Raven Press Ltd, NY, pp. 3105.
Meisenzahl EM, Frodl T, Zetzsche T, Leinsinger G, Maag K,
Hegerl U, Hahn K, Mller H-J (2002). Investigation of a
possible diencephalic pathology in schizophrenia. Psychiatry
Res 115: 127135.
Meister B, Elde R (1993). Dopamine transporter mRNA in
neurons of the rat hypothalamus. Neuroendocrinology 58:
388395.
Meister B, Hkfelt T, Steinbusch HWM, Skagerberg G, Lindvall
O, Geffard M, Joh TH, Cuello AC, Goldstein M (1988).
Do tyrosine hydroxylase-immunoreactive neurons in the
ventrolateral arcuate nucleus produce dopamine or only
L-dopa. J Chem Neuroanat 1: 5964.
Meister B, Villar MJ, Ceccatelli S, Hkfelt T (1990).
Localization of chemical messengers in magnocellular
neurons of the hypothalamic supraoptic and paraventricular
nuclei: an immunohistochemical study using experimental
manipulations. Neuroscience 37: 603633.
Meites J (1992). Short history of neuroendocrinology and
the international society of neuroendocrinology. Neuroendocrinology 56: 110.
Melberg A, Ripley B, Lin L, Hetta J, Mignot E, Nishino S
(2001). Hypocretin deficiency in familial symptomatic
narcolepsy. Ann Neurol 49: 136137.
Meldrum DR, Erlik Y, Lu JKH, Judd HL (1981). Objectively
recorded hot flushes in patients with pituitary insufficiency.
Melis MR, Argiolas A (1999). Yawning: role of hypothalamic

paraventricular nitric oxide. Acta Pharmacol Sinai 20:
778788.
Melis MR, Spano MS, Succu S, Argiolas A (1999). The oxytocin
antagonist d(CH2). 5Tyr(Me)2-Orn8-vasotocin reduces noncontact penile erections in male rats. Neurosci Lett 265:
171174.
Melis MR, Succu S, Spano MS, Argiolas A (2000). Effect of
excitatory amino acid, dopamine, and oxytocin receptor antagonists on noncontact penile erections and paraventricular nitric
oxide production in male rats. Behav Neurosci 114: 849857.
Melkersson K, Hulting A-L, Hall K (1999). Hormonal evaluation in schizophrenic patients treated with neuroleptics.
Meller WH, Grambsch PL, Bingham, C, Tagatz GE (2001).
Hypothalamic pituitary gonadal axis dysregulation in
depressed women. Psychoneuroendocrinology 26: 253259.
Mellinger RC, Zafar S (1983). Primary polydipsia. Syndrome
of inappropriate thirst. Arch Intern Med 143: 12491251.
Melmed S (Ed.) (1995). The Pituitary. Blackwell Science,
Cambridge, MA, USA.
Melmed S (1995). Tumor mass effects of lesions in the hypothalamus and pituitary. In: LJ de Groot (Ed.) Endocrinology,
Part II. Saunders, pp. 458466.
Mendel E, Khoo LT, Go JL, Hinton D, Zee C-Z, Apuzzo MLJ
(1999). Intracerebral Whipples disease diagnosed by stereotactic biopsy: a case report and review of the literature.
Menendez AA (1999). Abnormal ventilatory responses in
patients with PraderWilli syndrome. Eur J Pediatr 158:
941942.
Mengod G, Rigo M, Savasta M, Probst A, Palacios JM (1992).
Regional distribution of neuropeptide somatostatin gene
expression in the human brain. Synapse 12: 6274.
Menkes DB (1992). Triazolam-induced nocturnal bingeing with
amnesia. Aust NZ J Psychiatry 26: 320321.
Mense S (2000). Neurobiological concepts of fibromyalgia
the possible role of descending spinal tracts. Scand J
Rheumatol (Suppl) 113: 2429.
Merari A, Ginton A (1975). Characteristics of exaggerated
sexual behavior induced by electrical stimulation of the
medial preoptic area in male rats. Brain Res 86: 97108.
Mergen M, Mergen H, Ozata M, Oner R, Oner C (2001). A
novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. J Clin Endocrinol Metab 86:
34483451.
Mersch PPA, Middendorp HM, Bouhuys AL, Beersma DGM,
Van den Hoofdakker RH (1999). Seasonal affective disorder
and latitude: a review of the literature. J Affect Disord 53:
3548.
Meredith M (2001). Human vomeronasal organ function: a
critical review of best and worst cases. Chem Senses 26:
433445.
2014 Refs
2/12/03
1:39 pm
Page 503
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
503
change from female to male in classical congenital adrenal

hyperplasia. Horm Behav 30: 319332.
Meyer-Rochow VB, Brown PJ (1998). Possible natural
circaseptan rhythm in the beach beetle Chaerodes trachyscelides White. Acta Neurobiol Exp 58: 287290.
Meyers R (1961). Evidence of a locus of the neural mechanisms
for libido and penile potency in the septo-fornico-hypothalamic
region of the human brain. Trans Am Neural Assoc 86: 8185.
Meyerson BJ, Hglund U, Johansson C, Blomqvist A, Ericson
H (1988). Neonatal vasopressin antagonist treatment facilitates adult copulatory behavior in female rats and increases
hypothalamic vasopressin content. Brain Res 473: 344351.
Mezey E, Kiss JZ (1991). Coexpression of vasopressin and
oxytocin in hypothalamic supraoptic neurons of lactating rats.
Mezey E, Kiss JZ, Skirboll LR, Goldstein M, Axelrod J (1984).
Increase of corticotropin releasing factor staining in the rat
paraventricular nucleus staining by depletion of hypothalamic
adrenaline. Nature 310: 140141.
Michael RP, Zumpe D (1978). Annual cycles of aggression and
plasma testosterone in captive male rhesus monkeys.
Michael RP, Zumpe D (1983). Sexual violence in the united
states and the role of season. Am J Psychiatry 140: 883886.
Michael RP, Zumpe D (1986). An annual rhythm in the battering
of women. Am J Psychiatry 143: 637640.
Michaud JL (2001). The developmental program of the hypothalamus and its disorders. Clin Genet 60: 255263.
Michel A, Mormont C, Legros JJ (2001). A psycho-endocrinological overview of transsexualism. Eur J Endocrinol 145:
365376.
Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos
GP, Sternberg EM, Gold PW (1994). Multiple sclerosis is
associated with alterations in hypothalamic-pituitary-adrenal
axis function. J Clin Endocrinol Metab 79: 848853.
Michelson D, Gold PW (1998). Pathophysiology and somatic
investigations of hypothalamic-pituitary-adrenal axis activation
in patients with depression. Ann NY Acad Sci 840: 717722.
Middle F, Jones I, McCandless F, Barrett T, Khanim F, Owen
MJ, Lendon C, Craddock N (2000). Bipolar disorder and
variation at a common polymorphism (A1832G) within exon
8 of the Wolfram gene. Am J Med Genet 96: 154157.
Mignot E (2001). A commentary on the neurobiology of the
hypocretin/orexin system. Neuropsychopharmacology (5
Suppl) 25: S5S13.
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S,
Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader
H, Nishino S (2002). The role of cerebrospinal fluid
hypocretin measurement in the diagnosis of narcolepsy and
other hypersomnias. Arch Neurol 59: 15531562.
Miguel-Hidalgo JJ, Baucom C, Dilly G, Overholser JC, Meltzer
HY, Stockmeier CA, Rajkowska G (2000). Glial fibrillary
acidic protein immunoreactivity in the prefrontal cortex distin-
Merenich JA, McDermott MT, Asp AA, Harrison SM, Kidd

GS (1990). Evidence of endocrine involvement early in the
course of human immunodeficiency virus infection. J Clin
Merenich JA (1994). Hypothalamic and pituitary function in
AIDS. Ballieres Clin Endocrinol Metab 8: 757767
Merriam AE (1986). KleineLevin syndrome following acute
viral encephalitis. Biol Psychiatry 21: 13011304.
Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983).
Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal
band nuclei, nucleus basalis (substantia innominata), and
hypothalamus in the rhesus monkey. J Comp Neurol 214:
170197.
Mesulam MM, Musfon EJ, Levey AI, Wainer BH (1984). Atlas
of cholinergic neurons in the forebrain and brainstem of the
macaque based on monoclonal choline acetyltransferase
immunohistochemistry and acetylcholinerase histochemistry.
Mszros F, Vergesslich K, Riedl S, Husler G, Frisch H
(2000). Posterior pituitary ectopy in children with idiopathic
growth hormone deficiency. J Pediatr Endocrinol Metab 13:
629635.
Meyer G, Gonzalez-Hernandez T, Carrillo-Padilla F, FerresTorres R (1989). Aggregations of granule cells in the basal
forebrain (islands of Calleja): Golgi and cytoarchitectonic
study in different mammals, including man. J Comp Neurol
284: 405428.
Meyer MF, Gerresheim F, Pfeiffer A, Epplen JT, Schatz H
(2000). Association of polycystic ovary syndrome with an
interstitial deletion of the long arm of chromosome 11 [del(11)
(q21q231)]. Exp Clin Endocrinol Diabetes 108: 519523.
Meyer P, Pache M, Loeffler KU, Brydon L, Jockers R, Flammer
J, Wirz-Justice A, Savaskan E (2002). Melatonin MT-1receptor immunoreactivity in the human eye. Br J Ophthalmol
86: 10531057.
Meyer WJ, Webb A, Stuart CA, Finkelstein JW, Lawrence B,
Walker PA (1986). Physical and hormonal evaluation of transsexual patients: A longitudinal study. Arch Sex Behav 15:
121138.
Meyer-Bahlburg HFL, Feinman JA, MacGillivray MH, Aceto
T Jr (1978). Growth hormone deficiency, brain development,
and intelligence. Am J Dis Child 132: 565572.
Meyer-Bahlburg HFL, Ehrhardt AA (1987). A prenatal-hormone
hypothesis for depression in adults with a history of fetal
DES exposure. In: Halbreich U (Ed.) Hormones and
Depression. Raven Press, New York, 1987, pp. 325338.
Meyer-Bahlburg HFL, Ehrhardt AA, Rosen LR, Gruen RS,
Veridiano NP, Van FH, Neuwalder HF (1995). Prenatal
estrogens and the development of homosexual orientation.
Dev Psychol 31: 1221.
Meyer-Bahlburg HFL, Gruen RS, New MI, Bell JJ, Morishima
A, Shimshi M, Bueno Y, Vargas I, Baker SW (1996). Gender
503
2014 Refs
504
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 504
D.F. SWAAB
guishes younger from older adults in major depressive

disorder. Biol Psychiatry 48: 861873.
Mihly E, Fekete C, Tatro JB, Liposits Z, Stopa EG, Lechan RM
(2000). Hypophysiotropic thyrotropin-releasing hormone-synthesizing neurons in the human hypothalamus are innervated
by neuropeptide Y, agouti-related protein, and -melanocytestimulating hormone. J Clin Endocrinol Metab 85: 25962603.
Mihly E, Fekete C, Lechan RM, Liposits Z (2002).
Corticotropin-releasing hormone-synthesizing neurons of the
human hypothalamus receive neuropeptide Y-immunoreactive innervation from neurons residing primarily outside the
infundibular nucleus. J Comp Neurol 446: 235243.
Mikami A, Sugita Y, Teshima Y, Iijima S, Tachibana N,
Tsutsumi T (1987). A 48-hour sleepwake cycle in a patient
with Parkinsonism. Sleep Res 16: 625.
Milberger S, Biederman J, Faraone SV, Chen L, Jones J (1996).
Is maternal smoking during pregnancy a risk factor for
attention deficit hyperactivity disorder in children? Am J
Miles A, Philbrick DR (1988). Melatonin and psychiatry. Biol
Milionis HJ, Liamis GL, Elisaf MS (2002). The hyponatremic
patient: a systemic approach to laboratory diagnosis. Can Med
Assoc Y 166: 10561062.
Militello A, Vitello G, Lunetta C, Toscano A, Maiorana G,
Piccoli T, La Bella V (2002). The serum level of free testosterone is reduced in amyotrophic lateral sclerosis. J Neurol
Sci 195: 6770.
Millac P, Cook DB, Chase K (1969). Endocrine function in
multiple sclerosis. J Neurol Neurosurg Psychiatry 32:
414418.
Millefiorini E, Padovani A, Pozzilli C, Loriedo C, Bastianello
S, Buttinelli C, Di Piero V, Fieschi C (1992). Depression in
the early phase of MS: influence of functional disability,
cognitive impairment and brain abnormalities. Acta Neurol
Scand 86: 354358.
Miller BL, Cummings JL, McIntyre H, Ebers G, Grode M
(1986). Hypersexuality or altered sexual preference following
brain injury. J Neurol Neurosurg Psychiatry 49: 867873.
Miller CL, White R, Whitman TL, OCallaghan MF, Maxwell
SE (1995). The effect of cycled versus noncycled lighting on
growth and development in preterm infants. Infant Behav Dev
18: 8795.
Miller DC (1994). Pathology of craniopharyngiomas: clinical
import of pathological findings. Pediatr Neurosurg 21: 1117.
Miller DH, Thompson AJ, Morrissey SP, MacManus DG, Moore
SG, Kendall BE, Moseley IF, McDonald WI (1992). High
dose steroids in acute relapses of multiple sclerosis: MRI
evidence for a possible mechanism of therapeutic effect. J
Miller L, Angulo M, Price D, Taneja S (1996). MR of the pituitary
in patients with PraderWilli syndrome: size determination and
imaging findings. Pediatr Radiol 26: 4347.
Miller M (1997). Fluid and electrolyte homeostasis in the

elderly: physiological changes of ageing and clinical consequences. Baillieres Clin Endocrinol Metab 11: 367385.
Miller MJ, Mark LP, Yetkin FZ, Ho K-C, Haughton VM,
Estkowski L, Wong E (1994). Imaging white matter tracts
and nuclei of the hypothalamus: an MR-anatomic comparative study. Am J Neuroradiol 15: 117121.
Miller SP, Shevell MI, Patenaude Y, Poulin C, OGorman
AM (2000). Septo-optic dysplasia plus: a spectrum of
malformations of cortical development. Neurology 54:
17011703.
Miller WL (1993). Molecular genetics of familial central
diabetes insipidus. J Clin Endocrinol Metab 77: 592594.
Millet B, Touitou Y, Poirier M-F, Bourdel M-C, Hantouche E,
Bogdan A, Oli J-P (1998). Plasma melatonin and cortisol
in patients with obsessive-compulsive disorder: relationship
with axillary temperature, physical activity, and clinical symptoms. Biol Psychiatry 44: 874881.
Milligan NM, Newcombe R, Compston DAS (1987). A
double-blind controlled trial of high-dose intravenous methylprednisolone in patients with multiple sclerosis. 1. Clinical
effects. J Neurol Neurosurg Psychiatry 50: 511516.
Minamisawa H (1980). Characteristics of urinary incontinence
in bedridden geriatric patients. Gerontology 26: 290297.
Minden SL, Schiffer RB (1990). Affective disorders in multiple
sclerosis. Arch Neurol 47: 98104.
Ming X, Wang MM, Zee D, Katz RM, Freeman JM (1998).
Wernickes encephalopathy in a child with prolonged
vomiting. J Child Neurol 13: 187189.
Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope
T, Francis PT (2000). Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 55:
14601467.
Mirmiran M, Kok JH (1991). Circadian rhythms in early human
development. Early Hum Dev 26: 121128.
Mirmiran M, Overdijk J, Witting W, Klop A, Swaab DF (1988).
A simple method for recording and analyzing circadian
rhythms in man. J Neurosci Methods 25: 209214.
Mirmiran M, Kok JH, De Kleine MJK, Koppe JD, Overdijk J,
Witting,W (1990). Circadian rhythms in preterm infants: a
preliminary study. Early Hum Dev 23: 139146.
Mirmiran M, Kok JH, Boer K, Wolf H (1992a). Perinatal
development of human circadian rhythms: role of the
foetal biological clock. Neurosci Biobehav Rev 16:
371378.
Mirmiran M, Swaab DF, Kok JH, Hofman MA, Witting W,
Van Gool WA (1992b). Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and
Alzheimers disease. Prog Brain Res 93: 151163.
Mir J, Amado JA, Pesquera C, Lpez-Cordovilla JJ, Berciano
J (1990). Assessment of the hypothalamic-pituitary-adrenal
axis function after corticosteroid therapy for MS relapses.
Acta Neurol Scand 81: 524528.
2014 Refs
2/12/03
1:39 pm
Page 505
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
505
Miyamoto J, Hasegawa Y, Ohnami N, Onigata K, Kinoshita

E, Nishi Y, Tachibana K, Hasegawa T (2001).
Development of growth hormone and adrenocorticotropic
hormone deficiencies in patients with prenatal or perinatalonset hypothalamic hypopituitarism having invisible or
thin pituitary stalk on magnetic resonance imaging. Endocr
J 48: 355362.
Miyamoto S, Sasaki N, Tanabe Y (1991). Magnetic resonance
imaging in familial central diabetes insipidus. Neuroradiology
33: 272273.
Miyoshi Y, Yunoki M, Yano A, Nishimoto K (2003).
Diencephalic syndrome of emaciation in an adult associated
with a third ventricle intrinsic craniopharyngioma: case report.
Mizuguchi M, Takashima S (2001). Neuropathology of tuberous
sclerosis. Brain Dev 23: 508515.
Mizusawa H, Hedlund P, Andersson K-E (2002). -Melanocyte
stimulating hormone and oxytocin induced penile erections,
and intracavernous pressure increases in the rat. J Urol 167:
757760.
Mizuno Y, Hattori N, Matsumine H (1998). Neurochemical and
neurogenetic correlates of Parkinsons disease. J Neurochem
71: 893902.
Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein
C, Levin H (1998). Plasma oxytocin levels in autistic children. Biol Psychiatry 43: 270277.
Modan-Moses D, Weintraub M, Meyerovitch J, SegalLieberman G, Bielorai B, Shimon I (2001). Hypopituitarism
in Langerhans cell histiocytosis: seven cases and literature
review. J Endocrinol Invest 24: 612617.
Modell S, Yassouridis A, Huber J, Holsboer F (1997).
Corticosteroid receptor function is decreased in depressed
patients. Neuroendocrinology 65: 216222.
Modestin J, Ammann R, Wrmle O (1995). Season of birth:
comparison of patients with schizophrenia, affective disorders and alcoholism. Acta Psychiatr Scand 91: 140143.
Moe KE, Prinz PN, Vitiello MV, Marks AL, Larsen LH (1991).
Healthy elderly women and men have different entrained circadian temperature rhythms. J Am Geriatr Soc 39: 383387.
Moe KE, Vitiello MV, Larsen LH, Prinz PN (1995). Sleep/wake
patterns in Alzheimers disease: relationships with cognition
and function. J Sleep Res 4: 1520.
Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman
SM, Resnick SM (2002). Longitudinal assessment of serum
free testosterone concentration predicts memory performance
and cognitive status in elderly men. J Clin Endocrinol Metab
87: 50015007.
Moga MM, Duong T (1997). p75 Neurotrophin receptor
immunoreactivity in the aged human hypothalamus. Neurosci
Lett 231: 912.
Mohn A, Acerini CL, Cheetham TD, Lightman SL, Dunger DB
(1998). Hypertonic saline test for the investigation of posterior pituitary function. Arch Dis Child 79: 431434.
Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H,

Takahashi K (1994). Morning bright light therapy for sleep
and behavior disorders in elderly patients with dementia. Acta
Mishima K, Okawa M, Satoh K, Shimizu T, Hozumi S,
Hishikawa Y (1997a). Different manifestations of circadian
rhythms in senile dementia of Alzheimers type and multiinfarct dementia. Neurobiol Aging 18: 105109.
Mishima K, Satoh K, Shimizu T, Hishikawa Y (1997b).
Hypnotic and hypothermic action of daytime-administered
melatonin. Psychopharmacology 133: 168171.
Mishima K, Hishikawa Y, Okawa M (1998). Randomized, dim
light controlled, crossover test of morning bright light therapy
for rest-activity rhythm disorders in patients with vascular
dementia and dementia of Alzheimers type. Chronobiol Int
15: 647654.
Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y,
Okawa M (1999). Melatonin secretion rhythm disorders in
patients with senile dementia of Alzheimers type with
disturbed sleepwaking. Biol Psychiatry 45: 417421.
Mishima K, Okawa M, Shimizu T, Hishikawa Y (2001).
Diminished melatonin secretion in the elderly caused by insufficient environmental illumination. J Clin Endocrinol Metab
86: 129134
Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A
(1999). Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, and testosterone secretion before the onset
of male puberty. J Clin Endocrinol Metab 84: 2937.
Mitchell AJ (1998). The role of corticotropin releasing factor
in depressive illness: a critical review. Neurosci Biobehav
Rev 22: 635651.
Mitchell BF, Schmid B (2001). Oxytocin and its receptor in the
process of parturition. J Soc Gynecol Invest 8: 122133.
Mitchell LA, Thomas PQ, Zacharin MR, Scheffer IE (2002).
Ectopic posterior pituitary lobe and periventricular heterotopia: cerebral malformations with the same underlying
mechanism? Am J Neuroradiol 23: 14751481.
Mitchell MD, Haynes PJ, Anderson ABM, Turnbull AC (1980).
Oxytocin in human ovulation. Lancet 2 (8196): 704.
Mitchell A, OKeane V (1998). Steroids and depression. Brit
Med J 316: 244245.
Mitchell TN, Stevens JM, Free SL, Sander JW, Shorvon SD,
Sisodiya SM (2002). Anterior commissure absence without
callosal agenesis: a new brain malformation. Neurology 58:
12971299.
Miyako K, Takemoto M, Ihara K, Kuromaru R, Kohno H, Hara
T (2002). A case of growth hormone and gonadotropin
deficiency associated with unilateral anophthalmia, microphallus, cryptorchidism, and mental retardation. Endoc J 49:
1520.
Miyamoto A, Oki J, Takahashi S, Okuno A (1999). Serum melatonin kinetics and long-term melatonin treatment for sleep
disorders in Rett syndrome. Brain Dev 21: 5962.
505
2014 Refs
506
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 506
D.F. SWAAB
Mohr DC, Goodkin DE, Likosky W, Gatto N, Baumann KA,

Rudick RA (1997a). Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch
Neurol 54: 531533.
Mohr DC, Goodkin DE, Gatto N, Van der Wende J (1997b).
Depression, coping and level of neurological impairment in
multiple sclerosis. Mult Scler 3: 254258.
Moitinho E, Planas R, Baares R, Albillos A, Ruiz-del-Arbol
L, Glvez C, Bosch J, Variceal Bleeding Study Group (2001).
Multicenter randomized controlled trial comparing different
schedules of somatostatin in the treatment of acute variceal
bleeding. J Hepatol 35: 712718.
Mokrani M-C, Duval F, Crocq MA, Bailey B, Macher JP (1997).
HPA axis dysfunction in depression: correlation with
monoamine system abnormalities. Psychoneuroendocrinology
(Suppl 1) 22: S63S68.
Molina A, Maa J, Villabona C, Fernndez-Castaa M, Soler
J (2002). Hypothalamic-pituitary sarcoidosis with hypopituitarism. Long-term remission with methylprednisolone pulse
therapy. Pituitary 5: 3336.
Molina-Carballo A, Muoz-Hoyos A, Martin-Garca JA, UberosFernandz J, Rodriguez-Cabezas T, Acuna-Castroviejo D
(1996). 5-Methoxytryptophol and melatonin in children:
differences due to age and sex. J Pineal Res 21: 7379.
Mller K, Stolze Larsen F, Bie P, Skinhj P (2001). The
syndrome of inappropriate secretion of antidiuretic hormone
and fluid restriction in meningitis how strong is the
evidence? Scand J Infect Dis 33: 1326.
Monaghan KG, Van Dyke DL, Feldman GL (1998). Prader
Willi-like syndrome in a patient with an Xq23q25 duplication.
Am J Med Genet 80: 227231.
Money J, Hosta G (1967). Laughing seizures with sexual
precocity: report of two cases. Johns Hopkins Med J 120:
326336.
Money J, Erhardt AA (1972). Man and woman, boy and girl:
the differentiation and dimorphism of gender identity from
conception to maturity. Johns Hopkins University Press,
Baltimore.
Money J, Hampson JG, Hampson JL (1955a). Hermaphroditism:
recommendations concerning assignment of sex, change of
sex and psychological management. Bull Johns Hopkins Hosp
97: 284300.
Money J, Hampson JG, Hampson JL (1955b). An examination
of some basic sexual concepts: the evidence of human
hermaphroditism. Bull Johns Hopkins Hosp 97: 301319.
Money J, Schwartz M, Lewis VG (1984). Adult erotosexual
status and fetal hormonal masculinization: 46,XX congenital
virilizing adrenal hyperplasia and 46,XY androgen-insensitivity syndrome compared. Psychoneuroendocrinology 9:
405414.
Monk TM, Buysse DJ, Reynolds III CF, Kupfer DJ, Houck PR
(1995). Circadian temperature rhythms of older people. Exp
Gerontol 30: 455474.
Monk TM, Buysse DJ, Billy BD, Kennedy KS, Willrich LM

(1998). Sleep and circadian rhythms in four orbiting astronauts. J Biol Rhythms 13: 188201.
Montagna P, Cortelli P, Gambetti P, Lugaresi E (1995). Fatal
familial insomnia: sleep, neuroendocrine and vegetative alterations. Adv Neuroimmunol 5: 1321.
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau
H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN,
Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB,
ORahilly S (1997). Congenital leptin deficiency is associated
with severe early-onset obesity in humans. Nature 387:
903908.
Monteleone P, Maj M, Fusco M, Kemali D, Reiter RJ (1992).
Depressed nocturnal plasma melatonin levels in drug-free
paranoid schizophrenics. Schizophr Res 7: 7784.
Monteleone P, Maes M, Fabrazzo M, Tortorella A, Lin A,
Bosmans E, Kenis G, Maj M (1999). Immunoendocrine findings in patients with eating disorders. Neuropsychobiology
40: 115120.
Monteleone P, Luisi M, Colurgio B, Casarosa E, Monteleone
P, Ioime R, Genazzani AR, Maj M (2001). Plasma levels of
neuroactive steroids are increased in untreated women with
anorexia nervosa or bulimia nervosa. Psychosom Med 63:
6268.
Montfort JC, Javoy-Agid F, Hauw JJ, Dubois B, Agid Y (1985).
Brain glutamate decarboxylase in Parkinsons disease with
particular reference to a premortem severity index. Brain 108:
301313.
Monti-Bloch L, Grosser BI (1991). Effect of putative pheromones on the electrical activity of the human vomeronasal
organ and olfactory epithelium. J Steroid Biochem Mol Biol
39: 573582.
Monti-Bloch L, Jennings-White C, Dolberg DS, Berliner DL
(1994). The human vomeronasal system. Psychoneuroendocrinology 19: 673686.
Monti-Bloch L, Diaz-Sanchez V, Jennings-White C, Berliner
DL (1998). Modulation of serum testosterone and autonomic
function through stimulation of the male human vomeronasal
organ (VNO) with pregna-4,20-diene-3,6-dione. J Steroid
Biochem Mol Biol 65: 237242.
Montorsi F, Perani D, Anchisi D, Salonia A, Scifo P,
Rigiroli P, Deho F, De Vito ML, Heaton J, Rigatti P,
Fazio F (2003). Brain activation patterns during video
sexual stimulation following the administration of apomorphine: results of a placebo-controlled study. Eur Urol 43:
405411.
Moore RY (1989). The geniculohypothalamic tract in monkey
and man. Brain Res 486: 190194.
Moore RY (1992). The organization of the human circadian
timing system. Prog Brain Res 93: 99117.
Moore R, Mills IH, Forster A (1981). Naloxone in the treatment
of anorexia nervosa: effect on weight gain and lipolysis. J R
Soc Med 74: 129131.
2014 Refs
2/12/03
1:39 pm
Page 507
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
507
(2001). Association of calnexin with wild-type and mutant

AVPR2 that cause nephrogenic diabetes insipidus.
Biochemistry 40: 67666775.
Morgan J, Lacey JH (1996). Anorexia nervosa and steroid withdrawal. Int J Eat Disord 19: 213215.
Morgan JF, McCluskey SE, Brunton JN, Lacey JH (2002).
Polycystic ovarian morphology and bulimia nervosa: a 9-year
follow-up study. Fertil Steril 77: 928931.
Morgan LO (1930). The nuclei of the region of the tuber
cinereum. Arch Neurol Psychiatry 24: 267299.
Morgan LO (1939). Alterations in the hypothalamus in mental
deficiency. Psychosom Med 1: 496507.
Morgan LO, Gregory HS (1935). Pathological changes in the
tuber cinereum in a group of psychoses. J Nerv Ment Dis
82: 286298.
Morgane PJ, Panksepp J (1979) (Eds.) Anatomy of the
Hypothalamus. Handbook of the Hypothalamus (Vol. 1).
Marcel Dekker, Inc, NY.
Mori T, Murakami Y, Nishiki M, Kato Y (1998). Clinical
course of long term treatment with intremittent subcutaneous
injection of LHRH in combination with GH replacement in
a male patient with hypothalamic hypogonadism due to
disruption of the pituitary stalk. Endocr J (Suppl) 45:
S155S158.
Morikawa M, Tamaki N, Kokunai T, Imai Y (1997). Intrasellar
pituitary gangliocyto-adenoma presenting with acromegaly:
case report. Neurosurgery 40: 611615.
Morioka M, Marubayashi T, Masumitsu T, Miura M, Ushio Y
(1995). Basal encephaloceles with morning glory syndrome,
and progressive hormonal and visual disturbances: case report
and review of the literature. Brain Dev 17: 196201.
Morishima A, Aranoff GS (1986). Syndrome of septo-optic-pituitary dysplasia: the clinical spectrum. Brain Dev 8: 233239.
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K
(1995). Aromatase deficiency in male and female siblings
caused by a novel mutation and the physiological role of
estrogens. J Clin Endocrinol Metab 80: 36893698.
Morken G, Linaker OM (2000). Seasonal variation of violence
in Norway. Am J Psychiatry 157: 16741678.
Morken G, Lilleeng S, Linaker OM (2002). Seasonal variation
in suicides and in admissions to hospital for mania and depression. J Affect Disord 69: 3945.
Morris HH, McCormick WF, Reinarz JA (1980). Neuroleptic
malignant syndrome. Arch Neurol 37: 462463.
Morris M, Keller M (1982). A specific deficiency in paraventricular vasopressin and oxytocin in the spontaneously
hypertensive rat. Brain Res 249: 173176.
Morris ME, Viswanathan N, Kuhlman S, Davis FC, Weitz CJ
(1998). A screen for genes induced in the suprachiasmatic
nucleus by light. Science 279: 15441547
Morris PLP, Robinson RG, De Carvalho ML, Albert P, Wells
JC, Samuels JF, Eden-Fetzer D, Price TR (1996a). Lesion
characteristics and depressed mood in the stroke data bank.
J Neuropsychiatry Clin Neurosci 8:153159.
Moore RY, Speh JC (1994). A putative retinohypothalamic

projection containing substance P in the human. Brain Res
659: 249253.
Moore RY, Speh JC, Card JP (1995). The retinohypothalamic
tract originates from a distinct subset of retinal ganglion cells.
Moore RY, Abrahamson EA, Van den Pol (2001). The
hypocretin neuron system: an arousal system in the human
brain. Arch Ital Biol 139: 195205.
Mootha SL, Barkovich AJ, Grumbach MM, Edwards MS,
Gitelman SE, Kaplan SL, Conte FA (1997). Idiopathic
hypothalamic diabetes insipidus, pituitary stalk thickening,
and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab 82: 13621367.
Mootha SL, Riley WJ, Brosnan PG (1999). Hypothalamicpituitary dysfunction associated with moyamoya disease in
children. J Pediatr Endocrinol Metab 12: 449453.
Morales A, Bass NE, Verhulst SJ (1995). Serum prolactin levels
and neonatal seizures. Epilepsia 36: 349354.
Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen
SSC (1998). The effect of six months treatment with a
100 mg daily dose of dehydroepiandrosterone (DHEA) on
circulating sex steroids, body composition and muscle
strength in age-advanced men and women. Clin Endocrinol
49: 421432.
Morales DL, S, Gregg D, Helman DN, Williams MR, Naka Y,
Landry DW, Oz MC (2000). Arginine vasopressin in the
treatment of 50 patients with postcardiotomy vasodilatory
shock. Ann Thorac Surg 69: 102106.
Morales LM, Estvez J, Surez H, Villalobos R, Chacin de
Bonilla L, Bonilla E (1989). Nutritional evaluation of
Huntington disease patients. Am J Clin Nutr 50: 145150.
Morales-Asn F, Mauri JA, Iiguez C, Espada F, Mostacero E
(1998). The hypnic headache syndrome: report of three new
cases. Cephalalgia 18: 157158.
Moran DT, Jafek BW, Carter Rowley III J (1991). The vomeronasal (Jacobsons) organ in man: ultrastructure and frequency
of occurrence. J Steroid Biochem Mol Biol 39: 545552.
Morash B, Li A, Murphy PR, Wilkinson M, Ur E (1999).
Leptin gene expression in the brain and pituitary gland.
Moreau J-L, Kilpatrick G, Jenck F (1997). Urocortin, a novel
neuropeptide with anxiogenic-like properties. Neuroreport 8:
16971701.
Moreaud O, Dufoss N, Pellat J (1996). Maladie de
MarchiafavaBignami: evolution par pousses. Rev Neurol
152: 560562.
Morel F (1947). La massa intermedia ou commissure grise. Acta
Anat 4: 203207.
Morello J-P, Bichet DG (2001). Nephrogenic diabetes insipidus.
Annu Rev Physiol 63: 607630.
Morello J-P, Salahpour A, Petj-Repo UE, Laperrire A,
Lonergan M, Arthus M-F, Nabi IR, Bichet DG, Bouvier M
507
2014 Refs
508
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 508
D.F. SWAAB
Morris PLP, Robinson RG, Raphael B, Hopwood MJ (1996b).

Lesion location and poststroke depression. J Neuropsychiatry
Morrow GR, Hickok JT, Andrews PLR, Stern RM (2002).
Reduction in serum cortisol after platinum based chemotherapy for cancer: a role for the HPA axis in treatment-related
nausea? Psychophysiology 39: 491495.
Morse RP (1998). Tuberous sclerosis. Arch Neurol 55:
12571258.
Morton A (1969). A quantitative analysis of the normal neuron
population of the hypothalamic magnocellular nuclei in man
and of their projections to the neurohypophysis. J Comp
Neurol 136: 143158.
Morton A (1970). The time course of retrograde neuron loss in
the hypothalamic magnocellular nuclei of man. Brain 93:
329336.
Morton GJ, Schwartz MW (2001). The NPY/AgRP neuron and
energy homeostasis. Int J Obesity (Suppl 5) 25: 556562.
Moses SG, Robins E (1975). Regional distribution of norepinephrine and dopamine in brains of depressive suicides
and alcoholic suicides. Psychopharmacol Commun 1:
327337.
Moses AM, Thomas DG, Canfield MC, Collins GH (2003).
Central diabetes insipidus due to cytomegalovirus infection of
the hypothalamus in a patient with acquired immunodeficiency
syndrome: a clinical, pathological, and immunohistochemical
case study. J Clin Endocrinol Metab 88: 5154
Mosnaim AD, Chevesich J, Wolf ME, Freitag FG, Diamond S
(1986). Plasma methionine enkephalin. Increased levels
during a migraine episode. Headache 26: 278281.
Mourelatos Z, Yachnis A, Rorke L, Mikol J, Gonatas NK (1993).
The Golgi apparatus of motor neurons in amyotrophic lateral
sclerosis. Ann Neurol 33: 608615.
Mouri TK, Takahashi K, Kawauchi H, Sone M, Totsune K,
Murakami O, Itoi K, Ohneda M, Sasano H, Sasano N (1993).
Melanin-concentrating hormone in the human brain. Peptides
14: 643646.
Mtanda AT, Cruysberg JRM, Pinckers AJLG (1986). Optic
atrophy in Wolfram syndrome. Opthal Paediatr Genet 7:
159165.
Mudher A, Lovestone S (2002). Alzheimers disease do tauists
and baptists finally shake hands? Trends Neurosci 25: 2226.
Mufson EJ, Benoit R, Mesulam MM (1988). Immunohistochemical evidence for a possible somatostatin-containing
amygdalostriatal pathway in normal and Alzheimers disease
brain. Brain Res 453: 117128.
Mufson EJ, Presley LN, Kordower JH (1991). Nerve growth
factor receptor immunoreactivity within the nucleus basalis
(Ch4) in Parkinsons disease: reduced cell numbers and colocalization with cholinergic neurons. Brain Res 539: 1930.
Mufson EJ, Conner JM, Kordower JH (1995). Nerve growth
factor in Alzheimers disease: defective retrograde transport
to nucleus basalis. Neuroreport 6: 10631066.
Mufson EJ, Li J-M, Sobreviela T, Kordower JH (1996).

Decreased trkA gene expression within basal forebrain
neurons in Alzheimers disease. Neuroreport 8: 2529.
Mufson EJ, Lavine N, Jaffar S, Kordower JH, Quirion R,
Saragovi HU (1997). Reduction in p140-TrkA protein within
the nucleus basalis and cortex in Alzheimers disease. Exp
Neurol 146: 91103.
Mufson EJ, Kahl U, Bowser R, Mash DC, Kordower JH,
Deecher DC (1998). Galanin expression within the basal
forebrain in Alzheimers disease. Ann NY Acad Sci 863:
291304
Mufson EJ, Deecher DC, Basile M, Izenwasse S, Mash DC
(2000a). Galanin receptor plasticity within the nucleus basalis
in early and late Alzheimers disease: an in vitro autoradiographic analysis. Neuropharmacology 39: 14041412.
Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA,
Jaffar S, Saragovi HU, Kordower JH (2000b). Loss of nucleus
basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimers
disease. J Comp Neurol 427: 1930.
Mufson EJ, Counts SE, Ginsberg SD (2002). Gene expression
profiles of cholinergic nucleus basalis neurons in Alzheimers
disease. Neurochem Res 27: 10351048.
Muhlbauer M, Metcalf JC, Robertson JT, Fridland G, Desiderio
DM (1986). Opioid peptides in the cerebrospinal fluid of
Alzheimer patients. Biomed Chromatogr 1: 155158.
Muir JL, Pfister HP (1988). Influence of exogenously administered oxytocin on the corticosterone and prolactin response
to psychological stress. Pharmacol Biochem Behav 29:
699703.
Mulder EJH, Robles de Medina PG, Huizink AC, Van den
Bergh BRH, Buitelaar JK, Visser GHA (2002). Prenatal
maternal stress: effects on pregnancy and the (unborn) child.
Early Hum Dev 70: 314.
Mulhern RK, Hancock J, Fairclough D, Kun L (1992).
Neuropsychological status of children treated for brain
tumors: a critical review and integrative analysis. Med Pediatr
Oncol 20: 181191.
Mller J (1997). Hypogonadism and endocrine metabolic disorders in PraderWilli syndrome. Acta Paediatr (Suppl) 423:
5859.
Mller D, Roeder F, Orthner H (1973). Further results of stereotaxis in the human hypothalamus in sexual deviations. First
use of this operation in addiction to drugs. Neurochirurgia
16: 113126.
Mller EE, Parati EA, Cocchi D, Zanardi P, Caraceni T (1979).
Dopaminergic drugs on growth hormone and prolactin
secretion in Huntingtons disease. In: Chase TN, Wexler NS,
Barbeau A (Eds.) Huntingtons disease. Advances in
Neurology Vol. 23. New York; Raven, pp. 319334.
Mller EE, Cocchi D, Ghigo E, Arvat E, Locatelli V, Camanni
F (1993). Growth hormone response to GHRH during
lifespan. J Pediatr Endocrinol 6: 513.
2014 Refs
2/12/03
1:39 pm
Page 509
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
509
Municchi G, Marconcini S, DAmbrosio A, Berardi R,

Acquaviva A (2002). Central precocious puberty in multisystem Langerhans cell histiocytosis: a case report. Pediatr
Hematol Oncol 19: 273278.
Muoz-Hoyos A, Jaldo R, Molina-Carballo A, Escames G,
Macas M, Fernndez-Garca JM, Reiter RJ, AcuaCastroviejo D (2001). Characterization of nocturnal ultradian
rhythms of melatonin in children with growth-hormonedependent and independent growth delay. J Clin Endocrinol
Metab 86: 11811187.
Munt PW, Marshall RN, Underwood LE (1975). Hyperprolactinemia in sarcoidosis. Incidence and utility in
predicting hypothalamic involvement. Am Rev Respir Dis
112: 269272.
Muragaki Y, Timothy N, Leight S, Hempstead B, Chao MV,
Trojanowski JQ, Lee VM-Y (1995). Expression of Trk receptors in the developing and adult human central and peripheral
nervous system. J Comp Neurol 356: 387397.
Murakami N, Furuto-Kato S, Fujisawa I, Ohyama K, Nakao S,
Kuwayama A, Kageyama N (1998). Supra- and extrasellar
pituitary microadenoma as a cause of Cushings disease.
Endocr J 45: 631636.
Muramatsu T, Kato M, Matsui T, Yoshimasu H, Yoshino A,
Matsushita S, Higuchi S, Kashima H (1997). Apolipoprotein
E epsilon 4 allele distribution in Wernicke-Korsakoff
syndrome with or without global intellectual deficits. J Neural
Transm 104: 913920.
Murata Y, Harada T, Ishizaki F, Izumi Y, Nakamura S (1997).
Autonomic dysfunction in Parkinsons disease and vascular
parkinsonism. Acta Neurol Scand 96: 359365.
Murata J, Sawamura Y, Ikeda J, Hashimoto S, Honma K-I
(1998). Twenty-four hour rhythm of melatonin in patients
with a history of pineal and/or hypothalamo-neurohypophyseal germinoma. J Pineal Res 25: 159166.
Muratani H, Teruya H, Sesoko S, Takishita S, Fukiyama K
(1996). Brain angiotensin and circulatory control. Clin Exp
Pharmacol Physiol 23: 458464.
Murayama K, Meeker RB, Murayama S, Greenwood RS (1993).
Developmental expression of vasopressin in the human hypothalamus: double-labeling with in situ hybridization and
immunocytochemistry. Pediatr Res 33: 152158.
Murck H, Guldner J, Colla-Mller M, Frieboes RM, Schier T,
Wiedemann K, Holsboer F, Steiger A (1996). VIP decelerates non-REMREM cycles and modulates hormone secretion
during sleep in men. Am J Physiol 271: R905R911.
Murdoch I, Nicoll JAR, Graham DI, Dewar D (2002). Nucleus
basalis of Meynert pathology in the human brain after fatal
head injury. J Neurotrauma 19: 279284.
Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux
B, Agid Y, Hirsch E, Raisman-Vozari R (1999). An immunohistochemical study of the distribution of brain-derived
neurotrophic factor in the adult human brain, with particular
reference to Alzheimers disease. Neuroscience 88: 10151032.
Mller HL, Klinkhammer-Schalke M, Khl J (1998a). Final

height and weight of long-term survivors of childhood malignancies. Exp Clin Endocrinol Diabetes 106:
135139.
Mller HL, Handwerker G, Wollny B, Faldum A, Srensen N
(2002a). Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients. J Clin
Mller D, Marr N, Ankermann T, Eggert P, Deen PMT (2002b).
Desmopressin for nocturnal enuresis in nephrogenic diabetes
insipidus. Lancet 359: 495497.
Muller M, Hubbard SL, Fukuyama K, Dirks P, Matsuzawa K,
Rutka JT (1995). Characterization of a pineal region malignant rhabdoid tumor. Pediatr Neurosurg 22: 204209.
Mller MB, Keck ME, Zimmermann S, Holsboer F, Wurst W
(2000a). Disruption of feeding behavior in CRH receptor Ideficient mice is dependent on glucocorticoids. Neuroreport
11: 19631966.
Mller MB, Landgraf R, Keck ME (2000b). Vasopressin,
major depression, and hypothalamic-pituitary-adrenocortical
desensitization. Biol Psychiatry 48: 330333.
Mller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJG,
Holsboer F, Swaab DF (2001). Neither major depression nor
glucocorticoid treatment affects the cellular integrity of the
human hippocampus. Eur J Neurosci 14: 16031612.
Mller T, Kuhn W, Brnke C, Bttner T, Przuntek H (1998b).
KleineLevin syndrome and Parkinsonian symptoms a case
report. J Neurol Sci 157: 214216.
Mller W, Klein PJ, Newman RA, Uhlenbruck G (1980).
Histochemical methods for the further characterisation of the
tumourettes of the posterior lobe of the pituitary. Acta
Mller-Thomsen T, Arlt S, Ganzer S, Mann U, Mass R, Naber
D, Beisiegel U (2002). Depression in Alzheimers disease
might be associated with apolipoprotein E 4 allele frequency
in women but not in men. Dement Geriatr Cogn Disord 14:
5963.
Mulnard RA, Cotman CW, Kawas C, Van Dyck CH, Sano M,
Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M,
Thomas R, Thal LJ (2000). Estrogen replacement therapy of
mild to moderate Alzheimer disease: a randomized controlled
trial. Alzheimers disease Cooperative Study. JAMA 283:
10071015.
Munari C, Kahane P, Francione S, Hoffmann D, Tassi L, Cusmai
R, Vigevano F, Pasquier B, Betti OO (1995). Role of the
hypothalamic hamartoma in the genesis of gelastic fits
(a video-stereoEEG study). Electroencephalogr Clin
Mundigler G, Delle-Karth G, Koreny M, Zehetgruber M,
Steindl-Munda P, Marktl W, Fertl L, Siostrzonek P (2002).
Impaired circadian rhythm of melatonin secretion in sedated
critically ill patients with severe sepsis. Crit Care Med 30:
536540.
509
2014 Refs
510
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 510
D.F. SWAAB
Murialdo G, Tamagno G (2002). Endocrine aspects of neurosarcoidosis. J Endocrinol Invest 25: 650662.
Murialdo G, Fanciullacci M, Nicolodi M, Filippi U, De
Palma D, Sicuteri F, Polleri A (1989). Cluster headache in the male: sex steroid pattern and gonadotropic response
to luteinizing hormone releasing hormone. Cephalalgia 9:
9198.
Murialdo G, Costelli P, Fonzi S, Parodi C, Torre F, Cenacchi
T, Polleri A (1993). Circadian secretion of melatonin and
thyrotropin in hospitalized aged patients. Aging Clin Exp Res
5: 3946.
Murialdo G, Nobili F, Rollero A, Gianelli MV, Copello F,
Rodriguez G, Polleri A (2000). Hippocampal perfusion
and pituitaryadrenal axis in Alzheimers disease. Neuropsychobiology 42: 5157.
Murphy BEP (1997). Antiglucocorticoid therapies in major
depression: a review. Psychoneuroendocrinology (Suppl 1)
22: S125S132.
Murphy BE, Filipini D, Ghadirian AM (1993). Possible use of
glucocorticoid receptor antagonists in the treatment of major
depression: preliminary results using RU 486. J Psychiatry
Murphy BEP, Wolkowitz OM (1993). The pathophysiologic
significance of hypercorticism: antiglucocorticoid strategies.
Psychiatr Ann 23: 682690.
Murphy DGM, DeCarli C, Schapiro MB, Rapoport SI, Horwitz
B (1992a). Age-related differences in volumes of subcortical
nuclei, brain matter, and cerebrospinal fluid in healthy men
as measured with magnetic resonance imaging. Arch Neurol
49: 839845.
Murphy GM, Greenberg BD, Ellis WG, Forno LS, Salamat SM,
Gonzalez-DeWhitt PA, Lowery DE, Tinklenberg JR, Eng LF
(1992b). Alzheimers disease: -amyloid precursor protein
expression in the nucleus basalis of Meynert. Am J Pathol
141: 357361.
Murphy HM, Wideman CH, Nadzam GR (1998a). The role of
vasopressin in modulating circadian rhythm responses to
phase shifts. Peptides 19: 11911208.
Murphy JV, Wheless JW, Schmoll CM (2000). Left vagal nerve
stimulation in six patients with hypothalamic hamartomas.
Murphy LL, Muoz RM, Adrian BA, Villanua MA (1998b).
Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion. Neurobiol Dis 5: 432446.
Murphy MR, Seckl JR, Burton S, Checkley SA, Lightman SL
(1987). Changes in oxytocin and vasopressin secretion during
sexual activity in men. J Clin Endocrinol Metab 65: 738741.
Murphy MR, Checkley SA, Seckl JR, Lightman SL (1990).
Naloxone inhibits oxytocin release at orgasm in man. J Clin
Murphy PJ, Campbell SC (2001). Enhancement of REM sleep
during extraocular light exposure in humans. Am J Physiol
280: R1606R1612.
Murray SC, Muse KN (1997). Effective treatment of severe

menstrual migraine headaches with gonadotropin-releasing
hormone agonist and add-back therapy. Fertil Steril 67:
390393.
Murray G, Allen NB, Trinder J, Burgess H (2002). Is weakened circadian rhythmicity a characteristic of neuroticism? J
Affect Disord 72: 281289.
Murri L, Iudice A, Muratorio A, Polleri A, Barreca T, Murialdo
G (1980). Spontaneous nocturnal plasma prolactin and growth
hormone secretion in patients with Parkinsons disease and
Huntingtons chorea. Eur Neurol 19: 198206.
Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal
M, Cau P, Cremer H (2000). Disruption of the mouse necdin
gene results in hypothalamic and behavioral alteration reminiscent of the human PraderWilli syndrome. Hum Mol Genet
9: 31013110.
Musselman DL, Nemeroff CB (1996). Depression and endocrine
disorders: focus on the thyroid and adrenal system. Brit J
Psychiatry (Suppl) 168: 123128.
Muti Zaitoun AA, Chang J, Booker M (1999). Diprosopus
(partially duplicated head) associated with anencephaly: a
case report. Pathol Res Pract 195: 4550.
Myers DA, Myers TR, Grober MS, Nathanielsz PW (1993).
Levels of corticotropin-releasing hormone messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular
nucleus and proopiomelanocortin mRNA in the anterior pituitary during late gestation in fetal sheep. Endocrinology 132:
21092116.
Myers BL, Badia P (1995). Changes in circadian rhythms and
sleep quality with aging: mechanisms and interventions.
Myers SE, Carrel AL, Whitman BY, Allen DB (1999). Physical
effects of growth hormone treatment in children with
PraderWilli syndrome. Acta Paediatr (Suppl) 433: 112114.
Myers SE, Carrel AL, Whitman BY, Allen DB (2000). Sustained
benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth
in PraderWilli syndrome. J Pediatr 137: 4249.
Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri
M, Beck G, Wright AF, Iannaccone A, Elbedour K, Riise R,
Baldi A, Raas-Rothschild A, Gorman SW, Duhl DM,
Jacobson SG, Casavant T, Stone EM, Sheffield VC (2001).
Identification of the gene that, when mutated, causes the
human obesity syndrome BBS4. Nat Genet 28: 188191.
Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen H-j,
Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton
AB, Carmi R, Lleci G, Chandrasekharappa SC, Collins FS,
Jacobson SG, Heckenlively JR, Weleber RG, Stone EM,
Sheffield VC (2002). Identification of the gene (BBS1) most
commonly involved in BardetBiedl syndrome, a complex
human obesity syndrome. Nat Genet 31: 435438.
Ndvornk P, Sramka
M, Patropstr G (1977). Transventricular
anterior hypothalamotomy in stereotactic treatment of
2014 Refs
2/12/03
1:39 pm
Page 511
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
511
controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin
onset. J Sleep Res 7: 135143.
Nahon JL, Presse F, Bittencourt JC, Sawchenko PE, Vale W
(1989). The rat melanin-concentrating hormone messenger
ribonucleic acid encodes multiple putative neuropeptides
coexpressed in the dorsolateral hypothalamus. Endocrinology
125: 20562065.
Naidu S (1997). Rett syndrome: a disorder affecting early brain
growth. Ann Neurol 42: 410.
Naitoh M, Burrell LM (1998). Thirst in elderly subjects. J Nutr
Health Aging 2: 172177.
Najimi M, Chigr F, Leduque P, Jordan D, Charnay Y, Chayvialle
JA, Tohyama M, Kopp N (1989). Immunohistochemical
distribution of somatostatin in the infant hypothalamus. Brain
Res 483: 205220.
Najimi M, Chigr F, Jordan D, Leduque P, Bloch B, Tommasi
M, Rebaud P, Kopp N (1990). Anatomical distribution of
LHRH-immunoreactive neurons in the human infant
hypothalamus and extrahypothalamic regions. Brain Res 516:
280291.
Najimi M, Chigr F, Champier J, Tabib A, Kopp N, Jodani D
(1991). Autoradiographic distribution of TRH binding sites
in the human hypothalamus. Brain Res 563: 6676.
Najimi M, Bennis M, Chigr F, Kopp N, Moyse E, Miachon
S (1999). Benzodiazepine binding sites in the human
hypothalamus. Autoradiographic study. J Brain Res 39:
493502.
Najimi M, Bennis M, Moyse E, Miachon S, Kopp N, Chigr F
(2001a). Regional distribution of benzodiazepine binding sites
in the human newborn and infant hypothalamus. A quantitative autoradiographic study. Brain Res 895: 129138.
Najimi M, Bennis M, Moyse E, Chigr F (2001b). Distribution
of delta sleep-inducing peptide in the newborn and infant
human hypothalamus: an immunohistochemical study. Biol
Res 34: 3142.
Nakai T, Kitamura N, Hashimoto T, Kajimoto Y, Nishino N,
Mita T, Tanaka C (1991). Decreased histamine H1 receptors
in the frontal cortex of brains from patients with chronic
Nakajima K, Sakurai A, Kobuta, T, Katai M, Mori J-I, Aizawa
T, Fukushima Y, Hashizume K (1999). Multiple endocrine
neoplasia type 1 concomitant with PraderWilli syndrome:
case report and genetic diagnosis. Am J Med Sci 317: 346349.
Nakamura S, Kawamata T, Yasuhara O, Akiguchi I, Kimura J,
Kimura H, Kimura T (1991). The histochemical demonstration of monoamine oxidase-containing neurons in the human
hypothalamus. Neuroscience 44: 457463.
Nakamura S, Takemura M, Ohnishi K, Suenaga T, Nishimura
M, Akiguchi I, Kimura J, Kimura T (1993). Loss of large
neurons and occurrence of neurofibrillary tangles in the
tuberomammillary nucleus of patients with Alzheimers
disease. Neurosci Lett 151: 196199.
hedonia. In: Sweet WH et al. (Eds.) Neurosurgical Treatment

in Psychiatry, Pain, and Epilepsy. University Park Press,
Nagahata M, Hosoya T, Kayama T, Yamaguchi K (1998).
Edema along the optic tract: a useful MR finding for the
diagnosis of craniopharyngiomas. Am J Neuroradiol 19:
17531757.
Nagai K, Nagai N, Shimizu K, Chun S, Nakagawi H, Niijima
A (1996). SCN output drives the autonomic nervous system:
with special reference to the autonomic function related to
the regulation of glucose metabolism. Prog Brain Res 111:
253272.
Nagai I, Li CH, Hsieh SM, Kizaki T, Urano Y (1984). Two
cases of hereditary diabetes insipidus, with an autopsy finding
in one. Acta Endocrinol 105: 318323.
Nagai R, McGeer PL, Peng JH, McGeer EG, Dolman CE (1983).
Choline acetyltransferase immunohistochemistry in brains of
Alzheimers disease patients and controls. Neurosci Lett 36:
195199.
Nagasaki H, Ito M, Yuasa H, Saito H, Fukase M, Hamada K,
Ishikawa E, Katakami H, Oiso Y (1995). Two novel mutations in the coding region for neurophysin-II associated with
familial central diabetes insipidus. J Clin Endocrinol Metab
80: 13521356.
Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima
N, Tanaka A, Kotani H, Nomura N, Ohara O (1997).
Prediction of the coding sequences of unidentified human
genes. VII. The complete sequences of 100 new cDNA clones
from brain which can code for large proteins in vitro. DNA
Res 4: 141150.
Nagashima K, Zabriskie JB, Lyons MJ (1992). Virus-induced
obesity in mice: association with a hypothalamic lesion. J
Nagatsu I, Ikemoto K, Kitahama K, Nishimura A, Ichinose H,
Nagatsu T (1999). Specific localization of the guanosine
triphosphate (GTP) cyclohydrolase I-immunoreactivity in the
human brain. J Neural Transm 106: 607617.
Nagle DL, McGrail SH, Vitale J, Woolf EA, Dussault BJ,
DiRocco L, Holmgren L, Montagno J, Bork P, Huszar D,
Fairchild-Huntress V, Ge P, Keilty J, Ebelings C, Baldini L,
Gilchrist J, Burn P, Carlson GA, Moore KJ (1999). The
mahogany protein is a receptor involved in suppression of
obesity. Nature 398: 148152.
Nagtegaal J, Kerkhof GA, Smits MG, Van der Meer YG, FischerSteenvoorden MGJ (1996). Melatonin: a survey of suspected
adverse drug reactions. In: Beersma DGM, Coenen AML
(Eds.) Sleep-Wake Research in the Netherlands, Vol. 7, pp.
115118. Dutch Society for SleepWake Research, Leiden.
Nagtegaal JE, Kerkhof GA, Smits MG, Swart ACW, Van der
Meer YG (1997). Traumatic brain injury-associated delayed
sleep phase syndrome. Funct Neurol 12: 345348.
Nagtegaal JE, Kerkhof GA, Smits MG, Swart ACW, Van der
Meer YG (1998). Delayed sleep phase syndrome: a placebo-
511
2014 Refs
512
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 512
D.F. SWAAB
Nakamura S, Ohnishi K, Nishimura M, Suenaga T, Akiguchi

I, Kimura J, Kimura T (1996). Large neurons in the tuberomammillary nucleus in patients with Parkinsons disease and
multiple system atrophy. Neurology 46: 16931696.
Nakano KK (1973). Anencephaly: a review. Dev Med Child
Neurol 15: 383400.
Nakano I, Hirano A (1982). Loss of large neurons of the medial
septal nucleus in an autopsy case of Alzheimers disease. J
Nakano I, Kondo A, Iwasaki K (1997). Choroid plexus papilloma in the posterior third ventricle: case report. Neurosurgery
40: 12791282.
Nakashima T, Kimmelman CP, Snow JB (1985). Vomeronasal
organs and nerves of Jacobson in the human fetus. Acta
Otolaryngol 99: 266271.
Nakasu Y, Nakasu S, Nakajima M, Itoh R, Matsuda M (1999).
Atypical Rathkes cleft cyst associated with ossification. Am
J Neuroradiol 20: 12871289.
Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H,
Kangawa K, Matsukura S (2001). A role for ghrelin in the
central regulation of feeding. Nature 409: 194198.
Nanduri VR, Stanhope R (1999). Why is the retention of
gonadotrophin secretion common in children with panhypopituitarism due to septo-optic dysplasia? Eur J Endocrinol
140: 4850.
Nappi G, Sinforiani E, Martignoni E, Petraglia F, Facchinetti
F, Rossi F, Genazzani AR (1988). Aging brain and dementias:
changes in central opioids. Eur Neurol 28: 217220.
Nappi RE, Petraglia F, Genazzani AD, DAmbrogio G, Zara C,
Genazzani AR (1993). Hypothalamic amenorrhea: evidence
for a central derangement of hypothalamic-pituitary-adrenal
cortex axis activity. Fertil Steril 59: 571576.
Narang RL, Chaudhury RR, Wig NN (1973). Effect of
electroconvulsive therapy on the antidiuretic hormone level
in the plasma of schizophrenic patients. Indian J Med Res
61: 766770.
Naruki M, Mizutani S, Goto K, Tsujimoto M, Nakazato H,
Itakura A, Mizuno K, Kurauchi O, Kikkawa F, Tomoda Y
(1996). Oxytocin in hydrolized by an enzyme in human
placenta that is identical to the oxytocinase of pregnancy
serum. Peptides 17: 257261.
Natale V, Adan A, Chotai J (2002). Further results on the association between morningnesseveningness preference and the
season of birth in human adults. Neuropsychobiology 46:
209214.
Natelson BH, Cohen JM, Brassloff I, Lee H-J (1993). A
controlled study of brain magnetic resonance imaging in
patients with the chronic fatigue syndrome. J Neurol Sci 120:
213217.
Natelson BH (2001). Chronic fatigue syndrome. JAMA 285:
25572559.
Nauta WJH, Haymaker W (1969). Hypothalamic nuclei and
fiber connections. In: Haymaker W, Anderson E, Nauta WJH
(Eds.) The Hypothalamus, pp. 136203. Charles C Thomas,

Springfield, IL, USA.
Nave R, Herer P, Haimov I, Shlitner A, Lavie P (1996).
Hypnotic and hypothermic effects of melatonin on daytime
sleep in humans: lack of antagonism by flumazenil. Neurosci
Lett 214: 123126.
Naveilhan P, Hassani H, Canals JM, Ekstrand AJ, Larefalk ,
Chhaljani V, Arenas E, Gedda K, Svensson L, Thoren P,
Ernfors P (1999). Normal feeding behavior, body weight and
leptin response require the neuropeptide Y Y2 receptor.
Nature Med 5: 11881193.
Neal CR, Akil H, Watson SJ (2001). Expression of orphanin
FQ and the opioid receptor-like (ORL1) receptor in the
developing human and rat brain. J Chem Neuroanat 22:
219249.
Neeck G (2000). Neuroendocrine and hormonal perturbations
and relations to the serotonergic system in fibromyalgia
patients. Scand J Rheumatol (Suppl 13) 29: 812.
Neeck G, Crofford LJ (2000). Neuroendocrine perturbations in
fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin
North Am 26: 9891002.
Neil-Dwyer G, Lang DA, Doshi B, Gerber ChJ, Smith PWF
(1994). Delayed cerebral ischaemia: the pathological
substrate. Acta Neurochir (Wien) 131: 137145.
Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens
BF, Jelliffe LL, Hansen RL, Phillips TM (2001).
Neuropeptides and neurotrophins in neonatal blood of
children with autism or mental retardation. Ann Neurol 49:
597606.
Nelson RJ, Demas GE (1997). Role of melatonin in mediating
seasonal energetic and immunologic adaptations. Brain Res
Bull 44: 423430.
Nelson RJ, Demas GE, Klein SL, Kriegsfeld LJ (1995). The
influence of season, photoperiod, and pineal melatonin on
immune function. J Pineal Res 19: 149165.
Nemeroff CB (1991). Neuropeptides and schizophrenia. In:
Tamminga CA, Schulz SC (Eds.) Schizophrenia Research
(Advances in Neuropsychiatry and Psychopharmacology,
Vol. 1). Raven Press Ltd, New York, pp. 7789.
Nemeroff CB (1996). The corticotropin-releasing factor (CRF)
hypothesis of depression: new findings and new directions.
Mol Psychiatry 1: 336342.
Nemeroff CB (1998). Psychopharmacology of affective disorders in the 21st century. Biol Psychiatry 44: 517525.
Nemeroff CB (2001). Progress in the battle with the black dog:
advances in the treatment of depression. Am J Psychiatry
158: 15551557.
Nemeroff CB, Kizer JS, Reynolds GP, Bissette G (1989).
Neuropeptides in Alzheimers disease: a postmortem study.
Regul Pept 25: 123130.
Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G (1999).
Ovulatory and metabolic effects of D-chiro-inositol in the
polycystic ovary syndrome. N Engl J Med 340: 13141320.
2014 Refs
2/12/03
1:39 pm
Page 513
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
513
Ng SM, Kumar Y, Cody D, Smith CS, Didi M (2003). Cranial

MRI scans are indicated in all girls with central precocious
puberty. Arch Dis Child 88: 414418.
Ng TTC, OConnell IPM, Wilkins EGL (1994). Growth
hormone deficiency coupled with hypogonadism in AIDS.
Nguyen D, Singh S, Zaatreh M, Novotny E, Levy S, Testa F,
Spencer SS (2003). Hypothalamic hamartomas: seven cases
and review of the literature. Epilepsy Behav 4: 246258.
Nicholls RD (1999). Incriminating gene suspects, PraderWilli
style. Nat Genet 23: 132134.
Nicholls RD (2000). Mosaicism in PraderWilli syndrome. Am
J Med Genet 90: 175176.
Nicolau GY, Lakatua D, Sackett-Lundeen L, Haus E (1984).
Circadian and circannual rhythms of hormonal variables in
elderly men and women. Chronobiol Int 1: 301319.
Nicolodi M, Sicuteri F, Poggioni M (1993). Hypothalamic
modulation of nociception and reproduction in cluster
headache. II. Testosterone-induced increase of sexual activity
in males with cluster headache. Cephalalgia 13: 258260.
Nielsen J, Pelsen B, Strensen K (1988). Follow-up of 30
Klinefelter males treated with testosterone. Clin Genet 33:
262269.
Nijenhuis M, Zalm R, Burbach JPH (1999). Mutations in the
vasopressin prohormone involved in diabetes insipidus impair
endoplasmic reticulum export but not sorting. J Biol Chem
274: 2120021208.
Nijenhuis M, Van den Akker ELT, Zalm R, Franken AAM,
Abbes AP, Engel H, De Wied D, Burbach JPH (2001).
Familial neurohypophysial diabetes insipidus in a large Dutch
kindred: effect of the onset of diabetes on growth in children
and cell biological defects of the mutant vasopressin prohormone. J Clin Endocrinol Metab 86: 34103420.
Nilsson C, Lindvall-Axelsson M, Owman C (1992a).
Neuroendocrine regulatory mechanisms in the choroid plexuscerebrospinal fluid system. Brain Res Brain Res Rev 17:
109138.
Nilsson C, Sthlberg F, Thomsen C, Henriksen O, Herning M,
Owman C (1992b). Circadian variation in human cerebrospinal fluid production measured by magnetic resonance
imaging. Am J Physiol 262: R20R24.
Nishihara K, Horiuchi S, Eto H, Uchida S (2000). Mothers
wakefulness at night in the post-partum period is related to
their infants circadian sleep-wake rhythm. Psychiatry Clin
Nishihara K, Horiuchi S, Eto H, Uchida S (2002). The
development of infants circadian restactivity rhythm and
mothers rhythm. Physiol Behav 77: 9198.
Nishijima T, Sakurai S, Arihara Z, Takahashi K (2003). Plasmaorexin-A-like immunoreactivity in patients with sleep apnea
hypopnea syndrome. Peptides 24: 407411.
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000).
Hypocretin (orexin) deficiency in human narcolepsy. Lancet
355: 3940.
Neudeck P, Jacoby GE, Florin I (2001). Dexamethasone

suppression test using saliva cortisol measurement in bulimia
nervosa. Physiol Behav 72: 9398.
Neugebauer R, Hoek HW, Susser E (1999). Prenatal exposure
to wartime famine and development of antisocial personality
disorder in early adulthood. JAMA 282: 455462.
Neumeister A, Praschak-Rieder N, Heelmann B, Rao M-L,
Glck J, Kasper S (1997). Effects of tryptophan depletion on
drug-free patients with seasonal affective disorder during a
stable response to bright light therapy. Arch Gen Psychiatry
54: 133138.
Neumeister A, Pirker W, Willeit M, Praschak-Rieder N,
Asenbaum S, Brcke T, Kasper S (2000). Seasonal variation
of availability of serotonin transporter binding sites in healthy
female subjects as measured by [123I]-2-carbomethoxy-3(4-iodophenyl)tropane and single photon emission computed
tomography. Biol Psychiatry 47: 158160.
Nevus T, Lckgren G, Tuvemo T, Stenberg A (1999a).
Osmoregulation and desmopressin pharmacokinetics in
enuretic children. Pediatrics 103: 6570.
Nevus T, Lckgren G, Tuvemo T, Olsson U, Stenberg A
(1999b). Desmopressin resistant enuresis: pathogenetic and
therapeutic considerations. J Urol 162: 21362140.
Nevus T, Bader G, Silln U (2002). Enuresis, sleep and desmopressin treatment. Acta Paediatr 91: 11211125.
Newell-Price J, Jrgensen JOL, Grossman A (1999). The
diagnosis and differential diagnosis of Cushings syndrome.
Horm Res (Suppl 3) 51: 8194.
Newman CB, Kleinberg DL (1998). Adult growth hormone
deficiency. Endocrinologist 8: 178186.
Newman LC, Lipton RB, Solomon S (1990). The hypnic
headache syndrome: a benign headache disorder of the
elderly. Neurology 40: 19041905.
Newman NJ, Lessell S, Winterkorn JMS (1991). Optic chiasmal
neuritis. Neurology 41: 12031210.
Newman HM, Stevens RT, Apkarian AV (1996). Direct spinal
projections to limbic and striatal areas: anterograde transport
studies from the upper cervical spinal cord and the cervical
enlargement in squirrel monkey and rat. J Comp Neurol 365:
640658.
Newport DJ, Heim C, Owens MJ, Ritchie JC, Ramsey CH,
Bonsall R, Miller AH, Nemeroff CB (2003). Cerebrospinal
fluid corticotropin-releasing factor (CRF) and vasopressin
concentrations predict pituitary response in the CRF
stimulation test: a multiple regression analysis. Neuropsychopharmacology 28: 569576.
Ng PC (2000). The fetal and neonatal hypothalamic-pituitaryadrenal axis. Arch Dis Child Fetal Neonatal Ed 82:
F250F254.
Ng SES, Lau TN, Hui FKH, Chua GE, Lee WL, Chee MWL,
Chee TSG, Boey HK (1997). MRI of the fornix and mamillary body in temporal lobe epilepsy. Neuroradiology 39:
551555.
513
2014 Refs
514
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 514
D.F. SWAAB
Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ,

Vankova J, Okun M, Rogers W, Brooks S, Mignot E (2001).
Low cerebrospinal fluid hypocretin (orexin) and altered
energy homeostasis in human narcolepsy. Ann Neurol 50:
381388.
Nishino S, Ripley B, Mignot E, Benson KL, Zarcone VP
(2002). CSF hypocretin-1 levels in schizophrenics and
controls: relationship to sleep architecture. Psychiatry Res
110: 17.
Nishio S, Inamura T, Takeshita I, Fukui M, Kamikaseda K
(1993a). Germ cell tumor in the hypothalamo-neurohypophysial region: clinical features and treatment. Neurosurg
Rev 16: 221227.
Nishio S, Takeshita I, Fujiwara S, Fukui M (1993b). Opticohypothalamic glioma: an analysis of 16 cases. Childs Nerv
Syst 9: 334338.
Nishio S, Morioka T, Hamada Y, Kuromaru R, Fukui M (2001).
Hypothalamic hamartoma associated with an arachnoid cyst.
J Clin Neurosci 8: 4648.
Nishioka H, Li K, Llena JF, Hirano A (1991). Immunohistochemical study of granular cell tumors of the neurohypophysis.
Virchows Archiv B Cell Pathol 60: 413417.
Nishioka H, Ito H, Miki T, Hashimoto T, Nojima H, Matsumura
H (1999). Rathkes cleft cyst with pituitary apoplexy: case
report. Neuroradiology 41: 832834.
Nishioka T, Anselmo-Franci JA, Li P, Callahan MF, Morris M
(1998). Stress increases oxytocin release within the hypothalamic paraventricular nucleus. Brain Res 781: 5761.
Nishizawa S, Yokoyama T, Hinokuma K, Ohta S, Uemura K,
Takahashi H (1997). Pituitary astrocytoma: magnetic resonance and hormonal characteristics. J Neurosurg 87: 131.
Nisijima K, Oyafuso K, Shimada T, Hosino H, Ishiguro T
(1996). Cerebrospinal fluid monoamine metabolism in a case
of neuroleptic malignant syndrome improved by electroconvulsive therapy. Biol Psychiatry 39: 383384.
Nisipeanu P, Korczyn AD (1993). Psychological stress as risk
factor for exacerbations in multiple sclerosis. Neurology 43:
13111312.
Nitta M, Symon L (1985). Colloid cysts of the third ventricle.
A review of 36 cases. Acta Neurochir 76: 99104.
Nobin A, Bjrklund A (1973). Topography of the monoamine
neuron systems in the human brain as revealed in fetuses.
Acta Physiol Scand (Suppl) 388: 140.
Nol P, Hubert JP, Ectors M, Franken L, Flament-Durand J
(1973). Agenesis of the corpus callosum associated with
relapsing hypothermia. Brain 96: 359368.
Nofzinger EA, Thase ME, Reynolds III CF, Frank E, Jennings
JR, Garamoni GL, Fasiczka AL, Kupfer DJ (1993). Sexual
function in depressed men. Arch Gen Psychiatry 50: 2430.
Nonogaki K (1999). Obesity: Autonomic circuits versus feeding.
Nat Med 5: 742743.
Noonan JA, Ehmke DA (1963). Associated noncardiac malformations in children with congenital heart disease. J Pediatr
63: 468.
Nopoulos P, Flaum M, Andreasen NC (1997). Sex differences

in brain morphology in schizophrenia. Am J Psychiatry 154:
16481654.
Nopoulos PC, Giedd JN, Andreasen NC, Rapoport JL (1998).
Frequency and severity of enlarged cavum septi pellucidi in
childhood-onset schizophrenia. Am J Psychiatry 155:
10741079.
Nopoulos PC, Rideout D, Crespo-Facorro B, Andreasen NC
(2001). Sex differences in the absence of massa intermedia
in patients with schizophrenia versus healthy controls.
Schizophr Res 48: 177185.
Norbiato G, Bevilacqua M, Carella F, Chebat E, Raggi U,
Bertora P, Grassi MP, Mangoni A (1988). Alterations in vasopressin regulation in Alzheimers disease. J Neurol Neurosurg
Norbiato G, Bevilacqua M, Vago T (1997). Glucocorticoids and
the immune system in AIDS. Psychoneuroendocrinology
(Suppl 1) 22: S19S25.
Nordberg A (1996). Functional studies of new drugs for the
treatment of Alzheimers disease. Acta Neurol Scand 165:
137144.
Nrgaard JP, Pedersen EB, Djurhuus JC (1985). Diurnal antidiuretic-hormone levels in enuretics. J Urol 134: 10291031.
North KN, Ouvrier RA, McLean CA, Hopkins IJ (1994).
Idiopathic hypothalamic dysfunction with dilated unresponsive pupils: report of two cases. J Child Neurol 9: 320325.
Northcutt RG, Muske LE (1994). Multiple embryonic origins
of gonadotropin-releasing hormone (GnRH) immunoreactive
neurons. Brain Res Dev Brain Res 78: 279290.
Norton AJ, Jordan S, Yeomans P (1994). Brief, high-temperature heat denaturation (pressure cooking): a simple and
effective method of antigen retrieval for routinely processed
tissues. J Pathol 173: 371379.
Novitzky D (1991). Triiodothyronine replacement, the euthyroid sick syndrome, and organ transplantation. Transplant
Proc 23: 24602462.
Nowaczyk MJM, Ramsay JA, Mohide P, Tomkins DJ (1998).
Multiple congenital anomalies in a fetus with 45,X/46,
X,r(X)(p1122q12) mosaicism. Am J Med Genet 77: 306309.
Nunn K, Ouvrier R, Sprague T, Arbuckle S, Docker M (1997).
Idiopathic hypothalamic dysfunction: a paraneoplastic
syndrome? J Child Neurol 12: 276281.
Nurnberger JI, Adkins S, Lahiri DK, Mayeda A, Hu K, Lewy
A, Miller A, Bowman ES, Miller MJ, Rau L, Smiley C,
Davis-Singh D (2000). Melatonin suppression by light in
euthymic bipolar and unipolar patients. Arch Gen Psychiatry
57: 572579.
Nussey SS, Ang VT, Bevan DH, Jenkins JS (1986). Human
platelet arginine vasopressin. Clin Endocrinol 24: 427433.
Nussey SS, Page SR, Peterson DB, Byrne J, Crosby SR, White
A, Ang VTY, Jackson R, Jenkins JS (1991). Corticotrophinreleasing hormone (CRH141). stimulates the secretion of
adrenocorticotrophin, vasopressin and oxytocin but not
2014 Refs
2/12/03
1:39 pm
Page 515
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
adrenocorticotrophin precursors: evidence from petrosal sinus

sampling in man. Clin Endocrinol 34: 5156.
Nyberg F (2000). Growth hormone in the brain: characteristics
of specific brain targets for the hormone and their functional
significance. Front Neuroendocrinol 21: 330348.
Nye EJ, Hockings GI, Grice JE, Torpy DJ, Walters MM, Crosbie
GV, Wagenaar M, Cooper M, Jackson RV (1997). Aspirin
inhibits vasopressin-induced hypothalamic-pituitaryadrenal
activity in normal humans. J Clin Endocrinol Metab 82:
812817.
Oatridge A, Holdcroft A, Saeed N, Hajnal JV, Puri BK, Fusi
L, Bydder GM (2002). Change in brain size during and after
pregnancy: study in healthy women and women with
preeclampsia. Am J Neuroradiol 23: 1926.
Obata KI, Itoh N, Okamoto H, Yanihara C, Yanaihara N, Suzuki
T (1981). Identification and processing of biosynthetic
precursors to vasoactive intestinal polypeptide in human
neuroblastoma cells. FEBS Lett 136: 123126.
Oberfield SE, Garvin JH Jr (2000). Thalamic and hypothalamic
tumors of childhood: endocrine late effects. Pediatr Neurosurg
32: 264271.
OBrien A, Clapp L, Singer M (2002). Terlipressin for norepinephrine-resistant septic shock. Lancet 359: 12091210.
OBrien D, Skelton KH, Owens MJ, Nemeroff CB (2001b). Are
CRF receptor antagonists potential antidepressants? Hum
Psychopharmacol 16: 8187.
OBrien GM, Baughman RP, Broderick JP, Arnold L, Lower
EE (1994). Paranoid psychosis due to neurosarcoidosis.
Sarcoidosis 11: 3436.
OBrien J, Thomas A, Ballard C, Brown A, Ferrier N, Jaros E,
Perry R (2001a). Cognitive impairment in depression is not
associated with neuropathologic evidence of increased
vascular or Alzheimer-type pathology. Biol Psychiatry 49:
130136.
OBrien JT, Ames D, Schweitzer I, Colman P, Desmond P,
Tress B (1996). Clinical and magnetic resonance imaging
correlates of hypothalamic-pituitary-adrenal axis function in
depression and Alzheimers disease. Br J Psychiatry 168:
679687.
Ober KP, Alexander E, Challa VR, Ferree C, Elster A (1989).
Histiocytosis X of the hypothalamus. Neurosurgery 24:
9395.
Oberfield SE, Allen JC, Pollack J, New MI, Levine LS (1986).
Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function.
J Pediatr 108: 219223.
OCallahan FJK, Clarke AA, Hancock E, Hunt A, Osborne JP
(1999). Use of melatonin to treat sleep disorders in tuberous
sclerosis. Dev Med Child Neurol 41: 123126.
OConnor DB, Archer J, Hair WM, Wu FCW (2001).
Activational effects of testosterone on cognitive function in
men. Neuropsychologia 39: 13851394.
515
ODwyer JM (1997). Schizophrenia in people with intellectual

disability: the role of pregnancy and birth complications. J
Oelkers W (1989). Hyponatremia and inappropriate secretion
of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 321: 492496.
Oepen H (1963). ber 217 Korpersektionsbefunde bei der
Huntingtonscher Krankheit. Beitr Pathol Anat Alg Path 128:
1224.
Oepen H, Landzettel HJ, Streletzki R, von Koppenfels I (1963).
Statistische Befunde zur Klinik der Huntingtonschen Chorea.
Arch Psychiatr Nervenkr 204: 1124.
Ohama E, Ikuta F (1976). Parkinsons disease: distribution of
Lewy bodies and monoamine neuron system. Acta
Ohashi K, Yamamoto Y, Natelson BH (2002). Activity rhythm
degrades after strenuous exercise in chronic fatigue syndrome.
Ohashi Y, Okamoto N, Uchida K, Iyo M, Mori N, Morita Y
(1999). Daily rhythm of serum melatonin levels and effect
of light exposure in patients with dementia of the Alzheimers
type. Biol Psychiatry 45: 16461652.
Ohmori O, Shinkai T, Kojima H, Terao T, Suzuki T, Mita T,
Abe K (1998). Association study of a functional catechol-Omethyltransferase gene polymorphism in Japanese
schizophrenics. Neurosci Lett 243: 109112.
Oka K, Yamashita M, Sadoshima S, Tanaka K (1981). Cerebral
haemorrhage in moyamoya disease at autopsy. Virch Arch A
Pathol Anat Histol 392: 247261.
Okada F (1990). Psychiatric aspects of acute pandysautonomia.
Eur Arch Psychiatry Clin Neurosci 240: 134135.
Okado N, Yokota N (1980). An electron microscopic study on
the structural development of the neural lobe in the human
fetus. Am J Anat 159: 261273.
Okado N, Yokota N (1982). Axoglial synaptoid contacts in the
neural lobe of the human fetus. Anat Rec 202: 117124.
Okada Y, Kawamoto S, Yoshida S (1998). High serum
levels of somatomedin-C and diabetes mellitus caused by
obstructive hydrocephalus: case report. Neurosurgery 42:
11721175.
Okamura H (2003). Circadian and seasonal rhythms. J
Endocrinol 177: 36
Okatani Y, Okamoto K, Hayashi K, Wakatsuki A, Tamura S,
Sagara Y (1998). Maternalfetal transfer of melatonin in pregnant women near term. J Pineal Res 25: 129134.
Okawa M, Mishima K, Hishikawa Y, Hozumi S, Hori H,
Takahashi K (1991). Circadian rhythm disorders in sleepwaking and body temperature in elderly patients with
dementia and their treatment. Sleep 14: 478485.
Oke A, Keller R, Mefford Y, Adams RN (1978). Lateralization
of norepinephrine in human hypothalamus. Science 200:
14111413.
515
2014 Refs
516
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 516
D.F. SWAAB
OKeeffe ST (1997). The neuropathogenesis of delirium. Aging

(Suppl 4) 9: 3839.
Okin CR, Guido RS, Meyn LA, Ramanathan S (2001).
Vasopressin during abdominal hysterectomy: a randomized
controlled trial. Obstet Gynecol 97: 867872.
Oksanen V (1994). Neurosarcoidosis. Sarcoidosis 11: 7679.
lafsdttir BR, Rye DB, Scammell TE, Matheson JK,
Stefnsson K, Gulcher JR (2001). Polymorphisms in
hypocretin/orexin pathway genes and narcolepsy. Neurology
57: 18961899.
Olander E, Stamberg J, Steinberg L, Wulfsberg EA (2000).
Third PraderWilli syndrome phenotype due to maternal
uniparental disomy 15 with mosaic trisomy 15. Am J Med
Genet 93: 215218.
Oldehinkel AJ, Van den Berg MD, Flentge F, Bouhuys AL,
Horst GJ ter, Ormel J (2001). Urinary free cortisol excretion
in elderly persons with minor and major depression.
Oldfield EH, Chrousos GP, Schulte HM, Schaaf M, McKeever
PE, Krudy AG, Cutler GB, Loriaux DL, Doppman JL (1985).
Preoperative lateralization of ACTH-secreting pituitary
microadenomas by bilateral and simultaneous inferior petrosal
venous sinus sampling. N Engl J Med 312: 100103.
Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller
DL, Katz DA, Cutler GB, Loriaux DL (1991). Petrosal sinus
sampling with and without corticotropin-releasing hormone
for the differential diagnosis of Cushings syndrome. N Engl
J Med 325: 897905.
Olias G, Richter D, Schmale H (1996). Heterologous expression of human vasopressin-neurophysin precursors in a
pituitary cell line: defective transport of a mutant protein from
patients with familial diabetes insipidus. DNA Cell Biol 15:
929935.
Oliveira LMB, Seminara SB, Beranova M, Hayes FJ,
Valkenburgh SB, Schipani E, Costa EMF, Latronico C,
Crowley WF, Vallejo M (2001). The importance of autosomal genes in Kallmann syndrome: genotype-phenotype
correlations and neuroendocrine characteristics. J Clin
Olivieri G, Miescher GC (1999). Immunohistochemical localization of EphA5 in the adult human central nervous system.
J Histochem Cytochem 47: 855861.
Olson BR, Drutarosky MD, Stricker EM, Verbalis JG (1991a).
Brain oxytocin receptor antagonism blunts the effects of
anorexigenic treatments in rats: evidence for central oxytocin
inhibition of food intake. Endocrinology 129: 785791.
Olson BR, Drutarosky MD, Chow MS, Hruby VJ, Stricker EM,
Verbalis JG (1991b). Oxytocin and an oxytocin agonist
administered centrally decrease food intake in rats. Peptides
12: 113118.
Olsson J-E, Forsling ML, Lindvall B, kerlund M (1987).
Cerebrospinal fluid arginine vasopressin in Parkinsons
disease, dementia, and other degenerative disorders. Adv
Neurol 45: 239242.
Olsson R (1961). Subcommissural ependyma and pineal organ

development in human fetuses. Gen Comp Endocrinol 1:
117123.
Olsson T (1999). Activity in the hypothalamic-pituitaryadrenal axis and delirium. Dement Geriatr Cogn Disord 10:
345349.
Olsson T, Nsman B, Rasmuson S, Ahrn B (1998). Dual relation between leptin and cortisol in humans is disturbed in
OMeara G, Coumis U, Ma SY, Kehr J, Mahoney S, Bacon A,
Allen SJ, Holmes F, Kahl U, Wang FH, Kearns IR, OveOgren S, Dawbarn D, Mufson EJ, Davies C, Dawson G,
Wynick D (2000). Galanin regulates the postnatal survival of
a subset of basal forebrain cholinergic neurons. Proc Natl
Acad Sci 97: 1156911574.
ONeill M, Tridjaja B, Smith MJ, Bell KM, Warne GL, Sinclair
AH (1998). Familial Kallmann syndrome: a novel splice
acceptor mutation in the KAL gene. Hum Mutat 11: 340342.
ONeill PA, Faragher EB, Davies I, Wears R, McLean KA,
Fairweather DS (1990). Reduced survival with increasing
plasma osmolality in elderly continuing-care patients. Age
Ageing 19: 6871.
Ongerboer de Visser BW, Dankmeijer HF, Bots GThAM, Endtz
LJ (1976). Hypothalamic polio-encephalitis in influenza A
preceded by mononucleosis. J Neurol Sci 29: 3338.
Oosterbaan HP, Swaab DF (1987). Circulating neurohypophyseal hormones in anencephalic infants. Am J Obstet Gynecol
157: 117119.
Oosterbaan HP, Swaab DF (1989). Amniotic oxytocin and vasopressin in relation to human fetal development and labour.
Early Hum Dev 19: 253262.
ORahilly R, Mller F (1999). Minireview: summary of the
initial development of the human nervous system. Teratology
60: 3941.
ORahilly R, Mller F (2002). The two sites of fusion of the
neural folds and the two neuropores in the human embryo.
Teratology 65: 162170.
rbeck H, Oftedal G (1977). Familial dysautonomia in a nonJewish child. Acta Pediatr Scand 66: 777781.
Ordway GA, Smith KS, Haycock JW (1994). Elevated tyrosine
hydroxylase in the locus coeruleus of suicide victims. J
Oren DA, Levendosky AA, Kasper S, Duncon CC, Rosenthal
NE (1996). Circadian profiles of cortisol, prolactin, and
thyrotropin in seasonal affective disorder. Biol Psychiatry 39:
157170.
Oren DA, Cubells JF, Litsch S (2001). Bright light therapy for
schizoaffective disorder. Am J Psychiatry 158: 20862087.
Oren DA, Desan PH, Boutros N, Anand A, Charney DS
(2002a). Effects of light on low nocturnal bilirubin in winter
depression: a preliminary report. Biol Psychiatry 51: 422425.
Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS,
Terman JS, Terman M (2002b). An open trial of morning
2014 Refs
2/12/03
1:39 pm
Page 517
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
light therapy for treatment of antepartum depression. Am J

Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H
(1992). Long-term longitudinal measurements of plasma
dehydroepiandrosterone sulfate in normal men. J Clin
Orrego JJ, Russell-Aulet M, Demott-Friberg R, Barkan AL
(2001). Semiquantification of hypothalamic GH-releasing
hormone output in women: evidence for sexual dimorphism
in the mechanism of the somatopause. J Clin Endocrinol
Metab 86: 54855490.
Orthner H, Schiebler TH (1951). Pathologische Anatomie der
neuro-endokrinen Erkrankungen. I. Hypophysrer Infantilismus. Arch Psychiatr Zeitschr Neurol 186: 5987.
Orthner H (1982). Die theoretischen und tierexperimentellen
Grundlagen der vorderen Hypothalamotomie zur Behandlung
schwerer Sexualstrungen und die Zielsicherheit der
Methode. Fortschr Neurol Psychiatr 50: 316329.
Osamura RY, Watanabe K (1978). An immunohistochemical
study of epithelial cells in the posterior lobe and part tuberalis
of the human adult pituitary gland. Cell Tissue Res 194:
513524.
Osamura RY, Komatsu N, Watanabe K, Nakai Y, Tanaka I,
Imura H (1982). Immunohistochemical and immunocytochemical localization of -melanocyte stimulating hormone
(-MSH)-like immunoreactivity in human and rat hypothalamus. Peptides 3: 781787.
sterlund MK, Hurd YL (2001). Estrogen receptors in the
human forebrain and the relation to neuropsychiatric
disorders. Prog Neurobiol 64: 251267.
Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E, Grski
J (2001). Assessment of the relationship between circadian
variations of salivary melatonin levels and type I collagen
metabolism in postmenopausal obese women. Neuroendocrinol Lett 22: 121127.
Ostrowski AZ, Webster JE, Gurdjian ES (1960). The proximal
anterior cerebral artery: an anatomic study. Arch Neurol 3:
661664.
Othman SS, Kadir KA, Hassan J, Hong GK, Singh BB,
Raman N (1994). High prevalence of thyroid function test
abnormalities in chronic schizophrenia. Aust NZ J Psychiatry
28: 620624.
Otsuka F, Kageyama J, Ogura T, Hattori T, Makino H (1998).
Sheehans syndrome of more than 30 years duration: an
endocrine and MRI study of 6 cases. Endocr J 45: 451458.
Otsuka F, Morita K, Takeuchi M, Yamauchi T, Ogura T, Sekines
K, Miura M, Hirakawa M, Makino H (1999). The effects of
intrinsic vasopressin on urinary aquaporin-2 excretion and
urine osmolality during surgery under general anesthesia.
Anesth Analg 88: 181187.
Ouma JR, Farrell VJR (2002). Lymphocytic infundibulo-neurohypophysitis with hypothalamic and optic pathway
involvement: report of a case and review of the literature.
Surg Neurol 57: 4954.
517
Ouslander JG, Nasr SZ, Miller M, Withington W, Lee CS,

Wiltshire-Clement M, Cruise P, Schnelle JF (1998). Arginine
vasopressin levels in nursing home residents with nighttime
urinary incontinence. J Am Geriatr Soc 46: 12741279.
Ouvrier R, Nunn K, Sprague T, McLean C, Arbuckle S, Hopkins
I, North K (1995). Idiopathic hypothalamic dysfunction: a
paraneoplastic syndrome? Lancet 346: 1298.
Overand PT, Teply JF (1998). Vasopressin for the treatment of
refractory hypotension after cardiopulmonary bypass. Anesth
Analg 86: 12071209.
Overeem S, Mignot E, Van Dijk G, Lammers GJ (2001).
Narcolepsy: clinical features, new pathophysiologic insights,
and future perspectives. J Clin Neurophysiol 18: 78105.
Overeem S, Van Vliet JA, Lammers GJ, Zitman FG, Swaab
DF, Ferrari MD (2002). The hypothalamus in episodic brain
disorders. Lancet Neurol 1: 437444.
Overeem S, Kok SW, Lammers GJ, Vein AA, Frlich M,
Meinders AE, Roelfsema F, Pijl H (2003). Somatotropic axis
in hypocretin-deficient narcoleptic humans: altered circadian
distribution of GH-secretory events. Am J Physiol Endocrinol
Metab 284: E641E647.
Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, Holte A
(1999). The endocrine transition around menopause a fiveyears prospective study with profiles of gonadotropines,
estrogens, androgens and SHBG among healthy women. Acta
Obstet Gynecol Scand 78: 642647.
Oweity T, Scheithauer BW, Ching HS, Lei CMC, Wong KP
(2002). Multiple system ErdheimChester disease with
massive hypothalamic-sellar involvement and hypopituitarism. J Neurosurg 96: 344351.
Owen BM, Eccleston D, Ferrier IN, Young AH (2001). Raised
levels of plasma interleukin-1 in major and postviral
depression. Acta Psychiatr Scand 103: 226228.
Owen MJ (1998). Psychiatric disorders in Wolfram syndrome
heterozygotes. Mol Psychiatry 3: 1213.
Oxenkrug GF, Anderson GF, Dragovic L, Blaivas M, Riederer
P (1990). Circadian rhythms of human pineal melatonin,
related indoles, and beta adrenoreceptors: post-mortem
evaluation. J Pineal Res 9: 111.
Ozawa T, Tanaka H, Miyatake T, Tsuji S (1993). ShyDrager
syndrome with abnormal circadian rhythm of plasma antidiuretic hormone secretion and urinary excretion. Intern Med
32: 225227.
Ozawa T, Oyanagi K, Tanaka H, Horikawa Y, Takahashi H,
Morita T, Tsuji S (1998). Suprachiasmatic nucleus in a patient
with multiple system atrophy with abnormal circadian rhythm
of arginine-vasopressin secretion into plasma. J Neurol Sci
154: 116121.
Ozawa T, Tanaka H, Nakano R, Sato M, Inuzuka T, Soma Y,
Yoshimura N, Fukuhara N, Tsuji S (1999). Nocturnal
decrease in vasopressin secretion into plasma in patients with
multiple system atrophy. J Neurol Neurosurg Psychiatry 67:
542545.
517
2014 Refs
518
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 518
D.F. SWAAB
Ozawa T, Soma Y, Yoshimura N, Fukuhara N, Tanaka M, Tsuji

S (2001). Reduced morning cortisol secretion in patients with
multiple system atrophy. Clin Auton Res 11:271272.
Ozisik G, Achermann JC, Jameson JL (2002). The role of
SF1 in adrenal and reproductive function: insight from
naturally occurring mutations in humans. Mol Genet Metab
76: 8591.
Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET,
Von Wendt L (2003). Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder.
J Child Adolesc Psychopharmacol 13: 8395.
Pacchierotti C, Iapichino S, Bossini L, Pieraccini F,
Castrogiovanni P (2001). Melatonin in psychiatric disorders:
a review on the melatonin involvement in psychiatry. Front
Pache TD, Chadha S, Gooren LJG, Hop WCJ, Jaarsma KW,
Dommerholt HBR, Fauser BCJM (1991). Ovarian morphology
in long-term androgen-treated female to male transsexuals. A
human model for the study of polycystic ovarian syndrome?
Histopathology 19: 445452.
Packer RJ (2000). Chemotherapy: low-grade gliomas of
the hypothalamus and thalamus. Pediatr Neurosurg 32:
259263.
Padayachi T, Norman RJ, Dhavaraj K, Kemp M, Joubert SM
(1988). Serial oxytocin levels in amniotic fluid and maternal
plasma during normal and induced labour. Br J Obstet
Gynaecol 95: 888893.
Padfield PL, Brown JJ, Lever AF, Morton JJ, Robertson JIS
(1976). Changes of vasopressin in hypertension: cause or
effect? Lancet 1 (7972): 12551257.
Pagani M, Lucini D (1999). Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system. Clin Sci 96:
117125.
Page NM, Woods RJ, Gardiner SM, Lomthaisong K, Gladwell
RT, Butlin DJ, Manyonda IT, Lowry PJ (2000). Excessive
placental secretion of neurokinin B during the third trimester
causes pre-eclampsia. Nature 405: 797800.
Page RB, Galicich JH, Grunt JA (1973). Alteration of circadian temperature rhythm with third ventricular obstruction. J
Pagesy P, Croissandeau G, Le Dafniet M, Peillon F, Li JY
(1992). Detection of thyrotropin-releasing hormone (TRH)
mRNA by the reverse transcription-polymerase chain reaction
in the human normal and tumoral anterior pituitary. Biochem
Biophys Res Commun 182: 182187.
Paja M, Estrada J, Ojeda A, Ramn y Cajal S, Garcia-Uria J,
Lucas T (1994). Lymphocytic hypophysitis causing hypopituitarism and diabetes insipidus, and associated with
autoimmune thyroiditis, in a non-pregnant woman. Postgrad
Med J 70: 220224.
Paja M, Lucas T, Garcia-Uria J, Salam F, Barcel B, Estrada
J (1995). Hypothalamic-pituitary dysfunction in patients with
craniopharyngioma. Clin Endocrinol 42: 467473.
Pajer K, Gardner W, Rubin RT, Perel J, Neal S (2001).

Decreased cortisol levels in adolescent girls with conduct
disorder. Arch Gen Psychiatry 58: 297302.
Pakzaban P, Westmark K, Westmark R (2000). Chiasmal
apoplexy due to hemorrhage from a pituitary adenoma into
the optic chiasm: case report. Neurosurgery 46: 15111514.
Palacios JM, Probst A, Mengod G (1992). Receptor localization
in the human hypothalamus. Prog Brain Res 93: 5768.
Palchikov VE, Zolotarev DY, Danilenko KV, Putilov AA
(1997). Effects of the seasons and of bright light administered
at different times of day on sleep EEG and mood in patients
with seasonal affective disorder. Biol Rhythm Res 28:
166184.
Palinkas LA, Reed HL, Reedy KR, Van Do N, Case HS, Finney
NS (2001). Circannual pattern of hypothalamic-pituitarythyroid (HPT) function and mood during extended antarctic
residence. Psychoneuroendocrinology 26: 421431.
Palkovits M, Fischer J (1968). Karyometric investigations.
Akadmiai Kiad, Budapest, pp. 152153.
Pallas JE, Roger J, Soulayrol TM, Salamon G, Dravet C et al
(1969). Hamartome de lhypothalamus: tude clinique,
radiologique, histologique. Rsultats de lexrse. Rev Neurol
120: 177194.
Palm IF, Van der Beek EM, Wiegant VM, Buijs RM, Kalsbeek
A (2001). The stimulatory effect of vasopressin on the
luteinizing hormone surge in ovariectomized, estradiol-treated
rats is time-dependent. Brain Res 901: 109116.
Palm L, Blennow G, Wetterberg L (1991). Correction of non24-hour sleep/wake cycle by melatonin in a blind retarded
boy. Ann Neurol 29: 336339.
Palm L, Blennow G, Wetterberg L (1997). Long-term melatonin
treatment in blind children and young adults with circadian
sleep-wake disturbances. Dev Med Child Neurol 39: 319325.
Palmini A, Chandler C, Andermann F, Costa da Costa J,
Paglioli-Neto E, Polkey C, Rosenblatt B, Montes J, Martnez
JV, Farmer JP et al. (2002). Resection of the lesion in patients
with hypothalamic hamartomas and catastrophic epilepsy.
Neurology 58: 13381347
Pammer C, Fodor M, Palkovits M (1988). Localization of
corticotropin-releasing factor, somatostatin, and vasoactive
intestinal polypeptide in the parabrachial nuclei of the human
brain. J Neurosci Res 20: 109114.
Panayotacopoulou MT, Swaab DF (1993). Development of
tyrosine hydroxylase-immunoreactive neurons in the human
paraventricular and supraoptic nuclei. Brain Res Dev Brain
Res 72: 145150.
Panayotacopoulou MT, Guntern R, Bouras C, Issidorides MR,
Constantinidis J (1991). Tyrosine hydroxylase-immunoreactive neurons in paraventricular and supraoptic nuclei of
the human brain demonstrated by a method adapted to
prolonged formalin fixation. J Neurosci Methods 39: 3944.
Panayotacopoulou MT, Raadsheer FC, Swaab DF (1994).
Colocalization of tyrosine hydroxylase with oxytocin or
2014 Refs
2/12/03
1:39 pm
Page 519
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
519
cytoskeletal antigen immunoreactivity. Acta Neuropathol 80:

535540.
Paredes RG, Baum MJ (1995). Altered sexual partner preference
in male ferrets given excitotoxic lesions of the preoptic
area/anterior hypothalamus. J Neurosci 15: 66196630.
Paredes RG, Tzschentke T, Nakach N (1998). Lesions of the
medial preoptic area/anterior hypothalamus (MPOA/AH)
modify partner preference in male rats. Brain Res 813: 18.
Parent A, Boucher R, OReilly-Fromentin J (1981).
Acetylcholinesterase-containing neurons in pallidal complex,
morphologic characteristics and projection towards the
neocortex. Brain Res 230: 356361.
Parent A, Hazrati L-N (1995). Functional anatomy of the basal
ganglia. II. The place of subthalamic nucleus and external
pallidum in basal ganglia circuitry. Brain Res Brain Res Rev
20: 128154.
Parhar I, Pfaff D, Schwanzel-Fukuda M (1995). Genes and
behavior as studied through gonadotropin-releasing hormone
(GnRH) neurons: comparative and functional aspects. Cell
Mol Neurobiol 15: 107116.
Parisi V, Restuccia R, Fattapposta F, Mina C, Bucci MG, Pierelli
F (2001). Morphological and functional retinal impairment
in Alzheimers disease patients. Clin Neurophysiol 112:
18601867.
Parker A, Gaffan D (1997). Mamillary body lesions in monkeys
impair object-in-place memory: functional unity of the fornixmamillary system. J Cogn Neurosci 9: 512521.
Parker AJR, Wessely S, Cleare AJ (2001). The neuroendocrinology of chronic fatigue syndrome and fibromyalgia.
Parker CR Jr, Porter JC (1982). Postmortem stability and
characterization of immunoreactive luteinizing hormone
releasing hormone and thyrotropin releasing hormone in
human brain tissue. Brain Res Bull 8: 623630.
Parker CR Jr, Porter JC (1984). Luteinizing hormone-releasing
hormone and thyrotropin-releasing hormone in the hypothalamus of women: effects of age and reproductive status. J
Parker G, Walter S (1982). Seasonal variation in depressive
disorders and suicidal deaths in New South Wales. Br J
Psychiatr 140: 626632.
Parkes JD (1999). Genetic factors in human sleep disorders with
special reference to Norrie disease, PraderWilli syndrome
and Moebius syndrome. J Sleep Res (Suppl 1) 8: 1422.
Parlee MB (1973). The premenstrual syndrome. Psychol Bull
80: 454465.
Parrent AG (1999). Stereotactic radiofrequency ablation for the
treatment of gelastic seizures associated with hypothalamic
hamartoma. J Neurosurg 91: 881884.
Parry BL, Newton RP (2001). Chronobiological basis of femalespecific mood disorders. Neuropsychopharmacology (Suppl
5) 25: S102S108.
Parry BL, Mostofi N, LeVeau B, Cover Nahum H, Golshan S,
Laughlin GA, Gillin JC (1999). Sleep EEG studies during
vasopressin in neurons of the human paraventricular and

supraoptic nucleus. Brain Res Dev Brain Res 83: 5966.
Panayotacopoulou MT, Malidelis Y, Fliers E, Bouras C,
Ravid R, Swaab DF (2002). Increased expression of tyrosine
hydroxylase immunoreactivity in neurons of the paraventricular and supraoptic nucleus in illnesses with prolonged
osmotic or non-osmotic stimulation of vasopressin release.
Panidis D, Rousso D, Skiadopoulous S, Vavilis D,
Kalogeropoulos A (1994). Hypothalamic-pituitary deficiency
after Weils syndrome: a case report. Fertil Steril 62:
10771079.
Panula P, Airaksinen MS, Pirvola U, Kotilainen E (1990).
Histamine containing neuronal system in human brain.
Panula P, Aarnisalo AA, Wasowicz K (1996). Neuropeptide FF,
a mammalian neuropeptide with multiple functions. Prog
Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T,
Kalimo H, Relja M (1998). Neuronal histamine deficit in
Alzheimers disease. Neuroscience 82: 993997.
Panula P, Kalso E, Nieminen M-L, Kontinen VK, Brandt A,
Pertovaara A (1999). Neuropeptide FF and modulation of
pain. Brain Res 848: 191196.
Papageorgiou C, Papageorgaki P, Tolis G, Rabavilas AD,
Christodoulou GN (2003). Psychophysiological correlates in
male to female transsexuals studied with a P300 investigation.
Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ (2000).
Choline acetyltransferase activity and cognitive domain scores
of Alzheimets patients. Neurobiol Aging 21: 1117.
Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski
M, Frangione B, Ghiso J (1998). Inhibition of Alzheimer
-fibrillogenesis by melatonin. J Biol Chem 273: 71857188.
Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G,
Ghiso J, Reiter RJ (2000). An assessment of the antioxidant
and the antiamyloidogenic properties of melatonin: implications for Alzheimers disease. J Neural Transm 107: 203231.
Paradisi R, Frank G, Magrini O, Capelli M, Venturoli S, Porcu
E, Flamigni C (1993). Adenopituitary hormones in human
hypothalamic hypophysial blood. J Clin Endocrinol Metab
77: 523527.
Pramo C, De la Fuente J, Nodar A, Miramontes S, Quintela
JL, Garca-Mayor RV (2002). Intrasellar tuberculoma a
difficult diagnosis. Infection 30: 3537.
Paranjape SB, Thibonnier M (2001). Development and therapeutic indications of orally-active non-peptide vasopressin
receptor antagonists. Expert Opin Investig Drugs 10: 825834.
Parboosingh J, Lederis K, Singh N (1982). Vasopressin
concentration in cord blood: correlation with method of
delivery and cord pH. Obstet Gynecol 60: 179183.
Pardo CA, Martin LJ, Troncoso JC, Price DL (1990). The human
pineal gland in aging and Alzheimers disease: patterns of
519
2014 Refs
520
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 520
D.F. SWAAB
early and late partial sleep deprivation in premenstrual

dysphoric disorder and normal control subjects. Psychiatry
Res 85: 127143.
Parry BL, Javeed S, Laughlin GA, Hauger R, Clopton P (2000).
Cortisol circadian rhythms during the menstrual cycle and
sleep deprivation in premenstrual dysphoric disorder and
normal control subjects. Biol Psychiatry 48: 920931.
Parry-Jones LW, Parry-Jones B (1994). Implications of historical evidence for the classification of eating disorders. Br J
Partonen T, Lnnqvist J (1996). Seasonal variation in bipolar
disorder. Br J Psychiatry 169: 641646.
Partonen T, Lnnqvist J (2000). Bright light improves vitality
and alleviates distress in healthy people. J Affect Disord 57:
5561.
Partsch C-J, Sippell WG (2001). Pathogenesis and epidemiology
of precocious puberty. Effects of exogenous oestrogens. Hum
Reprod Update 7: 292302.
Parvizi J, Van Hoesen GW, Damasio A (1998). Severe pathological changes of parabrachial nucleus in Alzheimers
disease. Neuroreport 9: 41514154.
Pasel K, Schulz A, Timmermann K, Linnemann K, Hoeltzenbein
M, Jskelinen J, Grters A, Filler G, Schneberg T (2000).
Functional characterization of the molecular defects causing
nephrogenic diabetes insipidus in eight families. J Clin
Pasqualetti P, Festuccia V, Collacciani A, Acitelli P, Casale R
(1998). Circadian rhythm of arginine vasopressin in hepatorenal syndrome. Nephron 78: 3337.
Pasquali R, Vicennati V (2000a). Activity of the hypothalamicpituitary-adrenal axis in different obesity phenotypes. Int J
Obesity (Suppl 2) 24: S47S49.
Pasquali R, Vicennati V (2000b). The abdominal obesity phenotype and insulin resistance are associated with abnormalities
of the hypothalamic-pituitary-adrenal axis in humans. Horm
Metab Res 32: 521525.
Pasquali R, Anconetani B, Chattat R, Biscotti M, Spinucci G,
Casimirri F, Vicennati V, Carcello A, Morselli Labate AM
(1996). Hypothalamic-pituitary-adrenal axis activity and its
relationship to the autonomic nervous system in women with
visceral and subcutaneous obesity: effects of the corticotropinreleasing factor/arginine-vasopressin test and of stress.
Metabolism 45: 351356.
Pasqualini RQ, Vidal G, Bur GE (1957). Psychopathology of
Klinefelters syndrome. Lancet 2: 164167.
Pasqualini T, Diez B, Domene H, Escobar ME, Gruneiro L,
Heinrich JJ, Martinez A, Iorcansky S, Sackmann-Muriel F,
Rivarola M (1987). Long-term endocrine sequelae after
surgery, radiotherapy, and chemotherapy in children with
medullablastoma. Cancer 59: 801806.
Patel BM, Chittock DR, Russell JA, Walley KR (2002).
Beneficial effects of short-term vasopressin infusion during
severe septic shock. Anesthesiology 96: 576582.
Patel H, Tze WJ, Crichton JU, McCormick AQ, Robinson GC,

Dolman CL (1975). Optic nerve hypoplasia with hypopituitarism. Am J Dis Child 129: 175180.
Patient C, Davison JM, Charlton L, Baylis PH, Thornton S
(1999). The effect of labour and maternal oxytocin infusion
on fetal plasma oxytocin concentration. Br J Obstet Gynaecol
106: 13111313.
Patterson MC (2002). Holoprosencephaly. The face predicts
the brain; the image predicts its function. Neurology 59:
18331834.
Patwardhan AJ, Eliez S, Bender B, Linden MG, Reiss AL (2000).
Brain morphology in Klinefelter syndrome. Neurology 54:
22182223.
Pau A, Dorcaratto A, Pisani R (1996). Third ventricular meningiomas of infancy. A case report. Pathologica 88: 204206.
Paulin C, Dubois PM, Barry J, Dubois PM (1977).
Immunofluorescence study of LH-RH producing cells in the
human fetal hypothalamus. Cell Tissue Res 182: 341345.
Paulin C, Dubois PM, Czernichow P, Dubois MP (1978).
Immunocytological evidence for oxytocin neurons in the
human fetal hypothalamus. Cell Tissue Res 188: 259264.
Pauls AM, Lauer CJ, Wiegand M, Pirke K-M, Krieg JC (1991).
Hydrocephalus internus in a male patient with anorexic and
bulimic eating behavior. Int J Eat Disord 10: 227232.
Paulus W, Honegger J, Keyvani K, Fahlbusch R (1999).
Xanthogranuloma of the sellar region: a clinicopathological
entity different from adamantinomatous craniopharyngioma.
Acta Neuropathol 97: 377382.
Pv I, Morschl E, Szepes Z, Kiss J, Boda K, Vetro G, Varga
C, Lszlo F (2000). Vasopressin deficiency decreases the
frequency of gastroduodenal ulceration in humans. J Physiol
(Paris) 94: 6366.
Pawlikowski M, Lesnik H (1971). Plasma antidiuretic activity
in patients with hypothalamopituitary syndromes. Endokrynol
Pol 22:133137.
Pea L, Roda L, Boussaud V, Lonjon B (2003). Desmopressin
therapy for massive hemoptysis associated with severe
leptospirosis. Am J Respir Crit Care Med 167: 726728.
Peacey SR, Toogood AA, Shalet SM (1998). Hypothalamic
dysfunction in cured acromegaly is treatment modality
dependent. J Clin Endocrinol Metab 83: 16821686.
Pearson RCA, Sofroniew MV, Cuello AC, Powell TPS,
Eckenstein F, Esiri MM, Wilcock GK (1983). Persistence of
cholinergic neurons in the basal nucleus in a brain with senile
dementia of the Alzheimer type demonstrated immunohistochemical staining for choline acetyltransferase. Brain Res
289: 375379.
Peckham RS, Marshall MC, Rosman PM, Faraq A, Kabadi U,
Wallace EZ (1982). A variant of adrenomyeloneuropathy with
hypothalamic-pituitary dysfunction and neurologic remission
after glucocorticoid replacement therapy. Am J Med 72:
173176.
Pedersen EB, Johannesen P, Rasmussen AB, Danielsen H
(1985). The osmoregulatory system and the renin-angiotensin-
2014 Refs
2/12/03
1:39 pm
Page 521
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
521
Peres MFP, Rozen TD (2001). Melatonin in the preventive

treatment of chronic cluster headache. Cephalalgia 21:
993995.
Peres MFP, Seabra MLV, Zukerman E, Tufik S (2000). Cluster
headache and melatonin. Lancet 355: 147.
Peres MFP, Sanchez del Rio Seabra MLV, Tufik S, Abucham
J, Cipolla-Neto J, Silberstein SD, Zukerman E (2001).
Hypothalamic involvement in chronic migraine. J Neurol
Peretti-Viton P, Brunel H, Chinot O, Daniel C, Barri M,
Bouvier C, Figarella-Branger D, Fuentes S, Dufour H, Grisoli
F (2002). Histological and MR correlations in gliomatosis
cerebri. J Neurooncol 59: 249259.
Perilongo G, Carollo C, Salviati L, Murgia A, Pillon M, Basso
G, Gardiman M, Laverda A (1997). Diencephalic syndrome
and disseminated juvenile pilocytic astrocytomas of the
hypothalamicoptic chiasm region. Cancer 80: 142146.
Perkins A, Fitzgerald JA, Moss GE (1995). A comparison of
LH secretion and brain estradiol receptors in heterosexual
and homosexual rams and female sheep. Horm Behav 29:
3141.
Perkins RB, Hall JE, Martin KA (2001). Aetiology, previous
menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhea.
Hum Reprod 16: 21982205.
Perl DP, Good PF, Bussire T, Morrison JH, Erwin JM, Hof
PR (2000). Practical approaches to stereology in the setting
of aging- and disease-related brain banks. J Chem Neuroanat
20: 719.
Perlroth MG, Tschudy DP, Marver HS, Berard CW, Zeigel RF,
Rechcigl M, Collins A (1966). Acute intermittent porphyria.
Am J Med 41: 149162.
Perras B, Mlle M, Born J, Fehm HL (1996). Sleep and signs
of attention during 3 months of intranasal vasopressin: a pilot
study in two elderly subjects. Peptides 17: 12531255.
Perras B, Pannenborg H, Marshall L, Pietrowsky R, Born J,
Fehm HL (1999a). Beneficial treatment of age-related sleep
disturbances with prolonged intranasal vasopressin. J Clin
Perras B, Marshall L, Khler G, Born J, Fehm HL (1999b).
Sleep and endocrine changes after intranasal administration
of growth hormone-releasing hormone in young and aged
humans. Psychoneuroendocrinology 24: 743757.
Perras B, Petersen D, Lorch H, Fehm HL (2002).
Psychoneuroendocrine disturbances in a patient with a rare
granulomatous disease. Exp Clin Endocrinol Diabetes 110:
248252.
Perras B, Wagner U, Born J, Fehm HL (2003). Improvement
of sleep and pituitary-adrenal inhibition after subchronic
intranasal vasopressin treatment in elderly humans. J Clin
Perry EK (1986). The cholinergic hypothesis 10 years on. Br
Med Bull 42: 6369.
aldosterone system in preeclampsia and normotensive pregnancy. Scand J Clin Lab Invest 45: 627633.
Pedersen RS, Bentzen H, Bech JN, Pedersen EB (2001). Effect
of water deprivation and hypertonic saline infusion on urinary
AQP2 excretion in healthy humans. Am J Physiol 280:
F860F867.
Pedulla M, Silvestri R, Lasco A, Mento G, Lanuzza B, Sofia
L, Frisina N (1995). Sleep structure in essential hypertensive
patients: differences between dippers and non-dippers. Blood
Press 4: 232237.
Pel M, Heres MHB (1995). OBINT: a study of obstetric
intervention. Thesis, University of Amsterdam
Pelc S (1972). The diencephalic syndrome in infants: a review
in relation to optic nerve glioma. Eur Neurol 7: 321334.
Peled N, Shorer Z, Peled E, Pillar G (2001). Melatonin effect
on seizures in children with severe neurologic deficit
disorders. Epilepsia 42: 12081210.
Pelletier G, Dsy L (1979). Localization of ACTH in the human
hypothalamus. Cell Tissue Res 196: 525530.
Pelletier G, Dsy L, Lissitzky J-C, Labrie F, Li CH (1978).
Immunohistochemical localization of -LPH in the human
hypothalamus. Life Sci 22: 17991804.
Pelletier G, Dsy L, Ct J, Vaudry H (1983). Immunocytochemical localization of corticotropin-releasing factor-like
immunoreactivity in the human hypothalamus. Neurosci Lett
41: 259263.
Pelletier G, Desy L, Kerkerian L, Cte J (1984). Immunocytochemical localization of neuropeptide Y (NPY) in the human
hypothalamus. Cell Tissue Res 238: 203205.
Pelletier G, Dsy L, Cte J, Lefvre G, Vaudry H (1986). Lightmicroscopic immunocytochemical localization of growth
hormone-releasing factor in the human hypothalamus. Cell
Tissue Res 245: 461463.
Pelletier G, Guy J, Dsy L, Li S, Eberle AN, Vaudry H
(1987). Melanin-concentrating hormone (MCH) is colocalized with -melanocyte-stimulating hormone (-MSH) in the
rat but not in the human hypothalamus. Brain Res 423:
247253.
Pender MP (1987). Demyelination and neurological signs in
experimental allergic encephalomyelitis. J Neuroimmunol 15:
1124.
Penev P, Zee PC (1997). Melatonin: a clinical perspective. Ann
Neurol 42: 545553.
Penfield W (1929). Diencephalic autonomic epilepsy. Arch
Neurol Psychiatry 22: 358374.
Penman Splitt M, Wright C, Perry R, Burn J (1994). Autosomal
dominant transmission of PallisterHall syndrome. Clin
Dysmorphol 3: 301308.
Pepping J (1999). Melatonin. Am J Health Syst Pharm 56:
25202523.
Perachio AA, Marr LD, Alexander M (1979). Sexual behavior
in male rhesus monkeys elicited by electrical stimulation of
preoptic and hypothalamic areas. Brain Res 177: 127144.
521
2014 Refs
522
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 522
D.F. SWAAB
Perry EK, Kerwin J, Perry RH, Irving D, Fairbairn A (1990).

Cerebral cholinergic activity is related to the incidence of
visual hallucinations in senile dementia of Lewy body type.
Dementia 1: 24.
Perry EK, Lee MLW, Martin-Ruiz CM, Court JA, Volsen SG,
Merrit J, Folly E, Iversen PE, Bauman ML, Perry RH, Wenk
GL (2001). Cholinergic activity in autism: abnormalities in
the cerebral cortex and basal forebrain. Am J Psychiatry 158:
10581066.
Perry RH, Candy JM, Perry EK, Irving D, Blessed G, Fairbarn
AF, Tomlinson BE (1982). Extensive loss of choline acetyltransferase activity is not related by neuronal loss in the
nucleus of Meynert in Alzheimers disease. Neurosci Lett 33:
311315.
Perry-Keene DA, Connelly JF, Young RA, Wettenhall HNB,
Martin FIR (1976). Hypothalamic hypopituitarism following
external radiotherapy for tumours distant from the adenohypophysis. Clin Endocrinol 5: 373380.
Persani L, Ferretti E, Borgato S, Faglia G, Beck-Peccoz P
(2000). Circulating thyrotropin bioactivity in sporadic central
hypothyroidism. J Clin Endocrinol Metab 85: 36313635.
Persson JW, Humphrey K, Watson C, Taylor P, Leigh D,
McDonald B, Fraser IS (1999). Investigation of a unique male
and female sibship with Kallmanns syndrome and 46,XX
gonadal dysgenesis with short stature. Hum Reprod 14:
12071212.
Prusse L, Chagnon YC, Weisnagel SJ, Rankinen T, Snyder E,
Sands J, Bouchard C (2001). The human obesity map: the
2000 update. Obes Res 9: 135169.
Peskind ER, Pascualy M, Edland SD, Wingerson D, Dobie DJ,
Raskind MA (1995). Plasma arginine vasopressin response
to hypertonic saline infusion in Alzheimers disease.
Alzheimer Dis Assoc Dis 9: 238242.
Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD,
Raskind MA (2001). Increased CSF cortisol in AD is a
function of APOE genotype. Neurology 56: 10941098.
Pessin MS (1972). Transient diabetes insipidus in the
LandryGuillainBarr syndrome. Arch Neurol 27: 8586.
Peters-Bonn G (1958). Allgemeine differentialdiagnostische
Erwgungen ber die Entmarkungsencephalomyelitiden. In:
Lubarsch O, Henke F, Rssle R (Eds.) Handbuch der
speziellen pathologischen Anatomie und Histologie. W
Scholz, Mnchen, pp. 519602.
Peterson HR, Rothschild M, Weinberg CR, Fell RD, McLeish
KR, Pfeifer MA (1988). Body fat and the activity of the autonomic nervous system. N Engl J Med 318: 10771083.
Petraglia F, Florio P, Benedetto C, Gallo C, Woods RJ,
Genazzani AR, Lowry PJ (1996). High levels of corticotrophin-releasing factor (CRF) are inversely correlated with
low levels of maternal CRF-binding protein in pregnant
women with pregnancy-induced hypertension. J Clin
Petridou E, Papadopoulos FC, Frangakis CE, Skalkidou A,

Trichopoulos D (2002). A role of sunshine in the triggering
of suicide. Epidemiology 13: 106109.
Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S,
Kaplan DB, Tretta MG, Allen M (1991). Alterations in
brain high-energy phosphate and membrane phospholipid
metabolism in first-episode, drug-naive schizophrenics. Arch
Petterborg LJ, Thaln BE, Kjellman BF, Wetterberg L (1991).
Effect of melatonin replacement on serum hormone rhythms
in a patient lacking endogenous melatonin. Brain Res Bull
27: 181185.
Pevsner J (2002). Leonarda da Vincis contributions to neuroscience. Trends Neurosci 25: 217220.
Peyr R, Fernndez JR, Hermida RC (1999). Prominent
circaseptan pattern of invasive radial and pulmonary blood
pressures in critical care patients. Chronobiol Int (Suppl 1)
16: 84.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay
Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R et al.
(2000). A mutation in a case of early onset narcolepsy and
a generalized absence of hypocretin peptides in human
narcoleptic brains. Nat Med 6: 991997
Pfaus JG, Kleopoulos SP, Mobbs CV, Gibbs RB, Pfaff DW
(1993). Sexual stimulation activates c-fos within estrogenconcentrating regions of the female rat forebrain. Brain Res
624: 253267.
Pfeffer CR, Stokes P, Weiner A, Shindledecker R, Faughan L,
Mintz M, Stoll PM, Heiligenstein DP (1989). Psychopathology
and plasma cortisol responses to dexamethasone in prepubertal psychiatric inpatients. Biol Psychiatry 26: 677689.
Philbin DM, Coggins CH (1978). Plasma antidiuretic hormone
levels in cardiac surgical patients during morphine and
halothane anesthesia. Anesthesiology 49: 9598.
Phillips DIW (2001). Fetal growth and programming of the
hypothalamic-pituitary-adrenal axis. Clin Exp Pharmacol
Physiol 28: 967970.
Phillips PA, Rolls BJ, Ledingham JGG, Forsling ML, Morton
JJ, Crowe MJ, Wollner L (1984). Reduced thirst after water
deprivation in healthy elderly men. N Engl J Med 311:
753759.
Phillipson OT, Bird ED (1977). Plasma glucose, non-esterified
fatty acids and amino acid in Huntingtons chorea. Clin Sci
Mol Med 52: 311318.
Piao Y-S, Wakabayashi K, Hayashi S, Yoshimoto M, Takahashi
H (2000). Aggregation of -synuclein/NACP in the neuronal
and glial cells in diffuse Lewy body disease: a survey of six
patients. Clin Neuropathol 19: 163169.
Piccinelli M, Wilkinson G (2000). Gender differences in depression. Br J Psychiatry 177: 486492.
Pierangeli G, Provini F, Maltoni P, Barletta G, Contin M,
Lugaresi E, Montagna P, Cortelli P (2001). Nocturnal body
2014 Refs
2/12/03
1:39 pm
Page 523
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
523
Alzheimers disease. Dement Geriatr Cogn Disord 14:

123127.
Piven J (1997). The biological basis of autism. Curr Op
Pivonello R, Faggiano A, Arrichiello P, Di Sarno A, Di Somma
C, Ferone D, Lombardi G, Colao A (2001). Central diabetes
insipidus and heart: effect of acute arginine vasopressin
deficiency and replacement treatment with desmopressin on
cardiac performance. Clin Endocrinol 54: 97106.
Pivonello R, Faggiano A, Filippella M, Di Somma C, De
Martino MC, Gaccione M, Lombardi G, Colao A (2002).
Hypothalamus-pituitary-adrenal axis in central diabetes
insipidus: ACTH and cortisol responsiveness to CRH
administration. J Endocrinol Invest 25: 932937.
Pivonello R, De Bellis A, Faggiano A, Di Salle F, Petretta M,
Di Somma C, Perrino S, Altucci P, Bizzarro A, Bellastella
A, Lombardi G, Colao A (2003). Central diabetes insipidus
and autoimmunity: relationship between the occurrence of
antibodies to arginine vasopressin-secreting cells and clinical,
immunological, and radiological features in a large cohort of
patients with central diabetes insipidus of known and
unknown etiology. J Clin Endocrinol Metab 88: 16291636.
Placidi GPA, Boldrini M, Patronelli A, Fiore E, Chiovato L,
Perugi G, Marazziti D (1998). Prevalence of psychiatric
disorders in thyroid diseased patients. Neuropsychobiology
38: 222225.
Plagemann A, Harder T, Rake A, Melchior K, Rohde W, Drner
G (1999). Increased number of galanin-neurons in the
paraventricular hypothalamic nucleus of neonatally overfed
weanling rats. Brain Res 818: 160163.
Plata-Salamn CR (2000). Central nervous system mechanisms
contributing to the cachexia-anorexia syndrome. Nutrition 16:
10091012.
Plawner LL, Delgado MR, Miller VS, Levey EB, Kinsman SL,
Barkovich AJ, Simon EM, Clegg NJ, Sweet VT, Stashinko
EE, Hahn JS (2002). Neuroanatomy of holoprosencephaly as
predictor of function. Neurology 59: 10581066.
Plazzi G, Schutz Y, Cortelli P, Provini F, Avoni P, Heikkila E,
Tinuper P, Solieri L, Lugaresi E, Montagna P (1997). Motor
overactivity and loss of motor circadian rhythm in fatal
familial insomnia: an actigraphic study. Sleep 20: 739742.
Pleasure SJ, Fischbein NJ (2000). Correlation of clinical and
neuroimaging findings in a case of rabies encephalitis. Arch
Neurol 57: 17651769.
Plioplys AV (1997). Antimuscle and anti-CNS circulating antibodies in chronic fatigue syndrome. Neurology 48: 17171719.
Plotsky PM, Owens MJ, Nemeroff CB (1998). Psychoneuroendocrinology of depression. Psychiatry Clin North Am 21:
293307.
Podolsky S, Leopold NA (1974). Growth hormone abnormalities
in Huntingtons chorea: effect of L-dopa administration. J
core temperature falls in Parkinsons disease but not in

multiple-system atrophy. Mov Disord 16: 226232.
Pierpaoli W, Regelson W (1994). Pineal control of aging: effect
of melatonin and pineal grafting on aging mice. Proc Natl
Acad Sci USA 91: 787791.
Pihoker C, Owens C, Kuhn CM, Schanberg SM, Nemeroff CB
(1993). Maternal separation in neonatal rats elicits activation
of the hypothalamic-pituitary-adrenocortical axis: a putative
role for corticotropin-releasing factor. Psychoneuroendocrinology 18: 485493.
Pike M, Stores G (1994). KleineLevin syndrome: a cause of
diagnostic confusion. Arch Dis Child 71: 355357.
Pilavdzic D, Kovacs K, Asa SL (1997). Pituitary morphology
in anencephalic human fetuses. Neuroendocrinology 65:
164172.
Pilcher WH, Joseph SA, McDonald JV (1988). Immunocytochemical localization of proopiomelanocortin neurons in
human brain areas subserving stimulation analgesia. J
Pilgrim C, Reisert I (1992). Differences between male and
female brains developmental mechanisms and implications.
Horm Metab Res 24: 353359.
Pillard RC, Bailey M (1998). Human sexual orientation has a
heritable component. Hum Biol 70: 347365.
Pillemer SR, Bradley LA, Crofford LJ, Moldofsky H, Chrousos
GP (1997). The neuroscience and endocrinology of
fibromyalgia. Arthritis & Rheumatism 40: 19281939.
Pilz D, Quarrell OWJ, Jones EW (1994). Mitochondrial
mutation commonly associated with Lebers hereditary optic
neuropathy observed in a patient with Wolfram syndrome
(DIDMOAD). J Med Genet 31: 328330.
Pinkney J, Wilding J, Williams G, MacFarlane I (2002).
Hypothalamic obesity in humans: what do we know and what
can be done? Obesity Rev 3: 2734.
Pinto G, Bussires L, Recasens C, Souberbielle JC, Zerah M,
Brauner R (2000). Hormonal factors influencing weight and
growth pattern in craniopharyngioma. Horm Res 53: 163169.
Piovesan A, Panarelli M, Terzolo M, Osella G, Matrella C,
Paccotti P, Angeli A (1990). 24-Hour profiles of blood
pressure and heart rate in Cushings syndrome: relationship
between cortisol and cardiovascular rhythmicities. Chronobiol
Int 7: 263265.
Pique L, Jegou S, Bertagna X, Javoy-Agid F, Seurin D,
Proeschel MF, Girard F, Agid Y, Vaudry H, Luton JP (1985).
Pro-opiomelanocortin peptides in the human hypothalamus:
comparative study between normal subjects and Parkinson
patients. Neurosci Lett 54: 141146.
Pirskanen M, Hiltunen M, Mannermaa A, Iivonen S, Helisalmi
S, Lehtovirta M, Koivisto AM, Laakso M, Soininen H,
Alafuzoff I (2002). Interleukin 1 alpha gene polymorphism
as a susceptibility factor in Alzheimers disease and its influence on the extent of histopathological hallmark lesions of
523
2014 Refs
524
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 524
D.F. SWAAB
Poeck K, Pilleri G (1965). Release of hypersexual behaviour

due to lesion in the limbic system. Acta Neurol Scand 41:
233244.
Poeggeler B, Miravalle L, Zagorski MG, Wisniewski T, Chyan
YJ, Zhang Y, Shao H, Bryant-Thomas T, Vidal R, Frangione
B, Ghiso J, Pappolla MA (2001). Melatonin reverses the
profibrillogenic activity of apolipoprotein E4 on the
Alzheimer amyloid Abeta peptide. Biochemistry 40:
1499515001.
Pohjavuori M, Fyhrquist J (1980). Hemodynamic significance
of vasopressin in the newborn infant. J Pediatr 97: 462465.
Poirier J, Delisle M-C, Quirion R, Aubert I, Farlow M, Lahiri
D, Hui S, Bertrand P, Nalbantoglu J, Gilfix BM, Gauthier S
(1995). Apolipoprotein E4 allele as a predictor of cholinergic
deficits and treatment outcome in Alzheimer disease. Proc
Poisson M (1984). Sex steroid receptors in human meningiomas.
Clin Neuropharmacol 7: 320324.
Polak M, Azcoaga JE (1969). Morphology and distribution of
the neuroglia in the hypothalamus and neurohypophysis.
In: Haymaker W, Anderson E, Nauta WJH (Eds.) The Hypothalamus. Charles C Thomas, Springfield, Il. USA, pp.
251275.
Poliak S, Mor S, Conlon P, Wong T, Ling N, Rivier J, Vale
W, Steinman L (1997). Stress and autoimmunity. J Immunol
158: 57515756.
Polivy J, Herman CP (2002). Causes of eating disorders. Annu
Rev Psychol 53: 187213.
Pollack IF, Schor NF, Martinez J, Towbin R (1995). Bobblehead doll syndrome and drop attacks in a child with a cystic
choroid plexus papilloma of the third ventricle. J Neurosurg
83: 729732.
Pollak CP, Perlick D (1991). Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol 4: 204210.
Polman CH, Dijkstra CD, Sminia T, Koetsier JC (1986).
Immunohistological analysis of macrophages in the central
nervous system of Lewis rats with acute experimental allergic
encephalomyelitis. J Neuroimmunol 11: 215222.
Polymeropoulos MH, Gorman Swift R, Swift M (1994). Linkage
of the gene for Wolfram syndrome to markers on the short
arm of chromosome 4. Nat Genet 8: 9597.
Pomper MG, Passe TJ, Burger PC, Scheithauer BW, Brat DJ
(2001). Chordoid glioma: a neoplasm unique to the hypothalamus and anterior third ventricle. Am J Neuroradiol 22:
464469.
Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM,
Anderson L, Andreadis L, Andreadis A, Wiederholt WC,
Raskind M, Schellenberg GD (1998). Tau is a candidate gene
for chromosome 17 frontotemporal dementia. Ann Neurol 43:
815825.
Pop VJ, Maartens LH, Leusink G, Van Son MJ, Knottnerus
AA, Ward AM, Metcalfe R, Weetman AP (1998). Are autoimmune thyroid dysfunction and depression related? J Clin
Popa GT, Fielding U (1933). Hypophysio-portal vessels and

their colloid accompaniment. J Anat 67: 227232.
Pope HG, Kouri EM, Hudson JI (2000). Effects of supraphysiologic doses of testosterone on mood and aggression in
normal men. Arch Gen Psychiatry 57: 133140.
Post RM, Kramlinger KG, Joffe RT, Roy-Byrne PP, Rofoff A,
Frye MA, Huggins T (1997). Rapid cycling bipolar affective
disorder: lack of relation to hypothyroidism. Psychiatry Res
72: 17.
Posternak MA, Zimmerman M (2002). Lack of association
between seasonality and psychopathology in psychiatric
outpatients. Psychiatry Res 112: 187194.
Postina R, Ufer E, Pfeiffer R, Knoers NVAM, Fahrenholz F
(2000). Misfolded vasopressin V2 receptors caused by extracellular point mutations entail congenital nephrogenic
diabetes insipidus. Mol Cell Endocrinol 164: 3139.
Postnov YV, Strakhov EV, Glukhovets BI, Gorkova SI (1974).
Hypothalamic neurosecretory nuclei and nucleus habenularis
of epithalamus in essential hypertension. Virchows Arch A
Pathol Anat Histol 364: 275283.
Poteliakhoff A (1981). Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res
25: 9195.
Power DA, Noel J, Collins R, ONeill D (2001). Circulating
leptin levels and weight loss in Alzheimers disease patients.
Dement Geriatr Cogn Disord 12: 167170.
Powers RE, Walker LC, DeSouza EB, Vale WW, Struble RG,
Whitehouse PJ, Price DL (1987). Immunohistochemical study
of neurons containing corticotropin-releasing factor in
Alzheimers disease. Synapse 1: 405410.
Powner DJ, Hendrich A, Lagler RG, Ng RH, Madden RL (1990).
Hormonal changes in brain dead patients. Crit Care Med 18:
702708.
Prader A, Labhart A, Willi H (1956). Ein Syndrom von
Adipositas, Kleinwuchs, Krytorchismus und Oligophrenie
nach Myotonieartigem Zustand in Neugeborenalter. Schweiz
Med Wochenschr 86: 12601261.
Pralong E, Ghika J, Temperli P, Pollo C, Vingerhoets F,
Villemure J-G (2002). Electrophysiological localization of the
subthalamic nucleus in parkinsonian patients. Neurosci Lett
325: 144146.
Prasad S, Shah J, Patkar D, Gala B, Patankar T (2000). Giant
hypothalamic hamartoma with cystic change: report of two
cases and review of the literature. Neuroradiology 42:
648650.
Praschak-Rieder N, Willeit M, Winkler D, Neumeister A, Hilger
E, Zill P, Hornik K, Stastny J, Thierry N, Ackenheil M,
Bondy B, Kasper S (2002). Role of family history and 5HTTLPR polymorphism in female seasonal affective disorder
patients with and without premenstrual dysphoric disorder.
Eur Neuropsychopharmacol 12: 129134.
Prasko J, Horacek J, Klaschka J, Kosova J, Ondrackova I,
Sipek J (2002). Bright light therapy and/or imipramine for
2014 Refs
2/12/03
1:39 pm
Page 525
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
525
in Gerontology, Vol. 7, pp. 3354. Serdi/Paris; Springer/NY;

Nankodo/Tokyo.
Prinz PN, Christie C, Smallwood R, Vitaliano P, Bokan J,
Vitiello MV, Martin D (1984). Circadian temperature variation in healthy aged and in Alzheimers disease. J Gerontol
39: 3035.
Prinz P, Bailey S, Moe K, Wilkinson C, Scanlan J (2001).
Urinary free cortisol and sleep under baseline and stressed
conditions in healthy senior women: effects of estrogen
replacement therapy. J Sleep Res 10: 1926.
Pritchard III PB, Wannamaker BB, Sagel J, Nair R, DeVillier
C (1983). Endocrine function following complex partial
seizures. Ann Neurol 14: 2732.
Probst A, Ulrich J, Heitz PhU, Herschkowitz N (1980).
Adrenomyeloneuropathy. Acta Neuropathol 49: 105115.
Probst JC, Zetzsche T, Weber M, Theilemann P, Skutella T,
Landgraf R, Jirikowski GF (1996). Human intestinal trefoil
factor is expressed in human hypothalamus and pituitary:
evidence for a novel neuropeptide. FASEB J 10: 15181523.
Proulx F, Weber ML, Collu R, Lelivre M, Larbrisseau A,
Delisle M (1993). Hypothalamic dysfunction in a child: a
distinct syndrome? Eur J Pediatr 152: 526529.
Provenzale JM, Glass JP (1996). MRI in hemiballismus due to
subthalamic nucleus hemorrhage: an unusual complication of
liver transplantation. Neuroradiology (Suppl 1) 38: S75S77.
Ptak R, Birtoli B, Imboden H, Hauser C, Weis J, Schnider A
(2001). Hypothalamic amnesia with spontaneous confabulations: a clinicopathologic study. Neurology 56: 15971600.
Pu LP, Van Leeuwen FW, Tracer HL, Sonnemans MAF, Loh
YP (1995). Localization of vasopressin mRNA and
immunoreactivity in pituicytes of pituitary stalk-transected
rats after osmotic stimulation. Proc Natl Acad Sci USA 92:
1065310657.
Puelles L, Kuwana E, Pulles E, Bulfone A, Shimamura K,
Keleher J, Smiga S, Rubenstein JLR (2000). Pallial and
subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1,
Nkx-21, Pax-6, and Tbr-1. J Comp Neurol 424: 409438.
Puig-Domingo M, Webb S, Serrano J, Peinado MA, Corcoy R,
Ruscalleda J, Reiter RJ, Di Leiva A (1992). Melatonin-related
hypogonadotropic hypogonadism. N Engl J Med 327:
13561359.
Pujol J, Bello J, Deus J, Mart-Vilalta JL, Capdevilla A (1997).
Lesions in the left arcuate fasciculus region and depressive
symptoms in multiple sclerosis. Neurology 49: 11051110.
Pump B, Gabrielsen A, Christensen NJ, Bie P, Bestle M, Norsk
P (1999). Mechanisms of inhibition of vasopressin release
during moderate antiorthostatic posture change in humans.
Am J Physiol 277: R229R235.
Punnonen R, Viinamki O, Multamki S (1983). Plasma vasopressin during normal menstrual cycle. Horm Res 17: 9092.
Puolakka K, Korhonen T, Lahtinen R (1984). Diabetes
insipidus in preleukaemic phase of acute myeloid leukaemia
inpatients with recurrent non-seasonal depression. Neuroendocrinol Lett 23: 109113.

Prassopoulos P, Cavouras D, Ioannidou M, Golfinopoulous S
(1996). Study of subarachnoid spaces in children with idiopathic mental retardation. J Child Neurol 11:197200.
Prast H, Grass K, Philippu A (1997). The ultradian EEG
rhythm coincides temporally with the ultradian rhythm of
histamine release in the posterior hypothalamus. NaunynSchmiedebergs Arch Pharmacol 356: 526528.
Pratschke J, Wilhelm MJ, Kusaka M, Basker M, Cooper DKC,
Hancock WW, Tilney NL (1999). Brain death and its influence on donor organ quality and outcome after
transplantation. Transplantation 67: 343348.
Preibisz JJ, Sealy JE, Laragh JH, Cody RJ, Weksler BB (1983).
Plasma and platelet vasopressin in essential hypertension and
congestive heart failure. Hypertension 5: I129I138.
Preisser L, Teillet L, Aliotti S, Gobin R, Berthonaud V,
Chevalier J, Corman B, Verbavatz J-M (2000). Downregulation of aquaporin-2 and 3 in aging kidney is
independent of V2 vasopressin receptor. Am J Physiol 279:
F144F152.
Prell GD, Green JP, Kaufmann CA, Khandelwal JK, Morrishow
AM, Kirch DG, Linnoila M, Wyatt RJ (1995). Histamine
metabolites in cerebrospinal fluid of patients with chronic
schizophrenia: their relationships to levels of other aminergic
transmitters and ratings of symptoms. Schizophr Res 14:
93104.
Presse F, Sorokovsky I, Max JP, Nicolaidis S, Nahon JL (1996).
Melanin-concentrating hormone is a potent anorectic peptide
regulated by food-deprivation and glucopenia in the rat.
Preston FS, Bateman SC, Short RV, Wilkinson RT (1973).
Effects of flying and of time changes on menstrual cycle
length and on performance in airline stewardesses. Aerosp
Med 44: 438443.
Pretel S, Piekut DT (1990). Coexistence of CRF peptide and
oxytocin mRNA in the paraventricular nucleus. Peptides 11:
621624.
Preti A, Miotto P (2001). Diurnal variations in suicide by age
and gender in Italy. J Affect Disord 65: 253261.
Price JL (1990). Olfactory System. In: G Paxinos (Ed.) The
Human Nervous System. Chapter 29, pp. 979998. Academic
Press, Inc, Harcourt Brace Jovanovich, Publishers.
Price JL, Dembinska ME, Young MW, Rosbash M (1995).
Suppression of PERIOD protein abundance and circadian
cycling by the Drosophila clock mutation timeless. EMBO
J 14: 40444009.
Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aub M
(2002). Melatonin as adjunctive therapy in the prophylaxis
of cluster headache: a pilot study. Headache 42: 787792.
Prinz PN, Vitiello MV (1993). Sleep in Alzheimers disease.
In: Alberrede JL, Marley JE, Roth T, Vellas BJ (Eds.) Sleep
Disorders and Insomnia in the Elderly. Facts and Research
525
2014 Refs
526
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 526
D.F. SWAAB
in 2 patients with empty della turcica. Scand J Haematol 32:

364366.
Purba JS, Hofman MA, Portegies P, Troost D, Swaab DF (1993).
Decreased number of oxytocin neurons in the paraventricular
nucleus of the human hypothalamus in AIDS. Brain 116:
795809.
Purba JS, Hofman MA, Swaab DF (1994). Decreased number
of oxytocin-immunoreactive neurons in the paraventricular
nucleus of the hypothalamus in Parkinsons disease.
Neurology 44: 8489.
Purba JS, Raadsheer FC, Hofman MA, Ravid R, Polman CH,
Kamphorst W, Swaab DF (1995). Increased number of corticotropin releasing hormone (CRH) neurons in the
hypothalamic paraventricular nucleus of patients with
multiple sclerosis. Neuroendocrinology 62: 6270.
Purba JS, Hoogendijk WJG, Hofman MA, Swaab DF (1996).
Increased number of vasopressin- and oxytocin-expressing
neurons in the paraventricular nucleus of the hypothalamus
in depression. Arch Gen Psychiatry 53: 137143.
Purdon MJ (1950). Fits of laughter (sham mirth) in organic
cerebral disease. Brain 73: 453464.
Puritz R, Lightman SL, Wilcox CS, Forsling M, Bannister R
(1983). Blood pressure and vasopressin in progressive autonomic failure. Brain 106: 503511.
Putignano P, Dubini A, Toja P, Invitti C, Bonfanti S, Redaelli G,
Zappulli D, Cavagnini F (2001). Salivary cortisol measurement
in normal-weight, obese and anorexic women: comparison with
plasma cortisol. Eur J Endocrinol 145: 165171.
Putilov AA (1998). Multi-component physiological response
mediates therapeutic benefits of bright light in winter seasonal
affective disorder. Biol Rhythm Res 29: 367386.
Pyo H-J, Summer SN, Niederberger M, Kim JK, Schrier RW
(1995). Arginine vasopressin gene expression in rats with
puromycin-induced nephrotic syndrome. Am J Kidney Dis
25: 5862.
Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA,
Cullen MJ, Foulds Mathes W, Przypek J, Kanarek R, MaratosFlier E (1996). A role for melanin-concentrating hormone in
the central regulation of feeding behaviour. Nature 380:
243247.
Quanbeck C, Sherwood NM, Millar RP, Terasawa E (1997).
Two populations of luteinizing hormone-releasing hormone
neurons in the forebrain of the rhesus macaque during embryonic development. J Comp Neurol 380: 293309.
Quigg M (2000). Circadian rhythms: interactions with seizures
and epilepsy. Epilepsy Res 42: 4355.
Quigg M, Clayburn H, Straume M, Menaker M, Bertram EH
IIIrd (1999). Hypothalamic neuronal loss and altered circadian rhythm of temperature in a rat model of mesial temporal
lobe epilepsy. Epilepsia 40: 16881696.
Quigley CA (2002). The postnatal gonadotropin and sex steroid
surge insights from the androgen insensitivity syndrome. J
Quine L (1991). Sleep problems in children with mental

handicap. J Ment Defic Res 35: 269290.
Quinton R, Cheow HK, Tymms DJ, Bouloux P-MG, Wu FCW,
Jacobs HS (1999). Kallmanns syndrome: is it always for
life? Clin Endocrinol 50: 481485.
Raadsheer FC (1994). Increased activity of hypothalamic corticotropin-releasing hormone neurons in aging, Alzheimers
disease and depression. A study on human postmortem material. Thesis, University of Amsterdam
Raadsheer FC, Sluiter AA, Ravid R, Tilders FJH, Swaab DF
(1993). Localization of corticotropin-releasing hormone
(CRH) neurons in the paraventricular nucleus of the human
hypothalamus; age-dependent colocalization with vasopressin. Brain Res 615: 5062.
Raadsheer FC, Oorschot DE, Verwer RWH, Tilders FJH, Swaab
DF (1994a). Age-related increase in the total number of
corticotropin-releasing hormone neurons in the human
paraventricular nucleus in controls and Alzheimers disease:
comparison of the disector with an unfolding method. J Comp
Neurol 339: 447457.
Raadsheer FC, Tilders FJH, Swaab DF (1994b). Similar
age related increase of vasopressin colocalization in paraventricular corticoptropin-releasing hormone neurons in
controls and Alzheimer patients. J Neuroendocrinol 6:
131133.
Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab
DF (1994c). Increased numbers of corticotropin-releasing
hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology
60: 436444.
Raadsheer FC, Van Heerikhuize JJ, Lucassen PJ, Hoogendijk
WJG, Tilders FJH, Swaab DF (1995). Corticotropin-releasing
hormone mRNA levels in the paraventricular nucleus of
patients with Alzheimers disease and depression. Am J
Rabey JM, Scharf M, Oberman Z, Zohar M, Graff E (1990).
Cortisol, ACTH, and beta-endorphin after dexamethasone
administration in Parkinsons dementia. Biol Psychiatry 27:
581591.
Raboch J, Faltus F (1991). Sexuality of women with anorexia
nervosa. Acta Psychiatr Scand 84: 911.
Raboch J, Mellan J (1978). Hypogonadotropic eunuchoids and
Klinefelters: sexual development and activity. In: Drner C,
Kawakami M (Eds.) Hormones and Brain Development.
Radetti G, Paganini C, Rigon F, Gentili L, Gebert U, Ishikawa
S (2001). Urinary aquaporin-2 excretion in nocturnal enuresis.
Eur J Endocrinol 145: 435438.
Raff H (2000). Salivary cortisol: a useful measurement in
the diagnosis of Cushings syndrome and the evaluation of the
hypothalamic-pituitary-adrenal axis. Endocrinologist 10: 917.
Raghavan R, Khin-Nu C, Brown AG, Day KA, Tyrer SP, Ince
PG, Perry EK, Perry RH (1994). Gender differences in the
2014 Refs
2/12/03
1:39 pm
Page 527
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
527
Ram PT, Dai J, Yuan L, Dong C, Kiefer TL, Lai L, Hill SM

(2002). Involvement of the mt1 melatonin receptor in human
breast cancer. Cancer Lett 179: 141150.
Ramacciotti CE, Guidi L, Bondi E, Coli E, DellOsso L, Pistoia
S, Pucci E (1997). Differential dynamic responses of
luteinizing hormone to gonadotropin releasing hormone in
patients affected by bulimia nervosa purging versus nonpurging type. Eating Weight Disord 2: 150155.
Ramamurthi B (1988). Stereotactic operation in behaviour
disorders. Amygdalotomy and hypothalamotomy. Acta
Neurochir Suppl 44: 152157.
Rami B, Schneider U, Wandl-Vergesslich K, Frisch H, Schober
E (1998). Primary hypothyroidism, central diabetes insipidus and growth hormone deficiency in multisystem
Langerhans cell histiocytosis: a case report. Acta Paediatr 87:
112114.
Rance NE (1992). Hormonal influences on morphology and
neuropeptide gene expression in the infundibular nucleus of
post-menopausal women. Prog Brain Res 93: 221236.
Rance NE, Uswandi SV (1996). Gonadotropin-releasing
hormone gene expression is increased in the medial basal
hypothalamus of postmenopausal women. J Clin Endocrinol
Metab 81: 35403546.
Rance NE, Young III SW (1991). Hypertrophy and increased
gene expression of neurons containing neurokinin-B and
substance-P messenger ribonucleic acids in the hypothalamic of postmenopausal women. Endocrinology 128:
22392247.
Rance NE, McMullen NT, Smialek JE, Price DL, Scott Young
III W (1990). Postmenopausal hypertrophy of neurons
expressing the estrogen receptor gene in the human hypothalamus. J Clin Endocrinol Metab 71: 7985.
Rance NE, Uswandi SV, McMullen NT (1993). Neuronal hypertrophy in the hypothalamus of older men. Neurobiol Aging
14: 337342.
Rance NE, Scott Young III W, McMullen NT (1994). Topography of neurons expressing luteinizing hormone-releasing
hormone gene transcripts in the human hypothalamus and
basal forebrain. J Comp Neurol 339: 573586.
Randeva HS, Davison R, Chamoun V, Bouloux PMG (2002).
Isolated neurosarcoidosis a diagnostic enigma. Endocrine
17: 241247.
Rando TA, Horton JC, Layzer RB (1992). Wolfram syndrome:
evidence of a diffuse neurodegenerative disease by magnetic
resonance imaging. Neurology 42: 12201224.
Rantakallio P, Lr E, Isohanni M, Moilanen I (1992). Maternal
smoking during pregnancy and delinquency of the offspring:
an association without causation? Int J Epidemiol 21:
11061113.
Rantakallio P, Jones P, Moring J, Von Wendt L (1997).
Association between central nervous system infections during
childhood and adult onset schizophrenia and other psychoses:
a 28-year follow-up. Int J Epidemiol 26: 837843.
phenotypic expression of Alzheimers disease in Downs

syndrome (trisomy 21). Neuroreport 5: 13931396.
Raghavendra Rao VL, Richardson JS, Butterworth RF (1993).
Decreased activities of thiamine diphosphatase in frontal and
temporal cortex in Alzheimers disease. Brain Res 631:
334336.
Ragusa L, Elia M, Scifo R (1993). Growth hormone deficit in
autism. J Autism Dev Disord 23: 421422.
Rahman Q, Silber K (2000). Sexual orientation and the sleepwake cycle: a preliminary investigation. Arch Sex Behav 29:
127134.
Rahman Q, Wilson GD (2003). Sexual orientation and the 2nd
to 4th finger length ratio: evidence for organising effects of
sex hormones or developmental instability? Psychoneuroendocrinology 28: 288303.
Raine A, Brennan P, Mednick SA (1994). Birth complications
combined with early maternal rejection at age 1 year predispose to violent crime at age 18 years. Arch Gen Psychiatry
51: 984988.
Raine A, Brennan P, Mednick B, Mednick SA (1996). High
rates of violence, crime, academic problems, and behavioral
problems in males with both early neuromotor deficits and
unstable family environments. Arch Gen Psychiatry 53:
544549.
Raine CS (1994). Multiple sclerosis: immune system molecule
expression in the central nervous system. J Neuropathol Exp
Neurol 53: 328-337.
Raisman G (1997). An urge to explain the incomprehensible:
Geoffrey Harris and the discovery of the neural control of
the pituitary gland. Annu Rev Neurosci 20: 533566.
Raison CL, Klein HM, Steckler M (1999). The moon and
madness reconsidered. J Affect Disord 53: 99106.
Raitiere MN (1992). Clinical evidence for thyroid dysfunction
in patients with seasonal affective disorder. Psychoneuroendocrinology 17: 231241.
Raja M, Azzoni A, Giammarco V (1998). Diabetes insipidus
and polydipsia in a patient with Aspergers disorder and
an empty sella: a case report. J Autism Dev Disord 28:
235239.
Rajarethinam R, Miedler J, De Quardo J, Smet CI, Brunberg
J, Kirbat R, Tandon R (2001). Prevalence of cavum septum
pellucidum in schizophrenia studied with MRI. Schizophr Res
48: 201205.
Rajkowska G (2000). Postmortem studies in mood disorders
indicate altered numbers of neurons and glial cells. Biol
Rajmil O, Puig-Domingo M, Tortosa F, Viader M, Garcia
Patterson A, Schwarzstein D, De Leiva A (1997). Melatonin
concentration before and during testosterone replacement in
primary hypogonadic men. Eur J Endocrinol 137: 4852.
Ralph MP, Foster RG, Davis FC, Menaker M (1990).
Transplanted suprachiasmatic nucleus determines circadian
rhythms. Science 247: 975978.
527
2014 Refs
528
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 528
D.F. SWAAB
Rao ML, Klsch H (2003). Effects of estrogen on brain

development and neuroprotection implications for negative
symptoms in schizophrenia. Psychoneuroendocrinology 28:
8396.
Rao ML, Stefan H, Bauer J (1989). Epileptic but not
psychogenic seizures are accompanied by simultaneous
elevation of serum pituitary hormones and cortisol levels.
Rao ML, Gross G, Strebel B, Halaris A, Huber G, Brunig P,
Marler M (1994). Circadian rhythm of tryptophan, serotonin,
melatonin, and pituitary hormones in schizophrenia. Biol
Rao ML, Strebel B, Halaris A, Gross G, Brunig P, Huber G,
Marler M (1995). Circadian rhythm of vital signs, norepinephrine, epinephrine, thyroid hormones, and cortisol in
schizophrenia. Psychiatry Res 57: 2139.
Rao SM, Huber SJ, Bornstein RA (1992). Emotional changes
with multiple sclerosis and Parkinsons disease. J Consult
Clin Pathol 60: 369378.
Rapoport JL (1988). The neurobiology of obsessive-compulsive
disorder. JAMA 260: 28882890.
Rapp SR, Espeland MA, Shumaker SA, Henderson VW,
Brunner RL, Manson JE, Gass MLS, Stefanick ML, Lane
DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D
for the WHIMS investigators (2003). Effect of estrogen plus
progestin on global cognitive function in postmenopausal
women. JAMA 289: 26632672.
Rsnen P, Hakko H, Visuri S, Paanila J, Kapanen P, Suomela
T, Tiihonen J (1999). Serum testosterone levels, mental
disorders and criminal behaviour. Acta Psychiatr Scand 99:
348352.
Rasgon NL, Altschuler LL, Fairbanks L (2001). Estrogenreplacement therapy for depression. Am J Psychiatry 158:
1738.
Raskind MA, Weitzman RE, Orenstein H, Fisher DA, Courtney
N (1978). Is antidiuretic hormone elevated in psychosis? A
pilot study. Biol Psychiatry 13: 385390.
Rasmusson AM, Lipschitz DS, Wang S, Hu S, Vojvoda D,
Bremner JD, Southwick SM, Charney DS (2001). Increased
pituitary and adrenal reactivity in premenopausal women with
posttraumatic stress disorder. Biol Psychiatry 50: 965977.
Rasmussen AT (1933). The incidence of tubular glands and
concretions in the adult human hypophysis cerebri. Anatom
Rec 55: 139149.
Rasmussen AT, Nelson AA (1938). Pars intermedia basophil
adenoma of the hypophysis. Am J Pathol 14: 297310.
Rasmussen DD (1992). Human hypothalamic and pituitary
neuroendocrine function during in vitro perifusion. Prog Brain
Res 93: 6981.
Rasmuson S, Andrew R, Nsman B, Seckl JR, Walker BR,
Olsson T (2001). Increased glucocorticoid production and
altered cortisol metabolism in women with mild to moderate
Rasmuson S, Nsman B, Carlstrm K, Olsson T (2002).

Increased levels of adrenocortical and gonadal hormones in
mild to moderate Alzheimers disease. Dement Geriatr Cogn
Disord 13: 7479.
Ratcliffe PJ, Bell JI, Collins KJ, Frackowiak RS, Rudge P
(1983). Late onset post-traumatic hypothalamic hypothermia.
Ratnasuriya RH, Eisler I, Szmukler GI, GFM Russell (1991).
Anorexia nervosa: outcome and prognostic factors after 20
years. Br J Psychiatry 158: 495502.
Rauch F, Lenzner C, Nrnberg P, Frmmel C, Vetter U (1996).
A novel mutation in the coding region for neurophysin-II is
associated with autosomal dominant neurohypophyseal
diabetes insipidus. Clin Endocrinol 44: 4551.
Ravelli G-P, Stein ZA, Susser MW (1976). Obesity in young
men after famine exposure in utero and early infancy. N Engl
J Med 295: 349353.
Ravid R, Fliers E, Swaab DF, Zurcher C (1987). Changes in
vasopressin and testosterone in the senescent Brown-Norway
(BN/BiRij) rat. Gerontology 33: 8798.
Ravid R, Van Zwieten EJ, Swaab DF (1992). Brain banking
and the human hypothalamus factors to match for, pitfalls
and potentials. Prog Brain Res 93: 8395.
Ravnikar V, Elkind-Hirsch K, Schiff I, Ryan KJ, Tulchinsky D
(1984). Vasomotor flushes and the release of peripheral
immunoreactive luteinizing hormone-releasing hormone in
postmenopausal women. Fertil Steril 41: 881887.
Rawson NE, Brand JG, Cowart BJ, Lowry LD, Pribitkin EA,
Rao VM, Restrepo D (1995). Functionally mature olfactory
neurons from two anosmic patients with Kallmann syndrome.
Brain Res 681: 5864.
Ray CD (1981). Electrical and chemical stimulation of the CNS
by direct means for pain control: present and future. Clin
Raymond NC, Faris PL, Thuras PD, Eiken B, Howard LA,
Hofbauer RD, Eckert ED (1999). Elevated pain threshold in
anorexia nervosa subjects. Biol Psychiatry 45: 13891392.
Raz N, Torres IJ, Acker JD (1992). Age-related shrinkage of
the mamillary bodies: in vivo MRI evidence. Neuroreport 3:
713716.
Raz N, Torres IJ, Briggs SD, Spencer WD, Thornton AE, Loken
WJ, Gunning FM, McQuain JD, Driesen NR, Acker JD
(1995). Selective neuroanatomic abnormalities in Downs
syndrome and their cognitive correlates: evidence from MRI
morphometry. Neurology 45: 356366.
Rea MS, Bullough JD, Figueiro MG (2001). Human melatonin
suppression by light: a case for scotopic efficiency. Neurosci
Lett 299: 4548.
Realmuto GM, Jenson JB, Reeve E, Garfinkel BD (1990).
Growth hormone response to L-dopa and clonidine in autistic
children. J Autism Dev Disord 20: 455465.
Rebar RW, Spitzer IB (1987). The physiology and measurement of hot flushes. Am J Obstet Gynecol 156: 12841288.
2014 Refs
2/12/03
1:39 pm
Page 529
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
529
Reiner WG (1996). Case study: sex reassignment in a teenage

girl. J Am Acad Child Adolesc Psychiatry 35: 799803.
Reiner WG (2002). Gender identity and sex assignment: a reappraisal for the 21st century. In: Zderic et al. (Eds.) Pediatric
Gender Reassignment: a Critical Reappraisal. Kluwer
Academic/Plenum Publishers, pp. 175197.
Reinisch JM (1981). Prenatal exposure to synthetic progestins
increases potential for aggression in humans. Science 211:
11711173.
Reiter RJ, Tan D-X, Osuna C, Gitto E (2000). Actions of melatonin in the reduction of oxidative stress. J Biomed Sci 7:
444458.
Reiter RJ, Tan D-X, Manchester LC, El-Sawi MR (2002).
Melatonin reduces oxidant damageand promotes mitochondrial respiration. Ann NY Acad Sci 959: 238250.
Rem CE, Rol P, Grothmann K, Kaase H, Terman M (1996).
Bright light therapy in focus: lamp emission spectra and
ocular safety. Technol Health Care 4: 403413.
Ren J, Lee S, Pagliardini S, Grard M, Stewart CL, Greer JJ,
Wevrick R (2003). Absence of Ndn, encoding the Prader
Willi syndrome-deleted gene necdin, results in congenital
deficiency of central respiratory drive in neonatal mice. J
Neurosci 23: 15691573.
Ren P, Lenne F, Venture M-A, Bertagna X, De Keyzer Y
(2000). Nucleotide sequence and structural organization of the
human vasopressin pituitary receptor (V3) gene. Gene 241:
5764.
Reppert SM (1992). Pre-natal development of a hypothalamic
biological clock. Prog Brain Res 93: 119132.
Reppert SM, Weaver DR, Rivkees SA, Stopa EG (1988).
Putative melatonin receptors in a human biological clock.
Science 242: 7881.
Reppert SM, Weaver DR, Godson C (1996). Melatonin receptors step into the light: cloning and classification of subtypes.
Trends Pharmacol Sci 17: 100102.
Reske-Nielsen E, Lund E (1992). PraderWilli syndrome and
central nervous system calcifications: chance or fundamentally related findings. Clin Neuropathol 11: 610.
Resko JA, Perkins A, Roselli CE, Fitzgerald JA, Choate JVA,
Stormshak F (1996). Endocrine correlates of partner preference behavior in rams. Biol Reprod 55: 120126.
Rett A (1966). ber ein eigenartiges hirnatrophisches Syndrom
bei Hyperammonmie in Kindesalter. Wien Med Wochenschr
116: 723726.
Retzius G (1896). Das Menschenhirn: Studien in der
Makroskopischen Morphologie. Stockholm, Koeniglich
Buchdruckerei.
Reubi JC, Corts R, Maurer R, Probst A, Palacios JM (1986).
Distribution of somatostatin receptors in the human brain: an
autoradiographic study. Neuroscience 18: 329346.
Reul JM, De Kloet ER (1985). Two receptor systems for corticosterone in rat brain: microdistribution and differential
occupation. Endocrinology 117: 25052511.
Recht LD, Lew RA, Schwartz WJ (1995). Baseball teams beaten

by jet lag. Nature 377: 583.
Reckelhoff JF (2001). Gender differences in the regulation of
blood pressure. Hypertension 37: 11991208.
Recordon E, Griffiths GM (1938). A case of primary bilateral
anophthalmia. Br J Ophthalmol 22: 353360.
Reddy PH, Williams M, Tagle DA (1999). Recent advances in
understanding the pathogenesis of Huntingtons disease.
Trends Neurosci 22: 248255.
Redei E, Hilderbrand H, Aird F (1995). Corticotropin releaseinhibiting factor is preprothyrotropin-releasing hormone(178-199). Endocrinology 136: 35573563
Reder AT, Lowy MT, Meltzer HY, Antel JP (1987).
Dexamethasone suppression test abnormalities in multiple
sclerosis: relation to ACTH therapy. Neurology 37: 849853.
Reder AT, Makowiec RL, Lowy MT (1994). Adrenal size is
increased in multiple sclerosis. Arch Neurol 51: 151154.
Reeves AG, Plum F (1969). Hyperphagia, rage, and dementia
accompanying a ventromedial hypothalamic neoplasm. Arch
Neurol 20: 616624.
Regard M, Landis T (1997). Gourmand syndrome: eating
passion associated with right anterior lesions. Neurology 48:
11851190.
Regestein QR, Monk TH (1995). Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry 152:
602608.
Regier DA, Boyd JH, Burke JD, Rae DS, Myers JK, Kramer
M, Robins LN, George LK, Karno M, Locke BZ (1988).
One-month prevalence of mental disorders in the United
States. Arch Gen Psychiatry 45: 977986.
Rgis J, Bartolomei F, De Toffol B, Genton P, Kobayashi T,
Mori Y, Takakura K, Hori T, Inoue H, Schrttner O, Pendl
G, Wolf A, Arita K, Chauvel P (2000). Gamma knife surgery
for epilepsy related to hypothalamic hamartomas.
Rehman HU, Atkin SL (1999). Sleep disturbances and cardiac
arrhythmia after treatment of a craniopharyngioma. J R Soc
Med 92: 585586.
Reichlin S (1999). Is leptin a secretion of the brain. J Clin
Reid RL, Yen SSC (1981). Premenstrual syndrome. Am J Obstet
Gynecol 139: 85104.
Reid S, Towell AD, Golding JF (2000). Seasonality, social zeitgebers and mood variability in entrainment of mood.
Implications for seasonal affective disorder. J Affect Disord
59: 4754.
Reimann HA (1951). Periodic disease. Medicine 30: 219245.
Reinberg AE, Touitou Y, Soudant E, Bernard D, Bazin R,
Mechkouri M (1996). Oral contraceptives alter circadian
rhythm parameters of cortisol, melatonin, blood pressure,
heart rate, skin blood flow, transepidermal water loss, and
skin amino acids of healthy young women. Chronobiol Int
13: 199211.
529
2014 Refs
530
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 530
D.F. SWAAB
Reul MHM, Stec I, Sder M, Holsboer F (1993). Chronic treatment of rats with the antidepressant amitriptyline attenuates
the activity of the hypothalamo-pituitary-adrenocortical
system. Endocrinology 133: 312320.
Reus VI, Wolkowitz OM, Frederick S (1997). Antiglucocorticoid treatments in psychiatry. Psychoneuroendocrinology
(Suppl. 1) 22: S121S124.
Rezek DL (1987). Olfactory deficits as a neurologic sign in
dementia of the Alzheimer type. Arch Neurol 44: 10301032.
Rhodes RH, Dusseau JJ, Boyd AS, Knigge KM (1982).
Intrasellar neural-adenohypophyseal choristoma. J Neuropathol Exp Neurol 41: 267280.
Ribak CE, Kramer GW (1982). Cholinergic neurons in the basal
forebrain of the cat have direct projection to the sensorimotor
cortex. Exp Neurol 75: 453465.
Rice G, Anderson C, Risch N, Ebers G (1999). Male homosexuality: absence of linkage to microsatellite markers at
Xq28. Science 284: 665667.
Richard S, Zingg HH (1990). The human oxytocin gene
promoter is regulated by estrogens. J Biol Chem 265:
60986103.
Richards M, Kuh D, Hardy R Wadsworth M (1999). Lifetime
cognitive function and timing of the natural menopause.
Richardson DE (1982). Analgesia produced by stimulation of
various sites in the human beta-endorphin system. Appl
Richardson DE, Akil H (1977). Pain reduction by electrical
brain stimulation in man. J Neurosurg 47: 184194.
Richardson HB (1939). Simmonds disease and anorexia
nervosa. Arch Int Med 63: 128.
Richdale AL, Cotton S, Hibbit K (1999). Sleep and behaviour
disturbance in PraderWilli syndrome: a questionnaire study.
J Intellect Disabil Res 43: 380392.
Rickert CH, Grabellus F, Varchmin-Schulthei K, St H,
Paulus W (2001). Sudden unexpected death in young
adults with chronic hydrocephalus. Int J Legal Med 114:
331337.
Rieber I, Sigusch V (1979). Psychosurgery on sex offenders
and sexual deviants in West Germany. Arch Sex Behav 8:
523527.
Riecher-Rssler A (2002). Oestrogen effects in schizophrenia
and their potential therapeutic implications (Review). Arch
Womens Ment Health 5: 111118.
Riemann D, Hohagen F, Bahro M, Berger M (1994). Sleep in
depression: the influence of age, gender, and diagnostic
subtype on baseline sleep and the cholinergic REM induction
test with RS 86. Eur Arch Psychiatry Clin Neurosci 243:
279290.
Riemann D, Klein T, Rodenbeck A, Feige B, Horny A, Hummel
R, Weske G, Al-Shajlawi A, Voderholzer U (2002). Nocturnal
cortisol and melatonin secretion in primary insomnia.
Riemenschneider M, Schwarz S, Wagenpfeil S, Diehl J, Mller

U, Frstl H, Kurz A (2002). A polymorphism of the brainderived neurotrophic factor (BDNF) is associated with
Alzheimers disease in patients lacking the apolipoprotein
E4 allele. Mol Psychiatry 7: 782785.
Rienstein S, Adams EF, Pilzer D, Goldring AA, Goldman B,
Friedman E (2003). Comparative genomic hybridization
analysis of craniopharyngiomas. J Neurosurg 98: 162164.
Riggs HE, Rupp C (1963). Variation in form of circle of Willis.
Arch Neurol 8: 814.
Rigoli L, Arrigo T, Corigliano G, De Giorgi G, Franzese A,
Giorgetti R, Lasco A, Lucentini L, Marietti G, Martinucci
ME, Parrillo M, Oicco P, Iafusco D, De Luca F, Cucinotta
D (1998). Mitochondrial DNA studies and clinical findings
in Wolfram syndrome: an Italian multicenter survey. Diabetes
Nutr Metab 11: 114120.
Rimoin DL, Schechter JE (1973). Histological and ultrastructural studies in isolated growth hormone deficiency. J Clin
Rinne JO, Paljarvi L, Rinne K (1987). Neuronal size and density
in the nucleus basalis of Meynert in Alzheimers disease. J
Neurol Sci 79: 6776.
Rinne T, De Kloet ER, Wouters L, Goekoop JG, De Rijk R,
Van den Brink W (2002). Hyperresponsiveness of hypothalamo-pituitary-adrenal axis to combined dexamethasone/
corticotropin-releasing hormone challenge in female borderline personality disorder patients with a history of sustained
childhood abuse. Biol Psychiatry 52: 11021112.
Rinne UK, Kivalo E, Talanti S (1962). Maturation of human
hypothalamic neurosecretion. Biol Neonat 4: 351364.
Ripley B, Overeem S, Fujiki M, Nevsimalova S, Uchino M,
Yesavage J, Di Monte D, Dohi K, Melberg A, Lammers GJ,
Nishida Y, Roelandse FWC, Hungs M, Mignot E, Nishino S
(2001). CSF hypocretin/orexin levels in narcolepsy and other
neurological conditions. Neurology 57: 22532258.
Risse GL, LeDoux J, Springer SP, Wilson DH, Gazzaniga MS
(1978). The anterior commissure in man: functional variation
in a multisensory system. Neuropsychologia 16: 2331.
Risser D, You ZB, Cairns N, Herrera-Marschitz M, Seidl R,
Schneider C, Terenius L, Lubec G (1996). Endogenous
opioids in frontal cortex of patients with Down syndrome.
Rittig S, Knudsen UB, Nrgaard JP, Pedersen EB, Djurhuus JC
(1989). Abnormal diurnal rhythm of plasma vasopressin and
urinary output in patients with enuresis. Am J Physiol 256:
F664F671.
Rittig S, Robertson GL, Siggaard C, Kovcs L, Gregersen N,
Nyborg J, Pedersen EB (1996). Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds
with familial autosomal dominant neurohypophyseal diabetes
insipidus. Am J Hum Genet 58: 107117.
Rittig S, Siggaard C, Ozata M, Yetkin I, Gregersen N,
Pedersen EB, Robertson GL (2002). Autosomal dominant
neurohypophyseal diabetes insipidus due to substitution
2014 Refs
2/12/03
1:39 pm
Page 531
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
531
Robertsson B, Blennow K, Brne G, Edman , Karlsson I,

Wallin A, Gottfries CG (2001). Hyperactivity in the
hypothalamic-pituitary-adrenal axis in demented patients with
delirium. Int Clin Psychopharmacol 16: 3947.
Robinson AG, Amico JA (1991). Non-sweet diabetes of
pregnancy. N Engl J Med 324: 556558.
Robinson RG, Kubos KL, Starr BL, Rao K, Price TR (1984).
Mood disorders in stroke patients. Brain 107: 8193.
Robinson S, Rosca P, Durst R, Shai U, Ghinea C, Schmidt U,
Nir I (1991). Serum melatonin levels in schizophrenic and
schizoaffective hospitalized patients. Acta Psychiatr Scand
84: 221224.
Roca CA, Su T-P, Elpern S, McFarland H, Rubinow DR (1999).
Cerebrospinal fluid somatostatin, mood, and cognition in
multiple sclerosis. Biol Psychiatry 46: 551556
Rocha JL, Friedman E, Boson W, Moreira A, Figueiredo B,
Liberman B, De Lacerda L, Sandrini R, Graf H, Martins S,
Puales MK, De Marco L (1999). Molecular analysis of the
vasopressin type 2 receptor and aquaporin-2 genes in
Brazilian kindreds with nephrogenic diabetes insipidus. Hum
Mutat 14: 233239.
Rochira V, Balestrieri A, Madeo B, Baraldi E, Faustini-Fustini
M, Granata ARM, Carani C (2001). Congenital estrogen
deficiency: in search of the estrogen role in human male
reproduction. Mol Cell Endocrinol 178: 107115.
Rodenbeck A, Hajak G (2001). Neuroendocrine dysregulation
in primary insomnia. Rev Neurol 157: S57S61.
Rodenbeck A, Huether G, Rther E, Hajak G (1998). Altered
circadian melatonin secretion patterns in relation to sleep in
patients with chronic sleep-wake rhythm disorders. J Pineal
Res 25: 201210.
Rodriguez M, Scheithover B (1994). Ultrastructure of multiple
sclerosis. Ultrastruct pathol 18: 313.
Rodriguez MC, Obeso JA, Olanow CW (1998). Subthalamic
nucleus-mediated excitotoxicity in Parkinsons disease: a
target for neuroprotection. Ann Neurol (3 Suppl. 1) 44:
S175S188.
Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K,
Chockkman V, Vitek J, DeLong MR, Obeso JA (2001). The
subthalamic nucleus in Parkinsons disease: somatotopic
organization and physiological characteristics. Brain 124:
17771790.
Roeder F, Mller D (1969). The stereotaxic treatment of
paedophilic homosexuality. German Medical Monthly 6:
265271.
Roeling TAP, Veening JG, Kruk MR, Peters JPW, Vermelis
MEJ, Nieuwenhuys R (1994). Efferent connections of the
hypothalamic aggression area in the rat. Neuroscience 59:
10011024.
Roenneberg T, Aschoff J (1990). Annual rhythm of human
reproduction. I. Biology, sociology, or both? J Biol Rhythms
5:195216.
Roessmann U, Velasco ME, Small EJ, Hori A (1987).
Neuropathology of septo-optic dysplasia (De Morsier
of histidine for tyrosine-2 in the vasopressin moiety of

the hormone precursor. J Clin Endocrinol Metab 87:
33513355.
Rivarola MA, Mendilaharzu H, Warman M, Belgorosky A,
Iorcansky S, Castellano M, Caresana A, Chaler E, Maceiras
M (1992). Endocrine disorders in 66 suprasellar and pineal
tumors of patients with prepubertal and pubertal ages. Horm
Res 37: 16.
Rivarola MA, Belgorosky A, Mendilaharzu H, Vidal G (2001).
Precocious puberty in children with tumours of the suprasellar
and pineal areas: organic central precocious puberty. Acta
Paediatr 90: 751756.
Rivest S (2001). How circulating cytokines trigger the neural
circuits that control the hypothalamic-pituitary-adrenal axis.
Rivier C, Vale W (1983). Interaction of corticotropin-releasing
and arginine vasopressin on adrenocorticotropin secretion in
vivo. Endocrinology 113: 939942.
Rivkees SA (1997). Developing circadian rhythmicity. Pediatr
Rivkees SA (2001). Arrhythmicity in a child with septo-optic
dysplasia and establishment of sleep-wake cyclicity with
melatonin. J Pediatr 139: 463465.
Rivkees SA, Chaar MR, Hanley DF, Maxwell M, Reppert SM,
Uhl GR (1989). Localization and regulation of vasopressin
mRNA in human neurons. Synapse 3: 246254.
Rizzo V, Albanese A, Stanhope R (2001). Morbidity and
mortality associated with vasopressin replacement therapy in
children. J Pediatr Endocrinol Metab 14: 861867.
Rizzu P, Van Swieten J, Joosse M, Hasegawa M, Stevens M,
Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra
BA, Goedert M, Van Duijn CM, Heutink P (1999). High
prevalence of mutations in the microtubule-associated protein
tau in a population study of frontotemporael dementia in the
Netherlands. Am J Hum Genet 64: 414421.
Robben SGF, Oostdijk W, Drop SLS, Tanghe HLJ, Vielvoye
GJ, Meradji M (1995). Idiopathic isosexual central precocious
puberty: magnetic resonance findings in 30 patients. Br J
Radiol 68: 3438.
Robert F (1962). Sarcoidosis of the central nervous system.
Roberts GA, Eren E, Sinclair H, Pelling M, Burns A, Bradford
R, Maurice-Williams R, Black CM, Finer N, Bouloux P-MG
(1995). Two cases of Wegeners granulomatosis involving
the pituitary. Clin Endocrinol 42: 323328.
Robertson GL (2001). Antidiuretic hormone. Normal and
disordered function. Endocrinol Metab Clin North Am 30:
671-694.
Robertson GL, Rowe J (1980). The effect of aging on neurohypophyseal function. Peptides 1: 159162.
Robertson KM, Hramiak IM, Gelb AW (1989). Endocrine
changes and haemodynamic stability after brain death.
Transplant Proc 21: 11971198.
531
2014 Refs
532
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 532
D.F. SWAAB
syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropathol Exp Neurol 46:
597608.
Rogers C, Klatt EC (1988). Pathology of the testis in acquired immunodeficiency syndrome. Histopathology 12: 659665.
Rogers RC, Hermann GE (1985). Dorsal medullary oxytocin,
vasopressin, oxytocin antagonist, and TRH effects on gastric
acid secretion and heart rate. Peptides 6: 11431148.
Rogers RC, Hermann GE (1986). Oxytocin, oxytocin antagonist,
TRH, and hypothalamic paraventricular nucleus stimulation
effects on gastric motility. Peptides 8: 505513.
Rohner-Jeanrenaud F (1995). A neuroendocrine reappraisal of
the dual-centre hypothesis: its implications for obesity and
insulin resistance. Int J Obesity 19: 517534.
Rohr UD, Herold J (2002). Melatonin deficiencies in women.
Maturitas (Suppl. 1) 41: S85S104.
Rolandi E, Gandolfo C, Franceschini R, Cataldi A, Garibaldi A,
Barreca T (1992). Twenty-four-hour beta-endorphin secretory pattern in Alzheimers disease. Neuropsychobiology 25: 188192.
Rolls ET (1984). The neurophysiology of feeding. Int J Obesity
(Suppl. 1) 8: 139150.
Romeo E, Strhle A, Spalletta G, Di Michele F, Hermann B,
Holsboer F, Pasini A, Rupprecht R (1998). Effects of antidepressant treatment on neuroactive steroids in major
Romero J, Hillard CJ, Calero M, Rbano A (2002). Fatty acid amide
hydrolase localization in the human central nervous system: an
immunohistochemical study. Mol Brain Res 100 8593.
Romijn HJ (2002). Are virtual photons the elementary carriers
of consciousness? J Conscious Stud 9: 6181.
Romijn HJ, Van Uum JFM, Emmering J, Goncharuk V, Buijs
RM (1999). Colocalization of VIP with AVP in neurons of
the human paraventricular, supraoptic and suprachiasmatic
nucleus. Brain Res 832: 4753.
Romijn JA (1999). De conceptuele (r)evolutie in de endocrinologie. Acceptance speech, Chair Internal Medicine,
University of Leiden, 1999.
Romijn JA, Wiersinga WM (1990). Decreased nocturnal surge
of thyrotropin in nonthyroidal illness. J Clin Endocrinol
Metab 70: 3542.
Rondeau E, De Lima J, Caillens H, Ardaillou R, Vahanian A,
Acar J (1982). High plasma antidiuretic hormone in patients
with cardiac failure: influence of age. Min Electrolyte Metab
8: 267274.
Rondeel JMM, Klootwijk W, Linkels E, Van Haasteren GAC,
De Greef WJ, Visser TJ (1995). Regulation of thyrotropinreleasing hormone in the posterior pituitary. Neuroendocrinology 61: 421429.
Ronkainen H, Pakarinen A, Kirkinen P, Kauppila A (1985).
Physical exercise-induced changes and season-associated
differences in the pituitary-ovarian function of runners and
joggers. J Clin Endocrinol Metab 60: 416422.
Rnnberg L, Kauppila A, Leppluoto J, Martikainen H, Vakkuri
O (1990). Circadian and seasonal variation in human pre-
ovulatory follicular fluid melatonin concentration. J Clin

Roof RL, Hall ED (2000). Gender differences in acute CNS
trauma and stroke: neuroprotective effects of estrogen and
progesterone. J Neurotrauma 17: 367388.
Roscoe JA, Morrow GR, Hickok JT, Bushunow P, Matteson S,
Rakita D, Andrews PLR (2002). Temporal interrelationships
among fatigue, circadian rhythm and depression in breast
cancer patients undergoings chemotherapy treatment. Support
Care Cancer 10: 329336.
Rosn T, Bengtsson B- (1990). Premature mortality due to
cardiovascular disease in hypopituitarism. Lancet 336:
285288.
Rosn T, Edn S, Larson G, Wilhelmsen L, Bengtsson B-
(1993). Cardiovascular risk factors in adult patients with
growth hormone deficiency. Acta Endocrinol 129: 195200.
Rosenbaum M, Leibel RL, Hirsch J (1997). Obesity. N Engl J
Med 337: 396407.
Rosenberg P, Herishanu Y, Beilin B (1977). Increased appetite
(bulimia) in Parkinsons disease. J Am Geriatr Soc 25:
277278.
Rosenbloom AA, Sack J, Fisher DA (1975). The circulating
vasopressinage of pregnancy: series comparison using
radioimmunoassay. Am J Obstet Gynecol 121: 316320.
Rosenfeld JV, Harvey AS, Wrennall J, Zacharin M, Berkovic
SF (2001). Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic
epilepsy. Neurosurgery 48: 108118.
Rosenow F, Reuter S, Deu U, Szelies B, Hilgers R-D,
Winkelmann W, Heiss W-D (1996). Sleep apnoea in treated
acromegaly: relative frequency and predisposing factors. Clin
Rosenow F, McCarthy V, Caruso AC. (1998). Sleep apnoea in
endocrine disease. J Sleep Res 7: 311.
Rosenthal NE, Sack DA, Skwerer RG, Jacobsen FM, Wehr TA
(1988). Phototherapy for seasonal affective disorder. J Biol
Rhythms 3: 101120.
Rosenzweig MR, Bennett EL (1996). Psychobiology of
plasticity: effects of training and experience on brain and
behavior. Behav Brain Res 78: 5765.
Rosenzweig KE, Arceci RJ, Tarbell NJ (1997). Diabetes
insipidus secondary to Langerhans cell histiocytosis: is
radiation therapy indicated? Med Pediatr Oncol 29: 3640.
Rosete A, Cabral AR, Kraus A, Alarcn-Segovia D (1991).
Diabetes insipidus secondary to Wegeners granulomatosis:
report and review of the literature. J Rheumatol 18: 761765.
Rosler A, Witzum E (1998). Treatment of men with paraphilia
with a long-acting analogue of gonadotropin-releasing
hormone. N Engl J Med 338: 416422.
Rosmond R, Chagnon YC, Holm G, Chagnon M, Prusse L,
Lindell K, Carlsson B, Bouchard C, Bjrntorp P (2000). A
glucocorticoid receptor gene marker is associated with
abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. Obesity Res 8: 211218.
2014 Refs
2/12/03
1:39 pm
Page 533
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
533
Rotman-Pikielny P, Patronas N, Papanicolaou DA (2003).

Pituitary apoplexy induced by corticotrophin-releasing
hormone in a patient with Cushings disease. Clin Endocrinol
58: 545549.
Rottenberg GT, Chong WK, Powell M, Kendall BE (1994).
Cyst formation of the craniopharyngeal duct. Clin Radiol 49:
126129.
Rotterdam H, Dembitzer F (1993). The adrenal gland in AIDS.
Rousseau A, Petrn S, Plannthin J, Eklundh T, Nordin C (1999).
Serum and cerebrospinal fluid concentrations of melatonin:
a pilot study in healthy male volunteers. J Neural Transm
106: 883888.
Rousseau-Merck MF, Ren P, Derr J, Bienvenu T, Berger T,
De Keyzer Y (1995). Chromosomal localization of
the human V3 pituitary vasopressin receptor gene (AVPR3) to
1q32.
Rowe JW, Kilgore A, Robertson GL (1980). Evidence in man
that cigarette smoking induces vasopressin release via an
airway-specific mechanism. J Clin Endocrinol Metab 51:
170171.
Rowe JW, Minaker KL, Sparrow D, Robertson GL (1982). Agerelated failure of volume-pressure-mediated vasopressin
release. J Clin Endocrinol Metab 54: 661664.
Rowe R, Pickles A, Simonoff E, Bulik CM, Silberg JL (2002).
Bulimic symptoms in the Virginia twin study of adolescent
behavioral development: correlates, comorbidity, and
genetics. Biol Psychiatry 51: 172182.
Roy A, Wolkowitz OM, Bissette G, Nemeroff CB (1994).
Differences in CSF concentrations of thyrotropin-releasing
hormone in depressed patients and normal subjects: negative
findings. Am J Psychiatry 151: 600602.
Roy BN, Reid RL, Van Vugt DA (1999). The effects of estrogen
and progesterone on corticotropin-releasing hormone and
arginine vasopressin messenger ribonucleic acid levels in the
paraventricular nucleus and supraoptic nucleus of the rhesus
monkey. Endocrinology 140: 21912198.
Rozen TD, Niknam RM, Shechter AL, Young WB, Silberstein
SD (2001). Cluster headache in women: clinical characteristics and comparison with cluster headache in men. J Neurol
Rubenstein E (1998). Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the aged.
Lancet 351: 283285.
Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R,
Hauw JJ, Duyckaerts C, Gray F, Maroger-Morel A, Rascol
A, Serdaru M, Agid Y (1985). Dopaminergic and cholinergic
lesions in progressive supranuclear palsy. Ann Neurol 18:
523529.
Rubin K, Cassidy SB (1988). Hypogonadism and osteroporosis.
In: Greenswag, LR, Alexander RC (Eds.) Management of
PraderWilli Syndrome. Springer-Verlag, New York, pp.
2333.
Rosmond R, Ukkola O, Bouchard C, Bjrntorp P (2002).

Polymorphisms in exon 3 of the proopiomelanocortin gene
in relation to serum leptin, salivary cortisol, and obesity in
Swedish men. Metabolism 51: 642644.
Ross C, Morris B, Whitehouse W (1999). Melatonin treatment
of sleep-wake cycle disorders in children and adolescents.
Dev Med Child Neurol 41: 850.
Ross C, Davies P, Whitehouse W (2002). Melatonin treatment
for sleep disorders in children with neurodevelopmental disorders: an observational study. Devel Med Child Neurol 44:
339344.
Ross ED, Stewart RM (1981). Akinetic mutism from hypothalamic damage: successful treatment with dopamine
agonists. Neurology 31: 14351439.
Ross CA, Margolis RL, Rosenblatt A, Ranen NG, Becher MW,
Aylward E (1997). Huntington disease and the related
disorder, dentatorubral-pallidoluysian atrophy (DRPLA).
Medicine 76: 305338.
Rosse RB, Kendrick K, Tsui LC, Fay-McCarthy M, Collins JP,
Rosenberg P, Wyatt RJ, Deutsch SI (1995). Famotidine
adjunctive pharmacotherapy of schizophrenia: a case report.
Rossi G, Macchi G, Porro M, Giaccone G, Bugiani M,
Scarpini E, Scarlato G, Molini GE, Sasanelli F, Bugiani O,
Tagliavini F (1998a). Fatal familial insomnia. Neurology 50:
688692.
Rossi M, Kim MS, Morgan DGA, Small CJ, Edwards
CMB, Sunter D, Abusnana S, Goldstone AP, Russell SH,
Stanley SA, Smith DM, Yagaloff MA Ghatei Bloom SR
(1998b). A C-terminal fragment of Agouti-related protein
increases feeding and antagonizes the effect of alphamelanocyte stimulating hormone in vivo. Endocrinology 139:
44284431.
Rossi ML, Bevan JS, Esiri MM, Hughes JT, Adams CBT
(1987). Pituicytoma (pilocytic astrocytoma).. J Neurosurg 67:
768772.
Rosso SM, Van Herpen E, Deelen W, Kamphorst W, Severijnen
LA, Willemsen R, Ravid R, Niermeijer MF, Dooijes D, Smith
MJ, Goedert M, Heutink P, Van Swieten JC (2002). Ann
Neurol 51: 373376.
Rosso SM, Kamphorst W, De Graaf B, Willemsen R, Ravid R,
Niermeijer MF, Spillantini MG, Heutink P, Van Swieten JC
(2001). Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22. Brain 124:
19481957.
Rossor MN, Iversen LL, Hawthorn J, Ang VTY, Jenkins JS
(1981). Extrahypothalamic vasopressin in human brain. Brain
Res 214: 349355
Rtig A, Cormier V, Chatelain P, Francois R, Saudubray J-M,
Rustin P, Munnich A (1993). Deletion of mitochondrial DNA
in a case of early-onset diabetes mellitus, optic atrophy, and
deafness (Wolfram syndrome, MIM 2223000). J Clin Invest
91: 10951098.
533
2014 Refs
534
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 534
D.F. SWAAB
Rubin RT, Phillips JJ, McCracken JT, Sadow TF (1996).

Adrenal gland volume in major depression: relationship to
basal and stimulated pituitary-adrenal cortical axis function.
Rubin RT, Rhodes ME, Czambel RK (2003). Plasma leptin
suppression by arginine vasopressin in normal women and
men. Life Sci 72: 12091220.
Rubino GJ, King WA, Quinn B, Marroquin CE, Verity MA
(1993). Primary pineal melanoma: case report. Neurosurgery
33: 511515.
Rubinow DR, Schmidt PJ, Roca CA (1998). Estrogen-serotonin
interactions: implications for affective regulation. Biol
Rubio E, Arjona V, Rodriguez-Burgos F (1977). Stereotactic
cryohypothalamotomy in aggressive behavior. In: Sweet WH,
Obrador S, Martn-Rodrguez JG (Eds.) Neurosurgical treatment in psychiatry, pain and epilepsy. University Park Press,
Rudelli R, Deck JHN (1979). Selective traumatic infarction of
the human anterior hypothalamus. J Neurosurg 50: 645654.
Rudelli RD, Ambler MW, Wisniewski HM (1984). Morphology and
distribution of Alzheimer neuritic (senile) and amyloid plaques in
striatum and diencephalon. Acta Neuropathol 64: 273281.
Rugarli EI (1999). Kallmann syndrome and the link between
olfactory and reproductive development. Am J Hum Genet
65: 943948.
Rugarli EI, Ballabio A (1993). Kallmann syndrome: from
genetics to neurobiology. JAMA 270: 27132716.
Rugarli EI, Lutz B, Kuratani SC, Wawersik S, Borsani G,
Ballabio A, Eichele G (1993). Expression pattern of the
Kallmann syndrome gene in the olfactory system suggests a
role in neuronal targeting. Nat Genet 4: 1926.
Ruitenberg A, Ott A, Van Swieten JC, Hofman A, Breteler
MMB (2001). Incidence of dementia: does gender make a
difference? Neurobiol. Aging 22: 575580.
Rusak B, Zucker I (1979). Neural regulation of circadian
rhythms. Physiol Rev 59: 449526.
Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM,
Giller C, Nahas Z, Haines S Simpson Jr RK, Goodman R
(2000). Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 47:
276286.
Russell A (1951). A diencephalic syndrome of emaciation in
infancy and childhood. Arch Dis Child 26: 274.
Russell GFM, Bruce JT (1966). Impaired water diuresis in
patients with anorexia nervosa. Am J Med 40: 3848.
Russell JA, Leng G (1998). Sex, parturition and motherhood
without oxytocin. J Endocrinol 157: 343359.
Russell KL, Ming JE, Patel K, Jukofsky L, Magnusson M,
Krantz ID (2001). Dominant paternal transmission of
Cornelia de Lange syndrome: a new case and review of 25
previously reported familial recurrences. Am J Med Genet
104: 267276.
Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL

(1999). In vivo semiquantification of hypothalamic growth
hormone-releasing hormone (GHRH) output in humans:
evidence for relative GHRH deficiency in aging. J Clin
Rutila JE, Suri V, Le M, So WV, Rosbash M, Hall JC (1998).
CYCLE is a second bHLH-PAS Clock protein essential for
circadian rhythmicity and transcription of Drosophila period
and timeless. Cell 93: 805814.
Rutishauser J, Bni-Schnetzler M, Bni J, Wichmann W,
Huisman T, Vallotton MB, Froesch ER (1996). A novel
point mutation in the translation initiation codon of the
prepro-vasopressin-neurophysin II gene: cosegregation with
morphological abnormalities and clinical symptoms in autosomal dominant neurohypophyseal diabetes insipidus. J Clin
Rutishauser J, Kopp P, Gaskill M B, Kotlar TJ, Robertson GL
(1999). A novel mutation (R97C) in the neurophysin moiety
of prepro-vasopressin-neurophysin II associated with autosomal-dominant neurohypophyseal diabetes insipidus. Mol
Genet Metab 67: 8992.
Rutka JT, Hoffman HJ, Drake JM, Humphreys RP (1992).
Suprasellar and sellar tumors in childhood and adolescence.
Neurosurg Clin N Am 3: 803820.
Ryan JM (2000). Pharmacologic approach to aggression in
neuropsychiatric disorders. Semin Clin Neuropsychiatry 5:
238249.
Ryden G, Sjvholm I (1971). The metabolism of oxytocin in
pregnant and non-pregnant women. Acta Obstet Gynecol
Scand 50: 37.
Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H (1992).
Circadian rhythm abnormalities in totally blind people: incidence
and clinical significance. J Clin Endocrin Metab 75: 127134.
Sack RL, Brandes RW, Kendall AR, Lewy AJ (2000).
Entrainment of free-running circadian rhythms by melatonin
in blind people. N Engl J Med 343: 10701077.
Sadeghi M, Fakhrai A (2000). Transsexualism in female
monozygotic twins: a case report. Aust NZ J Psychiatry 34:
862864.
Sadeh A (1997). Sleep and melatonin in infants: a preliminary
study. Sleep 20: 185191.
Sadovnick AD, Ebers GC (1993). Epidemiology of multiple
sclerosis: a critical overview. Can J Neurol Sci 20: 1729.
Sadovnick AD, Remick RA, Allen J, Swartz E, Yee IML, Eisen
K, Farquhar R, Hashimoto SA, Hooge J, Kastrukoff LF,
Morrison W, Nelson J, Oger J, Paty DW (1996). Depression
and multiple sclerosis. Neurology 46: 628632.
Sadun AA, Smith LEH, Kenyon KR (1983). Paraphenylenediamine: a new method for tracing human visual pathways.
Sadun AA, Schaechter JD, Smith LEH (1984). A retinohypothalamic pathway in man: light mediation of circadian
rhythms. Brain Res 302: 371377.
2014 Refs
2/12/03
1:39 pm
Page 535
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
535
Saito Y, Nothacker H-P, Civelli O (2000b). Melanin-concentrating hormone receptor: an orphan receptor fits the key.
Trends Endocrinol Metab 11: 299303.
Saitoh Y, Nihonmatsu I, Kawamura H (1990). Location of the
suprachiasmatic nucleus grafts in rats which restored circadian
rhythmicity after transplantation. Neurosci Lett 118: 4548.
Sakamoto N, Pearson J, Shinoda K, Alheid GF, De Olmos JS,
Heimer L (1999). The human basal forebrain. Part 1. An
overview. In: Bjrklund, A, Hkfelt T (Eds.) Handbook of
Chemical Neuroanatomy, The Primate Nervous System, Part
III. Elsevier, Amsterdam, pp. 115.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM,
Tanaka H, Williams SC, Richardson JA, Kozlowski GP,
Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA,
Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy
NA, Bergsma DJ, Yanagisawa M (1998). Orexins and orexin
receptors: a family of hypothalamic neuropeptides and G
protein-coupled receptors that regulate feeding behavior. Cell
92: 573585.
Salazar H, MacAulay MA, Charles D, Pardo M (1969). The
human hypophysis in anencephaly. Arch Pathol 87: 201211.
Salehi A, Swaab DF (1998). Neurotrophin receptors in
Alzheimers disease. In: Van Leeuwen FW, Salehi A, Giger
R, Holtmaat AJGD, Verhaagen J Neuronal degeneration and
regeneration: from basic mechanisms to prospects for therapy
(Progress in Brain Research, Vol. 117), Elsevier, Amsterdam,
pp. 7189.
Salehi A, Lucassen PJ, Pool CW, Gonatas NK, Ravid R, Swaab
DF (1994). Decreased neuronal activity in the nucleus basalis
of Meynert in Alzheimers disease as suggested by the size
of the Golgi apparatus. Neuroscience 59: 871880.
Salehi A, Heyn S, Gonatas NK, Swaab DF (1995a). Decreased
protein synthetic activity of the hypothalamic tuberomamillary nucleus in Alzheimers disease as suggested by smaller
Golgi apparatus. Neurosci Lett 193: 2932.
Salehi A, Van de Nes JAP, Hofman MA, Gonatas NK, Swaab
DF (1995b). Early cytoskeletal changes as shown by Alz-50
are not accompanied by decreased neuronal activity. Brain
Res 678: 2939.
Salehi A, Ravid R, Gonatas NK, Swaab DF (1995c). Decreased
activity of hippocampal neurons in Alzheimers disease is
not related to the presence of neurofibrillary tangles. J
Salehi A, Verhaagen J, Dijkhuizen PA, Swaab DF (1996).
Colocalization of high affinity neurotrophin receptors in
nucleus basalis of Meynert neurons and their differential
reduction in Alzheimers disease. Neuroscience 75: 373387.
Salehi A, Dubelaar EJG, Mulder M, Swaab DF (1998a).
Aggravated decrease in the activity of nucleus basalis neurons
in Alzheimers disease is apolipoprotein E-type dependent.
Salehi A, Pool CW, Mulder M, Gonatas NK, Swaab DF (1998b).
Activity of hippocampal CA1 neurons in Alzheimers disease
Saeki N, Uchida D, Tatsuno I, Saito Y, Yamaura A (1999).

MRI detection of suprasellar germinoma causing central
diabetes insipidus. Endocr J 46: 263267.
Saeki N, Tamaki K, Murai H, Kubota M, Yamaura A, Uchida
D, Noguchi Y, Nakamuri S, Tatsuno I, Wada K, Minagawa
M, Yasuda T (2000). Long-term outcome of endocrine function in patients with neurohypophyseal germinomas. Endocr
J 47: 8389.
Saeki N, Sunami K, Kubota M, Murai H, Takanashi J-I,
Iuchi T, Yamaura A (2001). Heavily T2-weighted MR
imaging of white matter tracts in the hypothalamus: normal
and pathologic demonstrations. Am J Neuroradiol 22:
14681475.
Saeki N, Hoshi S, Sunada S, Sunami K, Murai H, Kubota M,
Tatsuno I, Iuchi T, Yamaura A (2002). Correlation of high
signal intensity of the pituitary stalk in macroadenoma and
postoperative diabetes insipidus. Am J Neuroradiol 23:
822827.
Sahu A (1998). Leptin decreased food intake induced by
melanin-concentrating hormone (MCH), galanin (GAL) and
neuropeptide Y (NPY) in the rat. Endocrinology 139:
47394742.
Sahn M, Villabona C, Rosel R, Navarro MA, Ramn JM,
Gmez JM, Soler J (2001). Water metabolism disturbances
at different stages of primary thyroid failure. J Endocrinol
168: 435445.
Said SI, Mutt V (1972). Isolation from porcine intestinal wall
of a vasoactive octacosapeptide related to secretion and to
glucagon. Eur J Biochem 28: 199204.
Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong S-S,
Feighner SD, Tan CP, Fukami T, Iwaasa H et al. (2001).
Identification and characterization of a second melaninconcentrating hormone receptor, MCH-2R. Proc Natl Acad
Sci USA 98: 75647569.
Saito E., Kinoshita M, Kawamura T, Kasahara K (1987). Large
molecular weight ACTH immunoactivity in a patient with
adrenoleukomyeloneuropathy. Am J Med 83: 777782.
Saito M, Tahara A, Sugimoto T, Abe K, Furuichi K (2000a).
Evidence that atypical vasopressin V2 receptor in inner
medulla of kidney is V1B receptor. Eur J Pharmacol 401:
289296.
Saito T, Ishikawa S-E, Ando F, Okada N, Nakamura T, Kusaka
I, Higashiyama M, Nagasaka S, Saito T. (1998). Exaggerated
urinated excretion of aquaporin-2 in the pathological state of
impaired water excretion dependent upon arginine vasopressin. J Clin Endocrinol Metab 83: 40344040.
Saito T, Higashiyama M, Nakamura T, Kusaka I, Nagasaka S,
Saito T, Ishikawa S-e (2001). Urinary excretion of the aquaporin-2 water channel exaggerated in pathological states of
impaired water excretion. Clin Endocrinol 55: 217221.
Saito Y, Nothacker H-P, Wang Z, Lin SHS, Leslie F, Civelli
O (1999). Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400: 265269.
535
2014 Refs
536
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 536
D.F. SWAAB
is not affected by the presence of adjacent neuritic plaques.

J Alzheimers Dis 107118.
Salehi A, Gonzalez-Martinez V, Swaab DF (1998c). A sex
difference and no effect of APOE type on the amount of
cytoskeletal alterations in the nucleus basalis of Meynert in
Alzheimers disease. Neurobiol Aging 19: 505510
Salehi A., Ocampo M, Verhaagen J, Swaab DF (2000). p75
neurotrophin receptors in the nucleus basalis of Meynert in
relation to age, sex and Alzheimers disease. Exp Neurol 161:
245258.
Salgado LR, Mendona BB, Pereira MAA, Goic MSZ, Semer
M, Moreira AC, Knoepfelmacher M, Nery M, Magalhes
ACA, Tovo R, Wajchenberg BL, Liberman B (1997). Use
of desmopressin in bilateral and simultaneous inferior
petrosal sinus sampling for differential diagnosis of
ACTH-dependent Cushings syndrome. Endocrinologist 7:
135140.
Salin-Pascual R, Gerashchenko D, Greco MA, Blanco-Centurion
C, Shiromani PJ (2001). Hypothalamic regulation of sleep.
Neuropsychopharmacology (Suppl. 5) 25: S21S27.
Salomez-Granier F, Leclerc-Coornaert L, Lefebvre J, Racadot
A, Linquette M (1983). tude de lhormone antidiurtique
(arginine-vasopressine) dans 24 cas dinsuffisance surrnale
primitive. Annales dEndocrinol 44: 371376.
Salter MS, White PD (1993). A variant of the KleineLevin
syndrome precipitated by both Epstein-Barr and VaricellaZoster virus infections. Biol Psychiatry 33: 388390.
Salvesen R, Bekkelund SI (2000). Migraine, as compared to
other headaches, is worse during midnight-sun summer than
during polar night. A questionnaire study in an arctic population. Headache 40: 824829.
Salzberg AD, Swedo SE (1992). Oxytocin and vasopressin in
obsessive-compulsive disorder. Am J Psychiatry 149:
713714.
Sample PA, Esterson FD, Weinreb RN, Boynton RM
(1988). The aging lens: in vivo assessment of light absorption
in 84 human eyes. Invest Ophthalmol Vis Sci 29: 13061311.
Samson WK, Resch ZT (2000). The hypocretin/orexin story.
Trends Endocrinol Metab11: 257262.
Sanberg PR, Fibiger HC, Mark RF (1981). Body weight and
dietary factors in Huntingtons disease patients compared with
matched controls. Med J Aust 1: 407409.
Sandberg AA, Eik-Nes K, Migeon CJ, Samuels LT (1956).
Metabolism of adrenal steroids in dying patients. J Clin
Sandberg DE, Vena JE, Weiner J, Beehler GP, Swanson M,
Meyer-Bahlburg HFL (2003). Hormonally active agents
in the environment and childrens behavior: assessing influences on gender-dimorphic outcomes. Epidemiology 14:
148154.
Sandfort TGM, De Graaf R, Bijl RV, Schnabel P (2001). Samesex sexual behavior and psychiatric disorders. Arch Gen
Sandyk R (1989). Hypothalamic compensatory mechanisms in

Parkinsons disease. Int J Neurosci 44: 135142
Sandyk R (1992a). Pineal and habenula calcification in schizophrenia. Int J Neurosci 67: 1930.
Sandyk R (1992b). Postpartum psychosis and the pineal gland.
Int J Neurosci 62: 101105.
Sandyk R, Awerbuch GI (1992). Nocturnal plasma melatonin
and alpha-melanocyte stimulating hormone levels during
exacerbation of multiple sclerosis. Int J Neurosci 67: 173186.
Sandyk R, Kay SR (1990). Pineal melatonin in schizophrenia:
a review and hypothesis. Schizophr Bull 16: 653662.
Sandyk R, Bamford CR, Iacono RP (1987). Sleep disorders in
Tourettes syndrome. Int J Neurosci 37: 5965.
Sandyk R, Iacono RP, Bamford CR (1987). The hypothalamus
in Parkinsons disease. Ital J Neurol Sci 8: 227234.
Sanghera MK, Zamora J-L, German DC (1995). CalbindinD28k-containing neurons in the human hypothalamus:
relationship to dopaminergic neurons. Neurodegeneration 4:
375381.
Sangruchi T, Kowall NW (1991). NADPH diaphorase histochemistry of the human hypothalamus. Neuroscience 40:
713724.
Sanides F (1957). Die Insulae terminales des Erwachsenengehirns des Menschen. J Hirnforsch 3: 243273.
Sano K (1966). Sedative stereoencephalotomy: fornicotomy,
upper mesencephalic reticulotomy and postero-medial hypothalamotomy. Prog Brain Res 21: 350372.
Sano K (1987). Neurosurgical treatment of pain a general
survey. Acta Neurochir Suppl 38: 8696.
Sano K, Mayanagi Y (1988). Posteromedial hypothalamotomy
in the treatment of violent, aggressive behaviour. Acta
Neurochir Suppl 44: 145151.
Sano K, Yoshioka M, Ogashiwa M, Ishijima B, Ohye C (1966).
Postero-medial hypothalamotomy in the treatment of aggressive behaviors. Confin Neurol 27: 164167.
Sano K, Ogashiwa M, Sekino H (1968). Clinical and physiological data obtained in stereotaxic surgery of the
hypothalamus. Proc Aust Assoc Neurol 5: 267275.
Sano K, Mayanagi Y, Sekino H, Ogashiwa M, Ishijima B (1970).
Results of stimulation and destruction of the posterior hypothalamus in man. J Neurosurg 33: 689707.
Sano K, Sekino H, Hashimoto I, Amano K, Sugiyama H (1975).
Posteromedial hypothalamotomy in the treatment of
intractable pain. Confin Neurol 37: 285290.
Sano T, Kovacs KT, Scheithauer BW, Young WF (1993).
Aging and the human pituitary gland. Mayo Clin Proc. 68:
971977.
Santiago JR, Nolledo MS, Kinzler W, Santiago TV (2001). Sleep
and disorders in pregnancy. Ann Intern Med 134: 396408.
Santiaprabhob J, Browning JE, Repaske DR (2002). A missense
mutation encoding Cys73Phe in neurophysin II is associated
with autosomal dominant neurohypophyseal diabetes
insipidus. Mol Genet Metab 77: 112118.
2014 Refs
2/12/03
1:39 pm
Page 537
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
537
Sassin I, Schultz C, Thai DR, Rb U, Arai K, Braak E, Braak

H (2000). Evolution of Alzheimers disease-related
cytoskeletal changes in the basal nucleus of Meynert. Acta
Satlin A, Volicer L, Ross V, Herz L, Campbell S (1992). Bright
light treatment of behavioral and sleep disturbances in patients with Alzheimers disease. Am J Psychiatry 149:
10281032.
Satlin A, Volicer L, Stopa EG, Harper D (1995). Circadian
locomotor activity and core-body temperature rhythms in
Alzheimers disease. Neurobiol Aging 16: 765771.
Satoh K, Mishima K (2001). Hypothermic action of exogenously administered melatonin is dose-dependent in humans.
Sato A, Kajita A, Sugita K, Izumi T, Fukuyama Y, Funata N,
Okeda R (1986). Cornelia de Lange syndrome with intracranial germinoma. Acta Pathol Jpn 36: 143149.
Sato N, Endo K, Ishizaka H, Matsumoto M (1993). Serial MR
intensity changes of the posterior pituitary in a patient with
anorexia nervosa, high serum ADH, and oliguria. J Comput
Assist Tomogr 17: 648650.
Sato N, Endo K, Kawai H, Shimada A, Hayashi M, Inoue T
(1995). Hemodialysis: relationship between signal intensity
of the posterior pituitary gland at MR imaging and level of
plasma antidiuretic hormone. Radiology 194: 277280.
Satoh F, Takahashi K, Murakami O, Totsune K, Sone M,
Ohneda M, Sasano H, Mouri T (1996). Immunocytochemical
localization of adrenomedullin-like immunoreactivity in the
human hypothalamus and the adrenal gland. Neurosci Lett
203: 207210.
Satoh J, Takeshige H, Hara H, Fukuyama Y (1982). Brain
shrinkage and subdural effusion associated with ACTH
administration. Brain Dev 4: 1320.
Satoh N, Ogawa Y, Katsuura G, Hayase M, Tsuji T, Imagawa
K, Yoshimasa Y, Nishi S, Hosoda K, Nakao K (1997). The
arcuate nucleus as a primary site of satiety effect of leptin
in rats. Neurosci Lett 224: 149152.
Savaskan E, Olivieri G, Brydon L, Jockers R, Kruchi K, WirzJustice A, Mller-Spahn F (2001). Cerebrovascular melatonin
MT1-receptor alterations in patients with Alzheimers disease.
Savaskan E, Wirz-Justice A, Oliveiri G, Pache M, Kruchi K,
Brydon L, Jockers R, Mller-Spahn F, Meyer P (2002a).
Distribution of melatonin MT1 receptor immunoreactivity in
human retina. J Histochem Cytochem 50: 519525.
Savaskan E, OlivieroG, Meier F, Brydon L, Jockers R, Ravid
R, Wirz-Justice A, Mller-Spahn F (2002b). Increased melatonin 1a-receptor immunoreactivity in the hippocampus of
Alzheimers disease patients. J Pineal Res 32: 5962.
Savastano S, Tommaselli AP, Valentino R, Scarpitta MT,
DAmore G, Luciano A, Covelli V, Lombardi G (1994).
Hypothalamic-pituitary-adrenal axis and immune system.
Acta Neurol 16: 206213.
Saper CB (1985). Organization of cerebral cortical afferent

systems in the rat. II Hypothalamocortical projections. J Comp
Neurol 237: 2146.
Saper CB (1990). Hypothalamus. In: Paxinos G (Ed.) The
Human Nervous System, pp. 389413, Academic Press, Inc.,
San Diego.
Saper CB (1998). All fall down: the mechanism of orthostatic
hypotension in multiple systems atrophy and Parkinsons
disease. Ann Neurol 43: 149151.
Saper CB, Chelimsky TC (1984). A cytoarchitectonic and histochemical study of nucleus basalis and associated cell groups
in the normal human brain. Neuroscience 13: 10231037.
Saper CB, German DC (1987). Hypothalamic pathology in
Alzheimers disease. Neurosci Lett 74: 364370.
Saper CB, Petito CK (1982). Correspondence of melaninpigmented neurons in human brain with A1A14
catecholamine cell groups. Brain 105: 87101.
Sapolsky RM (1996). Why stress is bad for your brain. Science
273: 749750.
Sapolsky RM, McEwen BS (1986). Stress, glucocorticoids, and
their role in degenerative changes in the aging hippocampus.
In: Crook T, Bartens RT, Ferris S, Gershon S (Eds.) Treatment
Development Strategies for Alzheimers Disease. Marc
Powley Ass., pp. 151171.
Sapolsky RM, Krey LC, McEwen BS (1986). The neuroendocrinology of stress and aging: the glucocorticoid cascade
hypothesis. Endocr Rev 7: 284301.
Sarai M, Matsunaga H (1989). ADH secretion in schizophrenic
patients on antipsychotic drugs. Biol Psychiatry 26: 576580.
Sarchielli P, Alberti A, Floridi A, Gallai V (2001). Levels of
nerve growth factor in cerebrospinal fluid of chronic daily
headache patients. Neurology 57: 132134.
Sarnat HB, Flores-Sarnat L (2001). Neuropathologic research
strategies in holoprosencephaly. J Child Neurol 16: 918931.
Sarrieau A, Najimi M, Chigr F, Kopp N, Jordan D, Rostene W
(1994). Localization and developmental pattern of vasoactive
intestinal polypeptide binding sites in the human hypothalamus. Synapse 17: 129140.
Sarter M, Bruno JP (2002). The neglected constituent of the
basal forebrain corticopetal projection system: GABAergic
projections. Eur J Neurosci 15: 18671873.
Sartoretti-Schefer S, Wichmann W, Aguzzi A, Valavanis A
(1997). MR differentiation of adamantinous and squamouspapillary craniopharyngiomas. Am J Neuroradiol 18: 7787.
Sarwar M (1989). The septum pellucidum: normal and
abnormal. Am J Neuroradiol 10: 9891005.
Sasano H, Takahashi K, Satoh F, Nagura H, Harada N (1998).
Aromatase in the human central nervous system. Clin
Sassi RB, Nicoletti M, Brambilla P, Harenski K, Mallinger AG,
Frank E, Kupfer DJ, Keshavan MS, Soares JC (2001).
Decreased pituitary volume in patients with bipolar disorder.
537
2014 Refs
538
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 538
D.F. SWAAB
Savic I, Berglund H, Gulyas B, Roland P (2001). Smelling of

odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans. Neuron 30: 661668.
Savoiardo M, Ciceri E, DIncerti L, Uziel G, Scott G (1995).
Symmetric lesions of the subthalamic nuclei in mitochondrial
encephalopathies: an almost distinctive mark of Leigh disease
with COX deficiency. Am J Neuroradiol 16: 17461747.
Sawchenko PE, Swanson LW (1982). Immunohistochemical
identification of neurons in the paraventricular nucleus of the
hypothalamus that project to the medulla or to the spinal cord
in the rat. J Comp Neurol 205: 260272.
Sawchenko PE, Swanson LW, Vale WW (1984). Corticotropinreleasing factor: co-expression within distinct subsets of oxytocin-, vasopressin-, and neurotensin-immunoreactive neurons
in the hypothalamus of male rat. J Neurosci 4: 11181129.
Sawin CT (2000). Vasopressin is a hormone: the work of Ernest
Basil Verney (18941967). Endocrinologist 10: 7982.
Sarzi-Puttini P, Rizzi M, Andreoli A, Panni B, Pecis M,
Colombo S, Turiel M, Carrabba M, Sergi M (2002).
Hypersomnolence in fibromyalgia syndrome. Clin Exp
Rheumatol 20: 6972.
Scacchi M, Pincelli AI, Caumo A, Tomasi P, Delitala G, Baldi
G, Cavagnini F (1997). Spontaneous nocturnal growth
hormone secretion in anorexia nervosa. J Clin Endocrinol
Metab 82: 32253229.
Scammell TE, Nishino S, Mignot E, Saper CB (2001).
Narcolepsy and low CSF orexin (hypocretin) concentration
after a diencephalic stroke. Neurology 56: 17511753.
Scaramella TJ, Brown WA (1978). Serum testosterone and aggressiveness in hockey players. Psychosom Med 40: 262265.
Schaap C, Ten Tusscher MPM, Schrander JJP, Kuijten RH,
Schrander-Stumpel CTRM (1998). Phenotypic overlap
between McKusickKaufman and BardetBiedl syndromes:
are they related? Eur J Pediatrics 157: 170171.
Schachter SC (1994). Neuroendocrine aspects of epilepsy.
Neurol Clin 12: 3140.
Schaechter JD, Sadun AA (1985). A second hypothalamic
nucleus receiving retinal input in man: the paraventricular
Schaefer GB, Bodensteiner JB, Thompson JN (1994). Subtle
anomalies of the septum pellucidum and neurodevelopmental
deficits. Dev Med Child Neurol 36: 554559.
Schalin-Jntti C, Valli-Jaakola K, Oksanen L, Martelin E,
Laitinen K, Krusius T, Mustajoki P, Heikinheimo M, Kontula
K (2003). Melanocortin-3-receptor gene variants in morbid
obesity. Int J Obesity 27: 7074.
Schally AV, Comaru-Schally AM, Nagy A, Kovacs M,
Szepeshazi K, Plonowski A, Varga JL, Halmos G (2001).
Hypothalamic hormones and cancer. Front Neuroendocrinol
22: 248291.
Schaltenbrand G, Bailey P (1959). Introduction to stereotaxis
with an atlas of the human brain. Vol. 1. Georg Thieme
Verlag, Stuttgart.
Scharrer B (1975). Neurosecretion and its role in neuroendocrine

regulation. In: Meites J, Donovan BT, McCann SM (Eds.)
Pioneers in Neuroendocrinology. Plenum Publishing Corp.
New York. pp. 257265.
Scharrer E (1933). Die erklrung der scheinbar pathologischen
Zellbilder im nucleus supraopticus und nucleus paraventricularis. Ges Neurol Psychiatr 145: 462470.
Scharrer E, Scharrer B (1940). Secretory cells within the hypothalamus. The Hypothalamus and Central Levels of
Autonomic Function. Nerv Ment Dis 20: 170194.
Scheer FAJL, Buijs RM (1999). Light affects morning salivary
cortisol in humans. J Clin Endocrinol Metab 84: 33953398.
Scheer FAJL, Van Doornen LJP, Buijs RM (1999). Light and
diurnal cycle affect human heart rate: possible role for the
circadian pacemaker. J Biol Rhythms 14: 202212.
Scheer FAJL, Ter Horst GJ, Van der Vliet J, Buijs RM (2001).
Physiological and anatomic evidence for regulation of the
heart by suprachiasmatic nucleus in rats. Am J Physiol 280:
H1391H1399.
Scheithauer BW, Kovacs K, Randall RV, Horvath E, Okazaki
H, Laws ER (1983). Hypothalamic neuronal hamartoma and
adenohypophyseal neuronal choristoma: their association with
growth hormone adenoma of the pituitary gland. J
Schenck CH, Mahowald MW (2002). REM sleep behavior
disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep
25: 120138.
Schenk CH, Hurwitz TD, Mahowald MW (1993). REM sleep
behaviour disorder: an update on a series of 96 patients and
a review of the world literature. J Sleep Res 2: 224231.
Scherbaum WA, Wass JAH, Besser GM, Bottazzo GF, Doniach
D (1986). Autoimmune cranial diabetes insipidus: its association with other endocrine diseases and with histiocytosis X.
Scherbaum WA (1992). Autoimmune hypothalamic diabetes
insipidus (autoimmune hypothalamitis). Prog Brain Res 93:
283293.
Scherder EJA (2000). Low use of analgesics in Alzheimers
disease. Possible mechanisms. Psychiatry 63: 112
Scherder EJA, Bouma A (1997). Is decreased use of analgesics
in Alzheimers disease due to a change in the affective component of pain? Alzheimer Dis. Assoc Disord 11: 171174.
Scherder EJA, Bouma A (2000a). Acute versus chronic, affective pain experience in Alzheimer patients. A new
questionnaire. Dement Geriatr Cogn Disord 11: 1116.
Scherder EJA, Bouma A (2000b). Visual analogue scales for
pain assessment in Alzheimers disease. Gerontology 46:
4753.
Scherder EJA, Bouma A, Steen AM (1995a). Effects of shortterm transcutaneous electrical nerve stimulation on memory
and affective behaviour in patients with probable Alzheimers
disease. Behav Brain Res 67: 211219.
2014 Refs
2/12/03
1:39 pm
Page 539
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
539
Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Mller D,

Olcese J (2003). The human myometrium as a target for melatonin. J Clin Endocrinol Metab 88: 908913.
Schlesinger B, Clayton B, Bodian M, Jones KV (1963).
Typus degenerativus amstelodamensis. Arch Dis Child 38:
349357.
Schmale H, Bahnsen U, Richter D (1993). Structure and expression of the vasopressin precursor gene in central diabetes
insipidus. Ann NY Acad Sci 689: 7482.
Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln
RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM,
Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL
(2002). Association of polymorphisms in the apolipoprotein
E region with susceptibility to and progression of multiple
sclerosis. Am J Hum Genet 70: 708717.
Schmitz L, Favara BE (1998). Nosology and pathology of
Langerhans cell histiocytosis. Hematol Oncol Clin North Am
12: 221246.
Schneider C, Risser D, Kirchner L, Kitzmller E, Cairns N,
Prast H, Singewald N, Lubec G (1997). Similar deficits of
central histaminergic system in patients with Down syndrome
and Alzheimer disease. Neurosci Lett 222: 183186.
Schneider F, Habel U, Volkman J, Regel S, Kornischka J, Sturm
V, Freund H-J (2003). Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson
disease. Arch Gen Psychiatry 60: 296302.
Schneider J, Gthert H (1975). Histiozytosis X des
Hypothalamus. Zentralbl Allg Pathol 119: 4955.
Schneider LS, Farlow MR, Henderson VW, Pogoda JM (1996).
Effects of estrogen replacement therapy on response to tacrine
in patients with Alzheimers disease. Neurology 46: 15801584.
Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemeroff
CB, Meyers BS, Fluoxetine Collaborative Study Group
(1997). Estrogen replacement and response to fluoxetine in
a multicenter geriatric depression trial. Am J Geriatr
Schochet SS, McCormick WF, Halmi NS (1974). Salivary gland
rests in the human pituitary, Arch Pathol 98: 193200.
Schfl C, Schleth A, Berger D, Terkamp C, Von zur Mhlen
A, Brabant G (2002). Sympathoadrenal counterregulation in
patients with hypothalamic craniopharyngioma. J Clin
Schnknecht P, Pantel J, Klinga K, Jensen M, Hartmann T,
Salbach B, Schrder J (2001). Reduced cerebrospinal fluid
estradiol levels are associated with increased -amyloid levels
in female patients with Alzheimers disease. Neurosci Lett
307: 122124.
Schpe M (1940). ber Vernderungen in pyramidalmotorischen System bei einer Chorea Huntington. Ges Neurol
Psychiatr 168: 679684
Schopohl J (1993). Pulsatile gonadotrophin releasing hormone
versus gonadotrophin treatment of hypothalamic hypogonadism in males. Hum Reprod 8: 175179.
Scherder E, Bouma A, Steen L (1995b) Effects of simultaneously applied short-term transcutaneous electrical nerve
stimulation and tactile stimulation on memory and affective
behaviour of patients with probable Alzheimers disease.
Behav Neurol 8: 313.
Scherder EJA, Bouma A, Steen L, Swaab D (1995c). Peripheral
nerve stimulation in Alzheimers disease. A meta-analysis.
Alzheimers Res 1: 183184.
Scherder EJA, Bouma A, Steen A (1996). Effects of a followup treatment of short-term transcutaneous electrical nerve
stimulation on memory and affective behaviour in a patient
with probable Alzheimers disease. Behav Neurol 9: 3335.
Scherder EJA, Bouma A, Steen LM (1998). Effects of isolated
transcutaneous electrical nerve stimulation on memory and
affective behavior in patients with probable Alzheimers
disease. Biol Psychiatry 43: 417424
Scherder E.JA, Van Someren EJW, Swaab DF (1999a).
Transcutaneous electrical nerve stimulation (TENS) improves
the rest-activity rhythm in midstage Alzheimers disease.
Behav Brain Res 101: 105107.
Scherder EJA, Bouma A, Borkent M, Rahman MO (1999b).
Alzheimer patients report less pain intensity and pain affect
than non-demented elderly. Psychiatry 62: 265272.
Scherder EJA, Van Someren EJW, Bouma A, Van den Berg M
(2000). Effects of transcutaneous electrical nerve stimulation
(TENS) on cognition and behaviour in aging. Behav Brain
Res 111: 223225.
Scherder EJA, Bouma A, Slaets J, Ooms M, Ribbe M, Blok A,
Sergeant JA (2001). Repeated pain assessment in Alzheimers
disease. Dement Geriatr Cogn Disord 12: 400407.
Scherder EJ, Sergeant JA, Swaab DF (2003). Pain processing
in dementia and its relation to neuropathology. Lancet Neurol
2: 677686.
Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter
DJ, Kawachi I, Colditz GA (2001). Rotating night shifts and
risk of breast cancer in women participating in the nurses
health study. J Natl Cancer Inst 93: 15631568.
Schielke, E, Nolte C, Mller W, Brck W (2001). Sarcoidosis
presenting as rapidly progressive dementia: clinical and
neuropathological evaluation. J Neurol 248: 522524.
Schiffmann R, Tedeschi G, Kinkel RP, Trapp BD, Frank JA,
Kaneski CR, Brady RO, Barton NW, Nelson L, Yanovski JA
(1997). Leukodystrophy in patients with ovarian dysgenesis.
Schijman E, Monges J, Raimondi AJ, Tomita T (1990). Choroid
plexus papillomas of the III ventricle in childhood. Childs
Nerv Syst 6: 331334.
Schill W-B (2001). Fertility and sexual life of men after their
forties and in older age. Asian J Androl 3: 17.
Schith HB, Muceniece R, Wikberg JES (1997). Characterization of the binding of MSH-B, HP-228, GHRP-6 and
153N-6 to the human melanocortin receptor subtypes.
Neuropeptides 31: 565571.
539
2014 Refs
540
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 540
D.F. SWAAB
Schorry EK, Dietrich KN, Saal HM, Blough RI, Dey S,

Chernausek S, Milatovich-Cherry A (1998). Partial trisomy
1q with growth hormone deficiency and normal intelligence.
Schorsch E, Schmidt G (1979). Hypothalamotomie bei sexuellen
Abweichungen. Nervenarzt 50: 689699.
Schaub RT, Anders D, Golz G, Ghringer K, Hellweg R
(2002). Serum nerve growth factor concentration and its role
in the preclinical stage of dementia. Am. J Psychiatry 159:
12271229.
Schreiber G, Avissar S, Tzahor Z, Grisaru N (1991a). Rhythms
of war. Nature 352: 574575.
Schreiber W, Schweiger U, Werner D, Brunner G, Tuschl RJ,
Laessle RG, Krieg J-C, Fichter MM, Pirke K-M (1991b).
Circadian pattern of large neutral amino acids, glucose,
insulin, and food intake in anorexia nervosa and bulimia
nervosa. Metabolism 40: 503507.
Schriefer JA, Lewis PR, Miller JW (1982). Role of fetal oxytocin
in parturition in the rat. Biol Reprod 27: 362368.
Schrier RW, Ohara M, Rogachev B, Xu L, Knotek M (1998).
Aquaporin-2 water channels and vasopressin antagonists in
edematous disorders. Mol Genet Metab 65: 255263.
Schrier RW, Cadnapaphornchai MA, Ohara M (2001). Water
retention and aquaporins in heart failure, liver disease and
pregnancy. J R Soc Med 94: 265269.
Schrijver HM, Crusius JBA, Uitdehaag BMJ, Gonzlez G.,
Kostense PJ, Polman CH, Pena AS (1999). Association of
interleukin-1 and interleukin-1 receptor antagonist genes
with disease severity in MS. Neurology 52: 595599.
Schroeder HWS, Warzok RW, Assaf JA, Gaab MR (1999).
Fatal subarachnoid hemorrhage after endoscopic third
ventriculostomy. J Neurosurg 90: 153155.
Schroeder S, Wichers M, Klingmller D, Hfer M, Lehmann
LE, Von Spiegel T, Putensen C, Hoeft A, Stber F (2001).
The hypothalamic-pituitary-adrenal axis of patients with
severe sepsis: altered response to corticotropin-releasing
hormone. Crit Care Med 29: 310316.
Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner
SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender
D, Stevenson RE (1998). Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet 76: 327336.
Schubert DSP, Foliart RH (1993). Increased depression in
multiple sclerosis patients; a meta-analysis. Psychosomatics
34: 124130.
Schubert F, George JM, Rao MB (1981). Vasopressin and
oxytocin content of human fetal brain at different stages of
gestation. Brain Res 213: 111117.
Schubiger O, Haller D (1992). Metastases to the pituitary-hypothalamic axis. Neuroradiology 34: 131134.
Schuelke M, Krude H, Finckh B, Mayatepek E, Janssen A,
Schmelz M, Trefz F, Trijbels F, Smeitink J (2002). Septooptic dysplasia associated with a new mitochondrial
cytochrome b mutation. Ann Neurol 51: 388392.
Schuld A, Blum WF, Uhr M, Haack M, Kraus T, Holsboer F,

Pollmcher T (2000). Reduced leptin levels in human
narcolepsy. Neuroendocrinology 72: 195198.
Schulz-Ertner D, Frank C, Herfarth KK, Rhein B,
Wannenmacher M, Debus J (2002). Fractionated stereotactic
radiotherapy for craniopharyngiomas. Int J Radiat Oncol Biol
Phys 54: 11141120.
Schulze A, Mogensen H, Hamborg-Petersen B, Graem N,
stergaard JR, Brndum-Nielsen K (2001). Fertility in
PraderWilli syndrome: a case report with Angelman
syndrome in the offspring. Acta Paediatr 90: 455459.
Schultz C, Braak H, Braak E (1996). A sex difference in
neurodegeneration of the human hypothalamus. Neurosci Lett
212: 103106.
Schultz C, Ghebremedhin E, Braak H, Braak E (1997a).
Neurofibrillary pathology in the human paraventricular and
supraoptic nuclei. Acta Neuropathol 94: 99102.
Schultz C, Koppers D, Braak H, Braak E (1997b). Cytoskeletal
alterations in the aged human neurohypophysis. Neurosci Lett
237: 9396.
Schultz C, Koppers D, Braak E, Braak H (1997c). Neurofibrillary degeneration in hypophysiotrophic nuclei of the
aging human hypothalamus. In: Korf HW, Usadel K-H (Eds.)
Neuroendocrinology: retrospect and perspectives. Springer,
Berlin, pp. 115126.
Schultz C, Koppers D, Sassin I, Braak E, Braak H (1998).
Cytoskeletal alterations in the human tuberal hypothalamus related
to argyrophilic grain disease. Acta Neuropathol 96: 596602.
Schultz C, Ghebremedhin E, Braak E, Braak H (1999). Sexdependent cytoskeletal changes of the human hypothalamus
develop independently of Alzheimers disease. Exp Neurol
160: 186193.
Schultz CH, Rivers EP, Feldkamp CS, Goad EG, Smithline HA,
Martin GB, Fath JJ, Wortsman J Nowak, RM (1993). A characterization of hypothalamic-pituitary-adrenal axis function
during and after human cardiac arrest. Crit Care Med 21:
13391347.
Schumacher M, Coirini H, Pfaff DW, McEwen BS (1990).
Behavioral effects of progesterone associated with rapid
modulation of oxytocin receptors. Science 250: 691694.
Schumann EM, Kmpfel T, Then Bergh F, Trenkwalder C,
Holsboer F, Auer DP (2002). Activity of the hypothalamicpituitary-adrenal axis in multiple sclerosis: correlations with
gadolinium-enhancing lesions and ventricular volume. Ann
Neurol 51: 763767.
Schupf N, Zigman W, Kapell D, Lee JH, Kline J, Levin B
(1997). Early menopause in women with Downs syndrome.
J Intellect Disabil Res 41: 264267.
Schut L, Stieg PE, Scott RM, Barnes PD, Folkerth RD (1996).
Management of a pediatric hypothalamic mass. Neurosurgery
38: 806811.
Schvarcz JR (1977). Results of stimulation and destruction of
the posterior hypothalamus: a long-term evaluation. In: Sweet
WH, Obrador S, Martn-Rodrguez JG (Eds.) Neurosurgical
2014 Refs
2/12/03
1:39 pm
Page 541
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
541
Schwarz GA (1967). The orthostatic hypotension syndrome of

ShyDrager. Arch Neurol 16: 123139.
Schweiger U, Deuschle M, Weber B, Krner A, Lammers CH, Schmider J, Gotthardt U, Heuser I (1999). Testosterone,
gonadotropin, and cortisol secretion in male patients with
major depression. Psychosom Med 61: 292296.
Schweitzer I, Tuckwell V, Maguire K, Tiller J (2001).
Personality pathology, depression and HPA axis functioning.
Hum Psychopharmacol Clin Exp 16: 303308.
Schwob JE, Leopold DA, Mieleszko-Szumowski KE, Emko P
(1993). Histopathology of olfactory mucosa in Kallmanns
syndrome. Ann Otol Rhinol Laryngol 102: 117122.
Scolding NJ, Kellar-Wood HF, Shaw C, Shneerson JM, Antoun
N (1996). Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol. 39:
352360.
Scothorne CM (1955). A glioma of the posterior lobe of the
pituitary gland. J Pathol Bact 69: 109112.
Scott LV, Salahuddin F Cooney J, Svec F, Dinan TG (1999a).
Differences in adrenal steroid profile in chronic fatigue
syndrome, in depression and in health. J Affect Disord 54:
129137.
Scott LV, Medbak S, Dinan TG (1999b). Desmopressin
augments pituitary-adrenal responsivity to corticotropinreleasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry 45:
14471454.
Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG
(1999c). Small adrenal glands in chronic fatigue syndrome:
a preliminary computer tomography study. Psychoneuroendocrinology 24: 759768.
Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA
(1995). Nerve growth factor in Alzheimers disease: increased
levels throughout the brain coupled with declines in nucleus
basalis. J Neurosci 15: 62136221.
Scott TF (1993). Neurosarcoidosis: progress and clinical aspects.
Neurology 43: 812.
Scott TF, Price TRP, George MS, Brillman J, Rothfus W (1993).
Midline cerebral malformations and schizophrenia. J
Neuropsychiatry Clin Neurosci 5: 287293.
Scully RE, Mark EJ, McNeeley BU (1983). Case 33-1983. A
55-year-old woman with diabetes insipidus. N Engl J Med
309: 418425.
Seckl JR, Dunger DB, Bevan JS, Nakasu Y, Chowdrey C, Burke
CW, Lightman SL (1990). Vasopressin antagonist in early
postoperative diabetes insipidus. Lancet 335: 13531356.
Sedehizade F, Hanck T, Stricker R, Horstmayer A, Bernstein
H-G, Reiser G (2002). Cellular expression and subcellular
localization of the human Ins (1,3,4,5)P4-binding protein,
p42IP4, in human brain and in neuronal cells. Mol Brain Res
99: 111.
Seed JA, Dixon RA, McCluskey SE, Young AH (2000).
Basal activity of the hypothalamic-pituitary-adrenal axis and
treatment in psychiatry, pain and epilepsy. University Park

Press, Baltimore, pp. 429438.
Schvarcz JR, Driollet R, Rios E, Betti O (1972). Stereotactic
hypothalamotomy for behaviour disorders. J Neurol
Schwanzel-Fukuda M, Pfaff DW (1991). Migration of LHRHimmunoreactive neurons from the olfactory placode
rationalizes olfacto-hormonal epithelium. J Steroid Biochem
Mol Biol 39: 565572.
Schwanzel-Fukuda M, Pfaff DW (1994). Luteinizing
hormone-releasing hormone (LHRH) and neural cell adhesion
molecule (NCAM)-immunoreactivity in development of the
forebrain and reproductive system. Ann Endocrinol 55:
235241.
Schwanzel-Fukuda M, Crossin KL, Pfaff DW, Bouloux PMG,
Hardelin J-P, Petit C (1996). Migration of luteinizing
hormone-releasing hormone (LHRH) neurons in early human
embryos J Comp Neurol 366: 547557.
Schwanzel-Fukuda M, Bick D, Pfaff DW (1989). Luteinizing
hormone-releasing hormone (LHRH)-expressing cells do not
migrate normally in an inherited hypogonadal (Kallmann)
syndrome. Mol Brain Res 6: 311326.
Schwanzel-Fukuda M, Jorgenson KL, Bergen HT, Weesner GD,
Pfaff DW (1992). Biology of normal LHRH neurons during
and after their migration from olfactory placode. Endocr Rev
13: 623633.
Schwartz ID, Root AW (1991). The Klinefelter syndrome of
testicular dysgenesis. Endocrinol Metab Clin North Am 20:
153163.
Schwartz J-C, Arrang J-M, Garbarg M, Pollard H, Ruat M
(1991). Histaminergic transmission in the mammalian brain.
Physiol Rev 71: 251.
Schwartz MJ, Seeley RJ (1997). Neuroendocrine responses to
starvation and weight loss. N Engl J Med 336: 18021811.
Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL Foster,
D Lasser, G, Prunkard DE, Porte D, Woods SC, Seeley RJ,
Weigle DS (1996a). Specificity of leptin action on elevated
blood glucose levels and hypothalamic neuropeptide Y gene
expression in ob/ob mice. Diabetes 45: 531535.
Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D
(1996b). Cerebrospinal fluid leptin levels: relationship to
plasma levels and to adiposity in humans. Nat icine 2:
589593.
Schwartz RB, Garada BM, Komaroff A.L, Tice HM, Gleit M,
Jolesz FA, Holman BL (1994). Detection of intracranial
abnormalities in patients with chronic fatigue syndrome:
comparison of MR imaging and SPECT. Am J Roentgenol
162: 935941.
Schwartz WJ, Bosis NA, Hedley-Whyte ET (1986). A discrete
lesion of ventral hypothalamus and optic chiasm that disturbed
the daily temperature rhythm. J Neurol 233: 1-4.
Schwartz WJ (1997). Understanding circadian clocks: from cfos to fly balls. Ann Neurol 41: 289297.
541
2014 Refs
542
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 542
D.F. SWAAB
cognitive function in anorexia nervosa. Eur Arch Psychiatry

Seed JA, McCue PM, Wesnes KA, Dahabra S, Young AH
(2002). Basal activity of the HPA axis and cognitive function in anorexia nervosa. Int J Neuropsychopharmacol 5:
1725.
Seedat S, Stein MB, Kennedy CM, Hauger RL (2003). Plasma
cortisol and neuropeptide Y in female victims of intimate
partner violence. Psychoneuroendocrinology 28: 796808.
Seeger G, Braus DF, Ruf M, Goldberger U, Schmidt MH (2002).
Body image distortion reveals amygdala activation in patients
with anorexia nervosa a functional magnetic resonance
imaging study. Neurosci Lett 326: 2528.
Seeman MV (1997). Psychopathology in women and men: focus
on female hormones. Am J Psychiatry 154: 16411647.
Seeman TE, Singer B, Wilkinson CW, McEwen B (2001).
Gender differences in age-related changes in HPA axis reactivity. Psychoneuroendocrinology 26: 225240.
Segarra G, Medina P, Domenech C, Vila JM, Martnez-Len
JB, Aldasoro M, Lluch S (1998). Role of vasopressin on
adrenergic neurotransmission in human penile blood vessels
J Pharmacol Exp Ther 286: 13151320.
Seidman SN, Walsh BT (1999). Testosterone and depression in
aging men. Am J Geriatr Psychiatry 7: 1833.
Seidman SN, Araujo AB, Roose SP, McKinlay JB (2001).
Testosterone level, androgen receptor polymorphism, and
depressive symptoms in middle-aged men. Biol Psychiatry
50: 371376.
Seidman SN, Araujo AB, Roose SP, Devanand DP, Xie S,
Cooper TB, McKinlay JB (2002). Low testosterone levels in
elderly men with dysthymic disorder. Am J Psychiatry 159:
456459.
Seiger , Nordberg A, Von Holst H, Bckman L, Ebendal T,
Alafuzoff I, Amberla K, Hartvig P, Herlitz A, Lilja A,
Lundqvist H, Lngstrm B, Meyerson B, Persson A, Viitanen
M, Winblad B, Olson L (1993). Intracranial infusion of
purified nerve growth factor to an Alzheimer patient: the first
attempt of a possible future treatment strategy. Behav Brain
Res 57: 255261.
Selenkow HA, Tyler HR, Matson DD, Nelson DH (1959).
Hypopituitarism due to hypothalamic sarcoidosis. Am J Med
Sci 238: 456463.
Sellmeyer DE, Grunfeld C (1996). Endocrine and metabolic
disturbances in human immunodeficiency virus infection and
the acquired immune deficiency syndrome. Endocr Rev 17:
518532.
Selten J-P, Van der Graaf Y, Van Duursen R, Gispen-de Wied
C, Kahn RS (1999a). Psychotic illness after prenatal exposure
to the 1953 Dutch flood disaster. Schizophr Res 35: 243245.
Selten J-P, Brown AS, Moons KGM, Slaets JPJ, Susser ES,
Kahn RS (1999b). Prenatal exposure to the 1957 influenza
pandemic and non-affective psychosis in the Netherlands.
Schizophr Res 38: 8591.
Seltzer GB, Schupf N, Wu H-S (2001). A prospective study of

menopause in women with Downs syndrome. J Intellect
Disabil Res 45: 17.
Seminara S.B, Hayes FJ, Crowley WF (1998). Gonadotropinreleasing hormone deficiency in the human (idiopathic
hypogonadotropic
hypogonadism
and
Kallmanns
syndrome).: pathophysiological and genetic considerations.
Endocr Rev 19: 521539.
Seminara SB, Achermann JC, Genel M, Jameson J.L, Crowley
WF jr. (1999). X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and
females. J Clin Endocrinol Metab 84: 45014509.
Senanarong V, Vamnasaeng S, Poungvarin N, Ploybutr S,
Udompunthurak S, Jamjuras P, Fairbanks L, Cummings JL
(2002). Endogenous estradiol in elderly individuals:
cognitive and noncognitive associations. Arch Neurol 59:
385389.
Sende P, Pantelakis N Suzuki, K Bashore R (1976). Plasma
oxytocin determinations in pregnancy with diabetes insipidus.
Obstet Gynecol (Suppl. 1) 48: 38s41s.
Sequeira A, Kim C, Seguin M, Lesage A, Chawky N, Desautels
A, Tousignant M, Vanier C, Lipp O, Benkelfat C, Rouleau
G, Turecki G (2003). Wolfram syndrome and suicide:
evidence for a role of WFS1 in suicidal and impulsive
behavior. Am J Med Genet Part B 119B: 108113.
Serfaty M., Kennell-Webb S, Warner J, Blizard R, Raven P
(2002). Double blind randomised placebo controlled trial of
low dose melatonin for sleep disorders in dementia. Int J
Geriatr Psychiatry 17: 11201127.
Sern-Ferr M, Ducsay CA, Valenzuela GJ (1993). Circadian
rhythms during pregnancy. Endocr Rev 14: 594609.
Sern-Ferr M, Riffo R, Valenzuela GJ, Germain AM (2001).
Twenty-four-hour pattern of cortisol in the human fetus at
term. Am J Obstet Gynecol 184: 12781283.
Servan J, Marchand F, Garma L, Seilhean D, Hauw JJ, Delattre
JY (1995). Narcolepsie rvlation dune neurosarcodose. Rev
Neurol 151: 281283.
Seshadri S, Zornberg GL, Derby LE, Myers MW, Jick H,
Drachman DA (2001). Postmenopausal estrogen replacement
therapy and the risk of Alzheimer disease. Arch Neurol 58:
435440.
Sethi PK, Rao TS (1976). Gelastic, quiritarian and cursive
seizures. J Neurol Neurosurg Psychiatry 39: 823828.
Seyrantepe V, Topaloglu H, Sim
sek E, zg M, Yordam N
(1996). Mitochondrial DNA studies in Wolfram (DIDMOAD)
Shafii M, MacMillan DR, Key MP, McCue Derrick A, Kaufman
N, Nahinsky ID (1996). Nocturnal serum melatonin profile
in major depression in children and adolescents. Arch Gen
Shalet SM (1982). Iatrogenic hypothalamic-pituitary disease. In:
Beardwell C, Robertson GL (Eds.) The Pituitary.
Butterworths, London, pp. 175210.
2014 Refs
2/12/03
1:39 pm
Page 543
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
543
neuroradiological diagnosis of Wernickes encepathology.

Sheehan HL, Kovacs K (1966). The subventricular nucleus of
the human hypothalamus. Brain 89: 589614.
Sheehan HL, Kovacs K (1982). Neurohypophysis and hypothalamus. In: Bloodworth JMB (Ed.) Endocrine Pathology.
General and Surgical. Williams and Wilkins, Baltimore, pp.
4599.
Shekhar A, Keim SR (1997). The circumventricular organs form
a potential neural pathway for lactate sensitivity: implications
for panic disorder. J Neurosci 17: 97269735.
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW
(1996). Hippocampal atrophy in recurrent major depression.
Shelton DL, Sutherland J, Gripp J, Camerato T, Armanini MP,
Phillips HS, Carroll K, Spencer SD, Levinson AD (1995).
Human Trks: molecular cloning, tissue distribution, and
expression of extracellular domain immunoadhesins. J
Shemyakov SE (2001). Monoamine oxidase activity, lipid
peroxidation, and morphological changes in human hypothalamus during aging. Bull Exp Biol Med 131: 586588.
Sher C, Bistritzer T, Reisler G, Reish O (2002). Congenital
hypothyroidism with Prader-Willi syndrome. J Pediatr
Sher L, Goldman D, Ozaki N, Rosenthal NE (1999). The role
of genetic factors in the etiology of seasonal affective disorder
and seasonality. J Affect Disord 53: 203-210.
Sherin JE, Shiromani PJ, McCarley RW, Saper CB (1996).
Activation of ventrolateral preoptic neurons during sleep.
Science 271: 216219.
Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998).
Innervation of histaminergic tuberomammillary neurons by
GABAergic and galaninergic neurons in the ventrolateral
preoptic nucleus of the rat. J Neurosci 18: 47054721.
Sherwin BB (2002). Estrogen and cognitive aging in women.
Trends Pharmacol Sci 23: 527534.
Sherwin RP, Grassi JE, Sommers SC (1962). Hamartomous
malformation of the posterolateral hypothalamus. Lab Invest
11: 8997.
Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M,
Miura M, Menjo M, Ikeda K (2001). Postoperative delirium
and melatonin levels in elderly patients. Am J Surg 182:
449454.
Shifren, JL, Braunstein GD, Simon JA, Casson PR, Buster JE,
Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum
SR, Caramelli KE, Mazer NA (2000) Transdermal testosterone treatment in women with impaired sexual function
after oophorectomy. N Engl J Med 343: 682688.
Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E
(1998). Mice lacking melanin-concentrating hormone are
hypophagic and lean. Nature 396: 670674.
Shamim W, Yousufuddin M, Bakhai A, Coats AJS, Honour JW

(2000). Gender differences in the urinary excretion rates of
cortisol and androgen metabolites. Ann Clin Biochem 37:
770774.
Shamir E, Rotenberg VS, Laudon M, Zisapel N, Elizur A (2000).
First-night effect of melatonin treatment in patients
with chronic schizophrenia. J Clin Psychopharmacol 20:
691694.
Shamir E, Barak Y, Shalman I, Laudon M, Nava Z, Tarrasch
R, Elizur A, Weizman R (2001). Melatonin treatment for
tardive dyskinesia. Arch Gen Psychiatry 58: 10491052.
Shangold MM, Freeman R, Kumaresan P, Feder AS, Vasicka
A (1983). Plasma oxytocin concentrations in a pregnant
woman with total vasopressin deficiency. Obstet Gynecol
61:662667.
Shanklin WB (1953). The origin, histology and senescence of
tumorettes in the human neurohypophysis. Acta Anat 18:120.
Shanklin WM (1951). Lymphocytes and lymphoid tissue in the
human pituitary. Anat Rec 111: 177192.
Shannon P, Becker L, Deck J (1999). Evidence of widespread
axonal pathology in Wolfram syndrome. Acta Neuropathol
98: 304308.
Share L, Crofton JT, Ouchi Y (1988). Vasopressin: sexual
dimorphism in secretion, cardiovascular actions and hypertension. Am J Med Sci 295: 314319.
Sharkey KM, Eastman CI (2002). Melatonin phase shifts human
circadian rhythms in a placebo-controlled simulated nightwork study. Am J Physiol 282: R454R463.
Sharland M, Burch M, McKenna WM, Paton MA (1992). A
clinical study of Noonan syndrome. Arch Dis Child 67:
178183.
Sharma MC, Gaikwad S, Mahapatra AK, Menon PSN, Sarkar
C (1998). Hypothalamic hamartoma. Report of a case
with unusual histologic features. Am J Surg Pathol 22:
15381541.
Sharma OP (1997). Neurosarcoidosis. A personal perspective
based on the study of 37 patients. Chest 112: 220228.
Sharma OP, Anders A (1985). Neurosarcoidosis. A report of
ten patients illustrating some usual and unusual manifestations. Sarcoidosis 2: 96106.
Sharp CW (1993). Anorexia nervosa and depression in a woman
blind since the age of nine months. Can J Psychiatry 38:
469471.
Shastry BS (2001). Molecular genetics of Rett syndrome.
Neurochem Int 38: 503508.
Shaw CM (1987). Correlates of mental retardation and structural changes of the brain. Brain Dev 9: 18.
Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert
SM (1997). Two period homologs: circadian expression and
photic regulation in the suprachiasmatic nuclei. Neuron 19:
12611269.
Sheedy D, Lara A, Garrick T, Harper C (1999). Size of mamillary bodies in health and disease: useful measurements in
543
2014 Refs
544
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 544
D.F. SWAAB
Shimamoto K, Watari I, Miyahara M (1977). A study of plasma

vasopressin in patients undergoing chronic hemodialysis. J
Shinoda M, Tsugu A, Oda S, Masuko A, Yamaguchi T,
Yamaguchi T, Tsugane R, Sato O (1993). Development of
akinetic mutism and hyperphagia after left thalamic and right
hypothalamic lesions. Childs Nerv Syst 9: 243245.
Shinohara K, Uchiyama M, Okawa M, Saito K, Kawaguchi M,
Funabashi T, Kimura F (2000). Menstrual changes in sleep,
rectal temperature and melatonin rhythms in a subject with
premenstrual syndrome. Neurosci Lett 281: 159162.
Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga
F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M,
Kangawa K, Nakao K (2001). Ghrelin, an endogenous growth
hormone secretagogue, is a novel orexigenic peptide that
antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:
227232.
Shioda S, Yada T, Nakajo S, Nakaya K, Nakai Y, Arimura A
(1997). Pituitary adenylate cyclase-activating polypeptide
(PACAP): a novel regulator of vasopressin-containing
neurons. Brain Res 765: 8190.
Shirakawa T, Honma S, Katsuno Y, Oguchi H, Honma K-i
(2000) Synchronization of circadian firing rhythms in cultured
rat suprachiasmatic neurons. Eur J Neurosci 12: 28332838.
Shirane R, Su C-C, Kusaka Y, Jokura H, Yoshimoto T (2002).
Surgical outcomes in 31 patients with craniopharyngiomas
extending outside the suprasellar cistern: an evaluation of the
frontobasal interhemispheric approach. J Neurosurg 96:
704712.
Shiruba RA, Spooner ET, Ishiguro K, Takahashi M, Yoshida
R, Wheelock TR, Imahori K, Cataldo AM, Nixon RA (1998).
Immunocytochemistry of formalin-fixed human brain tissues:
microwave irradiation of free-floating sections. Protoc Brain
Res 2: 109119.
Shochat T, Luboshitzky R, Lavie P (1997). Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J
Physiol 273: R364R370.
Shochat T, Martin J, Marler M, Ancoli-Israel S (2000).
Illumination levels in nursing home patients: effects on sleep
and activity rhythms. J Sleep Res 9: 373379.
Short RA, Bowen RL, OBrien PC, Graff-Radford NR (2001).
Elevated gonadotropin levels in patients with Alzheimers
disease. Mayo Clin Proc 76: 906909.
Shozu M, Akasofu K, Harada T, Kubota Y (1991). A new cause
of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab 72: 560566.
Shuangshoti S, Kirsch E, Bannan P, Fabian VA (2000).
Ganglioma of the optic chiasm: case report and review of
the literature. Am J Neuroradiol 21: 14861489.
Shulman LM (2002). Is there a connection between estrogen
and Parkinsons disease? Parkinsonism Relat. Disord 8:
289295.
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB,

Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD,
Morley Kotchen J, Wassertheil-Smoller S, WactawskiSmoller for the WHIMS investigators (2003) Estrogen plus
progestin and the incidence of dementia and mild cognitive
impairment in postmenopausal women. JAMA 289:
26512662.
Shuper A, Horev G, Michovitz S, Korenreich L, Zaizov R,
Cohen IJ (1997). Optic chiasm glioma, electrolyte abnormalities, nonobstructive hydrocephalus and ascites. Med
Pediatr Oncol 29: 3335.
Shuster S, Thody AJ, Goolamali SK, Burton JL, Plummer N,
Bates D (1973). Melanocyte-stimulating hormone and
Parkinsonism. Lancet (March 3): 463464.
Shuto T, Sekido K, Ohtsubo Y, Tanaka Y, Hara M, Yamaguchi
K, Yamamoto I (1995). Choroid plexus papilloma of the III
ventricle in an infant. Childs Nerv Syst 11: 664666.
Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura
H, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I (2002).
Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion feeding, and adiposity. J Clin
Invest 109: 14291436.
Shy GM, Drager GA (1960). A neurological syndrome associated with orthostatic hypotension. Arch Neurol 2: 511527.
Sichel DA, Cohen LS, Robertson LM, Ruttenberg A,
Rosenbaum JF (1995). Prophylactic estrogen in recurrent
postpartum affective disorder. Biol Psychiatry 38: 814818.
Siegel JM (1999). Narcolepsy: a key role for hypocretins
(orexins). Cell 98: 409412.
Siegel JM, Nienhuis R, Gulyani S, Ouyang S, Wu MF, Mignot
E, Switzer RC, McMurry G, Cornford M (1999). Neuronal
degeneration in canine narcolepsy. J Neurosci 19: 248257.
Siegel SF, Ahdab-Barmada M, Arslanian S, Foley Jr TP (1995).
Ectopic posterior pituitary tissue and paracentric inversion of
the short arm of chromosome 1 in twins. Eur J Endocrinol
133: 8792.
Siennicki-Lantz A, Lilja B, Elmsthl S (1999). Orthostatic
hypotension in Alzheimers disease: result or cause of brain
dysfunction? Aging Clin. Exp Res 11: 155160.
Silberstein S, Merriam G (1999). Sex hormones and headache
1999 (menstrual migraine). Neurology 53 (4 Suppl. 1):
S3S13.
Siggaard C., Rittig S., Corydon T.J., Andreasen P.H., Jensen
T.G., Andresen B.S., Robertson G.L, Gregersen N, Bolund
L, Pedersen EB (1999). Clinical and molecular evidence of
abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal
diabetes insipidus due to a signal peptide mutation. J Clin
Si-Hoe SL, De Bree FM, Nijenhuis M, Davies JE, Howell LMC,
Tinley H, Waller SJ, Zeng Q, Zalm R, Sonnemans M, Van
Leeuwen FW, Burbach JPH, Murphy D (2000). Endoplasmic
reticulum derangement in hypothalamic neurons of rats
2014 Refs
2/12/03
1:39 pm
Page 545
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
545
Simpson DA, Pawlak AM, Nigro MA, Wishnow R (1994). A

variant of adrenomyeloneuropathy in a family with adrenoleukodystrophy and adrenomyeloneuropathy. J Am Osteopath
Assoc 94: 745752.
Sinard JH, Hedreen JC (1995). Neuronal loss from the subthalamic nuclei in a patient with progressive chorea. Mov Disord
10: 305311.
Singer CM, Lewy AJ (1999). Does our DNA determine when
we sleep? Nat Med 5: 983.
Singer HS, Naidu S (2001). Rett syndrome. Well keep the
genes on for you. Neurology 56: 582585.
Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman
JM (1999). Panic induced by carbon dioxide inhalation and
lack of hypothalamic-pituitary-adrenal axis activation.
Sinha S, Singh AK, Tatke M, Singh D (2000). Hypophyseal
tuberculoma: direct radiosurgery is contraindicated for a
lesion with a thickened pituitary stalk: case report.
Sinsawaiwong S, Phanthumchinda K (1997). Progressive cerebral occlusive disease after hypothalamic astrocytoma
radiation therapy. J Med Assoc Thai 80: 338341.
Siponmaa L, Kristiansson M, Jonson C, Nydn A, Gillberg C
(2001). Juvenile and young adult mentally disordered
offenders: the role of child neuropsychiatric disorders. J Am
Acad Psychiatry Law 29: 420426.
Sirvent N, Brard E, Chastagner P, Feillet F, Wagner K,
Sommelet D (2003). Hypothalamic dysfunction associated
with neuroblastoma: evidence for a new paraneoplastic
syndrome. Brief Reports, Wiley Liss, Inc
Sisodiya SM, Free SL, Stevens JM, Fish DR, Shorvon SD
(1997). Widespread cerebral structural changes in two patients
with gelastic seizures and hypothalamic hamartomata.
Epilepsia 38: 10081010.
Sivan Y, Laudon M, Kuint J, Zisapel N (2000). Low melatonin
production in infants with a life-threatening event. Dev Med
Sivan Y, Laudon M, Tauman R, Zisapel N (2001). Melatonin
production in healthy infants: evidence for seasonal variations. Pediatr Res 49: 6368.
Skakkebaek NE, Leffers H, Rajpert-De Meyts E, Carlsen E,
Grigor KM (2000). Should we watch what we eat and drink?
Report on the International Workshop on Hormones and
Endocrine Disrupters in Food and Water: Possible Impact on
Human Health. Copenhagen, Denmark, 2730 May 2000
Trends Endocrinol Metab 11: 291293.
Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pvet P,
Ravid R, Swaab DF (1990). Daily variation in the concentration of melatonin and 5-methyloxytryptophol in the human
pineal gland: effect of age and Alzheimers disease. Brain
Res 528: 170174.
Skene DJ, Lockley SW, Thapan K, Arendt J (1999). Effects of
light on human circadian rhythms. Reprod Nutr Dev 39:
295304.
expressing a familial neurohypophyseal diabetes insipidus

mutant vasopressin transgene. FASEB J 14: 16801684.
Silberg JL, Parr T, Neale MC, Rutter M, Angold A, Eaves LJ
(2003). Maternal smoking during pregnancy and risk to boys
conduct disturbance: an examination of the causal hypothesis. Biol Psychiatry 53: 130135.
Silbert PL, Gubbay SS, Vaughan RJ (1993). Cavum septum
pellucidum and obstructive hydrocephalus. J Neurol
Siler-Khodr TM and Khodr GS (1978). Studies in human fetal
endocrinology. I. Luteinizing hormone-releasing factor
content of the hypothalamus. Am J Obstet Gynecol 130:
795800.
Sills IN, Rapaport R, Robinson LP, Lieber C, Shih LY, Horlick
MNB, Schwartz M, Desposito F (1993). Familial
PallisterHall syndrome: case report and hormonal evaluation. Am J Med Genet 47: 321325.
Silva MM, Goldman S, Keating G, Marymont MA, Kalapurakal
J, Tomita T (2000). Optic pathway hypothalamic gliomas in
children under three years of age: the role of chemotherapy.
Pediatr Neurosurg 33: 151158.
Silver R, LeSauter J, Tresco PA, Lehman MN (1996). A
diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms.
Nature 382: 810813.
Silverman A-J, Jhamandas J, Renaud LP (1987). Localization
of luteinizing hormone-releasing hormone (LHRH) neurons
that project to the median eminence. J Neurosci 7: 23122319.
Sima AAF, Defendini R, Keohane C, DAmato C, Foster NL,
Parchi P, Gambetti R, Lynch T, Wilhelmsen KC (1996). The
neuropathology of chromosome 17-linked dementia. Ann
Neurol 39: 734743.
Simeon D, Guralnik O, Knutelska M, Hollander E, Schmeidler
J (2001). Hypothalamic-pituitary-adrenal axis dysregulation
in depersonalization disorder. Neuropsychopharmacology 25:
793795.
Simerly RB, Gorski RA, Swanson LW (1986). Neurotransmitter
specificity of cells and fibers in the medial preoptic nucleus:
an immunohistochemical study in the rat. J Comp Neurol
246: 343362.
Simerly RB, McCall LD, Watson SJ (1988). Distribution of
opioid peptides in the preoptic region: immunohistochemical
evidence for a steroid-sensitive enkephalin sexual dimorphism. J Comp Neurol 276: 442459.
Simma B, Burger R, Falk M, Sacher P, Torresani T, Fanconi
S (2001). The release of antidiuretic hormone is appropriate
in response to hypovolemia and/or sodium administration in
children with severe head injury: a trial of lactated ringers
solution versus hypertonic saline. Anesth Analg 92: 641645.
Simpson J, Yates CM, Watts AG, Fink G (1988). Congo red
birefringent structures in the hypothalamus in senile dementia
of the Alzheimer type. Neuropathol Appl Neurobiol 14:
381393.
545
2014 Refs
546
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 546
D.F. SWAAB
Skinner DC, Malpaux B (1999). High melatonin concentrations

in third ventricular cerebrospinal fluid are not due to galen
vein blood recirculating through the choroid plexus.
Sklar CA (1994). Craniopharyngioma: endocrine abnormalities
at presentation. Pediatr Neurosurg 21 (Suppl. 1): 1820.
Sklar CA (2002). Childhood brain tumors. J Pediatr Endocrinol
Metab 15: 669673.
Skordis N, Patsalis PC, Hettinger JA, Kontou M, Herakleous
E, Krishnamani MRS, Phillips III JA (2000). A novel arginine vasopressin-neurophysin II mutation causes autosomal
dominant neurohypophyseal diabetes insipidus and morphologic pituitary changes. Horm Res 53: 239245.
Skowsky WR, Fisher DA (1977). Fetal neurohypophyseal arginine vasopressin and arginine vasotocin in man and sheep.
Skullerud K (1985). Variations in the size of the human brain.
Influence of age, sex, body length, body mass index, alcoholism, Alzheimer changes and cerebral atherosclerosis. Acta
Neurol Scand Suppl 102: 194.
Skuse DH (1999). Genomic imprinting of the X-chromosome:
a novel mechanism for the evolution of sexual dimorphism.
J Lab Clin Med 133: 2332.
Skuse DH (2000). Imprinting, the X-chromosome, and the male
brain: explaining sex differences in the liability to autism.
Slaugenhaupt SA, Blumenfield A, Gill SP, Leyne M, Mull
J, Cuajungco MP, Liebert CB, Chadwick B., Idelson M,
Reznik L, Robbins CM, Makalowska I, Brownstein MJ,
Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella
JF (2001). Tissue-specific expression of a splicing mutation
in the IKBKAP gene causes familial dysautonomia. Am J
Hum Genet 68: 598605.
Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green
JS, Heon E, Musarella MA, Parfry P.S, Sheffield VC,
Biesecker LG (2000). Mutations in MKKS cause
BardetBiedl syndrome. Nat Genet 26: 1516.
Slijper FME, Drop SLS, Molenaar JC, De Muinck KeizerSchrama SMPF (1998). Long-term psychological evaluation
of intersex children. Arch Sex Behav 27: 125144.
Slooter AJC, Bronzova J., Witteman JCM, Van Broeckhoven
C, Hofman A, Van Duijn CM (1999). Estrogen use and early
onset Alzheimers disease: a population-based study. J.
Smeets DFCM, Hamel BCJ, Smeets HJM, Bollen JHM, Smits
APT, Ropers HH, Van Oost BA (1992). PraderWilli
syndrome and Angelman syndrome in cousins from a family
with a translocation between chromosomes 6 and 15. N Engl
J Med 326: 807811.
Smirniotopoulos JG, Rushing EJ, Mena H (1992). Pineal region
masses: differential diagnosis. Radiographics 12: 577597.
Smith CD (2001). A hypothalamic stroke producing recurrent
hemihyperhidrosis. Neurology 56: 13941396.
Smith O (2000). Nota bene: sleep, eat, and be merry. Science

289: 17061707.
Smith R (1998). Alterations in the hypothalamic pituitary
adrenal axis during pregnancy and the placental clock that
determines the length of parturition. J Reprod Immunol 39:
215220.
Smith D, McKenna K, Moore K, Tormey W, Finucane J, Phillips
J, Bayliss P, Thompson CJ (2002). Baroregulation of vasopressin release in adipsic diabetes insipidus. J Clin Endocrinol
Metab 87: 45644568.
Smith DE, Roberts J, Gage FH, Tuszynski MH (1999). Ageassociated neuronal atrophy occurs in the primate brain and
is reversible by growth factor gene therapy. Proc Natl Acad
Sci USA 96: 1089310898.
Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker
B, Williams TC, Lubahn DB, Korach KS (1994). Estrogen
resistance caused by a mutation in the estrogen-receptor gene
in a man. N Engl J Med 331: 10561061.
Smith JW, Evans AT, Costall B, Smythe JW (2002). Thyroid
hormones, brain function and cognition: a brief review.
Smith PM, Mollaret V, Ferguson AV (1998). Leptin acts in the
rat hypothalamic paraventricular nucleus to induce gastric
mucosal damage. Am J Physiol 275: R2081R2084.
Smith YR, Minoshima S, Kuhl DE, Zubieta J-K (2001). Effects
of long-term hormone therapy on cholinergic synaptic concentrations in healthy postmenopausal women. J Clin Endocrinol
Metab 86: 679684.
Smits MG, Nagtegaal JE (2000). Post-traumatic delayed sleep
phase syndrome. Neurology 55: 902903.
Smits MG, Nagtegaal JE, Swart ACW (1996). Het synchroniseren van de biologische klok bij een verstoord
slaap-waakritme. Ned Tijdschr Geneeskd 140: 14291431.
Smits MG, Nagtegaal EE, Van der Heijden J, Coenen AML,
Kerkhof GA (2001). Melatonin for chronic sleep onset
insomnia in children: a randomized placebo-controlled trial.
J Child Neurol 16: 8692.
Smolensky MH (1983). Aspects of human chronopathology. In:
Reinberg, A, Smolensky MH (Eds.) Biological Rhythms and
Medicine. Springer-Verlag New York, pp. 131209.
Smyth CM, Bremner WJ (1998). Klinefelter syndrome. Arch
Intern Med 158: 13091314.
Snitker S, Macdonald I, Ravussin E, Astrup A (2000). The
sympathetic nervous system and obesity: role in aetiology
and treatment. Obesity Rev 1: 515.
Snow A, Gozal E, Malhotra A, Tiosano D, Perlman R, Vega
C, Shahar E, Gozal D, Hochberg Z, Pillar G (2002). Severe
hypersomnolence after pituitary/hypothalamic surgery in
adolescents: clinical characteristics and potential mechanisms.
Pediatrics 110 (6).
Snowdon D (2001). Aging with grace. Bantam Books, NY.
Soares CN, Almeida OP, Joffe H, Cohen LS (2001). Efficacy
of estradiol for the treatment of depressive disorders in perimenopausal women. Arch Gen Psychiatry 58: 529534.
2014 Refs
2/12/03
1:39 pm
Page 547
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
547
Sorenson EJ, Silbert PJ, Benarroch EE, Parisi JE (1995).

Transient amnestic syndrome after spontaneous haemorrhage
into a hypothalamic pilocytic astrocytoma. J Neurol
Sorensen KV (1984). Rapid postmortem decomposition of the
somatostatin cells in human brain. An immunohistochemical
examination. Biomed Pharmacother 38: 458461.
Srensen PS (1986). Studies of vasopressin in the human cerebrospinal fluid. Acta Neurol Scand 74: 81102.
Srensen K (1992). Physical and mental development of adolescent males with Klinefelter syndrome. Horm Res 37: 5561.
Srensen PS, Gjerris F, Hammer M (1984). Cerebrospinal fluid
vasopressin and increased intracranial pressure. Ann Neurol
15: 435440.
Srensen PS, Hammer M, Vorstrup S, Gjerris F (1983). CSF
and plasma vasopressin concentrations in dementia. J Neurol
Srensen PS, Hammer M, Gjerris F, Lundberg J (1985). 24hour cerebrospinal fluid levels of vasopressin in hydrocephalic
patients. Regul Pept 10: 115126.
Soutre E, Salvati E, Belugou J-L, Pringuey D, Candito M,
Krebs B, Ardisson J-L, Darcourt G (1989). Circadian rhythms
in depression and recovery: evidence for blunted amplitude
as the main chronobiological abnormality. Psychiatry Res 28:
263278
Sparks DL (1998). Anatomy of a new paired tract of the pineal
gland in humans. Neurosci Lett 248: 179182.
Sparks DL, Hunsaker JC (1988). The pineal gland in sudden
infant death syndrome: preliminary observations. J Pineal Res
5: 111118.
Sparks DL, Hunsaker JC (2002). Neuropathology of sudden
infant death (syndrome): literature review and evidence of a
probable apoptotic degenerative cause. Childs Nerv Syst 18:
568592.
Sparks DL, Hunsaker JC (1991). Sudden infant death syndrome:
altered aminergic-cholinergic synaptic markers in hypothalamus. J Child Neurol 6: 335339.
Sparks DL, Woeltz VM, Markesbery WR (1991). Alterations
in brain monoamine oxidase activity in aging, Alzheimers
disease, and Picks disease. Arch Neurol 48: 718721.
Sparks DL, Coyne CM, Sparks LM, Hunsaker III JC (1997).
Recommended technique for brain removal to retain anatomic
integrity of the pineal gland in order to determine its size in
sudden infant death syndrome. J Forensic Sci 42: 100102.
Spencer S, Saper CB, Joh T, Reis DJ, Goldstein M, Raese JD
(1985). Distribution of catecholamine-containing neurons in
the normal human hypothalamus. Brain Res 328: 7380.
Sperling MR, Pritchard PB, Engel J., Daniel C, Sagel J (1986).
Prolactin in partial epilepsy: an indicator of limbic seizures.
Spiegel R, Herzog A, Kberle S (1999). Polygraphic sleep
criteria as predictors of successful aging: an exploratory longitudinal study. Biol Psychiatry 45: 435442.
Sobel RA, Schneeberger EE, Colvin RB (1988). The

immunopathology
of
acute
experimental
allergic
encephalomyelitis. V. A light microscopic and ultrastructural
immunohistochemical analysis of fibronectin and fibrinogen.
Am J Pathol 131: 547558.
Sderlund D, Canto P, Mndez JP (2002). Identification of three
novel mutations in the KAL1 gene in patients with Kallmann
syndrome. J Clin Endocrinol Metab 87: 25892592.
Sofroniew MV (1980). Projections from vasopressin, oxytocin,
and neurophysin neurons to neural targets in the rat and
human. J Histochem Cytochem 28: 475478.
Sofroniew MV, Weindl A (1978). Extrahypothalamic neurophysin-containing perikarya, fiber pathways and fiber clusters
in the rat brain. Endocrinology 102: 334337.
Sohlstrm A, Carlsson C, Uvns-Moberg K (2000). Effects of
oxytocin treatment in early life on body weight and corticosterone in adult offspring from ad-libitum-fed and
food-restricted rats. Biol Neonate 78: 3340.
Solano SM, Miller DW, Augood SJ, Young AB, Penney JB
(2000). Expression of -synuclein, parkin, and ubiquitin
carboxy-terminal hydrolase L1 mRNA in human brain: genes
associated with familial Parkinsons disease. Ann Neurol 47:
201210.
Soliman AT, Rajab A, AlSalmi I, Asfour MG (1996). Empty
sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with
BardetBiedl syndrome. Metabolism 45: 12301234.
Solomon GE (1973). Diencephalic autonomic epilepsy caused
by a neoplasm. J Pediatr 83: 277280.
Solt V, Chen CJ, Roy A (1996). Seasonal pattern of posttraumatic stress disorder admissions. Comp Psychiatry 37: 4042.
Somers VK, Mark AL (1992). Sympathetic neural mechanisms
in hypertension. In: Bannister R, Mathias CJ (Eds.)
Autonomic failure. A Textbook of Clinical Disorders of the
Autonomic Nervous System. Oxford University Press,
Oxford, pp. 804821.
Sommer N, Weller M, Petersen D, Wiethlter H, Dichgans J
(1991). Neurosarcoidosis without systemic sarcoidosis. Eur
Arch Psychiatry Clin Neurosci 240: 334-338.
Son Y-S, Park H-J, Kwon O-B, Jung S-C, Shin H-C, Lim S
(2002). Antipyretic effects of acupuncture on the lipopolysaccharide-induced fever and expression of interleukin-6 and
interleukin-1 mRNAs in the hypothalamus of rats. Neurosci
Lett 319: 4548.
Sone M, Takahashi K, Murakami O, Totsune K, Arihara Z,
Satoh F, Sasano H, Ito H Mouri T (2000). Binding sites for
melanin-concentrating hormone in the human brain. Peptides
21: 245250.
Sonino N, Fava GA, Grandi S, Mantero F, Boscaro M (1988).
Stressful life events in the pathogenesis of Cushings
syndrome. Clin Endocrinol. 29: 617623.
Sorbi S, Nacmias B, Tedde A, Ricca V, Mezzani B, Rotella
CM (1998). 5-HT2A promoter polymorphism in anorexia
nervosa. Lancet 351: 1785.
547
2014 Refs
548
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 548
D.F. SWAAB
Spiegel R, Constantini S, Gavriel H, Siomin V, Horovitz Y

(2002). Association of prolonger fever and hypernatremia:
rare presentation of hypothalamic/third ventricle tumor in a
toddler. J Pediatr Hematol Oncol 24: 227228.
Spielman AJ, Thorpy MJ, Sher A (1985). Sleep in the
PraderWilli syndrome (Letters to the Editor). Arch Neurol
42: 110.
Spigset O, Hedenmalm K (1995). Hyponatraemia and the
syndrome of inappropriate antidiuretic hormone secretion
(SIADH) induced by psychotropic drugs. Drug Safety 12:
209225.
Spiliotis BE, August GP, Hung W, Sonis W, Mendelson W,
Bercu BB (1984). Growth hormone neurosecretory dysfunction. JAMA 251: 2223-2230.
Spillane JD (1947). Nutritional disorders of the nervous system.
E & S Livingstone Ltd., Edinburgh, 280 pp.
Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski
JQ (1997). -Synuclein in Lewy bodies. Nature 388:
839840.
Spillantini MG, Bird TD, Ghetti B (1998a). Frontotemporal
dementia and Parkinsonism linked to chromosome 17: a new
group of tauopathies. Brain Pathol 8: 387402.
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A,
Ghetti B (1998b). Mutation in the tau gene in familial multiple
system tauopathy with presenile dementia. Proc Natl Acad
Sci USA 95: 77377741.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert
M (1998c). -Synuclein in filamentous inclusions of Lewy
bodies from Parkinsons disease and dementia with Lewy
bodies. Proc Natl Acad Sci USA 95: 64696473.
Spitzer RL, Terman M, Williams JBW, Terman JS, Malt UF,
Singer F, Lewy AJ (1999). Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response
to melatonin in a randomized, double-blind trial. Am J
Spokes EGS, Koch DJ (1978). Post-mortem stability of
dopamine, glutamate decarboxylase and choline acetyltransferase in the mouse brain under conditions simulating the handling of human autopsy material. J. Neurochem 31: 381383.
Spokes EGS, Bannister R, Oppenheimer DR (1979). Multiple
system atrophy with autonomic failure. J Neurol Sci 43:
5982.
Spoudeas HA, Charmandari E, Brook CGD (2003).
Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours. Med Pediatr
Oncol 40: 224229.
Sprague JE, Banks ML, Cook VJ, Mills EM (2003).
Hypothalamic-pituitary-thyroid axis and sympathetic nervous
system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy). J Pharmacol Exp Ther
305: 159166.
Spratt D (2000). Sex differences in the brain. J Neuroendocrinol
12: 597598.
Squire LR, Amaral DG, Press GA (1990). Magnetic resonance

imaging of the hippocampal formation and mammillary nuclei
distinguish medial temporal lobe and diencephalic amnesia.
J Neurosci 10: 31063117.
Squires LA, Constantin S, Miller DC, Wisoff JH (1995).
Hypothalamic hamartoma and the PallisterHall syndrome.
Squires RF (1997). How a poliovirus might cause schizophrenia:
a commentary on Eagles hypothesis. Neurochem Res 22:
647656.
Sramka
M, Ndvornk P (1975). Surgical complication of posterior hypothalamotomy. Confin Neurol 37: 193194.
Srisurapanont M, Intaprasert S (1999). Seasonal variations in
mood and behaviour: epidemiological findings in the north
tropics. J Affect Disord 54: 9799.
Staal WG, Hulshoff Pol HE, Schnack HG, Hoogendoorn MLC,
Jellema K, Kahn RS (2000). Structural brain abnormalities
in patients with schizophrenia and their healthy siblings. Am
J Psychiatry 157: 416421
Stabler B., Clopper RR, Siegel PT, Nicholas LM, Silva SG,
Tancer ME, Underwood LE (1996). Links between growth
hormone deficiency, adaptation and social phobia. Horm Res
45: 3033.
Stachenfeld NS, DiPietro L, Palter SF, Nadel ER (1998).
Estrogen influences osmotic secretion of AVP and body water
balance in postmenopausal women. Am J Physiol 274:
R187R195.
Stachenfeld, NS, Silva C, Keefe DL, Kokoszka CA, Nadel ER
(1999). Effects of oral contraceptives on body fluid regulation. J Appl Physiol 87: 10161025.
Stalker HJ, Keller KL, Gray BA, Zori RT (2003). Concurrence
of fragile X syndrome and 47,XYY in an individual with a
PraderWilli-like phenotype. Am J Med Genet 116A:
176178.
Standaert DG, Lee VM-Y, Greenberg BG, Lowery DE,
Trojanowski JQ (1991). Molecular features of hypothalamic
plaques in Alzheimers disease. Am J Pathol 139: 681691.
Stanhope R, Preece MA, Brook CGD (1984). Hypoplastic optic
nerves and pituitary dysfunction. Arch Dis Child 59: 111114.
Stanley BG, Leibowitz SF (1984). Neuropeptide Y: stimulation
of feeding and drinking by injection into the paraventricular
nucleus. Life Sci 35: 26352642.
Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz SF
(1993). The perifornical area: the major focus of (a) patchily
distributed hypothalamic neuropeptide Y-sensitive feeding
system(s). Brain Res 604: 304317.
Stanton BR, David AS, Cleare AJ, Sierra M, Lambert MV,
Phillips ML, Porter RJ, Gallagher P, Young AH (2001). Basal
activity of the hypothalamic-pituitary-adrenal axis in patients
with depersonalization disorder. Psychiatry Res 104: 8589.
Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992).
Hippocampal formation volume, memory dysfunction, and
2014 Refs
2/12/03
1:39 pm
Page 549
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
549
Steinbusch HWM, Mulder AH (1984). Localization and projections of histamine immunoreactive neurons in the central
nervous system of the rat. In: Bjrklund A, Hkfelt T, Kuhar
MJ (Eds.) Handbook of Chemical Neuroanatomy 3, pp.
126140. Elsevier, Amsterdam.
Steiner M (1996). Premenstrual dysphoric disorder. Gen Hosp
Steinhausen H-C (2002). The outcome of anorexia nervosa in
the 20th century. Am J Psychiatry 159: 12841293.
Stener-Victorin E, Waldenstrm U, Tgnfors U, Lundeberg T,
Lindstedt G, Janson PO (2000) Effects of electro-acupuncture on anovulation in women with polycystic ovary
syndrome. Acta Obstet Gynecol Scand 79: 180188.
Stensaas LJ, Lavker RM, Monti-Bloch L, Grosser BI, Berliner
DL (1991). Ultrastructure of the human vomeronasal organ.
J Steroid Biochem Mol Biol 39: 553560
Stenzel-Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW
(1994). Overproduction of corticotropin-releasing factor in
transgenic mouse: a genetic model of anxiogenic behavior. J
Neurosci 14: 25792584.
Stephan H, Andy OJ (1962). The septum: a comparative study
on its size in insectivores and primates. J Hirnforsch 5:
229244.
Stephan MJ, Brooks KL, Moore DC, Coll EJ, Goho C (1994).
Hypothalamic hamartoma in oral-facial-digital syndrome type
VI (Vradi Syndrome). Am J Med Genet 51: 131136.
Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM,
Burgett SG, Craft L, Hale J, Hoffman J, Hsiung HM,
Kriauciunas A, MacKellar W, Rosteck jr PR, Schoner B,
Smith D, Tinsley FC, Zhang X-Y, Helman M (1995). The
role of neuropeptide Y in the antiobesity action of the obese
gene product. Nature 377: 530532.
Stephenson J (1996) More evidence links NSAID, estrogen use
with reduced Alzheimer risk. JAMA 275: 13891390.
Stern BJ, Krumholz A, Johns C, Scott P, Nissim J (1985).
Sarcoidosis and its neurological manifestations. Arch Neurol
42: 909917.
Sternbach H (1998). Age-associated testosterone decline in
men: clinical issues for psychiatry. Am J Psychiatry 155:
13101318.
Sternberg EM, Scott Young III W, Bernardini R, Calogero AE,
Chrousos GP, Gold PW, Wilder RL (1989). A central nervous
system defect in biosynthesis of corticotropin-releasing
hormone is associated with susceptibility to streptococcal cell
wall induced arthritis in Lewis rats. Proc Natl Acad Sci USA
86: 47714775.
Sternberg EM (1997). Neural-immune interactions in health and
disease. J Clin Invest 199: 26412647.
Stener-Victorin E, Lundeberg T, Gajander S, Aloe L, Manni L,
Waldenstrm Janson, PO (2003). Steroid-induced polycystic
ovaries in rats: effect of electro-acupuncture on concentrations of endothelin-1 and nerve growth factor (NGF), and
cortisol levels in patients with Cushings syndrome. Biol

Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA,
Schteingart DE (1999). Decrease in cortisol reverses human
hippocampal atrophy following treatment of Cushings
disease. Biol Psychiatry 46: 15951602.
Starzyj J, Kwiatkowski S, Urbanowicz W, Starzyk B,
Harasiewicz M, Kalicka-Kasperczyk A, Tylek-Lemanska D,
Dziatkowiak H (2003). Suprasellar arachnoidal cyst as a cause
of precocious puberty report of three patients and literature overview. J Pediatr Endocrinol Metab 16: 447455.
Stassen HH, Bridler R, Hgele S, Hergersberg M, Mehmann B,
Schinzel A, Weisbrod M, Scharfetter C (2000). Schizophrenia
and smoking: evidence for a common neurobiological basis.
Statnick MA, Schober DA, Gackenheimer S, Johnson D,
Beavers L, Mayne NG, Burnett JP Gadski, R, Gehlert DR
(1998). Characterization of the neuropeptide Y5 receptor in
the human hypothalamus: a lack of correlation between Y5
mRNA levels and binding sites. Brain Res 810: 1626.
Staudt J, Stber P (1977). Morphologische Untersuchungen der
Matrix im Bereich des Hypothalamus beim Menschen. Z
Mikrosk-Anat Forsch 91: 773786.
Staurenghi AH, Masera RG, Prolo P, Griot G, Sartori ML,
Ravizza L, Angeli A (1997). Hypothalamic-pituitary-adrenal
axis function, psychopathological traits, and natural killer
(NK) cell activity in anorexia nervosa. Psychoneuroendocrinology 22: 575590.
Steegers EAP, Van der Post JAM (1998). Hypertension in pregnancy. In: Kurjak A (Ed.) Textbook of perinatal medicine.
Parthenon Publishing Group, London, pp.18891911.
Steeves TDL, King DP, Zhao Y, Sangoram AM, Du F, Bowcock
AM, Moore RY, Takahashi JS (1999). Molecular cloning and
characterization of the human CLOCK gene: expression in
the suprachiasmatic nuclei. Genomics 57: 189200.
Stefano GB, Fricchione GL Slingsby BT, Benson H (2001).
The placebo effect and relaxation response: neural processes
and their coupling to constitutive nitric oxide. Brain Res Rev
35: 119.
Steiger A, Holsboer F (1997). Neuropeptides and human sleep.
Sleep 20: 10381052.
Stein JA, Curl FD, Valsamis M, Tschudy DP (1972) Abnormal
iron and water metabolism in acute intermittent porphyria
with new morphologica findings. Am J Med 53: 784789.
Stein D, Avni J (1988). Thyroid hormones in the treatment of
affective disorders. Acta Psychiatr Scand 77: 623636.
Stein MB, Yehuda R, Koverola C, Hanna C (1997). Enhanced
dexamethasone suppression of plasma cortisol in adult women
traumatized by childhood sexual abuse. Biol Psychiatry 42:
680686.
Steinbok P, Hentschel S, Almqvist P, Cochrane DD, Poskitt K
(2002). Management of optic chiasmatic/hypothalamic astrocytomas in children. Can J Neurol Sci 29: 132138.
549
2014 Refs
550
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 550
D.F. SWAAB
expression of NGF mRNA in the ovaries, the adrenal glands,

and the central nervous system. Reprod Biol Endocrinol 1:
33.
Stevens JR (1982). Neuropathology of schizophrenia. Arch Gen
Stevens JR (2002). Schizophrenia: reproductive hormones and
the brain. Am J Psychiatry 159: 713719.
Stevens MY, Challis JRG, Lye SJ. (1998a). Corticotrophinreleasing hormone receptor subtype 1 is significantly
up-regulated at the time of labor in the human myometrium.
Stevens M, Van Duijn CM, Kamphorst W, De Knijff P, Heutink
P, Van Gool WA, Scheltens P, Ravid R, Oostra BA,
Niermeijer MF, Van Swieten JC (1998b). Familial aggregation in frontotemporal dementia. Neurology 50: 15411545.
Stevenson JAF, Montemurro DG (1963). Loss of weight and
metabolic rate of rats with lesions in the medial and lateral
hypothalamus. Nature 198: 92.
Stewart L, Steinbok P, Daaboul J (1998). Role of surgical resection in the treatment of hypothalamic hamartomas causing
precocious puberty. J Neurosurg 88: 340345.
Stewart PM, Penn R, Gibson R, Holder R, Parton A, Ratcliffe
JG, London DR (1992). Hypothalamic abnormalities in
patients with pituitary-dependent Cushings syndrome. Clin
Stieber A, Mourelatos Z, Gonatas NK (1996). In Alzheimers
disease the Golgi apparatus of a population of neurons without
neurofibrillary tangles is fragmented and atrophic. Am J
Pathol 148: 415426.
Stieber A, Chen Y, Wei S, Mourelatos Z, Gonatas J, Okamoto
K, Gonatas NK (1998). The fragmented neuronal Golgi apparatus in amyotrophic lateral sclerosis includes the trans-Golgi
network: functional implications. Acta Neuropathol 95:
245253.
Stiell IG, Hbert PC, Wells GA, Vandemheen KL, Tang ASL,
Higginson LAJ, Dreyer JF, Clement C, Battram E, Watpool
E, Mason S, Klassen T, Weitzman BN (2001). Vasopressin
versus epinephrine for inhospital cardiac arrest: a randomised
controlled trial. Lancet 358: 105109.
Stokes PE, Sikes CR (1991). Hypothalamic-pituitary-adrenal
axis in psychiatric disorders. Annu Rev Med 42: 519531.
Stoler JM, Herrin JT, Holmes LB (1995). Genital abnormalities in females with BardetBiedl syndrome. Am J Med Genet
55: 276278.
Stones A, Groome D, Perry D, Hucklebridge F, Evans P (1999).
The effect of stress on salivary cortisol in panic disorder
patients. J Affect Disord 52: 197201.
Stopa EG, Koh ET, Svendsen CN, Rogers WT Schwaber JS,
King JC (1991). Computer-assisted mapping of immunoreactive mammalian gonadotropin-releasing hormone in adult
human basal forebrain and amygdala. Endocrinology, 128:
31993207.
Stopa EG, Volicer L, Kuo-Leblanc V, Harper D, Lathi D, Tate
B, Satlin A (1999). Pathologic evaluation of the human
suprachiasmatic nucleus in severe dementia. J Neuropathol

Storch AS (1971). Acute water retention associated with continuous slow infusion of oxytocin. Obstet Gynecol 37: 109111.
Stotz-Potter EH, Willis LR, DiMicco JA (1996). Muscimol acts
in dorsomedial but not paraventricular hypothalamic nucleus
to suppress cardiovascular effects of stress. J Neurosci 16:
1173-1179.
Stout NR, Kenny RA, Baylis PH (1999). A review of water balance in ageing in health and disease. Gerontology 45: 6166.
Stving RK, Vinten J, Handberg A, Ebbesen EN, Hangaard J,
Hansen-Nord M, Kristiansen K, Hagen C (1998). Diurnal
variation of the serum leptin concentration in patients with
anorexia nervosa. Clin Endocrinol 48: 761768.
Stving RK, Hangaard J, Hagen C (2001). Update on endocrine
disturbances in anorexia nervosa. J Pediatr Endocrinol Metab
14: 459480.
Stving RK, Bennedbaek FN, Hegeds L, Hagen C (2001).
Evidence of diffuse atrophy of the thyroid gland in patients
with anorexia nervosa. Int J Eat Disord 29: 230235.
Stving RK, Andersen M, Flyvbjergt A, Frystyk J, Hangaard
J, Vinten J, Koldkjr OG, Hagen C (2002). Indirect evidence
for decreased hypothalamic somatostatinergic tone in anorexia
nervosa. Clin Endocrinol 56: 391396.
Strakowski SM, Wilson DR, Tohen M, Woods BT, Douglas
AW, Stoll AL (1993). Structural brain abnormalities in firstepisode mania. Biol Psychiatry 33: 602609.
Stratakis CA, Karl M, Schulte HM, Chrousos GP (1994).
Glucocorticosteroid resistance in humans. Ann NY Acad Sci
746: 362374.
Strazielle N, Ghersi-Egea J-F (2000). Choroid plexus in the
central nervous system: biology and physiopathology. J
Strenge H (1975). ber den Nucleus tuberis lateralis im Gehirn
des Menschen. Eine pigmentarchitektonische Studie. Z
Mikrosk Anat Forsch 89: 10431067.
Strittmatter M, Isenberg E, Grauer MT, Hamann G, Schimrigk
K. (1996a). CSF substance P, somatostatin and monoaminergic transmitter metabolites in patients with narcolepsy.
Strittmatter M, Hamann GF, Grauer M, Fischer C, Blaes F,
Hoffmann K-H, Schimrigk K (1996b). Altered activity of the
sympathetic nervous system and changes in the balance of
hypophyseal, pituitary and adrenal hormones in patients with
cluster headache. Neuroreport 7: 12291234.
Strbel A, Issad T, Camoin L, Ozata M, Strosberg AD (1998).
A leptin missense mutation associated with hypogonadism
and morbid obesity. Nat Genet 18: 213215.
Strober, M, Freeman R, Lampert C, Diamond J, Kayne W
(2000). Controlled family study of anorexia nervosa and
bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry 157: 393-401.
Strom TM, Hrtnagel K, Hofmann S, Gekeler F, Scharfe C,
Rabl W, Gerbitz KD, Meitinger T (1998). Diabetes insipidus,
2014 Refs
2/12/03
1:39 pm
Page 551
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
551
Sullivan EV, Lane B, Deshmukh A, Rosenbloom MJ, Desmond

JE, Lim KO, Pfefferbaum A (1999). In vivo mammillary
body volume deficits in amnesic and nonamnesic alcoholics.
Sullivan F, Hutchinson M, Bahandeka S, Moore RE (1987).
Chronic hypothermia in multiple sclerosis. J. Neurol
Sullivan PF, Wilson DA, Mulder RT, Joyce PR (1997). The
hypothalamic-pituitary-thyroid axis in major depression. Acta
Sullivan WM, Kelley GG, OConnor PG, Dickey PS, Kim JH,
Robbins R, Shulman GI (1992). Hypopituitarism associated
with a hypothalamic CMV infection in a patient with AIDS.
Am J Med 92: 221223.
Sumaya IC, Rienzi BM, Deegan JF, Moss DE (2001). Bright
light treatment decreases depression in institutionalized older
adults: a placebo-controlled crossover study. J Gerontol 56A:
M356M360.
Sumida M, Arita K, Migita K, Tominaga A, Iida K, Kurisu K
(2001). Concomitant pituitary adenoma and Rathkes cleft
cyst. Neuroradiology 43: 755759.
Sun ZS, Albrecht U, Zhuchenko O, Bailey J, Eichele G, Lee
CC (1997). RIGUI, a putative mammalian ortholog of the
Drosophila period gene. Cell 90: 10031011.
Sundblom DM, Heikman P, Naukkarinen H, Fyhrquist F (1999).
Blood concentrations of vasopressin, neuropeptide FF and
prolactin are increased by high-dose right unilateral ETC.
Peptides 20: 319326.
Sunderland T, Merril CR, Harrington MG, Lawlor BA, Molchan
SE, Martinez R, Murphy DL (1989). Reduced plasma dehydroepiandrosterone concentrations in Alzheimers disease.
Lancet (8662): 570.
Sunderman FW, Webb Haymaker M (1947). Hypothermia and
elevated serum magnesium in a patient with facial hemangioma extending into the hypothalamus. Am J Med Sci 213:
562571.
Sundquist J, Forsling ML, Olsen JE, Akerlund M (1983).
Cerebrospinal fluid arginine-vasopressin in degenerative
disorders and other neurological diseases. J Neurol Neurosurg
Psychiatry 46: 1417
Supprian T, Sian J, Heils A, Hofmann E, Warmuth-Metz M,
Solymosi L (1999). Isolated absence of the septum pellucidum. Neuroradiology 41: 563566.
Suresh PA, Sebastian S, George A, Radhakrishnan K (1999).
Subclinical hyperthyroidism and hyperkinetic behavior in
children. Pediatr Neurol 20: 192194.
Susser E, Lin SP (1992). Schizophrenia after prenatal exposure
to the Dutch hunger winter of 19441945. Arch Gen
Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz
D, Gorman JM (1996). Schizophrenia after prenatal famine.
diabetes mellitus, optic atrophy and deafness (DIDMOAD)

caused by mutations in a novel gene (wolframin) coding for
a predicted transmembrane protein. Hum Mol Genet 7:
20212028.
Strmberg P, kerlund M, Forsling ML, Granstrm E, Kindahl
H. (1984). Vasopressin and prostaglandins in premenstrual
pain and primary dysmenorrhea. Acta Obstet Gynecol Scand
63: 533538.
Strous RD, Pollack S, Robinson D, Sheitman B, Lieberman JA
(2001) Seasonal admission patterns in first episode psychosis,
chronic schizophrenia, and non-schizophrenic psychoses. J
Nerv Ment Dis 189: 642644.
Struwe F (1929). Histopathologische untersuchungen ber
Entstehung und Wesen der senilen Plaques. Zeitschrift Ges
Neurol Psych 122: 291307.
Stunkard A (1997). Eating disorders: the last 25 years. Appetite
29: 181190.
Sturm JW, Andermann F, Berkovic SF (2000). Pressure to laugh:
an unusual epileptic symptom associated with small hypothalamic hamartomas. Neurology 54: 971973.
Sturner WQ, Lynch HJ, Deng MH, Gleason RE, Wurtman RJ
(1990). Melatonin concentrations in the sudden infant death
syndrome. Forensic Sci Int 45: 171180.
Styne DM (1993). The therapy for hypothalamic-pituitary
tumors. Endocrinol Metab Clin North Am 22: 631648.
Styne DM (1997). New aspects in the diagnosis and treatment
of pubertal disorders. Pediatr Clin North Am 44: 505529.
Styra R, Joffe R, Singer W (1991). Hyperthyroxinemia in major
affective disorders. Arch Psychiatr Scand 83: 6163.
Suarez JI, Cohen ML, Larkin J, Kernich DA, Hricik DE, Daroff
RB (1997). Acute intermittent porphyria: clinicopathologic
correlation. Neurology 48: 16781683.
Suganuma H, Yoshimi T, Kita T, Okano H, Suzuki Y, Oki Y,
Chida K, Sato A (1994). Rare case with metastatic involvement of hypothalamo-pituitary and pineal body presenting as
hypopituitarism and diabetes insipidus. Intern Med 33:
795798.
Sugimoto T, Sakano T, Kinoshita Y, Masui M, Yoshioka T
(1992). Morphological and functional alterations of the hypothalamic-pituitary system in brain death with long term bodily
living. Acta Neurochir 115: 3136.
Sugita K, Izumi T, Yamaguchi K, Fukuyama Y, Sato A, Kajita
A (1986). Cornelia de Lange Syndrome associated with a
suprasellar germinoma. Brain Dev 8: 541-546.
Sugiyama M, Takumi I, Node Y, Sanno N, Teramoto A,
Osamura RY (1999). Neurohypophyseal germinoma with
prolactinoma. J Neurosurg 90: 170.
Suh BY, Liu JH, Rasmussen DD, Gibbs DM, Steinberg J,
Yen SSC (1986). Role of oxytocin in the modulation of
ACTH release in women. Neuroendocrinology 44: 309313.
Sukhov RR, Walker LC, Rance NE, Price DL, Scott Young III
W (1995). Opioid precursor gene expression in the human
hypothalamus. J Comp Neurol 353: 604622.
551
2014 Refs
552
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 552
D.F. SWAAB
Sutherland ER, Martin RJ, Ellison MC, Kraft M (2002).

Immunomodulatory effects of melatonin in asthma. Am J
Respir Crit Care Med 166: 10551061.
Sutor AH (1998). Desmopressin (DDAVP) in bleeding disorders of childhood. Semin Thromb Hemost 24: 555-566.
Sutor AH (2000). DDAVP is not a panacea for children with
bleeding disorders. Br J Haematol 108: 217227.
Sutton LN, Molloy PT, Sernyak H, Goldwein J, Phillips PL,
Rorke LB, Moshang T, Lange B, Packer RJ (1995). Longterm outcome of hypothalamic/chiasmatic astrocytomas in
children treated with conservative surgery. J Neurosurg 83:
583589.
Suvisaari JM, Haukka JK, Lnnqvist JK (2001). Season of birth
among patients with schizophrenia and their siblings:
evidence for the procreational habits hypothesis. Am J
Suzuki N, Shinonaga M, Hirata K, Inoue S, Kuwabara T (1990).
Hypothalamic obesity due to hydrocephalus caused by aqueductal stenosis. J Neurol Neurosurg Psychiatry 53: 11021103.
Suzuki M, Takeuchi O, Mori I, Takegoshi K, Kurachi M (1992).
Syndrome of inappropriate secretion of antidiuretic hormone
associated with schizophrenia. Biol Psychiatry 31: 10571061.
Svendsen E, Hill RB (1987). Autopsy legislation and practice
in various countries. Arch Pathol Lab Med 111: 846850.
Swaab DF (1982). Neuropeptides. Their distribution and function in the brain. Prog Brain Res 55: 97122.
Swaab DF (1991). Brain aging and Alzheimers disease: wear and
tear versus use it or lose it. Neurobiol Aging 12: 317324.
Swaab DF (1995a). Aging of the human hypothalamus. Horm
Res 43: 811.
Swaab DF (1995b). Development of the human hypothalamus.
Neurochem Res 20: 509519.
Swaab DF (1997). PraderWilli syndrome and the hypothalamus. Acta Paediatr Suppl 423: 5054.
Swaab DF, Boer K (1972). The presence of biologically labile
compounds during ischemia and their relationship to the EEG
in rat cerebral cortex and hypothalamus. J Neurochem 19:
28432853.
Swaab DF, Boer K (2001). Functional teratogenic effects of
chemicals on the developing brain. In: Levene MI, Chervenak
FA, Whittle MJ, Bennett MJ, Punt J (Eds.) Fetal and Neonatal
Neurology and Neurosurgery. Churchill Livingstone, London,
pp. 126.
Swaab DF, Fliers E (1985). A sexually dimorphic nucleus in
the human brain. Science 228: 11121115.
Swaab DF, Fliers E (1986). Clinical strategies in the treatment
of Alzheimers disease. Prog Brain Res 70: 413427.
Swaab DF, Hofman MA (1984). Sexual differentiation of the
human brain. A historical perspective. Prog Brain Res 61:
361374.
Swaab DF, Hofman MA (1988). Sexual differentiation of
the human hypothalamus: ontogeny of the sexually dimorphic
nucleus of the preoptic area. Brain Res Dev 44: 314318.
Swaab DF, Hofman MA (1990). An enlarged suprachiasmatic

nucleus in homosexual men. Brain Res 537: 141148.
Swaab DF, Hofman MA (1995). Sexual differentiation of the
human hypothalamus in relation to gender and sexual orientation. Trends Neurosci 18: 264270.
Swaab DF, Honnebier WJ (1974). The role of the fetal hypothalamus in development of the feto-placental unit and in
parturition. Prog Brain Res 41: 255280.
Swaab DF, Jongkind JF (1971) Influence of gonadotropic
hormones on the hypothalamic neurosecretory activity in the
rat. Neuroendocrinology 8: 3647.
Swaab DF, Jongkind JF, De Rijke-Arkenbout AA (1971).
Quantitative histochemical study on the influence of lactation and changing levels of gonadotropic hormones on rat
supraoptic nucleus. Endocrinology 89: 11231125.
Swaab DF, Pool CW, Nijveldt F (1975). Immunofluorescence
of vasopressin and oxytocin in the rat hypothalamo-neurohypophyseal system. J Neural Transmiss 36: 195215.
Swaab DF, Boer K, Honnebier WJ (1977). The influence of the
fetal hypothalamus and pituitary on the onset and course of parturition. In: Knight J, OConnor M (Eds.), The Fetus and Birth,
pp 379400, Ciba Foundation Symposium 47, Elsevier/NorthHolland Biomedical Press, Amsterdam/New York.
Swaab DF, Boer GJ, Boer K, Dogterom J, Van Leeuwen FW,
Visser M (1978). Fetal neuroendocrine mechanisms in development and parturition. Prog Brain Res 48: 277289.
Swaab DF, Boer GJ, Boer K, Oosterbaan HP, Oosting PR
(1982). Neurohypophysial and intermediate lobe peptides
in intrauterine growth and labour. In: Baertsch AJ, Dreifuss
JJ (Eds.) Neuroendocrinology of Vasopressin, Corticoliberin
and opiomelanocortins, pp. 343352, Academic Press,
London.
Swaab DF, Fliers E, Partiman TS (1985). The suprachiasmatic
nucleus of the human brain in relation to sex, age and senile
dementia. Brain Res 342: 3744.
Swaab DF, Roozendaal B, Ravid R, Velis DN, Gooren L,
Williams RS (1987a). Suprachiasmatic nucleus in aging,
Alzheimers disease, transsexuality and PraderWilli
syndrome. Prog Brain Res 72: 301310.
Swaab DF, Fliers E, Hoogendijk JE (1987b). Vasopressin in
relationship to human aging and dementia. In: Gash DM,
Boer GJ (Eds.) Vasopressin: Principles and Properties, pp.
611625. Plenum Press, New York.
Swaab DF, Boer GJ, Feenstra MGP (1988). Concept of functional neuroteratology and the importance of neurochemistry.
Prog Brain Res 73: 314.
Swaab DF, Hofman MA, Honnebier MBOM (1990).
Development of vasopressin neurons in the human suprachiasmatic nucleus in relation to birth. Dev Brain Res 52:
289293.
Swaab DF, Eikelenboom P, Grundke-Iqbal I, Iqbal K, Kremer
HPH, Ravid R, Van de Nes JAP (1991) Cytoskeletal alterations in the hypothalamus during aging and in Alzheimers
2014 Refs
2/12/03
1:39 pm
Page 553
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
553
Alzheimers disease: use it or lose it. Prog Brain Res 138:

343373.
Swain MG (2000). Fatigue in chronic disease. Clin Sci 99:
18.
Swann AC, Stokes PE, Casper R, Secunda SK, Bowden CL,
Berman N, Katz MM, Robins E (1992) Hypothalamic-pituitary-adrenocortical function in mixed and pure mania. Acta
Swanson LW (1975). Hippocampo-hypothalamic connections:
origin in subicular cortex, not ammons horn. Science 189:
303304.
Swanson LW (1977). Immunohistochemical evidence for a
neurophysin-containing autonomic pathway arising in the
paraventricular nucleus of the hypothalamus. Brain Res 128:
346353.
Swanson LW, Sawchenko PE, Rivier J, Vale WW (1983).
Organisation of ovine corticotropin releasing factor
immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36: 165186
Swanwick GRJ, Kirby M, Bruce I, Buggy F, Coen RF, Coakley
D, Lawlor BA (1998). Hypothalamic-pituitary-adrenal axis
dysfunction in Alzheimers disease: lack of association
between longitudinal and cross-sectional findings. Am J
Swedo SE, Leonard HL, Kruesi MJP, Rettew DC, Listwak SJ,
Berrettini W, Stipetic M, Hamburger S, Gold PW, Potter WZ,
Rapoport JL (1992). Cerebrospinal fluid neurochemistry in
children and adolescents with obsessive-compulsive disorder.
Swedo SE, Leonard HL, Kiessling LS (1994). Speculations on
antineuronal antibody-mediated neuropsychiatric disorders of
childhood. Pediatrics 93: 323326.
Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport
JL, Dow SP, Kanter ME, Chapman F, Zabriskie J (1997).
Identification of children with pediatric autoimmune
neuropsychiatric disorders associated with streptococcal
infections by a marker associated with rheumatic fever. Am
Sweeney JA, Strojwas MH, Mann JJ, Thase ME (1998).
Prefrontal and cerebellar abnormalities in major depression:
evidence from oculomotor studies. Biol Psychiatry 43:
584594.
Swift GR, Sadler DB, Swift M (1990). Psychiatric findings in
Wolfram syndrome homozygotes. Lancet 336: 667669.
Swift GR, Perkins DO, Chase CL, Sadler DB and Swift, M
(1991). Psychiatric disorders in 36 families with Wolfram
syndrome. Am J Psychiatry 148: 775-779.
Swift M, Swift RG (2000). Psychiatric disorders and mutations
at the Wolfram syndrome locus. Biol Psychiatry 47:
787793.
Swift RG, Polymeropoulos, MH, Torres R, Swift M (1998).
Predisposition of Wolfram syndrome heterozygotes to psychiatric illness. Mol Psychiatry 3: 8691.
disease are not necessarily a marker for impending cell death.

In Iqbal K, McLachlan DRC, Winblad B, Wisniewski HM
(Eds.) Alzheimers disease: Basic mechanisms, diagnosis and
therapeutic strategies, pp. 181190. John Wiley and Sons,
New York.
Swaab DF, Gooren LJG, Hofman MA (1992a). The human
hypothalamus in relation to gender and sexual orietation. Prog
Brain Res 93: 205215.
Swaab DF, Grundke-Iqbal I, Iqbal K, Kremer HPH, Ravid R,
Van de Nes JAP (1992b). Tau and ubiquitin in the human
hypothalamus in aging and Alzheimers disease. Brain Res
590: 239249.
Swaab DF, Hofman MA, Lucassen PJ, Salehi A, Uylings HBM.
(1994a). Neuronal shrinkage, not cell death, is the main
hallmark in Alzheimers Disease. Neurobiol Aging 15:
369371.
Swaab DF, Zhou JN, Ehlhart T, Hofman MA (1994b).
Development of vasoactive intestinal polypeptide (VIP)
neurons in the human suprachiasmatic nucleus (SCN) in relation to birth and sex. Brain Res Dev 79: 249259.
Swaab DF, Raadsheer FC, Endert E, Hofman MA, Kamphorst
W, Ravid R (1994c). Increased cortisol levels in aging and
Alzheimers disease in postmortem cerebrospinal fluid. J
Swaab DF, Purba JS, Hofman MA (1995a). Alterations in the
hypothalamic paraventricular nucleus and its oxytocin
neurons (putative satiety cells) in Prader-Willi syndrome: a
study of five cases. J Clin Endocrinol Metab 80: 573579.
Swaab DF, Kamphorst W, Raadsheer FC, Purba JS, Ravid R,
Tilders FJH (1995b). Increased hypothalamo-pituitary-adrenal
axis activity is not pivotal in the pathogenesis of Alzheimers
disease. In: Iqbal K, MortimerJA, Winblad B, Wisniewski
HM (Eds.) Research Advances in Alzheimers Disease and
Related Disorders. John Wiley and Sons Ltd., pp. 461466.
Swaab DF, Slob AK, Houtsmuller EJ, Brand T, Zhou JN
(1995c). Increased number of vasopressin neurons in the
suprachiasmatic nucleus (SCN) of bisexual adult male rats
following perinatal treatment with the aromatase blocker
ATD. Brain Res Dev 85: 273279.
Swaab DF, Van Someren EJW, Zhou JN, Hofman MA (1996).
Biological rhythms in the human life cycle and their relationship to functional changes in the suprachiasmatic nucleus.
Swaab DF, Lucassen PJ, Salehi A, Scherder EJA, Van Someren
EJW, Verwer RWH (1998). Reduced neuronal activity and reactivation in Alzheimers disease. Prog Brain Res 117: 343377.
Swaab DF, Fliers E, Hoogendijk WJG, Veltman DJ, Zhou JN
(2000). Interaction of prefrontal cortical and hypothalamic
systems in the pathogenesis of depression. In: Uylings HBM,
Van Eden CG, De Bruin JPG, Feenstra MGP, Pennartz CMA
(Eds). Progress in Brain Research 126: 369396.
Swaab DF, Dubelaar EJG, Hofman MA, Scherder EJA, Van
Someren EJW, Verwer RWH (2002). Brain aging and
553
2014 Refs
554
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 554
D.F. SWAAB
Syed FA, Chalew SA (1999). Ketoconazole treatment of

gonadotropin independent precocious puberty in girls with
McCuneAlbright syndrome: a preliminary report. J Pediatr
Sylvester PE (1986). The anterior commissure in Downs
syndrome. J Ment Defic Res 30: 1926.
Symon L, Ganz JC, Chir B, Burston J (1971). Granular
cell myoblastoma of the neurohypophysis. J Neurosurg 35:
8289.
Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl T,
Schrier RW (1981). Radioimmunoassay of plasma arginine
vasopressin in hyponatremic patients with congestive heart
failure. N Engl J Med 305: 263266.
Szeifert GT, Sipos L, Horvth M, Sarker MH, Major O,
Salomvry B, Czirjk S, Blint K, Slowik F, Kolonics L,
Psztor E (1993). Pathological characteristics of surgically
removed craniopharyngiomas: analysis of 131 cases. Acta
Neurochir 124: 139143.
Szigethy E, Conwell Y, Forbes NT, Cox C, Caine ED (1994).
Adrenal weight and morphology in victims of completed
suicide. Biol Psychiatry 36: 374380.
Sztriha L, Vrady E, Hertecant J, Nork M (1998). Mediobasal
and mantle defect of the prosencephalon: Lobar holoprosencephaly, schizencephaly and diabetes insipidus. Neuropediatrics 29: 272275.
Szymusiak R (1995). Magnocellular nuclei of the basal
forebrain: substrates of sleep and arousal regulation. Sleep
18: 478500.
Tachibana N, Howard RS, Hirsch NP, Miller DH, Moseley IF,
Fish D (1994). Sleep problems in multiple sclerosis. Eur
Neurol 34: 320323.
Tada M, Aida T, Koiwa M, Chono Y, Kashiwaba T, Abe H
(1992). Papillary craniopharyngioma of the third ventricle.
Neurol Med Chir 32: 972975.
Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Mller
H-J, Dahmen N (2003). Association of a MAOA gene variant
with generalized anxiety disorder, but not with panic disorder
or major depression. Am J Med Genet Part B 117B: 16.
Tagliavini F, Pilleri, G (1983) Basal nucleus of Meynert. A
neuropathological study in Alzheimers disease, simple senile
dementia, Picks disease and Huntington chorea J Neurol Sci
62: 243260.
Tagliavini F, Pilleri G, Gemignani F, Lechi A (1983). Neuronal
loss in the basal nucleus of Meynert in progressive supranuclear palsy. Acta Neuropathol 61: 157160.
Tago H, McGeer PL, Bruce G, Hersh LB (1987). Distribution
of choline acetyltransferase-containing neurons of the hypothalamus. Brain Res 415: 4962.
Taivainen H, Laitinen K, Thtel R, Kilanmaa K, Vlimki MJ
(1995). Role of plasma vasopressin in changes of water
balance accompanying acute alcohol intoxication. Alcohol
Clin Exp Res 19: 759762.
Takahashi A (1991). Autonomic nervous system disorders in
Parkinsons disease. Eur Neurol (Suppl. 1) 31: 4147.
Takahashi K, Mouri T, Sone M, Murakami O, Itoi K, Imai Y,

Ohneda M, Yoshinaga K, Sasano N (1989). Calcitonin generelated peptide in the human hypothalamus. Endocrinol Jpn
36: 409415.
Takahashi K, Totsune K, Murakami O, Satoh F, Sone M,
Ohneda M, Sasano H, Mouri T (1994). Pituitary adenylate
cyclase activating polypeptide (PACAP)-like immunoreactivity in human hypothalamus: colocalization with arginine
vasopressin. Regul Pept 50: 267275.
Takahashi, T Shoji Y, Shoji Y, Haraguchi N, Takahashi I,
Takada G (1997). Active hypothalamic-pituitary-gonadal axis
in an infant with X-linked adrenal hypoplasia congenita. J
Pediatr 130: 485-488.
Takahashi M, Otsuka F, Miyoshi T, Ogura T, Makino H (1999).
An elderly patient with transient diabetes insipidus associated with lymphocytic infundibulo-neurohypophysitis. Endocr
J 46: 741746.
Takahashi K, Yoshinoya A, Arihara Z, Murakami O, Totsune
K, Sone M, Sasano H, Shibahara S (2000). Regional distribution of immunoreactive prolactin-releasing peptide in the
human brain. Peptides 21: 15511555
Takahashi S, Takahashi Y, Kondo N, Orii T (2001). Epileptic
seizures and structural abnormalities in a patient with holoprosencephaly. Brain Dev 23: 264268.
Takami S, Getchell ML, Chen Y, Monti-Bloch L, Berliner DL,
Stensaas LJ, Getchell TV (1993). Vomeronasal epithelial cells
of the adult human express neuron-specific molecules.
Takano K, Utsunomiya H, Ono H, Ohfu M, Okazaki M (1999).
Normal development of the pituitary gland: assessment with
three-dimensional MR volumetry. Am J Neuroradiol 20:
312315.
Takeda S, Kuwabara Y, Mizuno M (1985). Effects of pregnancy and labor on oxytocin levels in human plasma and
cerebrospional fluid. Endocrinol Jpn 32: 875880.
Takeda T, Kakigi A, Saito H (1995). Antidiuretic hormone
(ADH) and endolymphatic hydrops. Acta Otolaryngol Suppl
519: 219222.
Takeda T, Takeda S, Kitano H, Okada T, Kakigi A (2000).
Endolymphatic hydrops induced by chronic administration of
vasopressin. Hear Res 140: 16.
Takeda K, Inoue H, Tanizawa Y, Matsuzaki Y, Oba J, Watanabe
Y, Shinoda K, Oka Y (2001). WFS1 (Wolfram syndrome 1)
gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression
in rat brain. Hum Mol Genet 10: 477484.
Takeuchi N, Uchimura N, Hashizume Y, Mukai M, Etoh Y,
Yamamoto K, Kotorii T, Ohshima H, Ohshima M, Maeda H
(2001). Melatonin therapy for REM sleep behavior disorder.
Takrani LB, Cronin D (1976). Kleine-Levin syndrome in a
female patient. Can Psychiatr Assoc J 21: 315318.
Tamarkin L, Danforth D, Lichter A, De Moss E, Cohen M,
Chabner B, Lippman M(1982). Decreased nocturnal plasma
2014 Refs
2/12/03
1:39 pm
Page 555
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
555
Tasch E, Cendes F, Dubeau F, Montes J, Rosenblatt B,

Andermann F, Arnold D (1998). Hypothalamic hamartomas
and gelastic epilepsy. Neurology 51: 10461050.
Tashiro M, Mochizuki H, Iwabuchi K, Sakurada Y, Itoh M,
Watanabe T, Yanai K (2002). Roles of histamine in regulation of arousal and cognition: functional neuroimaging
of histamine H1 receptors in human brain. Life Sci 72:
409414.
Tataranni PA, Gautier J-F, Chen K, Uecker A, Bandy D, Salbe
AD, Pratley RE, Lawson M, Reiman EM, Ravussin E (1999).
Neuroanatomical correlates of hunger and satiation in humans
using positron emission tomography. Proc Natl Acad Sci USA
96: 45694574.
Tatemoto, K, Rkaeus , Jrnvall H, McDonald TJ, Mutt V
(1983). Galanin a novel biologically active peptide from
porcine intestine. FEBS Lett 164: 124128.
Tauman, R, Zisapel N, Laudon M, Nehama H, Sivan Y (2002).
Melatonin production in infants: association with perinatal
factors and development. Pediatr Neurol 26: 379-382.
Tauscher J, Pirker W, Willeit M, De Zwaan M, Bailer U,
Neumeister A, Asenbaum S, Lennkh C, Praschak-Rieder N,
Brcke T, Kasper S (2001). [123I]-CIT and single photon
emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa. Biol
Taylor IL (1999). Of mice and men the control of food intake
and body weight. Gastroenterology 116: 14871494.
Tchernof A, Desprs, J-P (2000). Sex steroid hormones, sex
hormone-binding globulin, and obesity in men and women.
Horm Metab Res 32: 526536.
Teasdale GM, Smith PA, Wilkinson R, Latner AL, Miller H
(1967). Endocrine activity in multiple sclerosis. Lancet
(7481): 6468.
Teclemariam-Mesbah R, Ter Horst GJ, Postema F, Wortel J, Buijs
RM (1999). Anatomical demonstration of the suprachiasmatic
nucleus-pineal pathway. J Comp Neurol 406: 171182.
Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose
M, Sakaki Y (1997). Circadian oscillation of a mammalian
homologue of the Drosophila period gene. Nature 389:
512516.
Teicher MH, Glod CA, Magnus E, Harper D, Benson G, Krueger
K, McGreenery CE (1997). Circadian rest-activity disturbances in seasonal affective disorder. Arch Gen Psychiatry
54: 124130.
Telenius H, Kremer B, Goldberg P, Theilmann J, Andrew SE,
Zeisler J, Adam S, Greenberg C, Ives E.J, Clarke LA, Hayden
MR (1994). Somatic and gonadal mosaicism of the
Huntington disease gene CAG repeat in brain and sperm. Nat
Genet 6: 409414.
Ten Bokkel Huinink D, Veltman GAM, Huizinga TWJ,
Roelfsema F, Keizer HJ (2000). Diabetes insipidus in
metastatic cancer: two case reports with review of the literature. Ann Oncol 11: 891895.
melatonin peak in patients with estrogen receptor positive

breast cancer. Science 216: 10031004.
Tan D-X, Manchester LC, Reiter RJ, Cabrera J, Burkhardt S,
Phillip T, Gitto E, Karbownik M, Li Q-D (2000). Melatonin
suppresses autoxidation and hydrogen peroxide-induced lipid
peroxidation in monkey brain homogenate. Neuroendocrinol
Lett 21: 361365.
Tan RS and Pu S-J (2001). The andropause and memory loss:
is there a link between androgen decline and dementia in the
aging male? Asian J. Androl 3: 169174.
Tanabe M, Watanabe T, Hori T (1994). Von Recklinghausens
disease with diencephalic syndrome in an adult. J Neurosurg
80: 556558.
Tanaka K, Sato A, Naito T, Kuramochi K, Itabashi H, Takemura
Y (1992). Noonan syndrome presenting growth hormone
neurosecretory dysfunction. Intern Med 31: 908-911.
Tanaka Y, Miyazawa Y, Akaoka F, Yamada T (1997). Amnesia
following damage to the mammillary bodies. Neurology 48:
160165.
Tanaka M, Naruo T, Muranaga T, Yasuhara D, Shiiya T,
Nakazato M, Matsukura S, Nozoe S-I (2002). Increased
fasting plasma ghrelin levels in patients with bulimia nervosa.
Eur J Endocrinol 146: R1R3.
Tanaka, M, Naruo T, Nagai N, Kuroki N, Shiiya T, Nakazato
M, Matsukura S, Nozoe S (2003). Habitual binge/purge
behavior influences circulating ghrelin levels in eating disorders. J Psychiatr Res 37: 1722.
Tandberg E, Larsen JP, Aarsland D, Cummings JL (1996). The
occurrence of depression in Parkinsons disease. Arch Neurol
53: 175179.
Tandon R (1999). Cholinergic aspects of schizophrenia. Br J
Psychiatry (Suppl. 37) 174: 711.
Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Surland
B, Andrews M, Mayeux R (1996). Effect of oestrogen during
menopause on risk and age of onset of Alzheimers disease.
Lancet 348: 429432.
Tanna NK, Kohn MI, Horwich DN, Jolles PR, Zimmerman RA,
Alves WM, Alavi A (1991). Analysis of brain and cerebrospinal fluid volumes with MR imaging: impact on PET
data correction for atrophy. Radiology 178: 123130.
Tantam D, Evered C, Hersov L (1990). Aspergers syndrome
and ligamentous laxity. J Am Acad Child Adolesc Psychiatry
29: 892896.
Taphoorn M.JB, Van Someren EJW, Snoek FJ, Strijers RLM,
Swaab DF, Visscher F, De Waal LP, Polman CH (1993).
Fatigue, sleep disturbances and circadian rhythm in multiple
sclerosis. J Neurol 240: 446448.
Tarng DC, Huang TP (1995). Diabetes insipidus as an early
sign of pineal tumor. Am J Nephrol 15: 161164.
Tarquini B, Cornlissen G, Tarquini R, Perfetto F, Halberg F
(1999). General and unspecific damping by malignancy of
the circadian amplitude of circulating human melatonin?
555
2014 Refs
556
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 556
D.F. SWAAB
Tence M, Guillon G, Bottari S, Jard S (1990). Labelling of

vasopressin and oxytocin receptors from the human uterus.
Eur J Pharmacol 191: 427436.
Tenedieva VD, Lyamin PV, Nepomnyaschi VP (1994). The
plasma and CSF vasopressin levels in brain tumors with brain
edema. Acta Neurochir Suppl 60: 387389.
Tenover JS, Matsumoto AM, Clifton DK, Bremner WJ (1988).
Age-related alterations in the circadian rhythms of pulsatile
luteinizing hormone and testosterone secretion in healthy
men. J Gerontol 43: M163169.
Tenreiro S, Dowse HB, DSouza S, Minors D, Chiswick M,
Simms D, Waterhouse J (1991). The development of ultradian and circadian rhythms in premature babies maintained
in constant conditions. Early Hum Dev 27: 3352.
Teramoto, Y, Ioki I, Rutkowska D, Tokura H (1997). The daily
rhythms in the core temperature during spring and autumn
under natural conditions in young women. Biol Rhythm Res
28: 161165.
Terao T, Soeda S, Yoshimura R, Nakamura J, Iwata N (2002).
Effect of latitude on suicide rates in Japan. Lancet 360: 1892.
Terasawa E, Keen KI, Mogi K, Claude P (1999). Pulsatile
release of luteinizing hormone-releasing hormone (LHRH) in
cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. Endocrinology 140:
14321441.
Terman M, Terman JS, Ross DC (1998). A controlled trial of
timed bright light and negative air ionization for treatment
of winter depression. Arch Gen Psychiatry 55: 875882.
Terman JS, Terman M, Lo E-S, Cooper TB (2001). Circadian
time of morning light administration and therapeutic response
in winter depression. Arch Gen Psychiatry 58: 6975.
Terzian H, Dalle Ore G (1955). Syndrome of Klver and Bucy.
Reproduced in man by bilateral removal of the temporal lobes.
Terzolo M, Reimondo G, Ali A, Borretta G, Cesario F, Pia A,
Paccotti P, Angeli A (2001). The limited value of the desmopressin test in the diagnostic approach to Cushings syndrome.
Testa, S, Opportuno A, Gallo P, Tavolato B (1987). A case of
multiple sclerosis with an onset mimicking the KleineLevin
syndrome. Ital J Neurol Sci 8: 151156.
Thacker MJ, Hainline B, St Dennis-Feezle L, Johnson NB,
Pescovitz OH (1998). Growth failure in PraderWilli
syndrome is secondary to growth hormone deficiency. Horm
Res 49: 216220.
Thal DR, Rb U, Orantes M, Braak H (2002). Phases of Adeposition in the human brain and its relevance for the
development of AD. Neurology 58: 17911800.
Thaln BE, Kjellman BF, Mrkrid L, Wibom R, Wetterberg
L(1995). Light treatment in seasonal and nonseasonal depression. Acta Psychiatr Scand 91: 352360.
Thaln BE, Mrkrid L, Kjellman BF, R Wetterberg, L (1997).
Cortisol in light treatment of seasonal and non-seasonal
depression: relationship between melatonin and cortisol. Acta

Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani
S, Aldrich M, Cornford M, Siegel JM (2000). Reduced
number of hypocretin neurons in human narcolepsy. Neuron
27: 469474.
Thapan K, Arendt J, Skene DJ (2001). An action spectrum for
melatonin suppression: evidence for a novel non-rod, noncone photoreceptor system in humans. J Physiol (Lond) 535:
261267.
Thapar K, Stefaneanu L, Kovacs K, Scheithauer BW, Lloyd
RV, Muller PJ, Laws jr ER (1994). Estrogen receptor gene
expression in craniopharyngiomas: an in situ hybridization
study. Neurosurgery 35: 10121017.
Thase ME, Dub S, Bowler K, Howland RH, Myers JE,
Friedman E, Jarrett DB (1996). Hypothalamic-pituitaryadrenocortical activity and response to cognitive behavior
therapy in unmedicated, hospitalized depressed patients. Am
Thase ME, Buysse DJ, Frank E, Cherry CR, Cornes CL,
Mallinger AG, Kupfer DJ (1997). Which depressed patients
will respond to interpersonal psychotherapy? The role of
abnormal EEG sleep profiles. Am J Psychiatry 154: 502509.
Then Bergh, F, Kmpfel T, Trenkwalder C, Rupprecht R,
Holsboer F (1999). Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS.
Then Bergh F, Kmpfel T., Grasser A, Rupprecht R, Holsboer
F, Trenkwalder C (2001). Combined treatment with corticosteroids and moclobemide favors normalization of
hypothalamo-pituitary-adrenal
axis
dysregulation
in
relapsing-remitting multiple sclerosis: a randomized, double
blind trial. J Clin Endocrinol Metab 86: 16101615.
Thibonnier M, Conarty DM, Preston JA, Plesnicher CL, Dweik
RA, Erzurum SC (1999a). Human vascular endothelial
cells express oxytocin receptors. Endocrinology 140:
13011309.
Thibonnier M, Kilani A, Rahman M, Pilumeli DiBlasi T, Warner
K, Smith MC, Leenhardt AF Brouard R. (1999b). Effects of
the nonpeptide V1 vasopressin receptor antagonist SR49059
in hypertensive patients. Hypertension 34: 12931300.
Thibonnier M, Graves MK, Wagner MS, Chatelain N, Soubrier
F, Corvol P, Willard HF, Jeunemaitre X (2000). Study of
V1-vascular vasopressin receptor gene microsatellite polymorphisms in human essential hypertension. J Mol Cell
Cardiol 32: 557564.
Thiele B, Weidemann W, Schnabel D, Romalo G, Schweikert
H-U, Spindler K-D (1999). Complete androgen insensitivy
caused by a new frameshift deletion of two base pairs in
exon 1 of the human androgen receptor gene. J Clin
Thijssen JHH (2002). Relations of androgens and selected
aspects of human behavior. Maturitas (Suppl. 1) 41: S47S54.
2014 Refs
2/12/03
1:39 pm
Page 557
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Thim L, Kristensen P, Larsen PJ, Wulff BS (1998). CART,

a new anorectic peptide. Int J Biochem Cell Biol 30:
12811284.
Thind KK, Goldsmith PC (1989). Corticotropin-releasing factor
neurons innervate dopamine neurons in the periventricular
hypothalamus of juvenile macaques. Neuroendocrinology 50:
351358.
Thind KK, Boggan JE, Goldsmith PC (1991). Interactions
between vasopressin- and gonadotropin-releasing-hormonecontaining neuroendocrine neurons in the monkey supraoptic
nucleus. Neuroendocrinology 53: 287297.
Thliveris JA, Currie RW (1980). Observations on the hypothalamo-hypophyseal portal vasculature in the developing
human fetus. Am J Anat 157: 441444.
Thobois S, Mertens P, Guenot M, Hermier M, Mollion H,
Bouvard M, Chazot G, Broussolle E, Sindou M. (2002).
Subthalamic nucleus stimulation in Parkinsons disease. J
Neurol 249: 529534.
Thodou E, Kontogeorgos G, Scheithauer BW, Lekka I, Tzanis
S, Mariatos P, Laws ER (2000). Intrasellar chordomas mimicking pituitary adenoma. J Neurosurg 92: 976982.
Thomas, BC, Stanhope R (1993). Long-term treatment with
growth hormone in Noonans syndrome. Acta Paediatr 82:
853855.
Thomas L, Drew JE, Abramovich DR, Williams LM (1998).
The role of melatonin in the human fetus. Int J Mol Med 1:
539543.
Thomas L, Purvis CC, Drew JE, Abramovich DR, Williams
LM (2002). Melatonin receptors in human fetal brain: 2[125]iodomelatonin binding and MT1 gene expression J Pineal
Res 33: 218224.
Thomas NS, Browne CE, Oley C, Healey S, Crolla JA (1999).
Investigation of a cryptic interstitial duplication involving the
PraderWilli/Angelman syndrome critical region. Hum Genet
105: 384387.
Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G,
Zacharin M, Cameron F, Hurst J, Woods K, Dunger D,
Stanhope R, Forrest S, Robinson ICAF, Beddington RSP
(2001). Heterozygous HESX1 mutations associated with
isolated congenital pituitary hypoplasia and septo-optic
dysplasia. Hum Mol Gen 10: 3945.
Thompson C, Syddall H, Rodin I, Osmond C, Barker DJP
(2001). Birth weight and the risk of depressive disorder in
late life. Br J Psychiatry 179: 450455.
Thompson CJ, Charlton J, Walford S, Baird J, Hearnshaw J,
McCullochs A, Kelly W, Bayliss PH (1989). Vasopressin
secretion in the DIDMOAD (Wolfram) syndrome. Q J Med
71: 333345.
Thompson CJ, Edwards CRW, Bayliss PH (1991). Osmotic and
non-osmotic regulation of thirst and vasopressin secretion in
patients with compulsive water drinking. Clin Endocrinol 35:
221228.
Thompson DA, Kriss A, Cottrell S, Taylor D (1999). Visual
evoked potential evidence of albino-like chiasmal misrouting
557
in a patient with Angelman syndrome with no ocular features

of albinism. Dev Med Child Neurol 41: 633638.
Thompson, RH, Canteras NS, Swanson LW (1996).
Organization of projections from the dorsomedial nucleus of
the hypothalamus: a PHA-L study in the rat. J Comp Neurol
376: 143173.
Thompson RH, Swanson, LW (1998). Organization of inputs
to the dorsomedial nucleus of the hypothalamus: a reexamination with fluorogold and PHAL in the rat. Brain Res Rev
27: 89118.
Thompson TP, Lunsford LD, Kondziolka D (2000). Successful
management of sellar and suprasellar arachnoid cysts with
stereotactic intracavitary irradiation: an expanded report of
four cases. Neurosurgery 46: 15181523.
Thomson M (1998). Does the CRH binding protein shield
the anterior pituitary from placental CRH? Endocrine 9: 221226.
Thorburn GD, Hollingworth SA, Hooper SB (1991). The trigger
for parturition in sheep: fetal hypothalamus or placenta? J
Dev Physiol 15: 7179.
Thorley RR, Wertsch JJ, Klingbeil GE (2001). Acute hypothalamic instability in traumatic brain injury: a case report.
Arch Phys Med Rehabil 82: 246249.
Thorner MO, Reschke J, Chitwood J, Rogol AD, Furlanetto R,
Rivier J, Vale W, Blizzard RM (1985). Acceleration of growth
in two children treated with human growth hormone-releasing
factor. N Engl J Med 312: 49.
Thornton S, Davison JM, Bayliss PH (1990). Effect of human
pregnancy on the metabolic clearance rate of oxytocin. Am
J Physiol 259: R21R24.
Thornton S, Davison JM, Bayliss PH (1992). Plasma oxytocin
during the first and second stage of spontaneous human
labour. Acta Endocrinol 126: 425-429.
Thornton S, Baldwin PJ, Harris PA, Harding F, Davison JM,
Baylis PH, Timmons PM, Wathes DC (2002). The role of
arginine vasopressin in human labour: functional studies, fetal
production and localisation of V1a receptor mRNA. Br J
Obstet Gynaecol 109: 5762.
Thorpy M (2001). Current concepts in the etiology, diagnosis
and treatment of narcolepsy. Sleep Med 2: 517.
Ticher A, Sackett-Lundeen L, Ashkenazi IE, Haus E (1994).
Human circadian time structure in subjects of different gender
and age. Chronobiol Int 11: 349355.
Tien R, Kucharczyk J, Kucharczyk W (1991). MR imaging of
the brain in patients with diabetes insipidus. Am J Neuroradiol
12: 533-542.
Tigges J, McDonald JK, Tigges M, Reich C (1997). Neuropeptide Y in the infundibular nucleus and hypophysis of great
apes. Cell Tissue Res 290: 665668.
Tilders FJH, Parker CR, Barnea A, Porter JC (1981). The major
immunoreactive -melanocyte-stimulating hormone (MSH)like substance found in human fetal pituitary tissue not MSH
but may be desacetyl MSH (adrenocorticotropin1-13NH2). J
557
2014 Refs
558
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 558
D.F. SWAAB
Tildesley HD, Toth E, Crockford PM (1983). Syndrome of

inappropriate secretion of antidiuretic hormone in association with chlorpromazine ingestion. Can J Psychiatry 28:
487488.
Timmers HJLM, Swaab DF, Van de Nes JAP, Kremer HPH
(1996). Somatostatin 1-12 immunoreactivity is decreased in
the hypothalamic lateral tuberal nucleus of Huntingtons
disease patients. Brain Res 728: 141148.
Timsit J, Valeyre D, Chanson P, Mourier K, Callat-Vigneron
N, Mikol J, Lubetzki J (1993). Isolated pseudo-tumoural
sarcoidosis of the hypothalamic-pituitary area. Eur J Med 2:
505506.
Tinschert S, Gerl H, Gewies A, Jung HP, Nrnberg P (1999).
McCuneAlbright syndrome: clinical and molecular evidence
of mosaicism in an unusual giant patient. Am J Med Genet
83: 100108.
Tinguy du Pouet M, Turpin G, Scherper H (1985). Troubles
endocriniens hypothalamiques rvlateurs dune sclrose
tubreuse de Bourneville. Presse Med 14: 599.
Tinuper P, Montagna P, Plazzi G, Avoni P, Cerullo A, Cortelli
P, Sforza E, Bonetti EP, Schoch P, Rothstein JD, Guidotti
A, Lugaresi E (1994). Idiopathic recurring stupor. Neurology
44: 621625.
Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E,
Thal LJ, Corey-Bloom J (2002). Early and widespread cholinergic losses differentiate dementia with Lewy bodies from
Alzheimer disease. Arch Gen Psychiatry 59: 946951.
Tirindelli R, Mucignat-Caretta C, Ryba NJP (1998). Molecular
aspects of pheromonal communication via the vomeronasal
organ of mammals. Trends Neurosci 21: 482486.
Titus-Ernstoff L, Perez K, Hatch EE, Troisi R, Palmer JR,
Hartge P, Hyer M, Kaufman R, Adam E, Strohsnitter W,
Noller K, Pickett KE, Hoover R (2003). Psychosexual characteristics of men and women exposed prenatally to
diethylstilbestrol. Epidemiology 14: 155160.
Tobet SA (2002). Genes controlling hypothalamic development
and sexual differentiation. Eur J Neurosci 16: 373376.
Todd JF, Edwards CMB, Ghatei MA, Bloom SR (2000). The
differential effects of galanin-(1-30) and -(3-30) on anterior
pituitary hormone secretion in vivo in humans. Am J Physiol
278: E1060E1066.
Togo T, Sahara N, Yen S-H, Cookson N, Ishizawa T, Hutton
M, De Silva R, Lees A, Dickson DW (2002a). Argyrophilic
grain disease is a sporadic 4-repeat tauopathy. J Neuropathol
Togo T, Cookson N, Dickson DW (2002b). Argyrophilic grain
disease: neuropathology, frequency in a dementia brain bank
and lack of relationship with apolipoprotein E. Brain Pathol
12: 4552.
Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM,
Ptcek LJ, Fu Y-H (2001). An hPER2 phosphorylation site
mutation in familial advanced sleep phase syndrome. Science
291: 10401042.
Tokuda T, Oide T, Tamaoke A, Ishii K, Matsuno S, Ikeda S

(2002). Prednisolone (3060 mg/day) for diseases other than
AD decreases amyloid -peptides in CSF. Neurology 58:
14151418.
Tol J, Roks G, Slooter AJC, Van Duijn CM (1999). Genetic
and environmental factors in Alzheimers disease. Rev Neurol
(Paris) (Suppl. 4) 155: S10S16.
Tolis G, Lewis W, Verdy M, Friesen HG, Solomon S, Pagalis
G Pavlatos F, Fessas Ph, Rochefort JG (1974). Anterior pituitary function in the PraderLabhartWilli (PLW) syndrome.
Tolle V, Kadem M, Bluet-Pajot M-T, Frere D, Foulon C, Bossu
C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum
J, Estour B (2003). Balance in ghrelin and leptin plasma
levels in anorexia nervosa patients and constitutionally thin
women. J Clin Endocrinol Metab 88: 109116.
Tomaszuk A, Simpson C, Williams G (1996). Neuropeptide Y,
the hypothalamus and the regulation of energy homeostasis.
Horm Res 46: 5358.
Tomita H, Tamaki N, Korosue K, Kokunai T (1996).
Xanthogranuloma with massive hematoma in the third
ventricle: case report. Neurosurgery 39: 591594.
Tomoda A, Miike T, Yonamine K, Adachi K, Shiraishi S (1997).
Disturbed circadian core body temperature rhythm and sleep
disturbance in school refusal children and adolescents. Biol
Tomoda A, Miike T, Iwatani N, Ninomiya T, Mabe H, Kageshita
T, Ito S (1999). Effect of long-term melatonin administration
on school-phobic children and adolescents with sleep disturbances. Curr Ther Res 60: 607612.
Tornatzky W, Miczek KA (1993). Long-term impairment of
autonomic circadian rhythms after brief intermittent social
stress. Physiol Behav 53: 983993.
Tonkonogy JM, Geller JL (1992). Hypothalamic lesions and
intermittent explosive disorder. J Neuropsychiatry Clin
Neurosci 4: 4550.
Toogood AA, Taylor NF, Shalet SM, Monson JP (2000). Sexual
dimorphism of cortisol metabolism is maintained in elderly
subjects and is not oestrogen dependent. Clin Endocrinol 52:
6166.
Tooley GA, Armstrong SM, Norman TR, Sali A (2000). Acute
increases in night-time plasma melatonin levels following a
period of meditation. Biol Psychol 53: 6978.
Torpy DJ, Papanicolau DA, Chrousos GP (1997). Sexual
dimorphism of the human stress response may be due to
estradiol-mediated stimulation of hypothalamic corticotrophin-releasing hormone synthesis. J Clin Endocrinol Metab
82: 982
Torrado C., Bastian W, Wisniewski KE, Castells S (1991).
Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J Pediatr
119: 478483.
2014 Refs
2/12/03
1:39 pm
Page 559
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
559
Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002).

Melatonin enters the cerebrospinal fluid through the pineal
recess. Endocrinology 143: 8490.
Tricoire H, Malpauz B, Mller M (2003). Cellular lining of the
sheep pineal recess studied by light-, transmission-, and scanning electron microscopy: morphologic indications for a direct
secretion of melatonin from the pineal gland to the cerebrospinal fluid. J Comp Neurol 456: 3947.
Tritos NA, Weinrib S, Kaye TB (1998a). Endocrine manifestations of ErdheimChester disease (a distinct form of
histiocytosis). J. Intern Med 244: 529535.
Tritos NA, Vicent D, Gillette J, Ludwig DS, Flier ES, MaratosFlier E (1998b). Functional interactions between
melanin-concentrating hormone, neuropeptide Y, and
anorectic neuropeptides in the rat hypothalamus. Diabetes 47:
16871692.
Triulzi F, Scotti G, Di Natale B, Pellini C, Lukezic M,
Scognamiglio M, Chiumello G (1994). Evidence of a congenital midline brain anomaly in pituitary dwarfs: a magnetic
resonance imaging study in 101 patients. Pediatrics 93:
409416.
Trotier D, Eloit C, Wassef M, Talmain G, Bensimon JL, Dving
KB, Ferrand J (2000). The vomeronasal cavity in adult
humans. Chem Senses 25: 369380.
Trottier S, Chotard C, Traiffort E, Unmehopa U, Fisser B, Swaab
DF, Schwartz J-C (2002). Co-localization of histamine with
GABA but not with galanin in the human tuberomamillary
Truog R.D (1997). Is it time to abandon brain death? Hastings
Center Report JanFeb: 2937.
Tsagarakis S, Kaskarelis IS, Kokkoris P, Malagari C,
Thalassinos N (2000). The application of a combined stimulation with CRH and desmopressin during bilateral inferior
petrosal sinus sampling in patients with Cushings syndrome.
Tsai T-F, Armstrong D, Beaudet AL (1999). Necdin-deficient
mice do not show lethality or the obesity and infertility of
PraderWilli syndrome. Nat Gen 22: 1516.
Tsai S-J, Wang Y-C, Hong CJ (2001). Association study
between cannabinoid receptor gene (CNR1) and pathogenesis
and psychotic symptoms of mood disorders. Am J Med Genet
105: 219221.
Tsuchiya K, Nakayama H, Iritani S, Arai T, Niizato K, Haga
C, Matsushita M, Ikeda K (2002). Distribution of basal
ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases. Acta
Tsui EYK, Yip S.F, Ng SH, Cheung YK (2002). Reversible
MRI changes of hypothalamus in a multiple sclerosis patient
with homeostatic disturbances. Eur Radiol 12: S28S31.
Tsuji M, Takahashi S, Akazawa S (1981). CSF vasopressin and
cyclic nucleotide concentrations in senile dementia.
Torres R, Leroy E, Hu X, Katrivanou A, Gourzis P,

Papachatzopoulou A, Athanasssiadou A, Beratis S, Collier C,
Polymeropoulos MH (2001). Mutation screening of the
Wolfram syndrome gene in psychiatric patients. Mol
Psychiatry 6: 3943.
Torrey, EF, Miller J, Rawlings R, Yolken RH (2000). Seasonal
birth patterns of neurological disorders. Neuroepidemiology
19: 177185.
Tortosa F, Puig-Domingo M, Peinado M-A, Oriola J, Webb
SM, De Leiva A (1989). Enhanced circadian rhythm of melatonin in anorexia nervosa. Acta Endocrinol 120: 574578.
Torvik A, Lindboe CF, Rogde S (1982). Brain lesions in alcoholics. J Neurol Sci 56: 233248.
Toscano V (1998). Polycystic ovary syndrome: What is it?
Pathogenetic enigma and therapeutic dilemma. J Endocrinol
Invest 21: 546550.
Tosini G (2000). Melatonin circadian rhythm in the retina of
mammals. Chronobiol Int 17: 599612.
Touitou Y (1995). Effects of aging on endocrine and neuroendocrine rhythms in humans. Horm Res 43: 1219.
Touitou Y (1997). Melatonin and aging: facts and artifacts.
Aging Clin Exp Res (Suppl. 4) 9: 11.
Touitou Y, Bogdan A, Haus E, Touitou C (1997). Modifications
of circadian and circannual rhythms with aging. Exp Gerontol
32: 603614.
Tran A, Kovacs K, Stefaneanu L, Kontogeorgos G, Scheithauer
BW, Melmed S (1999). Expression of leukemia inhibitory
factor in craniopharyngioma. Endocr Pathol 10: 103108.
Travis LB, Dodge WF, Waggener JD, Kashemsant C (1967).
Defective thirst mechanism secondary to a hypothalamic
lesion: studies in a child with adipsia, polyphagia, obesity,
and persistent hyperosmolality. J Pediatrics 70: 915926.
Treede R, Apkarian AV, Bromm B, Greenspan JD, Lenz FA
(2000). Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus. Pain 87:
113119.
Treip CS (1970a). Hypothalamic lesions in head injury. J Neurol
Treip CS (1970b). Hypothalamic and pituitary injury. J Clin
Pathol (Suppl. 4) 23: 178186
Treip CS (1992). The hypothalamus and pituitary gland. In:
Hume Adams J, Duchen LW (Eds.) Greenfields
Neuropathology, pp. 10461082. Edward Arnold, London.
Trenkwalder C, Kampe K, Barthenstein P, Hauser C,
Winkelmann J, Rothstein JD (1997). An unusual case of idiopathic recurrent stupor with circadian rhythm a new entity
of the disease? J Neurol Sci (Suppl. 1) 150: S203S204.
Trethowan WH, Cobb S (1952). Neuropsychiatric aspects
of Cushings syndrome. Arch Neurol Psychiatry 67:
283309.
Trick GL, Barris MC, Bickler-Bluth M (1989). Abnormal
pattern electroretinograms in patients with senile dementia of
the Alzheimer type. Ann Neurol 26: 226231.
559
2014 Refs
560
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 560
D.F. SWAAB
Tsukada T, Horovitch SJ, Montminy MR, Mandel G, Goodman

GH (1985). Structure of the human vasoactive intestinal
polypeptide gene. DNA 4: 293300.
Tsukahara H, Hata I, Sekine K, Miura M, Kotsuji F, Mayumi
M (1998). Renal water channel expression in newborns:
measurement of urinary excretion of aquaporin-2. Metabolism
47: 13441347.
Tubiana-Rufi N, Thizon-de Gaulle I, Czernichow P (1992).
Hypothalamopituitary deficiency and precocious puberty
following hyperhydration in diabetic ketoacidosis. Horm Res
37: 6063.
Tubridy N, Addison R, Schon F (1999). Long term use of
desmopressin for urinary symptoms in multiple sclerosis.
Mult Scler 5: 416417.
Tubridy N, Saunders D, Thom M, Asa SL, Powell M, Plant
GT, Howard R (2001). Infundibulohypophysitis in a man
presenting with diabetes insipidus and cavernous sinus
involvement. J Neurol Neurosurg Psychiatry 71: 798801.
Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen
J, Verbaten R (2000). Time course of effects of testosterone
administration on sexual arousal in women. Arch Gen
Tmer Z, Tommerup N, Binkert F, Back E, Brndum-Nielsen
K (1998). PraderWilli-like phenotype and the proximal long
arm of the X-chromosome. Am J Med Genet 80: 300301.
Tuomisto L, Lozeva V, Valjakka A, Lecklin A (2001).
Modifying effects of histamine on circadian rhythms and
neuronal excitability. Behav Brain Res 124: 129135.
Tuppy H (1968). The influence of enzymes on neurohypophysial
hormones and similar peptides. In: Berde B (Ed.) Hdb. d.
exp. Pharmakologie Bd. 13. Berlin, Springer, pp. 67129.
Turan MT, Esel E, Dndar M, Candemir Z, Bastrk M, Sofuoglu
S, zkul Y (2000). Female-to-male transsexual with 47,XXX
karyotype. Biol Psychiatry 48: 11161117.
Turetsky BI, Moberg PJ, Yousem DM, Doty RL, Arnold SE,
Gur RE (2000). Reduced olfactory bulb volume in patients
with schizophrenia. Am J Psychiatry 157: 828830.
Turgut M, Akalan N, zgen T, Ruacan S,
Erbengi A. (1996).
Subependymal giant cell astrocytoma associated with
tuberous sclerosis: diagnostic and surgical characteristics of
five cases with unusual features. Clin Neurol Neurosurg 98:
217221.
Turkenburg JL, Swaab DF, Endert E, Louwerse AL, Van de
Poll NE (1988). Effects of lesions of the sexually dimorphic
nucleus on sexual behaviour of testosterone-treated female
Wistar rats. Brain Res Bull 21: 215224.
Turkington RW, MacIndoe JH (1972). Hyperprolactinemia in
sarcoidosis. Ann Intern Med 76: 545549.
Turnbull AC (1987). An oxytocin inhibitor for suppressing
preterm labour. Br J Obstet Gynaecol 94: 10091011.
Turnbull IM, McGeer PL, Beattie L, Calne D, Pate B (1985).
Stimulation of the basal nucleus of Meynert in senile dementia
of Alzheimers type. Appl Neurophysiol 48: 216221.
Turner G (1996). Intelligence and the X chromosome. Lancet

347: 18141815.
Turner WJ (1995). Homosexuality, type 1: an Xq28 phenomenon. Arch Sex Behav 24: 109134.
Tuunainen A, Kripke DF, Cress AC, Youngstedt SD (2001).
Retinal circadian rhythms in humans. Chronobiol Int 18:
957971.
Tuunainen A, Kripke DF, Elliott JA, Assmus JD, Rex KM,
Klauber MR, Langer RD (2002). Depression and endogenous
melatonin in postmenopausal women. J Affect Disord 69:
149158.
Tweedle CD, Hatton GI (1976). Ultrastructural comparisons of
neurons of supraoptic and circularis nuclei in normal and
dehydrated rats. Brain Res Bull 1: 103121.
Twijnstra A, Minderhoud JM (1980). Inappropriate secretion of
antidiuretic hormone in patients with head injuries. Clin
Neurol Neurosurg 82: 263268.
Uchida K, Okamoto N, Ohara K, Morita Y (1996). Daily rhythm
of serum melatonin in patients with dementia of the degenerate type. Brain Res 717: 154159.
Uchida K, Aoki T, Ishizuka B (1999). Postoperative delirium
and plasma melatonin. Med Hypotheses 53: 103106.
Udry JR, Morris NM, Kovenock J (1995). Androgen effects on
womens gendered behaviour. J Biosoc Sci 27: 359368.
Ueno M, Tokunaga Y, Terachi S, Gondo K, Hara T (2000).
Asymmetric sweating in a child with multiple sclerosis.
Ueyama T, Krout KE, Van Nguyen X, Karpitsky V, Kollert
A, Mettenleiter TC, Loewy AD (1999). Suprachiasmatic
nucleus: a central autonomic clock. Nat Neurosci 2:
10511053.
Uhde TW, Tancer ME, Rubinow DR, Roscow DB, Boulenger
J-P, Vittone B, Gurguis G, Geraci M, Black B, Post RM
(1992). Evidence for hypothalamo-growth hormone dysfunction in panic disorder: profile of growth hormone (GH)
responses to clonidine, yohimbine, caffeine, glucose, GRF
and TRH in panic disorder patients versus healthy volunteers.
Uhl RG, Hilt DC, Hedreen JC, Whitehouse PJ, Price DL (1983).
Picks disease (lobar sclerosis), depletion of neurons in the
nucleus basalis of Meynert. Neurology 33: 14701473.
Uhl RG, Hedreen JC, Price DL (1985). Parkinsons disease;
loss of neurons from the ventral tegmental area contralateral
to therapeutic surgical lesions. Neurology 35: 12151218.
Ukkola O, Ravussin E, Jacobson P, Snyder EE, Chagnon M,
Sjstrm L, Bouchard C (2001) Mutations in the
preproghrelin/ghrelin gene associated with obesity in humans.
Ule G and Walter C (1983). Morphological feedback effect
on the nucleoli of the neurons in the nucleus arcuatus
(infundibularis) to hypophyseal hypogonadism in juvenile
haemochromatosis. Acta Neuropathol 61: 8184.
Ule G, Schwechheimer K, Tschahargane C (1983).
Morphological feedback effect on neurons of the nucl.
2014 Refs
2/12/03
1:39 pm
Page 561
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
561
Urioste M, Rosa A (1998). Anencephaly and faciocranioschisis:

evidence of complete failure of closure 3 of the neural tube
in humans. Am J Med Genet 75: 46.
Urwin RE, Bennetts B, Wilcken B, Lampropoulos B, Beumont
P, Clarke S, Russell J, Tanner S, Nunn KP (2002). Anorexia
nervosa (restrictive subtype) is associated with a polymorphism in the novel norepinephrine transporter gene promotor
polymorphic region. Mol Psychiatry 7: 652657.
Ushio Y, Kochi M, Kuratsu J-I, Itoyama Y, Marubayashi T
(1999). Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal
carcinoma. J Neurosurg 90: 133137.
Utiger RD (1992). Melatonin the hormone of darkness. N
Engl J Med 327: 13771379.
Uusitupa MIJ, Karvonen MK, Pesonen U, Koulu M (1998).
Neuropeptide Y: a novel link between the neuroendocrine
system and cholesterol metabolism. Ann Med 30: 508510.
Uvns-Moberg K (1997). Oxytocin linked antistress effects the relaxation and growth response. Acta Physiol Scand 161
Suppl. 640: 3842.
Uvns-Moberg K (1998). Oxytocin may mediate the benefits of
positive social interaction and emotions. Psychoneuroendocrinology 23: 819835.
Uvns-Moberg K, Sjgren C, Westlin L, Andersson PO, Stock
S (1989). Plasma levels of gastrin, somatostatin, VIP, insulin
and oxytocin during the menstrual cycle in women (with and
without oral contraceptives). Acta Obstet Gynecol Scand 68:
165169.
Uvns-Moberg K, Alster P, Petersson M (1996). Dissociation
of oxytocin effects on body weight in two variants of female
sprague-dawley rats. Integr Physiol Behav Sci 31: 4455.
Uvns-Moberg K, Alster P, Petersson M, Sohlstrm A,
Bjrkstrand E (1998). Postnatal oxytocin injections cause
sustained weight gain and increased nociceptive thresholds
in male and female rats. Pediatr Res 43: 344348.
Uvns-Moberg K, Bjrkstrand E, Hillegaart V, Ahlenius S
(1999). Oxytocin as a possible mediator of SSRI-induced
antidepressant effects. Psychopharmacology 142: 95101.
Vaisse C, Clement K, Guy-Grand B, Froguel P (1998). A
frameshift mutation in human MC4R is associated with a
dominant form of obesity. Nat Genet 20: 113114.
Vajtai I, Varga Z, Scheithauer BW, Bodosi M (1999). Chordoid
glioma of the third ventricle: confirmatory report of a new
entity. Hum Pathol 30: 723726.
Valcavi R, Zini M, Dieguez C, Portioli I (1993). Vasoactive
intestinal peptide-induced prolactin release in hypothyroid
patients. J Endocrinol Invest 16: 781785.
Valdenaire O, Giller T, Breu V, Gottowik J, Kilpatrick G (1997).
A new functional isoform of the human CRF2 receptor for
corticotropin-releasing factor 1. Biochim Biophys Acta 1352:
129132.
Valdueza JM, Cristante L, Dammann O, Bentele K, Vortmeyer
A, Saeger W, Padberg B, Freitag J, Herrmann H-D (1994a).
arcuatus (sive infundibularis) and nucl. subventricularis hypothalami due to gonadal atrophy. Virchows Arch A 400:
297308.
lfarsson E, Lindquist C, Roberts M, Rhn T, Lindquist M,
Thorn M, Lippitz B (2002). Gamma knife radiosurgery for
craniopharyngiomas: longterm results in the first Swedisch
patients. J Neurosurg (Suppl. 5) 97: 613622.
Ulfig N (1989). Configuration of the magnocellular nuclei in
the basal forebrain of the human adult. Acta Anat 134:
100105.
Ulfig N, Braak H (1989a). Neuronal types and their percent
distribution within the magnocellular nuclei of the human
basal forebrain. Acta Anat 134: 237241.
Ulfig N, Braak H (1989b). Amyloid deposits and neurofibrillary changes in the hypothalamic tuberomamillary nucleus. J
Neural Transm 1: 143.
Ulfig N, Braak E, Ohm TG, Pool CW (1990). Vasopressinergic
neurons in the magnocellular nuclei of the human basal forebrain. Brain Res 530: 176180.
Ulfig N, Rupp M, Vanselow B (1991). Der Nucleus tuberomamillaris hypothalami im fetalen, postnatalen und adulten
Gehirn des Menschen. Verh Anat Ges 85: 661662.
Uli N, Chin D, David R, Geneiser N, Roche K, Marino F,
Shapiro E, Prasad K, Oberfield S (1997). Menstrual bleeding
in a female infant with congenital adrenal hyperplasia: altered
maturation of the hypothalamic-pituitary-ovarian axis. J Clin
Umegaki, H Ikari H, Nakahata H, Endo H, Suzuki Y, Ogawa
O, Nakamura A, Yamamoto T, Iguchi A (2000). Plasma
cortisol levels in elderly female subjects with Alzheimers
disease: a cross-sectional and longitudinal study. Brain Res
881: 241243.
Umhau JC, Petrulis SG, Diaz R, Biddison JR, George DT
(2001). Hypothalamic function in response to 2-deoxy-Dglucose in long-term abstinent alcoholics. Alcohol Clin Exp
Res 25: 781786
Unger JW, Lange W (1991). Immunohistochemical mapping of
neurohypophysins and calcitonin gene-related peptide in the
human brainstem and cervical spinal cord. J Chem Neuroanat
4: 299309.
Unger F, Schrttner O, Haselsberger K, Krner E, Ploier R,
Pendl G (2000). Gamma knife radiosurgery for hypothalamic
hamartomas in patients with medically intractable epilepsy
and precocious puberty. J Neurosurg 92: 726731.
Unger F, Schrttner O, Feichtinger M, Bone G, Haselsberger
K, Sutter B (2002). Stereotactic radiosurgery for hypothalamic hamartomas. Acta Neurochir Suppl 84: 5763.
Unger H, Pommrich G, Beck R (1971). Der Oxytocingehalt
im menschlichen pathologischen Liquor. Experientia 27:
1486.
Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM (1989).
Hippocampal damage associated with prolonged and fatal
stress in primates. J Neurosci 9: 17051711.
561
2014 Refs
562
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 562
D.F. SWAAB
Hypothalamic hamartomas: with special reference to gelastic

epilepsy and surgery. Neurosurgery 34: 949958.
Valdueza JM, Lohmann F, Dammann O, Hagel Ch, Eckert B,
Freckmann N (1994b). Analysis of 20 primarily surgically
treated chiasmatic/hypothalamic pilocytic astrocytomas. Acta
Neurochir 126: 4450.
Vale WW, Spiess J Rivier C, Rivier J (1981). Characterization
of a 41-residue ovine hypothalamic peptide that stimulates
secretion of corticotropin and -endorphin. Science 213:
13941397
Vale WW, Vaughan J, Smith M, Yamamoto G, Rivier J, Rivier
C (1983a). Effects of synthetic ovine corticotropin-releasing
factor, glucocorticoids, catecholamines, neurohypophysial
peptides, and other substances on cultured corticotropic cells.
Endocrinology 113: 1121-1131.
Vale WW, Vaughan J, Yamamoto G, Bruhn T, Douglas C,
Dalton D, Rivier C, Rivier J (1983b). Assay of corticotropin
releasing factor. Methods Enzymol 103: 565577.
Valenti G (1996). Neuropeptide changes in dementia: pathogenetic implications and diagnostic value. Gerontology 42:
241256.
Valenti G (1997). DHEA replacement therapy for human aging:
a call for perspective. Aging Clin Exp Res (Suppl. 4) 9: 7172.
Valentin L, Sladkevicius P, Kindahl H, Broeders A, Marsal K,
Melin P (2000). Effects of vasopressin antagonist in women
in dysmenorrhea. Gynecol Obstet Invest 50: 170177.
Valenzuela, GJ Sanchez-Ramos L, Romero R, Silver HM,
Koltun WD, Millar L, Hobbins J, Rayburn W, Shangold G,
Wang J, Smith J, Creasy GW, for the Atosiban PTL-098
study group. (2000). Maintenance treatment of preterm labor
with the oxytocin antagonist atosiban. Am J Obstet Gynecol
182: 11841190.
Valero-Politi J, Fuentes-Arderiu X (1998). Annual rhythmic variations of follitropin, lutropin, testosterone and sex-hormonebinding globulin in men. Clin Chim Acta 271: 5771
Vallejo R, DeSouza G, Lee J (2002). Shy-Drager syndrome and
severe unexplained intraoperative hypotension responsive to
vasopressin. Anesth Analg 95: 50-52.
Vallet PG, Charnay Y, Bouras C (1990). Distribution and colocalization of delta sleep-inducing peptide and luteinizing
hormone-releasing hormone in the aged human brain: an
immunohistochemical study. J Chem Neuroanat 3: 207214.
Vallotton MB, Merkelbach U, Gaillard RC (1983). Studies of
the factors modulating antidiuretic hormone excretion in man
in response to the osmolar stimulus: effects of oestrogen and
angiotensin II. Acta Endocrinol 104: 295302.
Van Allen MI, Kalousek DK, Chernoff GF, Juriloff D, Harris
M, McGillivray BC, Yong S-L, Langlois S, MacLeod PM,
Chitayat D, Friedman JM, Wilson RD, McFadden D, Pantzar
J, Ritchie S, Hall JG (1993). Evidence for multi-site closure
of the neural tube in humans. Am J Med Genet 47: 723743.
Van Binsbergen CJM, Coelingh Bennink HJT, Odink J, Haspels
AA, Koppeschaar HPF (1990). A comparative and longitu-
dinal study on endocrine changes related to ovarian function

in patients with anorexia nervosa. J Clin Endocrinol Metab
71: 705711.
Van Cauter E, Linkowski P, Kerkhofs M, Hubain P, LHermiteBalriaux M, Leclerq R, Brasseur M, Copinschi G,
Mendlewicz J (1991). Circadian and sleep-related endocrine
rhythms in schizophrenia. Arch Gen Psychiatry 48: 348356.
Van Cauter E, Leproult R, Kupfer DJ (1996). Effects of gender
and age on the levels and circadian rhythmicity of plasma
cortisol. J Clin Endocrinol Metab 81: 24682473.
Van Cauter E, Spiegel K (1997). Hormones and metabolism
during sleep. In: Schwartz WJ (Ed.) Sleep Science: Integrating
Basic Research and Clinical Practice. Basel, Karger, pp.
144174.
Van Cauter E, Leproult R, Plat L (2000). Age-related changes
in slow-wave sleep and REM sleep and relationship with
growth hormone and cortisol levels in healthy men. JAMA
284: 861868.
Van Deerlin VMD, Gill LH, Nelson PT (2002). Optimizing
gene expression analysis in archival brain tissue. Neurochem
Res 27: 9931003.
Van de Nes JAP, Kamphorst W, Ravid R, Swaab DF (1993).
The distribution of Alz-50 immunoreactivity in the hypothalamus and adjoining areas of Alzheimers disease patients.
Brain 116: 103115
Van de Nes JAP, Sluiter AA, Pool CW, Kamphorst W, Ravid
R, Swaab DF (1994). The monoclonal antibody Alz-50, used
to reveal cytoskeletal changes in Alzheimers disease, also
reacts with a large subpopulationEof somatostatin neurons in
the normal hypothalamus and adjoining areas. Brain Res 655:
97109.
Van de Nes JAP, Kamphorst W, M. Ravid R, Swaab DF (1998).
E
Comparison of beta-protein/A4 deposits and Alz-50-stained
cytoskeletal changes in the hypothalamus and adjoining areas
of Alzheimers disease patients: amorphic plaques and
cytoskeletal changes occur independently. Acta Neuropathol
96: 129138.
Van de Nes JAP, Kamphorst W, Boon M, Ravid R, Swaab DF
(1995). Comparison of Alz-50, -protein/A4- and somatostatin1-12-like immunoreactivity in the hypothalamic nucleus
tuberalis lateralis of Alzheimers disease and demented
Downs syndrome patients. In: Independent occurrence of protein deposits and cytoskeletal changes in the brain of
Alzheimer disease patients. Thesis, University of Amsterdam,
1995.
Van den Berghe G (1999). Endocrine changes in critically ill
patients. Growth Horm IGF Res (Suppl. A) 9: 7781.
Van den Berghe G (2000). Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol 143: 113.
Van den Berghe G (2002). Neuroendocrine pathobiology of
chronic critical illness. Crit Care Clin 18: 509529.
Van den Berghe G, De Zegher F, Veldhuis JD, Wouters P,
Awouters M, Verbruggen W, Schetz M, Verwaest C, Lauwers
2014 Refs
2/12/03
1:39 pm
Page 563
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
563
Van der Post, JAM, Konijnenberg A, Boer K, Schaap MCL,

Van Boxtel CEA, Sturk A, Boer GJ, Swaab DF. (1993).
Preeclampsia is not associated with altered platelet vasopressin binding and cytosolic Ca++ concentration. Am J Obstet
Gynecol 169: 11691178.
Van der Post JA, Van Heerikhuize JJ, Boer K, Van Boxtel CE,
Swaab DF (1994). Radioimmunoassay of vasopressin during
pregnancy. Use and removal of cystylaminopeptidase
inhibitors. Clin Chim Acta 230: 125136.
Van der Post JA, Van Buul BJA, Hart AAM, Van Heerikhuize
JJ, Pesman G, Legros JJ, Steegers EAP, Swaab DF, Boer K
(1997). Vasopressin and oxytocin levels during normal pregnancy: effects of chronic dietary sodium restriction. J
Van der Post, JAM Douma CEA, Veerman DP Van Acker BAC,
Koomen CGM, Hart AM, Koopman MG, Swaab DF, Arisz
L, Boer K (2003). Circadian rhythm of sodium excretion in
third trimester human pregnancy (submitted).
Vandertop WP (1996). Familial colloid cyst of the third
ventricle: case report and review of associated conditions.
Van der Woude PF, Goudsmit E, Wierda M, Purba JS, Hofman
MA, Bogte H, Swaab DF (1995). No vasopressin cell loss
in the human paraventricular and supraoptic nucleus during
aging and in Alzheimers disease. Neurobiol Aging 16: 1118.
Van Dijk JG, Haan J, Zwinderman K, Kremer B, Van Hilten
BJ, Roos RAC (1993). Autonomic nervous system dysfunction in Parkinsons disease: relationships with age,
medication, duration, and severity. J Neurol Neurosurg
Van Dongen HPA, Kerkhof GA, Souverijn JHM (1998).
Absence of seasonal variation in the phase of the endogenous
circadian rhythm in humans. Chronobiol Int 15: 623632.
Vandoolaeghe E, Maes M, Vandevyvere J, Neels H (1997).
Hypothalamic-pituitary-thyroid axis function in treatment
resistant depression J Affect Disord 43: 143150.
Van Duijn CM (1999). Hormone replacement therapy and
Alzheimers disease. Maturitas 31: 201-205.
Van Eerdenburg FJCM, Swaab DF (1991). Increasing neuron
numbers in the vasopressin and oxytocin containing nucleus
of the adult female pig hypothalamus. Neurosci Lett 132:
8588.
Van Esseveldt KE, Lehman MN, Boer GJ (2000). The suprachiasmatic nucleus and the circadian time-keeping system
revisited. Brain Res Rev 33: 3477.
Van Geel BM, Assies J, Wanders RJA, Barth PG (1997). X
linked adrenoleukodystrophy: clinical presentation, diagnosis,
and therapy. J Neurol Neursurg Psychiatry 63: 414.
Van Goozen SHM, Matthys W, Cohen-Kettenis PT, Gispen-de
Wied C, Wiegant VM, Van Engeland H (1998a). Salivary
cortisol and cardiovascular activity during stress in oppositional-defiant disorder boys and normal controls. Biol
P, Bouillon R, Bowers CY (1997a). The somatotropic axis

in critical illness: effect of continuous growth hormone (GH)releasing hormone and GH-releasing peptide-2 infusion. J
Clin Endocrinol Metabol 82: 590599.
Van den Berghe G, De Zegher F, Veldhuis JD, Wouters P,
Gouwy S, Stockman W, Weekers F, Schetz M, Lauwers P,
Bouillon R, Bowers CY (1997b). Thyrotropin and prolactin
release in prolonged critical illness: dynamics of spontaneous
secretion and effects of growth hormone-secretagogues. Clin
Van den Berghe G, De Zegher F, Baxter RC, Veldhuis JD,
Wouters P, Schetz M, Verwaest C, Van der Vorst E., Lauwers
P, Bouillon R, Bowers CY (1998). Neuroendocrinology of
prolonged critical illness: effects of exogenous thyrotropinreleasing hormone and its combination with growth hormone
secretagogues. J Clin Endocrinol Metab 83: 309319.
Van den Hoofdakker RH (1994). Chronobiological theories of
nonseasonal affective disorders and their implications for
treatment. J Biol Rhythms 9: 157183.
Van den Ouweland AMW, Knoop MT, Knoers VVAM,
Markslag PWB, Rocchi M, Warren ST, Ropers HH,
Fahrenholz F, Monnens LAH, Van Oost BA (1992).
Colocalization of the gene for nephrogenic diabetes insipidus
(DIR) and the vasopressin type 2 receptor gene (AVPR2) in
the Xq28 region. Genomics 13: 13501352.
Van den Pol AN (2000). Narcolepsy: a neurodegenerative
disease of the hypocretin system? Neuron 27: 415418.
Van der Beek EM, Wiegant VM, Van der Donk HA, Van den
Hurk R, Buijs RM (1993). Lesions of the suprachiasmatic
nucleus indicate the presence of a direct VIP containing
projection to gonadotropin-releasing hormone neurons in the
female rat. J Neuroendocrinol 5: 137144.
Van der Beek EM, Horvath TL, Wiegant VM, Van den Hurk
R, Buijs RM (1997). Evidence for a direct neuronal pathway
from the suprachiasmatic nucleus to the gonadotropinreleasing hormone system: combined tracing and light and
electron microscopic immunocytochemical studies. J Comp
Neurol 384: 569579.
Van der Horst GTJ, Muijtjens M, Kobayashi K, Takano R,
Kanno S-I, Takao M, De Wit J, Verkerk A, Eker APM, Van
Leenen D, Buijs RM, Bootsma D, Hoeijmakers JHJ, Yasui
A (1999). Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627630.
Van der Ploeg LHT (2000). Obesity: an epidemic in need of
therapeutics. Curr Opin Chem Biol 4: 452460.
Van der Ploeg LHT, Martin WJ, Howard AD, Howard AD,
Nargund RP, Austin CP, Guan X, Drisko J, Cashen D, Sebhat
I, Patchett AA, Figueroa DJ, DiLella AG, Connolly BM,
Weinberg DH, Tan CP, Palyha OC, Pong SS, MacNeil T,
Rosenblum C, Vongs A, Tang R, Yu H, Sailer AW, Fong TM,
Huang C, Tota MR, Chang RS, Stearns R, Tamvakopoulos C,
Christ G, Drazen DL, Spar BD, Nelson RJ, MacIntyre DE
(2002). A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 99: 1138111386.
563
2014 Refs
564
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 564
D.F. SWAAB
Van Goozen SHM, Matthys W, Cohen-Kettenis PT, Thijssen

JHH, Van Engeland H (1998b). Adrenal androgens and
aggression in conduct disorder prepubertal boys and normal
controls. Biol Psychiatry 43: 156158.
Van Goozen SHM, Matthys W, Cohen-Kettenis PT, Buitelaar
JK, Van Engeland H (2000a). Hypothalamic-pituitary-adrenal
axis and autonomic nervous system activity in disruptive children and matched controls. J Am Acad Child Adolesc
Van Goozen SHM, Van den Ban E, Matthys W, Cohen-Kettenis
PT, Thijssen JHH, Van Engeland H (2000b). Increased
adrenal androgen functioning in children with oppositional
defiant disorder: a comparison with psychiatric and normal
controls. J Am Acad Child Adolesc Psychiatry 39: 11.
Van Heeringen K, Audenaert K, Van de Wiele L, Verstraete A
(2000). Cortisol in violent suicidal behaviour: association with
personality and monoaminergic activity. J Affect Disord 60:
181189.
Van Hilten JJ, Weggeman M, Van der Velde EA, Kerkhof GA,
Van Dijk JG, Roos RAC (1993). Sleep, excessive daytime
sleepiness and fatigue in Parkinsons disease. J Neural Transm
5: 235244
Van Hilten B, Hoff JI, Middelkoop HAM, Van der Velde EA,
Kerkhof GA, Wauquier A, Kamphuisen HAC, Roos RAC
(1994). Sleep disruption in Parkinsons disease. Arch Neurol
51: 922928.
Van Hilten JJ, Roelfsema F, Van der Meer JWM, Van Dijk JG
(1997). Periodic fever associated with intermittent rhythmic
delta activity: a syndrome of hypothalamic origin?
Electroencephalogr. Clin Neurophysiol 102: 138141.
Vanhala R, Turpeinen U, Riikonen R (2001). Low levels of
insulin-like growth factor-I in cerebrospinal fluid in children
with autism. Dev Med Child Neurol 43: 614-616.
Vanhoof J, Wilms G, Bouillon R (1992). Hypothalamisch
hypopituitarisme met hyperfagie en subacute dementie op
basis van neurosarcoidose: een geval en literatuuroverzicht.
Acta Clin Belg 47: 319328.
Van Houwelingen CAJ, Beersma DGM (2001). Seasonal
changes in 24-h patterns of suicide rates: a study on train
suicides in the Netherlands. J Affect Disord 66: 215223.
Van Karnebeek CDM, Van Gelderen I, Nijhof GJ, Abeling NG,
Vreken P, Redeker EJ, Van Eeghen AM, Hoovers JMN,
Hennekam RCM (2002). An aetiological study of 25 mentally
retarded adults with autism. J Med Genet 39: 205214.
Van Kesteren PJ, Gooren LJ, Megens JA (1996). An epidemiological and demographic study of transsexuals in the
Netherlands. Arch Sex Behav 25: 589598.
Van Leeuwen FW and Caff AR (1983). Vasopressinimmunoreactive cell bodies in the bed nucleus of the stria
terminalis of the rat. Cell Tissue Res 228: 525534.
Van Leeuwen FW, Fischer DF, Kamel D, Sluijs JA, Sonnemans
MAF, Benne R, Swaab DF, Salehi A, Hol EM (2000).
Molecular misreading: a new type of transcript mutation
expressed during aging. Neurobiol Aging 21: 879891.
Van Lieburg AF, Knoers NVAM, Monnens LAH (1999).

Clinical presentation and follow-up of 30 patients with
congenital nephrogenic diabetes insipidus. J Am Soc Nephrol
10: 19581964.
Van Londen L, Goekoop JG, Van Kempen GMJ, FrankhuijsenSierevogel AC, Wiegant VM, Van der Velde EA, De Wied D
(1997). Plasma levels of arginine vasopressin elevated in
patients with major depression. Neuropsychopharmacology
17: 284292.
Van Londen L, Goekoop JG, Zwinderman AH, Lanser JBK,
Wiegant VM, De Wied D (1998a). Neuropsychological
performance and plasma cortisol, arginine vasopressin and
oxytocin in patients with major depression. Psychol Med 28:
275-284.
Van Londen L, Kerkhof GA, Van den Berg F, Goekoop JG,
Zwinderman KH, Frankhuijzen-Sierevogel AC, Wiegant
VM, De Wied D (1998b). Plasma arginine vasopressin and
motor activity in major depression. Biol Psychiatry 43:
196204.
Van Londen L, Goekoop JG, Kerkhof GA, Zwinderman KH,
Wiegant VM, De Wied D (2001). Weak 24-h periodicity of
body temperature and increased plasma vasopressin in melancholic depression. Eur Neuropsychopharmacol 11: 714.
Van Os, J and Selten JP (1998). Prenatal exposure to maternal
stress and subsequent schizophrenia. The May 1940 invasion
of the Netherlands. Br J Psychiatry 172: 324326
Van Oudheusden A (1986). Oxytocinase. In: Bergmeier (Ed.)
Methods of Enzymatic Analysis. Chemie Verlag 5, pp. 1520.
Van Overbeeke JJ, Hillen B, Tulleken CAF (1991). A comparative study of the circle of Willis in fetal and adult life. The
configuration of the posterior bifurcation of the posterior
communicating artery. J Anat 176: 4554.
Vannelli, S, Stasiowska B, Bellone J, Aimaretti G, Bellone S,
Avataneo T, Cirillo S, Benso L (1997). Is the persistence of
isolated GH deficiency in adulthood predicted by anatomical
hypothalamic-pituitary alterions? J Endocrinol Invest 20:
312318.
Van Someren EJW (2000a). Circadian and sleep disturbances
in the elderly. Exp Gerontol 35: 12291237.
Van Someren EJW (2000b). More than a marker: interaction
between the circadian regulation of temperature and sleep,
age-related changes, and treatment possibilities. Chronobiol
Int 17: 313354.
Van Someren EJW (2002). Article reviewed: chronic jet lag
produces temporal lobe atrophy and spatial cognitive deficits.
Sleep Med 3: 8182.
Van Someren EJW, Van Gool WA, Vonk BFM, Mirmiran M,
Speelman JD, Bosch DA, Swaab DF (1993). Ambulatory monitoring of tremor and other movements before and after thalamotomy: a new quantitative technique. J Neurol Sci 117: 1623.
Van Someren EJW, Hagebeuk EEO, Lijzenga C, Scheltens P,
De Rooij SEJA, Jonker C, Pot A-M, Mirmiran M, Swaab DF
(1996). Circadian rest-activity rhythm disturbances in
2014 Refs
2/12/03
1:39 pm
Page 565
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Van Someren EJW, Kessler A, Mirmiran M, Swaab DF (1997a).

Indirect bright light improves circadian rest-activity rhythm
disturbances in demented patients. Biol Psychiatry 41:
955963.
Van Someren EJW, Lijzenga C, Mirmiran M, Swaab DF
(1997b). Long-term fitness training improves the circadian
rest-activity rhythm in healthy elderly males. J Biol Rhythms
12: 146156.
Van Someren, EJW, Scherder EJA, Swaab DF (1998).
Transcutaneous electrical nerve stimulation (TENS) improves
circadian rhythm disturbances in Alzheimers disease.
Alzheimer Dis Assoc Disord 12: 114118.
Van Someren EJW, Scherder EJA, Swaab DF (1999).
Stimulation of the circadian timing system in healthy and
demented elderly. In: Iqbal K, Swaab DF, Winblad B,
Wisniewski HM (Eds.) Alzheimers disease and related disorders. John Wiley & Sons., New York, pp. 771779.
Van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M,
De Koning I, Kamphorst W, Ravid R, Spillantini MG,
Niermeijer MF, Heutink P (1999). Phenotypic variation in
hereditary frontotemporal dementia with tau mutations. Ann
Neurol 46: 617626.
Van Wieringen S, Jansen T, Smits MG, Nagtegaal JE, Coenen
AML (2001). Melatonin for chronic whiplash syndrome with
delayed melatonin onset. Clin Drug Invest 21: 813820.
Van Wimersma Greidanus TB, Grossman AB (1991). Opioid
regulation of pituitary function. Prog Sens Physiol 12: 264.
Van Zwieten EJ, Ravid R, Hoogendijk W, Swaab DF (1994).
Stable vasopressin innervation in the degenerating human
locus coeruleus in Alzheimers disease. Brain Res 649:
329333.
Van Zwieten EJ, Ravid R, Swaab DF (1996). Differential vasopressin and oxytocin innervation of the human parabrachial
nucleus: no changes in Alzheimers disease. Brain Res 711:
146152
Vaquero J, Zurita M., De Oya S, Coca S, Morales C, Salas C
(1999). Expression of vascular permeability factor in craniopharyngioma. J Neurosurg 91: 831-834.
Varlotto JM, Flickinger, JC Kondziolka, D Lunsford, LD,
Deutsch M (2002). External beam irradiation of craniopharyngiomas: long-term analysis of tumor control and
morbidity. Int J Radiat Oncol Biol Phys 54: 492-499.
Vataja R, Elomaa E (1998). Midline brain anomalies and schizophrenia in people with CATCH-22 syndrome. Br J
Psychiatry 172: 518-520.
Veith RC, Lewis N, Langohr JI, Murburg MM, Ashleigh EA,
Castillo S, Peskind ER, Pascualy M Bissette G, Nemeroff
CB, Raskind MA (1993). Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor
in human subjects. Psychiatry Res 46: 18.
Vela-Bueno A, Kales A Soldatos CR, Dobladez-Blanco B,
Campos-Castello J, Espino-Hurtado P, Olivan-Palacios J
(1984). Sleep in the Prader-Willi syndrome. Clinical and polygraphic findings. Arch Neurol 41: 294296.
565
Velasco ME, Roessman U, Gambetti P (1982). The presence

of glial fibrillary acidic protein in the human pituitary gland.
Veldhuis JD (2000). Recent neuroendocrine facets of male
reproductive aging. Exp Gerontol 35: 1281-1308.
Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe C,
Barkan A, Johnson ML, Pincus S (2001). Secretory
process regularity monitors neuroendocrine feedback and
feedforward signaling strength in humans. Am J Physiol 280:
R721R729.
Venero JL, Vizuete ML, Machado A, Cano J (2001). Aquaporins
in the central nervous system. Prog Neurobiol 63: 321336.
Venes JL, Latack J, Kandt RS (1984). Postoperative regression
of opticochiasmatic astrocytoma: a case for expectant therapy.
Ventriglia M, Bocchio Chiavetto L, Benussi L, Binetti G, Zanetti
O, Riva MA, Gennarelli M (2002). Association between the
BDNF 196 A/G polymorphism and sporadic Alzheimers
disease. Mol Psychiatry 7: 136139.
Verbalis JG, Blackburn RE, Hoffman GE, Stricker EM (1995).
Establishing behavioral and physiological functions of central
oxytocin: insights from studies of oxytocin and ingestive
behaviors. Adv Exp Med Biol 395: 209225.
Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Telera
MP, Pede S, Gattobigio R, Porcellati C (1998). Adverse
prognostic value of a blunted circadian rhythm of heart rate
in essential hypertension. J Hypertension 16: 13351343.
Verdin E, Smitz S, Thibaut A, Born J, Legros JJ, Luyckx A
(1985). Adipsic hypernatremia in a patient with pseudotumor
cerebri and the primary empty sella syndrome. J Endocrinol
Invest 8: 369372.
Verdoux H, Sutter A-L (2002). Perinatal risk factors for schizophrenia: diagnostic specificity and relationships with
maternal psychopathology. Am J Med Genet 114: 898905.
Verga A (1851). Sul ventriculo della volta a tre pilastri. Gazz
Med Lombarda 2: 89
Verghese C, De Leon J, Simpson GM (1993). Neuroendocrine
factors influencing polydipsia in psychiatric patients: an
hypothesis. Neuropsychopharmacology 9: 157166.
Verhage TL, Godfried MH, Alberts C (1990). Hypothalamicpituitary dysfunction with adrenal insufficiency and
hyperprolactinaemia in sarcoidosis. Sarcoidosis 7: 139141.
Verhoeven WMA, Curfs LMG, Tuinier S (1998). PraderWilli
syndrome and cycloid psychoses. J Intellect Disabil Res 42:
455462.
Verhulst J, Onghena P (1997). Cranial suture closing in Homo
sapiens: evidence for circaseptennian periodicity. Ann Hum
Biol 24: 141156.
Verloes A, Temple IK, Bonnet S, Bottani A (1997). Coloboma,
mental retardation, hypogonadism, and obesity: critical review
of the so-called biemond syndrome type 2, updated nosology,
and delineation of three new syndromes. Am J Med Genet
69: 370379.
565
2014 Refs
566
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 566
D.F. SWAAB
Vermeulen A (1990). Androgens and male senescence. In:

Nieschlag E, Behre HM (eds) Testosterone. Action,
Deficiency, Substitution, pp. 629645. Springer-Verlag,
Berlin.
Vermeulen S, Messiaen L, Scheir P, De Bie S, Speleman F,
De Paepe A (2002). Kallmann syndrome in a patient with
congenital spherocytosis and an interstitial 8p11.2 deletion.
Vernant J-C, Cabre P, Smadja D, Merle H, Caubarrre I,
Mikol J, Poser CM (1997). Recurrent optic neuromyelitis with
endocrinopathies: a new syndrome. Neurology 48: 5864.
Vertes RP, Crane AM (1996). Descending projections of the
posterior nucleus of the hypothalamus: Phaseolus vulgaris
leucoagglutinin analysis in the rat. J Comp Neurol 374:
607631.
Verwer RWH, Hermens WTJMC, Dijkhuizen PA, Ter Brake
O, Baker RE, Salehi A, Sluiter AA, Kok MJM, Mller LJ,
Verhaagen J, Swaab DF (2002). Cells in human postmortem
brain tissue slices remain alive for several weeks in culture
FASEB J 16: 5460.
Vescovi PP, Rastelli G, Volpi R, Chiodera P, Di Gennaro C,
Coiro V (1996). Circadian variations in plasma ACTH,
cortisol and -endorphin levels in normal-weight bulimic
women. Neuropsychobiology 33: 7175
Vessey MP, Fairweather DVI, Norman-Smith B, Buckley J
(1983). A randomized double-blind controlled trial of the
value of stilboestrol therapy in pregnancy: long-term followup of mothers and their offspring. Br J Obstet Gynaecol 90:
10071017.
Vgontzas AN, Bixler EO, Lin H-M, Prolo P., Mastorakos G,
Vela-Bueno A, Kales A, Chrousos GP (2001a). Chronic
insomnia is associated with nyctohemeral activation of the
hypothalamic-pituitary-adrenal axis: clinical implications. J
Vgontzas, AN Bixler EO, Wittman AM, Zachman K, Lin HM, Vela-Bueno A, Kales A, Chrousos GP (2001b).
Middle-aged men show higher sensitivity of sleep to the
arousing effects of corticotropin-releasing hormone than
young men: clinical implications. J Clin Endocrinol Metab
86: 14891495.
Vgontzas AN, Zoumakis M, Bixler EO, Lin H-M, Prolo P,
Vela-Bueno A, Kales A, Chrousos GP (2003). Impaired nighttime sleep in healthy old versus young adults is associated
with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. J Clin Endocrinol Metab
88: 20872095.
Viale, A, Zhixing Y, Breton C, Pedeutour F, Coquerel A, Jordan
D, Nahon J-L (1997). The melanin-concentrating hormone
gene in human: flanking region analysis, fine chromosome
mapping, and tissue-specific expression. Mol Brain Res 46:
243255.
Victor M (1994). Alcoholic dementia. Can J Neurol Sci 21:
8899.
Vidal S, Horvath E, Bonert V, Shahinian HK, Kovacs K (2002).

Neural transformation in a pituitary corticotroph adenoma.
Vierhapper H, Nowotny P, Waldhusl W (1998). Sex-specific
differences in cortisol production rates in humans.
Metabolism 47: 974976.
Vigan D, Lissoni P, Rovelli F, Roselli MG, Malugani F,
Gavazzeni C, Conti A, Maestroni G (2001). A study of
light/dark rhythm of melatonin in relation to cortisol and
prolactin secretion in schizophrenia. Neuroendocrinol Lett 22:
137141.
Vigh S, Arimura A, Kves K, Somogyvri-Vigh A, Sitton J,
Fermin CD (1991). Immunohistochemical localization of the
neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), in human and primate hypothalamus. Peptides
12: 313318.
Viinamaki O, Erkkola R, Kanto J (1986). Plasma vasopressin
concentrations and serum vasopressinase activity in pregnant
and non-pregnant women. Biol Res Pregnancy Perinatol 7:
1719.
Villas PA, Dronsfield MJ, Blankenhorn EP (1991). Experimental
allergic encephalomyelitis and corticosteroid studies in resistant and susceptible rat strains. Clin Immun Immunopathol
61: 2940.
Villette JM, Bourin P, Doinel C, Mansour I, Fiet J, Boudou P,
Dreux C, Roue R, Debord M, Levi F (1990). Circadian variations in plasma levels of hypophyseal, adrenocortical and
testicular hormones in men infected with human immunodeficiency virus. J Clin Endocrinol Metab 70: 572577.
Vincent JB, Kovacs M, Krol R, Barr CL, Kennedy JL (1999).
Intergenerational CAG repeat expansion at ERDA1 in a family
with childhood-onset depression, schizoaffective disorder,
and recurrent major depression. Am J Med Genet 88: 7982.
Vink JM, Groot AS, Kerkhof GA, Boomsma DI (2001a).
Genetic analysis of morningness and eveningness. Chronobiol
Int 18: 809822.
Vink T, Hinney A, Van Elburg AA, Van Goozen SHM,
Sandkuijl LA, Sinke RJ, Herpertz-Dahlmann B-M, Hebebrand
J, Remschmidt H, Van Engeland H, Adan RAH (2001b).
Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol Psychiatry 6: 325328.
Virkkunen M Rawlings R, Tokola R, Poland RE, Guidotti A,
Nemeroff C, Bissette G, Kalogeras K, Karonen S-L, Linnoila
M (1994). CSF biochemistries, glucose metabolism, and
diurnal activity rhythms in alcoholic, violent offenders, fire
setters, and healthy volunteers. Arch Gen Psychiatry 51:
2027.
Visscher F, Smit LME, Smith F, Boer F, Njiokiktjien C (1989).
Het KleineLevin-syndroom Tijdschr. Kindergeneeskd 57:
218-221.
Visser M, Swaab DF (1979). Life span changes in the presence
of -melanocyte-stimulating-hormone-containing cells in the
human pituitary. J Dev Physiol 1: 161178.
2014 Refs
2/12/03
1:39 pm
Page 567
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
567
Von Bardeleben U, Holsboer F (1989). Corticol response to a

combined dexamethasone-human corticotrophin-releasing
hormone challenge in patients with depression. J
Von Buttlar-Brentano K (1952). Pathohistologische feststellungen am basalkern schizophrener. J Nerv Ment Dis 116:
646653.
Vonderahe AR (1940). Changes in the hypothalamus in organic
disease. In: The Hypothalamus. The Williams and Wilkins
Company, Baltimore, USA, pp. 689712.
Vondrasov-Jelnkov D, Hjek I, Illnerov H (1999).
Adjustment of the human melatonin and cortisol rhythms to
shortening of the natural summer photoperiod. Brain Res 816:
249253.
Von Economo C (1930). Sleep as a problem of localization. J
Nerv Ment Dis 71: 249259.
Voorn P, Buijs RM (1983). An immuno-electronmicroscopical
study comparing vasopressin, oxytocin, substance P and
enkephalin containing nerve terminals in the nucleus of the
solitary tract of the rat. Brain Res 270: 169173.
Voracek M, Fisher ML (2002). Sunshine and suicide incidence.
Epidemiology 13: 492493.
Vrs E, Kiss M, Hank J, Nagy E (1997). Moyamoya with
arterial anomalies: relevance to pathogenesis. Neuroradiology
39: 852856.
Vrang N, Mikkelsen JD, Larsen PJ (1997). Direct link from the
suprachiasmatic nucleus to hypothalamic neurons projecting
to the spinal cord: a combined tracing study using cholera
toxin subunit B and Phaseolus vulgaris-leucoagglutinin. Brain
Res Bull 44: 671680.
Vrang N, Larsen PJ, Kristensen P, Tang-Christensen M (2000).
Central administration of cocaine-amphetamine-regulated
transcript activates hypothalamic neuroendocrine neurons in
the rat. Endocrinology 141: 794801.
Vuilleumier, N, Kvari E, Michon A, Hof PR, Mentenopoulos
G, Giannakopoulos P, Bouras C (2002). Neuropathological
analysis of an adult case of the Cornelia de Lange syndrome.
Vythilingam M, Anderson GM, Owens MJ, Halaszynski
TM, Bremner JD, Carpenter LL, Heninger GR, Nemeroff
CB, Charney DS (2000). Cerebrospinal fluid corticotropinreleasing hormone in healthy humans: effects of yohimbine and naloxone. J Clin Endocrinol Metab 85:
41384145.
Wada H, Inagaki N, Yamatodani A, Watanabe T (1991). Is the
histaminergic neuron system a regulatory center for wholebrain activity? Trends Neurosci 14: 415418.
Wade TD, Bulik CM, Neale M, Kendler KS (2000). Anorexia
nervosa and major depression: shared genetic and environmental risk factors. Am J Psychiatry 157: 469471.
Wagner S, Castel M, Gainer H, Yarom Y (1997). GABA in
the mammalian suprachiasmatic nucleus and its role in diurnal
rhythmicity. Nature 387: 598603.
Vitiello B, Veith RC, Molchan SE, Martinez RA, Lawlor BA,

Radcliffe J, Hill JL, Sunderland T (1993). Autonomic
dysfunction in patients with dementia of the Alzheimer type.
Vitiello MV (1997). Sleep disorders and aging: understanding
the causes. J Gerontol 52A: M189M191.
Voderholzer, U, Laakmann G, Becker U, Haag C, Baghai T,
Riemann D, Demisch L (1997). Circadian profiles of melatonin in melancholic depressed patients and healthy subjects
in relation to cortisol secretion and sleep. Psychiatry Res 71:
151161.
Voderholzer U, Riemann D, Gann H, Hornyak M, Juengling F,
Schumacher M, Reincke M, Von Herbay A., Nishino S,
Mignot E, Berger M, Lieb K (2002). Transient total sleep
loss in cerebral Whipples disease: a longitudinal study. J
Sleep Res 11: 321329.
Voessing R, Berthold F, Richard KE, Thun F, Schroeder R
(1992). Primary myeloblastoma of the pineal region. Clin
Vogels O (1997). How should brain nuclei be delineated? They
dont need to be! Trends Neurosci 20(8): 343344.
Vogels OJM, Broere CAJ, Ter Laak HJ, Ten Donkelaar HJ,
Nieuwenhuys R, Schulte BPM (1990). Cell loss and shrinkage
in the nucleus basalis Meynert complex in Alzheimers
disease. Neurobiol Aging 11: 313.
Vogl, TJ Stemmler J, Heye B, Schopohl J, Danek A, Bergman
C, Balzer JO, Felix R (1994). Kallmann syndrome versus
idiopathic hypogonadotropic hypogonadism at MR imaging.
Radiology 191: 5357.
Vogt C, Vogt O (1951). Precipitating and modifying agents in
chorea. J Nerv Ment Dis 116: 601607.
Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A
(2001). Sundowning and circadian rhythms in Alzheimers
disease. Am J Psychiatry 158: 704711.
Vollmann-Honsdorf GK, Flgge G, Fuchs E (1997). Chronic psychosocial stress does not affect the number of pyramidal neurons in tree shrew hippocampus. Neurosci Lett 233: 121124.
Volpi R, Caffarra P, Boni S, Scaglioni A, Malvezzi L, Saginario
A, Chiodera P, Coiro V (1997). ACTH/cortisol involvement
in the serotonergic disorder affecting the Parkinsonian brain.
Volpi R, Chiodera P, Giuliani N, Capretti L, Caffarri G, Magotti
MG, Coiro V (1998). 5-HT3 serotonergic receptor mediation
of hypoglycemia-induced arginine-vasopressin but not
oxytocin secretion in normal men. J Endocrinol Invest 21:
711.
Von den Velden R (1913). Die Nierenwirkung van Hypophyseextrakten bei Menschen, Berl. Klin Wschr 50: 20832086.
Von Mhlendahl KE, Heinrich U (1994). Sexual precocity in
Klinefelter syndrome: report on two new cases with idiopathic central precocious puberty. Eur J Pediatr 153: 322324.
Von Baer KE (18281837). Ueber die Entwicklungsgeschichte
der Tiere, Vol. 1-3. Knigsberg.
567
2014 Refs
568
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 568
D.F. SWAAB
Wahlbeck K, Sundblom M, Kalso E, Tigerstedt I, Rimn R

(1996). Elevated plasma vasopressin and normal cerebrospinal fluid angiotensin-converting enzyme in chronic pain
disorder. Biol Psychiatry 40: 994999.
Wahlund L-O, Andersson-Lundman G, Basun Almkvist O,
Sparring Bjrkstn K, Sf J, Wetterberg L (1993). Cognitive
functions and brain structures: a quantitative study of CSF
volumes on Alzheimer patients and healthy control subjects.
Magn Reson Imaging 11: 169174.
Wahren W (1952). The changes of hypothalamic nuclei in schizophrenia. In: Proceedings of the first international congress
of neuropathology 3. Torino, Rosenberg and Sellier, pp.
660673.
Wahren W (1959). Anatomie des Hypothalamus. In:
Schaltenbrand G, Bailey P (Eds.) Einfhrung in die
Stereotaktischen Operationen mit einem Atlas des
Menschlichen Gehirns, vol. 1, Thieme, Stuttgart, pp. 119151.
Wahren W (1964). Zur Pathoklise des Nucleus Tuberis Lateralis.
Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998).
-Synuclein immunoreactivity in glial cytoplasmic inclusions
in multiple system atrophy. Neurosci Lett 249: 180182.
Wakai S, Nikaido K, Nihira H, Kawamoto Y, Hayasaka H (2002).
Gelastic seizure with hypothalamic hamartoma: proton magnetic resonance spectrometry and ictal electroencephalographic
findings in a 4-year-old girl. J Child Neurol 17: 4446.
Wakeling A (1972). Comparative study of psychiatric patients
with Klinefelters syndrome and hypogonadism. Psychol Med
2: 139154.
Wakeling A (1996). Epidemiology of anorexia nervosa.
Wakschlag LS, Lahey BB, Loeber R, Green SM, Gordon RA,
Leventhal BL (1997). Maternal smoking during pregnancy
and the risk of conduct disorder in boys. Arch Gen Psychiatry
54: 670676.
Waldenlind E and Gustafson SA (1987). Prolactin in cluster
headache: diurnal secretion, response to thyrotropin-releasing
hormone, and relation to sex steroids and gonadotropins.
Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B,
Waldhauser M, Schemper M, Frisch H (1988). Alterations in
nocturnal serum melatonin levels in humans with growth and
aging. J Clin Endocrinol Metab 66: 648652.
Waldrop MF, Bell RQ, Halverson CF Jr (1978). Newborn minor
physical anomalies predict short attention span, peer aggression, and impulsivity at age 3. Science 199: 563564.
Waldrop TG (1991). Poserior hypothalamic modulation of the
respiratory response to CO2 in cats. Pflugers Arch 418: 713.
Walker AE, Diamond EL, Moseley J (1975). The neuropathological findings in irreversible coma. J Neuropathol Exp
Neurol 34: 295323.
Walker BR, Phillips DIW, Noon JP, Panarelli M, Andrew R,
Edwards HV, Holton DW, Seckl JR, Webb DJ, Watt GCM
(1998). Increased glucocorticoid activity in men with cardiovascular risk factors. Hypertension 31: 891895.
Walker BR (2001). Steroid metabolism in metabolic syndrome
X. Best Pract Res Clin Endocrinol Metab 15: 111122.
Walker DL, Toufexis DJ, Davis M (2003). Role of the bed
nucleus of the stria terminalis versus the amygdala in fear,
stress, and anxiety. Eur J Pharmacol 463: 199216.
Walker EF, Walder DJ, Reynolds F (2001). Developmental
changes in cortisol secretion in normal and at-risk youth. Dev
Psychopathol 13: 721732.
Walker FO, McLean WT, Elster A, Stanton C (1990). Chiasmal
sarcoidosis. Am J Neuroradiol 11: 12051207.
Walker LC, Rance NE, Price DL, Scott Young III W (1991).
Galanin mRNA in the nucleus basalis of Meynert complex
of baboons and humans. J Comp Neurol 303: 113120.
Wallace AM, Hunter I, Galloway P., Greene SA, Donaldson
MD (1999). Obesity in PraderLabhartWilli syndrome is not
due to leptin deficiency but is accentuated by hypogonadism
in male patients. Clin Endocrinol 51: 816817.
Waller, G, Watkins B, Potterton C, Niederman M, Sellings J,
Willoughby K, Lask B (2002). Pattern of birth in adults with
anorexia nervosa. J Nerv Ment Dis 190: 752756.
Walsh CH, Baylis PH, Malins JM (1979). Plasma arginine vasopressin in diabetic ketoacidosis. Diabetologia 16: 9396
Walsh, BT, Wilson GT, Loeb KL, Devlin MJ, Pike KM, Roose
SP, Fleiss J, Waternaux C (1997). Medication and
psychotherapy in the treatment of bulimia nervosa. Am J
Walsh BT, Devlin MJ (1998). Eating disorders: progress and
problems. Science 280: 13871390.
Walter A, Mai JK, Jimnez-Hrtel W (1990). Mapping of
neuropeptide Y-like immunoreactivity in the human forebrain.
Brain Res Bull 24: 297311.
Walter A, Mai JK, Lanta L, Grcs T (1991). Differential distribution of immunohistochemical markers in the bed nucleus
of the stria terminalis in the human brain. J Chem Neuroanat
4: 281298.
Walther EU, Hohlfield R (1999). Multiple sclerosis. Side effects
of interferon beta therapy and their management Neurology
53: 16221627.
Wand GS (1999). Alcohol and the hypothalamic-pituitaryadrenal axis. Endocrinologist 9: 333341.
Wand GS, Mangold D, El Deiry S, McCaul ME, Hoover D
(1998). Family history of alcoholism and hypothalamic opioidergic activity. Arch Gen Psychiatry 55: 11141119.
Wang, C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ,
Cunningham G, Matsumoto AM, Weber T, Berman N,
Testosterone Gel Study Group (2000a). Transdermal testosterone gel improves sexual function, mood, muscle strength,
and body composition parameters in hypogonadal men. J Clin
Wang, J, Akabayashi A, Yu HJ, Dourmashkin J, Alexander JT,
Silva I, Lighter J, Leibowitz SF (1998). Hypothalamic galanin:
control by signals of fat metabolism. Brain Res 804: 720.
2014 Refs
2/12/03
1:39 pm
Page 569
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
569
insipidus caused by nonspecific chronic inflammation of the

hypothalamus: case report. Surg Neurol 42: 7073.
Watanabe K, Yamaoka S, Vanecek J (1998). Melatonin inhibits
spontaneous and VIP-induced vasopressin release from
suprachiasmatic neurons Brain Res 801: 216219.
Watanabe T, Taguchi Y, Shiosaka S, Tanaka J, Kubota H,
Terano Y, Tohyama M, Wada H (1984). Distribution of
the histaminergic neuron system in the central nervous
system of rats: a fluorescent immunohistochemical analysis
with histidine decarboxylase as a marker. Brain Res 295:
1325.
Watanabe T, Kajimura N, Kato M, Sekimoto M, Hori T,
Takahashi K (2000). Case of a non-24h sleep-wake syndrome
patient improved by phototherapy. Psychiatry Clin Neurosci
54: 369370.
Watanobe H, Tamura T, Takahashi K (1994). Anomalous growth
hormone response to vasoactive intestinal peptide and peptide
histidine methionine in patients with prolactinoma or hypothalamic hyperprolactinemia. Neuropeptides 27: 137142.
Wathes DC, Borwick SC, Timmons PM, Leung ST, Thornton
S (1999). Oxytocin receptor expression in human term and
preterm gestational tissues prior to and following the onset
of labour. J Endocrinol 161: 143151.
Watson S, Gallagher P, Del-Estal D, Hearn A, Ferrier IN, Young
AH (2002). Hypothalamic-pituitary-adrenal axis function
in patients with chronic depression. Psychol Med 32:
10211028.
Watts AG, Sanchez-Watts G, Kelly AB (1999). Distinct patterns
of neuropeptide gene expression in the lateral hypothalamic
area and arcuate nucleus are associated with dehydrationinduced anorexia. J Neurosci 19: 61116121.
Watzka M, Bidlingmaier Beyenburg, S Henke RT, Clusmann
H, Elger CE, Schramm J, Klingmller D, Stoffel-Wagner B
(2000). Corticosteroid receptor mRNA expression in the
brains of patients with epilepsy. Steroids 65: 895901.
Wauters M, Mertens I, Chagnon M, Rankinen T, Considine RV,
Chagnon YC, Van Gaal LF, Bouchard C (2001).
Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int
J Obesity 25: 714720.
Weaver DR, Stehle JH, Stopa EG, Reppert SM (1993).
Melatonin receptors in human hypothalamus and pituitary:
implications for circadian and reproductive responses to melatonin. J Clin Endocrinol Metab 76: 295301.
Webb M, Ziauddin A, Okusa MD (2002). Coccidioidomycosis
meningitis and syndrome of inappropriate antidiuretic
hormone. Am J Med Sci 324: 155157.
Weber B, Lewicka S, Deuschle M, Colla M, Vecsei P, Heuser
I (2000a). Increased diurnal plasma concentrations of cortisone in depressed patients. J Clin Endocrinol Metab 85:
11331136.
Weber B, Lewicka S, Deuschle M, Colla M, Heuser I (2000b).
Testosterone, androstenedione and dihydrotestosterone
Wang, J, Killinger DW, Hegele RA (1999). A microdeletion

within DAX-1 in X-linked adrenal hypoplasia congenita and
hypogonadotrophic hypogonadism. J Invest Med 47: 232235.
Wang L-N and Huang KW (1991). Hypothalamic encephalitis
with oligodendrocytic glial nodules. Chin Med J 104:
428431.
Wang PN, Liao SQ, Liu CY, Chao HT, Lu SR, Yu HY, Wang
SJ, Liu HC (2000b). Effects of estrogen on cognition, mood,
and cerebral blood flow in AD. A controlled study. Neurology
54: 20612066.
Wang Q-S, Tian L, Huang Y-L, Qin S, He L-Q, Zhou J-N
(2002). Olfactory identification and apolipoprotein E4 allele
in mild cognitive impairment. Brain Res 951: 7781.
Wang RH, Dillon J, Reme C, Whitt R, Roberts JE (1992). The
potential ocular phototoxicity of antidepressant drugs. Lens
Eye Toxic Res 9: 483491.
Wannarachue N, Ruvalcaba RHA, Kelley VC (1975).
Hypogonadism in PraderWilli syndrome. Am J Ment Defic
79: 592603.
Wanschitz J, Klppel S, Jarius C, Birner P, Flicker H,
Hainfellner JA, Gambetti P, Guentchev M, Budka H (2000).
Alteration of the serotonergic nervous system in fatal familial
insomnia. Ann Neurol 48: 788791.
Ward OB (1992). Fetal drug exposure and sexual differentiation of males. In: Gerall, AA, Moltz H, Ward IL (Eds)
Handbook of Behavioral Neurobiology 11. Plenum Press,
New York. pp. 181219
Ward TN, St Germain DL, Comi RJ, Cromwell LD (2001).
Rathkes cleft cyst as a secondary cause of headache: a case
report. Cephalalgia 21: 921923.
Warnes KE, Morris MJ, Symonds ME, Phillips ID, Clarke IJ,
Owens JA, McMillen IC (1998). Effects of increasing gestation, cortisol and maternal undernutrition on hypothalamic
neuropeptide Y expression in the sheep fetus. J.
Warren MP (1996). Evaluation of secondary amenorrhea. J Clin
Warren MP, Fried JL (2001). Hypothalamic amenorrhea. The
effects of environmental stresses on the reproductive system:
a central effect of the central nervous system. Endocrinol
Warren WS, Champney TH, Cassone VM (1994). The suprachiasmatic nucleus controls the circadian rhythm of heart rate via
the sympathetic nervous system. Physiol Behav 55: 10911099.
Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE,
Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield
VC (2001). Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 105: 406413.
Watabe T, Endo A (1994). Sexual orientation of male mouse
offspring prenatally exposed to ethanol. Neurotoxicol Teratol
16: 2529.
Watanabe A, Ishii R, Hirano K, Suzuki Y, Okamura H, Kamada
M, Ichihashi K, Kitahata T, Shirabe T (1994). Central diabetes
569
2014 Refs
570
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 570
D.F. SWAAB
concentrations are elevated in female patients with major

depression. Psychoneuroendocrinology 25: 765771
Webster EL, Torpy DJ, Elenkov IJ, Chrousos GP (1998).
Corticotropin-releasing hormone and inflammation. Ann NY
Acad Sci 840: 2132.
Webster, J.E, Gurdjian ES, Lindner DW, Hardy WG (1960).
Proximal occlusion of the anterior cerebral artery. Arch
Neurol 2: 1926.
Webster MJ, Knable MB, OGrady J, Orthmann J, Weickert
CS (2002). Regional specificity of brain glucocorticoid
receptor mRNA alterations in subjects with schizophrenia and
mood disorders. Mol Psychiatry 7: 985994.
Wedekind D, Bandelow B, Broocks A, Hajak G, Rther E
(2000). Salivary, total plasma and plasma free cortisol in
panic disorder. J Neural Transm 107: 831837.
Weel AEAM, Uitterlinden AG, Westendorp ICD, Burger H,
Schuit SCE, Hofman A, Helmerhorst TJM, Van Leeuwen
JPTM, Pols HAP (1999). Estrogen receptor polymorphism
predicts the onset of natural and surgical menopause. J Clin
Endocrinol Metab 84: 3146-3150.
Wehr TA (1998). Effect of seasonal changes in daylength on
human neuroendocrine function. Horm Res 49: 118124.
Wehr TA, Duncan WC, Sher L, Aeschbach D, Schwartz PJ,
Turner EH, Postolache TT, Rosenthal NE (2001). A circadian signal of change of season in patients with seasonal
affective disorder. Arch Gen Psychiatry 58: 11081114.
Wehrle J (1950). Histologische Untersuchungen des
Zwischenhirns bei genuiner Hypertonie. Beitrage Pathol Anat
111: 381390.
Wei T, Lightman SL (1997). The neuroendocrine axis in patients
with multiple sclerosis. Brain 120: 10671076
Wei YQ, Hang ZB, Liu KF (1992). In situ observation of inflammatory cell tumor cell interaction in human seminomas
(germinomas): light, electron microscopic, and immunohistochemical study. Hum Pathol 23: 421428.
Weibel L, Brandenberger G (2002). The start of the quiescent
period of cortisol remains phase locked to the melatonin onset
despite circadian phase alterations in humans working the
night schedule. Neurosci Lett 318: 8992.
Weidenheim KM, Goodman L, Dickson DW, Gillberg C,
Rstam M, Rapin I (2001). Etiology and pathophysiology of
autistic behavior: clues from two cases with an unusual variant
of neuroaxonal dystrophy. J Child Neurol 16: 809819.
Weill-Engerer S, David J-P, Sazdovitch V, Liere P,
Eychenne B, Pianos A, Schumacher M, Delacourte A,
Baulieu E-E, Akwa Y (2002). Neurosteroid quantification
in human brain regions: comparison between Alzheimers
and nondemented patients. J Clin Endocrinol Metab 87:
51385143.
Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay
VS, Lipska BK, Berman KF, Goldberg TE (2001). Prefrontal
neurons and the genetics of schizophrenia. Biol Psychiatry
50: 825844.
Weiner, MF, Vobach S, Olsson K, Svetlik D, Risser RC (1997).

Cortisol secretion and Alzheimers disease progression. Biol
Weis, FR, Markello R, Mo B, Bochiechio P (1975). Cardiovascular
effects of oxytocin. Obstet Gynecol 46: 211214.
Weiss EL, Longhurst JG, Mazure CM (1999). Childhood sexual
abuse as a risk factor for depression in women: psychosocial
and neurobiological correlates. Am J Psychiatry 156:
816828.
Weiss JP, Blaivas JG (2000). Nocturia. J Urol 163: 512.
Weissenberger AA, Dell ML, Liow K, Theodore W, Frattali
CM, Hernandez D, Zametkin AJ (2001). Aggression and
psychiatric comorbidity in children with hypothalamic hamartomas and their unaffected siblings. J Am Acad Child Adolesc
Weitzman ED, Moline ML, Czeisler CA, Zimmerman JC
(1982). Chronobiology of aging: temperature, sleep-wake
rhythms and entrainment. Neurobiol Aging 3: 299-309.
Weller RO, Shulman K (1972). Infantile hydrocephalus: clinical, histological, and ultrastructural study of brain damage.
Weller RO, Weller EB (1982). Anorexia nervosa in a patient
with an infiltrating tumor of the hypothalamus. Am J
Wells T (1998). Vesicular osmometers, vasopressin secretion
and aquaporin-4: a new mechanism for osmoreception? Molec
Cell Endocrinol 136: 103107.
Welsh DK, Logothetis DE, Meister M, Reppert SM (1995).
Individual neurons dissociated from rat suprachiasmatic
nucleus express independently phased circadian firing
rhythms. Neuron 14: 697706.
Weltzin TE, McConaha C, McKee M, Hsu LKG, Perel J, Kaye
WH (1991). Circadian patterns of cortisol, prolactin, and
growth hormonal secretion during bingeing and vomiting in
normal weight bulimic patients. Biol Psychiatry 30: 3748.
Wenk GL (1997a). Rett syndrome: neurobiological changes
underlying specific symptoms. Progr Neurobiol 51: 383391.
Wenk GL (1997b). The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiol Learn
Mem 67: 8595.
Wenning GG, Wietholter H, Schnauder G, Muller PH, Kanduth
S, Renn W (1994). Recovery of the hypothalamic-pituitaryadrenal axis from suppression by short-term, high-dose
intravenous prednisolone therapy in patients with MS. Acta
Wenzel V, Padosch SA, Lindner KH (1998). Vasopressin als
alternativer vasopressor bei der kardiopulmonalen reanimation. Dtsch Med Wochenschr 123: 877882.
Werth E, Savaskan E, Knoblauch V, Fontana Gasio P, Van
Someren EJW, Hock C, Wirz-Justice A (2002). Decline
in long-term circadian rest-activity cycle organization
in a patient with dementia. J Geriatr Psychiatry Neurol 15:
5559.
2014 Refs
2/12/03
1:39 pm
Page 571
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
571
Whiteford HA, Stedman TJ, McGrath JJ, Welham J, Pond S

(1995). An open-label study of famotidine as a treatment for
schizophrenia. J Psychiatry Neurosci 20: 239240.
Whitehead HM, Boreham C, McIlrath EM, Sheridan B, Kennedy
L, Atkinson AB, Hadden DR (1992). Growth hormone treatment of adults with growth hormone deficiency: results of
a 13-month placebo controlled cross-over study. Clin
Whitehead R (1963). The hypothalamus in post-partum hypopituitarism. J Pathol Bacteriol 86: 5567.
Whitehouse, PJ, Price DL, Clark AW, Coyl JR, Delong MR
(1981). Alzheimers disease, evidence for selective loss of
cholinergic neurons in the nucleus basalis. Ann Neurol 10:
122126.
Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT,
Delong MR (1982). Alzheimers disease and senile dementia;
loss of neurons in the basal forebrain. Science 215:
12371239.
Whitehouse PJ, Parhad IM, Hedreen JC, Clark AW, White CL,
Stuble RG, Price DL (1983a). Integrity of the nucleus basalis
of Meynert in normal aging. Neurology 33 (Suppl. 2): 159.
Whitehouse PJ, Hedreen JC, Jones BE, Price DL (1983b). A
computer analysis of neuronal size in the nucleus basalis of
Meynert in patients with Alzheimers disease. Ann Neurol
14: 149150.
Whitehouse PJ, Hedreen JC, White CL III, Price DL (1983c).
Basal forebrain neurons in the dementia of Parkinsons
disease. Ann Neurol 13: 243248.
Whitehouse PJ, Lynch D, Kuhar MJ (1984). Effects of postmortem delay and temperature on neurotransmitter receptor
binding in a rat model of the human autopsy process. J
Whitehouse PJ (1986). Clinical and neurochemical consequences of neuronal loss in the nucleus basalis of Meynert
in Parkinsons disease and Alzheimers disease. In: Yahr MD,
Bergmann KJ (Eds.) Advances in Neurosciences 45, Raven
Press, New York, pp. 393397.
Whitlock FA, Siskind MM (1980). Depression as a major
symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry
43: 861865.
Whitmore D, Sassone-Corsi P (1999). Cryptic clues to clock
function. Nature 398: 557558.
Whitnall MH, Kiss A, Aguilera G (1993). Contrasted effects of
central alpha-1 adrenoreceptor activation on stress-responsive
and stress non-responsive subpopulations of corticotropinreleasing hormone neurosecretory cells in the rat.
Whitten W (1999). Pheromones and regulation of ovulation.
Nature 401: 232.
Whittle WL, Patel FA, Alfaidy N, Holloway AC, Fraser M,
Gyomorey S, Lye SJ, Gibb W, Challis JRG (2001).
Glucocorticoid regulation of human and ovine parturition: the
relationship between fetal hypothalamic-pituitary-adrenal axis
Westberg L, Melke J, Landn M, Nilsson S, Baghaei F,

Rosmond R, Jansson M, Holm G, Bjrntorp P, Eriksson E
(2003). Association between a dinucleotide repeat polymorphism of the estrogen receptor alpha gene and personality
traits in women. Mol Psychiatry 8: 118122.
West MJ, Coleman PD, Flood DG, Tronsoco JC (1994). Differences
in the pattern of hippocampal neuronal loss in normal ageing and
Alzheimers disease. Lancet 344: 769772.
Westlake WH, Heath JD, Spalton DJ (1995). Sarcoidosis
involving the optic nerve and hypothalamus. Arch
Westrin , Ekman R, Regnll G, Trskman-Bendz L (2001).
A follow-up study of suicide attempters: increase of
CSF-somatostatin but no change in CSF-CRH. Eur Neuropsychopharmacol 11: 135143.
Wetter TC, Collado-Seidel V, Oertel H, Uhr M, Yassouridis A,
Trenkwalder C (2002). Endocrine rhythms in patients with
restless legs syndrome. J Neurol 249: 146151.
Wetterberg L, Arendt J, Paunier L, Sizonenko PC, Van
Donselaar W, Heyden T (1976). Human serum melatonin
changes during the menstrual cycle. J Clin Endocrinol Metab
42: 185188.
Wever RA (1984). Sex differences in human circadian rhythms:
intrinsic periods and sleep fractions. Experientia 40:
12261234.
Weyl N (1987). Hormonal influences on sexual inversion: a
dual inheritance model of Prousts homosexuality. J Soc Biol
Struct 10: 385390.
Whalley PJ, Pritchard JA (1963). Oxytocin and water intoxication. JAMA 186: 601603.
Wharton RH, Bresman MJ (1989). Neonatal respiratory depression and delay in diagnosis in PraderWilli syndrome. Dev
Wheatland R (2002). Alternative treatment considerations in
anorexia nervosa. Med Hypotheses 59: 710715.
Whitaker A, Davies M, Shaffer D, Johnson J, Abrams S, Walsh
BT, Kalikow K (1989). The struggle to be thin: a survey of
anorexic and bulimic symptoms in a non-referred adolescent
population. Psychol Med 19: 143163.
Whitcomb RW, Crowley WF (1993). Male hypogonadotropic
hypogonadism. Endocrinol Metab Clin North Am 22: 125143.
White H, Pieper C, Schmader K (1998). The association of
weight change in Alzheimers disease with severity of disease
and mortality: a longitudinal analysis. J Am Geriatr Soc 46:
12231227.
White KD, Scoones DJ, Newman PK (1996). Hypothermia in
multiple sclerosis. J Neurol Neurosurg Psychiatry 61: 369375
White LE, Hain RF (1959). Anorexia in association with a
destructive lesion of the hypothalamus. Arch Pathol 68:
275281.
White REB, McCluskey SE, Varma TR, Lacey JH (1993).
Kallmanns syndrome and anorexia nervosa: a diagnostic
dilemma. Int J Eat Disord 13: 415419.
571
2014 Refs
572
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 572
D.F. SWAAB
activation and intrauterine prostaglandin production. Biol

Reprod 64: 10191032.
Whybrow PC, Prange AJ, Jr, Treadway CR (1969). Mental
changes accompanying thyroid gland dysfunction. Arch Gen
Wichers M, Maes M (2002). The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J
Neuropsychopharmacol 5: 375388.
Wicki W, Angst J, Merikangas KR (1992). Epidemiology of
seasonal depression. Eur Arch Psychiatry Clin Neurosci 241:
301306.
Wiegand M, Mller AA, Lauer C-J, Stolz S, Schreiber W, Dose
M, Krieg J-C (1991). Nocturnal sleep in Huntingtons disease.
J Neurol 238: 203208.
Wiegand SJ, Terasawa E (1982). Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in
regulation of gonadotropin secretion in the female rat.
Wiegant VM, Ronken E, Kovcs G, De Wied, D (1992)
Endorphins and schizophrenia. Prog Brain Res 93: 433453.
Wierda M, Goudsmit E, Van der Woude PF, Purba JS, Hofman
MA, Bogte H, Swaab DF (1991). Oxytocin cell number in the
human paraventricular nucleus remains constant with aging
and in Alzheimers disease. Neurobiol Aging 12: 511516.
Wierman, ME (Ed.) (1997). Diseases of the Pituitary. Humana
Press, Totowa, NJ, USA.
Wiesner G., Vaz M, Collier G, Seals D, Kaye D, Jennings G,
Lambert G, Wilkinson D, Esler M (1999). Leptin is released
from the human brain: influence of adiposity and gender. J.
Wiggs L, Stores G (1996). Severe sleep disturbance and daytime
challenging behaviour in children with severe learning disabilities. J Intellect Disabil Res 40: 518528.
Wik G (1996). Energy metabolism in the hypothalamus and
plasma cortisol levels in patients with schizophrenia. Horm
Metab Res 28: 205206.
Wikner J, Hirsch U, Wetterberg L, Rjdmark S (1998).
Fibromyalgia a syndrome associated with deceased
nocturnal melatonin secretion. Clin Endocrinol 49: 179183.
Wilcox BJ, Raskind MA, Ko GN, Baskin DG, Pascualy M,
Dorsa DM (1990). Localization of 3H-prazosin binding sites
in the supraoptic and paraventricular nuclei of the human
hypothalamus. Neuroendocrinology 51: 315319.
Willcutts MD, Felner E, White PC (1999). Autosomal recessive familial neurohypophyseal diabetes insipidus with
continued secretion of mutan weakly active vasopressin. Hum
Mol Genet 8: 13031307.
Wildin RS, Cogdell DE, Valadez V (1998). AVPR2 variants
and V2 vasopressin receptor function in nephrogenic diabetes
insipidus. Kidney Int 54: 19091922.
Wildin RS, Cogdell DE (1999). Clinical utility of direct mutation testing for congenital nephrogenic diabetes insipidus in
families. Pediatrics 103: 632639.
Wildt L, Leyendecker G, Sir-Petermann T, Waibel-Treber S

(1993). Treatment with naltrexone in hypothalamic ovarian
failure: induction of ovulation and pregnancy. Hum Reprod
8: 350358.
Wileman SM, Eagles JM, Andrew JE, Howie FL, Cameron IM,
McCormack K, Naji SA (2001). Light therapy for seasonal
affective disorder in primary care. Br J Psychiatry 178:
311316.
Wilke G (1956). Die granulomatse Encephalitis mit Bezug auf
bekannte oder unbekannte tiologie. Nervenarzt 27: 244251.
Wilkins RH (1975). Hypothalamic dysfunction and intracranial
arterial spasms. Surg Neurol 4: 472480.
Wilkinson A, Davies I (1978). The influence of age and
dementia on the neurone population of the mammillary
bodies. Age Ageing 7: 151160.
Williams DJ, Metcalfe KA, Skingle L, Stock AI, Beedham T,
Monson JP (1993). Pathophysiology of transient cranial
diabetes insipidus during pregnancy. Clin Endocrinol 38:
595600.
Williams G, McKibbin PE, McCarthy HD (1991). Hypothalamic
regulatory peptides and the regulation of food intake
and energy balance: signals or noise? Proc. Nutr Soc 50:
527544.
Williams G, Waterhouse J, Mugarza J, Minors D, Hayden K
(2002). Therapy of circadian rhythm disorders in chronic
fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest 32: 831837.
Williams M, Pennybacker J (1954). Memory disturbances in
third ventricle tumours. J Neurol Neurosurg Psychiatry 17:
115123.
Williams MS, Rooney BL, Williams J, Josephson K, Pauli R
(1994). Investigation of thermoregulatory characteristics in
patients with PraderWilli syndrome. Am J Med Genet 49:
302307.
Williams TDM, Abel DC, King CMP, Jelley RY, Lightman SL
(1986). Vasopressin and oxytocin responses to acute and
chronic osmotic stimuli in man. J Endocrinol 108: 163168.
Willis JA, Scott RS, Darlow BA, Lewy H, Ashkenazi I, Laron
Z (2002). Seasonality of birth and onset of clinical disease
in children and adolescents (019 years) with type 1 diabetes
mellitus in Canterbury, New Zealand. J Pediatr Endocrinol
Metab 15: 645647.
Willner A, Kantrowitz AB, Cohen AF (1994). Intrasphenoidal
encephalocele: diagnosis and management. Otolaryngol Head
Neck Surg 111: 834837.
Willnow S, Kiess W, Butenandt O, Drr HG, Enders A, StrasserVogel B, Egger J, Schwartz HP (1996). Endocrine disorders
in septo-optic dysplasia (De Morsier syndrome) evaluation
and follow up of 18 patients. Eur J Pediatr 155: 179184.
Wilsher ML (1998). Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur Respir J 12: 11971199.
Wilson JD (1999). The role of androgens in male gender role
behavior Endocr Rev 20: 726737.
2014 Refs
2/12/03
1:39 pm
Page 573
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
573
Wit JM, Donckerwolcke RAMG, Schulpen T.WJ, Deutman AF

(1986). Documented vasopressin deficiency in a child with
Wolfram syndrome. J Pediatr 109: 493494.
Wittert, GA, Crock PA, Donald RA, Gilford EJ, Boolell M,
Alford FP, Espiner EA (1990). Arginine vasopressin in
Cushings disease. Lancet 335: 991994.
Witting, W Kwa, IH, Eikelenboom P, Mirmiran M, Swaab DF
(1990). Alterations in the circadian rest-activity rhythm
in aging and Alzheimers disease. Biol Psychiatry 27:
563572.
Wolf OT, Kirschbaum C. (2002). Endogenous estradiol and
testosterone levels are associated with cognitive performance
in older women and men. Horm Behav 41: 259266.
Wolf OT, Convit A, Thorn E, De Leon MJ (2002). Salivary
cortisol day profiles in elderly with mild cognitive impairment. Psychoneuroendocrinology 27: 777789.
Wolff SM, Adler RC, Buskirk ER, Thompson RH (1964). A
syndrome of periodic hypothalamic discharge. Am J Med 36:
956967.
Wolfram DJ, Wagener HP (1938). Diabetes mellitus and simple
optic atrophy among siblings: report of four cases. Proc Staff
Meet Mayo Clinic 13: 715718.
Wolkowitz OM, Reus VI, Weingartner H, Thompson K, Breier
A, Doran A, Rubinow D, Pickar D (1990). Cognitive effects
of corticosteroids. Am J Psychiatry 147: 12971303.
Wolkowitz, OM, Reus VI, Roberts E, Manfredi F, Chan T,
Raum WJ, Ormiston S, Johnson R, Canick J, Brizendine L,
Weingartner H (1997). Dehydroepiandrosterone (DHEA)
treatment of depression. Biol Psychiatry 41: 311318.
Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W,
Johnson R, Canick J (1999). Antiglucocorticoid treatment of
depression: double-blind ketoconazole. Biol Psychiatry 45:
1070-1074.
Wolkowitz OM, Kramer JH, Reus VI, Costa MM, Yaffe K,
Walton P, Raskind M, Peskind E, Newhouse P, Sack D, De
Souza E, Sadowsky C, Roberts E, and the DHEA-Alzheimers
disease collaborative research group (2003). DHEA treatment
of Alzheimers disease. Neurology 60: 10711076.
Wolman L, Balmforth GV (1963). Precocious puberty due to a
hypothalamic hamartoma in a patient surviving to late middle
age. J Neurol Neurosurg Psychiat 26: 275280.
Wolpert SM (1997). The circle of Willis. Am J Neuroradiol 18:
10331034.
Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly
SL, Ravan SA, Vance JM, Gilbert JR, Abramson RK, Wright
HH, Cuccaro ML, Pericak-Vance MA (2000). Three probands
with autistic disorder and isodicentric chromosome 15. Am
J Med Genet 96: 365372.
Wolters ECh, Riekkinen P, Lowenthal A, Van der Plaats JJ,
Zwart JMT, Sennef C (1990). DGAVP (Org 5667). in early
Alzheimers disease patients: an international double-blind,
placebo-controlled, multicenter trial. Neurology 40:
10991101.
Wilson JD, Griffin JE, Russell DW (1993). Steroid 5-reductase

2 deficiency. Endocr Rev 14: 577593.
Winblad B, Bucht G, Gottfries CG, Roos BE (1979).
Monoamines and monoamine metabolites in brains from
demented schizophrenics. Acta Psychiatr Scand 60: 17-28.
Winkler C (1934). Introduction of Een greep uit het werk van
G. van Rijnberk. Van Dishoeck, Bussum.
Winn P, Clark A, Hastings M, Clark J, Latimer M, Rugg E,
Brownlee B (1990). Exitotoxic lesions of the lateral hypothalamus made by N-methyl-D-aspartate in the rat:
behavioural, histological and biochemical analyses. Exp Brain
Res 82: 628636.
Wiriyathian S, Rosenfeld CR, Arant BS, Porter JC, Faucher DJ,
Engle WD (1986). Urinary arginine vasopressin: pattern of
excretion in the neonatal period. Pediatr Res 20: 103108.
Wirz-Justice A, Graw P, Kruchi K, Gisin B, Jochum A, Arendt
J, Fisch H-U, Buddeberg C, Pldinger W (1993). Light
therapy in seasonal affective disorder is independent of
time of day or circadian phase. Arch Gen Psychiatry 50:
929937.
Wirz-Justice A (1995). Biological rhythms in mood disorders. In:
Bloom FE, Kupfer DJ (Eds.) Psychopharmacology: the Fourth
Generation of Progress. Raven Press, NY, pp. 9991017
Wirz-Justice A, Werth E, Savaskan E, Knoblauch V, Gasio PF,
Mller-Spahn F (2000). Haloperidol disrupts clozapine reinstates the circadian rest-activity cycle in a patient with
early-onset Alzheimer disease. Alzheimer Dis Assoc Disord
14: 212215.
Wisbeck JM, Huffman LC, Freund L, Gunnar MR, Davis EP,
Reiss AL (2000). Cortisol and social stressors in children with
fragile X: a pilot study. J Dev Behav Pediatr 21: 278282.
Wise LA, Zierler S, Krieger N, Harlow BL (2001). Adult onset
of major depressive disorder in relation to early life violent
victimisation: a case-control study. Lancet 358: 881887.
Wise PM (1998). Female reproductive aging. In: Mobbs CV,
Hof PR (Eds.) Reproduction. Functional Endocrinology of
Aging, Vol. 29. Basel, Karger, pp. 89104.
Wise PM, Krajnak KM, Kashon ML (1996). Menopause: the
aging of multiple pacemakers. Science 273: 6770.
Wislocki GB, King LS (1936). The permeability of the hypophysis and hypothalamus to vital dyes with a study of the
hypophysial vascular supply. Am J Anat 58: 421472.
Wisner KL, Stowe ZN (1997). Psychobiology of postpartum
mood disorders. Semin Reprod Endocrinol 15: 7789.
Wisniewski AB, Migeon CJ, Meyer-Bahlburg HFL, Gearhart
JP, Berkovitz GD, Brown TR, Money J (2000). Complete
androgen insensitivity syndrome: long-term medical, surgical,
and psychosexual outcome. J Clin Endocrinol Metab 85:
26642669.
Wisniewski KE, Bobinski M (1991). Hypothalamic abnormalities in Down syndrome. In: Epstein CH, Epstein CJ,
Rosenthal DM (Eds.) The Morphogenesis of Down
Syndrome, pp. 153167. Wiley-Liss Inc., New York.
573
2014 Refs
574
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 574
D.F. SWAAB
Wong M-L, Kling MA, Munson PJ, Listwak S, Licino J, Prolo P,

Karp B, McCutcheon IE, Geracioti TD, DeBellis MD, Rice KC,
Goldstein DS, Veldhuis JD, Chrousos GP, Oldfield EH, McCann
SM, Gold PW (2000). Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing
hormone. Proc Natl Acad Sci USA 97: 325330.
Wong F, Blei AT, Blendis LM, Thuluvath PJ (2003). A vasopressin receptor antagonist (VPA-985) improves serum
sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology 37:
182191.
Wood CE, Tong H (1999). Central nervous system regulation
of reflex responses to hypotension during fetal life. Am J
Physiol 277: R 1541R1552.
Woods AJ, Stock MJ (1996). Leptin activation in hypothalamus. Nature 381: 745.
Woods MO, Young TL, Parfrey PS, Hefferton D, Green JS,
Davidson WS (1999). Genetic heterogeneity of BardetBiedl
syndrome in a distinct Canadian population: evidence for a
fifth locus. Genomics 55: 29.
Woolf PD, Schalch MD (1973). Hypopituitarism secondary to
hypothalamic insufficiency. Ann Intern Med 78: 8890.
Woolsey RM, Nelson JS (1975). Asymptomatic destruction of
the fornix in man. Arch Neurol 32: 566568.
Woywodt A, Knoblauch H, Kettritz R, Schneider W, Gbel U
(2000). Sudden death and Wegeners granulomatosis of the
pituitary. Scand J Rheumatol 29: 264266.
Wree A, Braak H, Schleicher A, Zilles K (1980).
Biomathematical analysis of the neuronal loss in the aging
human brain of both sexes demonstrated in pigment preparations of the pars cerebellaris loci coerulei. Anat Embryol
160: 105119.
Wren AM, Small CJ, Fribbens CV, Neary NM, Ward HL, Seal
LJ, Ghatei MA, Bloom SR (2002). The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.
Wright KP, Czeisler CA (2002). Absence of circadian phase
resetting in response to bright light behind the knees. Science
297: 571.
Wright KP, Myers BL, Plenzler SC, Drake CL, Badia P (2000).
Acute effects of bright light and caffeine on nighttime melatonin and temperature levels in women taking and not taking
oral contraceptives. Brain Res. 873: 310317.
Wright KP, Hughes RJ, Kronauer RE, Dijk DJ, Czeisler
CA (2001). Intrinsic near 24-h pacemaker period determines limits of circadian entrainment to a weak
synchronizer in humans. Proc Natl Acad Sci USA 98:
1402714032.
Wroe SJ, Henley R, John R, Richens A (1989). The clinical
value of serum prolactin measurement in the differential
diagnosis of complex partial seizures. Epilepsy Res 3:
248252.
Wu, L-Z, Cui C-L, Tian JB, Ji D, Han J-S (1999). Suppression
of morphine withdrawal by electroacupuncture in rats: dynorphin and -opioid receptor implicated. Brain Res 851:
290296.
Wygnanski T, Kokia E, Barak P, Terlo L, Caine YG (1996).
The sleeping aviator aeromedical disposition of Kleine
Levin syndrome. Aviat Space Environ Med 67: 6162.
Wyllie E, Lders H, MacMillan JP, Gupta M (1984). Serum
prolactin levels after epileptic seizures. Neurology 34:
16011604.
Wysocki CJ (1979). Neurobehavioral evidence for the involvement of the vomeronasal system in mammalian reproduction.
Neurosci Behav Rev 3: 301341.
Xiang F, Buervenich S, Nicolao P, Bailey MES, Zhang Z,
Anvret M (2000). Mutation screening in Rett syndrome
patients. J Med Genet 37: 250255.
Xin W, Rubin MA, McKeever PE (2002). Differential expression of cytokeratins 8 and 20 distinguishes craniopharyngioma
from Rathke cleft cyst. Arch Pathol Lab Med 126: 11741178.
Xita N, Georgiou I, Tsatsoulis A (2002). The genetic basis of
polycystic ovary syndrome. Eur J Endocrinol 147: 717725.
Xu H, Hu X-Y, Wu L, Zhou JN (2003). Neurotensin expressing
neurons developed earlier than vasoactive intestinal polypeptide and vasopressin-expressing neurons in the human
suprachiasmatic nucleus. Neurosci Lett 335: 175178.
Yaffe K, Haan M, Byers A, Tangen C Kuller, L (2000a).
Estrogen use, APOE, and cognitive decline. Evidence of
geneenvironment interaction. Neurology 54: 19491953.
Yaffe K, Lui L-Y, Grady D, Cauley J, Kramer J, Cummings
SR (2000b). Cognitive decline in women in relation to nonprotein-bound oestradiol concentrations. Lancet 356:
708712.
Yaffe K, Krueger K, Sarkar S, Grady D, Barrett-Connor E, Cox
DA, Nickelsen T (2001). Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med
344: 12071213.
Yaffe K, Lui L-Y, Grady D, Stone K, Morin P (2002). Estrogen
receptor 1 polymorphisms and risk of cognitive impairment
in older women. Biol Psychiatry 51: 677682.
Yahalom D, Chen A, Ben-Aroya N, Rahimipour S, Kaganovsky
E, Okon E, Fridkin M, Koch Y (1999). The gonadotropinreleasing hormone family of neuropeptides in the brain of
human, bovine and rat: identification of a third isoform. FEBS
Lett 463: 289294.
Yahr P, Finn PD, Hoffman NW, Sayag N (1994). Sexually dimorphic cell groups in the medial preoptic area that are essential
for male sex behavior and the neural pathways needed for their
effects. Psychoneuroendocrinology 19: 463470.
Yamada N., Martin-Iverson MT, Daimon K, Tsujimoto T,
Takahashi S (1995). Clinical and chronobiological effects of
light therapy on nonseasonal affective disorders. Biol
Yamadera H, Ito T, Suzuki H, Asayama K, Ito R, Endo S
(2000). Effects of bright light on cognitive and sleep-wake
2014 Refs
2/12/03
1:39 pm
Page 575
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
575
Yehuda R, Kahana B, Binder-Brynes K, Southwick SM, Mason

JW, Giller EL (1995a). Low urinary cortisol excretion in
holocaust survivors with posttraumatic stress disorder. Am J
Yehuda R, Boisoneau D, Lowy MT, Giller EL (1995b). Doseresponse changes in plasma cortisol and lymphocyte
glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic
stress disorder. Arch Gen Psychiatry 52: 583593.
Yehuda R, Teicher MH, Trestman RL Levengood RA, Siever
LJ (1996). Cortisol regulation in posttraumatic stress disorder
and major depression: a chronobiological analysis Biol
Yehuda R, Schmeidler J, Wainberg M, Binder-Brynes K,
Duvdevani T (1998). Vulnerability to posttraumatic stress
disorder in adult offspring of holocaust survivors. Am J
Yehuda R, Halligan SL, Bierer LM (2002). Cortisol levels in
adult offspring of Holocaust survivors: relation to PTSD
symptom severity in the parent and child. Psychoneuroendocrinology 27: 171180.
Yen SSC (1993). Female hypogonadotropic hypogonadism.
Endocrinol Metab Clin North Am 22: 2958.
Yen SSC (1994). The placenta as the third brain. J Reprod Med
39: 277280.
Yeo GSH, Farooqi IS, Aminian S, Halsall DJ Stanhope, RG,
ORahilly S (1998). A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:
111112.
Yeo GSH, Lank EJ, Farooqi IS, Keogh J, Challis BG, ORahilly
S (2003). Mutations in the human melanocortin-4 receptor
gene associated with severe familial obesity disrupts receptor
function through multiple molecular mechanisms. Hum Molec
Genet 12: 561574.
Yip PSF, Chao A, Chiu CWF (2000). Seasonal variation in suicides: diminished or vanished. Br J Psychiatry 177: 366369
Yoo H-W (1998). Growth hormone deficiency associated with
pituitary stalk interruption syndrome. Horm Res (Suppl. 1)
49: 56.
Yoon B-K, Kim DK, Kang Y, Kim J-W, Shin MH, Na DL
(2003). Hormone replacement therapy in postmenopausal
women with Alzheimers disease: a randomized prospective
study. Fertil Steril 79: 274280.
Yoon I-Y, Kripke DF, Elliott JA, Youngstedt SD (2003).
Luteinizing hormone following light exposure in healthy
young men. Neurosci Lett 341: 2528.
Yoshida T, Tanaka M, Okamoto K, Hirai S (1996).
Neurosarcoidosis following augmentation mammoplasty with
silicone. Neurol Res 18: 319320.
Yoshimatsu H, Itateyama E, Kondou S, Tajima D, Himeno K,
Hidaka S, Kurokawa M, Sakata T (1999). Hypothalamic
neuronal histamine as a target of leptin in feeding behavior.
Diabetes 48: 22862291
(circadian) rhythm disturbances in Alzheimer-type dementia.

Psychiatry Clin. Neurosci 54: 352353.
Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto
K (1999). Chronic intracerebroventricular administration of
orexin-A to rats increases food intake in daytime, but has no
effect on body weight. Brain Res 849: 248252.
Yamashita, Y, Matsuishi T, Murakami Y, Kato H (1999). Sleep
disorder in Rett syndrome and melatonin treatment. Brain
Dev 21: 570.
Yanagimoto M, Honda K, Goto Y, Negoro H (1996). Afferents
originating from the dorsal penile nerve excite oxytocin cells
in the hypothalamic paraventricular nucleus of the rat. Brain
Res 733: 292-296.
Yanovski JA, Nieman LK, Doppman JL, Chrousos GP, Wilder
RL, Gold PW, Kalogeras KT (1998). Plasma levels of corticotropin-releasing hormone in the inferior petrosal sinuses of
healthy volunteers, patients with Cushings syndrome, and
patients with pseudo-Cushing states. J Clin Endocrinol Metab
83: 14851488.
Yaron M, Bennett CM (1978). Mechanism of impaired water
excretion in acute right ventricular failure in conscious dogs.
Circulation Res 42: 801805.
Yaswen L, Diehl N, Brennan MB, Hochgeschwender U (1999).
Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med 5:
10661070.
Yatagai T, Kusaka I, Nakamura T, Nagasaka S, Honda K,
Ishibashi S, Ishikawa S-E (2003). Close association of severe
hyponatremia with exaggerated release of arginine vasopressin in elderly subjects with secondary adrenal
insufficiency. Eur J Endocrinol 148: 221226.
Yates CM, Butterworth J, Tennant MC, Gordon A (1990).
Enzyme activities in relation to pH and lactate in postmortem
brain in Alzheimer type and other dementias. J Neurochem
55: 16241630.
Yates FE, Maran JW (1974). Stimulation and inhibition of
adrenocorticotropin release. In: Knobil E, Sawyer WH (Eds.)
Handbook of Physiology. Am Physiol Soc, pp. 367404,
Washington, DC.
Yates WR (2000). Testosterone in psychiatry. Arch Gen
Yeh ER, Erokwu B, LaManna JC, Haxhiu MA (1997).
The paraventricular nucleus of the hypothalamus influences
respiratory timing and activity in the rat. Neurosci Lett 232:
6366.
Yehuda R (1997). Stress and glucocorticoid. Science 275: 1662.
Yehuda R (2001). Are glucocorticoids responsible for putative
hippocampal damage in PTSD? How and when to decide.
Hippocampus 11: 8589.
Yehuda R, Teicher MH, Levengood RA, Trestman RL, Siever
LJ (1994). Circadian regulation of basal cortisol levels
in posttraumatic stress disorder Ann NY Acad Sci 746:
378380.
575
2014 Refs
576
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
2/12/03
1:39 pm
Page 576
D.F. SWAAB
Young EA, Korszun A (2002). The hypothalamic-pituitarygonadal axis in mood disorders. Endocrinol Metab Clin North
Am 31: 6378.
Young JK, Stanton GB (1994). A three-dimensional reconstruction of the human hypothalamus. Brain Res Bull 35: 323327.
Young WB, Silberstein SD (1997). Paroxysmal headache caused
by colloid cyst of the third ventricle: case report and review
of the literature. Headache 37: 1520.
Young EA, Midgley R, Carlson NE, Brown MB (2000).
Alteration in the hypothalamic-pituitary-ovarian axis in
depressed women. Arch Gen Psychiatry 57: 11571162
Young EA, Carlson NE, Brown MB (2001). Twenty-four-hour
ACTH and cortisol pulsatility in depressed women.
Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil
H (2003). Mineralocorticoid receptor function in major
depression. Arch Gen Psychiatry 60: 2428.
Young LJ, Wang Z, Insel TR (1998). Neuroendocrine bases of
monogamy. Trends Neurosci 21: 7175.
Young JM, Burley MW, Jeremiah SJ, Jeganathan D, Ekong R,
Osborne JP, Povey S (1998). A mutation screen of the TSC1
gene reveals 26 protein truncating mutations and 1 splice site
mutation in a panel of 79 tuberous sclerosis patients. Ann
Hum Genet 62: 203213.
Young RR, Asbury AK, Adams RD, Corbett JL (1969). Pure
pan-dysautonomia with recovery. Trans Am Neurol Assoc
94: 355357.
Young T-L, Penney L, Woods MO, Parfrey PS, Green JS,
Hefferton D, Davidson WS (1999). A fifth locus for
BardetBiedl syndrome maps to chromosome 2q31. Am J
Hum Genet 64: 900904.
Youngstrom TG, Nunez AA (1987). Neurons in the suprachiasmatic area are labelled after intravenous injections of
horseradish peroxidase. Exp Brain Res 67: 127130.
Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM
(1997). Role of leptin in hypothalamic-pituitary function. Proc
Yuasa H, Ito M, Nagasaki H, Oiso Y, Miyamoto S, Sasaki N,
Saito H (1993). Glu-47, which forms a salt bridge between
neurophysin-II and arginine vasopressin, is deleted in patients
with familial central diabetes insipidus. J Clin Endocrinol
Metab 77: 600604.
Yceer N, Baskaya M, Gkalp HZ (1996). Huge colloid cyst
of the third ventricle associated with calcification in the cyst
wall. Neurosurg Rev 19: 131133.
Zacay G, Bedrin L, Horowitz Z, Peleg M, Yahalom R,
Kronenberg J, Taicher S, Talmi YP (2002). Syndrome of
inappropriate antidiuretic hormone or arginine vasopressin
secretion in patients following neck dissection. Laryngoscope
112: 20202024.
Zafeiriou DI, Koliouskas D, Vargiami E, Gombakis N (2001).
Russells diencephalic syndrome. Neurology 57: 932.
Zahn TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA,

Rapoport JL (1997). Autonomic nervous system markers of
psychopathology in childhood-onset schizophrenia. Arch Gen
Zajicek JP, Scolding NJ, Foster O, Rovaris M, Evanson J,
Moseley IF, Scadding JW, Thompson EJ, Chamoun V, Miller
DH, McDonald WI, Mitchell D (1999). Central nervous system
sarcoidosis diagnosis and management. QJ Med 92: 103117.
Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA,
Mayer LS, Steffens DC, Breitner JCS (2002). Hormone
replacement therapy and incidence of Alzheimer disease in
older women. JAMA 288: 21232129.
Zrate A, Soria J, Canales ES, Kastin AJ, Schally AV, Toledano
RG (1974). Pituitary response to synthetic luteinizing hormonereleasing hormone in PraderWilli syndrome, prepubertal and
pubertal children. Neuroendocrinology 13: 321326.
Zazgornik J, Jellinger K, Waldhusl W, Schmidt P (1974).
Excessive hypernatremia and hyperosmolality associated with
germinoma in the hypothalamic and pituitary region. Eur
Neurol 12: 3846.
Zderic SA, Canning DA, Carr MC, Kodman-Jones C, Snyder
HMcC (2002). The chop experience with cloacal exstrophy
and gender reassignment. In: Zderic et al. (Eds.) Pediatric
Gender Reassignment: A Critical Reappraisal, Kluwer
Academic/Plenum Publishers. pp. 135147.
Zecevic N, Verney C (1995). Development of the catecholamine
neurons in human embryos and fetuses, with special emphasis
on the innervation of the cerebral cortex. J Comp Neurol 351:
509535.
Zeitzer JM, Kronauer RE, Czeisler CA (1997). Photopic transduction implicated in human circadian entrainment. Neurosci
Lett 232: 135138.
Zeitzer JM, Daniels JE, Duffy JF, Klerman EB, Shanahan TL,
Dijk D-J, Czeisler CA (1999). Do plasma melatonin concentrations decline with age? Am. J Med 107: 432436.
Zeitzer JM, Dijk DJ, Kronauer RE, Brown EN, Czeisler CA
(2000). Sensitivity of the human circadian pacemaker to
nocturnal light: melatonin phase resetting and suppression. J
Physiol 526: 695702.
Zeki SM, Hollman AS, Dutton GN (1992). Neuroradiological
features of patients with optic nerve hypoplasia J Pediatr
Ophthalmol Strabismus 29: 107112.
Zeman W, King FA (1959). Tumors of the septum pellucidum
and adjacent structures with abnormal affective behavior: an
anterior midline structure syndrome. J Nerv Mental Dis 127:
490502.
Zervoudakis IA, Krauss A, Fuchs F, Wilson KH (1980). Infants
of mothers treated with ethanol for premature labor. Am J
Zhang X, Hense H-W, Riegger GAJ, Schunkert H (1999).
Association of arginine vasopressin and arterial blood pressure in a population-based sample J Hypertension 17: 319324
2014 Refs
2/12/03
1:39 pm
Page 577
REFERENCES
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
577
salivary melatonin begin during middle-age. J Pineal Res 34:

1116.
Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF
(2003b). Early neuropathological Alzheimers changes in
aged controls are accompanied by decreased cerebrospinal
fluid melatonin levels. J Pineal Res 35: 125130.
Zimmerman HM, Netzky MG (1950). The pathology of multiple
sclerosis. Rec Publ Assoc Res Nerv Ment Dis 28: 271312.
Zizi F, Jean-Louis G, Magai C, Greenidge KC, Wolintz AH,
Heath-Phillip O (2002). Sleep complaints and visual impairment among older Americans: a community-based study. J
Gerontol 57A: M691M694.
Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell
CL (2000). Differential regulation of leptin transport by the
choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the bloodcerebrospinal fluid barrier. Endocrinology 141: 14341441.
Zlotogora J (1995). Major gene is responsible for anencephaly
among Iranian Jews. Am J Med Genet 56: 8789.
Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M
(2001). Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted
depression: a prospective study. J Psychiatr Res 35: 8394.
Zorgdrager A, De Keyser J (1997). Menstrually related worsening of symptoms in multiple sclerosis. J Neurol Sci 149:
9597.
Zorgdrager A, De Keyser J (2002). The premenstrual period
and exacerbations in multiple sclerosis. Eur Neurol 48:
204206.
Zornberg GL, Buka SL, Tsuang MT (2000). Hypoxic-ischemiarelated fetal/neonatal complications and risk of schizophrenia
and other nonaffective psychoses: a 19-year longitudinal
study. Am J Psychiatry 157: 196202.
Zubenko GS, Moossy J (1988). Major depression in primary
dementia. Clinical and neuropathologic correlates. Arch
Neurol 45: 11821186.
Zubenko GS, Moossy J, Kopp U (1990). Neurochemical correlates of major depression in primary demention. Arch Neurol
47: 209214.
Zubenko GS, Stiffler JS, Hughes HB, Hurtt MR, Kaplan BB
(1998). Initial results of a genome survey for novel
Alzheimers disease risk genes: association with a locus on
the X chromosome. Am J Med Genet 81: 98107.
Zubenko GS, Zubenko WN, McPherson S, Spoor E, Marin DB,
Farlow MR, Smith GE, Geda YE, Cummings JL, Petersen
RC, Sunderland T (2003). A collaborative study of the emergence and clinical features of the major depressive syndrome
of Alzheimers disease. Am J Psychiatry 160: 857866.
Zucchini S, Di Natale B, Ambrosetto P, De Angelis R, Cacciari E,
Chiumello G (1995). Role of magnetic resonance imaging
in hypothalamic-pituitary disorders. Horm Res (Suppl. 3) 44:
814.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,

Friedmann JM (1994). Positional cloning of the mouse obese
gene and its human homologue. Nature 372: 425432
Zhang Y-Q, Wang C-C, Ma Z-H (2002). Pediatric craniopharyngiomas: clinicomorphological study of 189 cases.
Zhao Z-Y, Fu YR, Li X-H, Li Y-Y, Bogdan A, Touitou Y
(2002). Age-related modifications of circadian rhythm of
serum leptin in healthy men. Gerontology 48: 309314.
Zhao Z-Y, Xie Y, Fu YR, Bogdan A, Touitou Y (2002). Aging
and the circadian rhythm of melatonin: a cross-sectional study
of Chinese subjects 30110 yr of age. Chronobiol Int 19:
11711182.
Zhdanova IV, Wurtman RJ, Wagstaff J (1999). Effects of a low
dose of melatonin on sleep in children with Angelman
syndrome. J Pediatr Endocrinol Metab 12: 5767.
Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP,
Leclair OU (2001). Melatonin treatment for age-related
insomnia. J Clin Endocrinol Metab 86: 47274730.
Zheng X, Zhang T, Ding H, Wang C (1995). Plasma levels of
-endorphin, leucine enkephalin and arginine vasopressin in
patients with essential hypertension and the effects of clonidine. Int J Cardiol 51: 233244.
Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S,
Li Q, Sun ZS, Eichele G, Bradley A, Lee CC (2001).
Nonredundant roles of the mPer1 and mPer2 genes in the
mammalian circadian rock. Cell 105: 683694.
Zhou JN (1996). Vasoactive intestinal polypeptide in the human
hypothalamus. Relationship to development, sex, aging and
Alzheimers disease, rhythmicity and depression. PhD Thesis.
University of Amsterdam.
Zhou JN, Hofman MA, Swaab DF (1995a). No changes in the
number of vasoactive intestinal polypeptide (VIP)-expressing
neurons in the suprachiasmatic nucleus of homosexual men;
comparison with vasopressin-expressing neurons. Brain Res
672: 285288.
Zhou JN, Hofman MA, Swaab DF (1995b). VIP neurons in the
human SCN in relation to sex, age, and Alzheimers disease.
Zhou JN, Hofman MA, Gooren LJG, Swaab DF (1995c). A sex
difference in the human brain and its relation to transsexuality. Nature 378: 6870.
Zhou JN, Hofman MA, Swaab DF (1996). Morphometric
analysis of vasopressin and vasoactive intestinal polypeptide
neurons in the suprachiasmatic nucleus: influence of
microwave treatment. Brain Res 742: 334338.
Zhou JN, Riemersma RF, Unmehopa U, Hoogendijk WJG, Van
Heerikhuize JJ, Hofman MA, Swaab DF (2001). Alterations
in arginine vasopressin neurons in the suprachiasmatic
nucleus in depression. Arch Gen Psychiatry 58: 655662.
Zhou JN, Liu RY, Van Heerikhuize JJ, Hofman MA,
Swaab DF (2003a). Alterations in the circadian rhythm of
577
2014 Refs
578
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
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3
4
5
6
7
8
9
301
1
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3
4
5
6
7
8
9
401
1
2
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4
5
6
7
8
911
2/12/03
1:39 pm
Page 578
D.F. SWAAB
Zuccoli G, Ferrozzi F, Sigorini M, Virdis R, Bassi P, Bellomi

M (2000). Early spontaneous regression of a hypothalamic/chiasmatic mass in neurofibromatosis type 1: MR
findings. Eur Radiol 10: 10761078.
Zucker KJ (2002). Intersexuality and gender identity differentiation. J Pediatr Adolesc Gynecol 15: 313.
Zucker KJ, Bradley SJ, Hughes HE (1987). Gender dysphoria
in a child with true hermaphroditism. Can J Psychiatry 32:
602609.
Zucker KJ, Bradley SJ, Oliver G, Blake J, Fleming S, Hood J
(1996) Psychosexual development of women with congenital
adrenal hyperplasia. Horm Behav 30: 300318.
Zurak N (1997). Role of the suprachiasmatic nucleus in the
pathogenesis of migraine attacks. Cephalalgia 17: 723728.
Zwangzer P, Baghai TC, Padberg F, Ella R, Minov C, Mikhaiel

P, Schle C, Thoma H, Rupprecht R (2003) The combined
dexamethasone-CRH test before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.
Zweig RM, Ross CA, Hedreen JC, Steele C, Cardillo JE,
Whitehouse PJ, Folstein MF, Price DL (1988). The
neuropathology of aminergic nuclei in Alzheimers disease.
Zylka MJ, Shearman LP, Weaver DR, Reppert SM (1998). Three
period homologs in mammals: differential light responses in
the suprachiasmatic circadian clock and oscillating transcripts
outside of brain. Neuron 20: 11031110.
2014 Index
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101
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Index of Volumes 79 and 80 The Human Hypothalamus.

Parts I and II
Note, underlined page numbers indicate in-depth treatment.
Acetylcholine, 4558(I)
Alzheimers disease, 329(II)
Acetylcholinesterase
islands of Calleja, 61(I)
ACTH
corticotropin releasing hormone, 200(I)
depression, 257(II)
Acute intermittent porphyria
periodic disorders, 305(II)
Addiction, see also Pain, and Opioid peptides
behavior, 377(II)
opioid peptides, 373378(II)
Addisons disease
hyponatremia, 150(II)
Adipsia, 142144(II)
Adrenoleucodystrophy, 343(II)
Adrenomyeloneuropathy, 343(II)
Age/aging
Alzheimers disease, 51(I), 106(I), 191194(I), 313330(II)
androgen receptor, 143147(I)
antemortem factors, 1517(I)
circadian rhythms, 92(I), 103107(I)
growth hormone, 3844(II)
hypothalamus-pituitary-gonadal system, 201202(II)
hypothyroidism, 227(I)
lateral tuberal nucleus, 267(I)
melatonin, 118120(I)
nucleus basalis of Meynert, 39(I), 5152(I), 53(I)
paraventricular nucleus, 191194(I)
sexually dimorphic nucleus, 131133(I)
sleep, 369(II)
suprachiasmatic nucleus, 102(I)
supraoptic nucleus, 191194(I)
ventromedial nucleus, 242(I)
Aggression, 283288(II)
developmental factors, 283285(II)
hypothalamic structures, 285(II)
nucleus basalis of Meynert, 45(I)

septum, 162(I)
sex hormones, 286287(II)
stereotactic hypothalamy, 287288(II)
tuberomamillary complex, 278(I)
ventromedial hypothalamic syndrome, 246248(II)
Agouti-related peptide
infundibular nucleus, 253(I)
PraderWilli syndrome, 172175(II)
premorbid state, 2223(I)
AIDS
bed nucleus stria terminalis, 159(I)
circadian rhythms, 9899(II)
hypothalamus, 9599(II)
hypothalamus-pituitary-adrenal system, 97(II)
oxytocin, 96(II)
vasopressin, 95(II)
Alcohol consumption
vasopressin secretion, 194(I)
Alcoholism
Korsakoff syndrome, 339343(II)
Alstrms syndrome, 190(II)
hypogonadotropic hypogonadism, 196(II)
aggression, 284(II)
bed nucleus stria terminalis, 150(I), 157(I)
beta amyloid, 318320(II)
circadian disorder, 69(I), 103107(I)
conventional neuropathology, 313315(II)
corpora mamillaria, 293294(I)
cytoskeletal changes, 322324(II)
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decreased metabolism, 320321(II)

depression, 255(II)
dorsomedial nucleus, 248(I)
Downs syndrome, 317318(II)
glucocorticoid cascade, 217(I), 222223(I)
Golgi apparatus, 55(I)
hormones/receptors, 327329(II)
hyperphosphorylated tau, 318(II), 320(II)(II)
hypothalamus reactivation, 324325(II)
light/melatonin therapy, 106107(I)
melatonin, 123(I)
mental deficiency, 275(II)
neurofibrillary tangles, 323(II)
neuronal metabolic activity, 29(I)
neuropeptides, 325327(II)
nucleus basalis of Meynert, 39(I), 46(I), 4956(I)
olfactory dysfunction, 205(II)
pain, 380(II)
septum, 161162(I)
sex differences, 18(I), 315317(II)
somatostatin, 235(I)
subthalamic nucleus, 287(I)
Amenorrhea
Amines
Amygdala
brain sexual differentiation, 220226(II)
Amyotropic lateral sclerosis, 348(II)
Analgesia, see Pain
Anatomy
diagonal band of Broca, 4548(I)
hypothalamus borders, 59(I)
hypothalamus nuclei, 4145(I),164(I)
pineal gland, 112(I)
vascular supply, 315(II)
vomeronasal organ, 206207(II)
Androgen (receptor)
distribution, 140147(I)
INDEX

resistance syndrome, 230(II)
sex differences, 138140(I)
ventromedial nucleus, 240(I), 242(I)
Anencephaly
brain pituitary remnants, 2224(II)
fusion failures, 2122(II)
intrauterine growth/birth, 2425(II)
transplantation, 2628(II)
Angelmans syndrome
eating disorders, 168(II)
Anorexia nervosa
eating disorders, 168(II), 180189(II)
genetics, 181(II)
hypothalamus-pituitary-adrenal system, 214(I)
Klinefelter syndrome, 220(II)
sexual dysfunction, 230(II)
sociocultural factors, 182(II)
symptoms, 182186(II)
therapy, 188(II)
Anosmia
Kallmanns syndrome, 203205(II), 215218(II)
Antemortem factors
age, 1517(I)
circadian variation, 22(I)
extracellular volume, 2122(I)
lateralization, 21(I)
seasonal variation, 1920(I)
sex difference, 1619(I)
Anterior commissure
Anxiety
oxytocin, 182(I)
panic disorder, 278279(II)
social anxiety, 279(II)
Aphasia
Aquaporin
diabetes insipidus, 140(II)
gene mutation, 140(II)
Arachnoid cysts
precocious puberty, 200(II)
Arcuate nucleus, see Infundibular nucleus
Arginine vasopressin, see also Vasopressin
depression, 252(II), 263265(II)
Aromatase mutation
Aspergers syndrome
autism, 299(II)
KleineLevin syndrome, 303(II)
Asthma
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1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
anatomy, 151153(I)
development, 156(I), 160(I)
neuron numbers, 159(I)
volume, 158(I), 160(I)
Behavior disorders
Biemonds syndrome, 190(II)
Binge eating syndrome, 190(II)
Biological clock, see Circadian rhythms
Blindness
circadian rhythm, 67(I), 103(I)
Blood pressure regulation
Blood supply, see Vascular supply
Body weight regulation
lateral hypothalamic area, 281(I)
BournevillePringle syndrome, see Tuberous sclerosis
Brain
autopsy, 1215(I)
banking, 1215(I), 28(I)
injury, 233234(II)
glucocorticoid cascade, 216222(I)
metastases, 85(II)
pH, 25(I)
Brain death, 391398(II)
coma, 393(II)
dying factors
agonal state, 2324(I)
illness, 2223(I)
stress, 24(I)
fetal brain tissue, 395(II)
motor cortex, 394(II), 396(II)
postmortem perfusion, 395(II)
process of dying, 391395(II)
tissue culture, 396397(II)
transgene expression, 396(II)
vasopressin, 394395(II)
Breast cancer
melatonin, 121(I)
Bulimia nervosa
borderline personality, 188(II)
Parkinsons disease, 187(II)
therapy, 188(II)
Astrocytomas
glioma, 64(II)
radiation injury, 239(II)
Atherosclerosis
Atrophy
Attention deficit hyperactivity disorder
aggression, 284(II)
thyroid hormone resistance, 232233(I)
Autism
development, 297299(II)
septum, 162(I)
Autoimmunity
Autonomic disorders, 351371(II)
autonomic dysfunction syndrome
head/brain injury, 234(II)
autonomic storm, 351(II)
behavior disorder, 352(II)
brain death, 353(II)
cardiovascular regulation, 360362(II)
circumventricular organs, 362364(II)
hyperphagia, 351(II)
micturition, 364(II)
orgasm, 352(II)
sleep center, 351(II)
sleep, 364371(II)
syndromes, 354355(II)
autonomic failure, 355(II)
hypoventilation, 354(II)
pandysautonomia, 354(II)
RileyDay syndrome, 355(II)
sensory neuropathy, 354(II)
thermoregulation, 355360(II)
Autopsy
brain, 1215(I)
diagnosis, 1415(I)
hypothalamus, 15(I)
Bacterial infections
Ballism
Baroreception
Bed nucleus stria terminalis, 149162(I)
AIDS, 159(I)
Alzheimers disease, 158(I)
Cachexia
Calbindin
Cancer, see Tumors
Cardiovascular regulation
autonomic disorders, 360362(II)
hypertension, 361(II)
581
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582
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
orthostatic hypotension, 361(II)

subarachnoid hemorrhage, 361(II)
Cataplexy
narcolepsy, 306(II)
Catecholaminergic system
periventricular nucleus, 236(I)
Cavernous malformation
Cerebrospinal fluid
circadian rhythms, 81(I)
melatonin, 112(I)
postmortem delay, 24(I)
Cerebrovascular accidents
Chemical markers
hypothalamic nuclei, 3034(I)
Chemoarchitecture
diagonal band of Broca, 4849(I)
Choline acetyltransferase
Cholinergic system
schizophrenia, 58(I)
Chondroma, 87(II)
Chordoma, 87(II)
Choroid plexus third ventricle
colloid cysts, 1819(II)
papilloma, 20(II)
xanthogranuloma, 18(II)
Chronic fatigue syndrome
Chronic pain disorder, 380(II)
Circadian rhythms, 63125(I)
aging, 103107(I)
AIDS, 9899(II)
antemortal factors, 2021(I)
cerebrospinal fluid, 81(I)
chemoarchitecture, 7173(I)
development, 99103(I)
disorders, 6671(I)
headache, 384(II)
melatonin, 88(I), 115116(I)
molecular genetics, 7376(I)
INDEX

retinohypothalamic tract, 7680(I)
timing system, 6466(I)
Circannual rhythms
aggression, 286(II)
aging, 103107(I)
hormone levels, 94(I)
light therapy, 265267(II)
melatonin, 115116(I), 261(II)
seasonal affective disorder, 253(II), 261267(II)
vasoactive intestinal peptide, 110(I)
Circaseptan rhythms
Suprachiasmatic nucleus, 99(I)
Circle of Willis
vascular supply, 45(II), 14(II)
Circumventricular organs
organum vasculosum lamina terminalis,
362363(II)
subfornical organ, 363364(II)
Colloid cysts
choroid plexus third ventricle, 20(II)
Congenital midline defects, 2934(II)
optic nerve hypoplasia, 29(II)
septo-optic dysplasia, 3034(II)
Cornelia de Lange syndrome, 388389(II)
Coronary heart disease
melatonin, 121(I)
Corpora mamillaria, 291295(I)
development, 291(I)
mamillotegmental tract, 292(I)
mamillothalamic tract, 292(I)
neurodegenerative disorders, 294295(I)
other pathologies, 295(I)
sex differences, 137138(I), 291(I)
Corticotropin releasing hormone
aging, 205206(I)
autism, 298(II)
chronic fatigue syndrome, 279280(II)
Cushings syndrome, 210212(I)
hypertension, 212213(I)
metabolic syndrome X, 212213(I)
number of cells in PVN, 201(I)
other disorders, 214216(I)
paraventricular nucleus, 171(I), 199223(I)
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1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
vasopressin, 200(I)
zona incerta, 288(I)
Cortisol
disorders, 210216(I)
feedback, 202(I)
Craniopharyngioma, 7275(II)
chiasm 78(II)
infundibulum, 72(II)
MRI, 72(II)
squamous papillary type, 74(II)
symptoms, 74(II)
third ventricle, 74(II)
CreutzfeldtJakobs disease
variant, 349(II)
Critical illness
growth hormone deficiency, 44(II)
Cushings syndrome
circadian disorder, 69(I)
depression, 259(II)
melatonin, 122(I)
menopause, 272(II)
neuropeptides, 248252(II)
oxytocin, 260261(II)
pathogenesis, 254256(II)
postpartum mood disorders, 272(II)
premenstrual syndrome, 271(II)
sex hormones, 270(II)
thyroid axis, 268270(II)
thyrotropin releasing hormone, 230(I)
vasopressin, 260261(II)
Dermoid/epidermoid tumors, 7677(II)
Development/growth disorders, 2149(II), see also
Fetal development
Diabetes insipidus, 135141
autoimmune, 135137(II)
drinking disorders, 130141(II)
familial central, 131135(II)
gene mutations, 133(II)
hypothalamic tumor, 85(II)
Langerhans cell histiocytosis, 117118(II)
myeloid leukemia, 85(II)
nephrogenic, 138141(II)
neurohypophysis, 167(I)
other causes, 138(II)
pregnancy induced, 137138(II)
vasopression administration, 198(I)
Wolframs syndrome, 150155(II)
Diabetes mellitus
vasopressin hypersecretion, 145147(II)
Diagnosis
autopsy, 1415(I)
Diagonal band of Broca
anatomy, 4548(I)
Diencephalic idiopathic gliosis, 390(II)
Diencephalic syndrome
glioma, 6570(II)
Diencephalons agenesis, 390(II)
Dopaminergic system
infundibular nucleus, 253(II)
Dorsomedial nucleus, 243248(I)
anatomy, 244247(I)
autism, 248(I)
catecholaminergic system, 248(I)
pheromones, 243(I)
De Morsiers syndrome, see Septo-optic dysplasia

Deafness
Dehydroepiandrosterone sulfate (DHEAS)
Dementia with argyrophilic grains, 330332(II)
lateral tuberal nucleus, 268(I), 331(II)
Depression
amines, 252254(II)
antepartum depression, 271(II)
antidepressive agents, 267(II)
circadian rhythms, 253(II), 261265(II)
circannual rhythms, 96(I), 253(II), 261267(II)
corticotropin releasing hormone, 256260(II)
electric stimulation, 268(II)
electroconvulsive therapy, 267(II)
hypothalamus-pituitary-adrenal system, 214(I),
248(II)
light therapy, 116(I), 265267(II)
583
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2
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2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Downs syndrome
anterior commissure, 137(I)
Drinking disorders, 125155(II)
cerebral/central salt wasting, 149(II)
diabetes mellitus, 145147(II)
neurohypophysis pathology, 125130(II)
nocturnal diuresis, 144145(II)
primary polydipsia/adipsia, 141144(II)
schizophrenia, 293(II)
SchwartzBartter syndrome, 147149(II)
vasopressin hypersecretion, 145147(II)
Wolframs syndrome, 138(II), 150155(II)
Drosophila
Dying, see Brain death
Eating disorders, 157191(II), see also Feeding
Alstrms syndrome, 190(II)
anorexia nervosa, 180189(II)
Biemonds syndrome, 190(II)
binge eating syndrome, 190(II)
bulimia nervosa, 180189(II)
epigenetic factors, 168(II)
hypothalamic nuclei, 159161(II)
LaurenceMoon/BardetBiedl syndrome,
189190(II)
leptin, 161162(II)
molecular genetics, 167168(II)
neuropeptides/hormones, 162167(II)
night eating syndrome, 190(II)
other disorders, 191(II)
Encephalitis lethargica
Endocrine dysfunction
Endodermal cyst, 89(II)
Enkephalin
Epilepsy, see also Gelastic epilepsy
circadian rhythm and sleep, 308(II)
circannual rhythms, 95(I)
hamartoma, 57(II), 310(II)
hormone release, 309(II)
hypothalamus pathology, 310(II)
INDEX

laughter attacks, 244246(II)
melatonin, 118(I)
ErdheimChester disease
Estrogen receptor
nucleus basalis of Meynert, 49(I), 330(II)
Exophthalamus
Extracellular volume
Familial glucocorticoid resistance
Fatal familial insomnia
Fatigue, 279283(II)
fibromyalgic syndrome, 282283(II)
postviral fatigue syndrome, 283(II)
Feeding, see also Eating disorders
autonomic system, 159(II)
eating behavior
energy storage, 158(II)
food intake regulation, 158159(II)
infundibular nucleus, 249, 256257(I)
leptin, 158(II)
neuropeptides/hormones, 162167(II)
Fetal development
aggression, 284(II)
brain tissue, 395(II)
circadian rhythm, 100101(I)
disorders, 2149(II)
hypothalamic nuclei, 3538(I)
melatonin, 118(I)
pituitary stalk, 241(II)
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1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911

Fibromyalgia
muscle pain, 379(II)
Follicle stimulating hormone
Fragile-X syndrome
melatonin, 120(I)
Frlichs syndrome
Frontotemporal dementia, 344(II)
Fungal infections
Glucocorticoid receptor polymorphism

Glucose metabolism
Glutamic acid decarboxylase
Golgi apparatus
Alzheimers disease, 52(I), 323(II)
neuronal metabolic activity, 29(I), 171(I)
nucleus basalis of Meynert, 52(I), 5455(I)
supraoptic nucleus, 173(I), 192(I)
Granular cell tumor
glioma, 71(II)
neurohypophysis, 127129(II)
Granular ependymitis, 122(II)
Growth hormone
aging, 3844(II)
AIDS, 98(II)
autism, 298(II)
deficiency, 4044(II)
adults, 4344(II)
development disorders, 3844(II)
Noonan syndrome, 3941(II)
Growth hormone releasing hormone
deficiency, 4244(II), 255(II)
depression, 255(II)
Noonan syndrome, 41(II)
GuillainBarr syndrome, 123(II)
Galanine
Gamma aminobutyric acid (GABA)
Gastroduodenal ulcer
Gastrointestinal bleeding
Gelastic epilepsy
hamartomas, 57(II), 244(II)
multiple sclerosis, 244(II)
seizures, 246(II)
Germ cell tumors
differentiation, 78(II)
germinoma, 79(II)
pineal region, 7783(II)
teratoma, 79(II)
yolk sac tumor, 81(II)
Germinoma
hypothalamic tumor 5456(II)
Germinoma, 79(II)
Gestation
hypothalamic development, 3538(I)
Gitelman disease
Glial fibrillary acidic protein
Glial neoplasms, 83(II)
Glioma
astrocytomas, 64(II)
chiasmatic, 66(II)
diencephalic syndrome, 6570(II)
optic pathway, 6470(II)
other gliomas, 70(II)
Glucocorticoid cascade
brain damage, 216222(I)
Hallucinations
Hamartoblastomas
hamartoma, 64(II)
Hamartoma
depression, 256(II)
epilepsy, 310(II)
hamartoblastomas, 64(II)
intrasellar gangliocytoma, 6264(II)
nodules, 62(II)
symptoms, 5760(II)
therapy, 61(II)
585
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1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
HandSchlerChristian disease, see Langerhans

cell histiocytosis
Headache
cluster headache, 383385(II)
hypnic headache syndrome, 385386(II)
melatonin, 122(I)
migraine, 385(II)
Heart failure
Heart frequency regulation
Hematoma
hydrocephalus, 93(I)
Hemophilia
Hemorrhage
Hepatorenal syndrome
Herpes simplex encephalitis
Hippocampus
damage, 217(I)
sclerosis, 346(II)
Histaminergic system
Histidine decarboxylase
Histiocytosis-X, see Langerhans cell histiocytosis
Histology
Homosexuality
sexual orientation/behavior, 229230(II)
Hunger
depression, 260(II)
Huntingtons disease, 337339(II)
hypothalamic changes, 338339(II)
lateral tuberal nucleus, 264(I), 266(I), 338339(II)
Hydrocephalus
etiology, 4647(II)
hematoma, 93(I)
hypothalamic symptoms, 46(II)
intracerebroventricular tumor, 92(I)
INDEX

subcommissural organ, 4446(II)
5-Hydroxytryptamine
circadian variation, 21(I)
seasonal variation, 19(I)
Hyperandrogenemia
melatonin, 121(I)
Hypercortisolism
Hyperphagia
Hyperphosphorylated tau
Alzheimers disease, 318(II), 320(II)
Hyperprolactinemia
melatonin, 121(I)
Hypertension
Hypocretin
narcolepsy, 306308(II)
Hypogonadism
Hypogonadotropic hypogonadism
gonadotropic hormone regulation disorders,
196199(II)
Kallmanns syndrome, 215218(II)
melatonin, 119(I)
Hyponatremia
Hypopituitarism
Hypotension
Hypothalamoneurohypophysial system, 163165(I)
Hypothalamus
adult markers, 3538(I)
aging, 143147(I)
amenorrhea, 121(I)
anatomy, 59(I), 4145(I), 9091(I), 164(I),
244247(I), 264(I), 275276(I)
atrophy, 388(II)
chemical markers, 3034(I)
confounding factors, 1529(I)
developmental/growth disorders, 2149(II)
fetal development, 3538(I)
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INDEX
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
other infections, 94(II)

post-/parainfectious encephalitis, 9394(II)
Infundibular nucleus, 249261(I)
ependyma and internal glia layer, 255(I)
leptin and adipose tissue, 256(I)
LHRH neurons, 257(I)
neurologic/psychiatric disorders, 260261(I)
postmenopause, 257260(I)
thyroid hormone receptors, 229(I)
Insulae terminalis, see Islands of Calleja
Intelligence
Intermediate hypothalamic area, 284(I)
attack area, 284(I)
Interstitial nucleus anterior hypothalamus
sexual dimorphism, 135136(I)
Interthalamic adhesion
Intracerebroventricular tumor
hydrocephalus, 92(I)
Intrasellar gangliocytoma
hamartoma, 6264(II)
Islands of Calleja, 6162(I)
lesions, 233241(II)
MRI, 6(I)
nuclei representation, 812(I), 4145(I)
strategic research, 912(I)
structure-function relationships, 912(I)
tuberous sclerosis, 8485(II)
tumors, 5189(II)
vascular lesions, 1517(II)
vascular supply, 36(II), 13(II)
Hypothalamus-pituitary-adrenal system
aggression, 284(II)
AIDS, 97(II)
autism, 298(II)
depression, 248(II)
upright position, 214(I)
vasopressin, 200(I)
Hypothalamus-pituitary dysfunction, 344(II)
Hypothalamus-pituitary-gonadal system
aging, 201202(II)
AIDS, 98(II)
menopause, 201202(II)
transsexuality, 227(II)
Hypothalamus-pituitary-thyroid system
depression, 268270(II)
Hypothermia, 234(II)
Hypothyroidism
aging, 227(I)
alcoholism, 227(I)
Hypotonia
Jet-lag
melatonin, 118(I)
anosmia, 203205(II)
endocrine disorders, 218(II)
functional deficits, 217(II)
molecular genetics/migration, 216217(II)
Kennedys disease
Kidney failure
neuroimmunological disorders, 123(II)
sleep disorder, 301303(II), 371(II)
clinical aspects, 219(II)
psychosocial problems, 220(II)
Idiopathic hypothalamic syndrome

childhood, 121(II), 354(II)
paraneoplastic syndrome, 387390(II)
Infarction
Infections, 9199(II)
acute viral meningoencephalitis, 9193(II)
AIDS, 9599(II)
bacterial, 9192(II)
encephalitis lethargica, 9495(II)
fungal, 94(II)
587
587
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588
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Korsakoff syndrome
alcoholism, 339341(II)
Kuru
septum, 162(I)
Lactic acidosis, 390(II)
Lamina terminalis
diabetes insipidus, 117118(II), 138(II)
ErdheimChester disease, 120(II)
exophthalamus, 118(II)
lytic bone disease, 118(II)
pathology, 119(II)
therapy, 119(II)
Lateral geniculate nucleus, 288(I)
Lateral hypothalamic area, 281283(I)
development, 283(I)
function, 281283(I)
melanin-concentrating hormone, 282(I)
Lateral tuberal nucleus, 263268(I)
function, 265(I)
Huntingtons disease, 338339(II)
neurodegenerating diseases, 266267(I)
Lateralization
Lateromamillary nucleus
Laughter attacks, see Gelastic epilepsy
LaurenceMoon/BardetBeidl syndrome, 189190(II)
Leigh disease, 388(II)
Subthalamic nucleus, 286(I)
Leptin
food intake regulation, 158(II)
Lesions
neuroleptic malignant syndrome, 234236(II)
pituitary stalk, 240241(II)
Lewy body disease, 348(II)
INDEX
Life span
Light/melatonin therapy
elderly, 120(I)
Lipoma, 88(II)
Listeriosis
Liver cirrhosis
melatonin, 122(I)
Liver disease
Lung diseases
Luteinizing homone releasing hormone
function, 194(II)
infundibular nucleus, 250(I), 257(I), 259(I)
polycystic ovary syndrome, 203(II)
reproduction, 193196(II)
septum, 159160(I)
Lymphoblastic leukemia
Lytic bone disease
Malignant lymphoma, 88(II)
Malignant neuroleptic syndrome
Mamillary body
Mania, 272273(II)
MarchiafavaBignami disease, 343(II)
McCuneAlbright syndrome
Median eminence
adenohypophysis, 255(I)
portal system, 254(I)
catecholamines, 255256(I)
melanin, 255256(I)
Medulloblastoma
Melanin
Melanin-concentrating hormone
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INDEX
1
2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Mortality
Moyamoya disease
MRI
glioma, 69(II)
hypothalamus, 6(I)
postcommissural fornix, 5(I)
sarcoidosis, 103(II)
Multiple endocrine neoplasia
Multiple sclerosis, 108116
differential diagnosis, 116(II)
hypothalamic-pituitary-adrenal system, 108110(II)
inflammation/demyelination, 110116(II)
mood changes, 108(II)
optic neuritis, 116(II)
Multisystem atrophy
neurodegeneration, 347348(II)
Myeloid leukemia

Melatonin (receptors), 112125(I)
age and sex, 118120(I)
analgesic effects, 380(II)
biosynthesis/metabolism, 113115(I)
circadian rhythms, 68(I), 78(I), 88(I), 115(I)
circannual rhythms, 9798(I), 115(I)
development, 118(I)
light intensity, 114(I)
light therapy, 116(I)
seasonal affective disorder, 261(II)
therapy, 106107(I)
side effects, 123125(I)
Memory impairment
Memory loss
Mnires disease
Meningioma, 86(II)
Meningitis
Menopause/postmenopause
aging, 115116(I)
depression, 272(II)
hot flushes, 259(I)
SPECT, 50(I)
subventricular nucleus, 257260(I)
vasopressin, 171(I)
Menstrual cycle
depression, 271(II)
melatonin, 120(I)
monthly rhythms, 9799(I)
Mental deficiency, 273276(II)
Metabolic syndrome X
Micturition
autonomic disorders, 364(II)
Midline developmental anomaly
Minamata disease
Mitochondrialencephalomyopathy, 390(II)
Molecular genetics
Monthly rhythms
menstrual cycle, 9799(I)
Narcolepsy
Narcolepsy, 123(II)
Nasopharyngeale carcinoma
Nerve growth factor receptor
Neural tube defect
anencephaly, 2122(II)
Neuroendocrine function
oxytocin, 174179(I)
vasopressin, 174179(I)
Neurohypophysis
dystopia
anterior pituitary abnormalities, 3536(II)
ectopia, 34(II)
granular cell tumors, 127(II)
granulomas, 127(II)
metastatic carcinomas, 128(II)
neurosecretion, 165168(I)
pathology in drinking disorders, 125130(II)
589
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Neuroimmunological disorders, 101123(II)
other disorders, 121123(II)
sarcoidosis, 101106(II)
Neuroleptic malignant syndrome, 234236(II)
autopsy, 235(II)
pathology, 235(II)
therapy, 235(II)
Neurologic disorders, see also Psychiatric
disorders
hamartoma, 59(II)
immunologic disorders, 102123(II)
melatonin, 122(I)
neurodegeneration, 313349(II)
reset osmostat, 149(II)
Neuronal metabolic activity
postmortem tissue, 2935(I)
Neuropeptide EI
Neuropeptide Y
suprachiasmatic nucleus, 7173(I), 79(I)
Neuropeptides
Neurosecretory cell
cellular/molecular properties, 172(I)
Neurotensin
Neurotransmittors/modulators
central pathways, 179182(I)
Neurotropin receptors
Night eating syndrome, 190(II)
INDEX
Nocturnal diuresis
desmopressin, 144145(II)
Noonan syndrome
Nucleus basalis of Meynert, 4558(I)
aggression, 45(I)
aging, 39(I), 5152(I)
Alzheimers disease, 39(I), 4958(I), 330(II)
anatomy, 4548(I)
atrophy, 29(I)
baroreception, 45(I)
feeding, 45(I)
narcolepsy, 308(II)
neurologic disorders, 5658(I)
neuronal loss vs. atrophy, 5152(I)
neurotropin receptors, 5256(I)
thermosensitivity, 45(I)
Nucleus of Cajal, see Ventromedial nucleus
Obesity
epigenetic factors, 168(II)
melatonin, 121(I)
Obsessive-compulsive disorder
neuroendocrine changes, 277(II)
therapy, 277(II)
Olfaction, 203(II), see also Vomeronasal organ
neurologic/psychiatric diseases, 205(II)
sex, 206215(II)
structures, 204(II)
Opioid peptides
addiction, 373378(II)
cocaine and amphetamine regulated transcript, 378(II)
enkephalins, 374(II), 376(II)
marijuana, 378(II)
neuropeptide AF, 378(II)
neuropeptide FF, 378(II)
orphanin peptides, 374(II)
prodynorphin, 375(II)
proenkaphelin B, 373(II)
pro-opiomelanocortin, 373(II)
Optic chiasm
misrouting in albinism, 3638(II)
non-degussating retinal-fugal fiber syndrome, 38(II)
other pathologies, 38(II)
Optic chiasm
Anatomy of region, 89(I)
Optic nerve hypoplasia
congenital midline defects, 29(II)
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2
3
4
5
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8
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9
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anatomy, 7(I), 166(I)
fixation, 27(I)
glutamic acid decarboxylase, 233(I)
hypophysectomy cell loss, 240241(II)
hypothalamoneurohypophysial system, 163165(I)
LHRH, 234(I)
model, 166(I)
neurosecretory pathway, 167(I)
oxytocin
production/release, 168171(I)
peptides/hormones, 233235(I)
suprachiasmatic nucleus efferents, 80(I)
thyroid hormone, 232(I)
tyroxine hydroxylase, 189191(I)
vasoactive intestinal peptide, 88(I)
vasopressin, 88(I), 164(I)
Parkinson dementia complex of Guam
nucleus basalis of Meynert,56(I)
autonomic symptoms, 334(II)
bulimia nervosa, 187(II)
depression, 335(II)
hormones/neuropeptides, 335336(II)
levodopa therapy, 332(II)
Lewy bodies, 336337(II)
sleep, 334(II)
tuberomamillary complex, 277(I), 279(I)
Parkinsonism linked to chromosome 17, 344(II)
Pars distalis
Perifornical area, 283284 (I)
feeding, 283(I)
hypocretin, 283284(I)
Periodic disorders, 301311
acute intermittent porphyria, 305(II)
Cushings syndrome, 305(II)
epilepsy, 308311(II)
Optic neuritis
Optic pathway glioma, 6470(II)
Oral contraception
melatonin, 121(I)
Osmoregulation
pregnancy, 184185(I)
Oxytocin
AIDS, 96(II)
neuroendocrien function, 174179(I)
osmoregulation in pregnancy, 184185(I)
paraventricular nucleus, 164, 170(I)
pre-ecclampsia, 185186(I)
preterm labor, 178(I)
reproduction, 182184(I)
Pain, 379383(II), see also Addiction
acupuncture, 382383(II)
analgesia, 382383(II)
anatomy, 379(II)
chronic, 380(II)
deep brain electrostimulation, 382(II)
headache, 383386(II)
hereditary disorders, 378(II)
nociceptive signals, 379(II)
placebo analgesia, 381(II)
sex steroids, 380(II)
stereotactic lesions, 382383(II)
symptoms
PallisterHall syndrome
hamartoma, 64(II)
Papilloma
Parabrachial nucleus
oxytocin, 182(I)
vasopressin, 182(I)
Paraneoplastic encephalitis
hypothalamic tumor 54(II)
neuroimmunological disorders, 123(II)
aging, 191194(I)
alcoholism, 345(II)
591
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7
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1
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3
4
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8
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1
2
3
4
5
6
7
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9
301
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2
3
4
5
6
7
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9
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1
2
3
4
5
6
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fever, 303304(II)
hypothermia, 304(II)
narcolepsy, 305308(II)
Shapiros syndrome, 304(II)
Periventricular nucleus
Parkinsons disease, 237(I)
Pheromones
Picks disease, 348(II)
Pineal gland, see also Melatonin
depression, 264(II)
germ cell tumors, 7783(II)
glial neoplasms, 83(II)
innervation, 114(I)
lipoma, 83(II)
malignant melanoma, 84(II)
malignant rhabdoid tumor, 84(II)
melatonin (receptors), 112125(I)
myeloblastoma, 84(II)
neural pathways, 112(I)
pineal cysts, 83(II)
pineoblastoma, 83(II)
pineocytoma, 83(II)
tumor symptoms, 84(II)
Pineoblastoma, 83(II)
Pineocytoma, 83(II)
Pituitary gland
deficiencies, 4042(II)
failure, 85(II)
neurohypophysis, dystopia, 3536(II)
Pituitary stalk
hypophysectomy lesion, 240241(II)
Pituitary tumors
adenoma, 89(II)
Polycystic ovary syndrome
hypothalamus-pituitary-adrenal system, 202(II), 216(I)
LHRH, 203(II)
Polydipsia
primary, 141142(II)
psychogenic, 142(II)
Portal system
Post-/parainfectious encephalitis
INDEX
Postcommissural fornix
MRI, 5(I)
Posterior fossa tumors
Postmortem factors/tissue
archival brain tissue, 28(I)
cooling, 26(I)
culture conditions, 28(I)
delay, 2426(I)
freezing, fixation, storage, 2628(I)
Postoperative delirium
melatonin, 121(I)
Post-traumatic stress disorder
hypothalamus-pituitary-adrenal system, 214(I),
220221(I)
PraderWilli syndrome
comorbidity, 179180(II)
hypothalamic abnormalities, 170178(II)
obesity, 170(II)
sleep disorder, 371(II)
Precocious puberty
hamartoma, 59(II)
Pregnancy
labor/birth, 186189(I)
aggression, 284(II)
vasopressin/oxytocin, 182184(I)
Primary empty sella syndrome
cerebrospinal fluid pressure, 28(II)
Progesterone receptor
Progressive supranuclear palsy
subthalamic nucleus, 286(I), 347(II)
Prolactin
Pro-opiomelanocortin
protein sequence, 164(II)
Psychiatric disorders, 246297, see also Neurologic disorders
aggression, 246248(II), 283288(II)
anxiety, 278279(II)
fatigue syndromes, 279(II)283(II)
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9
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2
3
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2
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5
6
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911

melatonin, 122(I)
neurotransmitters/-modulators/-hormones, 292297(II)
third ventricle tumor symptoms, 243(II)
SchwartzBartter syndrome
vasopressin secretion, 147149(II)
Seasonal variation, see Circannual rhythms
Seizures, see Epilepsy
Septic shock
Septo-optic dysplasia
congenital midline defects, 3034(II)
Septum, 158162 (I)
aggression, 162(I)
autism, 161(I)
development, 160(I)
Kuru, 162(I)
nuclei, 161(I)
pelludidum abnormalities, 4749(II)
structure, 158159(I)
tumors, 49(II)
Serotonin
autism, 298(II)
Sex difference/dimorphism
aggression, 286287(II)
aging, 143147(I)
androgen receptors, 138147(I)
antemortem factors, 1519(I)
hypothalamus/amygdala, 224226(II)
mechanism, 220224(II)
depression, 254(II)
homosexuality, 112(I)
interstitial nucleus ant. hypothalamus, 135136(I)
interthalamic adhesion, 137(I)
melatonin, 119(I)
neurologic diseases, 19(I)
sleep, 107109(I)
smelling, 215(II)
vasopressin, 171174(I)
Sex hormone receptors
Sexual behavior/orientation
laughter attacks/gelastic epilepsy, 244246(II)

mania, 272273(II)
obsessive-compulsive disorder, 276278(II)
ventromedial hypothalamus syndrome, 246248(II)
Puberty disorders, 199201(II)
delayed, 199(II)
precocious, 199(II)
Pulmonary hemorrhage
Radiation injury
hypothalamic symptoms, 236238(II)
other complications, 239241(II)
postradiation tumors, 239(II)
tumors, 238(II)
vascular complications, 239(II)
Yttrium90 in pituitary, 239(II)
Rathkes cleft cysts, 7576(II)
REM sleep
circadian rhythm, 104(I), 117(I)
Reproduction
aging, 201202(II)
LHRH, 193196(II)
menopause, 201202(II)
polycystic ovary syndrome, 202203(II)
puberty disorders,199201(II)
sexual arousal, 195(II)
Retinitis pigmentosa
Rett syndrome
Salla disease
Sarcoidosis
clinical aspects, 101102(II)
endocrine changes, 104105(II)
pathology, 102(II)
therapy, 106(II)
Schizophrenia
brain structures, 290(II)
developmental abnormalities, 289292(II)
593
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gender identity, 226228(II)
homosexuality, 229230(II)
pedophiles, 231(II)
preoptic area, 127(I)
reproduction, 193196(II)
septum, 225(II)
transsexualism, 226229(II)
ventromedial nucleus hypothalamus, 226(II)
ventromedial nucleus, 239(I), 242(I)
violent sexual offender, 231(II)
Sexual dysfunction
epilepsy, 309(II)
hypothalamopituitary disorders, 230231(II)
Sexually dimorphic nucleus (preoptic area),
123133(I)
aging, 15, 131133(I)
development, 130(I)
LHRH neurons, 206215(II)
nomenclature, 129(I)
rat homology, 129130(I)
topography, 128(I)
volume, 111(I)
Shapiros syndrome
ShyDrager syndrome, see Multisystem atrophy
Sick euthyroid syndrome
Sleep disorder, 364371(II)
autism, 299(II)
circadian disorder, 6768(I), 104(I), 117118(I)
familial fatal insomnia, 370(II)
KleineLevin syndrome, 123(II), 301303(II),
371(II)
melatonin, 117118(I)
narcolepsy, 123(II), 305308(II), 370(II)
neurological disorders, 370371(II)
Parkinsons disease, 335(II), 370(II)
retinitis pigmentosa, 370(II)
SmithMagenis syndrome, 365(II)
Wipples disease, 365(II)
Sleepwake regulation
aging, 369(II)
basal forebrain nuclei, 368(II)
melatonin, 117(I), 367(II)
INDEX
neuroendocrine changes, 368(II)

ventrolateral preoptic region, 367(II)
Smelling, see Olfaction
SmithMagenis syndrome
melatonin, 120(I)
SmithMajor syndrome
Somatostatin
depression, 252(II)
SPECT
hippocampus, 223(I)
Stalk
Stress
dying, 24(I)
glucocorticoid cascade, 217(I), 222(I)
Stria terminalis, see Bed nucleus stria terminalis
Stroke
Stroke-like episodes, 390(II)
Structure-function
hypothalamus, 912(I)
Subarachnoid cysts, 87(II)
Subarachnodale aneurysm
Subcommissural organ
hydrocephalus, 4446(II)
Substance P
Substantia innominata
corpora amylacia, 58(I)
Subthalamic nucleus, 285287(I)
emotion regulation, 286(I)
Subventricular nucleus
Sudden infant death syndrome
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2
3
4
5
6
7
8
9
101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
vasopressin, 88(I), 164(I)

Sympathetic system

LHRH, 236(I)
melatonin, 120(I)
Suicide
Suprachiasmatic nucleus, 63125(I)
afferents, 7980(I)
aggression, 284(II)
aging, 15(I)
cardiovascular regulation, 360(II)
circadian system, see Circadian rhythms
circaseptan rhythms, 99(I)
distribution of fibers, 9091(I)
efferents, 8081(I)
fixation, 28(I)
melatonin receptors, 123(I)
monthly rhythms, 9799(I)
multisystem atrophy, 348(II)
retinohypothalamic tract, 7680(I)
sex/reproduction, 107112(I)
sleep, 364366(II)
stimulation, 65(I)
volume, 111(I)
Supraoptic nucleus
aging, 15(I), 191194(I)
alcoholism, 345(II)
hypophysectomy cell loss, 240241(II)
hypothalamoneurohypophysial system, 163165(I)
LHRH, 234(I)
NADPH diaphorase, 233(I)
neurosecretory pathway, 167(I)
nitric oxide synthase, 233(I)
oxytocin
suprachiasmatic nucleus efferents, 80(I)
Teratoma, 7980(II)
hypothalamus tumor, 5657(II)
Testicular dysgenesis, see Klinefelter syndrome
Testosterone
Thermoregulation, 355360(II)
climacterium, 356(II)
malignant hypothermia, 358(II)
Nasu-Hakola disease, 358(II)
pilocarpine, 356(II)
preoptic anterior hypothalamic area, 355(II)
Thermosensitivity
Thirst, see Drinking disorders
Thyroid hormone (receptors)
hypothalamus, 228(I)
infundibular nucleus, 229(I), 251(I)
Thyroid stimulating hormone
Thyrotropin releasing hormone
thyroid hormone receptors, 226227(I)
vasopressin, 225(I)
Tourette syndrome
circadian disorder, 69(I), 390(II)
Trabecula
Transsexuality
sexual orientation/behavior, 226229(II)
Transsphenoidal encephalocele, 28(II)
Tremor
Triple H syndrome
Trypanosomiasis
595
595
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Tuberculosis
Tuberomamillary complex, 269279(I)
anatomy, 275276(I)
functions, 269(I)
histaminergic system, 269275(I)
neurodegenerative diseases, 276278(I)
posterior hypothalamic area, 278279(I)
Tuberous sclerosis
Tumors
breast cancer, 121(I)
craniopharyngioma, 7275(II)
dermoid/epidermoid, 7677(II)
germinoma, 5456(II)
glioma, 6472(II)
hamartoma, 5764(II)
idiopathic hypothalamic syndrome, 387388(II)
melatonin, 121(I)
metastases, 8586(II)
pineal region, 7784(II)
Rathkes cleft cysts, 7576(II)
symptoms
cognitive/behavior, 5354(II)
endocrine/autonomic, 5152(II)
teratoma, 5657(II)
tuberous sclerosis, 8485(II)
xanthogranuloma, 76(II)
Tyrosine hydroxylase
Tyrosine receptor kinases
Vascular lesions
Vascular supply
infundibular process, 12(II)
trabecula, 12(II)
pars distalis, 12(II)
optic chiasm, 13(II)
lamina terminalis, 1314(II)
hypothalamus, 36(II), 13(II)
stalk/median eminence, 68(II)
pituitary, 78(II)
portal system, 812(II)
Vasoactive intestinal peptide
INDEX

anterior hypothalamus innervation, 88(I)
circadian rhythms, 76 (I)
development, 101(I)
dorsomedial nucleus hypothalamus, 89(I)
hypothalamus, 82(I)
Vasopressin
adipsia, 143(II)
administration in disorders, 198199(I)
aggression, 286(II)
aging, 105(I)
AIDS, 95(II)
anterior hypothalamus innervation, 88(I)
autoimmunity , 136(II)
brain death, 392(II), 394395(II)
cerebral/central salt wasting, 149(II)
circadian rhythms, 67(I), 176(I)
development, 101(I), 186189(I)
diabetes insipidus, 132134(II), 139(II)
dorsomedial nucleus hypothalamus, 89(I)
hypothalamus, 82(I)
neuroendocrien function, 174179(I)
osmoregulation in pregnancy, 184185(I)
paraventricular nucleus, 88(I), 164(I), 170(I)
reproduction, 182184(I)
SchwartzBartter syndrome, 147149(II)
secretion in disorders, 194198(I)
septum, 161(I)
supraoptic nucleus, 22(I), 164(I)
water regulation, 177(I)
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2
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4
5
6
7
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101
1
2
3
4
5
6
7
8
9
201
1
2
3
4
5
6
7
8
9
301
1
2
3
4
5
6
7
8
9
401
1
2
3
4
5
6
7
8
911
Weils disease
Wernickes encephalopathy, 339343(II)
hormone/neurotransmitter disturbances, 339(II)
thiamine deficiency, 340(II)
Wests syndrome
laughter attacks, 246(II)
Whiplash injury
Whipples disease
clinical symptoms, 150(II)
hypothalamoneurohypophysial system, 153155(II)
psychiatric symptoms, 152(II)

Ventromedial hypothalamic syndrome
aggression, 246248(II)
psychiatric disorder, 246248(II)
Ventromedial nucleus, 239242(I)
aggression, 239(I), 246248(II), 284(II)
androgen receptor, 141(I), 242(I)
eating disorders, 159162(II), 239(I)
sexual behavior, 226(II), 242(I)
sexually dimorphic functions, 239240(I)
Viral infections
meningoencephalitis, 9193(II)
postviral fatigue syndrome, 283(II)
Visual system
hypothalamus tumor, 85(II)
Vomeronasal organ, see also Olfaction
anatomy/histology, 206(II)
embryology, 207208(II)
LHRH neurons preoptic area, 206215(II)
menstrual cycle, 215(II)
sexuality, 206215(II)
vomeropherins, 211(II)
Von Eeconomos encephalitis, see Encephalitis
lethargica
Von Willebrands disease
Xanthogranuloma, 76(II)
Yolk sac tumor, 81(II)
Zona incerta, 287289(I)
GABA, 287(I)
tyrosine hydroxylase, 288(I)
597
597

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2014 Prels(2) Rev

2014 Prels(2) Rev

dosage-sensitive sex-reversal, adrenal

2014 Prels(2) Rev

2014 Prels(2) Rev

tyrosine kinase neurotrophin receptor A,

Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)

Vascular supply and vascular disorders

. . . the vital spirit in the blood from the heart is changed

from the internal carotid artery, the fetal configuration.

. . . the central nervous system regulates the activity of the

17.1. Blood supply to the hypothalamus and

VASCULAR SUPPLY AND VASCULAR DISORDERS

(a) Stalk/median eminence region

histological observations Wislocki and King, in 1936,

VASCULAR SUPPLY AND VASCULAR DISORDERS

Intermediate group of arteries

Posterior group of arteries

From Haymaker, 1969, table 51, with permission.

rodents. One can, however, distinguish an upper

the case (for historical references, see Meites, 1992;

Fig. 17.4. Floor of the diencephalon in man. 1 = optic chiasm,

carotid, and the superior artery having its origin shortly

VASCULAR SUPPLY AND VASCULAR DISORDERS

capillary loops of characteristic form and varying degree

stalk into the anterior pituitary and empty there into a

VASCULAR SUPPLY AND VASCULAR DISORDERS

tuber cinereum, but apart from this there is no outflow of

capillary loops similar to those of the pituitary stalk. These

portal vessels that open into the sinusoids of the adjacent

(e) Artery of the trabecula

VASCULAR SUPPLY AND VASCULAR DISORDERS

retrograde blood flow from the pituitary, the authors

1960). The precommunicating part of the anterior cerebral

(i) Lamina terminalis

groups of arteries that descend from the anterior cerebral

ing to the arterial supply of the central portion of

VASCULAR SUPPLY AND VASCULAR DISORDERS

used for lesions that occur within the anterior third

crucial role in the development of intracranial arterial

17.2. Vascular lesions of the hypothalamus

(b) Infarction and hemorrhage

artery was the likeliest cause of the infarction. Horners

Multiple endocrine abnormalities have been reported

VASCULAR SUPPLY AND VASCULAR DISORDERS

small vessels, as an expression of chronic tissular anoxia.

(e) Radiation therapy

(d) Cavernous malformation

17.3. Choroid plexus of the third ventricle

substance. By a narrow pedicle or broad base, the cysts

VASCULAR SUPPLY AND VASCULAR DISORDERS

macrophages, lymphoplasmatic chronic inflammatory

They often extend into the lateral ventricle through the

Handbook of Clinical Neurology, Vol. 80 (3rd Series Vol. 2)

Disorders of development and growth

syndrome (Christensen et al., 2000), with amphalocele,

(a) Failures of fusion and the factors involved

Fig. 18.1. Anencephaly.

Mller, 2002). Anencephaly is proposed to originate as

DISORDERS OF DEVELOPMENT AND GROWTH

the pituitary in any of the seven anencephalics of 3048

fetuses with holoprosencephaly (cyclopsia and median

are similar in anencephalics without hydramnios and in

(c) Intrauterine growth and birth