Journal of the Neurological Sciences 289 (2010) 7480

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Journal of the Neurological Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Cardiovascular autonomic dysfunction in Parkinson's disease

Tjalf Ziemssen a,b,, Heinz Reichmann b
a
ANF-lab, Neurological University Clinic, Dresden; Germany
b
Neurological University Clinic, Dresden; Germany

a r t i c l e i n f o a b s t r a c t

Available online 8 September 2009 Symptoms of cardiovascular dysautonomia are a common occurrence in Parkinson's disease (PD). In addition
to this dysautonomia as part of PD itself, dysfunction of the autonomic nervous system (ANS) can be
Keywords: triggered as a side-effect of drug treatment interacting with the ANS or if prominent and early an
Parkinson's disease indication of a different disease such as multiple system atrophy (MSA).
Cardiovascular dysautonomia Various diagnostic tests are available to demonstrate autonomic failure. While autonomic function tests can
Orthostatic hypotension differentiate parasympathetic from sympathetic dysfunction, cardiac imaging can dene the pathophysio-
logically involved site of a lesion. Standard tests such as 24-h ambulatory blood pressure measurements can
identify signicant autonomic failure which needs treatment.
The most frequent and disturbing symptom of cardiovascular autonomic dysfunction is orthostatic
hypotension. Symptoms include generalized weakness, light-headiness, mental clouding up to syncope.
Factors like heat, food, alcohol, exercise, activities which increase intrathoraric pressure (e.g. defecation,
coughing) and certain drugs (e.g. vasodilators) can worsen a probably asymptomatic orthostatic
hypotension. Non-medical and medical therapies can help the patient to cope with a disabling symptomatic
orthostatic hypotension. Supine hypertension is often associated with orthostatic hypotension. The
prognostic role of cardiovagal and baroreex dysfunction is still not yet known.
2009 Elsevier B.V. All rights reserved.

1. Introduction several extremities, Stellwag's and Graefe's sign, one- or both-sided

Clinically, Parkinson's disease (PD) is mainly characterized by
motor symptoms such as bradykinesia, rigidity, tremor and postural
instability. In addition, it has become increasingly apparent that PD
patients also suffer from non-motor symptoms which impair their
quality of life quite considerably. These non-motor symptoms of the
Parkinson's disease and others include behavioural, sleep or percep-
tion dysfunctions as well as dysautonomia [1]. These dysfunctions can
be seen as the rst signs of the disease and even dominate the overall
picture of the disease [2]. This is what James Parkinson refers to in his
Essay on the shaking palsy published in 1817 with reoccurrence of
autonomic regulatory disorders. He also hints at the end of his book
with this statement mysterious sympathetic inuence at a connec-
tion with the autonomic nervous system [3]. 100 years later Lewy
described rigor, tremor and sympathetic dysfunctions as typical
Parkinson's symptoms, to which he included incontinence, saliva-
tion, lacrimation, rhinorrhoea, oedemas, and cyanosis of one or
sweating [4].
Although all autonomic subsystems are involved in PD, we will
concentrate on cardiovascular autonomic dysfunction in this review.
2. Autonomic nervous system
The autonomic nervous system controls, often without our
knowledge, various functions of our body in order to maintain the
homeostasis of the human body. The importance of the autonomic
nervous system results from the fact that every organ in the human
body is connected to the autonomic nervous system and consequently
regulated by it. Various areas in the brain are considered to be
complex centres for an autonomic network. The incoming informa-
tion from the periphery (autonomic afference) is processed and a
correlating response is sent to the peripheral target organ (autonomic
efference). Within this efferent system there are usually two
commonly antidromic components to differentiate between:

Sympathetic nervous system is the so-called Emergency System.

Corresponding author. Autonomes und neuroendokrinologisches Funktionslabor,
Klinik und Poliklinik fr Neurologie, Universittsklinikum Carl Gustav Carus, Tech-
nische Universitt Dresden, Fetscherstrae 74, D-01307 Dresden, Germany. Tel.: +49
351 458 3859; fax: +49 351 458 5873.
E-mail address: Tjalf.Ziemssen@uniklinikum-dresden.de (T. Ziemssen).
URL: http://www.neuro.med.tu-dresden.de/anf (T. Ziemssen).
After being activated it controls among others the widening of the
pupils, increasing of the heart rate, increases in heart strength and
vessel resistance. After the sympathetic nerves have left the spinal
cord in the chest and lumbar vertebrae area, they must change to
prevertebral or paravertebral ganglia at the second sympathetic
neuron. If there is a dysfunction before this ganglia change area then

0022-510X/$ see front matter 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2009.08.031
 T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 289 (2010) 7480
we speak of preganglionic damage, otherwise it is postganglionic
damage. Acetylcholine is set free as a transmitter at the ends of all
preganglionic as well as postganglionic at the perspiratory glands,
whereas postganglionic at the effector organs norepinephrine is
produced with the exception of the perspiratory glands.
Parasympathetic nervous system is generally understood as the
opponent to the sympathetic nervous system, so to say the rest and
relaxation system, this is for example mainly responsible for the
controlling of the digestion. After being activated it controls among
others the closing of the pupils, decreasing of the heart rate and
activating the digestion. In the upper region it also supports, after
the ganglia changes, the eyes, lacrimal glands, salivary glands, heart,
lungs as well as the digestive tract. The nerve bres existing in the
area of the coccyx are important for controlling the urinary tract and
the lower digestive tract. The primary neurotransmitter of the
postganglionic parasympathetic neuron is acetylcholine.
Langley already described the third part of the autonomic nervous
system as being the enteric nervous system, which can be inuenced
by the sympathetic nervous system and/or the parasympathetic
nervous system to regulate motility as well as secretion within the
gastrointestinal tract.
In order to keep up the internal homeostasis, the autonomic ner-
vous system needs various autonomic reex arcs as a control circuit,
that consist of an afferent, a central processing and an efferent com-
ponent. The afferent signal originates mainly from specialized sensors,
for example the pressure receptor, that registers changes in blood
pressure and can convert this into nerve impulses. The signal reaches
the nervous system via peripheral nerves or cerebral nerves. Here the
afferent signal is compared to other control signals which are
processed by regulatory centres, whereas for most of the reex arcs
there are many specic central neural processing centres. An efferent
response is generated by dened central nervous centres and is sent
to specic actuators of the control loop such as the smooth muscling
of the blood vessels. The reaction of the efferent organ assists in
correcting dysfunctional conditions which have been noticed by the
sensors with help from specic counter-regulatory mechanisms.
An abnormal regulation within the reex arc and with this a
dysfunction in the autonomic nervous system can be caused by a
dysfunction or defect in the afferent, central or efferent parts of the
autonomic reex arc.
3. Parkinson's disease and dysautonomia
References concerning how often dysautonomia appears with PD
vary depending on the collective and methodology between 14 and
80% [5], a subjective impairment of daily life is expressed by more
than half of PD patients [6]. The dysautonomia commonly occurs more
frequently the further the disease advances, it inuences the sub-
jective picture of the symptoms, the quality of life and the treatment
of the disease [7,8]. What are the possible causes for dysautonomia in
patients with idiopathic and atypical PD [9]?
The almost ubiquitous loss of neurons and the appearance of Lewy
bodies within completely different parts of the nervous system can
be a primary cause of this dysautonomia. Braak et al. explain lesions
in the dorsal vagal nucleus and in other autonomic cerebral stem
centres within PD patients already before any clinical period as well
as before the appearance of characteristic histopathological changes
in the subtantia nigra [10]; the peripheral nervous system was not
included in this research.
Multiple system atrophy (MSA) is an important differential
diagnosis that must be considered, especially in early dysautonomia.
There are only minor differences of autonomic dysfunction between
the different MSA subtypes [11]. However, the differentiation
between PD with advanced dysautonomia and an MSA is not easy
75
and requires the use of innovative diagnostic techniques [12]. Even
in patients with progressive supranuclear palsy (PSP), we could
demonstrate signicant autonomic dysfunction [13,14].
It can also be possible that secondary dysautonomia is due to other
separate illnesses within PD patients such as diabetes mellitus.
More commonly, however, is the fact that medication is responsible
for secondary dysautonomia [15,16]. For instance, selegiline, aman-
tadine and dopamine agonists can exacerbate orthostatic hypoten-
sion to a greater degree than levodopa does. Many other drugs cause
unwanted interactions that lead to dysfunctions between various
components of the autonomic nervous system. Important examples
of this are psychotropic drugs with their numerous effects, such as
anticholinergic, antiadrenergic and other effects [17,18].
4. Pathophysiology of dysautonomia in IPD
With help from modern technology such as the scintigraphy with
123
J-metaiodobenzylguanidin (MIBG), a pharmacologic-interactive
urea derivative could be used, which like epinephrine is active from
the metabolism of postganglionic adrenergic neurons, to greatly
reduce the intake of MIBG in cardial sympathetic efferences within
over 250 PD patients [19,20].
This explains that in PD a degree of damage to the postganglionic
sympathetic efferences is the main cause of dysautonomia. The
postganglionic lesions do not appear within patients of MSA, this
suggests that a cardiosympathetic denervation expresses the exis-
tence of PD. Parallel to cardiodenervation, a histological loss of
neurons and Lewy bodies in peripheral parts of the sympathetic
nervous system, for example in the sympathetic ganglia paraverteb-
ralia or a loss in tyrosine hydrolase colour in the epicardium area can
also be found in PD patients [21]. Furthermore, neuroendocrinologi-
cally, a signicant reduction in epinephrine levels in the serum could
be seen as well as a postganglionic denervation hypersensitivity of
adrenergic neurons, which is reected in high blood pressure results
related to specic amounts of epinephrine [19,21]. A pathophysiolo-
gically-orientated classication is provided in Table 1.
5. Autonomic cardiovascular testing
The techniques most widely used in the clinical setting entail the
measurement of an end-organ response to a physiological provoca-
tion [22,23]. The non-invasive evaluation of cardiovascular parasym-
pathetic function involves the analysis of the heart rate variability
while the measures of cardiovascular sympathetic function assess the
blood pressure response to physiological stimuli.
5.1. Tests of cardiovagal function
Respiratory-mediated heart rate variability is the most widely used
index of cardiovagal parasympathetic function. Heart rate variability
during deep metronomic breathing (6 cycles/min) is the most com-
monly used including the expiratoryinspiratory ratio (E:I ratio).
Table 1
Proposed pathophysiological classication of dysautonomia in extrapyramidal disease.
76 T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 289 (2010) 7480
The Valsalva manoeuvre (VM) is typically performed by blowing
through a mouthpiece connected to a mercury manometer (40 mm
Hg) for 15 s. As a marker of parasympathetic function, the Valsalva
ratio, the ratio of the shortest RR interval (the tachycardia) during or
after phase II of the manoeuvre to the longest RR interval (the
bradycardia) in phase IV of the manoeuvre, is the most commonly
used measure derived from the manoeuvre [24].
Active standing results in an abrupt increase in heart rate that
peaks at approximately 3 s followed by a more gradual increase
that peaks at approximately 12 s after standing. The 30:15 ratio
assesses this physiological response by measuring the ratio of the
heart rate increase that occurs at approximately 15 s after standing
to the relative bradycardia that occurs at approximately 30 s after
standing.
5.2. Tests of sympathetic adrenergic function
The most frequently performed cardiovascular test of sympathetic
nervous system function is the blood pressure response to postural
change (active standing or passive tilting). Passive tilting on a tilt-
table, by minimizing the compensatory response due to active
muscle contraction may, theoretically, exaggerate this response and
thus result in a more sensitive test. In contrast, active standing can
be used as a bedside test. In normal subjects, the systolic blood
pressure falls minimally after 12 min of standing, diastolic blood
pressure increases by approximately 10 mm Hg and heart rate
increases by 10 beats/min. When severe autonomic failure is
present, blood pressure and heart rate abnormalities are apparent
after 510 min of head up tilt or active standing. Early or mild
adrenergic failure may require a longer period of standing or
duration of tilt. Orthostatic hypotension is dened as a reduction in
systolic blood pressure of at least 20 mm Hg or diastolic blood
pressure of at least 10 mm Hg within 3 min of upright tilt to an angle
of at least 60 or standing [25].
Robertson suggested the so-called standing time, this means the
time needed for actively standing up, until the patient, due to
orthostatic symptoms, is forced to again sit down [26]. According to
Robertson's test, a person is considerably impaired in his daily life if
the standing time is less than 30 s, whereas a standing time of more
than 1 min usually allows for an independent life.
A direct measure of the hemodynamic response to the Valsalva
manoeuvre can be made with a non-invasive beat-to-beat blood
pressure monitor. The decrease in blood pressure during early phase
II, the recovery in late phase II and the increase in blood pressure
during phase IV of the Valsalva manoeuvre are measures of the
vasomotor adrenergic function although there are not well-
established normative values for this test [24].
The blood pressure response to sustained isometric muscle contrac-
tion (sustaining a xed, isometric handgrip contraction for 3 min at
30% of maximum effort), to cold water immersion (immersing a
hand in a container of ice water for 13 min) and to mental stress
tests (mental arithmetic (e.g. subtracting 7 serially from 100) and
the Stroop colour word-naming test) is a marker for sympathoexci-
tation, but the inter-subject response is quite variable [23]. Overall,
these tests have low sensitivity and specicity to detect sympathetic
dysfunction.
5.3. Spectral analysis
Heart rate uctuations, which reect modulation of sinus node
activity by autonomic and other homeostatic mechanisms, can be
quantied and displayed using spectral analysis. So, the spectral
analysis of the heart rate may identify autonomic inputs to the heart
[27,28]. Two major spectral bands are usually identied: high-
frequency (HF) power of heart rate (RR-HF) relates to respiratory
sinus arrhythmia and therefore to parasympathetic cardiovagal tone.
We could describe the pathological heart rate spectra in PD patients
correlating with the disease stage of the patients [28].
5.4. Baroreex analysis
The response of the heart rate to a given change of systolic blood
pressure mediated by the baroreex arc is a fundamental character-
istic of the short-term regulation of the cardiovascular system [29].
An increase of blood pressure will be responded by a decrease of
heart rate, and vice versa. To assess function of the baroreex arc,
baroreex gain or sensitivity (BRS) is calculated by measuring the
changes of heart rate related to blood pressure changes [30]. The
impairment of baroreex function plays an adverse role in a wide
range of diseases as we have recently shown in extrapyramidal
diseases [28].
5.5. 24-h ambulatory blood pressure measurement (ABPM)
Unfortunately, autonomic laboratories are still rare and not
available for most of the patients. That is why broadly available
clinical tests would be preferable to screen and monitor cardiovas-
cular autonomic dysfunction. Today, 24-h ambulatory blood pressure
monitoring (ABPM) is widely used in diagnosis and in the evaluation
of treatment for arterial hypertension. This non-invasive technique
allows the determination of the blood pressure load of the 24-h blood
pressure prole. On the other side, arterial hypertension is one of the
most frequently encountered risk factors in cardiovascular diseases,
and one-third of affected patients are unaware of the diagnosis. As
reported previously, a high nocturnal blood pressure load is
associated with an increased prevalence of end-organ damage. In
our recent cross-sectional study, we demonstrated that a large pro-
portion of PD and MSA patients presented with an altered 24-h blood
pressure prole including loss of the nocturnal blood pressure dip.
There are quite good correlations between orthostatic hypotension
and altered ABPM. An example of an ABPM of a PD patient and control
patients is given in Fig. 1.
5.6. Cardiac sympathetic imaging
Imaging of the postganglionic sympathetic noradrenergic cardiac
innervation uses agents that are taken up into sympathetic nerves by
the uptake-1 process and are sequestered in storage vesicles within
sympathetic neurons. The radiolabeled sympathomimetic amine,
123
I-metaiodobenzylguanidine (123I-MIBG), the most widely used
agent, is a substrate for the cell membrane and vesicular norepi-
nephrine transporter and can be imaged with single photon emission
computed tomography (SPECT) scanning [31]. MIBG uptake is im-
paired in PD patients particularly when autonomic failure is present
(Fig. 2) [32]. These abnormalities are not usually present in MSA
patients [31]. These changes may be present early in PD and may
precede abnormalities in autonomic reexes [33].
Positron emission tomography (PET) scanning holds superior
spatial and temporal resolution. Radiolabeled catecholamines, e.g.
6-[18F] uorodopamine, are also a substrate for the cell membrane
and vesicular norepinephrine transporter and, in addition, are a
substrate for the enzymes that degrade catecholamines such as
monoamine oxidase and catechol-O-methyltransferase [34]. Several
studies using 6-[18F] uorodopamine have demonstrated that PD
patients have a loss of cardiac sympathetic innervation lending
support to the concept that in addition to the well-established loss
of dopamine in the nigrostriatal system there is also postganglionic
loss of sympathetic noradrenergic innervation [35].
 T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 289 (2010) 7480
Fig. 1. 24-h ambulatory blood pressure monitoring (ABPM) prole with nocturnal hypertension in a PD patient (upper panel) in comparison with a healthy person demonstrating a
blood pressure dip during night (lower panel).
6. Orthostatic hypotension
The most frequent symptom of cardiovascular autonomic dys-
function is orthostatic hypotension [26,36]. Roughly 50% of PD pa-
tients especially in advanced disease stage complain about general
symptoms of orthostatic hypotension such as giddiness, dizziness,
empty headedness, and nausea or pain mostly while standing [37].
Orthostatic hypotension results from a dysfunction of the sympathetic
noradrenergic innervation of the cardiovascular target organs [38].
Besides the primary dysautonomia, other situations could also cause
such symptoms such as not taking in enough liquids as well as
medication like dopamine agonists and selegiline [39]. The tendency
to hypotension can be related to nutritional intake and results in
serious postprandial orthostatic hypotension 30 to 50 min after lunch.
Furthermore, a typical post-stress orthostatic hypotension can be seen
during relaxation periods after exercise stress in PD patients [40,41].
According to the American Autonomic Society, the denition of
orthostatic hypotension is a constant decrease of the systolic blood
Fig. 2. MIBG scintigraphy of a healthy person (A) in contrast to a PD patient (B). MIBG
accumulation as indicated by the arrows in (A) is not present in (B) (provided by Prof.
Kotzerke, Dresden).
77
pressure to 20 mm Hg and the diastolic blood pressure to 10 mm
Hg within 3 min after change in a standing position [25]. Orthostatic
hypotension can be asymptomatic, if the patient does not develop any
symptoms, or symptomatic, when it comes to the development of, for
example, dizziness, weakness, nausea, pain or unclear sight. Factors
like heat, food, alcohol, exercise, activities which increase intrathora-
ric pressure (e.g. defecation, coughing) and of course certain drugs
(e.g. vasodilators) can worsen a probably asymptomatic orthostatic
hypotension.
7. Treatment of orthostatic hypotension
If orthostatic hypotension is symptomatic and repeated intake of
uids and modications in the PD medication do not bring about
considerable symptom relief, there are various treatments available,
presented in Table 2 [42]. These therapies are often used depending
upon their implementation levels and acceptance, independent of the
level of orthostatic hypotension, and in some cases in combination.
For example, if patients mainly complain about postprandial hypo-
tension, then the intake of several meals during the day is suggested in
which the intake of carbohydrates is split up. If orthostatic hypo-
tension is caused by hypovolemia, due to medications (e.g. cardio-
vascular, psychiatric drugs, selegiline), it may be reversed by adjusting
the dosage or by discontinuing the medication. If the condition is
caused by prolonged bed rest, improvement may occur by sitting up
with increasing frequency each day. Susceptible people should not sit
or stand up rapidly or remain standing still for long periods. They
should sit or stand up slowly. Wearing tted elastic stockings up to the
waist may help reduce pooling of blood in the leg veins.
For PD and MSA patients who have severe symptoms, taking
hormones that cause salt to be retained, such as udrocortisone can
increase blood volume. However, use of such hormones increases the
risk of heart failure, particularly for older people and people who have
78 T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 289 (2010) 7480

Table 2
Non-medical and medical therapies of orthostatic hypotension.

Non-medical procedures

Avoid sudden changes in the position of the body, from long periods of lying as in such situations that lead to a vasodilatation of the veins (i.e. hot baths)
Intake of a salt-rich diet (36 g NaCl) and simultaneously intake of 23 l of uids daily
Nutrition with a low concentration of carbohydrates; several small meals throughout the day and not one large meal
Light exercises (like isotonic) such as swimming, aerobic training, bicycling or walking without being too stressful
Usage of counter manoeuvres such as squatting or Derby chair
Wearing elastic stockings or an elastic suit
A raised upper body while sleeping (up to 1530 cm)

Medical procedures
Increasing the amount of blood
Fludrocortisone beginning 0.10.2 mg/d; up to a max. of 1 mg/d. CAVE heart insufciency, hypocalcemia, oedema
Erythropoietin 4000 IE s.c. twice a week CAVE satisfactory iron substitution; increase in hematocrit; arterial hypertension
Desmopressin as a nose spray especially with Nyctury. CAVE hyponatriemia, arterial hypertension
Increase the peripheral vasoconstriction
Midodrin three times 2.510 mg/d, up to a max. 40 mg/d; last dosage at 5:00 p.m. CAVE supine hypertension, pruritus
Ephedrine three times 12.525 mg/d. CAVE tachycardia, tremor, supine hypertension
Yohimbine two to three times 8 mg/d p.o. CAVE diarrhea, nervousness, panic attacks
Caffeine 250 mg (= 2 cups of coffee) mornings. CAVE tachyphylaxia
Various
Methylphenidate twice 510 mg/d p.o.; last dosage before 6:00 p.m. CAVE agitation, tremor, sleeplessness
Metoprolol 12.5100 mg/d p.o. or pindolol in the case of bradycardia two to three times 2.550 mg/d p.o. CAVE hypotension, bradycardia, heart insufciency
Clonidine twice 0.10.3 mg/d p.o. or 1 plaster per week. CAVE dry mouth, bradycardia, hypotrophy
Dihydroxyphenylserine (DOPS) twice 250500 mg p.o.; especially for dopamine--hydroxylase deciency

heart disease. Use of udrocortisone can also cause a loss of potas-
sium, so taking a potassium supplement may be necessary. Midodrine
may be taken with udrocortisone to help prevent blood pressure
from falling. Midodrine constricts arterioles, thereby reducing their
capacity to hold blood and increasing resistance to blood ow.
8. Supine hypertension
Alongside orthostatic hypotension, there can be a somewhat
paradox situation called supine hypertension within PD patients
with advanced dysautonomia and especially within MSA patients
[43]. Supine hypertension occurs commonly in chronic autonomic
failure. Goldstein et al. demonstrated that among patients with PD or
MSA, those with orthostatic hypotension had higher mean arterial
pressure during supine rest than did those lacking orthostatic hypo-
tension. In addition to orthostatic hypotension, supine hypertension
is linked to low baroreex-cardiovagal gain which is quite common
in patients with extrapyramidal disease [28]. The nding of lower
plasma norepinephrine levels in patients with than without supine
hypertension suggests involvement of pressor mechanisms indepen-
dent of the sympathetic nervous system.
The presence of orthostatic hypotension has been shown to be a
signicant, independent predictor of all-cause mortality [44]. Systolic
and diastolic orthostatic hypotension, reversal of the circadian
pattern, and postprandial hypotension are some of the hemodynamic
factors that may contribute to the increased mortality seen in patients
with orthostatic hypotension. The high variability of blood pressure in
orthostatic hypotension cannot usually be adequately assessed by a
one-time measurement. In this group of patients, 24-h ambulatory
blood pressure monitoring may be more useful [45]. In Fig. 2, a PD
patient presents with an apparent increase in blood pressure during
the nocturnal phase, whereas, at this time, it usually should decrease.
So in our recent cross-sectional study, we demonstrated that a large
proportion of PD and MSA patients presented with an altered 24-
h blood pressure prole including loss of the nocturnal blood pressure
dip. There are quite good correlations between orthostatic hypoten-
sion, supine hypertension and altered ABPM.
Supine hypertension must be taken into consideration when
treating orthostatic hypotension. This means that the medication for
increasing blood pressure cannot be taken later than 5 pm. It can also
be necessary along with the therapy for increasing the blood pressure
daily to implement a therapy for decreasing the blood pressure noc-
turnally (e.g. clonidine), in order to avoid severe nocturnal increases
in blood pressure. Again for evaluating effects of therapy, we re-
commend repetitive 24-h ABPMs.
9. Cardiovascular effects of antiparkinsonian drugs
The question of whether antiparkinsonian drugs are the cause of
orthostatic hypotension in PD patients or not has been debated for a
long time. One problem is that studies on the effects of levodopa are
quite rare and controversial, since levodopa has variously been
reported as diminishing the HR response and enhancing the fall in
BP as a result of standing up [46,47], other authors were not able to
reproduce this [4749]. Chronic levodopa treatment has not been
shown to cause changes in sympathetic reex mechanisms controlling
blood ow when assessed with the 133-Xenon washout technique
[50], nor has it inuenced the myocardial 6-[18F]; uorodopamine-
derived radioactivity reecting functional sympathetic nerve term-
inals [51].
The use of dopamine receptor agonists as PD medication has been
associated with low resting BP [52] and a pronounced fall in
orthostatic BP [5356]. Although orthostatic hypotension occurred
frequently in PD patients starting dopamine agonist therapy in a
recent study, patients seldom considered it noteworthy, and there
was no relation to the use of a specic dopamine agonist [56]. In a
long-term, prospective, placebo-controlled trial on selegiline, Turkka
et al. demonstrated a slight blockade of sympathetic autonomic
responses [57] whereas others demonstrated an association of sele-
giline medication combined with levodopa with orthostatic hypoten-
sion [39]. Withdrawal of selegiline considerably diminished the fall in
blood pressure during orthostasis.
10. Cardiovagal and baroreex failure
In addition to orthostatic hypotension, we and others have re-
ported about cardiovagal and baroreex dysfunction in PD patients
and patients with atypical Parkinsonian syndromes [13,24,28,58,59].
Whereas sympathetic autonomic dysfunction seems to be a very early
symptom, even before motor symptoms arise, parasympathetic dys-
function seems to occur later in the disease course [33]. From studies
from cardiology and diabetology, we know that the impairment of
 T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 289 (2010) 7480
cardiovagal and baroreex function plays an important adverse role.
Recently, several studies including prospective, randomized, multi-
centre studies like the ATRAMI study in patients after myocardial
infarction have shown that depressed BRS is an independent predictor
for sudden cardiac death and life threatening arrhythmias. As for
patients with diabetes or after myocardial infarction, increased
cardiovascular mortality has been reported in patients with different
extrapyramidal disorders. Here, we would like to state the hypothesis
that cardiovascular autonomic dysfunction can be at least partly
responsible for the increased mortality in patients with extrapyrami-
dal disease. The mortality of PD patients is almost doubled compared
with healthy controls matched in age and sex [60]. Ben-Shlomo and
Marmot demonstrated in a 20-year follow-up study an increase in
heart ischemia related deaths which may account for the increased
mortality [61].
11. Conclusions
Cardiovascular autonomic dysfunction is a common and serious
symptom in patients with extrapyramidal disease. Every patient
should be screened for cardiovascular autonomic dysfunction. Al-
though there are advances in therapy and diagnosis of autonomic
dysfunction, these innovations are usually limited to certain centres
and not to primary care. Because there are still a lot of issues on
cardiovascular autonomic dysfunction unknown especially on the role
of PD medication, large prospective studies are necessary to get more
information on the development of autonomic dysfunction, on auto-
nomic changes over the time of disease, on optimal treatment and on
a potential prognostic role of autonomic dysfunction for patients with
extrapyramidal diseases.
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