Pharm1Cv2aaPrtstPath

A male neonate is noted at birth to have paralysis of the lower

limbs. The infant fails to thrive and expires. The brainstem

and cerebellum are examined at autopsy (shown in the image).

What is the diagnosis?

A) Anencephaly
(B) Arnold-Chiari malformation
(C) Holoprosencephaly
(D) Hydromyelia
(E) Lissencephaly

female neonate is noted to have a pronounced enlargement

of her head (shown in the image). She develops convulsions.
MRI reveals excessive accumulation of cerebrospinal fl uid,
ventricular enlargement, and atrophy of the cerebral cortex.
This developmental birth defect was most likely caused by
which of the following mechanisms of disease?
(A) Atresia of the aqueduct of Sylvius
(B) Birth trauma
(C) Congenital brain tumor
(D) Maternal folate defi ciency
6 A 3-year-old girl who has been mentally retarded since birth
is killed in a drowning accident. The superior surface of the
brain at autopsy is shown in the image. What is the diagnosis
for this gross deformity of the brain?
(A) Arrhinencephaly
(B) Holoprosencephaly
(C) Lissencephaly
(D) Pachygyria
(E) Polymicrogyria

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3 The answer is B: Arnold-Chiari malformation. Arnold-Chiari
malformation is a condition in which the brainstem and cerebellum
are compacted into a shallow, bowl-shaped posterior
fossa with a low-positioned tentorium. The cerebellar vermis
is herniated below the level of the foramen magnum in the
photograph shown. Anencephaly (choice A) refers to the congenital
absence of all or part of the brain. Holoprosencephaly
(choice C) is a microcephalic brain in which the interhemispheric
fi ssure is absent. Hydromyelia (choice D) is the term
for dilation of the central canal of the spinal cord.
Diagnosis: Arnold-Chiari malformation
4 The answer is A: Atresia of the aqueduct of Sylvius. Congenital
hydrocephalus refers to an excessive amount of CSF and
ventricular enlargement. Congenital atresia of the aqueduct of
Sylvius is the most common cause of congenital hydrocephalus,
occurring in 1 in 1,000 live births. Histologic examination
of the midbrain may disclose multiple atretic channels
or an aqueduct narrowed by gliosis. Congenital brain tumors
(choice C) are rare. The other choices are not associated with
congenital hydrocephalus. Because the infantile cranium
expands easily, symptoms of increased intracranial pressure
are generally absent. However, convulsions are common, and
optic atrophy with blindness can occur.
Diagnosis: Hydrocephalus

6 The answer is E: Polymicrogyria. Abnormalities of the cerebral

gyri are frequently associated with mental retardation. Polymicrogyria
is a congenital disorder in which the surface of the
brain exhibits an excessive number of small, irregularly sized,
randomly distributed gyral folds. Arrhinencephaly (choice A)
refers to absence of the olfactory tracts. Lissencephaly (choice
C) is a congenital disorder in which the cortical surface of
the cerebral hemispheres is smooth or has imperfectly formed
gyri. Pachygyria (choice D) is a condition in which the gyri are
reduced in number and usually broad.

7The answer is C: Chromosomal abnormality. Congenital

defects of the CNS are often associated with chromosomal
abnormalities, which are best exemplifi ed by trisomies of
chromosomes 13 to 15 (holoprosencephaly) and chromosome
21 (Down syndrome). Holoprosencephaly refers to a microcephalic
brain in which the interhemispheric fi ssure is absent.
The horseshoe-shaped cerebral hemispheres have fused frontal
poles, across which the gyri show an irregular horizontal
orientation. Holoprosencephaly is rarely compatible with life
beyond a few weeks or months. All of the other choices are
acquired disorders that do not affect gross brain morphology.
Diagnosis: Holoprosencephaly

10 The answer is E: APrP. The brain biopsy shows spongiform

degeneration of the gray matter, characterized by individual
and clustered vacuoles, with no evidence of infl ammation.
Prion diseases are recognized clinically by slowly progressive
ataxia and dementia and pathologically by the accumulation of
fi brillar or insoluble prion proteins, degeneration of neurons,
and vacuolization (spongiform degeneration). Spongiform
encephalopathies are transmissible, and inadvertent human
transmission of Creutzfeldt-Jakob disease (CJD) has followed
the administration of contaminated human pituitary growth
hormone, corneal transplantation from a diseased donor,
insuffi ciently sterilized cal implantation of contaminated dura. APrP amyloid is found
in patients with spongiform encephalopathies. Prion proteins
(PrPs) are natural plasma membrane constituents found in
a variety of cells, including the central nervous system. The
residual PrP, now in an altered conformation, may serve as
a template for the association of additional PrP molecules.
In so doing, they confer the new PrP conformation (PrP sc).
Such altered PrP and its aggregates form fi brils with the characteristic
of amyloid and are believed to play a role in a group
of human and animal degenerative diseases of the central
nervous system, such as kuru, CJD, Gerstmann-Straussler-
Sheinker disease, scrapie, and bovine spongiform encephalopathy
(mad cow disease). The other forms of amyloid are not
associated with spongiform encephalopathies.
Diagnosis: Creutzfeldt-Jakob disease, spongiform encephalopathy
17 The answer is A: Astrogliosis. Multiple sclerosis is punctuated
by abrupt and brief episodes of clinical progression interspersed with periods of relative stability. Each exacerbation
refl ects the formation of additional demyelinated
plaques. Plaques of demyelinated white matter are typically
found around the lateral ventricles of the cerebrum, in the
cerebellum, and in the spinal cord. End-stage lesions feature
astrogliosis, thick-walled blood vessels, moderate perivascular
infl ammation, and a secondary loss of axons. Lewy bodies
(choice B) are features of Parkinson disease. Negri bodies
(choice C) are encountered in rabies. Neurofi brillary tangles
(choice D) are features of Alzheimer disease. Whorled “myelin
fi gures” (choice E) represent lysosomal storage of unmetabolized
gangliosides in the neurons of patients with Tay-Sachs
disease.
Diagnosis: Multiple sclerosis

19 The answer is D: a-Synuclein. Parkinson disease (PD) is a

common movement disorder characterized pathologically by
the loss of neurons, primarily in the substantia nigra, and the
accumulation of eosinophilic inclusions termed Lewy bodies,
formed by fi lamentous aggregates of a-synuclein. Accumulating
evidence suggests that oxidative stress produced by the
auto-oxidation of catecholamines during melanin formation
injures pigmented neurons in the substantia nigra by promoting
the misfolding of a-synuclein. Clinically, PD features
tremors at rest, muscular rigidity, expressionless countenance,
emotional liability, and, less commonly, cognitive impairments,
including dementia late in the disease course. The
other choices are not characterized by demarcated inclusions
within neurons of the substantia nigra.
Diagnosis: Parkinson disease

21

The answer is D: Reduced levels of dopamine. The substantia

nigra is a component of the extrapyramidal system that
relays information to the basal ganglia through dopaminergic

synapses. Normal aging is associated with a loss of neurons

in the substantia nigra and reduced levels of dopamine, but
these features are more exaggerated in patients with Parkinson
disease (PD). Degeneration in the pars compacta of the substantia
nigra is characterized by macroscopic nigral pallor,
microscopic loss of pigmented neurons, pigment granules
found extracellularly or within macrophages, gliosis, and, in
some surviving neurons, cytoplasmic inclusions that have an
eosinophilic core surrounded by a clear halo (Lewy bodies).
The vast majority of cases of Parkinson disease are idiopathic,
but the disease has been recorded after viral encephalitis (von
Economo encephalitis) and after intake of the toxic chemical
methyl-phenyl-tetrahydropyridine. None of the other choices
refl ects damage to the substantia nigra.
Diagnosis: Parkinson disease

25 The answer is D: Transtentorial herniation. Head trauma can

cause extensive intracranial hemorrhage and cerebral edema.
After compensatory mechanisms have been exhausted, the
brain is shifted laterally away from the side of the lesion. The
medial temporal lobe on the side of the hematoma is compressed
against the midbrain to displace it downward through
the opening created by the tentorium, a fatal event known as
transtentorial herniation. Thus, the oculomotor nerve may be
compressed against the edge of the tentorium, causing thirdnerve
palsy. The pupil, generally on the side of the lesion,
becomes fi xed and dilated. The herniated uncus also compresses
the vasculature of the midbrain, especially the mesencephalic
veins. Venous stagnation in the midbrain causes
further hypoxia and impairs neuronal function. Choices B and
E are related to global anoxia. Diffuse axonal shearing (choice
A) is a microscopic diagnosis.
Diagnosis: Transtentorial herniation

29 The answer is C: Gliosis. Astrocytes are star-shaped glial cells

that far outnumber neurons throughout the CNS. Astrocytes
proliferate locally in response to injuries (e.g., trauma, abscess,
tumors, infarcts, and hemorrhages). This process, referred to
as astrocytosis or gliosis, is readily demonstrated by immunostaining
for glial fi brillary acidic protein (shown in photomicrograph).
Astrocytosis evolves in hours to days and persists to
an extent that is usually commensurate with the severity of the
initiating injury. The result is a “glial scar” composed of reactive
astrocytes and their processes. Neuronophagia (choice E)
is a function of microglia.
Diagnosis: Astrogliosis

35 The answer is C: Escherichia coli. E. coli is the prime cause of

meningitis in the newborn, whose resistance to Gram-negative
bacteria has not fully developed. The transplacental transfer of
maternal IgG imparts protection to the newborn against many
bacteria, but E. coli requires IgM for neutralization. At autopsy,
the brain shows a creamy exudate in the leptomeninges (see
photograph). Choices A and B do not lead to meningitis.
Haemophilus infl uenzae (choice D) and Neisseria meningitides
(choice E) cause meningitis at a later age.
Diagnosis: Bacterial meningitis

40 The answer is B: Cryptococcus neoformans. Cryptococcal

meningitis is an indolent infection in which the virulence of
the causative agent marginally exceeds the resistance of the
host. In most cases, it acts opportunistically in immunocompromised
persons (e.g., patients who have AIDS). The organisms
vary in size from 5 to 15 mm in diameter and reproduce
by budding. When a drop of contaminated CSF is mixed with
India ink, microscopic examination shows a clear halo about
the encapsulated organism. The tissue response to C. neoformans
in the meninges is typically sparse. The other choices are
not typical CNS infections in patients with AIDS.
Diagnosis: Cryptococcal meningitis

47 The answer is B: Alcoholism. Central pontine myelinolysis is

a rare demyelinating disorder that features selective demyelination
in the pons. The lesions are often too small to have
clinical manifestations and are discovered only at autopsy.
However, some patients develop quadriparesis, pseudobulbar
palsy, or severe depression of consciousness (pseudocoma).
Central pontine myelinolysis is thought to arise from overly
rapid correction of hyponatremia in alcoholics or malnourished
persons. Demyelination in patients with multiple sclerosis
(choice D) is preferentially located in other parts of the
brain.
Diagnosis: Central pontine myelinosis

52 The answer is C: Middle cerebral artery. The diversity of the

neurologic defi cits caused by stroke directly refl ects the consequences
of occluding different cerebral vessels. For example,
the lengthy and slender striate arteries, which take origin from
the proximal middle cerebral artery, are commonly occluded
by atherosclerosis and thrombosis. The resultant infarct often
transects the internal capsule and produces hemiparesis or
hemiplegia. The trifurcation of the middle cerebral artery is
a favored site for lodgment of emboli and for thrombosis secondary
to atherosclerotic damage. Occlusion of the middle
cerebral artery at this site deprives the parietal cortex of circulation
and produces motor and sensory defi cits. When the
dominant hemisphere is involved, these lesions are commonly
accompanied by aphasia. Occlusion of the vertebral artery
(choice E) results in infarcts of the cerebellum

Diagnosis: Cerebral infarction

53 The answer is D: Thrombosis. Aneurysms caused by atherosclerosis

are localized mainly in major cerebral arteries (vertebral,
basilar, and internal carotid), which are favored sites of
atherosclerosis. Fibrous replacement of the media and destruction
of the internal elastic membrane weakens the arterial wall
and causes aneurysmal dilation. Although hemorrhage (choice
B) and dissection (choice A) may occur, the major complication
of an atherosclerotic aneurysm is thrombosis.
Diagnosis: Atherosclerotic aneurysm

61 The answer is A: Aqueduct of Sylvius. Hydrocephalus refers to

dilation of the ventricles by accumulated CSF. When obstruction
to the fl ow of CSF in the brain is within the ventricles,
hydrocephalus is designated “noncommunicating.” In noncommunicating
hydrocephalus, the fl ow of CSF through the
ventricular system may be obstructed at the aqueduct of Sylvius
by congenital malformations, neoplasms (as in this case),
infl ammation, or hemorrhage. The mass of an intracranial
neoplasm, combined with edema or hydrocephalus, causes
increased intracranial pressure, which leads to headaches and

vomiting. Choices C and D connect the 4th ventricle with the

subarachnoid space and are the primary routes for escape of
CSF into the posterior cerebellomedullary cistern (cisterna
magna). Virchow-Robin spaces (choice E) surround blood
vessels as they enter the brain.
Diagnosis: Hydrocephalus

67 The answer is D: Glioblastoma multiforme. Glioblastoma

multiforme is a brain tumor composed of malignant astroglial
cells, which show marked pleomorphism and are often multinucleated.
Because of their invasive properties and vascular
changes (“arteritic obliteration”), the tumors feature patchy
yellow areas of necrosis and red zones of hemorrhage. The
term multiforme derives from the variegated gross appearance
of these tumors and the histologic pleomorphism of
the tumor cells. The other choices do not display the characteristic
palisading of tumor cells around necrotic areas (see
photomicrograph).
Diagnosis: Glioblastoma multiforme
68 The answer is A: Astrocytes. Unlike the

68 The answer is A: Astrocytes. Unlike the other choices,

glioblastoma multiforme can invade the contralateral hemisphere
across the corpus callosum and present as a bilateral
“butterfl y-like” lesion. None of the other cells contribute to
glioblastoma multiforme.
Diagnosis: Glioblastoma multiforme
69 The answer is B: Ependymoma. Ependymoma originates
in the lining of the cavities that contain cerebrospinal fl uid.
The tumor is most common in the fourth ventricle, where
it produces obstruction and results in hydrocephalus. The
cells of an ependymoma characteristically have an “epithelial”
appearance, similar to that of normal ependymal cells. They
may arrange around blood vessels forming perivascular pseudorosettes.
Ependymomas may also originate from the lining
of the central canal of the spinal cord and the fi lum terminale.
Together with astrocytomas (choice A), ependymomas are the
most common neoplasms of the spinal cord. Because of their
central location, they cannot be easily resected.
Diagnosis: Ependymoma
70 The answer is D: Meningioma. Meningiomas are benign
intracranial tumors that arise from the arachnoid villi and
produce symptoms by compressing adjacent brain tissue.
They account for almost 20% of all primary intracranial neoplasms.
Meningiomas occur at almost any intracranial site
but are most common in parasagittal regions of the cerebral
hemispheres, the olfactory groove, and the lateral wing. On gross examination, most meningiomas appear as
well-circumscribed, fi rm, bosselated masses of variable size.
The histologic hallmark of meningiomas is a whorled pattern
of “meningothelial” cells (see photomicrograph). The
indolent growth of meningiomas enables them to enlarge
slowly for years before becoming symptomatic, during which
time they displace the brain but do not infi ltrate it. Although
benign, meningiomas have a propensity to erode contiguous
bone. Choices A, C, and E are malignant bone tumors.
Choice B (hemangioblastoma) is characterized by vascular
proliferation.
Diagnosis: Meningioma

71 The answer is C: Nasopharynx. Craniopharyngiomas are solid

and cystic lesions located above the sella turcica that arise
from the epithelium of Rathke pouch. This structure is a part
of the embryonic nasopharynx that migrates cephalad and
gives origin to the anterior lobe of the hypophysis. Some cystic
lesions are lined by squamous epithelium, whereas others,
referred to as adamantinomas, are solid and resemble tumors
of dentigerous origin. Neoplasms derived from ectopic tissues
compress adjacent structures. Craniopharyngiomas generally
become symptomatic in the fi rst two decades of life, creating
visual defi cits and headaches. They may cause pituitary
failure, including diabetes insipidus. Choices A, B, and D represent
neural structures. The third pharyngeal arch (choice E)
is distal to the nasopharynx and gives rise to the thymus and
parathyroid glands.
Diagnosis: Craniopharyngioma

74 The answer is E: Oligodendroglioma. Oligodendrogliomas

arise in the white matter and grow slowly. They occur predominantly
in the white matter of the cerebral hemispheres of
adults. Histologically, the tumors have small rounded nuclei
similar to normal oligodendrocytes, but they also exhibit

increased cell density and cellular pleomorphism. Calcospherites,

which may be visualized radiographically, are occasionally
scattered randomly throughout the lesion. The other choices
do not feature uniform monomorphic cells.
Diagnosis: Oligodendroglioma

76 The answer is C: Neuritic plaques. Microscopic changes in

Alzheimer disease are dominated by the presence of senile
(neuritic) plaques, neurofi brillary tangles, and neuron loss. In
end-stage disease, neuritic plaques converge to occupy large
volumes of the cerebral gray matter. The plaques are positive
for Congo red and exhibit immunoreactivity for Ab at the core
and periphery. Neurofi brillary tangles are formed by large intracytoplasmic
masses of tau fi laments. Remarkably, most cases of
Alzheimer disease are also associated with Lewy bodies. Thus,
Alzheimer disease features a “triple” brain amyloidosis, owing to
accumulations of fi lamentous tau, Ab, and a-synuclein. Granulovacuolar
degeneration (choice A), Lewy bodies (choice B),
and neurofi brillary tangles (choice D) are all seen in the brains
of patients with Alzheimer disease, however, these lesions are
not evident in the slide that accompanies this case (see photomicrograph).
Spongiform encephalopathy (clustered vacuoles
within the gray matter, choice E) is featured in prion disease.
Diagnosis: Alzheimer disease