A 37-year-old man who is HIV-1-positive has had increasing memory problems for the past year. He is depressed.
During the past 3 months, he has had increasing problems with motor function and is now unable to stand or walk. For the
past 3 days, he has had fever, cough, and dyspnea. A bronchoalveolar lavage shows cysts of Pneumocystis jiroveci. MRI
of the brain shows diffuse cerebral atrophy; no focal lesions are identified. On microscopic examination of the brain, which
of the following findings is most likely to be present?
E. White matter microglial nodules with multinucleate cells
(E) This patient has AIDS dementia complex late in the course of HIV infection. HIV-1 produces an encephalitis that is
characterized by a collection of reactive microglial cells (microglial nodules). HIV-1-infected mononuclear cells, particularly
macrophages, can fuse to form multinucleate cells, which are seen in association with microglial nodules. Plaques of
demyelination are typical of multiple sclerosis. Senile plaques and tangles are typical of Alzheimer disease and are unlikely
to manifest at this patient's age. Lacunar infarcts are small, cavitary infarcts that result from arteriolosclerosis of the deep
penetrating arteries and arterioles. Such arteriolar lesions occur in individuals with long-standing hypertension and are
unlikely to be found in a 37-year-old man. Spongiform change suggests Creutzfeldt-Jakob disease, a rapidly progressive
dementia unrelated to HIV infection.
BP7 829–830BP8 877–878PBD7 1375–1376PBD8 1305
A term infant is born to a 32-year-old woman whose pregnancy was uncomplicated. A newborn physical examination
shows a small lower lumbar skin dimple with a protruding tuft of hair. A radiograph shows that the underlying L4 vertebra
has lack of closure of the posterior arches. What is the most likely diagnosis?
B. Spina bifida occulta
(B) Spina bifida occulta is the mildest form of neural tube defect. It is characterized by defective closure of the vertebral
arches with intact meninges and spinal cord. A radiograph may show its presence in 20% of the population. Dandy-Walker
malformation is detected by ultrasound evidence of a cyst in the fourth ventricle and agenesis of the cerebellar vermis.
Tuberous sclerosis is a rare disease that causes firm hamartomatous “tubers” in the cortex. In an Arnold-Chiari
malformation, there is a small posterior fossa and extension of the cerebellum into the foramen magnum and a lumbar
meningomyelocele. Meningomyeloceles are open neural tube defects.
BP7 821–822BP8 872PBD7 1354PBD8 1284
A 5-year-old boy has been irritable for the past 2 days and has complained of an earache for the past 5 days. On
physical examination, he has a temperature of 39.1°C. Laboratory examination of the CSF from a lumbar puncture shows
numerous neutrophils, slightly increased protein level, and decreased glucose concentration. On Gram staining of the
CSF, which of the following is most likely to be seen microscopically?
B. Gram-positive cocci
(B) This patient has acute bacterial meningitis. In his age group, the most common etiologic organism is now
Streptococcus pneumoniae, a gram-positive coccus. The number of CNS infections with Haemophilus influenzae, a gramnegative
bacillus, in this age group has decreased because of widespread immunization. Pneumococci also are likely to
be seen in an adult. The gram-negative diplococci of Neisseria meningitidis are seen in young adults. The short, grampositive
rods of Listeria monocytogenes appear sporadically or in epidemics caused by food contamination. The gramnegative
bacilli of Escherichia coli are most often seen in neonates. With these clinical and CSF features, it would be
unusual if bacteria were not present in the CSF.
BP7 825–827BP8 874–875PBD7 1369–1370PBD8 1299–1300
A 55-year-old man who had been healthy all his life now has progressive, symmetric muscular weakness. Two years
ago, he noted weakness in the area of the head and neck, which caused difficulty with speech, eye movements, and
swallowing. In the past year, the weakness in the upper and lower extremities has increased, and he can no longer stand,
walk, or feed himself. His mental function remains intact. What is the most likely diagnosis?
A. Amyotrophic lateral sclerosis
(A) The progressive and symmetric nature of this patient's disease is a classic feature of amyotrophic lateral sclerosis
(ALS). The muscles show a denervation type of grouped atrophy from loss of upper motor neurons. The “bulbar” form of
ALS affects mainly cranial nerve nuclei and has a more aggressive course. Huntington disease causes abnormal
movements, not weakness, and there can be associated dementia over time. Mental function is preserved in ALS. The
demyelinating plaques of multiple sclerosis can produce various motor signs and symptoms over time, but symmetry is not
a feature of this disease. Guillain-Barré syndrome usually occurs after a viral infection and manifests as a rapidly
progressive ascending motor weakness. Parkinson disease is characterized by rigidity and involuntary movements, not by
BP7 846BP8 896PBD7 1396–1397PBD8 1324–1325
A neonate is born prematurely at 28 weeks gestation to a 22-year-old primigravida. The infant is initially stable, and a
newborn physical examination shows no abnormalities. The infant becomes severely hypoxemic 24 hours later, and
seizure activity is observed. There is poor neurologic development during infancy. CT scan of the head shows
symmetrically enlarged cerebral ventricles at 8 months of age. Which of the following perinatal complications most likely
produced these findings?
A. Germinal matrix hemorrhage
(A) Germinal matrix hemorrhage is the most common cause of intraventricular hemorrhage in premature infants. The
germinal matrix, composed of highly vascularized tissue with primitive cells, is most prominent between 22 and 30 weeks
of gestation. Hemorrhages within this area readily occur with common neonatal problems such as hypoxemia, hypercarbia,
acidosis, and changes in blood pressure. Hemorrhages in the germinal matrix can extend into the cerebral ventricles and
from there into the subarachnoid space. Smaller hemorrhages can resolve without sequelae. With larger hemorrhages,
organization of the blood in the aqueduct of Sylvius or the fourth ventricle or foramina of Luschka may obstruct the flow of
CSF, producing hydrocephalus. Infants with Down syndrome may have vascular malformations that can bleed into the
parenchyma. The bilirubin staining of kernicterus does not result in scarring. Cytomegalovirus infection can cause
considerable necrosis of the brain parenchyma, but not hemorrhage. Medulloblastomas are tumors that occur in children
(not typically in infants) that could cause obstruction of CSF flow.
BP7 824BP8 873PBD7 1356PBD8 1286
A 79-year-old woman was driving her automobile when she had a sudden, severe headache. She drove to a service
station, stopped the vehicle, and slumped over the wheel. She was taken to the emergency department, where she
remained comatose and died 6 hours later. The gross appearance of the brain at autopsy is shown in the figure. What is
the most likely diagnosis?
D. Rupture of a berry aneurysm
(D) The figure shows an aneurysm in the circle of Willis and extensive subarachnoid hemorrhage. The hemorrhage
occurs at the base of the brain because berry aneurysms involve the circle of Willis and its branches. The vasospasm
caused by the leakage of blood can lead to ischemia, which complicates the course further. A glioblastoma often has
extensive necrosis and some hemorrhage, but the blood remains intraparenchymal. Thromboembolic infarctions can be
hemorrhagic because the embolus does not completely occlude the vessel, but the hemorrhage is localized. Rupture of
bridging veins occurs at the vertex beneath the dura, producing a subdural hematoma. Hypertensive hemorrhages most
often occur in the basal ganglia, the pons, or the cerebellum from rupture of small arteries in hyaline arteriolosclerosis, and
the blood typically remains intraparenchymal.
BP7 816–818BP8 866–867PBD7 1366–1368PBD8 1297–1298
A study is conducted to identify causes of neuronal loss in patients 18 to 90 years old who died in the hospital from a
natural manner of death and who had autopsies performed. Histologic sections are taken from multiple areas of the brain
in each patient. The sections are analyzed for the appearance of red, shrunken neurons, decreased numbers of neurons,
or absent neurons. A subset of patients is identified in which the hippocampal pyramidal cells, the cerebellar Purkinje cells,
and the superior parasagittal neocortical pyramidal cells are affected. The medical records of these patients are reviewed
to determine what risk factors for neuronal loss were present before death. What condition is most likely to be the major
cause of neuronal loss in this subset of patients?
E. Global hypoxia
(E) The neurons that are most sensitive to anoxia reside in the hippocampus, along with the Purkinje cells and the
larger neocortical neurons. In addition, the first areas in the neocortex to be affected are the “watershed” areas between
the three major cerebral circulations, including the watershed located superiorly between the anterior cerebral and middle
cerebral circulations, as in this study. “Red” shrunken neurons, especially in the areas mentioned, are typically seen in the
early stages of global hypoxia, as may occur in a severe hypotensive episode. Focal hypoxia leads to infarcts.
Autoimmunity can lead to vasculitis and subsequent hypoxemia. Chemotherapy tends to damage actively dividing cells
more severely. Diabetes mellitus causes atherosclerosis, which can lead to hypoxemia. HIV infection can produce an
encephalitis, and there can be opportunistic infections of the CNS. Lead poisoning leads to encephalopathy, not ischemia.
Poor nutrition with a deficiency of thiamine (vitamin B1) can lead to Wernicke disease, which affects the mamillary bodies
and periaqueductal gray matter most severely.
BP7 813–814BP8 863–865PBD7 1350–1351PBD8 1291–1292
An 83-year-old woman slips in the bathtub in her home and falls backward, striking her head. She is taken to the
emergency department, where examination shows a 3-cm, reddish, slightly swollen area over the occiput. She is
arousable but somnolent. There are no motor or sensory deficits. There is no papilledema. CT scan of the head is
performed. Acute hemorrhage in which of the following locations is most likely to be seen?
D. Inferior frontal lobe
(D) This patient has the classic “contrecoup” type of injury, in which the moving head strikes an object, and the force is
transmitted to the opposite side of the head. A fall backward is most likely to produce contusions to the inferior frontal
lobes, temporal tips, and inferior temporal lobes. A blow to a stationary head is more likely to produce a “coup” injury
directly adjacent to the site of the blow. Hemorrhage into the pons is typical of a Duret hemorrhage, seen in medial
temporal lobe herniation. Hemorrhage into the cerebral ventricles may occur in premature infants from germinal matrix
hemorrhage; in adults, it is uncommon, but may occur with dissection of blood from an intraparenchymal lesion. A blow to
the side of the head is more likely to lacerate the middle meningeal artery and produce an epidural hematoma. Putaminal
hemorrhage is most likely to occur in hypertension. Subarachnoid hemorrhage at the base of the brain may dissect into the
BP7 819–821BP8 869PBD7 1357–1358PBD8 1287–1288
A 36-year-old woman is involved in a motor vehicle accident. She is not wearing a safety belt and is ejected from the
vehicle. When paramedics arrive, her vital signs are stable with pulse 80/min, respirations 17/min, and blood pressure
125/80 mm Hg. On examination in the emergency department, she has multiple contusions and abrasions over the skin of
her head, torso, and extremities. There is no papilledema, there is no decerebrate posturing, and she has no spontaneous
movements. She is not conscious. CT scan of the head shows no intracranial hemorrhage or edema and no skull
fractures. She remains in a persistent vegetative state. What lesion is most likely to be present in this patient?
C. Diffuse axonal injury
(C) Angular acceleration with torsional forces applied to white matter tracts can cause stretching and tearing of axons,
followed by axonal swelling or “retraction balls” within hours. Acute hydrocephalus requires a blockage of CSF flow, and
there is no mass lesion, hemorrhage, or brain swelling in this case. Herniation requires brain swelling or a large
hemorrhage or a mass that enlarges rapidly. Hypoxic injury is most likely to affect neurons of the hippocampus, Purkinje
cells, and cortical neurons in watershed areas first; the patient's vital signs suggest that this did not occur. Contusions
represent areas of superficial cortical hemorrhage. Central pontine myelinolysis can occur from rapid correction of
BP7 819–821BP8 869PBD7 1358–1359PBD8 1288
A 4-year-old girl developed clumsiness and difficulty ambulating over 6 months. On physical examination, she showed
difficulty with balance while walking, dysarthria, poor hand coordination, absent deep tendon reflexes, and a bilateral
Babinski sign. Light touch and vibratory sensation were greatly diminished. There was no muscular weakness. Over the
next 5 years, she developed congestive heart failure from hypertrophic cardiomyopathy. She also had hyperglycemia. At
autopsy, there was increased perinuclear iron deposition within cardiac myocytes. Which of the following genetic
abnormalities with trinucleotide repeat expansions was most likely present in this patient?
E. GAA repeats in the frataxin gene
(E) She had Friedreich ataxia, an autosomal recessive progressive illness that most often has an onset in the first
decade of life. The frataxin gene encodes for a protein involved in iron regulation in cells. The other options listed have no
cardiac involvement. Mutations of the huntingtin gene are seen with Huntington disease marked by choreoathetosis
beginning in young to middle-aged adults. There are several forms of spinocerebellar ataxia. Increased tandem repeats in
the FMR1 gene account for cases of fragile X syndrome characterized by mental retardation. The dystrophila myotonia–
protein kinase gene is abnormal in cases of myotonic dystrophy with muscular weakness and dementia.
BP8 410, 896PBD8 1323
A 63-year-old man had increasing irritability over 3 years. He spent a lot of time wandering about his neighborhood,
complaining to the neighbors about everything. He had no memory loss and was always able to find his way home. The
neighbors were pleased when he developed aphasia. On physical examination, there were no motor or sensory deficits
and no gait disturbances or tremor. MRI of the brain showed bilateral marked temporal and frontal lobe gyral atrophy. He
died of pneumonia 1 year later. At autopsy, the frontal cortex microscopically shows extensive neuronal loss, and some
remaining neurons show intracytoplasmic, faintly eosinophilic, rounded inclusions that stain immunohistochemically for tau
protein. What is the most likely diagnosis?
F. Pick disease
(F) Pick disease has clinical features similar to the features of Alzheimer disease, but initially it causes less memory
loss and more behavioral changes. The “knifelike” gyral atrophy of frontal and temporal lobes and relative sparing of
parietal and occipital lobes are characteristic of Pick disease. Pick bodies are seen in remaining neurons, but the neuritic
plaques and neurofibrillary tangles seen in Alzheimer disease are not increased. Huntington disease affects mainly the
caudate nuclei and basal ganglia; onset occurs in middle age, and choreiform movements are common. Leigh disease is a mitochondrial encephalomyopathy that can cause muscular weakness and neurologic deterioration beginning at a young
age. Multiple system atrophy (MSA) has features that overlap those of striatonigral degeneration, olivopontocerebellar
atrophy, and Shy-Drager syndrome; most patients with MSA exhibit symptoms similar to those of Parkinson disease. MSA
is characterized microscopically by the appearance of glial cytoplasmic inclusions. In Parkinson disease, loss of pigmented
neurons in the substantia nigra leads to movement problems. Vascular dementia, or multi-infarct dementia, can have
clinical features that mimic those of Alzheimer disease, but there are multiple small infarcts that collectively produce
dementia, and the neurologic decline occurs in a stepwise fashion.
BP7 843–844BP8 891PBD7 1390PBD8 1318
A 20-year-old, mentally retarded woman saw the physician because she had flank pain for 1 week. Physical
examination showed right costovertebral angle tenderness. Patches of leathery-appearing (shagreen patches) and
hypopigmented (ash-leaf patches) skin were scattered over her body. There was a subungual nodule on her right index
finger. Abdominal CT scan showed bilateral renal cysts and tumor masses. MRI of the brain showed subependymal
nodules and 1- to 4-cm cortical foci with loss of the gray-white distinction. CT scan of the chest showed a 3-cm mass
involving the interventricular septum. Two years later, she has sudden, severe headache. MRI now shows a nodule
obstructing the cerebral aqueduct. Neurosurgery is performed, and a subependymal giant-cell astrocytoma is removed.
What is the most likely diagnosis?
E. Tuberous sclerosis
(E) Tuberous sclerosis is one of the phakomatoses—rare inherited disorders in which hamartomas and neoplasms
develop throughout the body, along with cutaneous abnormalities. Patients with tuberous sclerosis have cortical tubers,
which are hamartomas of neuronal and glial tissue; other characteristic findings include renal angiomyolipomas, renal
cysts, subungual fibromas, and cardiac rhabdomyomas. In Down syndrome (trisomy 21), patients may develop acute
leukemia, but not brain neoplasms, and individuals who survive to middle age develop Alzheimer disease. Krabbe disease
is a leukodystrophy that results in deficiency of galactocerebroside β-galactosidase and an onset of neurologic
deterioration in infancy. Neurofibromatosis type 1 is characterized by deforming cutaneous and visceral neurofibromas,
cutaneous café-au-lait spots, and neurofibrosarcomas. In neurofibromatosis type 2, acoustic schwannomas, meningiomas,
gliomas, and ependymomas are present. Von Hippel–Lindau disease is characterized by hemangioblastomas in the
cerebellum, retina, and spinal cord, and by pheochromocytomas.
BP7 821BP8 901PBD7 1413PBD8 1342–1343
A 40-year-old man, who rarely had headaches, now has been experiencing headaches for the past 6 months. He
comes to the physician because of a seizure that occurred 1 day ago. On physical examination, there are no remarkable
findings. MRI of the brain shows a solitary, circumscribed 3-cm mass in the right parietal centrum semiovale. The mass
has small cysts and areas of calcification and hemorrhage. Neurosurgery is performed, and the mass is removed.
Microscopically, the mass consists of sheets of cells with round nuclei that have granular chromatin. The cells have a
moderate amount of clear cytoplasm. These cells mark with GFAP by immunohistochemical staining. The patient receives
adjuvant radiation and chemotherapy, and there is no recurrence. Which of the following neoplasms was most likely
present in this patient?
(G) Oligodendrogliomas tend to have a better prognosis than most other glial neoplasms. Astrocytomas tend to be less
circumscribed. Diffuse large B-cell lymphomas can occur in association with AIDS; they are negative for glial fibrillary
acidic protein (GFAP), but positive for CD19 and CD20. Intracranial germ cell tumors are most likely to arise in the pineal
body. Glioblastomas are highly aggressive, infiltrative gliomas. Medulloblastomas are posterior fossa tumors that occur in
children. Renal cell carcinoma has cells with clear cytoplasm, but it is not positive for GFAP and often produces multiple
metastases. In rare cases, removal of a solitary metastasis of renal cell carcinoma can be beneficial.
BP7 833–834BP8 883–884PBD7 1404PBD8 1333–1334
A 46-year-old woman has had increasing weakness and loss of sensation in the lower extremities for the past 5
months. She comes to the physician because she has been unable to walk without assistance for the past week. On
physical examination, there is 4/5 motor strength in the right lower extremity and 3/5 motor strength in the left lower
extremity. There is bilateral loss of sensation to light touch from the lateral midthigh distally. MRI of the spine shows a 1 ×
4 cm lesion in the filum terminale. The mass is removed. Microscopically, the mass is composed of cuboidal cells around
papillary cores in a myxoid background. Which of the following was most likely present in this patient?
(B) This patient had the myxopapillary variant of ependymoma, which is more common in adults than in children. The
tumors that arise in the ventricles (usually the fourth ventricle) are more common in the first 2 decades of life. Choroid
plexus papillomas are rare tumors that arise in the cerebral ventricles. Meningiomas most often arise in the cranial cavity
and have plump, pink, round to spindle-shaped cells, often with psammoma bodies. Metastases to the spinal cord are
uncommon. Neurofibromas are more likely to arise in peripheral nerves, although in neurofibromatosis type 1, they can
arise in many sites. A pilocytic astrocytoma is a common pediatric primary intracranial neoplasm; it arises in the posterior
fossa. A schwannoma most often occurs in cranial nerve VIII, although neurofibromatosis may be associated with multiple
BP7 834BP8 884PBD7 1405PBD8 1334–1335
A 52-year-old woman has had malaise for the past 6 months. On physical examination, there are no remarkable
findings. Laboratory studies show hemoglobin, 9.3 g/dL; hematocrit, 27.9%; platelet count, 549,000/mm3; and WBC count,
282,000/mm3 with 64% segmented neutrophils, 10% bands, 3% metamyelocytes, 2% myelocytes, 2% lymphocytes, 1%
monocytes, 9% eosinophils, and 9% basophils. She undergoes chemotherapy. Two months later, she develops neurologic
deficits with ataxia, motor weakness in the right arm, difficulty swallowing, and sensory changes in the left leg. MRI of the
brain shows irregular areas of increased attenuation in white matter of the cerebral hemispheres and the cerebellum. A
stereotaxic biopsy specimen shows perivascular chronic inflammation, marked gliosis, large reactive astrocytes with
bizarre nuclei, and intranuclear inclusions within oligodendroglia. What infection most likely caused these findings?
C. JC papovavirus
(C) This patient has progressive multifocal leukoencephalopathy, which is caused by the JC papovavirus and occurs in
immunocompromised individuals, including individuals with AIDS. The patient was treated for chronic myelogenous
leukemia. Cytomegalovirus infection also complicates the course of immunocompromised patients, but it causes large
intranuclear inclusions, most often in endothelial cells. Herpes simplex virus is uncommon, even in immunocompromised
patients, and it most often produces a hemorrhagic encephalitis in temporal lobes. Rabies virus produces CNS excitability
with convulsions, meningismus, and hydrophobia. Subacute sclerosing panencephalitis is a rare complication of measles
(rubeola) virus infection and leads to progressive mental decline, spasticity, and seizures. West Nile virus, similar to many
arboviruses, can cause a meningoencephalitis.
BP7 830BP8 878–879PBD7 1376–1377PBD8 1305–1306
A 39-year-old man who has been HIV-positive for at least 8 years has received no antiretroviral therapy. He has had
left-sided weakness for the past month. He sees the physician 1 day after experiencing a generalized seizure. On physical
examination, he is afebrile. There is 4/5 motor strength in the left upper extremity. CT scan of the head shows no
intracranial hemorrhage, but there is a midline shift. MRI of the brain shows a 4-cm mass in the region of the putamen near
the right internal capsule, a 3-cm mass in the right centrum semiovale, and a 1-cm mass near the splenium of the corpus
callosum. These masses are circumscribed and solid. CSF from a lumbar puncture shows an elevated protein
concentration and a normal glucose level. Cytologic examination shows large cells with large nuclei and scant cytoplasm
that mark with CD19, but not with GFAP or cytokeratin. What is the most likely diagnosis?
D. Large B-cell lymphoma
(D) Non-Hodgkin lymphomas, including large B-cell lymphomas, are uncommon in the brain, but they may be seen in
immunocompromised patients, particularly patients with AIDS. They tend to be multifocal. Cytomegalovirus infection is
common in AIDS, but it is unlikely to produce mass lesions. A glioblastoma multiforme can be a large infiltrative and
destructive mass, but the cells are typically GFAP positive and CD19 negative. Kaposi sarcoma can occur in association
with HIV infection, but CNS involvement is rare, and the cells are CD34 positive. Progressive multifocal
leukoencephalopathy produces granular white matter lesions with large, bizarre oligodendrocytes infected with JC
papovavirus. Toxoplasmosis can produce multiple mass lesions, but they are chronic abscesses that are filled with necrotic material and surrounded by gliosis; Toxoplasma pseudocysts may be found in the abscesses.
BP7 835BP8 885PBD7 1408PBD8 1337
A 60-year-old woman had problems related to movement for 5 years. Physical examination showed cogwheel rigidity of
limbs and a festinating gait, which she had difficulty initiating. Her face was expressionless. She was given levodopa, and
her condition improved. Two years later, she had difficulty performing activities of daily living and showed marked
cognitive decline. She died of aspiration pneumonia. Autopsy findings include mild cerebral atrophy and loss of substantia
nigra pigmentation. Microscopically, there is loss of pigmented neurons, and the remaining substantia nigra neurons and
cortical neurons show spheroidal, intraneuronal, cytoplasmic, and eosinophilic inclusions. Immunohistochemical staining
for which of the following proteins is most likely to be positive in these inclusions?
(A) This patient has findings of dementia with Lewy bodies (DLB), a form of dementia with clinical features similar to
those of Alzheimer disease and idiopathic Parkinson disease. Mutations in the gene for α-synuclein have been linked to
idiopathic Parkinson disease, and Lewy bodies can be found in the substantia nigra neurons, but the clinical dementia and
cortical Lewy bodies point to DLB. Amyloid precursor protein is encoded by a gene on chromosome 21 (perhaps
explaining early Alzheimer disease in trisomy 21) and is processed to form the Aβ amyloid of neuritic plaques in Alzheimer
disease. The e4 allele of apolipoprotein E can bind Aβ and increase the risk of Alzheimer disease. Huntingtin is the protein
product of the HD gene in Huntington disease. Presenilin 1 and 2 mutations can increase production of Aβ and increase
the risk of early-onset Alzheimer disease. Tau protein is found in neurofibrillary tangles of Alzheimer disease and in Pick
bodies of Pick disease.
BP7 844BP8 891, 895PBD7 1386, 1392PBD8 1321–1322
A 70-year-old woman comes to the physician because of an episode 2 days earlier during which she lost
consciousness for several minutes. Afterward, she had difficulty speaking clearly and had paresthesias in the lower right
arm that persisted for several minutes. On physical examination, there is 4/5 motor strength in the right upper extremity
and decreased sensation to pinprick on the ulnar aspect of the lower right arm and hand. There are bilateral carotid bruits.
A lumbar puncture is performed with normal opening pressure. Laboratory studies on 10 mL of clear, colorless CSF show
two mononuclear WBCs/mm3, no RBCs, protein concentration of 40 mg/dL, and glucose concentration of 70 mg/dL. The
serum glucose concentration is 95 mg/dL. CT scan of the head shows no intracranial hemorrhage, but there is a slight
midline shift; MRI of the brain shows an ill-defined area of edema near the left internal capsule. Which of the following
laboratory findings is most suggestive of the risk factor for this patient's disease?
(E) This patient has findings consistent with an acute cerebral infarction from obstruction of blood flow causing focal
cerebral ischemia. After 2 days, there would be some cerebral softening and edema with ischemia of neurons, but little
else. Hypercholesterolemia is a risk factor for atherosclerosis, which is the major cause of thrombotic cerebral arterial
occlusions. The antiphospholipid syndrome can produce thrombotic and embolic disease, but an embolic “stroke” is
typically hemorrhagic, and antiphospholipid syndrome is uncommon at this age. A positive blood culture suggests sepsis
with the possibility of meningitis or cerebral abscess formation, but abscesses typically have ring enhancement on CT
scans. Elevated serum levels of very long chain fatty acids are present in patients with adrenoleukodystrophy, a rare
disorder that leads to myelin loss at an early age. Hyperammonemia occurs in hepatic encephalopathy with liver failure; it
produces Alzheimer type II gliosis, but no focal or gross lesions. Oligoclonal bands are characteristic of multiple sclerosis,
which typically has an onset in youth or middle age, with formation of plaques of demyelination in white matter. The ANA
test result is positive in many autoimmune diseases and may be accompanied by vasculitis, which can produce scattered
areas of ischemic injury, resulting in a clinical picture of encephalopathy. Neurosyphilis is now rare; it does not produce
focal ischemic lesions.
BP7 814–815BP8 863–865PBD7 1361–1365PBD8 1292–1295
A 15-year-old girl is brought to the physician because she has had progressive difficulty speaking during the past 6
months. She becomes dizzy and falls frequently. She complains of headache and facial and neck pain. During the past
month, she has had decreasing bladder and bowel control. On physical examination, there is loss of pain and temperature
sensation over the nape of the neck, shoulders, and upper arms, but vibration and position sensation are preserved. She
has muscle wasting in the lower neck and shoulders. MRI of the spinal cord shows cervical and thoracic enlargement with
a CSF collection dilating the central canal. MRI of the brain shows gross findings similar to those shown in the figure.
Which of the following is the most likely diagnosis?
A. Arnold-Chiari II malformation
(A) This patient has an Arnold-Chiari II malformation, which results in a small posterior fossa, misshapen midline
cerebellum with downward displacement of the vermis, and tenting of the tectal plate. MRI in this case is characteristic of
hydromyelia. Cerebral palsy is a general term describing nonprogressive motor deficits that are present from birth. Dandy-
Walker malformation includes hypoplasia or absence of the cerebellar vermis and cystic enlargement of the posterior
fossa. Holoprosencephaly is a severe malformation with total (alobar) or incomplete (semilobar) separation of the cerebral
hemispheres in brain development. Multiple sclerosis results in white matter plaques of demyelination, not malformation.
Polymicrogyria is characterized by numerous, small, irregularly formed gyral contours.
BP7 823BP8 872PBD7 1355–1356PBD8 1285–1286
An infant was born at 36 weeks' gestation to a 22-year-old primigravida. A fetal screening ultrasound study at 18 weeks
showed a single large cerebral ventricle and fused thalami. On physical examination at birth, the infant was small for
gestational age and had multiple anomalies, including postaxial polydactyly of hands and feet, cyclopia, microcephaly, cleft
lip and palate, and rocker-bottom feet. The infant died 1 hour after birth. Which of the following CNS abnormalities best
explains these findings?
(D) Holoprosencephaly is a midline defect in which there is absent (alobar) or partial (semilobar) cerebral hemispheric
development. It can occur in trisomy 13, as in this case, with other midline defects. It also may be seen in cases of
maternal diabetes mellitus. Anencephaly is the absence of a fetal cranial vault, which leads to absence of most of the
brain. Arnold-Chiari II malformation results in a small posterior fossa, a misshapen midline cerebellum with downward
displacement of the vermis, and tenting of the tectal plate. Dandy-Walker malformation is characterized by aplasia or
hypoplasia of the cerebellar vermis, cystic enlargement of the fourth ventricle, and hydrocephalus. Periventricular
leukomalacia is a form of perinatal injury that is caused by hypoxic-ischemic events or infections. A subdural hematoma
results from trauma.
BP7 823BP8 872PBD7 1355PBD8 1285
An 86-year-old man has become progressively unable to live independently for the past 10 years, and he now requires
assistance with bathing, dressing, toileting, feeding, and transfers in and out of chairs and bed. On physical examination,
he has no motor or sensory deficits. He cannot give the current date or state where he is. Six months later, he suddenly
becomes comatose and dies. At autopsy, there is a large superficial left parietal lobe hemorrhage. Histologic examination
of the brain shows numerous neocortical neuritic plaques and neurofibrillary tangles. The peripheral cerebral arteries and
the core of each plaque stain positively with Congo red. Which of the following mechanisms is most likely responsible for
A. Aggregation of Aβ peptide
(A) This patient had Alzheimer disease (AD) complicated by cerebral amyloid angiopathy and terminal hemorrhagic
stroke. Formation and aggregation of the Aβ peptide is now considered central to the pathogenesis of AD. Aβ peptide is
derived from abnormal processing of amyloid precursor protein (APP). When APP, a transmembrane protein, is cleaved by
α-secretase within the Aβ sequence, followed by γ-secretases, a soluble nontoxic fragment is formed. Cleavage of the Aβ
sequence by β-secretase and then γ-secretase gives rise to Aβ peptides that aggregate and form the amyloid cores that
elicit a microglial and astrocytic response to form neuritic plaques. Conformational change in prion protein leads to
Creutzfeldt-Jakob disease, a rapidly progressive dementia with spongiform encephalopathy but not neuritic plaques or
amyloid deposition. Although abnormally phosphorylated forms of tau protein are found in neurofibrillary tangles seen in AD, there is no mutation of the tau gene, and the tangles are not considered primary in the pathogenesis of AD. Mutation
of the tau gene leads to frontotemporal dementia with parkinsonism. Mutations in the frataxin gene lead to Friedreich
ataxia, an autosomal recessive progressive illness, generally beginning in the first decade of life. Loss of dopaminergic
neurons with deficiency of dopamine is central to the pathogenesis of Parkinson disease. Expansion of polyglutamine
repeats owing to CAG trinucleotide repeat-expansion underlies Huntington disease.
BP7 841–843BP8 891–893PBD7 1386–1389PBD8 1313–1317
A 55-year-old man has experienced headaches for the first time in his life beginning 2 months ago. He comes to the
emergency department following a generalized tonic-clonic seizure. MR imaging of his brain shows an ill-defined 2 cm
mass in the right posterior parietal cortex. A stereotaxic biopsy of the mass microscopically shows pleomorphic cells
positive for glial fibrillary acidic protein (GFAP). Molecular analysis shows abnormalities of p53 and platelet-derived growth
factor-alpha (PDGF-α). He receives treatment for this lesion. Which of the following neoplasms is he most likely to develop
in the future?
(B) He initially had an infiltrating astrocytoma that is the most common primary brain neoplasm in adults, typically
arising in a cerebral hemisphere. Lower grade astrocytomas in adults may have a more indolent course. Some of these
patients go on to develop a high-grade glioma known as “secondary” glioblastoma. Most glioblastomas arise de novo
(“primary glioblastoma”) and have MDM2 mutations. Regardless of origin, glioblastomas are aggressive and have a poor
prognosis. Diffuse large B cell lymphoma is the most common type of “primary” CNS lymphoma (without evidence for
disease elsewhere); some arise in immunocompromised patients. Hemangioblastomas are uncommon neoplasms arising
in the cerebellum, often with von Hippel-Lindau disease, and associated with polycythemia. Medulloblastomas and
pilocytic astrocytomas are usually childhood brain tumors arising in the posterior fossa.
BP7 832–833BP8 882PBD7 1401–1403PBD8 1330–1332