Neuropathology Case Studies

OBJECTIVES:The following cases are designed to illustrate the clinical presentations, pathological
changes, and treatment of common neurological diseases. This session will familiarize you with the
differential diagnoses in each clinical setting.

CASE 1: Hypertensive haemorrhage

Clinical History:

This 61-year-old man, who has a long history of alcohol abuse, was sitting on a bar stool when he was
noted to suddenly fall to the floor. He was unable to arise and the paramedics were called. When they
arrived, he was able to answer questions and he stated that he had a severe headache. Upon arrival
to the hospital the admitting physical examination demonstrated a right hemiparesis. The patient
became increasingly somnolent after admission.
Further history:
In spite of supportive care, the patient became comatose and died two hours after admission.

Image 1.1:
This is a CT scan of the patient's head upon admission. 

What is the probable diagnosis?

The scan shows a large hematoma in the deep basal ganglia on the left with shift of the brain to the
right, occlusion of the Foramen of Monro, and enlarged lateral ventricles on the right. This represents
an intraparenchymal bleed most likely due to long standing hypertension, although a vascular
malformation could have caused a picture similar to this one. Hypertensive hemorrhages are most
common in basal ganglia, but may also be seen in pons and cerebellum.

Image 1.2:
This is a coronal section of the brain and midbrain at autopsy. What is the mechanism of death in this
case?
The coronal section of the hemispheres demonstrates a large hematoma in the basal ganglia on the
left which has pushed the brain to the right. The left medial temporal lobe has been pushed medially
and has caused a Duret hemorrhage in the midbrain (from uncal herniation and damage to the small
perforating arteries supplying midbrain and pons). The bleeding into the brainstem caused death.

Answers:

What are possible causes of this acute incident?

There are several possibilities. Because of the acuteness of the symptoms, one should think of a
vascular problem, either due to trauma or to underlying vessel disease. This man could have suffered
a skull fracture and epidural hemorrhage upon hitting the floor. Embolic stroke, hypertensive bleed
(from long-standing hypertension), or bleed from a vascular malformation are all possible. Bleeding
into a tumor is another possibility.

What treatment could have prevented this event?

Treatment of hypertension with use of antihypertensive medications will produce a marked reduction
in the incidence of hypertensive bleeds in the brain. It is important to do blood pressure screening for
hypertension. Hypertension remains a "silent disease" for years, and patients do not know they have
it, before enough organ damage occurs to produce clinical signs and symptoms. Hypertensive bleeds
of the brain are a major cause of "stroke" that is the third most common cause of death.

The treatment of hypertension depends upon a variety of parameters, including the severity of the
hypertension and the presence of other diseases. Persons with "high normal" pressures from 140-
159/90-99 mm Hg can be followed to determine if the presence of organ damage or diabetes mellitus
warrants pharmacologic therapy. Dietary modifications (reduction in salt intake) and exercise
regimens with promotion of lifestyle modifications (stop smoking, lose weight) and having a pet (dog
or cat) can aid in normalizing blood pressures in this range.

Persons with pressures above 160/100 mm Hg require drug therapy. Initial therapy typically consists
of diuretics and/or beta-adrenergic blockers.

Diuretics aid in sodium excretion to reduce intravascular volume. The most common diuretics block
sodium reabsorption and include the thiazides which act in the distal convoluted tubule, such as
hydrochlorothiazide, and the loop diuretics, such as furosemide that act in the loop of Henle.

The beta blockers work by competitive inhibition of the effects of catecholamines on beta-adrenergic
receptors. They can be cardioselective with primarilty beta-1 blocking effects, such as metoprolol, or
non-selective with action on beta-2 receptors as well, such as propranolol.
Beta blockers are indicated for persons who have had a myocardial infarction. Such persons who
cannot tolerate beta blockers may benefit from a calcium channel blocker such as diltiazem that
causes arteriolar dilation.
For persons with congestive heart failure or with diabetic nephropathy, the angiotensin converting
enzyme (ACE) inhibitors such as captopril, are recommended. Angiotensin-II receptor blockers, such
as losartan, may be used in persons who cannot tolerate the ACE inhibitors.

Much higher blood pressures, or malignant hypertension, require more aggressive therapies, such as
sodium nitroprusside which is a potent direct vasodilator.

Is there any treatment after the event occurs?

Evacuation of the blood from a hypertensive bleed in this location is rarely helpful. Hypertensive
bleeds into the cerebellum can be life saving, if evacuation is performed before tonsillar herniation
and brainstem compression.

CASE 2: Acute bacterial meningitis   

Clinical History:
This 81-year-old man was in good health until developing a cough with the production of yellow
sputum. He complained to his relatives of a headache the day before admission. He was found
stuporous by his son on the day of admission. In the emergency room, the physical examination
demonstrated an elderly man who was not responding very well to questions. His temperature was
99.7 degrees F, respirations 16, pulse 100 and weak, and blood pressure 110/50. His neck was stiff. A
lumbar puncture revealed cloudy cerebrospinal fluid with a marked pleocytosis with 1500 WBC's (90%
of them PMN's), no RBC's, glucose of 31 mg/dL, and protein of 60 mg/dL.
Further history:
The patient does not respond to treatment and dies.

Image 2.1:
This is a gross photograph of his brain. Describe the appearance. What is the pathogenesis of this
lesion?
The brain shows a whitish exudate in the meninges with hyperemia of the vessels over the surface of
the brain. This appearance is caused by numerous white blood cells responding to the presence of
bacteria and represents frank pus. The vessels are engorged as a response to the infection and the
need to bring more inflammatory cells to the area. Although not very evident here, the underlying
brain parenchyma becomes edematous in response to the infection.

Image 2.2:
This is a microscopic photograph with H&E staining of the subarachnoid space. Describe the
microscopic findings.
The subarachnoid space is filled with polymorphonuclear leukocytes and the vessels are engorged
with blood.

Answers:

What is the diagnosis? What is the most likely organism in this man?

Acute meningitis is the diagnosis. The CSF findings with the elevated WBC count consisting of mostly
neutrophils, the decreased glucose, and the elevated protein are characteristic for a bacterial
meningitis. In most cases the gram stain of the CSF will reveal organisms. Culture of the CSF offers a
definitive diagnosis. Serologic assays can be done for the most common etiologic agents, such as S.
pneumoniae, N. meningitidis, E. coli, H. influenzae, type b, and group B streptococcus. At his age the
most common cause is Streptococcus pneumoniae.

What would be your treatment?

Immediate institution of intravenous penicillin G. Persons allergic to penicillin can be given

chloramphenicol or vancomycin.

What is a possible cause of death in this man?

Uncal and tonsillar herniation with brainstem compression can occur because of brain edema.

CASE 3: Alzheimer's disease      

Clinical History:

This 68-year-old man was noted by his family to have become forgetful in the months before being
seen by his family physician. He was brought to his physician by his son because he had been found
wandering in the streets. On physical examination, he was unable to remember any objects after five
minutes and, although an avid football fan, he was unable to recount the previous Monday night's
game which he had watched with his son. A CT scan was obtained and showed mild cerebral atrophy.

Image 3.1:
This is the gross appearance of the brain from a man who died from the same disease suffered by this
patient. Describe the findings.
There is atrophy of the cortex with ex-vacuo dilation of the lateral ventricles. No focal lesions are
seen.

Image 3.2:

This is a microscopic section of brain stained with H&E. Describe the abnormalities. Do these changes
help make a definitive diagnosis?
The section demonstrates neurofibrillary tangles in the cytoplasm of the neurons. These changes are
seen in Alzheimer's disease.

Image 3.3:

This is another microscopic section of brain stained with a silver stain. In the center there is a senile
plaque. What is the significance of the senile plaque? What would you advise the family about this
disease?
The number of senile plaques found in the cortex is correlated with the presence of Alzheimer's
disease. Only a few plaques need to be found in those under the age of 65 to make the diagnosis,
while in those aged 75 or 80 many more plaques need to be found in order to make a diagnosis. This
suggests that some senile plaques are part of normal aging. Although there are familial cases of
Alzheimer's disease, most cases are not known to be hereditary.

Answers:

What is the apparent diagnosis?

Dementia is the most likely diagnosis, although depression in the elderly must be ruled out.

What other tests would you order on this man?

Thyroid function tests, vitamin B12 level, and serologic test for syphilis (e.g., VDRL) will help rule out
more treatable causes of dementia. A toxicology screen will help rule out possible unknown drugs.

What are the major causes for this condition?

Alzheimer's disease, multi-infarct dementia, hydrocephalus, chronic subdural, and diffuse Lewy body
disease are major causes for dementia. Pick's disease is uncommon. Dementia can be seen late in
Parkinson's disease. Alzheimer's disease is by far the most common.

Are there potential therapies for this condition?

Cholinesterase inhibitors, which increase the availability of acetylcholine in central synapses, include
the drugs tacrine, donepezil, metrifonate, rivastigmine and galantamine. In addition to an effect on
improved cognition and slowing of cognitive decline, they have a positive effect on mood and
behavior. The length of the effect is uncertain. The majority of patients with Alzheimer's disease have
at least one copy of apolipoprotein E4, and these patients seem to have a greater impairment of
presynaptic cholinergic function than patients without the apolipoprotein E4 allele, and this might be
expected to reduce their response to treatment.

The drug propentofylline (a xanthine derivative), a neuroprotective glial cell modulator, has been
shown to reduce the effects of Alzheimer's disease (AD) and vascular dementia (VaD), by antagonizing
glial cell activation and increased production of cytokines, free radicals, and glutamate.

Ginkgo biloba extract (EGb 761) is a plant extract containing two major groups of constituents--
flavonoids and terpenoids. EGb 761 has antioxidant and free radical scavenging activities. EGb 761 has
shown effectiveness when used for symptomatic treatment of cerebral insufficiency of normal aging
or degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory
disturbances. Depressive symptoms of patients with Alzheimer's disease and older non-Alzheimer
patients may also respond to treatment with EGb 761, which has a stress reducing effect.

Explain the biochemistry and genetics of his disease.

The amyloid beta-protein (Aß) is derived by cleavage of the larger amyloid precursor protein (APP).
APP is expressed in all mammals. In humans, the APP gene is on chromosome 21. Mutations in the
APP gene have been found in familial cases of AD. Mutations in APP increase production of Aß. There
are additional genetic mutations that play a role in development of AD. The epsilon4 allele of
apolipoprotein E is a major risk for AD of late onset, particularly if both alleles are epsilon 4. The gene
is located on chromosome 19. Over half of AD patients have the epsilon 4 allele. Apo epsilon 4
increases levels of Aß in the brain. Mutations in the presenilin 1 gene on chromosome 14 and the
presenilin 2 gene on chromosome 1 have been associated with early onset AD. These mutations
increase Aß production.

In AD there are extracellular deposits of Aß. In the more numerous, smaller diffuse plaques this Aß
alone is present as filamentous masses. However, the diagnostic neuritic plaques also have dystrophic
dilated and tortuous neurites, microglia, and surrounding reactive astrocytes.

Neurofibrillary tangles are composed of the hyperphosphorylated microtubule-associated proteins

known as tau.

The Aß may be deposited in cortical vessels, principally small arteries and arterioles, leading to an
amyloid angiopathy. These small vessels are prone to bleed.

Neuritic plaques and neurofibrillary tangles can occur independently of each other. Increased
numbers of neuritic plaques for age are diagnostic of AD, but tangles are not diagnostic of AD.

CASE 4: Subdural hematoma     

Clinical History:

This 58-year-old man had a history of alcohol abuse. He developed increasing weakness on his right
side over several days. Upon admission he was mildly agitated and complaining of a headache. His
right arm and leg were weak and there was flattening of the nasolabial fold on the right. He denied
any recent head trauma. A head CT scan was obtained.

Image 4.1:

This is the CT scan. What does it show? What is the diagnosis?

There is a hematoma in the subdural space on the left. This would make the diagnosis of subdural
hemorrhage.

Image 4.2:
This is a gross photograph of a similar lesion in a patient who died. What would have been the
treatment for this lesion?
This picture shows a more chronic subdural hematoma which has a capsule around it. The treatment
is evacuation of the blood through burr holes in the skull.

Answers:

What are the possible causes for his weakness?

A progressive stroke due to vascular occlusion on the left side or an enlarging subdural are possible
causes in spite of the negative history of trauma. An intraparenchymal tumor or abscess are other
possibilities.

Why did the patient deny any history of recent trauma?

With his history of alcoholism, he most likely was intoxicated (drunk) at the time and did not
remember striking his head.

What age groups commonly present with this type of lesion after head trauma?

Subdural hematomas are most commonly seen in the very young and the very old. Alcoholics
commonly present with subdurals because of their propensity to fall.

What blood vessels are rupture to produce this lesion?

The crossing dural veins are ruptured. Because of the slower accumulation of blood, the patient may
not present acutely with the symptoms of a space occupying mass. Chronic subdurals are thought to
be caused mainly by minor movements of the head, tearing the small vessels taking part in the
resorption of the original clot.

CASE 5: Multiple sclerosis     

Clinical History:

This 52-year-old man had presented at age 37 with blurred vision. This lasted for several weeks. Five
years later he suffered an episode of right leg weakness which resolved over several months. Over the
ensuing 10 years he developed dysarthria, internuclear ophthalmoplegia, and paraplegia with
spasticity. He became bedridden and died of a pulmonary embolus. At the time of his initial
evaluation, a spinal tap revealed a normal CSF pressure, 6 cells (all lymphocytes), an elevated protein,
and a normal glucose. Protein electrophoresis revealed an elevation in IgG. An MRI was performed six
years before his death and showed several T2 bright images in the white matter of the cerebral
hemispheres.

Image 5.1:
This is a CT scan from another patient with the same disease. Describe the findings. What is the
normal age range for this disease?
There are lucent areas around the lateral ventricles representing multiple sclerosis plaques. The
normal age range for this disease is young adulthood - 20's to 40's.
Image 5.2:
This is a gross photograph of the brain from this patient. Describe the abnormalities. Are these old or
new lesions?
There are sunken greyish areas around the ventricles. These represent old lesions with gliosis.

Image 5.3:
This is a microscopic section with myelin stain of one of the lesions. Describe the changes.
There is loss of myelin in the area of the plaque.

Image 5.4:
This is a microscopic section with a silver stain for axons of one of the lesions. What appears to be
preserved?
Although the myelin is gone as evidenced by the myelin stain, the axons are relatively preserved.

Image 5.5:
On this H&E stained microscopic section, note the perivascular lymphocytes in the lesion. What are
some of the theories regarding pathogenesis in this disease? What are some of the treatment
modalities for this disease?
There are many theories for the pathogenesis of this disease, including immunological and viral.
Corticosteroids have been used as treatment. Cytoxan and other immunosuppressive drugs have also
been used. Beta interferon is presently being used in more acute cases. Large series need to be
evaluated over long periods because of the tendency for the disease to have natural remissions.

Answers:

What is the most likely diagnosis?

Multiple sclerosis.

What other test would help in confirming your diagnosis? What would you tell the patient about
the prognosis?

CSF agarose gel electrophoresis to look for oligoclonal bands. Visual evoked responses and brain stem
evoked responses may demonstrate abnormalities not noted on examination. 
The prognosis varies with each patient and many patients do not progress to severe disabilities. Many
patients have periods of remission.

CASE 6: Glioblastoma multiforme     

Clinical History:
This 50-year-old woman was in her normal state of good health when she began to notice a funny
feeling in her left hand. Over the ensuing weeks she began to notice a continual nagging headache
which was partially relieved with Tylenol. On the morning of admission she had a grand mal seizure
witnessed by her husband. Upon arrival at the emergency room she was awake and slightly
disoriented but could give a good history. On physical examination there was mild weakness of the
left arm and leg with paresthesias of the left hand.

Image 6.1:

This is an enhanced MRI scan of the right hemisphere as seen sagittally. Describe the findings and give
possible etiologies for the lesion seen.

There is a large mass in the right hemisphere. This is most likely tumor because of the irregular shape.
Abscesses tend to be rounded and have an even ring enhancing edge. Tumors can have a ring
enhancing edge with a lucent center, but the ring enhancement tends to be irregular. A bleed would
have to be ruled out with an unenhanced scan.

Image 6.2:

This is an H&E stained microscopic section of the biopsy taken from the lesion. Describe the changes.
What is the diagnosis? What is the treatment for this lesion?

This is a cellular tumor with pleomorphic nuclei infiltrating brain. There is an area of necrosis in the
center of the section and mitoses are found. The diagnosis is glioblastoma multiforme. The treatment
is radiation and chemotherapy.

Image 6.3:

This is a gross photograph of a similar lesion from an elderly man who died. Describe the gross
changes. What is the usual age at presentation for patients with this lesion?

This photograph shows a horizontal section of brain with a hemorrhagic yellowish mass involving the
corpus callosum posteriorly and both sides of the brain adjacent to the corpus callosum. The usual
age at presentation of patients is the 50's to 60's.

Answers:

What are possible causes for these symptoms?

Since the symptoms progressed over weeks, tumor or abscess should be considered. A chronic
subdural is another possibility.

What would be part of your workup on this patient?

A scan to rule out a localized lesion. CT scans are better at identifying intracranial hemorrhages, while
MRI scans are better at identifying neoplasms.

CASE 7: Cerebral abscess     

Clinical History:

A 25-year-old woman was admitted to the hospital for left sided focal seizures and obtundation. She
had complained of increasing headaches over the weeks prior to admission. There was also some
clumsiness of her left hand and leg. She noted clonic jerking of her right arm lasting approximately
five minutes which resolved with some weakness in her arm. Twenty minutes later, a similar episode
occurred. On admission she was barely responsive and had a temperature of 37.8 C (100 F). She was
then noted to have a left hemiparesis.

Image 7.1:
This is an enhanced head CT scan. Describe the findings. Do they help narrow down the differential
diagnosis?
There is a thin enhancing ring lesion with central lucency and surrounding edema. This narrows the
diagnosis to abscess.

Further history:
The patient was found to have alpha streptococcus growing in one of her blood cultures, and an
echocardiogram demonstrated an atrial septal defect.
Image 7.2:
This is a gross photograph of a section of brain from another patient with the same problem. Describe
the findings.
This image shows an abscess with surrounding hyperemia and discoloration in the occipital lobe. Most
of the pus has fallen out of the lesion.

Image 7.3:
This is a microscopic section with connective tissue (trichrome) stain of the lesion after some months
have passed. What are the various layers of this lesion?
The central area would contain the inflammatory cells or pus, the first layer represents the
granulation tissue which is surrounded by the collagen of the capsule which was laid down by the
adventitia of the vessels responding to the lesion. Within the surrounding brain parenchyma outside
the capsule, one finds astrocytosis and edema.

Answers:

What are the possible causes for this type of presentation?

Because of the fever one would think of infection. With the focality of the symptoms and the
progression of symptoms over several weeks, an abscess would be suspected. Tumor would also have
to be considered.

What studies would help define this situation?

Scans would help localize a lesion and define what type of lesion was present.

What further studies would help define the etiology of the lesion in the brain?
Blood cultures might isolate an organism. An echocardiogram might localize the source of infection. A
chest x-ray might also help localize a source of infection.

How would you treat her disease? What is the prognosis?

Antibiotics specific to the organism would be given. If subsequent scans did not show improvement,
surgical drainage could be considered. The prognosis with response to therapy is good.

CASE 8: Metastatic carcinoma    

Clinical History:

This 55-year-old man presented with the acute onset of left sided headache and mild right leg paresis.
On CT scan a focal area of hemorrhage was seen near the gray white junction in the mid left frontal
area. There was a questionable lesion in the right parietal lobe, but this was not well defined. It was
decided to evacuate the lesion because of the mild mass effect and symptoms.

Image 8.1:
This T1 weighted post-contrast MRI scan in coronal view demonstrates the lesion. The mass lesion is
brightly enhancing and could represent either blood or a neoplasm.

Image 8.2:
This microscopic section shows the cellular portion of the lesion evacuated and sent to surgical
pathology.
The tumor cells are only mildly pleomorphic with clear cytoplasm. The lesion was well demarcated
from the surrounding brain tissue.

Further history:
On questioning, the patient admitted to noting some blood-tinged urine in the weeks prior to his
admission. He did not have any dysuria or urgency. A CT scan of the abdomen revealed a large mass in
the right kidney.

Image 8.3:
This microscopic section of the brain is from another individual with the same disease. There is a well
circumscribed hemorrhagic lesion in the right occipital lobe with some surrounding edema. What
tumors commonly metastasize to brain?
Lung carcinoma, breast carcinoma, renal cell carcinoma, and melanoma.

Answers:

What are the possible etiologies for this lesion? What would be your follow-up after the discovery
of the lesion?

Primary or metastatic tumor are possible etiologies. Follow-up consists of a more thorough exam and
history to see if there is a primary tumor elsewhere in the body. Special stains can be done on the
biopsy tissue to discern whether it is primary or metastatic. In general, well circumscribed tumors in
brain are metastatic. The pattern of clear cells would suggest renal cell carcinoma.

What is the most likely diagnosis which explains both lesions? What is the treatment?

A renal cell carcinoma is the most likely diagnosis. Surgical removal of the kidney and a search for
possible other metastatic sites is indicated. Over half of cases of metastases to the brain prove to
have a lung primary. In women, breast cancer can metastasize to the brain. The neoplasm that is most
likely to go to the brain when metastatic is melanoma.