Compare and contrast the causes, clinical presentations, and neuropathologic findings in patients with Alzheimer's disease, Parkinson's disease, and Huntington's disease. (<300 words)

The etiology of Alzheimer's disease is unknown, though about 10% of cases are familial and persons who survive with trisomy 21 to middle age will develop Alzheimer's. Loss of cholinergic neurons in the nucleus basalis of Meynert may play a role. Clinically, patients show dementia with memory loss and inability to function independently. They become debilitated, with a course to death of about 5 to 7 years. Onset typically occurs after age 50. Grossly, the brain shows cortical atrophy. Microscopically, the hallmark of Alzheimer's disease is the finding of neurofibrillary tangles and senile plaques, along with neuronal granulovacuolar degeneration and amyloid angiopathy, particularly in the cerebral cortex and hippocampus.

Parkinson's disease is seen from age 50 onwards. Most cases are idiopathic; however, some were "postencephalitic" following the influenza epidemic of 1917-18. Exposure to MPTP as a toxin also can produce Parkinsonism. Patients develop progressive symptoms of tremor at rest (so-called "pill rolling" type), bradykinesia, cogwheel rigidity, festinating gait, and mask-like facies. Most patients do not become demented. Pathologically, the dopaminergic pigmented neurons of the substantia nigra, locus ceruleus, and dorsal motor nucleus of cranial nerve X are affected by loss and by formation of Lewy bodies in remaining neurons.

Huntington's disease is inherited, with an autosomal dominant pattern and a defect mapped to chromosome 4. The onset is usually between the ages of 20 and 50. Patients present with progressive dementia and/or psychosis accompanied by choreiform and athetotic movements. Later, they may have bradykinesia and rigidity. The major pathologic feature is atrophy with loss of neurons and gliosis, most pronounced in the caudate, but to a lesser extent also involving the putamen, leading to ex-vacuo hydrocephalus. Frontal cortical atrophy may also be seen. The patients become progressively debilitated, with a course averaging 15 years to death.

Discuss the etiologies for, the clinical presentations of, and the pathologic appearances of the major types of intracranial hemorrhage. (<300 words)

Intracranial hemorrhage may be the result of trauma. Older persons with cerebral atrophy may develop acute subdural hematoma after a fall with tearing of the bridging veins. Blood collects under the dura to compress the brain and increase intracranial pressure. This can result in headache, blurred vision, somnolence, and coma. Brain herniation can occur. A chronic subdural hematoma results when blood collects and organizes, persisting as a mass that slowly accumulates fluid and leads to increased intracranial pressures over weeks to months. A blow to the head may also result in a tear of the middle meningeal artery and collection of blood acutely in the epidural space. This type of hemorrhage can lead to clinical appearance of a "lucid" interval between the time of trauma and significant blood collection resulting in loss of consciousness.

Subarachnoid hemorrhage in adults is often a result of a ruptured intracranial artery aneurysm (berry aneurysm) at the base of the brain. Sudden loss of consciousness is the typical presentation. The blood extends along the surface of the brain. This can lead to vasospasm with resultant infarction. In some cases, the blood may dissect into the cerebrum.

Intracerebral hemorrhage in adults is most often a complication of hypertension, though patients with bleeding disorders or patients with vascular malformations may also suffer intracerebral hemorrhage. Hypertensive hemorrhages typically occur in the basal ganglia, particularly the putamen. Patients may lose consciousness and may show findings typical of a "stroke" with focal motor or sensory deficits.

Discuss the clinical, laboratory, and pathologic appearances in the central nervous system that could result from head trauma. (<250 words)

Head trauma with concussion may result in clinical delerium or confusion, but there are no pathologic findings. A greater or more localized force may produce brain contusions, focal cortical disruption with hemorrhages, when gyral surfaces strike calvarium. The injury pattern may be a "coup" on the same side as the blow or "contracoup" appearing on the opposite side, as in a fall backwards with contusions on the inferior frontal lobes.

Hemorrhages within the brain are far more serious. A blow to temporal-parietal area may disrupt the middle meningeal artery, with blood forced out under arterial pressure quickly forming an epidural hematoma appearing bi-convex on CT or MRI. The patient classically has a "lucid" interval between initial injury and coma from brain compression. A blow disrupting the bridging veins between the dura and brain can produce a subdural hematoma, seen more frequently in the elderly with cerebral atrophy, when vessels are more easily traumatized. Since blood is under venous pressure, the onset of symptoms may be acute, with a fluctuating level of consciousness, or more insidious, over weeks to months, with headaches, confusion, and obtundation. Scans may show a crescent-shaped hematoma. Clinical findings with these hematomas are related to the pressure effect with possible herniation. A lumbar puncture should not be done if herniation is present or imminent.

Trauma may produce penetrating injuries with risk for infection or subarachnoid hemorrhage, particularly with basal skull fractures. Meningeal irritation from the blood may produce findings similar to meningitis, stiff neck, headache, seizure.

Discuss clinical findings, laboratory tests, and types of pathologic appearances that can occur with bacterial, fungal, and viral infection of the central nervous system. (<250 words)

Bacterial infections are usually of rapid onset and the patient presents with fever, headache, and stiff neck. Examination of cerebrospinal fluid (CSF) will show a decreased glucose relative to serum glucose, elevated protein, and a leukocytosis with many PMN's. Gram stain can reveal the organisms. The meninges typically show a purulent exudate that obscures the sulci. The brain can be edematous and herniation can result. A chronic complication could be an abscess. Common organisms include N. meningitidis in young persons, S. pneumoniae in older adults, H. influenzae in children, and E. coli in neonates.

Fungal infections, which are more frequent in immunocompromised patients, can have a more insidious onset with low grade fever, though cryptococcal meningitis can be quite acute. CSF findings may include an elevation in WBC's, mostly lymphs, with increased protein and decreased glucose, but not as marked as in bacterial meningitis. A cryptococcal antigen test is useful. Aspergillus can cause vasculitis with hemorrhage and infarction. Organisms such as C. immitis may produce a granulomatous reaction.

Viral infections often produce a meningoencephalitis, though initially there may be findings resembling bacterial meningitis, but the CSF shows a mild lymphocytosis, while the glucose is usually normal and protein possibly elevated. Herpesvirus can cause a hemorrhagic encephalitis. In immunocompromised patients, progressive multifocal leukoencephalopathy caused by JC papova virus can evolve over months with neurologic decline due to white matter degeneration. Human immunodeficiency virus mediates its effects primarily through macrophages that cause focal destruction in grey or white matter.

Discuss the clinical and pathologic findings in a patient with central and/or peripheral nervous system disease from complications of diabetes mellitus. (<250 words)

Patients with diabetes mellitus can have accelerated atherosclerosis which can affect the vascular supply of the central nervous system. Stenosis, thrombosis, and embolism of the arteries can lead to cerebral ischemia and infarction. Emboli often originate in the heart, where ischemia and chronic hypertension have led to myocardial damage with dilation and mural thrombosis. Atherosclerotic narrowing of the carotid arteries can produce transient ischemic attacks. Diabetics are more prone to develop renal disease with hypertension. Arterioles can rupture, particularly in the region of the basal ganglia in patients with hypertension, leading to intraparenchymal hemorrhage.

Peripheral nervous system complications of diabetes mellitus may include neuropathy. This may be due to peripheral vascular disease or injury to nerves from excess glucose uptake and osmotic injury from sorbitol accumulation. Extremities are more affected and sensory nerves more than motor nerves, often with a "stocking-glove" distribution bilaterally with numbness and paresthesias. Autonomic neuropathy may lead to incontinence, gastrointestinal motility disorders, and impotence in males.

Diabetic retinopathy is an important cause for blindness. Initially there may be arteriolar narrowing, dot and flame hemorrhages, exudates, and cotton wool spots which may be asymptomatic. Later, ischemia may lead to a proliferative retinopathy characterized by a proliferation of new vessels that are prone to hemorrhage, with subsequent fibrosis that can lead to retinal detachment.

Discuss, in 250 words or less, clinical and pathologic findings in the workup of an adult patient with a brain tumor. (<250 words)

(Example 1)

Brain tumors account for 8 to 10% of neoplasms in adults. Most are supratentorial. The peak age range is 40 to 60 years. Patient complaints suggesting brain tumor include a progressive, unrelenting headache present for weeks or months. The headache may be worse in the morning or awaken the patient at night. A mass effect may produce symptoms and signs of increased intracranial pressure, including nausea with vomiting and papilledema. Focal or localizing signs due to a mass effect include aphasia and unilateral hemiparesis. Seizures may be present with a more slow-growing mass. Both CT and MRI scans can aid in localizing the tumor and indicate the differential diagnosis based upon location.

Pathologically, the most common primary brain tumor in adults is a glioma. These can range from low grade astrocytomas to anaplastic astrocytomas to glioblastoma multiforme. They tend to be irregular without distinct margins and tend to involve the cerebral hemispheres. Glioblastomas are highly malignant, aggressive neoplasms with areas of necrosis and hemorrhage, but they rarely metastasize. They demonstrate marked cellular pleomorphism with mitoses. Another common neoplasm is the meningioma, which arises from arachnoid cap cells and is typically well-circumscribed, located over the lateral convexity, and histologically benign. Metastases account for about half of brain tumors, and about half the time they are solitary masses. The most common primary sites are lung, breast, and kidney. They are often found at the grey-white junction.

Discuss, in 250 words or less, clinical and pathologic findings in the workup of an adult patient with a brain tumor. (<250 words)

(Example 2)

An adult patient with a brain tumor may present with localizing signs such as anosmia, visual disturbances, or motor or sensory deficits. False localizing signs such as a 6th nerve palsy may be present. General findings such as change in behavior, mentation, or obtundation may be found by taking a complete history. History could help rule out more acute processes such as hemorrhages or infarctions that are associated with patient improvement over time. The tumor can increase intracranial pressure from mass effect or from edema around the tumor and lead to herniation, so a CT or MRI scan should be done prior to a lumbar puncture. If CSF is obtained, a high protein can be present, but rarely are there malignant cells seen. Angiography may demonstrate neovascularization around a tumor.

A patient with a schwannoma could present with a hearing loss or tinnitus because of the common involvement of the 8th cranial nerve. These tumors are usually benign histologically and have well-circumscribed borders. A patient with a pituitary adenoma could present with bitemporal hemianopsia due to pressure on the optic chiasm. Such a benign tumor could also lead to endocrinopathies because of hormone secretion, such as amenorrhea-galactorrhea from prolactinomas, acromegaly from growth hormone secreting adenomas, or Cushing's disease from ACTH-secreting adenomas. An ependymoma, often seen involving the 4th ventricle and usually benign histologically, could cause obstruction to CSF flow with resultant hydrocephalus.

A 70 year old man has been diagnosed with Alzheimer's disease. In 150 words or less, describe the key clinical and pathologic features of his illness.

Alzheimer's disease usually presents in adults over the age of 50 as progressive memory loss and inability to perform activities of daily living. The diagnosis is clinical, after excluding other possible problems such as depression, vitamin B12 deficiency, hypothyroidism, and multiple strokes. The definitive diagnosis is made by finding a grossly atrophic brain at autopsy, with occipital sparing, and consequent hydrocephalus ex vacuo. The pathognomonic feature is the appearance of increased numbers of neuritic plaques in the cerebral cortex, often with amyloid cores. Other findings include neuronal neurofibrillary tangles and granulovacuolar degeneration, mainly in hippocampus and neocortex. There is loss of neurons and gliosis. Most cases are sporadic, but perhaps 10% are familial. A genetic basis for the disease is based upon association with the gene coding for cerebral amyloid on chromosome 21.