Digital Library: Lectures: Neuropathology The nervous system functions as the primary messaging system of the body. It is comprised of highly specialized cells, including neurons, astrocytes and oligodendroglia. Each cell type serves a different function. From an anatomic and functional point of view, the nervous system is the most complex structure in the body. Neurons have tentacle-like dendrites and constitute the circuitry of the brain. They receive and send chemical and electrical signals throughout the body. Neurons are generally thought to be incapable of regeneration; however, recent evidence suggests that there is limited capacity for regrowth of axons under certain conditions. Astrocytes provide structural support, regulate electrolyte balance, and influence the microenvironment of neuronal synapses. Astrocytes multiply in areas of injury (astrogliosis). Oligodendrocytes are the myelin-producing cells of the central nervous system. Myelin provides insulation for axonal processes. Myelin sheaths are an adaptation seen in vertebrates that serves to accelerate the speed of transmission of electrical impulses. The various anatomic regions of the brain are linked to specific mental functions, such as memory, speech, vision, and cognition. Damage to one region may have specific psychiatric or cognitive manifestations. It may also impact the flow of information between distant brain regions. Thus, the relationship between a pathologic lesion in the brain and its clinical presentation is complex. Like other organs of the body, the central nervous system is susceptible to trauma, circulatory disorders, infectious diseases, and neoplasia. Therefore, as you learn about the intricacies of the brain, please take this opportunity to review your understanding of basic mechanisms of disease (e.g., inflammation and hemodynamic disorders). Neuropathology introduces many new concepts, but also provides an excellent review of key topics covered previously. Here are the Key Points: Epidural hematoma refers to accumulation of blood between the calvarium and dura. It is usually the result of trauma to the side of head that fractures the temporal bone and transects the middle meningeal artery. Epidural hematomas are often fatal if not surgically treated. Subdural hematoma refers to accumulation of blood in the subdural space as a consequence of bleeding from torn bridging veins. Acute subdural hematomas are most often fatal. Subdural hematomas are caused by rapid rotation of the head. A history of trauma may or may not be present. To tear the bridging veins requires that the brain be accelerated to a critical rate within the head. Cerebral contusion refers to a bruise on the cortical surface resulting from head trauma. Histologically, the contusion shows phagocytosis of a damaged cortex and white matter by macrophages, focal hemosiderin deposition and surrounding reactive astrocytosis. Saccular (berry) aneurysms occur at the branch points of arteries at the base of the brain, e.g., circle of Willis. Risk factors for rupture include hypertension, female sex, atherosclerosis, and collagen deficiency. Rupture of a saccular aneurysm is a life-threatening event, with over 35% mortality. Atherosclerotic aneurysms typically involve large intracranial arteries, vertebral arteries, and the basilar artery. The major complication of atherosclerotic aneurysms in the brain is thrombosis. Hypertensive intracerebral hemorrhage occurs most often (65%) in the basal ganglia-thalamus. Approximately 15% occur in the pons, resulting in loss of consciousness. Hypoxia (low flow states) can produce areas of ischemic necrosis at the watershed areas between circulations of the cerebral arteries. Global ischemia produces severe damage in areas of the brain that are most sensitive to anoxic/ischemic cell injury, namely Sommer's sector of the hippocampus, Purkinje cells of the cerebellum, and cortical neurons. Cerebrovascular occlusive diseases (both thrombotic and embolic) remain a major cause of morbidity and mortality in the Western world. Atherosclerosis predisposes to vascular thrombosis and embolic events, which result in local ischemia and infarction. The geographic location of the infarct determines clinical symptoms. The site of ischemic necrosis eventually undergoes liquifaction, cyst formation, and reactive astrogliosis. Narrowing (arteriosclerosis) of brain parenchymal arterioles due to hypertension can lead to small cystic ischemic infarcts referred to as lacunar infarcts. Severe disease with numerous such infarcts can result in the clinical entity of "multi-infarct dementia". The normal volume of cerebral spinal fluid (CSF) is 120-150 ml. Aproximately 500 ml is produced daily (primarily by the choroid plexus) and reabsorbed by the arachnoid villi. Noncommunicating hydrocephalus refers to physical obstruction to flow of CSF, resulting in dilatation of the ventricular system of the brain. Communicating hydrocephalus is most commonly an acquired abnormality in reabsorption of CSF, most frequently secondary to infection, hemorrhage, or tumor. Leptomeningitis refers to inflammation of the leptomeninges, the thin membranes enveloping the brain. This compartment contains the CSF and provides a rich culture medium for bacteria. The most common bacterial causes of acute leptomeningitis are E. coli, H. influenza, Streptococcus pneumoniae and Neisseria meningitidis. The presence of polymorphonuclear leukocytes (neutrophils) in the CSF is a reliable marker of bacterial or fungal meningitis. Viral meningitis is the most common viral disease in the central nervous system. Unlike bacterial meningitis, viral meningitis is almost always self-limited and benign. Patients present with fever and severe headache. It is most commonly caused by enteroviruses such as coxsackievirus, but may be caused by mumps virus, Epstein-Barr virus, or herpes simplex virus. Cryptococcal meningitis is most commonly an opportunistic infection in immunocompromised hosts. The encapsulated organisms reproduce by budding and disseminate within the leptomeninges. Cerebral abscess occurs when bacteria lodge in capillaries in the brain and elicit an acute inflammatory reaction (cerebritis). Multiplication of organisms and the ensuing inflammatory response can result in the formation of an abscess. Viral encephalitis is more severe than viral meningitis, because the inflammation primarily involves the brain parenchyma. Typical symptoms include serious neurologic deficits and impaired consciousness. Viral infections of the brain parenchyma are caused by herpes simplex virus, rabies, poliomyelitis, and arboviruses. Herpes simplex virus is the most common cause of sporadic cases of viral encephalitis and causes a hemorrhagic, necrotizing encephalitis. It is the most important viral infection of the human nervous system. Cytomegalovirus is another herpes virus, commonly seen in patients with AIDS. Rabies is transmitted to humans through the saliva of an infected animal. However, there are reports of patients with rabies with no known bite exposure. Several of these cases involve people visiting caves inhabited by bats, where inhalation of viral particles in bat feces appears to be the route of infection. Poliomyelitis is caused by a small non-enveloped single-stranded RNA virus. The virus infects neurons in the spinal cord and brain stem. Mortality ranges from 5 to 25% with death resulting from respiratory failure. Subacute sclerosing panencephalitis is an encephalitis of insidious onset that predominates in childhood. It is caused by a measles virus that is defective in replication. Progressive multifocal leukoencephalopathy is a viral disease that principally targets oligodendroglial cells in the white matter. It is caused by JC virus (a polyoma virus) and is typically seen in immunocompromised persons (e.g., patients with AIDS or bone marrow suppression). AIDS encephalopathy refers to dementia associated with HIV infection. This disease is thought to be related to the actions of cytokines released by mononuclear cells in response to HIV infection. HIV in the brain is characterized histologically by the presence of perivascular, multinucleated giant cells that contain the virus. Prion diseases are degenerative diseases of the central nervous system most probably caused by the presence of an abnormal protein (PrP). Prion diseases have both inherited and transmissible forms. Examples include Kuru and Creutzfeldt-Jakob disease. Prion diseases are characterized pathologically by the presence of "spongiform degeneration". Leukodystrophies are a heterogenous group of diseases of disturbances of myelin formation and preservation. Examples include metachromatic leukodystrophy and Krabbe Disease. Multiple sclerosis is a chronic demyelinating disease of the CNS in which there are numerous patches of demyelination throughout the white matter. The disease has a genetic contribution and a possible autoimmune etiology. The plaque is the hallmark of multiple sclerosis. Patients frequently present with blurred vision or loss of vision in one eye. Plaques within the spinal cord cause weakness of one or both legs. Wernicke syndrome is an encephalopathy caused by deficiency of thiamine. Patients exhibit lateral rectus palsy, nystagmus, ataxia and mental confusion. Wernicke syndrome arises most commonly in association with chronic alcoholism. Alzheimer disease is a progressive dementing illness that occurs predominantly in persons over 45 years of age, with the highest incidence in the ninth decade of life. Males and females are affected equally. Alzheimer disease is the most common cause of senile dementia among the elderly. Alzheimer disease is defined pathologically by the presence of numerous senile plaques, neurofibrillary tangles, and neuronal loss. Huntington disease is a progressive neurodegenerative disease characterized clinically by involuntary movements and cognitive deterioration. Gross examination of the brain reveals marked atrophy of the caudate nucleus. The huntingtin gene contains long stretches of trinucleotide repeats (CAG), which can expand in subsequent generations. This results in the clinically observed phenomenon of "anticipation", in which future generations show symptoms of disease at a younger age. The mechanism of neuronal cell death in Huntington disease is not understood. Parkinson disease is characterized pathologically by loss of neurons in the substantia nigra and disruption of specific dopaminergic pathways. Clinically, patients with Parkinson disease have tremors at rest and muscular rigidity. Amyotrophlc lateral sclerosis (ALS) is a degenerative disease of motor neurons. ALS is the most common form of adult onset, progressive motor neuron disease. The principal clinical features of this disease are muscular weakness and atrophy. Most cases occur sporadically, but approximately 10% of cases are familial (autosomal dominant). Astrocytomas are tumors of astrocytic origin. They represent the largest and most diverse group of glial cell tumors, including astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Other CNS tumors include the following: Oligodendrogliomas arise in the cerebral hemispheres of adults. Ependymomas have a peak incidence between 10 and 15 years of age. Medulloblastomas are poorly differentiated neuroepithelial tumors. Meningiomas are CNS tumors of mesenchymal cell origin. The following images illustrate Key Morphological Concepts: 1. This is an example of a CEREBRAL ABSCESS. The patient was an intravenous drug user who introduced bacteria into his blood stream from a contaminated needle. Cerebral abscess can also occur as a complication of dental procedures and otitis media (middle ear infection). Cerebral abscesses undergo liquifactive necrosis and cyst fomation. 2. This is an example of a hemorrhagic HERPES ENCEPHALITIS. Pathologic changes in viral encephalitis are characterized by perivascular "cuffs" of lymphocytes, neuronophagia, and formation of microglial nodules. This infection has a predilection for the temporal lobes of the brain. 3. This CAT scan (computerized axial tomography) of the brain shows evidence of a space-filling lesion in the temporal lobe (note circular feature). Such lesions are often associated with an infectious disease, high-grade glioma, or lymphoma. In this case, the AIDS patient has toxoplasmosis. 4. This is an example of CRYPTOCOCCUS from an AIDS patient. Cerebral spinal fluid was collected and treated with India ink to reveal the fungi. The yeast capsule is thick and forms a broad halo impenetrable to the ink. Fungi are seen in the center of these halos. 5. This is an example of a PERIVENTRICULAR PLAQUE in the white matter of a patient with multiple sclerosis. The plaque represents a region of demyelination. Multiple sclerosis is the single most common chronic disease of the central nervous system of young adults in the US affecting nearly one in 1000. 6. This is an example of BRAIN ATROPHY in a patient with Alzheimer Disease. Note the widened sulci and thinned gyri. Recent studies have demonstrated that dementia in patients with Alzheimer disease is related to the loss of neurons and synapses, particularly in the neocortex and hippocampus. 7. This is an example of a SENILE (NEURITIC) PLAQUE in the brain of a patient with Alzheimer disease. The central core of these circular plaques contains amyloid. 8. This is an example of a MENINGIOMA. This tumor is a relatively common neoplasm, accounting for 20% of all primary intracranial tumors. Although benign, this tumor may kill patients by compressing vital centers in the brain. 9. This is an example of an EPENDYMOMA. These tumors arise most commonly in the fourth ventricle, producing obstruction and hydrocephalus. 10. This is an example of GLIOBLASTOMA MULTIFORME. These poorly differentiated tumors are derived from astrocytes. They infiltrate within the brain and may cross the corpus callosum ("butterfly tumor").