This patient had severe cerebrovascular atherosclerosis, and therefore his infarct may have been due to atherosclerotic-thrombotic occlusion rather than to an embolus. However, in intracranial vessels (except for the basilar system) embolism is more often the cause of infarction. Thrombosis as a complication of atherosclerosis is more common in the basilar system and in the extracerebral carotid system. Cerebrovascular emboli can originate in a wide variety of places, but the most common are atherosclerotic plaques in the internal carotid arteries, cardiac mural thrombi, and heart valves.
Vessels themselves are also damaged by the period of ischemia resulting in petechial hemorrhages when reflow occurs.
This infarct is in the distribution of the right middle cerebral artery and was most likely the cause of the patient's left arm and leg weakness during a "stroke" the previous year.
In contrast to the fibrosis and "scarring" that occur with organization of infarcts in other organs, which cause traction on surrounding noninvolved tissues, cerebral infarcts organize with cavitation, resulting in cystic spaces. The function of the infarcted portion of the brain is lost and cannot be recovered. However, were infarcts to organize in brain as in other organs, fibrosis and traction would compromise the function of areas adjacent to an infarct.
This infarct is in the distribution of the right anterior cerebral artery.
A bland infarct is due to total occlusion of the artery supplying that region and may be due to either atherosclerotic thrombosis or embolism, while a hemorrhagic infarct involves either occlusion with reperfusion (most common with emboli that break up or get resorbed) or prolonged vasospasm. In either case, the vessel itself suffers ischemic damage, and blood "leakage" from this vessel results in petechiae.
The necrosis in this case is remote, with loss of layers of neurons in deep gray matter rather than loss of parenchyma in a specific arterial distribution. This is what results in the "laminar" appearance of the infarct in cases of global hypoxic/ischemic damage.
Focal infarcts are located in the distribution of a specific arterial branch. Watershed (border zone) infarcts are located at the distal borders of major cerebral arteries and are usually found in the parasagittal frontoparietal region (the border of the regions supplied by the middle and anterior cerebral arteries) or, less commonly, the temporo occipital region (the border of the regions supplied by the middle and posterior cerebral arteries) or parieto occipital region (the border of the regions supplied by the anterior and posterior cerebral arteries). Global hypoxic-ischemic encephalopathy appears acutely as necrotic neurons, and with organization there is segmental neuronal drop-out with gliosis. Susceptible areas include the pyramidal layer of the hippocampus (particularly Sommer sector) and the Purkinje cells of the cerebellum. If severe, there is also diffuse cortical pseudolaminar necrosis (necrosis of layers of cortical neurons).
A primary intra parenchymal hemorrhage is due to rupture of a vessel. In the case of hypertensive hemorrhage, the most common type, the rupture is thought to be of a "Charcot-Brouchard" type aneurysm that forms at small artery bifurcations. These aneurysms have been shown to increase in the brain with age and with the duration of hypertension.
The most common risk factors for intraparenchymal hemorrhage are hypertension, hemorrhagic diatheses, bleeding into tumors, amyloid angiopathy, and vascular malformations. The most common sites are the basal ganglia/thalamus (about 70%), cerebellum and pons (almost 13% each), and cerebral white matter (about 5%).
A primary intraparenchymal hemorrhage usually dissects through the parenchyma, sometimes into either the ventricle or the subarachnoid space, rather than causing parenchymal destruction. In any case, the extra mass, and any hydrocephalus that may occur, results in increased intracranial pressure and possible herniation. Rapidity of accumulation of blood determines the outcome: slow leakage can be accommodated, rapid accumulation cannot.
The three main types of hemorrhages or hematomas that may be located between the brain and skull are subarachnoid, subdural, and epidural. Both subdural and epidural hemorrhages are almost always the result of trauma. While subarachnoid hemorrhage (SAH) is most often the result of trauma, it may also be the result of rupture of an aneurysm or an arteriovenous malformation hemorrhage. This patient has an acute epidural hematoma, which occurs following rupture of one of the meningeal arteries, usually the middle meningeal artery, almost always as the result of skull fracture, as in this case. Emergency surgery is necessary because if the epidural hematoma is not drained, it will produce, in rapid succession, uncal herniation, tonsillar herniation, medullary compression, respiratory arrest, and death.
Complications that can develop from cerebral edema include: transtentorial uncal herniation, cerebellar tonsillar herniation, secondary brainstem (Durét) hemorrhage, and death.
The diffuse process in this case causing increased intracranial pressure is the cerebral edema, while the focal process is the right epidural hemorrhage.
Cerebral edema can occur because of the accumulation of fluid in the extracellular space (vasogenic edema), either via damaged capillaries that have lost their blood-brain barrier (BBB) function (as in this case, damage from the acute contrecoup contusions) or through neovascularization, which lacks a BBB. Other etiologies for vasogenic edema include neoplasms, abscesses, and infarcts. The result of the combination of edema and hemorrhage is increased intracranial pressure. A rapid and diffuse rise in intracranial pressure can result in herniation: medial temporal or "uncal" herniation at the tentorium, or cerebellar tonsillar herniation into the foramen magnum.
Cerebellar tonsillar herniation can be fatal because it causes compression of the medullary respiratory centers.
The mechanism of formation of a secondary brain stem (Durét) hemorrhage is downward displacement of the brainstem with increased intracranial pressure from above, while the small arteries feeding the brainstem from the basilar artery are held relatively immobile. This can result in kinking of these vessels, with ischemic damage resulting in hemorrhage upon reflow or in actual tearing of the vessels and resulting hemorrhage.
Increased intracranial pressure can compress the posterior cerebral arteries against the tentorium. The posterior cerebral arteries supply the medial occipital lobes, and compression of these vessels can result in ischemic damage to the areas supplied, which includes the vessels. Reflow results in hemorrhagic infarcts in the medial occipital lobes.
The visual cortex is in the medial occipital lobes. Hemorrhagic infarction to the visual cortex can result in full or partial cortical blindness.
The term for the area of fresh hemorrhagic discoloration in the left lateral parietal cortex is "contusion." A contusion is a focal leakage of blood into the parenchyma ("bruise") and ultimately results in the death of neurons in that region. As in this case, contusions predominantly affect the crests of gyri because the force there is greater than in the sulci. Specifically, this is a "contrecoup" contusion, because it is located opposite the site of impact. A contrecoup contusion is the result of rotational force produced when the moving skull and brain hit a non-moving surface and there is abrupt deceleration. The skull takes slightly longer to stop moving than the brain does, resulting in the skull "hitting" and "bruising" the brain on the side of the brain opposite the point of impact. N.B.: A coup contusion occurs at the point of impact, when a moving object hits a non-moving skull and brain. Contrecoup contusions occur when there is rotational motion of the head before the moment of impact with a non-moving surface and occurs opposite or away from the point of impact.
Saccular aneurysms are present in approximately 1% of the general population. Their incidence is higher in patients with polycystic kidney disease, coarctation of aorta, collagen disorders (e.g., Marfan syndrome, Ehlers Danlos syndrome), and hypertension. They are caused, presumably, by a congenital defect of the media of the involved blood vessels.
Common sites include branches of the middle cerebral artery, the junction between the anterior cerebral and anterior communicating arteries, and the junction between the internal carotid and middle cerebral arteries. They are much less frequent in the posterior circulation (basilar, vertebral arteries).
The motor innervation of the extremities arises from upper motor neurons in the contralateral motor region. Motor strips are in the frontal lobes. The focal seizures and progressive hemiplegia correlate with the CT scan showing a right frontal mass, and both are localized mass effects. Headaches and papilledema are related to generalized increased intracranial pressure.
The three most important lesions in the differential diagnosis of a ring-enhancing mass are: Glioblastoma multiforme, metastatic carcinoma, and abscess.
The microscopic features used in grading astrocytic neoplasms include cellularity, nuclear pleomorphism, mitoses, vascular proliferation, and pseudopalisading necrosis. High cellularity and nuclear pleomorphism define the diagnosis of astrocytoma. An anaplastic astrocytoma generally has frequent mitoses, while glioblastomas usually have microvascular proliferation and pseudopalisading necrosis.
Glioblastoma multiforme are both histologically and biologically malignant. Most patients with glioblastoma multiforme die within a year of diagnosis, with the mean survival time approximately seven months. Because of the closed space of the cranial vault, even neoplasms that are histologically benign may ultimately be biologically malignant. Biologic malignancy may be the result of the inability to resect because of the location (e.g., brainstem) or because of the diffusely infiltrative nature of glial neoplasms. Primary brain tumors almost never metastasize, so the criteria of malignancy used for tumors in other organ systems does not apply.
The region of the frontal lobe involved by this neoplasm probably includes the motor cortex, because of the patient's history of seizures in the left upper extremities, the increased deep tendon reflexes on the left, and the left Babinski reflex.
The cut surface of a glioblastoma looks grossly heterogeneous because of the hemorrhage and necrosis.
Glial tumors are the most common intracranial neoplasms (40-50% of all intracranial tumors and approximately 80% of adult primary brain tumors). Over half of the these are glioblastoma multiforme.
The cells of origin of meningiomas are the meningothelial cells of the arachnoid mater. Meningiomas usually become secondarily attached to the dura mater although their cell of origin is not dural.
This is an example of a CNS neoplasm that can be biologically malignant, but is generally histologically benign. Simply by progressive growth, even a benign meningioma can act biologically malignant, because a mass lesion in the closed cranial vault can result in the progressive, often fatal, cascade of events that occur with increased intracranial pressure.
The relatively minimal mass effects of this neoplasm indicate that it is very slow growing. The lateral ventricle on the right is minimally compressed. There is no cingulate gyrus herniation or right medial temporal herniation, and the third ventricle is still visible. The temporal horn of the lateral ventricle remains patent.
While cerebellar astrocytomas do occur in adults, they are most common in children. The prognosis after resection is usually excellent, with cure rates approaching 100%.
Gliomas or neurogliomas are tumors of glial cells. In addition to astrocytomas, glial cell tumors also include oligodendrogliomas and ependymomas. Each of these two latter types is much less common than astrocytomas, accounting together for about 20% of all intracranial neoplasms in adults. Oligodendrogliomas occur most commonly in cerebral hemispheres, whereas ependymomas arise from the ependyma and hence are located within or next to the ventricles.
The presumed cells of origin of the medulloblastomas are the external granular neurons of the cerebellum.
Medulloblastomas like cerebellar astrocytomas are also more common in childhood but have a worse prognosis than juvenile cerebellar astrocytomas, with 5-year survival approximately 50%.
Metastases are very common, with incidence nearly equivalent to astrocytomas (approaches 50%).
The black pigmentation of these metastases indicates that the primary was malignant melanoma.
This patient has a degenerative disease affecting the cerebral cortex, because she has dementia, or progressive cognitive decline. Clinical features that are significant include increasing forgetfulness, getting lost in familiar surroundings (classic early sign of involvement of association cortex), problem with recent but not immediate memory, disorientation as to time and place, not knowing her daughter. The clinical diagnosis is Alzheimer's disease (AD). The radiographic abnormality (cortical atrophy in frontal, temporal, and parietal lobes) is often, but not always, present in AD, along with a mild increase in the size of the ventricles (hydrocephalus ex vacuo), both abnormalities indicating atrophy due to loss of neurons. This is a typical clinical and radiographic presentation. The clinical course is also typical, with progressive deterioration in cognitive function leading, ultimately, to a total vegetative state.
The autopsy findings are compatible with AD, and the only difference from those of normal aging is quantity. The gross and microscopic findings of Creutzfeldt-Jakob disease (CJD) are different. Typically, there is little if any gross atrophy because the course is rapid. The microscopic pathognomonic feature is spongiform change, seen mostly in the cortex and consisting of intra neuronal vacuolation, neuronal loss, and reactive astrocytosis. These features are not seen in normal aging.
The pathogenesis of this disease is not fully understood. According to one view, deposition of amyloid is important. This is supported by the rare familial forms of this disease. Three genes have been linked to familial Alzheimer's disease. They encode amyloid precursor protein (chromosome 21), presenilin 1 (chromosome 14), and presenilin 2 (chromosome 1). A cleavage product of the amyloid precursor protein (Ab peptide) is deposited in the form of amyloid in neuritic plaques and neurofibrillary tangles. It is thought that a mutation in the APP gene yields Ab fragments that tend to aggregate. Presenilins are also thought to affect the formation of abnormal Ab fragments. It is still not clear whether in sporadic forms of AD, amyloid deposition precedes neuronal death. The inheritance of the e4 allele of the apoprotein E has also been linked to the development of Alzheimer's disease. What role the apoE protein plays in Alzheimer's disease is not clear.
The dark pigment in the substantia nigra is the result of neuromelanin found within neurons of the substantia nigra.
This pigment is a byproduct of the formation of dopamine, produced by substantia nigra neurons, and it accumulates throughout life.
The secondary diagnosis is idiopathic Parkinson disease. Neuronal loss in the substantia nigra with round eosinophilic cytoplasmic bodies (Lewy bodies) in some of the remaining neurons is highly suggestive of idiopathic Parkinson disease, but without a clinical history of parkinsonism (extrapyramidal motor signs: expressionless facies, stooped posture, slowness of voluntary movement, shuffling gait, rigidity, and intention tremor) the diagnosis cannot be definitively made on the basis of pathology alone.
The substantia nigra neurons produce dopamine. Their processes project to the striatum, where dopamine has its effect. The severity of the parkinsonism is proportional to the dopamine deficiency. The extrapyramidal motor syndrome can at least in part be corrected by replacement therapy with levodopa (L-dopa). Unlike dopamine, L-dopa is able to cross the blood-brain barrier and then is metabolized to dopamine.
The inheritance pattern of Huntington disease is autosomal dominant. The clinical hallmark is choreiform (uncontrolled jerky and dystonic) movements, together with progressive dementia. The time course until death is approximately 15 years. The pathologic hallmark is neuronal loss and gliosis in the striatum, more severe in the caudate than in the putamen.
Huntington disease is caused by trinucleotide repeat mutation in the huntingtin gene. At the normal huntingtin locus there are 11 to 34 copies of the trinucleotide CAG. In Huntington disease the number of triplets is greatly increased. The affected individuals can therefore be identified, prior to the onset of symptoms, by testing for the presence of excessive CAG repeats.
CJD and other spongiform encephalopathies (e.g., kuru) are caused by a unique category of infectious particles, termed prions, that lack DNA and RNA. Infectious prions are a modified form of a normal protein found in the nervous system. The pathogenic prions have an abnormal conformation, and they propagate themselves by contacting their normal counterparts and inducing them to fold in the pathogenetic conformation.
The diagnosis is multiple sclerosis (MS). This diagnosis can be made clinically: age usually 20-40, female:male ratio 2:1, initial presentation of a focal neurologic deficit followed by at least partial recovery of function with a subsequent relapsing and remitting course. CT scans can be helpful but MRI is better at visualizing the well-demarcated demyelinated areas called plaques. Oligoclonal immunoglobulin bands are found in the spinal fluid; these are not directed against any known antigen (they are not anti-myelin antibodies) but are nearly always present in spinal fluid during an attack and are quite helpful in making the diagnosis of MS.
This patient's clinical course, as expected, was that of a relapsing and remitting disease. White matter (long tract) signs, such as spasticity and weakness, predominate over gray matter signs such as cognitive impairment or seizures, reflecting the major site of involvement. Although not strictly confined to white matter, the lesions are much more distinct in white matter. Generally, patients live a normal life span and die with the disease rather than of the disease.
Plaque A is in the lateral corticospinal tract and may represent either a partial plaque as stated in the text of the image or could also be descending Wallerian degeneration from a more rostral lesion. In any case, the corticospinal tract lesion might result in lower extremity weakness.
Plaque B is in the posterior column, specifically the fasciculus cuneatous. A plaque in this area might result in the lower extremity vibratory and position deficits that the patient had. A lesion such as plaque C might involve both the spinothalamic and spinocerebellar tracts. Lesions in the spinothalamic region usually result in loss of pain and temperature sensation, below the level of the lesion, on the opposite side of the body. A lesion in the spinocerebellar tract might result in loss of proprioceptive information from one side of the body to the same side of the cerebellum.
MS affects only the central nervous system, where oligodendrocytes produce myelin. In the lesions there is depletion of oligodendrocytes. In the peripheral nervous system Schwann cells produce myelin, and they are not affected.
Although the cause of MS is unknown it is highly likely that it is an autoimmune disease in which T cells reactive against myelin components develop. Both CD4+ and CD8+ T cells reactive to myelin can be found in the lesions. A genetic component is suggested by the increased risk of MS in first degree relatives, associated with certain MHC class II genes and a higher rate of concordance in identical vs. dizygotic twins. What triggers autoimmunity is unknown but environmental factor(s) are strongly suspected. The environmental factor may be an infectious agent that initiates autoimmunity in genetically susceptible hosts.
In multiple sclerosis, normally formed myelin is injured, possibly by autoimmunity. By contrast in leukodystrophies an inborn error of metabolism interferes with myelin development. Leukodystrophies are rare inherited disorders that are fatal in early life. In terms of distribution of lesions, leukodystrophies affect the brain and may also involve peripheral nerves. The lesions occur diffusely in the brain and spinal cord. They tend to spare subcortical U fibers.
This patient's age, manner of presentation, physical examination, and family history are typical of DMD. DMD is an X-linked recessive disorder that affects males. Patients usually present by age three to six with difficulty walking, running, and climbing stairs. There is increasing swayback (lordosis) and waddling gait. Fatty replacement of atrophic muscles, particularly in the calves, often out of proportion to the amount of muscle tissue lost, results in "pseudohypertrophy." There may also be mild, non-progressive mental retardation. Eventually, there is foot drop and toe walking, marked wasting, contractures, and involvement of the diaphragm muscles and heart. By the teen years patients are usually wheelchair-bound. The prognosis is dismal: death is usually by the age of about twenty and is due to respiratory weakness, pulmonary infections, or cardiac decompensation. In approximately one-third of cases there is no positive family history; they represent new mutations.
DMD is a primary muscle disorder resulting from a mutation in the gene coding for the protein "dystrophin." The most common mutation is deletion. Dystrophin probably stabilizes the sarcolemmal membrane during muscle contraction by linking subsarcolemmal cytoskeletal components with extracellular components such as laminin. In a patient with ALS, the site of dysfunction is both upper and lower motor neurons, and the resulting pathology is neurogenic atrophy. Dysfunction at the neuromuscular junction can result in myasthenia gravis. Antibody production to the acetylcholine receptor results in neuromuscular junction "simplification" and clinical weakness and fatigue with increasing muscle activity. Botulism also results from dysfunction at the neuromuscular junction.
The clinical presentation of motor neuron disease (amyotrophic lateral sclerosis, or ALS) is much different from that of DMD, as can be seen in the following table:
|
ALS |
DMD |
|
|
Sex ratio |
Men>women |
Virtually all males |
|
Genetics |
90% sporadic, 10% autosomal dominant |
2/3 X-linked recessive, 1/3 sporadic |
|
Onset |
50s |
3-6 |
|
Prognosis |
1/2 dead in 3 yrs., 90% dead in 6 yrs. |
Death by 20s |
|
Pathology |
Angular atrophy, fiber-type grouping, group atrophy |
degeneration & regeneration, myophagocytosis, endomysial fibrosis |
The most common form of diabetic neuropathy is distal, symmetric neuropathy, primarily sensory, with mild motor involvement. Progression is very slow, over several years. This patient's symptoms were numbness and paresthesias (sensory), and he had only slight weakness (motor), by physical exam. He also had absence of the ankle jerk reflexes. These features are all typical of diabetic distal neuropathy. Skin ulcerations at pressure points such as the heel are presumably due to sensory loss.
A patient with Guillain-Barré syndrome (GBS) usually presents with progressive weakness, beginning distally in the lower extremities, extending upward and proximally over days to a couple of weeks. Sensory abnormalities are generally a minor component of the illness. GBS can be rapidly fatal due to respiratory muscle paralysis, or the patient can recover slowly, sometimes with assisted ventilation. In up to two thirds of the cases the onset of neurologic symptoms is preceded by an influenza-like viral illness.
Myelin ovoids reflect axonal degeneration. Thickening of the vessel wall in diabetics is probably due to non-enzymatic glycosylation of the basement membrane and is most likely the basis for the depopulation and axonal degeneration. Demyelination may also be present, but it is minor. On the other hand, a nerve biopsy from a patient with Guillain-Barré syndrome would show predominantly demyelination, with a relatively minor component of axonal degeneration. There is also a variable degree of inflammation. The demyelination is most likely due to an immunologic attack on myelin, most likely by T cells.
This patient most likely had neurofibromatosis (NF) I. NF I is associated with prolific peripheral nerve (skin) neoplasms. NF II is usually associated with bilateral cranial nerve schwannomas and multiple meningiomas. NF I usually has cafe-au-lait skin spots and Lisch nodules in the iris.