Reyes Syndrome

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This rare disease, predominantly of young children, usually develops acutely after a viral infection. Salicylate toxicity as a precipitating factor has been implicated in some cases. It manifests with fever, vomiting, enlarging liver, and rapidly progressing encephalopathy leading to death within days or a few weeks. High blood ammonia and low sugar levels are characteristic laboratory findings. Death occurs due to liver failure and raised intra-cranial pressure.

Grossly, the brain is swollen, displaying cerebellar and hippocampal herniations. The histology is characterized by fatty infiltration of the liver and cerebral cytotoxic edema, with neuronal and astrocytic swelling. Hepatic and cerebral mitochondrial dysfunctions are considered in the pathogenesis.

Hyperthermia

Excessive heat gain or insufficient heat loss lead to hyperthermia. Environmental exposure to high temperature (heat waves), exercises (marching, jogging), infection, and the neuroleptic malignant syndrome lead to hyperthermia. Old age, debility, use of anticholinergic drugs, and sympathetic autonomic failure predispose to insufficient heat loss.

Heat stroke refers to an elevated body temperature over 40°C. A rise in body temperature over 41°C is associated with a number of systemic and neurologic disorders: headache, vomiting, incoordination, acute respiratory distress with alkalosis, acute renal failure, electrolyte disorder, and intravascular coagulation. Confusion, depressed alertness, delirium, and seizures develop, and even death may ensue.

The pathology of heat-induced injury is characterized by selective degeneration of the Purkinje cells in both vermis and hemispheres. Replacement Bergmann glia expresses heat shock protein 70 during the acute stage. Purkinje cell degeneration is associated with the trans-synaptic loss of dentate neurons and pallor of efferent cerebellar pathways.

Late sequelae are cerebellar dysfunction due to cerebellar atrophy and occasional extrapyramidal syndrome, due to degeneration of the substantia nigra.

Multifocal Necrotizing Leukoencephalopathy

Multifocal necrotizing leukoencephalopathy (focal pontine leukoencephalopathy), a rare disease of undetermined pathogenesis, has been associated with immu-nosuppression, leukemia, use of cytotoxic drugs, and X-irradiation. The pathology is characterized by multiple small foci of parenchymal spongiosis and necrosis with calcification preferentially in the pons and also in the cerebral white matter. The cerebral lesions are microscopic, although pontine lesions may reach grossly detectable sizes (Fig. 10.8).

CALCIUM METABOLIC DISORDERS Cerebral Calcification

Calcium deposits in the globus pallidus, less often in the Ammon horn and the dentate nucleus of the cerebellum, are frequent incidental autopsy findings, particularly in the brains of elderly individuals.

Striatopallidodentate calcification or Fahr's disease in some texts, refers to a distinct group of cerebral cal-cinoses. It commonly occurs in hypo- or hyperpara-thyroid disorders. It may also occur sporadically or be inherited in an autosomal dominant or autosomal recessive fashion. Characteristically, in the familial form, the serum calcium and phosphorous levels are normal, as is the endocrine function.

Cerebral calcinosis in young individuals may remain clinically asymptomatic for some time, then it presents with a wide range of symptoms: extrapyramidal such as, choreoathetosis, parkinsonian features, dystonia; cerebellar ataxias; seizures; mental retardation; intellectual decline and dementia. The calcifications are readily demonstrated on CT scan (Fig. 10.9).

Pathology: Calcifications, in addition to the basal ganglia and dentate nuclei, may involve the thalamus, internal capsule, cerebral and cerebellar cortex, and the white matter. In HE-stained sections, the calcium deposits appear as basophilic concretions varying in size from small globules to mulberry-like or larger coalescent masses. Some are dispersed in the tissue, and some are deposited within the walls of capillaries and small arteries (see Fig. 10.9). Their colloid matrix contains calcium, iron, aluminum, magnesium, phosphate, and bicarbonate.

NEUROLOGIC COMPLICATIONS OF CHRONIC ALCOHOLISM

Chronic alcohol (ethanol) abuse affects the nervous system, visceral organs, skeletal muscles and, in pregnant women, the fetus. Neurologic and psychiatric complications, acute or chronic, are frequent and comprise a wide

Reye Syndrome Diagnosing

figure 10.8

Multifocal necrotizing leukoencephalopathy. The disease of a 53-year-old man began with spasticity of his legs and difficulty walking. A. A CT scan of the head at age 55 years revealed a massive calcified lesion in the basis of the pons and enlarged fourth ventricle. At age 60 years, he underwent resection of a left maxillary "osteoma." His neurologic condition slowly progressed and, by age 66 years, he was spastic quadriparetic, dysarthric, dysphagic, and confused. One year later, he became bedridden, tube-fed, and incontinent. B. A CT scan at age 69 showed tiny calcified lesions in the hemispheric white matter and a large left maxillary tumor extending into the temporal fossa, diagnosed postmortem as an ameloblastoma. At age 72, he died, following a 19-year clinical course. C. Basal view of the brain shows severe atrophy of the pons. D. Macrosection of the pons shows extensive myelin destruction in pontine basis and multiple mineral deposits (myelin stain). E. Higher-magnification view shows large calcium-positive deposits in the parenchyma (von Kossa/HE). F. Cerebral hemispheric white matter shows multiple small areas of spongiosis with granular mineral deposits (LFB-CV). G. Spinal cord shows small basophilic mineral granules (HE).

figure 10.8

Multifocal necrotizing leukoencephalopathy. The disease of a 53-year-old man began with spasticity of his legs and difficulty walking. A. A CT scan of the head at age 55 years revealed a massive calcified lesion in the basis of the pons and enlarged fourth ventricle. At age 60 years, he underwent resection of a left maxillary "osteoma." His neurologic condition slowly progressed and, by age 66 years, he was spastic quadriparetic, dysarthric, dysphagic, and confused. One year later, he became bedridden, tube-fed, and incontinent. B. A CT scan at age 69 showed tiny calcified lesions in the hemispheric white matter and a large left maxillary tumor extending into the temporal fossa, diagnosed postmortem as an ameloblastoma. At age 72, he died, following a 19-year clinical course. C. Basal view of the brain shows severe atrophy of the pons. D. Macrosection of the pons shows extensive myelin destruction in pontine basis and multiple mineral deposits (myelin stain). E. Higher-magnification view shows large calcium-positive deposits in the parenchyma (von Kossa/HE). F. Cerebral hemispheric white matter shows multiple small areas of spongiosis with granular mineral deposits (LFB-CV). G. Spinal cord shows small basophilic mineral granules (HE).

range of clinical manifestations: ocular, motor, sensory, and autonomic; memory and cognitive deficits slowly progressing to dementia; and altered mentation ranging from delirium, hallucinosis, and stupor to coma.

Etiologies include malnutrition; vitamin deficiencies, particularly thiamine deficiency; metabolic derangements, mainly hepatic; and a direct toxic effect of alcohol on the neural tissue. Alcohol-associated central nervous system diseases may occur individually or in various combinations, and may be joined with peripheral neuropathy and myopathy.

Wernicke-Korsakoff encephalopathy, a serious complication of thiamine deficiency, is discussed in the section on vitamin deficiencies.

Thiamine Deficiency

Cerebral calcinosis associated with hypoparathyroidism. A 19-year-old man developed tonic-clonic seizures and was diagnosed with hypoparathyroidism. He died of an acute viral infection, at age 38 years. A. A CT scan of the head reveals calcifications in the basal ganglia and frontal lobes. Basophilic (calcium and iron positive) granules are deposited in (B) walls of small arteries, (C) capillaries and parenchyma of basal ganglia (von Kossa), (D) cerebral cortex, and (E) dentate nucleus (HE).

Cerebellar atrophy, probably a complication of thiamine deficiency, presents with slowly progressive ataxia of the trunk and lower extremities and a broad-based irregular gait.

Grossly, the atrophy is typically confined to the superior vermis. In severe chronic cases, it involves the entire vermis and the hemispheres (Fig. 10.10). The histology is characterized by a degeneration of the Purkinje cells and, to a lesser degree, the granule cells. The molecular layer and the myelin core of the folia are atrophic. A prominent Bergmann astrocytic layer replaces the lost Purkinje cells. Axonal torpedoes of the degenerated Purkinje cells are common in the granular cell layer (see Fig. 10.10). The inferior olivary nuclei show neuronal losses (retrograde trans-synaptic degeneration) and gliosis.

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