Several systemic metabolic derangements may produce CNS dysfunction; only those associated with abnormal glucose levels and liver dysfunction are considered here.
Since the brain requires glucose as a substrate for energy production, the cellular effects of diminished glucose generally resemble those of global hypoxia. Hippocampal neurons are particularly susceptible to hypoglycemic injury, while cerebellar Purkinje cells are relatively spared. As with anoxia, if the level and duration of hypoglycemia are sufficiently severe, there may be widespread injury to many areas of the brain.
Hyperglycemia is most common in the setting of inadequately controlled diabetes mellitus and can be associated with either ketoacidosis or hyperosmolar coma. Patients develop confusion, stupor, and eventually coma associated with intracellular dehydration caused by the hyperosmolar state. The hyperglycemia must be corrected gradually, because rapid correction can produce severe cerebral edema.
Decreased hepatic function may be associated with depressed levels of consciousness and sometimes coma. In the early stages, patients exhibit a characteristic “flapping” tremor (asterixis) when extending the arms with palms facing the observer. Elevated levels of ammonia, which the liver normally clears through the urea cycle, in combination with inflammation and hyponatremia, cause the changes in brain function. Because it is only one contributing factor, ammonia levels in symptomatic patients vary widely. Within the CNS, ammonia metabolism occurs only in astrocytes through the action of glutamine synthetase, and in the setting of hyperammonemia, astrocytes in the cortex and basal ganglia develop swollen, pale nuclei (referred to as Alzheimer type II cells).
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The list of toxins with effects on the brain is extremely long. Among the major categories of neurotoxic substances are metals, including lead, arsenic, and mercury; industrial chemicals, including organophosphates (in pesticides) and methanol (causing blindness from retinal damage); and environmental pollutants such as carbon monoxide (combining hypoxia with selective injury to the globus pallidus).
Ethanol has a variety of effects on the brain. While acute intoxication is reversible, excessive intake can result in profound metabolic disturbances, including brain swelling and death. Chronic alcohol exposure leads to cerebellar dysfunction in about 1% of cases, with truncal ataxia, unsteady gait, and nystagmus, associated with atrophy in the anterior vermis of the cerebellum.
Ionizing radiation, commonly used to treat intracranial tumors, can cause rapidly evolving signs and symptoms including headache, nausea, vomiting, and papilledema, even months to years after irradiation. Affected brain regions show large areas of coagulative necrosis, edema, and blood vessels with thickened walls containing intramural fibrin like material.
Neurodegenerative diseases are characterized by the progressive loss of neurons, typically affecting groups of neurons with functional interconnections. Different diseases tend to involve particular neural systems and therefore have relatively stereotypic presenting signs and symptoms (
Table 23.3
Diseases that involve the hippocampus and associated cortices present with cognitive changes, often including disturbances of memory, behavior, and language. With time these progress to dementia, as occurs with Alzheimer disease.
Diseases that affect the basal ganglia manifest as movement disorders; these may be hypokinetic, as with Parkinson disease, or hyperkinetic, as with Huntington disease.
Diseases that affect the cerebellum or its input and output circuitry result in ataxia, as seen in the spinocerebellar ataxias.
When the motor system bears the burden, weakness and difficulty with swallowing and respiration are often seen first, as with amyotrophic lateral sclerosis.
A pathologic process shared by most neurodegenerative diseases is the accumulation of protein aggregates,