Abnormalities of Thermal Regulation and the Nervous System

Hypothalamic Lesions

Hypothalamic lesions may produce either hyperthermia or hypothermia, although hypothermia is more common. Hyperthermia has been described with tumors, stroke, encephalitis, trauma, and surgery. Hypothermia has been reported with tumors, stroke, subarachnoid hemorrhage, sarcoidosis, multiple sclerosis, neuromyelitis optica, limbic encephalitis, Parkinson disease, and idiopathic gliosis. Hypothermia is common in Wernicke encephalopathy and may be the presenting feature. In contrast, although fever occurs in about 12 percent of patients with Wernicke encephalopathy, a superimposed infection is almost always responsible. Prominent abnormalities of sweating (anhidrosis or hypohidrosis) have been described in primary autonomic failure, multiple system atrophy, and as an isolated condition, and hyperthermia may develop when these patients are exposed to hot climates without air conditioning.

Lesions of Effector Pathways

Interruption of the autonomic outflow from the hypothalamus may produce either hyperthermia or hypothermia by impairing the effector mechanisms necessary for heat dissipation or production, respectively. Lesions of the spinal cord above the thoracic level may interrupt descending input to the thoracic intermediolateral cell column, producing both vasomotor abnormalities and disorders of sweating, or to anterior horn cells, impairing or eliminating shivering below the level of the lesion.

Any neuromuscular disease that is severe enough to cause profound weakness can impede shivering. Polyneuropathies that involve autonomic fibers can produce abnormalities of vasomotor activity and sweating, and either hypothermia or hyperthermia may result. For example, hypothermia is common in patients with diabetes, probably because of impaired vasomotor reflexes. In contrast, some patients with diabetes manifest a syndrome of heat intolerance that is attributed to anhidrosis. Because the autonomic nerve involvement in diabetes is usually predominantly distal, these patients sometimes exhibit profuse sweating over the head and upper trunk (“compensatory hyperhidrosis”).

Miscellaneous Lesions

Disorders that produce widespread damage to the central nervous system (CNS) can impair thermoregulation, but the precise mechanism is often difficult to establish. Degenerative diseases can be associated with hypothermia, possibly because of impaired behavioral adaptations to cold. Hyperthermia has been reported in patients with acute hydrocephalus, posterior fossa surgery, ischemic strokes, and intracranial hemorrhage, but as a general rule, hyperthermia should not be attributed to “neurogenic factors” even when a patient has CNS disease unless there is clear involvement of the hypothalamus or its effector pathways and other causes of fever have been excluded.

Agenesis or dysplasia of the corpus callosum may be associated with episodic hyperhidrosis and hypothermia (Shapiro syndrome). There may also be associated structural abnormalities in the septal region, cingulate gyrus, and posterior hypothalamus. The periods of sweating may last from minutes to hours, and the hypothermia may last from 30 minutes up to several weeks. Episodes may be separated by intervals of months to years. There is often ataxia and impaired cognition during the hypothermic episodes. A similar syndrome has occasionally been seen without any associated abnormality of the corpus callosum, and neurotransmitter abnormalities have been identified in some cases. Episodic hypothermia without hyperhidrosis has also been described. Recurrent hypothermia has also been attributed to “diencephalic epilepsy,” but electrographic seizures have not been demonstrated consistently.

Cases of periodic hyperthermia associated with agenesis of the corpus callosum (“reverse Shapiro syndrome”) have been reported. Episodic hyperthermia (or hypothermia) associated with other manifestations of autonomic dysfunction has also been described after head trauma and many other neurologic disorders.

Thermoregulatory System Overload

Several neurologic diseases produce thermoregulatory disorders by creating conditions that overwhelm the capacity of the thermoregulatory system. Just as paralysis may eliminate effective shivering and result in hypothermia, muscle hyperactivity may result in hyperthermia. Elevated body temperatures are common after generalized seizures, tetanus, and delirium tremens, for example. Three important examples of hyperthermia associated with increased muscle activity are malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome.

Malignant hyperthermia is characterized by vigorous muscle contractions and an abrupt increase in temperature on exposure to certain drugs, most commonly inhalational anesthetics and succinylcholine. It can occur at any time during anesthesia administration or shortly thereafter. The hyperthermia is probably a direct result of the heat produced by sustained muscle activity resulting from defective regulation of intracellular free calcium. Malignant hyperthermia is inherited as an autosomal dominant trait with variable penetrance, and a predominance of expression in young males. More than 50 percent of patients have mutations in the gene for the ryanodine receptor, the primary channel for release of calcium stored in the sarcoplasmic reticulum; other cases are due to mutations in the gene encoding the main subunit of the dihydropyridine receptor, a voltage sensor that interacts closely with the ryanodine receptor, or in the gene coding for Stac3 protein, which is thought to be important for effective co-location of dihydropyridine receptors and ryanodine receptors. Mutations in the gene for the ryanodine receptor have also been implicated in several congenital myopathies including central core disease, centronuclear myopathy, multiminicore disease, congenital fiber-type disproportion, and nemaline rod myopathy; some, but not all, patients with these conditions are also at risk of malignant hyperthermia. Although patients with other myopathies, muscular dystrophies, and myotonia may have adverse effects from anesthesia (e.g., contractures after administration of succinylcholine, increased susceptibility to respiratory depression after receiving barbiturates or opiates, disease-related cardiac complications, or rhabdomyolysis), they do not appear to have an increased risk of malignant hyperthermia.

Both neuroleptic malignant syndrome and serotonin syndrome are characterized by hyperthermia, diaphoresis, rigidity, mental status changes, tachypnea, tachycardia, and hypertension or labile blood pressure. Patients with neuroleptic malignant syndrome typically have hyporeflexia, normal pupillary responses, and normal or decreased bowel sounds, whereas serotonin syndrome is associated with hyperreflexia, dilated pupils, and hyperactive bowel sounds. Patients with neuroleptic malignant syndrome often have laboratory abnormalities that are not present in serotonin syndrome, including peripheral leukocytosis, elevated serum creatine kinase, increased liver enzymes, and low serum iron, magnesium, and calcium levels. The pathophysiology of these two syndromes is poorly understood. The elevated body temperatures are at least partly due to increased muscle activity, but increased sympathetic activity and increased levels of acute-phase reactants probably contribute to the hyperthermia of neuroleptic malignant syndrome, and nonshivering thermogenesis in brown adipose tissue and cutaneous vasoconstriction may contribute to the hyperthermia of serotonin syndrome. Neuroleptic malignant syndrome is typically triggered by exposure to neuroleptic agents, including atypical antipsychotic agents, but it has also been described in patients being treated for presumed Parkinson disease after sudden withdrawal of dopaminergic agents or changes in their medication regimen (sometimes referred to as parkinsonism hyperpyrexia). When associated with neuroleptics, the condition typically arises within 2 weeks of starting therapy or increasing the dose, but at times it may begin within hours or after a delay of months. Serotonin syndrome can occur with any serotonergic drugs—notably tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and meperidine—especially when used in combination.