Abnormalities of Thermal Regulation and the Nervous System

Keywords

autonomic nervous system, heat exhaustion, heat stress disorder, heat stroke, hyperthermia, hypothalamus, hypothermia, malignant hyperthermia, neuroleptic malignant syndrome, ryanodine, serotonin syndrome, thermoregulation

Thermoregulatory System

Thermoregulatory regions in the preoptic, anterior, and dorsomedial hypothalamus integrate thermal inputs to produce an output that adjusts body temperature to match a set point. Thermoregulatory disorders may be produced either by malfunction of this system or by conditions that overwhelm its capacity.

Thermoregulatory disorders should be distinguished from other causes of abnormal body temperature, in which the thermoregulatory system functions properly but the set point is shifted. The most common condition of this type is fever, which is produced by an abnormal upward shift of the set point. Shifts in the set point may also be responsible for variations of body temperature with the menstrual cycle and for diurnal temperature fluctuations.

The afferent limb of the thermoregulatory system includes skin thermosensors, visceral thermosensors, vascular thermosensors, and neurons within the hypothalamic regulatory areas that are sensitive to the temperature in the hypothalamus itself. Thermosensitive neurons are also present in the brainstem and spinal cord and, possibly, in the abdominal viscera. The molecular mechanisms mediating temperature sensitivity are not known, but the transient receptor potential family of cation channels appear to play a role, at least in the skin thermosensors.

The efferent limb of the system generates or dissipates heat, as necessary. Basal metabolic activity produces heat, and within a narrow range of ambient temperatures called the thermoneutral zone, the core temperature can be maintained by adjusting metabolic rate. Outside this range, heat generation is achieved primarily by shivering. Newborn infants do not shiver, and shivering is probably not fully effective until several years of age; before then, non-shivering thermogenesis occurs in brown adipose tissue. The mitochondria of brown adipose tissue contain an uncoupling protein that, when induced, diverts the energy generated by oxidative phosphorylation into heat production rather than ATP synthesis, so that heat becomes the primary product of metabolism rather than a byproduct as in other tissues. Nonshivering thermogenesis may possibly also occur in older children and adults. Heat dissipation is achieved by evaporation (sweating) and by nonevaporative heat loss (conduction, convection, and radiation). Evaporative heat loss is the most important of these mechanisms in most clinical situations. Nonevaporative heat loss can occur only when the ambient temperature is lower than the skin temperature. The amount of heat dissipated is then a function of vasomotor activity; increased skin blood flow promotes heat dissipation, and reduced skin blood flow minimizes it. These thermoregulatory vasomotor effects are controlled by both the hypothalamus and local reflexes, and can be modified by exercise, reproductive hormones, aging, and disease. The local vasomotor reflexes can override the hypothalamic regulation under extreme local temperature conditions.

Neurologic Causes of Abnormal Thermoregulation

The main neurologic causes of abnormal thermoregulation are diseases of the hypothalamus or its autonomic outflow. In addition, a few neurologic disorders result in excessive heat production that overwhelms the thermoregulatory system. Tables 37-1 and 37-2 summarize the main causes of hyperthermia and hypothermia.

Table 37-1

Causes of Hyperthermia

Malfunction of Thermoregulatory System

Hypothalamic disorders

Tumor

Stroke

Encephalitis

Head trauma

Surgery

Other lesions

Hydrocephalus

Posterior fossa surgery

Interruption of Effector Pathways

Spinal cord lesions

Autonomic neuropathies

Overwhelming Heat Production or Exposure

Neurologic conditions

Status epilepticus

Delirium tremens

Tetanus

Malignant hyperthermia

Neuroleptic malignant syndrome

Serotonin syndrome

Non-neurologic conditions

Heat stress disorders (exertional or nonexertional)

Heat shock

Heat exhaustion

Endocrine disorders

Thyrotoxicosis

Pheochromocytoma

Drugs

Inadequate Heat Dissipation

Dehydration

Skin disorders

Occlusive dressings

Drugs

Table 37-2

Causes of Hypothermia

Malfunction of Thermoregulatory System

Hypothalamic disorders

Tumor

Stroke

Subarachnoid hemorrhage

Sarcoidosis

Wernicke encephalopathy

Parkinson disease

Primary autonomic failure

Multiple system atrophy

Multiple sclerosis

Agenesis of the corpus callosum (Shapiro syndrome)

Disease at the mesencephalic-diencephalic junction

Interruption of Effector Pathways

Spinal cord lesions

Autonomic neuropathies

Neuromuscular causes of weakness

Inadequate Heat Production

Accidental hypothermia (exposure)

Endocrine disorders

Hypothyroidism

Hypoadrenalism

Hypopituitarism

Derangements of glucose regulation

Hypoglycemia

Diabetic ketoacidosis

Hyperosmolar coma

Malnutrition

Drugs

Excessive Heat Dissipation

Severe burns

Skin disorders (exfoliative dermatitis, psoriasis, ichthyosis, erythroderma)

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 diabetics 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 CNS can impair thermoregulation, but the precise mechanism is often difficult to establish. Degenerative diseases including multiple sclerosis can be associated with hypothermia, and hyperthermia has been reported in patients with acute hydrocephalus, posterior fossa surgery, ischemic strokes, and intracranial hemorrhage. As a general rule, however, 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

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 calsequestrin, a calcium-binding protein that modulates ryanodine receptor function. Mutations in the gene for the ryanodine receptor also cause central core disease, a congenital myopathy; some, but not all, patients with central core disease are also at risk of malignant hyperthermia. Nemaline rod myopathy and multiminicore disease are myopathies that are also caused by mutations in the ryanodine receptor, but these conditions do not appear to be associated with an increased 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.

Neuroleptic Malignant Syndrome and Serotonin Syndrome

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 there may also be an elevation of the hypothalamic temperature set point. 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. 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.

Neurologic Consequences of Abnormal Thermoregulation

Most cases of abnormal thermoregulation occur in individuals without a primary neurologic disease and are caused by external temperature conditions (or, less commonly, internal metabolic derangements) that overwhelm the thermoregulatory system. Regardless of the underlying cause, neurologic manifestations are often prominent.

Neuronal function is significantly affected by even moderate changes in temperature. Basic electrical parameters (such as membrane capacitance, axoplasmic resistance, maximal sodium and potassium conductances, and ion channel rate constants) vary systematically with temperature. Consequently, temperature affects the action potential amplitude, duration, maximal rate of rise, net ionic movements, and conduction velocity, and therefore changes the likelihood of signal propagation or conduction block. Clinical electrophysiologic tests reflect these effects; for example, the maximal motor conduction velocity of the ulnar nerve falls by 2.4 m/sec for every 1°C decline in temperature. As the temperature drops, compound action potential amplitudes increase, the duration of motor unit action potentials increases, mean amplitude declines, and polyphasic potentials become more frequent. Hypothermia also prolongs the latencies of visual, somatosensory, and brainstem auditory evoked potentials.

Although these alterations in function can have clinical consequences, actual nervous system injury does not occur until extreme temperatures are reached. Direct thermal injury to the brain and spinal cord results in the production of a variety of cytokines and altered expression of heat-shock proteins, leading to endothelial cell injury and diffuse microvascular thrombosis, ultimately causing cell death, edema, and hemorrhage.

Cerebral metabolic rate and oxygen metabolism increase with rising temperatures between 38°C and 42°C, but decline as temperatures rise further. Hypothermia leads to slowing of the rate of chemical reactions, decrease in the metabolic requirement for oxygen, and reduction of cerebral blood flow by 4.4 to 6.0 percent for every 1°C decline in temperature. This reduction in metabolic rate is protective, but neural damage still occurs. It is difficult to know to what extent the neuronal damage is a direct effect of low temperatures rather than a consequence of secondary injury from the systemic effects of hypothermia (including cardiovascular collapse).

Hyperthermia

The neurologic causes of hyperthermia were considered earlier.

Non-Neurologic Causes

Conditions in which the thermoregulatory system is overwhelmed by extremely high external temperatures are called heat stress disorders. The most severe form is heat stroke, defined as a core body temperature exceeding 40°C (or 41°C according to older sources) associated with CNS dysfunction such as delirium, seizures, or coma. Heat stroke is characterized by hot, dry skin, but this is not used as a diagnostic criterion. Heat exhaustion is a milder form, characterized by progressive lethargy, headache, vomiting, tachycardia, and hypotension, with less severe neurologic impairment than occurs in heat stroke. These two conditions form a continuum: if untreated, heat exhaustion may progress to heat stroke.

Classic heat stroke results from prolonged exposure to high environmental temperatures while the individual undertakes normal activities; exertional heat stroke occurs in situations of physical exertion, typically in healthy young individuals, often athletes or military personnel. Inadequate cardiovascular conditioning, poor acclimatization, dehydration, heavy clothing, low work efficiency, and reduced ratio of skin area to body mass all are risk factors. Congenital or acquired abnormalities of sweat gland function may contribute. Classic heat stroke is typically seen in the elderly, especially in those with chronic diseases (e.g., alcoholism, malnutrition, diabetes, cardiovascular dysfunction, obesity). Some medications predispose to the condition, including anticholinergics, β-blockers, diuretics, antihistamines, antidepressants, and amphetamines. People in lower socioeconomic groups are at particular risk, especially those living in urban areas, because they may be exposed to a greater thermal load and live in apartments with inadequate ventilation.

The most common cause of hyperthermia is simple dehydration because it results in vasoconstriction and decreased sweating, interfering with heat dissipation. Heat dissipation may also be impaired in advanced scleroderma or in miliaria, or by extensive use of occlusive dressings. Both thyrotoxicosis (mainly during thyroid storm) and pheochromocytoma may cause hyperthermia on the basis of hypermetabolism. Drug exposure can also produce hyperthermia in several ways, including increased metabolic rate, hyperactivity, and impaired heat dissipation ( Table 37-3 ).

Table 37-3

Pharmacologic Agents that Promote Hyperthermia

Agent	Excess Heat Production		Impaired Heat Dissipation		Other Mechanisms
	Occurrence	Cause or Comment	Occurrence	Cause
Anticholinergic agents			+
Vasoconstricting agents			+
β-Blockers			+
Diuretics			+
Antihistamines			+
Barbiturates			+
Alcohol			+
Topiramate			+	Hypohidrosis
Zonisamide			+	Hypohidrosis
Tricyclic antidepressants	+	Increased motor activity	+	Anticholinergic effects
Cocaine	+
Amphetamines	+
Opiates	+
Lysergic acid diethylamide (LSD)	+
Cannabinoids	+
Phenothiazines	+	Neuroleptic malignant syndrome	+	Anticholinergic effects	Possible effect on hypothalamus
Butyrophenones	+	Neuroleptic malignant syndrome			Failure to recognize thirst, possible effect on hypothalamus
Atypical antipsychotics	+	Neuroleptic malignant syndrome
Salicylate overdose	+
Anticholinesterase agents					Cause unknown
Methyldopa					Idiosyncratic
Propylthiouracil					Idiosyncratic
Inhalational anesthetics	+	Malignant hyperthermia
Monoamine oxidase inhibitors (overdose in conjunction with meperidine or biogenic amine precursors)	+	Serotonin syndrome
Serotonin reuptake inhibitors	+	Serotonin syndrome
Triptans (in conjunction with SSRIs or SNRIs)	+	Serotonin syndrome