Last week there was a startling article in the New York Times about the area of the brain responsible for fever. In light of last week’s Medical Monday’s posts from Plum and Posner’s Diagnosis of Stupor and Coma we decided to revisit the text to learn more about fevers. Below is an enlightening excerpt.
Fever, the most common cause of hyperthermia in humans, is a regulated increase in body temperature in response to an inflammatory stimulus. Fever is caused by the action of prostaglandin E2, which is made in response to inflammatory stimuli, on neurons in the preoptic area. The preoptic neurons then activate thermogenic pathways in the brain that increase body temperature. It is rare for fever to produce a body temperature above 40C to 41C, which has only limited effects on cognitive function. Hence, changes in consciousness in patients with fever are mainly due to neuronal effects of the underlying inflammatory condition itself, not the change in body temperature.
On the other hand, hyperthermia of 42C or higher, which is sufficient to produce stupor or coma, can occur with heatstroke. Heat stroke, caused by failure of the brain’s physiologic mechanisms for heat dissipation, occurs most commonly in young people who exercise unduly in heat to which they are not acclimatized, and in older people (who presumably possess less plastic adaptive mechanisms), particularly during the summer’s first hot spell. It is a particular threat in patients taking anticholinergic drugs, which interfere with heat dissipation by inhibiting sweating, and is also seen in rare patients with hypothalamic lesions who lack appropriate thirst and vasopressin responses to conserve fluid.
Clinically, heat stroke typically begins with headache and nausea, although some patients may first come to attention due to a period of agitated and violent delirium, sometimes punctuated by generalized convulsions, or they may just lapse into stupor or coma. The patient’s skin is usually hot and dry, although sweating occasionally persists during the course of heat stroke. The patient is tachycardic, may be normotensive or hypotensive, and may have a serum pH that is normal or slightly acidotic. The pupils are usually small and reactive, caloric responses are present except terminally, and the skeletal muscles are usually diffusely hypotonic in contradistinction to malignant hyperthermia (see below). The diagnosis is made by recording an elevated body temperature, generally in excess of 42C.As with hypothermia, clinical thermometers usually reach a maximum at 108F or 42C, but a temperature of this level does not mean that the patient cannot be warmer.
Heatstroke is easily distinguished from fever because fever of all types is governed by neural mechanisms and does not reach 42C. It is produced by peripheral vasoconstriction and increased muscle tone and shivering (i.e., the opposite pattern to hyperthermia). The main danger of heatstroke is vascular collapse due to hypovolemia often accompanied by ventricular arrhythmias. Patients with heat stroke must be treated emergently with rapid intravenous volume expansion and vigorous cooling by immersion in ice water, or ice, or evaporative cooling (a cooling blanket is far too slow). If cardiac arrest is avoided, permanent neurologic sequelae are rare. However, some patients exposed to very high temperatures for a prolonged time are left with permanent neurologic residua including cerebellar ataxia, dementia, and hemiparesis.
Hyperthermia may also occur in patients after severe traumatic brain injury. In most cases this is a fever response due to the presence of inflammatory cytokines within the blood-brain barrier. However, in some cases (e.g., preoptic lesions or pontine hemorrhages) it may be due to damage to descending neural pathways that inhibit thermogenesis. Risk factors in patients with traumatic brain injury include diffuse axonal injury and frontal lobe injury of any type, but hyperthermia is common when there is subarachnoid hemorrhage as well. Characteristically the patient is tachycardic, the skin is dry, and the temperature rises to a plateau that does not change for days to a week. The fever is resistant to antipyretic agents and usually occurs several days after the injury. The prognosis in patients with fever due to brain injury is worse than those without it, but whether that is related to the extent of the injury or the hyperthermia is unclear.
Three related syndromes related to intake of drugs may cause severe hyperthermia. These syndromes are the neuroleptic malignant syndrome, malignant hyperthermia, and the serotonin syndrome. The syndromes, although clinically similar, can be distinguished both by the setting in which they occur and by some differences in their physical sign. The neuroleptic malignant syndrome is an idiosyncratic reaction either to the intake of neuroleptic drugs or to the withdrawal of dopamine agonists. The disorder is rare and generally begins shortly after the patient has begun the drug (typical drugs include high-potency neuroleptics such as haloperidol, and atypical neuroleptics such as risperidone or prochlorperazine, but phenothiazines and metoclopramide have also been reported). The onset is usually acute with hyperthermia greater than 3C and delirium, which may lead to coma. Patients are tachycardic and diaphoretic with rigid muscles and may have dystonic or choreiform movements. There is usually leukocytosis and there may be a dramatically elevated creatine kinase level. Rhabdomyolysis leading to renal failure may occur. The diagnosis can be made by recognizing that the patient has been on a neuroleptic agent (usually for a short time) or has withdrawn from dopamine agonists. Hyperreflexia, clonus, and myoclonus, which characterize the serotonin syndrome (see below), are usually not present. The neuroleptic malignant syndrome does not typically occur on first exposure to the drug, or if the patient is rechallenged, and may be due to the coincident occurrence of a febrile illness and increased muscle tone in a patient with limited dopaminergic tone.
Malignant hyperthermia occurs in about one in 50,000 adults during induction of general anesthesia. As the name indicates, the patients become hyperthermic and develop tachycardia and muscle rigidity with lactic acidosis. Serum creatine kinase is elevated and patients may develop rhabdomyolysis. Pulmonary and cerebral edema can develop late and be potentially fatal. The syndrome occurs with a variety of anesthetics and muscle relaxants in patients who have genetic defects of one of several receptors controlling the release of sarcoplasmic calcium in skeletal muscle. When exposed to the agent, sudden increases in intracellular calcium result in the clinical findings. Dantrolene sodium is an effective
The serotonin syndrome results when patients take agents that either increase the release of serotonin or inhibit its uptake. Common causes include cocaine and methamphetamine as well as serotonin reuptake inhibitors. Less common causes include dextromethorphan,meperidine, l-dopa, bromocriptine, tramadol, and lithium. Patients become delirious or stuporous. They are febrile, diaphoretic, and tachycardic and demonstrate mydriasis. Reflexes are hyperactive with clonus. Spontaneous myoclonus as well as muscular rigidity may be present. More serious intoxication may lead to rhabdomyolysis, metabolic acidosis, and hyperkalemia. The disorder usually begins within 24 hours of having taken the medication. It is rather abrupt in onset; patients usually