Malignant Hyperthermia

Malignant hyperthermia is a hereditary skeletal muscle disease characterized by a hypercatabolic reaction of muscle to anesthetic agents or to physical or emotional stress.

Pathogenesis and Pathophysiology. The central event in malignant hyperthermia appears to be an increase in the calcium concentration, which results in continuous activation of the actin-myosin contraction apparatus and sustained muscle contraction. This increase in calcium level is due to an increased release of calcium from the sarcoplasmic reticulum of the muscle combined with a reduction in calcium reuptake. The continuous muscle activity results in muscle rigidity, muscle necrosis, hyperpyrexia, and hypermetabolism. Linkage has been found to chromosome 19q13.1. A ryanodine receptor gene in this region has been shown to have mutations in a proportion of cases. The ryanodine receptor is a calcium-releasing channel involved in calcium homeostasis. Linkage has also been found to chromosome 17q1.2-24, which codes for the alpha subunit of the sodium channel, and to chromosomes 7q and 3q. y , y

Epidemiology and Risk Factors. Malignant hyperthermia has a worldwide distribution and an incidence of 1 in 12,000 anesthetic incidents in children and 1 in 50,000 anesthetic events in adults. y However, it is possible that many mild cases are unrecognized and are mistaken for other anesthetic complications. Males are more often affected than females, and there is a peak incidence at the age of 30 years. Thereafter, the incidence declines, and cases are virtually unheard of beyond the age of 75 years. y

Clinical Features and Associated Disorders. The most common precipitating event is halothane general anesthesia. The muscle relaxant succinylcholine is a milder trigger of attacks when administered alone but is more potent when combined with halothane. The likelihood of triggering an attack with these agents is increased if the patient has been exercising vigorously beforehand or is under stress at the time of anesthetic induction. Between attacks of malignant hyperthermia, patients rarely have any muscle symptoms, although some muscle diseases, such as congenital myopathies, are associated with attacks of malignant hyperthermia. In 50 percent of cases of malignant hyperthermia, patients may have had previous anesthesia without complications. y Attacks often start with jaw spasm followed by generalized muscle spasm and rigidity. These signs are associated with hyperventilation, tachycardia, and an unstable blood pressure. A mottled, flushed, and cyanotic skin rash may appear. After an interval of 15 to 16 minutes, the body temperature may start to rise precipitously. Metabolic and respiratory acidosis, hypoxemia, generalized vasoconstriction, and an increased cardiac output occur. The serum potassium may rise, and the CK may rise 100-fold. Consequent complications of myoglobinuria and disseminated intravascular coagulation may occur, either of which can lead to renal failure. During recovery, patients may experience a further relapse with signs and symptoms.

Differential Diagnosis. The condition that most closely resembles malignant hyperthermia is the neuroleptic malignant syndrome (NMS), in which patients have an abnormal response to dopamine-blocking agents or levodopa withdrawal. Patients with NMS develop rigidity with hyperthermia and have many of the same biochemical features seen in malignant hyperthermia. Neuroleptic malignant syndrome usually occurs in patients with psychiatric disease who are undergoing neuroleptic drug treatment or, rarely, with the abrupt cessation of levodopa. Acute dystonic reactions to drugs such as neuroleptics or antiemetics may produce a similar picture of increased muscle tone. Patients with myotonia may also develop rigidity with the use of depolarizing agents during anesthetic induction.

Evaluation. During the acute illness the main emphasis of the evaluation is on monitoring possible hyperkalemic, cardiac, respiratory, or renal complications, so that appropriate measures can be taken. Evaluation of well patients thought to be at risk of developing malignant hyperthermia can be difficult. Only a few have a raised CK level. The genetic heterogeneity of the disease and the fact that even the recognized point mutations cover only a small percentage of the patients at risk limit the value of genetic testing. A variety of in vivo tests have been purported to highlight individuals at risk, but these are not particularly reliable. The screening test typically used is the in vitro caffeine and halothane contracture test. In this study an exaggerated response to these agents in freshly isolated muscle is observed in patients with a predisposition to malignant hyperthermia. This test is performed only in specialized centers. Unfortunately, an overlap between normal and affected individuals occurs, and false-positive tests are possible. y

Management and Prognosis. Preventive measures include the avoidance of precipitating agents, namely, halothane and succinylcholine, but many other agents pose some risk in susceptible individuals. Patients should be advised to wear Med-Alert bracelets to warn of their susceptibility to malignant hypothermia. Narcotics, barbiturates, benzodiazepines, nitrous oxide, and nondepolarizing muscle relaxants are generally safe. Acute management consists of removal of the triggering agents and supportive measures as required. Body cooling may be required in response to the hyperthermia, which if allowed to continue aggravates the metabolic derangement. Dantrolene is the mainstay of treatment; when given intravenously, it results in the reversal of the abnormalities. The mortality rate has dropped since the use of this agent has been instituted. Improved recognition of this complication and better supportive measures with the availability of dantrolene have

resulted in a dramatic drop in mortality from 65 to 2 percent. Brody's Disease

This disorder was first described by Brody in 1969. y Although it resembles myotonia clinically, the crucial difference is that the EMG of affected muscle shows no myotonic discharges. This is a rare disorder, and only about 21 cases have been recorded in the literature. y

This disorder usually begins in childhood, and patients often have difficulty in keeping up with their peers in physical activities. They have poor relaxation of muscles, initially in the limbs but later in the face and trunk as well. This pseudomyotonia is made worse by exercise and cold weather, and myoglobinuria occurs in some. On examination, these patients are found to have eyelid and grip but not percussion myotonia. There may be mild muscle atrophy and weakness in the final stages of the disease.

This pseudomyotonia is thought to result from abnormalities in sarcoplasmic reticulum Ca2+ ATPase, a transmembrane protein responsible for extruding calcium out of the cytoplasm and into the sarcoplasmic reticulum. This 100-kD protein is coded for on chromosome 16 and is deficient in amount or activity, particularly in type 2 muscle fibers.y Genetic heterogeneity is suggested by reports of autosomal dominant and either autosomal or X-linked recessive inheritance.

The differential diagnosis of Brody's disease includes myotonia and pseudomyotonia as described earlier. The CK level may be normal or slightly elevated, particularly in patients with associated myoglobinuria. Muscle biopsy shows type 2A and B atrophy with angulated fibers. eMg shows electrical silence during the time of apparent myotonia. Biochemical and immunological assays of sarcoplasmic reticulum Ca2+ ATPase may be employed to make the diagnosis.

Empirical treatment with dantrolene and calcium channel blockers has been used with varying success. The disease is slowly progressive or stationary, but in some individuals exercise-induced pseudomyotonia becomes worse as they get older.

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