The pathogenesis of malignant hyperthermia has been the subject of numerous investigations. During the rigor phase, oxygen consumption in muscle increases threefold and serum lactate, 15to 20-fold. Muscle from most affected individuals is abnormally sensitive to caffeine, which induces contracture in vitro. It has been postulated that halothane acts in a manner similar to caffeine—that is, to release calcium from the sarcoplasmic reticulum and prevent its reaccumulation, thus interfering with relaxation of the muscle. The essential physiologic change is one of increased intracellular calcium.
Insight into the disease has been gained from a breed of pigs, inbred for muscular development, in which muscle spasm (true contracture) and hyperthermia follow the administration of anesthetic agents. These swine have an inherited defect in the ryanodine receptor, a protein component of the calcium channel of the sarcoplasm that is sensitive to both caffeine and ryanodine. However, one of several similar defects in ryanodine is found in somewhat fewer than 20 percent of people with the susceptibility to malignant hypothermia. It is presumed that other yet unidentified allelic mutations of this receptor protein or another that controls the structure of the calcium channel account for the remainder of cases. The cause of the high fever is unknown; it is probably caused by the muscle spasm, but an effect of the anesthetic on heat-regulating centers has not been excluded.
Clues as to which patients are at risk for this condition come from several sources. Other members of the family may have difficulties or have died during anesthesia. Some susceptible individuals exhibit myopathic and musculoskeletal abnormalities (Isaacs and Barlow). One such dysmorphic constellation consists of short stature, ptosis, strabismus, highly arched palate, dislocated patellae, and kyphoscoliosis, which have been present in several families (King-Denborough syndrome, see Denbrough, Forster and Lovell). As mentioned just above and in Chap. 45 on the congenital myopathies, central core (sometimes called multicore) myopathy is frequently complicated by malignant hyperthermia. This is understandable insofar as both disorders have been linked to the gene encoding the ryanodine receptor; the 2 diseases are a result of allelic variations (Quane et al). It has been pointed out that another rare muscle disease (Evans myopathy, named after the affected family) may also be a predisposing condition. It is inherited as an autosomal trait and may be asymptomatic until the anesthetic reaction but some patients have wasting of the distal thigh muscles and an elevation of serum CK concentration (see Harriman et al).
Diagnostic testing Various tests for susceptibility to malignant hyperthermia have undergone phases of popularity. The only currently valid one involves in vitro exposure of a muscle biopsy specimen to halothane and to caffeine and the detection of muscle contracture with both agents. This is performed only in a few centers, which are listed at http://www.mhaus.org. The review by Denborough may be consulted for further details on the testing and clinical aspects of the disease.