Aetiology
It is believed that MH-susceptible individuals may differ in muscular performance and sensitivity to heat. Susceptibility to MH is inherited in an autosomal-dominant pattern with highly variable penetrance.[29] For this reason, a positive family history greatly increases the risk of an individual developing MH. Susceptibility to MH is sub-clinical, and MH itself seems to only be triggered by an exacerbating factor.[10]
The most common trigger is exposure to a potent inhalation anaesthetic.[6] Any potent inhalation anaesthetic can cause MH, including desflurane and sevoflurane.[1][30] Succinylcholine (suxamethonium) exacerbates the effect of the anaesthetic, and can sometimes trigger MH on its own.[5][6][16][27] Rarer triggers include intense physical activity, exercise-induced rhabdomyolysis, febrile illness, or repeated episodes of heat-related illness.[8][11][12][13] Case reports of non-anaesthetic-triggered MH episodes have inspired the search for a link between exercise-induced rhabdomyolysis, stress-induced malignant hyperthermia, and malignant hyperthermia susceptibility.[9][14][31] Computational analyses of the molecular RYR1 gene sequence variations show that some RYR1 sequence variations are associated with these three phenotypes. This shared characteristic among phenotypes underscores the importance of screening these patients for RYR1 variants to determine possible malignant hyperthermia susceptibility.[19][31][32] Longer exposure and higher doses of inhalation anaesthetics increase the risk of triggering an MH episode.[27]
The risk of MH may be altered by the presence of other muscle pathologies. Some myopathies, such as central core disease, multi-minicore disease, and syndromes such as the King-Denborough syndrome, are associated with MH, and therefore affected patients should have non-triggering anaesthetic techniques such as regional or total intravenous anaesthesia.[7][33][34]
In a retrospective study investigating the reason for referral for MH testing in non-anaesthetic related cases, a positive caffeine halothane contracture test (CHCT) among probands suggested the presence of an underlying muscle disorder whereby patients may exhibit muscle symptoms without exposure to MH-triggering anaesthetics.[35]
Pathophysiology
The process that leads to MH is initiated by an increase in calcium levels in the sarcoplasm. This can be produced by several mechanisms, primarily by gain-of-function mutations in the proteins that constitute the excitation-contraction coupling mechanism in skeletal muscle:[36]
Increased basal calcium influx: RYR1 channels, present in muscles susceptible to MH, have an increased calcium channel open probability, and therefore allow an abnormally high baseline calcium influx from the sarcoplasmic reticulum to the sarcoplasm.[37]
Increased stimulated calcium influx: RYR1 channels susceptible to MH are more sensitive to activators such as inhalation anaesthetics and less sensitive to inhibitors such as magnesium. This produces more easily triggered and prolonged calcium influx in response to stimulation.[38]
The redox state of muscle cells can alter the function of the RYR1 channel.[39]
Elevated temperature can alter the function of RYR1 channels.[40] Temperature elevation in a patient susceptible to MH could therefore accelerate MH by producing a further increase in calcium influx.
Other intracellular pathways implicated in the regulation of intracellular calcium and the extracellular calcium reservoir include store operated calcium entry (SOCE) and calcium-binding proteins such as calsequestrin-1, which influence the function of the RYR1 receptor in the sarcoplasmic reticulum.[41]
Gene variants in CACNA1S (coding for the alpha-1 subunit of the dihydropyridine receptor [DHPR]) have been identified as causative for MH, although these account for less than 1% of MH cases.[7][23] During excitation-contraction, depolarisation of the DHPR is followed by opening of the RYR1 channel.
Stac3 is a protein that interacts with the DHPR alpha-1 subunit and with RYR1 in muscle triads.[42] Mutations in STAC3, the gene that encodes this protein, have been found in myopathic people who experienced MH episodes.[42][43]
The extra calcium allowed into the sarcoplasm by the abnormal RYR1 channels must be moved back into the sarcoplasmic reticulum. This process requires ATP and therefore drives an increase in metabolism.[44][45][46] As metabolism rises, heat and carbon dioxide production rises with it. Once metabolism has increased to elevate core temperature to critical levels, multi-organ system failure can evolve from the effects of heat alone.[47]
Tissue susceptible to MH may also be more susceptible to heat injury, as it has sometimes been noted that central nervous system injury following an episode of MH is greater than expected given the status of the circulation and core temperature measurement.
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