Malignant hyperthermia

History

Malignant hyperthermia (MH) is a serious and possibly fatal syndrome of skeletal muscle hypermetabolism and calcium dysregulation that occurs when genetically susceptible individuals are exposed to certain anesthetic “triggering” agents, specifically the potent halogenated inhaled volatile anesthetics and the nondepolarizing neuromuscular blocker succinylcholine. The reaction was first alluded to in a textbook published in 1952 by Arthur E. Guedel and more clearly delineated in 1960 by Denborough and Lovell, Australian physicians who took an interest in a young man who required surgery for a fractured tibia, claiming that 10 members in his family developed a fatal hyperthermic reaction during or immediately after the administration of general anesthesia for minor procedures. The same authors published a more definitive account of this family in 1962, demonstrating that the susceptibility to this strange reaction occurred in an apparent autosomal dominant fashion with incomplete penetrance ( ). The term “malignant hyperthermia” was first coined by Dr. Rod Gordon, *

* According to Tom Nelson (who learned of this from his interview with Beverly Britt), Dr. Gordon chose “malignant hyperthermia” rather than “malignant hyperpyrexia” because the word “hyperthermia” is entirely of Latin derivation, whereas the word “hyperpyrexia” is a mixture of Latin and Greek, which, to him, would have been inappropriate. (Dr. Gordon’s undergraduate degree was in the classics.)

then Chair of the University of Toronto Department of Anesthesia ( ). But, as our understanding of MH has moved beyond the mysterious presentation of high temperature and high mortality, many experts agree the syndrome should be more appropriately named “malignant hypermetabolism.” This would reflect the range of hypermetabolic signs that characterize and more closely reflect the underlying pathophysiology, such as sinus tachycardia, hypercarbia, and a mixed respiratory and metabolic acidosis (see later discussion) ( ). We know now that this presentation of the classically defined MH crisis is only one type of clinical presentation of MH-related disorders. Inheritance of an MH-causative RYR1 variant (see section on genetic origins) is associated with a wide range of phenotypic varieties of normal and abnormal muscle strength, from exceedingly strong to severely debilitated ( ). These individuals might be particularly susceptible to chronic pain and fatigue ( ), exertional heat stroke ( ), statin myopathy ( ), exercise-induced rhabdomyolysis ( ; ; ), or spontaneous development of life-threatening MH-like symptoms in the absence of anesthetic triggering agents ( ; ).

In this chapter, we provide an overview of the most current knowledge of MH. Most of this information has been gleaned from research and case reports in adult patients; very little is known about the differences between adult and pediatric patients who develop MH, but these differences have been noted when available.

Genetic origins of MH

MH susceptibility is conferred by the inherited or spontaneous (de novo) acquisition of a variant in genetic loci that encodes for proteins that are integral for normal functioning of the skeletal muscle excitation-contraction (EC) complex. They include RYR1 , which encodes for the ryanodine receptor; CACNA1S , which encodes for the alpha-1 subunit of the dihydropyridine receptor; and STAC3 , which has an unknown function in the complex. *

* By convention, the names of protein structures, such as RYR1, are written in normal font, whereas the genes that encode for them are written in italicized font (e.g., RYR1 ).

A comprehensive discussion of genetic terminology is beyond the scope of this chapter; however, to be consistent with the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology, the terms “pathogenic variant” or “likely pathogenic variant” indicate a single nucleotide change in the genetic sequence that likely leads to MH susceptibility ( ). In contrast to most other genetic diseases, the variants in MH do not lead to a loss of function but rather induce a gain of function—that is, increased myoplasmic calcium concentration. A current listing of these MH-causative variants is located on the European MH Group (EMHG) website ( http://www.emhg.org ).

RYR1

In 1990, two research groups independently sequenced the RYR1 gene, located on chromosome 19 ( ; ). The same RYR1 variant found in MH-susceptible pigs (c.1841C>T, p.Arg615Cys) was identified in MH-susceptible humans (c.1840C>T, p.Arg614Cys). The following years of research focused on RYR1, a relatively large gene with more than 150,000 base pairs coding for over 500 amino acids in 106 exons. Molecular genetic technology was less sophisticated than it is today, and sequencing of the full coding sequence of RYR1 was laborious and expensive. Therefore research laboratories focused primarily on previously identified “hotspot” areas with a relatively higher concentration of abnormal variants ( ). This led to a selection bias, and these hotspots are occasionally still cited today. With advances in technology, high throughput sequencing has confirmed that there are no hotspots; rather, sequence variants are spread out along the entire RYR1 gene ( ).

For a novel variant to be recognized as pathogenic (or likely pathogenic) it has to be investigated for its functional effect ( ). This is a laborious process that is only performed by highly specialized research laboratories. Thus functional testing is currently the bottleneck of testing for MH-causative variants. Although more than 400 variants have been identified in RYR1 , less than 50 have been classified as pathogenic and considered diagnostic (see https://www.emhg.org/diagnostic-mutations ). Very few variants are classified as benign, whereas the remainder of RYR1 variants is currently classified as variants of unknown significance (VUS).

CACNA1S

CACNA1S is the gene encoding for the alpha-1 subunit of the dihydropyridine receptor. Pathogenic variants in CACNA1S have been identified in a small subset of MH-susceptible patients, which are approximately 1% of all MH-susceptible families ( ). Thus far, RYR1 and CACNA1S remain the only loci where these variants have been identified in patients that experienced MH ( ; ).

STAC3

STAC3 is a protein required for EC coupling in skeletal muscle. It appears to facilitate calcium release from the sarcoplasmic reticulum, probably through interaction with calcium channels, and has a direct influence on the function of the dihydropyridine receptor. When subjected to functional analysis, variants in the STAC3 gene are associated with a disturbance of EC coupling, whereas the function of RYR1 remains intact ( ). The homozygous variant c.851G>C p.Trp284Ser in the STAC3 gene leads to an autosomal recessive muscle disease known as Native American myopathy (NAM) ( ), which has been associated with MH susceptibility ( ; ).

Testing for MH susceptibility

There are currently two methods to determine MH susceptibility: molecular genetic testing for known MH-causative variants, and an open muscle contracture biopsy test.

Molecular genetic testing

Molecular genetic testing uses an individual’s DNA specimen, such as blood or buccal smear. It is noninvasive, and the sample can be sent from anywhere in the world. A positive result (finding the presence of a pathogenic or likely pathogenic variant) confirms MH susceptibility. A negative result, however, cannot rule out MH susceptibility because of known discordances between contracture testing and molecular genetic results; many families exist in whom a pathogenic variant has not been detected but has been proven MH susceptible either by a convincing clinical event or a positive contracture biopsy ( ; ; ; ). Thus MH can only be excluded by negative contracture biopsy testing.

Contracture biopsy

A contracture biopsy test requires an open incision (usually from the quadriceps muscle, using either regional anesthesia or trigger-free general anesthesia) for immediate testing to determine the muscle’s contracture properties when exposed to halothane and caffeine. Its most important advantage is its high sensitivity (at least 99%); a negative result rules out MH susceptibility. Its main disadvantages are its surgical invasiveness and limited availability at only several centers throughout the world. *

* https://www.mhaus.org/testing/muscle-biopsy-chct/chct-muscle-biopsy-testing-centers/

It must be performed at one of these centers to obtain a fresh muscle sample (mass at least 3 grams). In North America the test is called the caffeine-halothane contracture test (CHCT), and in European centers it is called the in-vitro contracture test (IVCT). The protocols differ slightly but both have a sensitivity close to 100% and a reasonably high specificity (yielding some possible false positive tests). Because of the size of the muscle required for analysis, children who weigh less than about 40 kg are usually excluded from testing, but this is biopsy-center dependent. ^†

† For a video of the CHCT, see: https://www.mhaus.org/videos/faq-video-muscle-biopsy-testing/

See Box 52.1 and Figs. 52.1 and 52.2 .

BOX 52.1

Contracture Test for MH

Test performed within 5 hours of excision
Strips exposed to 0.5, 1, 2, 4, 8, 32 mmol/L caffeine
Strips exposed to 3% halothane
Positive caffeine test: increase tension of 0.2 g in presence of 2 mmol/L or less
Positive halothane test: increase of 0.2 to 0.7 g tension in 3%

Fig. 52.1, Contracture Testing with a Bolus of 3% Halothane.

Fig. 52.2, Contracture Testing with Incremental Concentrations of Caffeine.

Who should undergo testing for MH susceptibility?

A person should be tested for susceptibility to MH if they or someone in their family has experienced a clinically suspicious episode of MH during or immediately after exposure to a general anesthetic triggering agent. However, it is very difficult to assess the accuracy of an intraoperative MH diagnosis in the absence of a bedside diagnostic test. When these clinical events are examined carefully, very few are unambiguously attributable to MH. In 1994 a team of MH experts developed a clinical grading scale to classify MH events and assist in eventual diagnosis ( ). Because of its autosomal dominant inheritance, confirmation or exclusion of MH is of great importance because the diagnosis will affect an entire family.

A less common reason for MH susceptibility testing is when a person has experienced exaggerated and unexpected muscle breakdown (i.e., rhabdomyolysis) in response to nonextreme heat exposure or exercise ( ).

The European MH Group (EMHG) has published a suggested diagnostic pathway for MH susceptibility testing ( ) ( Fig. 52.3 ). Individuals who have experienced a clinically convincing MH event should initially obtain noninvasive molecular genetic testing. This testing, however, is only useful when the analysis demonstrates a known diagnostic MH variant, which confirms MH susceptibility. If a family member has experienced the suspicious MH event, then they should ideally be the first member of the family to undergo testing. In the absence of finding a pathogenic or likely pathogenic MH-diagnostic variant, a contracture test is required to exclude or confirm MH susceptibility.

Fig. 52.3, Diagnostic Pathway for Investigation of MH Susceptibility.

Patients with a positive contracture biopsy should subsequently undergo molecular genetic analysis. If this investigation reveals a pathogenic variant for MH, then other members of the family can initially be tested for that particular variant at less expense.

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