Malignant Hyperthermia Update
Jerome Parness MD PhD
Today’s PAAD is written and dedicated to the memory of Ron Litman MD, whose enthusiasm for pediatric anesthesia, his colleagues and, above all, his patients, was boundless. Ron died on April 21, 2021. I asked Dr. Jerome (“Jerry”) Parness, one of Ron’s close friends and colleagues to write an article about malignant hyperthermia, a topic that was very close to Ron’s heart, to commemorate the anniversary or his death. Myron Yaster MD
Ron and I shared a particular interest in Malignant Hyperthermia (MH), both on the clinical side and on the molecular mechanisms that led to the generation of this pharmacogenetic phenomenon. Both Ron and I were members of the MHAUS sponsored MH Hotline, and he eventually became its director in 2013. Under his direction, the Hotline database of cases was expanded and the data contained therein was used in publications designed to increase our knowledge of what occurred in clinical cases of MH. In this short PAAD, I would like to concentrate on what we’ve learned about MH since Ron’s untimely passing in 2021 and some pathophysiology that has intrigued me for over a decade.
As you all should know, MH is a pharmacogenetic sensitivity to volatile anesthetics and succinylcholine, a depolarizing skeletal muscle relaxant, exposure to which results in a hypermetabolic response in skeletal muscle, with resultant dramatically increased CO2 production, tachycardia, accompanied often by skeletal muscle rigidity. Untreated, it will result in cardiovascular collapse and death. Specific, early treatment with dantrolene, the only drug in our pharmacologic armamentarium for the suppression of the pathophysiology, is lifesaving. (From MY: Don’t rely on your memory if you are faced with this crisis…open the Pedi Crisis app which should be on your phone!)
The genetic site of of the majority of mutations that have been found causative in MH are to be found in the gene for the skeletal muscle ryanodine receptor (RyR1), the primary Ca2+ release channel in sarcoplasmic reticulum (SR) responsible for Excitation-Contraction Coupling (ECC). Indeed, the presumed pathophysiological trigger is the associated and wildly unregulated release of SR Ca2+ which dantrolene suppresses and even reverses. The list of proven pathophysiologically causative MH mutations in the ryr1 gene continues to grow. As of this writing, there are 66 ryr1 mutations that are known to be pathogenic or likely pathogenic (see list curated by the European Malignant Hyperthermia Group at https://www.emhg.org/diagnostic-mutations). What complicates the genetics is that there are likely six genetic loci conferring susceptibility to MH, only three of which have been identified: 1) ryr1; 2) the alpha-1 subunit of the skeletal muscle plasma membrane depolarization sensitive Ca2+ channel gene, cacna1s, for which only 2 mutations have been identified; and the gene responsible for Native American Myopathy, stac3, for which there is a single, canonical, mutation. This myopathy has recently been found in non-Native Americans, and is now renamed STAC3 myopathy, and has been associated both with the canonical mutation and with non-canonical mutations.1 I personally cared for a set of twins of Somali twins, the result of a consanguineous pregnancy, with the canonical STAC3 mutation (not reported). Recently, three more pathogenetic mutations in ryr1 have been identified,2 which have yet to be curated by formally EMHG.
The major issue with MH genetics is that ryr1 mutations cover only ~50-70% of all proven MH episodes. All the other MH loci together cover about 1% of proven MH episodes, which leaves a significant minority of cases without a known genetic cause. Clinical genetic screening, then, is unprofitable, as only a positive answer is clinically helpful, and will allow for appropriate, non-triggering anesthetic care to be planned for. A negative answer is clinically unhelpful. We will have to know all the genetic inputs before comprehensive genetic screening can be clinically viable. While gene hunting is being conducted, the rarity of the clinical presentation makes this a long-term project still.
A further barrier to the understanding of the pathophysiology of MH resides in the clinical presentation, which makes life for MHAUS Hotline consultants a bit crazy! Symptoms of MH may present anywhere from induction, to hours into the case, to the recovery room. Why? While most MH-susceptible individuals do not trigger during their first anesthetic, a large percentage do so by their 4th anesthetic. There is even one case in the MH Registry that triggered after their 30th anesthetic! What mechanism(s) that we know about could possibly explain such discrepancies of pathophysiological behavior? The answer(s) likely lie in many places and may have multiple inputs that need to be taken into consideration. In short, the more we know, the more we realize we don’t know. Here are a number of possibilities:
1) Immediate onset of MH is usually due to the use of Succinylcholine, and the immediate, total skeletal muscle depolarization signal in a susceptible individual releases so much Ca2+, that whatever pathophysiological threshold needs to be reached is reached immediately. On the other hand, MH may occur immediately even in the absence of Succinylcholine, with just volatile anesthetic alone. This must mean that the individual’s physiological state is primed to react with MH pathophysiology immediately. Why and how?
2) Later onset MH in a case suggests that the mechanism(s) of MH must be primed by the volatile anesthetic. How does this occur? Early studies in the porcine model of MH (homozygous, single RYR1 mutation) show that there is a slow rise in skeletal muscle Ca2+ that suddenly becomes an acute rise, and is then accompanied by all the pathophysiological signs of MH. What needs to be primed over the period of slow rise in Ca2+? Is it the stimulation and activation of a new gene product? Is it slow accumulation of pathophysiological product in the in situ milieu of the the muscle cytoplasm and mitochondria that reaches threshold and suddenly takes off?
3) What does having 30 anesthetics before triggering mean? Does this imply loss of a preventative mechanism or activation of a stimulative mechanism, or both? Over such a long period of time, one would think that this would involve gene activation or gene suppression in a cumulative manner. Do volatile anesthetics cause changes in gene activation status? These are huge questions, ones that will require manifold efforts to elucidate.
Finally, there is the question of the relationship of MH susceptibility to Exertional Heat Stroke (EHS).3 There have been reports in the literature of young people dying after developing an MH-like, EHS syndrome during August High School football practice. One such case had a post mortem genetic exam, and the young man had a classic MHS ryr1 mutation. Since then, people have attempted to find a link between EHS and MH.
One such attempt was the creation of a heterozygous mouse model of MH in the RyR1-Y522S/wt mouse (Tyrosine at position 522 mutated to a Serine, a known MH causing mutation in humans) by the laboratory of Susan Hamilton and colleagues at Baylor College of Medicine.4 This mouse gets MH when exposed to volatile anesthetic, and gets EHS when exposed to high temperatures with the same biochemical and pathophysiologic changes as MH. It turns out that these mice had redox mechanisms that are tilted towards the oxidative state at baseline, and that volatile anesthetics induced runaway oxidative changes in a Ca2+ dependent manner associated with serine nitrosylation of the mutated RyR1 from elevated nitric oxide, which made this Ca2+ channel extremely leaky during exposure to volatile anesthetic or heat. This could be suppressed by pretreatment with anti-oxidants (no, they didn’t examine the effects of dantrolene, nor did they specifically measure mitochondrial metabolic activity which would have been expected to rise dramatically in both MH and EHS, were they directly related mechanistically.). In this model, then, clinical MH and EHS are linked… 100%.
Not surprisingly, the population on MH susceptible humans does not uniformly support these results, as not every MHS individual gets EHS, nor is every human who has had EHS susceptible to MH. In the only study I was able to find on EHS and MH came from the French Armed Forces.5 EHS subjects from the French Armed Forces were routinely subject to a muscle biopsy for MH susceptibility testing (IVCT) with halothane-caffeine contracture testing of muscle biopsies. Of 466 subjects, only 17.2% were MH positive for both halothane and caffeine, but 18.5% positive for halothane only, and 9.9% to caffeine only. Clearly, by IVCT, the overlap between MHS and EHS is quite low. None of these biopsy specimens were subject to genetic testing. There might be genetic mutations is which the overlap between MHS and EHS is 100% as in the Y522S mutation in mice, but in humans, this mutation is very rare. Humans are not laboratory inbred mice; human MH is multigenic, and we likely have multiple mechanisms of physiologic adaptative diversity that mice do not have, but at least we have an entré to the mechanisms of oxidative stress and MH and EHS where they do overlap.
There is yet much to learn. Much.
Ron, we miss you. May your memory continue to inspire us all.
References
1. Gromand M, Gueguen P, Pervillé A, et al. STAC3 related congenital myopathy: A case series of seven Comorian patients. Eur J Med Genet. Oct 2022;65(10):104598. doi:10.1016/j.ejmg.2022.104598
2. White R, Schiemann AH, Burling SM, et al. Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia. British journal of anaesthesia. Dec 2022;129(6):879-888. doi:10.1016/j.bja.2022.08.029
3. Laitano O, Murray KO, Leon LR. Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture. Sports Med. Sep 2020;50(9):1581-1592. doi:10.1007/s40279-020-01318-4
4. Durham WJ, Aracena-Parks P, Long C, et al. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell. Apr 4 2008;133(1):53-65. doi:10.1016/j.cell.2008.02.042
5. Sagui E, Montigon C, Abriat A, et al. Is there a link between exertional heat stroke and susceptibility to malignant hyperthermia? PloS one. 2015;10(8):e0135496. doi:10.1371/journal.pone.0135496