The annual meeting of the European MH group took place in the charming city of Lille, France. About 80 physicians, scientists, students and clinicians who are studying the problem of malignant hyperthermia attended, giving 41 presentations. Attendees came from many countries inside and outside Europe including the Soviet Union, South America, Australia, New Zealand, Canada, and the US. MHAUS was well represented by Drs. Sheila Muldoon, Sheila Riazi, Barbara Brandom, Ron Litman and me.
Drs. Renee Krivosic and Anne-Ferderique Dalmas hosted the meeting. Dr. Krivosic recently retired from her position as Director of the MH investigation unit. She originally established the center in Lille and provided guidance for many patients in addition to performing research and publishing many articles about MH. Dr. Dalmas will take over the directorship of the center.
It would take far too many pages to cover all the topics discussed at the meeting, but I will try to provide information on some of the highlights of the meeting. One of the reasons I enjoy attending the EMHG meeting is that the meeting is small enough so that there is a good deal of interaction among the investigators, both formally and informally and new and original information, not yet in the literature is presented. . The abstracts of the meeting are often published in a special supplement of the British Journal of Anesthesiology.
The major topic areas covered include 1. Education and training for MH using simulation 2. Epidemiology of MH 3. Molecular genetic diagnosis of MH and MH like syndromes 4. Relationship between genetic changes in the Ryanodine Receptor type 1 gene and the clinical manifestations of those changes 5. Cellular physiology related to muscle metabolism 6. Case reports and 7.Exertional Heat Stroke and its relation to MH.
This year’s emphasis was somewhat different, in my opinion, from previous years, in that there were not many presentations and discussions on standardizing the muscle biopsy caffeine-halothane contracture test. There was a shift in emphasis from contracture testing (although such testing is still very important) to molecular genetic (i.e.DNA) analysis to characterize MH and MH like disorders. One of the reasons for the shift is that the capability for analyzing genetic changes has been increased thanks to new technology, making genetic analysis less expensive, more available and less invasive than muscle biopsy. It is now possible to have more complete analysis of DNA changes in a gene due to the new techniques referred to often as “Next Generation Sequencing”. How Next Gen differs from standard sequencing would require a long explanation of how genetic analysis is performed which, for this report, would be much too technical.
The first sessions of the meeting were a demonstration followed by discussions of the use of high fidelity manikin simulation of an MH event. Simulation using manikins that “respond” to medications, where vital signs change and physiologic changes can be simulated has become a standard tool for education in the medical and nursing profession. Most medical and nursing schools have simulation centers, much like flight training simulators in the airline industry to facilitate education of clinical personnel. The motto among modern medical educators is that no one should practice for the first time on a patient. Manikin simulators are very sophisticated and are now incorporated into training of students at all levels and are also used to assess competence among certified clinicians in order to demonstrate maintenance of their skills, although expensive, the reduction in patient harm is well worth the cost. As MH may present in several different manners, and the treatment is somewhat standardized, but requiring a team response, the disorder is perfectly adapted to simulation training. In the United States, major simulation centers at Stanford, Harvard Hospitals, Johns Hopkins, Duke University, University of Pittsburgh, Vanderbilt, Uniformed Services University, to name a few, have incorporated MH in the their simulation scenarios.
Several presentations centered on the identification of DNA changes in the two major genes associated with MH susceptibility, the ryanodine receptor gene (RYR-1) and the dihydropyridine receptor gene (CACNA1S). Hundreds of variants have been identified in these genes in MH susceptibles, but to date only 34 have passed the rigorous tests to declare that truly cause changes that are found during an MH crisis. The other variants may be of no clinical significance or relate to changes that are not associated with MH. The major research effort is to clarify the role of these many other variants. For example, some muscle disorders, such as Central Core Disease are associated with mutations in the RYR 1 gene, an also predispose to MH. On the other hand, a presentation from Holland showed that some patients with muscle symptoms such as weakness or muscle breakdown harbor changes in the RYR1 gene but the patients are not MH susceptible. Although about 50-70% of MH patients demonstrate a DNA change in one of the genes, only about 30% of MH susceptibles harbor a mutation that has been shown to be causal for MH. It is hoped that additional DNA variants will be characterized as to their role in MH, making the genetic diagnosis of MH more accurate and reliable. The gold standard diagnostic test for MH susceptibility is the caffeine halothane contracture test (referred to as IVCT or CHCT). This test is valuable for patients who do not demonstrate a genetic change or where the genetic change is discordant with the contracture test. Several presentations demonstrated how using next generation sequencing might resolve these discrepancies, increasing the accuracy of genetic testing.
Very recently a third gene that is causal for MH has been identified. It is called the STAC-3 gene. This gene elaborates a protein that works in conjunction with the dihydropyridine receptor and the ryanodine receptor to mediate calcium release from the sarcoplasmic reticulum ( for a more complete description of how malignant hyperthermia is caused by calcium release in skeletal muscle, refer to the presentations on the MHAUS web site). The gene was first identified in a Native American tribe in North Carolina, the Lumbee Indians, and the muscle changes associated with variants in this gene has been termed Native American Myopathy. There is a constellation of muscle changes, including scoliosis, cleft palate and muscle weakness associated with mutations in this gene. In addition, those harboring mutations in the gene are also MH susceptible. A presentation by Elaine Langton from New Zealand, described a family who emigrated from South Africa to New Zealand where some members experience MH crises. These individuals displayed the characteristic myopathy and changes in the STAC-3 gene described in Native American Myopathy. It is likely that this genetic change will be found in only a small number of MH susceptibles and will not explain the many patients who are MH susceptible but do not have a mutation in the RYR 1 or CACNA1S gene.
The study reminds us that there are many other proteins, not yet well characterized, in skeletal muscle that are or may influence calcium release. For example, Isabelle Marty from Grenoble, a well know French MH diagnostic center, described the possible function of the protein Triadin in skeletal muscle. Alexis Ruiz , who works in Basel, Switzerland with the well know investigators, Susan Treves and Francesco Zorzato, described yet another protein, SRP35 that effects muscle performance and metabolism, but has not yet been related to the MH syndrome.
Several presentations addressed the epidemiology of MH. Ron Litman, the director of the MHAUS hotline presented data collected over the past 18 months following introduction of a data capture program for hotline calls. Between October 2013 and March 2015, of 552 calls that were capable of being analyzed (of 700 calls), 381 represented ongoing cases while 171 were about non-active cases. Of the 82 cases deemed likely MH by the hotline experts, one patient died, 11 developed MH with succinylcholine only while the others received an MH trigger agent. Further analysis of the cases is ongoing. However, one significant limitation is the lack of ability to follow the outcome of the presentation. In some cases the details of the case are incorporated into the database of the North American MH Registry for further analysis. The MHAUS experts are discussing how best to capture the missing data.
Catherine Daly of the Leeds, UK diagnostic center, described their efforts in developing a database of MH patients and their families based initially on the over 6500 contracture test results in thousands of patients performed in Leeds. This database will relate clinical findings to test results using both genetic and contracture tests along with a biorepository of muscle samples for further research.
My research, done in conjunction with Dr. Guohua Li of the Department of Anesthesiology at Columbia University, determined that there did not appear to be a difference in prevalence of MH based on hospital discharges among four states in the US: Florida, New York, Wisconsin, and California. Prevalence represents both incident cases as well as preexisting diagnosis of MH. The average prevalence of MH was about 1 in 42,000 surgical procedures.
However, the prevalence in those undergoing surgery in Ambulatory Surgery Centers was about 1 in 300,000 surgeries. This is most likely due to exclusion of MH susceptibles from elective surgery at non-hospital facilities. Further work is focusing on the actual incidence of MH.
Given the limitations of both contractures testing and genetic testing to clearly identify MH susceptible individuals and distinguish them from both normal patients and patients with muscle disorders other approaches are under study. For example, Dr. Sheila Riazi who is the director of the MH diagnostic laboratory in Toronto, in conjunction with Dr. Eduardo Rios of Rush University, described preliminary findings using sophisticated measurement of calcium movements in muscle cells that might clarify how MH cells differ from normal cells and cells from patients with muscle disorders... Unlike other diagnostic techniques, direct measurement of calcium flux examines the basic biochemical/physiologic change that results in MH rather than the result of such changes (i.e. the muscle biopsy contracture test) or the genetic changes that might influence calcium flux in muscle.
There were also several interesting case reports. Gunilla Islander Director of the MH diagnostic center in Lund, Sweden presented a thought provoking case report. A 15-year-old male with a strong family history of MH together with a mutation in the RYR 1 gene developed muscle breakdown when started on methylphenidate (Ritalin) for Attention Deficit Disorder. The signs abated when the Ritalin was stopped. (Muscle breakdown has not been reported with methylphenidate previously) and recurred when the drug was restarted. Might there be an association between the genetic change characteristic of MH and the response to Ritalin? His symptoms of ADHD are now controlled on very much reduced dose of the drug.
A major focus of the meeting was the relation between exertional heat stroke (EHS) and MH. Dr Emmanuel Sagui and Dr. Julien Faure described the French experience with Heat Stroke and MH. In their experience, two cases of exertional heat stroke could be expected, among 1000 runners in 10K races. There are between 50 and 100 cases of EHS in French armed services each year. Significant muscle breakdown and other serious complications may result from heat stroke, including death as has been described previously. Most of the cases occurred during training. There was no difference in body mass index between those that did and did not develop heat stroke. Contracture testing of 180 patients with EHS demonstrated that 46% of those tested were MH positive by contracture test, and many exhibited genetic changes found also in MH susceptibles. A recent report from the Leeds UK MH unit described MH found that 40% of those who suffered from exertional heat stroke manifest mutations found in MH susceptibles. What remains unclear is whether those who are MH susceptibles should be advised to avoid strenuous exertion in hot environments or whether those who suffered from EHS should be considered at risk for MH and investigated for genetic changes characteristic of MH My personal opinion is that they should be advised to avoid strenuous exercise in very hot environments and also to be investigated for genetic changes as found in MH susceptibles. Dr. Sagui presented his group’s opinion that the development of EHS results from an accumulation of factors, both environmental such as heat, muscle metabolism with exercise, conditioning and other factors, among which are mutations associated with MH susceptibility. The significance of each of these factors in precipitating EHS in each person has yet to be clarified. Several centers in the US, including the Uniformed Services University in Bethesda and the Korey Stringer Institute in Connecticut are actively engaged in studying the relation between MH and heat syndromes.
Many aspects of MH were not covered during the meeting due to time constraints such as, new treatments of MH (i.e. the new formulation of dantrolene, Ryanodex), the relation between other drug induced hyperthermia syndromes and MH, clinical after effects of an MH episode, epidemiology of MH in non –Western countries, the anatomy and function of the ryanodine receptor.
The EMHG meeting is always thought provoking, informative and provides those with an interest in the problem of MH to share data, speculate on the explanation for puzzling aspects of MH and, enjoy a glass of wine with friends.
Check the EMHG web site, EMHG.org, for information about MH, and next year’s meeting in Ulm, Germany.
I would be pleased to answer any questions and respond to comments.