Central Line

Episode Number: 151

Episode Title: Inside the Monitor – Genetic Breakthroughs in Malignant Hyperthermia

Recorded: November 2024

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VOICE OVER:

Welcome to ASA’s Central Line, the official podcast series of the American Society of Anesthesiologists, edited by Dr. Adam Striker.

DR. ZACH DEUTCH:

Hello and welcome to the Central Line Podcast. I'm your host, Dr. Zach Deutch. Today I'm here with Drs. Henry Rosenberg and Kumar Belani, who are the guest editors for the February issue of The Monitor, which is giving an update, both scientific and clinical, about the condition malignant hyperthermia. We're very pleased to have these two learned gentlemen with us today, and I'm looking forward to speaking with them. So first off, if we could get both of our guests to introduce yourselves to the listeners and explain what their interest is in this topic, and we'll start off with Dr. Rosenberg, please.

DR. HENRY ROSENBERG:

Hi. So I'm Henry Rosenberg. I did my training in anesthesiology at the University of Pennsylvania in the early 1970s. I became interested in malignant hyperthermia. In 1971 at the first International Workshop on Malignant Hyperthermia. And that really struck me as something that needed intensive investigation. I was an academic anesthesiologist doing clinical work as well as research work, and my interest in MH has persisted these many years as I've watched this syndrome grow and develop and get better understanding. And it's been exciting, interesting, and at this point, we're at another crucial point in understanding the syndrome and how it can help clinicians take better care of patients and how patients can deal with the problems themselves. I worked as a clinical anesthesiologist and then director of medical education before I, uh, retired a couple of years ago, but still very actively involved in the Malignant Hyperthermia Association.

DR. DEUTCH:

And very pertinent to a recent issue we had about hanging up the scrub cap, which is how people later on in career or even retired, can still contribute to the specialty, to clinical care knowledge. So very glad to hear that from you, Dr. Rosenberg. Dr. Belani, please feel free to give a little intro to our listeners.

DR. KUMAR BELANI:

Hi, this is Dr. Kumar Belani and I'm a graduate of Saint John's Medical College, which is in Bangalore, India. I came to the University of Minnesota in 1976, and during my residency, I came across a case of malignant hyperthermia in a child who received halothane and succinate. And so my interest perked up there, and I have been interested in this problem since then, being the only disease at that time that was induced by. Anesthesia. I have been then connected to the malignant hyperthermia. Association of the USA, where I met Dr. Rosenberg and I've been. A hotline consultant for over 25 years and have been involved in setting up the muscle contracture test, for many, many years. And so have been interested in this disorder and was happy to see that the ASA Monitor could, uh, do a section on this disease for which we have learned a lot.

DR. DEUTCH:

Very good. So we have two true experts that are also deeply invested in the subject matter. So let's get right into it. Um, tell us what is new in this diagnosis and in this In this condition. Dr. Belani, I'm going to have you answer that for me, please.

DR. BELANI:

Oh, great. So we all know that malignant hyperthermia is a life threatening pharmacogenetic disorder of skeletal muscle, calcium regulation, and can be triggered by certain anesthetic drugs as well as extreme stress. Now, what's new is that MH was historically seen as an isolated event that anesthesiologists managed in the operating room. However, our understanding has significantly involved. It is now recognized as a genetic condition that extends far beyond anesthesia. It is associated with mutations in the Ryr1 and cacans1 genes and some other genes like the native myopathy genes, and these genetic mutations are inherited in an autosomal dominant pattern. Importantly, the condition is no longer viewed as exclusively tied to anesthesia. It's part of a broader spectrum of disorders. Recent research suggests that MH may be the first manifestation of neuromuscular diseases or neurological disorders--disorders such as central core disease or Denboro syndrome, and these underlying conditions may not present themselves until later in life, until an MH episode reveals them. So this evolution in understanding requires anesthesiologists and other specialties to collaborate. For example, anesthesiologists need to recognize MH susceptibility before surgery, identify at risk patients, and involve genetic counseling. Patients and families must be informed about the genetic nature so they can notify other health care providers, as well as their family members. Neurologists, geneticists, primary care physicians need to consider MH susceptibility in the broader context of care. Now to illustrate an example. In a teaching hospital in New York City, a family with a known MH susceptible member used this knowledge to inform care for the grandmother who had undergone surgery. They recognized that symptoms previously dismissed in a family history aligned with malignant hyperthermia susceptibility. By involving geneticists, neurologists, and others. They were able to better manage not just the patient's care, but also understand the broader family implications. This shift from viewing MH as just an anesthesia problem to a systemic issue reflects why it is critical to recognize its broader implications in clinical care.

DR. DEUTCH:

Okay, so I get the message that there's a a very important biological underpinning and genetic component to this condition. So Dr. Rosenberg, I'd like to hear from you. Can you talk about the role of genetic testing as it applies to MH in a general sense.

DR. ROSENBERG:

Well, malignant hyperthermia after it was first noted by Mike Denborough and colleagues and Jim Villiers was the anesthesiologist, and he noted very quickly that this was an autosomal dominant pattern and that it was marked by elevation of CK, indicating a neuromuscular or muscular problem. And so in the early 70s and 80s, the test for diagnosis of malignant hyperthermia was based on a excision of muscle, placing it in a in a bath and measuring the contracture responses to the anesthetic halothane and to caffeine, which stimulates calcium release from the sarcoplasmic reticulum. Very cumbersome process requiring a trip to the OR, set up in a Laboratory, and technologists interpretation and very expensive, but very useful for some families for personal reasons, for themselves, and also for an understanding of how the syndrome manifests itself.

The revolution started in about 2003, when the human genome was sequenced for the first time. Marked development and introducing the era of genetics into clinical medicine. Of course, the genetic tests that were developed at that time were crude, and over the years there has been a tremendous growth in the understanding of the human genome and to dissect the gene itself. And concomitantly, interestingly, the cost of doing genetic analysis has gone down. One of the few things in medicine where it costs have gone down remarkably. And although many of the genetic tests are not reimbursed by insurance companies at this point, the cost of genetic testing is not extravagant. So now, instead of having to do this muscle biopsy test, which is invasive, it can be done in a standard blood specimen or other specimen in the laboratory, with results that are pretty well defined.

The problem or the issue with genetic testing, it's, at this point in time, all the variants that occur in the main genes for malignant hyperthermia are not well defined in terms of their likelihood to be associated with MH. But in the 80% of patients who have had a positive contracture test harbor one of the DNA variants that lead to malignant hyperthermia, and these studies have been done in Europe through the European Malignant Hyperthermia Group scientists and in the United States. So now, instead of having the difficulties of either clinical definition or invasive tests, it's possible to do a genetic test to define susceptibility with high accuracy, not such that you can rule out malignant hyperthermia, but you can rule it in virtually, uh, without a problem. Uh, so there's there's a way to go. But given the results that you get with a non-invasive test, it's very valuable.

And this is part of the whole change in medicine that the introduction of genetics is leading to, often labeled as precision medicine because the genetics of a patient defines the proteins which defines the makeup of the organs, which defines how people's organs function. It's not 1 to 1. There are variables, but we're learning about that all the time. So this is a disorder that can be defined not only in the individual but in relatives as well, which is always a question as to what to tell the family of a person who's susceptible. So I'm very excited about this development, and I consider it, as a landmark, almost equivalent to the introduction of the life saving drug Dantrolene. Because this introduction of genetic testing predicts the susceptibility and defines what may have happened with the patient, and has defined the relationship of malignant hyperthermia to other disorders. And we're still learning about that.

DR. DEUTCH:

So that's an excellent summation. And clearly things have changed since the days of people like myself studied this condition for the oral and written boards. So in light of that, Dr. Belani, I'd like you to bring us up to speed on what's happening currently. What parts of genetic testing are helpful and useful now, and what gaps do we have in the ability of those type of assays to help us?

DR. BELANI:

Well, there are two primary methods as as illustrated already for diagnosing malignant hyperthermia susceptibility. One is genetic testing that we just talked about. It's non-invasive rapidly advancing. And it involves analyzing mutations in genes like the Ryr1. And the cacna1is. They are strongly associated with the image. And the other one is the gold standard contractual testing, caffeine Halothane contracture test, or the in vitro contracture test that involves an invasive muscle biopsy, typically from the vastus from the vastus lateralis muscle, and then it's exposed to caffeine and halothane. So this invasive muscle biopsy is quite expensive. Uh, many places have stopped doing it because insurance companies do not pay for it without much difficulties, you know, to get prior approvals. I looked at the costs at our hospital, and it's close to $16-$20,000. So that's why the goal is to try to do as many patients as possible, do genetic testing.

But genetic testing doesn't identify all these mutations. And in those patients where there is no defined mutation with malignant hyperthermia, those patients will need to get a muscle biopsy done. And so the centers that do that are diminishing.

So we predict that at least 20% to 30% of patients where the diagnosis is questionable, will need to get skeletal muscle contraction testing done to see if they are susceptible to malignant hyperthermia or not. The sad part is that it's very, very difficult for primary care physicians to get the consent from insurance companies to go ahead and and get this done. In fact, I have several patients on the list now who need the biopsy, and we are still waiting for insurance company approval to get that done.

So in conclusion, what we need is advancement in genetic testing that have been revolutionized in our ability to diagnose and manage MH susceptibility. But challenges remain. We hope to phase out invasive procedures that, like the skeletal muscle biopsy, that are essential for this subset of patients. And bridging the gaps in genetic testing coverage and ensuring equitable access will be key to unlocking the full potential in the years to come.

DR. DEUTCH:

Well gentlemen, you've brought us up to speed for sure about diagnostic and scientific possibilities. Let's shift gears a little bit to talk about clinical presentation, which was alluded to earlier in that there's a variety of presentations of this condition. It's not very cut and dried as many of us were taught. So, Dr. Rosenberg, I'm going to ask you, can you talk with us a little bit about things like awake MH, overlapping myopathies that may exist, central core disease or a related condition which I think we alluded to earlier, exertional heat illness. What can you tell our readers to bring them up to speed on that topic?

DR. ROSENBERG:

Well, certainly I think that, first of all, many people think of malignant hyperthermia coming in one format, that the patients develop the onset of the syndrome immediately on induction, and it advances after that. But the truth is that the syndrome has multiple formats. And so that's what's that's what makes it hard to define. Fortunately, Capnography has been a giant step in helping to understand what's going on. Whether it occurs in the early postoperative period or not is somewhat questionable, but that's one of the issues with malignant hyperthermia.

Now, the animal model for malignant hyperthermia was a certain breed of pig. And that was notable because these animals with high stress will develop an MH like syndrome. Their muscles would get rigid and the muscle when it when the animal was slaughtered was looked like it was partially cooked and was called a pale soft exudative pork syndrome. And that has been a useful model because those animals also develop anesthesia induced malignant hyperthermia.

Now the incidence of awake malignant hyperthermia, which is MH without anesthesia, is pretty, pretty uncommon. But it does happen. And there is a book that was written by a patient who had a child who developed awake, malignant hyperthermia, called the Angel in My Pocket by Suki Forbes. And it details, from a patient's point of view, the tragedy that happened. There are a number of patients who have succumbed to this disorder, and sometimes it's not clear, but genetic testing can straighten that out in terms of saying that this person's sudden death was likely related to malignant hyperthermia on a genetic basis, not in all cases.

One of the other early questions about this is things like exertional heat illness and heat stroke, which has many, uh, clinical symptomatology similar to malignant hyperthermia. And what's the relationship? And that's been a challenge to sort that through. But there are many good studies now that show that somewhere about 30 to 40% of people who experience exertional heat illness have the underlying genetic changes that are typical for malignant hyperthermia. Now, anybody can develop exertional heat illness under the right conditions, but the people who have the MH gene do that more readily. Um, and every year there are athletes, young athletes, that die. And some of them--this hasn't been studied in any great detail--but some of them do have the underlying genetic changes found in malignant hyperthermia.

And some people developed rhabdomyolysis, muscle breakdown, without the whole syndrome. And neurologists searched for the reason for that. And many of those patients also have the underlying genetic change found in malignant hyperthermia. And why they develop it is yet to be really defined. There are patients with statin induced myopathy. 16% of patients on statins will develop statin myopathy related to the ryanodine receptor. And then there are series of ryanodine myopathies. And this is actually now part of a another patient Foundation called the RYR1 foundation, and these patients develop muscle weakness, progressive muscle weakness. It's not a dystrophy. It's muscle loss beginning at roughly age 25 or 30. And there are about six disorders with names like central core disease, multi minicore disease, fiber type disproportion, etc. 1 in 90,000 people have one of those disorders, and those patients have the same genetic changes as in malignant hyperthermia. However, those patients do not seem to respond to dantrolene as the patients do under anesthesia. There's active NIH investigations exploring that relationship.

But that's why I say that genes are the architectural drawing. But architectural drawings change. It's not necessarily destiny just because it's in your genes. It gives you the predisposition to developing the problem. And so the anesthesiologist and the anesthesia caregiver have to be well aware of the onset of these type of disorders. So the genetic era is really extended our understanding of the disorder. And like I tell people, malignant hyperthermia is like the tip of the iceberg, pardon the metaphor or pun. And it's part of a much larger conglomeration of symptomatology related to the calcium channels known as the ryanodine receptors. And as a consequence, I advise patients and the MH association as well, that when you deal with a patient with MH and very proud of what you've done to save the patient, the patient nevertheless needs to have consultation by at least the geneticist and neurologist for continuing care. So that's kind of an overview of what we're learning about the disorder. And I will say the European malignant hyperthermia group and the Australia New Zealand MH group have been very important in advancing our understanding of the disorder.

DR. DEUTCH:

Well, gentlemen, clearly your your passion for this topic is extensive, as is your knowledge. So that's great. And you've you've educated myself and I'm sure our listeners a lot already. Let's move into the pertinent present in that we have identified a hypothetical patient with MH. And at this point we have to manage this patient. I'm assuming the approach would be multidisciplinary. What would that necessarily look like? And who would be participating in that care. And, uh, Dr. Belani, I'm going to have you answer this for us, please.

DR. BELANI:

Thank you. Zach. Uh, now, as we've learned, MH is just not an anesthesia disease. So it does require a multi-disciplinary approach to managing such patients. involving various specialists, . Genetics for sure. Patients interested in neuromuscular disease as well as the anesthesiology implications. So the key members of this care team should include a genetics clinic. They are responsible for ordering and interpreting genetic tests. And I do work closely with the genetic clinic here at the University of Minnesota. And we use the data that's provided in interpreting the results, assessing family risk, and guiding decisions for further testing or interventions. Once a variant is identified, then neurologists get involved and they evaluate for any overlapping conditions like central core disease or any other myopathies that may have broader implications for the care of the patient. And as anesthesiologists, we are typically the front-line responders for MH crises and caring for the critical aspects, including preoperative evaluation, crisis management, and . educating patients on the safe anesthetic options that are available to us. Now the primary care physicians will act as coordinators for ongoing care, ensuring patients receive necessary follow up, and that relevant specialists are involved. The other specialists may be needed, for example, cardiologists, pulmonologists, or physical therapists, depending on the patient's specific clinical presentations and muscle involvement and diseases that might be implicated, like exertional heat illness or muscular complication.

So typically we will begin with the patient's history, family history, or even those that might suggest an MH susceptibility, the presence of a perioperative crisis or an unexplained muscle disorder. Then the genetic clinic will typically order and interpret the genetic tests, working with the families. And testing may extend to family members to determine if others are at risk. And then the neurological evaluation where indicated. If a pathologic variant is identified, the neurologist will then assess for associated neuromuscular condition, providing guidance on long term care, and then the patients and families must understand the implications of MH susceptibility, including avoiding triggers, recognizing early signs, and carrying emergency identifiers such as a medic alert bracelet. And the patients identified as MH susceptible then should be flagged in the electronic medical records that we currently use, with clear notes on anesthesia protocol and contraindicated agents and preoperative consultations with anesthesiologists and pre-op clinics will ensure safe surgical planning, and therefore there needs to be coordination across specialties. There needs to be seamless communication between geneticists, urologists, anesthesiologists, primary care physicians and this certainly can be challenging in a siloed health care system. So not all health care settings have access to all these modalities, and it can make it harder for patients in rural or underserved areas to receive comprehensive care, and more so, ensuring patients adhering to follow up plans and remaining aware of their the susceptibilities will require an ongoing effort.

So it's not just, you know, something that we need to take care of, anesthesiologists. It does require a broad approach, a multidisciplinary approach, and all these specialties have to be involved. And the hope is that we can provide precision care for these patients. And getting people to realize that this is not just an anesthesia disease.

DR. DEUTCH:

So it's clear that having other health professionals involved is helpful in management. But the majority of us, as ASA members, our wheelhouse is perioperative care and procedural medicine. So within that framework, moving from the O.R. and beyond, how would we best manage patients and their families? And, Dr. Rosenberg, if you would, I'm going to have you answer that, please.

DR. ROSENBERG:

Well, certainly. That's really a very complex, uh, question because of the variability of malignant hyperthermia. So, for example, the military will not accept patients for service if they have a history of malignant hyperthermia. There are questions as to if a patient has had an episode or is at risk because of a family history, are they eligible to play, uh, professional sports so collegiate sports where there is a great deal of heat, stress and muscle stress? Is that going to affect their performance? That's really an open discussion. And there are a group of specialists interested in sports medicine, and they define certain criteria for prevention of heat illness. Dantrolene is only approved for the treatment of malignant hyperthermia intravenously. It's not approved for the treatment of heat stroke. And so they have different approaches to that. It's something I think that should be paid attention to.

The other thing that is important to know is that about one in between 600 to 800 people have one of the underlying defects, or should say mutations in the genes that predispose to MH. So you take that number and expand that based on the population. You're talking about over 500,000 people who have one of the genetic traits predisposing to malignant hyperthermia. Fortunately, the penetrance is fairly low. We don't completely understand that. Uh, but I think it's important part of the family to inform their physicians and people who will be taking care of them of their susceptibility.

Fortunately, in the United States, the Joint Commission recognized malignant hyperthermia as a problem and require every hospital to have training programs for dealing with malignant hyperthermia, and that's been marvelous. Now, that covers hospitals, not necessarily ambulatory care centers. In other countries, that's not the case. Matter of fact, in other countries, some other countries don't even have dantrolene. And so for example, recently in China, the mortality from malignant hyperthermia in parts of China is over 50% because they don't have dantrolene easily available. So it's really important for the families to understand what this means as we learn more about it.

And the last thing I will add is very soon, newborn genetic screening developed in the in the 1960s for about 30 different disorders, will be changing over to newborn genetic sequencing. In other words, it seems that all newborns will have their genetic sequencing done and that will come up with a huge number of other disorders. Among the investigations by the geneticists and statisticians, malignant hyperthermia is high on that list of disorders that need to be understood, and the interpretation of the genetic changes that underlie malignant hyperthermia. When a patient presents the report to the physician that they have one of these traits, and it's the anesthesiologists that are going to be best to educate the physicians as well as the patient as to the meaning of this disorder. Most importantly, of course, is the avoidance of the MH trigger drugs, which have been pretty clearly defined. But there are lots of other questions that come up in particularly the issue of exercise and heat exposure. And what that does to patients with these underlying disorders is a is an important one. And so it's really, as the anesthesiologists, virtually the only disorder of anesthesia, in my opinion, it's important for the leaders in anesthesiology to understand that there needs to be more resources placed in the study of this disorder for the benefit not only of anesthesia care, but care of the patients in general.

DR. DEUTCH:

Well, we've covered a lot, and we're coming to the end here. But I'd like to ask both of you, having been guest editors for this issue of the Monitor and obviously being very knowledgeable and passionate about the topic, could you kind of condense down for our listeners from that vast knowledge base one most important single salient piece of information or take home point that they can get from these articles that we have? Um, maybe something especially that we haven't really touched on yet. And Dr. Belani, I'm going to start with you.

DR. BELANI:

I like to point out is that there's a lack of awareness amongst many healthcare providers, especially outside of anesthesiology and critical care. Uh, they have limited awareness of MH and its broader implications. This can lead to delays in diagnosis, inappropriate anesthetic care, and inadequate crisis preparedness. The accessibility to genetic testing which is now being shown to be quite invaluable, remains underutilized, partly due to cost, which is now significantly better than it was, and in some cases, logistical challenges in some healthcare systems in rural or underserved areas, access to specialists like geneticists and neurologists is often limited, creating gaps in care for these patients and in hospital, the resources can be limited. They may not be equipped to handle an image crisis due to insufficient access to dantrolene untrained staff or inadequate protocols, so smaller facilities may not have the infrastructure for preoperative imaging care. So these things will require attention. And then a lack of comprehensive education for patients and their families on MH susceptibility. The newer modalities for diagnosis are something that we need to make sure that this gets through both in the primary care field as well as in for the patients who are going to be the other other receiving end of this problem.

So MH, as we learned today, is a condition that has far reaching implications beyond the operating room, touching on genetics, multidisciplinary care and patient education. Understanding is evolving more and more, and the responsibility of the health care providers to stay informed is also important. And collaboration across specialties and empowering patients and families with the knowledge and tools to need safe needs to be publicized. The other thing is, we need to make sure that we come up with a system where we can have easier insurance approvals for these, for the few that might need muscle biopsy testing, because that's been a big hold up at our facilities to get those insurance approvals.

DR. DEUTCH:

Thank you, Dr. Belani. Dr. Rosenberg, same question to you.

DR. ROSENBERG:

Well, I would say that it's important to remember that anesthesiologists are not the only ones using the trigger drugs. Uh, emergency medicine people also use succinylcholine, uh, to intubate patients. And occasionally on the hotline, we get calls from the emergency room of patients who come in with heat stroke, and they're asking about how to treat it. Or they may develop, uh, signs of MH after administering a dantrolene. And the other area that is developing not yet in the United States, but elsewhere, is the administration of potent volatile agents as a sedative in the intensive care unit. About 47 countries are doing this now, and there are there are studies ongoing in the United States about this. So we need to remember that the operating room is not the only place where trigger drugs for malignant hyperthermia may be used. And so education of those other specialists will need to be included. I think Dr. Belani has summarized many of the other points that are important to make, but I wanted people to know that anesthesiology or anesthesia medications are not limited to the operating room, and it's important to educate those people. It's important to educate the geneticists as well, because several of the geneticists I've spoken to don't know that there's a genetics component to malignant hyperthermia. I'm sorry to say. So there's a lot of education that needs to take place.

DR. DEUTCH:

Well, gentlemen, it's been great having you on the podcast and you've really shared a lot of interesting information and illuminated a topic that clearly is evolving rapidly for listeners. Thank you for joining us. And you can always go to ASA. Org for more information and to access articles and other points of interest. Thanks again and we'll see you next time on the Central Line Podcast.

DR. BELANI:

Thank you, Zach.

DR. ROSENBERG:

And thank you very much.

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