The Evolution of Our Understanding of Malignant Hyperthermia Syndrome

[Note: I apologize that this blog is fairly complex in terms of concepts and terminology.  If there are questions please post them and I will respond as soon as possible.] 

Identification of MH

July 2010 will mark the 50th anniversary of a publication that identified an inherited condition that would eventually be named Malignant Hyperthermia Syndrome. That publication, actually a letter to the editor, by Michael Denborough and Roger Lovell of Melbourne, Australia was entitled “Anaesthetic Deaths in a Family,” and described a case of a young man who when confronted with emergency surgery revealed that many members of his family died unexpectedly during or shortly after anesthesia (1). This syndrome had never been described previously.  When the anesthesiologist, James Villiers, administered the “new” anesthetic halothane, he detected physiologic changes of increased heart rate and perspiration as well as elevated body temperature; he urged the surgeon to finish the procedure, packed the patient in ice and completed the anesthetic. Because of the history that the patient provided, Dr. Villiers referred him to the Chair of Medicine, Dr. Roger Lovell, who, in turn, assigned his young colleague, Dr. Michael Denborough to research and verify the family history, which he did.  

By the mid 1960s many similar cases had been reported from all over the world, especially Canada. It was probably the chief of Anesthesia, Dr. RA Gordon who named the syndrome.  He and Dr. Beverly Britt organized the first symposium on MH which was published in the Canadian Journal of Anesthesiology in 1966. 

MH as Induced by Anesthetics or Triggers Outside the Operating Room

The name of the syndrome soon came to denote a dominantly inherited condition marked by elevated temperature, muscle rigidity, acidosis, muscle breakdown and death if untreated. The aforementioned patient had no outward signs of susceptibility but during exposure to certain gas anesthetics and the paralyzing drug succinylcholine, most patients would display the signs I just mentioned.  

By the mid 1980s MH was more or less defined by not only the clinical signs noted above but also by reversibility with dantrolene. Further studies demonstrated that isolated muscle from MH-susceptible (MHS) patients will develop increased muscle tone (a contracture) when incubated with either caffeine or halothane in the laboratory. 

By this time, there already were suspicions that some humans could develop “MH” without the intervention of anesthetics.  Certainly the original animal model for MH -  certain pig breeds - developed the syndrome with “stress” alone.  The problem researchers faced (and still face now) in dealing with humans outside the operating room  is that in the absence of  physiologic monitoring it was impossible to trace the evolution of the increased metabolism and be definitive as to the diagnosis of MH, even if  the caffeine halothane contracture response was abnormal.   

Connection to Duchenne Muscular Dystrophy

Another strange observation was noted in the late 1980s. Some patients with classic muscular dystrophy (Duchenne Muscular Dystrophy [DMD]), who display an abnormality in another muscle protein not related to calcium movements directly, dystrophin, also developed many of the signs of MH when anesthetized with “trigger agents” for MH.  DMD is entirely different from MH. It affects only boys and there is an inexorable progression to death at an early age because of muscle weakness. The muscle from some, but not all DMD patients displayed an abnormal contracture to halothane and caffeine. Was this MH or “MH-like?” Why did it occur?  The patients and their families usually did not have evidence of “true” anesthetic- induced MH. 

Connection to Neuroleptic Malignant Syndrome

The neuroleptic malignant syndrome (NMS) is another syndrome that features many clinical signs of MH. Here the acidosis, high fever, and muscle breakdown (often ending in death) is triggered by drugs used in the treatment of psychiatric disorders, not anesthetics.  In some cases, dantrolene could also reverse the signs of NMS. One study showed that isolated muscle from some of the patients who survived displayed an abnormal contracture to halothane and caffeine, but other studies did not observe this. Was/Is this a “form” of MH? 

Other Triggers of MH?

Every now and again someone reported a case of “MH” but anesthesia was conducted with agents that are not thought to be MH triggers. Some of these cases occurred incident to cardiopulmonary bypass where patients were cooled and then rewarmed after surgery. How was this possible? That was not the dogma of MH. One had to be anesthetized with a trigger agent in order to develop MH. In some cases the diagnosis was most likely sepsis, or severe shock from infection, but not in all such cases. Could rewarming and the stress of cardiac surgery trigger MH by itself? 

Porcine Model Provides a Window into the Molecular Mechanism of MH

A major breakthrough in our understanding of the inheritance of MH occurred in 1990 when David MacLennan and colleagues at the University of Toronto found that MH- susceptible pigs had a specific mutation in the gene that elaborates the calcium channel protein in muscle, the “ryanodine receptor (RYR1).” This channel, in association with other proteins located adjacent to it, such as the dihydropyridine receptor (DHPR), controls release of calcium into the muscle cell from the storage site called the sarcoplasmic reticulum (SR). When the RYR1 protein is mutated, calcium levels would become elevated in the muscle cell during exposure to anesthesia or to “stress” and lead to muscle contracture and increased cellular metabolism .  This RYR1 mutation was found regularly in all pigs who developed MH, but was only found in a very small percent of humans who experienced MH. 

Connection to Central Core Disease (CCD)

Intense study of the RYR1 gene in humans revealed that there were many other mutations in this very large gene but only some were predictive of MH susceptibility in humans. Other mutations in the same gene were predictive of another muscle disease, neither rare nor common, called Central Core Disease (CCD). This is an inherited syndrome manifest by muscle weakness in the afflicted patient (at least in many of them).  Furthermore these patients often developed MH on exposure to MH trigger agents.  In these instances, was it proper to call the reaction MH?  Many began to refer to the syndrome as MH/CCD. 

The Connections to MH Abound: RYR1 Mutations Discovered in Cases of Exercise and, Heat Stroke, and Elevated CK

In the 1990s, molecular genetic testing began to reveal that some patients who developed exercise-induced muscle breakdown, others with chronically elevated enzyme levels of Creatine Kinase (CK, associated with muscle breakdown), still others who developed heat stroke Some would say that those problems were not really MH because they were self-limiting and did not result in death in over 80% of cases. Clearly some of the patients with these conditions most likely displayed the changes because they harbored an MH gene, but others did not. Should those conditions be termed MH, MH-like, what?  Certainly the strict definition of MH as being induced by anesthesia no longer held, but in the absence of better terminology they were and are still referred to as MH by some. Furthermore, the anesthesia providers were now becoming more concerned because they were unclear as to whether patients with these conditions should receive MH trigger agents.  There still are no clear guidelines. 

Genetically Engineered Mice Help Elucidate Role of RYR1, Importance of the Regulation of Intracellular Calcium, in Anesthetic and Heat-Induced MH

Fast forward to the early 2000s. Thanks to the marvels of gene technology, mice were genetically engineered to harbor within their genome a mutation known to be causal for MH. These mice display all the signs of MH not only upon exposure to anesthesia but also when placed in a hot environment. Still the central dogma was holding, namely that a mutation in calcium channel (RYR1) gene was necessary for the syndrome to occur.  But then another genetically engineered mouse was created, one lacking in the gene to manufacture a calcium buffering protein, Calsequestrin. Ordinarily this compound regulates the concentration of calcium in the cell by soaking up extra calcium.  These mice had normal ryanodine receptors, but they developed all the signs of MH when anesthetized with MH trigger agents. The syndrome was even reversed with dantrolene. Was it because the calcium levels were elevated because of the absence of the buffer that limited the increase in intracellular calcium?   It was now clear that MH could occur with a “normal” ryanodine receptor calcium channel.  This finding underlined a key concept in our understanding of MH - that the essential biologic problem in MH (or MH- like syndromes) is not necessarily a mutation or abnormality in the structure of RYR1, but an increase in intracellular calcium in muscle cells, whether due to a faulty RYR1 gene or some other mechanism.  

Switching gears a bit, in 2009, Dr. Susan Hamilton and her colleagues at Baylor University performed studies aimed at understanding why genetically engineered mice with RYR1 mutations could develop an MH syndrome on exposure to heat. They showed that when intracellular calcium was increased, a variety of intermediate compounds and radicals could alter the function and activity of the abnormal RYR1, causing the receptor to remain in an “open” state and further increase cellular calcium levels. Elevated temperature increased the metabolic process and calcium release even further. This led to a vicious cycle of more calcium in the cell which in turn led to increased binding of reactive intermediates to the mutated RYR1 and increased sensitivity to heat, thus potentiating an MH response. 

Mutated RYR1 Not Necessarily Required

The disruption of intracellular calcium regulation in patients with certain conditions may account for MH-like reactions, even in patients with normal RYR1.  This is illustrated by another recent study from the laboratory of Dr. Andrew Marks (Columbia University).  Dr Marks’ group demonstrated that genetically engineered mice with the genetic change that causes Duchenne Muscular Dystrophy had chronically increased intracellular calcium levels (which had been known) but also displayed an increase in production of reactive intermediates (described by Dr. Hamilton and colleagues).  In this case, however, the binding of the reactive intermediates was to a “normal” RYR1. Again, this binding altered the function of RYR1 and the subsequent regulation of intracellular calcium. This then might be the explanation of why, when MH trigger agents (which also accentuate calcium release) were used, a patient with muscular dystrophy would display an “MH-like” syndrome (3). Was this malignant hyperthermia also? 

The Search for MH Causal Mutations

More recently, scientists, now even curious about the RYR1gene, started to look for MH-causal mutations in other disorders. Some found “classic MH” RYR1 mutations in some patients with statin-induced myopathy, in NMS, as well as in patients with exercise- induced muscle breakdown, chronically elevated CK levels, and even in a rare patient with sudden death without drug treatment. 

So, what exactly is “Malignant Hyperthermia” and how should we define this syndrome? Certainly not every patient with muscle breakdown, high fever and increased acidity also has a mutation in RYR1 or even an intrinsic abnormality of the ryanodine receptor (calcium channel) . On the other hand, some patients with heat stroke or exercise-induced muscle breakdown clearly do experience problems because they have an abnormal ryanodine receptor. As of now, we don’t know what percentage of MH cases accounts for heat stroke patients, for example. 

Furthermore what advice do we give patients who experienced heat stroke or exercise induced muscle breakdown, or even NMS, in terms o f their exposure to anesthetics that trigger MH? These important questions will require the cooperation and interest of scientists and clinicians from many different backgrounds and specialties such as Neurology, Anesthesiology, molecular biology, psychiatry, metabolic diseases, etc. For now it is important to clearly define the label of Malignant Hyperthermia in a specific situation, such as MH due to anesthesia, or MH syndrome due to exercise and heat, or MH-like syndrome associated with muscular dystrophy. The term Malignant Hyperthermia Syndrome by itself is clearly not adequate to capture all the variants of this syndrome.  

Malignant Hyperthermia as initially described by Denborough and colleagues is a complex disorder with varied manifestations and represents only one of many syndromes where the primary physiologic derangement is an abnormally elevated intracellular calcium level. Fortunately, dantrolene sodium seems to be effective in controlling the adverse effects of such increased calcium levels in almost all cases. 

Stay tuned for more developments in the near future.

 References:

1.      Denborough MA, R Lovell R.  –Anesthetic Deaths in a Family.  Lancet, 2;45. 1960.

2.      Durbin CG, Rosenberg H:  A laboratory animal model for malignant hyperpyrexia.  J. of Pharmacology and Experimen­tal Therapeutics 210:70-74, 1979.

3.      Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L, Matecki S, Lacampagne A, Marks AR. Nature Medicine 15(3) ; 325-330,2009.