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Further thoughts on the Definition of MH

Over the past several months, since our April scientific conference, I have been thinking about the question “How should we define MH”?  Sounds like a pretty straightforward question, but in reality it is quite complex.

For example, MH to an anesthesiologist or anesthesia provider is a set of signs that occur during general anesthesia using specific gases and/or succinylcholine.  These signs include muscle rigidity, temperature elevation, increased excretion of carbon dioxide and increased acid content in the blood.  In addition many of the patients will manifest signs of muscle destruction following the anesthetic (rhabdomyolysis). The syndrome is always dramatically reversed with the drug Dantrium (dantrolene sodium).  If it is not, then it is probably not MH. When handling this problem, the anesthesia provider knows that the patient needs to recover in an ICU and that other family members need to be informed that they may be at risk to the syndrome. S/he hopefully will tell the patient and his/her family about MHAUS and the resources the organization offers. Let’s call this MH of anesthesia.

However on occasion, the anesthesia provider will note certain signs that are compatible with MH, but not all the manifestations are clear, such as jaw muscle rigidity after succinylcholine or unexplained increase in heart rate and increase in carbon dioxide excretion that resolves without dantrolene.  He/she will then consider sending the patient for further testing in order to determine whether in fact the patient did experience MH or some other problem.  In the example of jaw rigidity, it may have occurred because of a problem with the patient’s temperomandibular joint (the joint responsible for jaw movement), or perhaps not waiting long enough for the succinylcholine to cause paralysis. The type of test (muscle biopsy vs genetic test) requires individual consideration and discussion. 

Fortunately most patients who have experienced an MH episode have few, if any, problems without anesthesia.  There are some exceptions however.  About 20 years ago clinicians and researchers found that patients who have an unusual muscle disorder marked by muscle weakness (Central Core Disease) are also susceptible to MH.  Then yet another unusual muscle disorder Multiminicore disease also characterized by muscle weakness was found to predispose to MH.  It is not necessary to go into the fine points of how the names were derived, but the important point is that many of the patients with these disorders are also at risk for MH and that DNA changes are found on the same gene as those for MH.  It is presumed that the protein that this gene is responsible for is altered by these mutations in a somewhat similar manner, but not entirely like the changes that underlie MH, since as mentioned MH susceptibles usually do not have muscle weakness.

So here might be another way to define MH.  That is, a mutation or set of mutations in a gene that leads to the development of a protein, the calcium channel also called the ryanodine receptor of muscle that leads to enhanced release of calcium into the muscle cell.  Without anesthesia, depletion of calcium from the storage sites in the muscle leads to muscle weakness.  With anesthesia there is a more dramatic release of calcium which leads to clinical MH. As mentioned in previous blogs, one of the great advances in the science of MH was the incorporation of an MH mutation into the genome of a mouse. When that happens, the mouse will display signs of MH with anesthesia.  If the right mutation is chosen, the mouse will display the signs of Central Core Disease.  I wish to reiterate that in most cases the genetic basis for MH is a mutation in the ryanodine gene and in Central Core Disease there are also mutations in the same gene.  

It may be concluded that if a patient has a specific mutation on this specific gene and then displays the signs mentioned above, then that should be considered as MH.   To some, that indeed is the definition of MH.

However, try as scientists might, not all patients and their families who have experienced clinical MH are found to have one of the mutations that correlate with MH.  That may be because there are other genes and other mutations that “cause” predisposition to MH.    

Then in the 1990s with the further advances in identifying DNA changes, reports came in describing how some healthy, athletic individuals, usually males, developed muscle breakdown with exercise only, without anesthesia.  Furthermore, some, not all, were found to be MH susceptible on standard muscle biopsy testing and even with genetic testing.  So is this a subcategory of MH of anesthesia, or a completely different entity?   Maybe we should call it exercise induced MH or exercise induced ryanodinopathy.  Furthermore, because there has not been much experience with this problem, it is not clear if Dantrium would prevent the muscle breakdown.

The laboratory test for measuring muscle breakdown is the measurement of an enzyme called creatine kinase, important in the biochemistry of energy production in the cell.

Elevated CK can happen any time there is significant muscle damage, such as overexertion in an unconditioned person or in the presence of a muscle disorder.

In some cases the cause of the elevated CK is apparent, however, in some CK is chronically elevated for no apparent reason.  Guess what? About 50% of those patients with unexplained elevation of CK will test positive with the muscle biopsy test for MH and some will have one of the MH mutations in the ryanodine gene.  So, if a patient develops muscle breakdown with exercise or heat exposure or for no apparent reason, are they at risk for MH of anesthesia and should they and their family be labeled as MH susceptible?  Ask five experts this question and you will get at least three different answers.  Since some of these patients are at risk for MH of anesthesia, but some are not. It would be unethical to expose them to MH trigger agents to get the answer. 

So now, the spectrum of the MH syndrome has been expanded from a strictly OR/anesthesia problem to one involving exercise and possibly certain muscle disorders.

Should every patient with a muscle disorder be considered MH susceptible? Clearly not. However, aside from Central Core Disease and Multiminicore disease and perhaps a few others, our knowledge of the relation between MH and a variety of other disorders is limited to reports in the medical literature.  It is hard to find reports of patients who might have been thought to be at risk for MH, but did not display MH.  Not many physicians will report that “we took care of X number of patients with an unusual muscle disorder, anesthetized them with MH trigger agents, and nothing bad happened.” 

There are other confusing points. Some patients with muscular dystrophy, which is inherited in a different manner from MH and is also marked by muscle weakness will develop muscle breakdown, elevated CK, elevated potassium levels when anesthetized with MH trigger agents.  Sounds in many ways like MH, but the basic biochemical, cellular defect is different. This is not MH, but it “rhymes” with MH, as Mark Twain said about history repeating itself.  Furthermore, dantrolene does not seem to affect the course of this problem.

Only recently, as mentioned in my previous blogs, has there been an indirect connection identified between muscular dystrophy and the ryanodine receptor. 

To add to the confusion, some patients and certainly genetically engineered mice with the typical MH causal mutation will develop muscle rigidity, acidosis, muscle breakdown and high body temperature from environmental causes better known as heat stroke. Therefore if a patient with a known MH mutation develops heat stroke is that “MH” or is it heat stroke. We don’t have any basis to believe that most patients with heat stroke also are at risk for MH.  However, a subset might be.  I could not even hazard a guess as to what percent of heat stroke patients are at risk for MH or have a ryanodine mutation.   We don’t know at present and investigations into the relationship are proceeding very slowly.  But that is for another blog. 

Finally, since MH of anesthesia is clearly related to a rise in cellular calcium in the muscle cell due to release from the storage organelles for calcium in the muscle, is it possible for a clinical MH episode to occur when intracellular calcium is increased despite “normal” ryanodine receptors, or at least without evidence of genetic change in the ryanodine receptor gene?  The answer is a tentative yes.  Some drugs release calcium to an abnormal extent depending on the dose of drug when applied to a muscle cell. One such drug is caffeine, another is serotonin, another MDMA (also known as Ecstasy, used at rave parties) and the inhalation agents that trigger MH do so.  In addition heat may lead to increased intracellular calcium levels as well.  At least in animals it is possible to induce an MH-like syndrome by combining significant amounts of calcium releasing agents. For example, many years ago, I showed that halothane and high doses of caffeine will lead to an MH-like syndrome in rabbits. 

So, to summarize it is very difficult to come up with one all encompassing definition of MH.  I propose that MH be subdivided in several types:

The classic MH related to anesthesia.  Patients have an inherited change in the calcium channel leading to enhanced calcium release on exposure to certain anesthetic agents.

Patients with an inherited change in the ryanodine receptor but are triggered by drugs and agents other than anesthetics, such as heat.

MH in association with certain myopathies that predispose to the syndrome whether because of alterations in the ryanodine receptor or from some other mechanism that directly or indirectly elevates intracellular calcium.

MH in association with a deficiency of a specific calcium buffering protein that controls calcium levels in the cell. When absent, calcium levels can increase to an abnormal extent (not discussed here).

Finally MH in patients with normal ryanodine receptor gene.  They may develop the syndrome or partial expression of the syndrome on exposure to calcium releasing drugs or environmental factors. Dantrolene may or may not be helpful in these situations. 

     To make this distinction easier to remember, I suggest the following:

MH related to anesthesia should be named Denborough’s syndrome after the scientist who brought the syndrome to the world’s attention.

MH in patients with abnormal gene for ryanodine receptor but triggered by non anesthetic factors should be named Britt’s syndrome, after Dr. Beverly Britt who did so much of early work in describing MH.

MH in association with muscle disorders should be named MacLennan’s syndrome, after Dr. David Maclennan who identified the ryanodine gene as causal for most cases of MH.

MH in association with loss of calcium binding proteins in skeletal muscle and

MH in association with normal ryanodine receptors are yet to be named. 

The anesthesia and scientific community have done a great job in clarifying many of the aspects of anesthesia induced MH, however, in my personal opinion there is much more to be learned about the function of the ryanodine receptor particularly in different cellular environments and in different species. Two quick examples:

When the mutations that are found in the skeletal muscle ryanodine receptor occur in the ryanodine receptor in the heart, then the patients are at risk for sudden death from an arrhythmia.  (Heart is a muscle and there are ryanodine receptors in the heart muscle also, but the physiologic activation and control of the channel differs from skeletal muscle.)

In pigs who are at risk for MH, they must inherit a double dose of the gene. That is, it is a recessive gene. 

Thank you for your support of MHAUS.  If there are specific topics you wish me to address, please let me know.  

Reference to the study of induction of MH in rabbits:

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


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