The Doctor’s Dilemma

On behalf of MHAUS, its Board, Staff, Professional Advisory Council, and Hotline Consultants I would like to wish all of you a Happy and Healthy New Year.  Our hope for the future is to fulfill the mission of eliminating death and disability related to MH and MH-related syndromes.

As I look back over the past year, I see continued progress in our goal to insure that facilities of all kinds are prepared to provide, optimal safe care to MH susceptibles and their family whether they require elective surgery or should an MH crisis develop unexpectedly.  There continues to be steady advances in our understanding of the science of MH and MH-like syndromes as well as application of those advances to the direct care of patients. From that point of view the highlight of the past year was our scientific conference in April 2010. Many of the leading clinicians and scientists in the study of MH reviewed the present understanding of MH, the relation of MH to other muscle disorders, the role of the ryanodine receptor in muscle physiology.  Also discussed was the similarities between the skeletal muscle and cardiac muscle ryanodine receptor in the development of two very different life threatening problems, MH and CPVT.  The latter is an inherited heart rhythm disturbance that predisposes those affected to sudden death. Dr. Alexander Kushnir from the Center for Molecular Cardiology at Columbia University College of Physicians and Surgeons explains, in a recent issue of The Communicator, the connection between those two syndromes.

In science, every time a question is answered, new ones appear.  As we learned more and more about the molecular genetics of MH, i.e. the changes in DNA that can make a person susceptible to the syndrome, new questions arose.  For example, although the results of DNA testing predicts the response of the muscle biopsy test, i.e. whether it is positive or negative, in patients who experienced MH or where family members experienced an MH crisis, there is discordance between the DNA test and the contracture  test in about 10% of cases. Is this because the muscle biopsy test is inaccurate, or because the DNA change is not activated such that the physiologic response of the muscle remains normal?  A second question, even with complete analysis of the DNA of the gene that leads to the elaboration of the ryanodine receptor, about 30% of MH susceptibles have no variations in the DNA.

There is another truth in Medicine, one that is taught early on in medical school. One can never say “never” or “always” in Medicine.  Therefore as much as is learned about medical science the practice of Medicine always is partly an art. For example, I recently was made aware of a young man who developed extensive muscle breakdown after being intubated with succinylcholine by emergency medical technicians after he experienced mild loss of consciousness after exercise along with a temperature of 101 degrees.  It was not environmental heat stroke since the air temperature was in the 60s. There was no history of MH in the family nor had he had anesthesia previously.  Over the next half hour or so his body temperature rose to over 106 degrees and he was acidotic.  Dantrolene was given and helped resolve the crisis, although the muscle breakdown was so severe that he developed renal failure.  It took weeks for him to return towards normal.  Thinking that this might be MH a DNA test was done, but none of the definitive mutations associated with MH was found.  The family was not interested in the muscle biopsy because of the invasive nature of the test. After the episode his muscle damage resolved.

Was this really a manifestation of MH?  Did he harbor a mutation that has not yet been identified?  Since there is at least one other gene associated with MH, did he have a mutation in that gene?  Mutations are not usually sought in other genes than the ryanodine receptor gene, because of limited clinical experience and expense of testing.

Perhaps the changes were due to another enzymatic defect.  Our knowledge is too rudimentary to be certain. However, given the signs that he developed after the trigger drug succinylcholine, he and his family were advised to consider themselves as at risk for MH.

However, the situation gets more complex.  Not too long ago a young boy suddenly developed increased heart rate, temperature elevation, and extreme muscle rigidity without any apparent cause.  He was simply playing with other children in a warm environment. Because of the rigidity involving his jaw to the extent that he could not open his mouth easily, he was brought to the emergency room.  In order to produce relaxation succinylcholine was administered.  Instead of the jaw relaxing a cardiac arrest occurred and he died.  It was not at all clear as to the cause of death and the case was analyzed by the medical examiner in the area.  Through the determination and astuteness of the medical examiner, the question of MH was raised.  Eventually, analysis of the DNA from specimens taken at autopsy revealed mutations in the ryanodine receptor gene.  In addition his father also had a similar mutation. Curiously too both of them had a spinal deformity, a marked form of scoliosis.

Reports from several MH investigative units in different countries have reported a few similar cases including DNA changes predictive of MH susceptibility.  In addition, as I have described previously MH susceptible pigs and genetically engineered MH susceptible mice also may develop life threatening MH like events on exposure to heat and in the case of pigs to stress.  For the MH “experts” what do we advise those who known MH susceptible based on anesthetic exposure?  Which of these patients is like to develop life-threatening events in absence of anesthesia and under what conditions?  Can we predict those at risk based on their genetic profile and if so, which profile?

This is the dilemma we face at this time. Fortunately non anesthesia related crises seem to be very, very uncommon. Nevertheless how can we advice a particular patient?  For the many years that I was performing MH contracture testing I told patients that if they have lived 15, 20 or more years with their MH susceptibility and never had a problem outside of anesthesia, then the chances of developing a problem in regard to heat and exercise is vanishingly small and one should not change one’s life style. Some of the experts are however, advising some of their patients to avoid extremes of heat and exercise, particularly the combination.  I feel that the individual MH susceptible and their family need to carefully monitor responses to such conditions and err on the side of desisting from continuing the exposure rather than “tough it out”.  What to monitor?  The development of muscle rigidity or extreme muscle weakness, the feeling that one is suffering from heat exhaustion or the color of the urine turning brown.  Some of the semi professional or professional athletes are now measuring body temperature when they are exposed to extreme heat. If so, when is the time to stop?  A temperature of 103, 104, 105? What evidence is there to support such active intervention?  Should sports teams have a supply of dantrolene available to treat heat shock?  Should MH susceptibles who are athletes let their coaches know of their condition and have dantrolene available and the local hospital on notice?

As we enter the second half century since MH was first described, these are the questions that are emerging and are of concern to clinicians, patients and their families.

Most of all, research is needed to understand the incidence of heat stroke and exercise induced muscle breakdown and the percentage of patients who develop such problems who have the DNA changes found in the MH susceptible. Finally more research is needed to identify all the DNA changes and other biochemical changes that may lead to the onset of MH.  The next fifty years are likely to reveal the answers to these and many other questions arising from the study of MH, the ryanodine receptor and calcium control in muscle cell.  I hope that MHAUS will be there during this time, encouraging, educating and supporting these major advances in understanding of the disorder that we know as MH.

Why do some patients who are MH susceptible develop life-threatening events under certain conditions of heat and vigorous exercise and others not?  But more importantly how can we identify those who are at risk to non anesthesia related MH or MH like crises?  What do we advise the thousands of individuals who have been identified to date as being MH susceptible in regard to vigorous exercise and exposure to high environmental temperature?