"Awake" MH

From the beginning descriptions of the MH syndrome in the 1960s it was noted that the animal model for MH, i.e., certain pig breeds, would develop muscle breakdown, acidosis, and high body temperature with stress alone (“awake MH”, i.e., MH signs without exposure to anesthetic agents). The biopsied muscle from these animals displayed all the characteristic changes found in the muscle of MH susceptibles.  Furthermore, the pig could develop MH upon exposure to the inhalation anesthetic halothane or other MH trigger agents.  The stressors that would produce all the signs of MH in the animals included fighting, coitus, and transportation.  This problem, termed Porcine Stress Syndrome or Pale Soft Exudative Pork syndrome was a real economic issue for breeders of swine for high meat quality.  The meat quality after the pig had experienced Porcine Stress Syndrome was unacceptable for market.  As a result animal scientists began to investigate the Porcine Stress Syndrome (PSP) as early as the late 1960s. The object of the studies was to identify which animals were at risk to Porcine Stress Syndrome and cull them from the herd.  Initially, this was done by a “barnyard challenge” with halothane by mask.  The pigs developing muscle rigidity were identified as being at risk to PSP.  This, however, was cumbersome and inefficient and studies were begun to find another test. By the early 1990s molecular genetics had developed sufficiently such that a candidate gene (the ryanodine receptor gene) had been identified as well as a mutation that was common to both MH and PSP in pigs.  Studies carried out at the University of Toronto, and the University of Minnesota eventually led to the identification of a specific mutation in the ryanodine receptor gene that was found in animals who displayed the syndrome. 

For human MH, almost all cases were related to exposure to inhalation anesthetics and succinylcholine. However, there were occasional case reports in humans suggesting that MH might occur with stress alone. The information and scientific validity of such observations was flimsy at best.  The cases were mostly based on occasional case reports of instances where someone who had a family history of MH died unexpectedly under “stressful “situations.  But it was difficult to pin down the relationship between the death and MH susceptibility. Since muscle from MH susceptibles often has no distinctive microscopic appearance, the conclusion that MH was the cause of death was subject to debate. Unlike under anesthesia, where a patient’s physiologic functions are carefully monitored, the physiologic changes associated with death under such stressful situations (however defined) are difficult if not impossible to measure. Further, most studies of sudden death, particularly in young people, found an association with unsuspected cardiac abnormalities. Nevertheless, over 10% of sudden death in young athletes or others was not explained by cardiac, infectious or vascular causes. 

The few, limited studies of humans with MH who were monitored during stress of exercise in a physiology laboratory situation, did not show dramatic MH-like physiologic changes as might have been expected to be demonstrated during an MH episode.  Others argued that the failure to demonstrate MH in the exercise laboratory was not like the real life situation where environmental heat, sustained exercise and/or viral illness might trigger awake MH. 

However, a small number of studies did report that some patients who displayed muscle breakdown or heat stroke demonstrated MH susceptibility on the muscle biopsy contracture test.   For example, a study of 12 young male patients from Germany with exercise-induced muscle breakdown showed that ten had evidence of MH susceptibility on the contracture test, and three demonstrated a ryanodine mutation known to be causal for MH. This study was done when the MH-related mutations were just being discovered.   Why was this study not expanded to a larger population of patients with such problems? In my opinion, it was because there was still limited information about the genetic basis of MH and the expense associated with such a study was, and still is, significant. Furthermore, those who deal with heat and exercise-related syndromes are not anesthesiologists and their knowledge base related to MH was, and is, often limited. Even emergency medicine physicians often have incomplete information concerning MH. This is the problem of an orphan disease.  In addition, major funding agencies gravitate towards medical problems that are common. 

Most of the studies on heat stroke focused on prevention through adequate hydration physiologic adaptation to a high heat environment. It seemed logical to these investigators that heat and exercise-related problems were related to environmental conditions as well as physical conditioning, rather than a rare genetic disorder.

Slowly however, with the advance of molecular biology and a deeper understanding of MH, focus began to shift to the possibility that ryanodine mutations (called RYR-1 mutations) such as found in MH susceptibles, may predispose patients to non-anesthetic-induced MH.  RYR-1 mutations (both those known to cause MH susceptibility and others whose significance is yet to be determined) may be found in anywhere from one in 400 (recent data) to one in 2,000 patients. The one in 2,000 prevalence has been documented in at least two excellent studies, one from France and one from Japan.

Could the presence of a mutation in the RYR-1 gene predispose a patient to heat stroke or exercise-induced muscle breakdown or even muscle breakdown from other medications such as the statins? Why does one athlete who is of similar build to his/her colleagues exposed to similar environmental conditions develop heat stroke or even “awake” MH while another does not? Could the one who collapsed harbor a mutation in the ryanodine gene?  The study to answer this question has not been done. Furthermore, for a whole host of reasons, there has not been a coming together of the MH community with those interested in exercise and heat-related complications.  The reasons are complex and, with limited resources on both sides, the delay and lack of movement is understandable, (perhaps).

Nevertheless, in recent years the answer to the question of whether MH in all its manifestations can appear without the presence of anesthesia has been clarified to an extent.  Studies in mice genetically engineered to be MH susceptible show that these mice develop all the signs of MH on exposure to high environmental heat. There are now several instances of young (human) patients who developed the signs of MH and died without anesthesia. In two well documented instances, the patients, ages 12 and 6 survived an anesthesia-induced MH crisis only to succumb to awake MH months or years later. Furthermore, ryanodine mutations were identified in one case in other family members.  In a recent paper in Anesthesiology, the group at the Uniformed Services University along with Dr. Robert Dirksen at the University of Rochester, identified near identical mutations in two young patients who developed “awake” MH and succumbed. In another report, now under review by a journal a 6-year-old boy developed awake MH and died after being administered succinylcholine in an attempt to relieve severe rigidity. In this case a ryanodine receptor mutation was identified. Furthermore, other family members were identified with the same mutation. In this family, those with the mutation had evidence of marked scoliosis and the muscle histology showed evidence of Central Core Disease. This disorder is also uncommon, usually marked by muscle weakness and /or muscle abnormality, is inherited, predisposes to anesthesia-induced MH and mutations in the ryanodine receptor gene are common.

There are several other well documented cases that clearly show that some MH susceptible may develop life-threatening MH, heat stroke or muscle breakdown without anesthesia

These findings now raise some challenging questions for clinicians and patients.

First, are patients with certain RYR-1 mutations more at risk for non-anesthesia induced MH?

Second, what are the precipitating factors that led to the manifestations of MH without anesthesia?

Third, what should patients who are MH-susceptible be told about alteration of their or their children’s life style?

Fourth, should some patients be on prophylactic dantrolene or take dantrolene prior to strenuous exercise?

Fifth, when sudden death,”heat stroke” or muscle breakdown occur, how can we differentiate between MH and non-MH causes?

Sixth, what are the steps in treating muscle rigidity and hyperthermia in the field, without immediate dantrolene availability, as in the hospital environment?

Seventh, should all patients with a history of heat stroke or unexplained muscle breakdown with exercise be treated as if they are MH susceptible when requiring anesthesia?

Eighth, should all patients who develop heat stroke and/or exercise induced muscle breakdown undergo genetic testing for ryanodine mutations?  And if so, what is the cost benefit ratio of such testing?

Ninth, how should first responders be educated in identifying the possibility that heat stroke, particularly with muscle rigidity might require dantrolene in addition to standard cooling measures?

Tenth, how common or uncommon is the problem of awake MH?

To give you an idea of the difficulties involved, last month a young baseball player in Rhode Island collapsed during practice and died in the hospital with high body temperature. The newspaper described the problem as malignant hyperthermia.  Who will advise the family on investigations for MH and further evaluation?  Physicians associated with MHAUS might seem the logical choice, but there must be a request for such consultation, otherwise there is a risk of accusation of practice of medicine in a jurisdiction where the physician does not have a license.

In some cases, MHAUS has been contacted by a medical examiner who could not understand the reason for a young patient dying with signs of hyperthermia and muscle breakdown without evidence of either strenuous activity or high environmental heat.  We don’t really know how many medical examiners would think of MH in such cases.  MHAUS needs to reach out to this community to make them aware of the problem.

So there is a huge amount of work to be done and many implications of these new findings.  Answering even some of the questions I posed will require a multiyear, large multicenter grant well beyond, at present, the capabilities of our small organization. What we can and will do, is make others aware of this problem and encourage further research.

Meanwhile, I am sure your are asking your selves, what should MH susceptibles and their families be advised about the danger of awake MH?  We recently discussed this topic at our annual meeting of hotline experts and there were differences of opinion as to what the responsible, prudent advice should be.  However, what was agreed on by all is that when very high body temperature occurs in a young patient along with muscle rigidity, immediate cooling by any means available should begin.  Secondly, when the patient is brought to the hospital succinylcholine (Anectine) must be avoided during any resuscitation. Thirdly, administration of dantrolene should be considered, particularly in the face of high body temperature and evidence of muscle breakdown.  Fourth, the patient should be evaluated for muscle breakdown and elevated potassium level. Finally, the patient should be referred to MHAUS and, if possible, an MH expert for further discussion and evaluation including genetic or muscle biopsy contracture testing.

For now, it would seem appropriate to advise against exercise in hot environments or very strenuous exercise if heat stroke or muscle breakdown has occurred previously in the individual or family where MH susceptibility already exists.

Over the next several years as the power of molecular genetic testing increases and the cost decreases, the feasibility of testing all patients with exercise-induced muscle breakdown or heat stroke, in an economic fashion will become more realistic in an economic fashion.

We certainly have entered a new phase in our understanding of Malignant Hyperthermia. One that raises significant questions that previously could be dismissed because of lack of scientific evidence.

In closing, I would like to remind readers of this blog that awake episodes of MH are very rare, with fewer than twenty such cases reported in the world’s scientific literature.  That may be because awake MH is indeed a very rare phenomenon in humans or because the association between heat stroke, exercise-induced muscle breakdown and MH has not been made by those most likely to deal with such problems, i.e., sports medicine physicians, emergency medicine physicians and  internists.

References

Tobin JR. Jason DR. Challa VR. Nelson TE. Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA. 286(2):168-9, 2001

A case report of a patient who developed signs of awake MH and was found to have RYR-1 mutation as did others in his family.

 Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J: Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. ANESTHESIOLOGY 2001; 94:95–100

A study of 12 young men with exercise (body building) induced muscle breakdown. Ten were positive on the contracture test, three on genetic testing.

Groom, Linda; Muldoon, Sheila M.; Tang, Zhen Zhi; Brandom, Barbara W.; Bayarsaikhan, Munkhuu; Bina, Saiid; Lee, Hee-Suk; Qiu, Xing; Sambuughin, Nyamkhishig; Dirksen, Robert T.Identical de novo Mutation in the Type 1 Ryanodine Receptor Gene Associated with Fatal, Stress-induced Malignant Hyperthermia in Two Unrelated Families.Anesthesiology. 115(5):938-9451.   

Investigation of two patients with awake MH who were demonstrated to have RYR-1 mutations that were shown to induce cellular changes as found in MH susceptibles with other mutations.  

Gronert GA, Tobin JR, Muldoon S: Malignant hyperthermia – Human stress triggering. Biochimica et Biophysica Acta 2011; 1813:2191-2192

MacLennan DH, Zvaritch E: Response to “Malignant yperHyHyperthermia – human stress triggering” in reference to original article “Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum” http://dx.doi.org/10.1016/j.bbamcr.2010.11.009. Biochimica et Biophysica Acta 2011; 1813:2193-2194

Recent comments on a review article concerning MH pointing out several instances of awake MH. 

Note:
I wish to thank Dianne Daugherty and Sharon Dirksen for their  helpful comments.