MHAUS is hosting a 45-minute live presentation and discussion for Ambulatory Surgical Center healthcare professional and administrative staff to answer questions about MH basics and transferring a patient to a hospital—You can post comments and questions that you would like to discussion below.

Space limited to 95 attendees. More information about the event and registration can be found at this link: http://bit.ly/IVK8DB.

$10 for MHAUS members, $20 for non-MHAUS members

Attendees receive follow up email and packet by mail.

Speaker: Mohanad Shukry, M.D.: Associate Chief, Division of Pediatric Anesthesia at The Children’s Hospital, Oklahoma City, OK; and Program Director, Pediatric Anesthesia Fellowship at University of Oklahoma Health Sciences Center, and Division Chief, Pediatric Cardiac Anesthesia at University of Oklahoma Health Sciences Center.

Related information:

• Emergency Therapy for MH Poster
• MHAUS MH Hotline Consultants
• Transfer Plans for Suspected MH Patients – Moving a patient to a hospital.

Please Comment on the Following Recommendations by June 9, 2012

• Review of literature does not indicate an increased susceptibility to MH by patients diagnosed with Mitochondrial Myopathy (MM).
• Patients suffering from MM should receive an anesthetic appropriate for the patient’s co-morbid conditions and type of surgery they are undergoing.
• Volatile agents should not be avoided out of concern for possible MH susceptibility in MM patients.
• Use caution when using succinylcholine in myopathic patients due to evidence suggestive of succinylcholine-induced hyperkalemia in such patients.

Read more

Post your comment below.

Recommendations

• Review of literature does not indicate an increased susceptibility to MH by patients diagnosed with Mitochondrial Myopathy (MM).
• Patients suffering from MM should receive an anesthetic appropriate for the patient’s co-morbid conditions and type of surgery they are undergoing.
• Volatile agents should not be avoided out of concern for possible MH susceptibility in MM patients.
• Use caution when using succinylcholine in myopathic patients due to evidence suggestive of succinylcholine-induced hyperkalemia in such patients.

Supporting Evidence

Literature Review: Multiple literature searches of the National Library of Medicine, beginning the year 1970, were done using key words: Malignant Hyperthermia; Mitochondrial Myopathy and Cytopathy; Mitochondrial Syndromes; Anesthetic Management; Pediatrics and Perioperative Complications. Individual database searches were performed as well as searches within the major anesthesiology journals (Anesthesiology and Anesthesia & Analgesia) beginning the year 1970. All articles that described anesthetic management of patients with mitochondrial disorders and articles that conducted original research examining the role of mitochondria in relationship to MH were reviewed.

Background: It is unclear how the attribute of MH first came about in association with MM. The phenotypical presentations of patients with MM involve acidosis that is of a chronic nature and hypotonia of varying severity. Myopathic illnesses that carry known risk for MH such as central core disease (CCD) share similar clinical features and hence an association may have been first considered. The majority of available literature suggests no or weak association between MM and MH.

Evidence Thus Far: Ohtani et al (1985) in a letter to the editor reported a successfully treated case of MH in a 2 year old diagnosed with MM. The child had clinically evident motor weakness; elevated CK and pyruvate levels, but received halothane and succinylcholine for an unknown procedure. Generalized muscle rigidity, hyperkalemia and rise in temperature to 380 C followed the induction of anesthesia. 50 mg dantrolene (patient’s weight unknown, but presumably a large dose for a 2 year old myopathic child) an unknown amount of bicarb and cooling were the treatment instituted. The child recovered in 30 minutes and underwent a muscle biopsy performed with local anesthesia the same day, the analysis of which suggested defective oxidative phoshorylation of the mitochondria.

This brief case report describes a clinical situation where MH is diagnosed in a myopathic child after administering succinylcholine and halothane. All the symptoms and signs except for the temperature of 380C could be due to cytoskeletal disruption of muscle from succinylcholine (Theroux, 2001; Van der Spek, 1987) especially in a child with evidence of ongoing muscle cell damage (elevated CK preoperatively). This case at best provides weak evidence of an association between MM and MH. Nevertheless this letter to the editor has been consistently quoted and referenced by numerous other authors as evidence for their statement of MH susceptibility of patients with MM.

Thompson et al (1997) reported the anesthetic course of a 20 year old man with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes) syndrome. The patient had difficulty with anesthesia at a different hospital (other than the author’s), and the report clearly notes that MH was excluded in that particular event. However, the authors chose a non-triggering anesthesia quoting Ohtani et al (1985). Unfortunately this is a common practice among anesthesiology practitioners to resort to a non-triggering anesthetic rather than tease out the patient’s history which often consumes much time and effort.

Wiesel et al (1991) describes the anesthetic for a 13 month old boy for skin and muscle biopsy. MH triggering agents are avoiding, quoting Ohtani et al (1985). One sees a pattern emerging where a single case report, has a snow balling effect going forward.

Maslow and Lisbon (1993) report a 40 year old man with MM was given a spinal anesthetic for reduction of an ankle fracture. One of the reasons stated for performing spinal anesthetic was to avoid triggering anesthesia. Authors mention that there is no evidence to believe that MM renders MH susceptibility but they wished to avoid triggering agents quoting Ohtani et al (1985).

Casta et al (1997) describe the perioperative course of a 13 month old who had rapid deterioration of CNS function with MRI findings in the immediate post operative period following general anesthesia for gangrenous gall bladder surgery. Anesthetics consisted of thiopental, isoflurane and nitrous. She developed generalized posturing in the postoperative period indicative of significant CNS dysfunction. It was postulated that this child’s worsening condition was due to her defect in oxidative phosphorylation further exacerbated by inhibition of complex III of the electron transport chain by circulating cytokines especially TNF. There was no suspicion of MH as a causative factor. Post operative CNS dysfunction is likely in MM and pathophysiology is directly attributable to the patient’s primary pathology of dysfunctional mitochondria. This case report describes the effect of stress induced by anesthesia and surgery on a defective mitochondrial energy resource thus resulting in adverse outcome; there is no relation to MH.

Gronert et al (1979), in an animal study using susceptible swine, concluded ‘that the reduced respiratory and calcium binding activities in mitochondria from susceptible swine supported the diagnosis of a myopathy, but that these do not account for the functional and biochemical derangement observed in clinical malignant hyperthermia’. Findings in this study do not support a link between biochemical abnormalities described in MH and those found in the swine in their experiment.

Driessen et al (2007) describe 122 patients with MM who received a variety of anesthetic agents. Only 15 patients were anesthetized using ‘total intravenous anesthesia’ and the rest received potent Inhalational anesthetics. There were no significant adverse effects related to the choice of anesthetics. This is an important study as the discussion about anesthetic agents revolves around ‘to use or not to use volatile anesthetics.’ This study supports use of volatile anesthetic agents.

Muravchick et al (2006), in an extensive review of MM state, “Only the very rare mitochondrial myopathies with multicore or minicore histology seem to warrant concerns of an increased risk of MH. Therefore, at least at the present time, there is inadequate data to support the recommendation of some authors that the anesthetic plan for patients with mitochondrial disease should routinely include MH precautions.”

Cheam et al (1998) reported the use of a non triggering anesthetic to anesthetize a known case of MM in a child from the Chinese University of Hong Kong. The authors refer to several articles only remotely related or associated with MH.

Fricker et al (1997) describe a 41 year old man with severe exercise intolerance and myalgia with CK 3,700 admitted for MH work up prior to hernia repair. He carried a combined diagnosis of MM and Myoadenylate Deaminase deficiency. [These authors also quote ‘Ohtani et al (1985)]. An IVCT test with caffeine and halothane (contracture at 1.5 mm caffeine: 4.5 mN and at 0.11 mm halothane: 2.5 mN, respectively) established the diagnosis MHS (contracture thresholds: more than 2 mN at ? 2 mm caffeine and ?0.44 mm halothane). This study describes a situation where an IVCT performed is positive for MH in an individual with two myopathic conditions. While it proves that this particular patient is MH susceptible it cannot be extrapolated to mean an increased susceptibility of patients with MM to MH.

With regard to the use of succinylcholine in MM patients, although the literature does not support an outright statement regarding use of succinylcholine leading to hyperkalemia in MM, there are reports (Al-Takrouri et al., 2004, Larach et al., 1997) which indicate fatalities from succinylcholine-induced hyperkalemia and rhabdomyolysis in patients with undiagnosed myopathies. Therefore, caution must be utilized when using succinylcholine in myopathic patients due to evidence suggestive of succinylcholine- induced hyperkalemia. Though not directly related to MH, due to the profound and often irreversible adverse effects from succinylcholine in some myopathic patients, a cautionary statement is warranted in the recommendations.

Author Commentary

Mitochondrial diseases are a group of myopathic conditions encompassing a broad spectrum of defects in mitochondria, the clinical features of which can be worsened by illness or stress. Any surgical intervention would mean a finite amount of stress on an individual and in a mitochondrial myopathic patient this stress itself could worsen their clinical status. No controlled clinical trials have been conducted in patients with mitochondrial myopathy to study the effects of anesthetic agents. As such available clinical evidence of Malignant Hyperthermia Susceptibility (MHS) in mitochondrial myopathy predominantly consists of level 4 (case reports, retrospective reviews of patients anesthetics and expert opinion). One could speculate on a scenario which if MH occurs in a mitochondrial myopathic patient the burden on the already defective mitochondria might result in a clinical presentation which may be completely unrecognizable.

References

1. Al-Takrouri, H., T. W. Martin, et al. (2004). Hyperkalemic cardiac arrest following succinylcholine administration: The use of extracorporeal membrane oxygenation in an emergency situation. J Clin Anesth. 2004; 16(6):449-451.
2. Casta A, Quackenbush EJ, Houck CS, Korson MS. Perioperative White Matter Degeneration and Death in a Patient with a Defect in Mitochondrial Oxidative Phosphorylation. Anesthesiology 1997; 87:420-5.
3. Cheam EW, Critchley LA: Anesthesia for a child with complex I respiratory chain enzyme deficiency. J Clin Anesth 1998; 10:524–7.
4. Driessen J, Willems S, DERCKSEN S, Giele J, van der Staak F, Smeitink J. Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects: Pediatric Anesthesia 2007; 17: 16–21.
5. Fricker RM, Raffelsberger T, Rauch-Shorny S, Finsterer J, Müller-Reible C, Gilly Hermann, Bittner RE. Positive Malignant Hyperthermia Susceptibility In Vitro Test in a Patient with Mitochondrial Myopathy and Myoadenylate Deaminase Deficiency: Anesthesiology: December 1997; 97:1635-37.
6. Gronert GA, Heffron JJA. Skeletal Muscle Mitochondria in Porcine Malignant Hyperthermia. Anesthesia & Analgesia. 1979;58(2):76-81.
7. Larach, M. G., H. Rosenberg, et al. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila).1997; 36(1):9-16.
8. Maslow A, Lisbon A. Anesthetic Considerations in Patients with Mitochondrial Dysfunction. Anesthesia & Analgesia. 1993;76(4):884-6.
9. Muravchick S, Levy RJ. Clinical Implications of Mitochondrial Dysfunction. Anesthesiology 2006;105(4):819-37.
10. Ohtani Y, Miike T, Ishitsu T, et al. A case of malignant hyperthermia with mitochondrial dysfunction [letter]. Brain Dev. 1985;7:249.
11. Theroux MC, Rose JB, Iyengar S, Katz MS. Succinylcholine pretreatment using gallamine or mivacurium during rapid sequence induction in children: a randomized, controlled study. J Clin Anesth. 2001;13(4):287-92.
12. Thompson VA, Wahr JA. Anesthetic considerations in patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Anesth Analg. 1997;85(6):1404-6.
13. Van der Spek AF, Fang WB, Ashton-Miller JA, Stohler CS, Carlson DS, Schork MA. The effects of succinylcholine on mouth opening. Anesthesiology. 1987;67(4):459-65.
14. Wiesel S, Bevan JC, Samuel J, Donati F. Vecuronium neuromuscular blockade in a child with mitochondrial myopathy. Anesth Analg. 1991;72(5):696-9.

 The World Congress of Anesthesia is a meeting of anesthesiologists representing many countries that convenes in a different country every four years.

From the MHAUS President’s Blog. The Congress is the meeting of the World Federation of Societies of Anesthesiologists (www.anaesthesiologists.org), an organization that represents scores of anesthesia societies around the world. In March of this year the meeting was held in Buenos Aires, Argentina. I was invited to put together a four-hour segment of the meeting related to MH. With the able assistance of Dr. Sheila Muldoon, Dr. Kumar Belani, Dr. Jerry Parness, and Dr. Tae Kim, all of the US, and Dr. Robyn Gillies from Australia, we covered topics related to the clinical presentations of MH, pathophysiology of MH, genetic testing for MH, treatment and management of MH, management of MH in the outpatient setting as well as anesthesia machine preparation for the MH susceptible. Even though the session took place on the last day of the meeting, the room was filled. The attendees asked good questions and were very complimentary of the presentations. It was a great event and I believe we provided important information concerning MH for anesthesiologists who ordinarily do not have the opportunity to hear in depth presentations on the subject. We learned that there are still many countries that do not have dantrolene and as a result people still die from MH in many parts of the world. In particular, Dr. Belani has learned of deaths and near misses from MH in India, where most hospitals do not have dantrolene. He has been in active communication with anesthesiologists in India who are now interested in obtaining the drug and educating anesthesiologists about the management of the disorder. India has a population of over 1 billion people! In addition several of hospitals in India have been established by highly trained physicians who gained their experience in the US, UK and other European countries. A brisk “medical tourism” business has developed in India. There is no doubt that there are many cases of MH that are not reported regularly. India is not an exception. Many other countries also lack adequate supplies of dantrolene. Additionally, education on recognition and management of MH patients is also limited. MHAUS will do whatever we can to assist health care providers in any country to recognize, treat and prevent MH.

Read more.

The World Congress of Anesthesia is a meeting of anesthesiologists representing many countries that convenes in a different country every four years.

The Congress is the meeting of the World Federation of Societies of Anesthesiologists (www.anaesthesiologists.org), an organization that represents scores of anesthesia societies around the world. In March of this year the meeting was held in Buenos Aires, Argentina. I was invited to put together a four-hour segment of the meeting related to MH. With the able assistance of Dr. Sheila Muldoon, Dr. Kumar Belani, Dr. Jerry Parness, and Dr. Tae Kim, all of the US, and Dr. Robyn Gillies from Australia, we covered topics related to the clinical presentations of MH, pathophysiology of MH, genetic testing for MH, treatment and management of MH, management of MH in the outpatient setting as well as anesthesia machine preparation for the MH susceptible. Even though the session took place on the last day of the meeting, the room was filled. The attendees asked good questions and were very complimentary of the presentations. It was a great event and I believe we provided important information concerning MH for anesthesiologists who ordinarily do not have the opportunity to hear in depth presentations on the subject. We learned that there are still many countries that do not have dantrolene and as a result people still die from MH in many parts of the world. In particular, Dr. Belani has learned of deaths and near misses from MH in India, where most hospitals do not have dantrolene. He has been in active communication with anesthesiologists in India who are now interested in obtaining the drug and educating anesthesiologists about the management of the disorder. India has a population of over 1 billion people! In addition several of hospitals in India have been established by highly trained physicians who gained their experience in the US, UK and other European countries. A brisk “medical tourism” business has developed in India. There is no doubt that there are many cases of MH that are not reported regularly. India is not an exception. Many other countries also lack adequate supplies of dantrolene. Additionally, education on recognition and management of MH patients is also limited. MHAUS will do whatever we can to assist health care providers in any country to recognize, treat and prevent MH.

At the end of the meeting, I met with Ms. Laura Vitcop from Buenos Aires who has a history of MH in her family and is interested in providing more in depth education about MH to patients and families who are affected by MH in Argentina. She and a lawyer from Buenos Aires, Alfredo Mayo, along with others have organized a patient advocacy umbrella group, APAC (www.apac.org.ar) which stands for the Civil Association Help for Critical Patients. The organization provides information for patients with liver diseases, rheumatoid arthritis, Crohn’s disease and MH. It is the intent of the organizers to develop an MH organization in Argentina patterned after MHAUS. They have secured support from Astra Zeneca Company and are seeking additional funding to develop the MH component of the organization. I offered that MHAUS would be pleased to provide guidance, copies of our educational material and assistance in whatever way we can. I look forward to continued communication with Ms. Vitcop and the organization. I will keep you informed of our progress, or you may follow the conversations on the MHAUS Facebook site.

Yet another important event took place shortly after the World Congress Meeting. The Society for Inherited Metabolic Disorders (www.simd.org) is a society of scientists and clinicians that focuses on inhertited disorders of metabolism. Many of them are included in mandatory screening in the newborn period by blood tests. Generally the disorders are genetically determined enzyme deficiencies that require special diets, medications, or avoidance of triggers to reduce the occurrence of significant problems that may have implications for growth and development and malfunction of a variety of important organs. These include amino acidopathies (e.g., phenylketonuria.) Other examples of inborn errors of metabolism include lysosomal storage diseases, organic aciopathies, and metabolic muscle diseases, to name a few. Through communication and collaboration with Dr. Georgirene Vladutiu at the NY State University at Buffalo, MHAUS was invited to provide a lecture at the Society’s annual meeting on April 1, 2012. Dr. Cynthia Wong graciously accepted the offer to present an overview of MH for the group. This was the first time MH was discussed in a formal way with members of the Society. I am told that Dr. Wong’s talk was a great success and there is a lot of interest in furthering communication and possible collaboration between the two societies. This makes a good deal of sense to me because MH is indeed an inherited metabolic disorder, even though the manifestations are generally episodic. Common ground between the two societies is based primarily on an interest in genetic changes that affect organ system function. We are indebted to Dr. Vladutiu for making us aware of the Society. Although Dr. Vladutiu is in charge of a laboratory that provides testing for inborn errors of metabolism (the Guthrie lab at the University of Buffalo), she is also interested in the effects of cholesterol lowering drugs (statins) on muscle function. A significant percentage of patients taking such statins complain of muscle pain and some have significant muscle pain, muscle destruction and even life-threatening symptoms related to these medications. Her investigations have shown that some of the patients with severe muscle pain from statin agents also harbor mutations associated with MH susceptibility! The implications are obvious. She is now forming collaborations with various MH testing laboratories to further investigate the relation between muscle destruction, statin ingestion and MH.

I would also like to provide a follow up to our ongoing efforts to create consensus statements on topics of importance related to MH. To date there are two such statements, one concerning anesthesia machine preparation and the other temperature monitoring during anesthesia. These statements are now posted on the MHAUS web site. We have also just concluded work on a statement related to the association of heat and exercise with MH susceptibility. It is important to point out that the information is not intended to be a guideline, which has a very specific meaning in medicine, but a statement of best evidence, together with the rationale for the statement. We intend for these recommendations to assist patients and clinicians in the care of the MH susceptible or potentially susceptible patient in a straightforward, direct and succinct manner. Other statements are in process, including some on the relation of various muscle disorders to MH. We have previously made recommendations on management of the pregnant woman who is not MH susceptible but whose husband is MH susceptible; the risk for MH-susceptibles to work in an operating room where they might be exposed to anesthetic gases (it is safe). We have followed a rigorous process in the development of such statements including review by our hotline consultant and professional advisory committee members along with a period of public comment and revision based on feedback from the various groups.

Here is the most recent statement:

Topic: Adverse Effects of Heat and Exercise in Relation to MH Susceptibility

Recommendations

1. Any MHS (MH-susceptible) patient who experiences sudden collapse in association with muscle rigidity and hyperthermia should be immediately treated for MH. This includes immediate cooling measures, and transport to the nearest medical facility in order to treat with the drug dantrolene. Succinylcholine should be avoided during resuscitation and management.
2. MHS patients or their relatives who have not experienced adverse effects of heat and exercise should not restrict their activity. They should carry identification of their susceptibility and inform those responsible for their care of their MH status.
3. MHS patients who have experienced adverse effects of heat or exercise should restrict their activity based on their own experience.
4. Patients who develop documented recurrent rhabdomyolysis after exercise or with heat stroke should be referred to a neuromuscular specialist for evaluation. Malignant Hyperthermia Susceptibility should be considered as part of the evaluation.

The entire statement and rationale is posted on the MHAUS web site.

Our MHAUS Scientific Officer, Sharon H. Dirsken, PhD has brilliantly coordinated these statements. Sadly, Sharon has recently advised us she will be leaving her position at MHAUS to take on new challenges incorporating her strong writing talents in order to teach courses on science writing at the University of Rochester, her home town, as of May 11, 2012. We will miss Sharon’s drive and enthusiasm and the strong bridge she provided between the clinical and patient perspective, and her role as a conduit to bring educational projects to fruition. We wish her all the best in her new path and know that she will be a positive influence to those she interacts with in the future.

This is just a sample of some of the activities and concerns of MHAUS more projects are in the pipeline. Our dedicated hotline consultants and professional advisory council members contribute their time and expertise to the development and implementation of our panoply of educational and patient care activities.

Of course our Board of Directors and the MHAUS staff are fully engaged in the mission of MHAUS.

Your encouragement and support in word and deed is essential as well. We always want to hear of your comments.

MHAUS is hosting a 45-minute live presentation and discussion for Ambulatory Surgical Center healthcare professional and administrative staff in a few weeks on March 26 to answer questions about MH basics and transferring a patient to a hospital—

Space limited to 95 attendees. More information about the event and registration can be found at this link http://bit.ly/xcUVC0.

$10 for MHAUS members, $20 for non-MHAUS members

Post your comments and questions for discussion below.

Attendees receive follow up email and packet by mail.

Speaker: Ronald S. Litman, DO – Children’s Hospital of Philadelphia: Attending Anesthesiologist, Director of Clinical Research for the General Division, Chair, Hospital Sedation Committee, Professor of Anesthesiology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, and MHAUS MH Hotline Consultant.
Related information:

• Emergency Therapy for MH Poster
• MHAUS MH Hotline Consultants
• Transfer Plans for Suspected MH Patients – Moving a patient to a hospital.

In recent years, as DNA testing for diagnosis of many disorders has grown rapidly thanks to scientific advances, there has been a profusion of laboratories offering DNA testing to both the medical profession as well as the public. Although there are a few disorders where DNA testing of specific genes and specific mutations will predict susceptibility to a disorder, the problem for most inherited disorders is that all the DNA changes associated with the disorder have yet to be discovered. In medical parlance, DNA analysis for many conditions is specific, but not necessarily sensitive. That is if the patient’s gene manifests specific DNA changes then the patient will, with almost certainty, be at risk for the disorder. However, the complete list of DNA changes or mutations that are predisposed to most disorders are not known. For example, one of the better-studied disorders, Cystic Fibrosis (CF), DNA testing for a panel of over 100 known mutations will predict susceptibility with over 91% sensitivity (the ability to detect all those with the disorder). However, there are about 1500 mutations that may lead to some or all manifestations of cystic fibrosis and many appear only in a small fraction of those who develop Cystic Fibrosis. It would be extremely expensive and cumbersome to routinely screen for all the mutations. Since Cystic Fibrosis is inherited in a recessive manner (requires a mutation from each parent for the disorder to be manifest), when prospective parents are tested for determining the likelihood of their offspring having the disorder, someone with understanding of the complexities of genetic testing as well as the presentation of the disorder are necessary to provide best guidance to the patient. To add to the complexity, different ethnic groups will display different mutations that predict CF susceptibility. So someone who might not have Caucasian ancestry might not harbor the classic mutations predicting CF but have another mutation that was not part of the testing panel. Like most tests in medicine, the result of the test must be interpreted in the context of a whole variety of other factors. Read more

Buyer of DNA testing Beware

In recent years, as DNA testing for diagnosis of many disorders has grown rapidly thanks to scientific advances, there has been a profusion of laboratories offering DNA testing to both the medical profession as well as the public. Although there are a few disorders where DNA testing of specific genes and specific mutations will predict susceptibility to a disorder, the problem for most inherited disorders is that all the DNA changes associated with the disorder have yet to be discovered. In medical parlance, DNA analysis for many conditions is specific, but not necessarily sensitive. That is if the patient’s gene manifests specific DNA changes then the patient will, with almost certainty, be at risk for the disorder. However, the complete list of DNA changes or mutations that are predisposed to most disorders are not known. For example, one of the better-studied disorders, Cystic Fibrosis (CF), DNA testing for a panel of over 100 known mutations will predict susceptibility with over 91% sensitivity (the ability to detect all those with the disorder). However, there are about 1500 mutations that may lead to some or all manifestations of cystic fibrosis and many appear only in a small fraction of those who develop Cystic Fibrosis. It would be extremely expensive and cumbersome to routinely screen for all the mutations. Since Cystic Fibrosis is inherited in a recessive manner (requires a mutation from each parent for the disorder to be manifest), when prospective parents are tested for determining the likelihood of their offspring having the disorder, someone with understanding of the complexities of genetic testing as well as the presentation of the disorder are necessary to provide best guidance to the patient. To add to the complexity, different ethnic groups will display different mutations that predict CF susceptibility. So someone who might not have Caucasian ancestry might not harbor the classic mutations predicting CF but have another mutation that was not part of the testing panel. Like most tests in medicine, the result of the test must be interpreted in the context of a whole variety of other factors.

Much of what I have described for CF pertains to the DNA diagnosis of MH but with even more uncertainty. As many of you know, mutations in one gene, the ryanodine receptor gene (RYR-1), a very large gene harbors hundreds of mutations that may be found in over 70% of patients and family members who are MH susceptible. However, it is still unclear which of these many genes really lead to changes in the protein structure of the cell that are responsible for the cell’s response to MH trigger agents and are manifest clinically as MH. To date only about 30 of over 300 mutations are specifically predictive for MH susceptibility. Undoubtedly, many of the other mutations are also “causal” for MH, but for many reasons, not the least of which is funding, scientists have not studied the ramifications of the DNA change. So when one of those that are not on the list of the 30 predictive mutations are found, it is denoted as indeterminate significance. In addition, we know that there are other genes and mutations that are associated with MH mutations, but scientists have not found all of them yet. Hence, as with CF, if a person has a DNA test for diagnosis of MH, that test requires interpretation by someone very familiar with the disorder , such as one of the MHAUS experts or a genetic counselor.

Interesting, yes, helpful, not really

All of this is background to what I wish to comment on in this blog. As some of you know, there are a variety of companies who advertise DNA testing “directly to the consumer” (i.e. the patient). In general, the patient pays a fee and sends a sputum sample to the lab, which usually costs a few hundred dollars and receives a report. The report usually contains wording such that the results require interpretation and the company cannot be held liable for mistakes in interpretation or analysis. When I sent in my sample to one of the companies, I received a report that I had a somewhat higher likelihood than the general population of developing a certain type of heart rhythm disturbance. But what does that mean? How should I change my lifestyle to reduce the chances of developing the problem? Should I take a certain medication? If so, which one? Should I undergo cardiac catheterization? Therefore, the report is almost meaningless because it is not actionable. Interesting, yes, helpful, not really.

Recently one of our experts submitted a sample to one of these commercial direct to consumer labs and got a report back that he was not MH susceptible. Why? Because he did not manifest one of the known MH mutations. However, he was not told whether his DNA contained other RYR1 mutations that have been associated with MH susceptibility but not proven to cause the syndrome as of yet. In other words, he was given, in my opinion, incomplete and perhaps misleading information. Just because a person does not have one of the causal MH mutations does not mean that s/he is NOT MH susceptible. DNA testing is specific but not terribly sensitive. We believe that the false positive rate on DNA testing is vanishingly low, but the false negative rate is significant. In fact the test result was not helpful to him and incomplete. Fortunately, he is very familiar with the MH syndrome and understood the results in context. Then I received an e-mail from a relative who also had his DNA analyzed by this company and was told he was not MH susceptible because he did not have one of the known mutations. I had to clarify the genetics and inheritance of MH for him.

So, if any of you have been told to obtain a DNA test for MH, please utilize one of the laboratories that are recommended by our experts, listed on our web site, or have your doctor determine how the laboratory does the test, who interprets the results and what experience they have with diagnosing MH. Of course the laboratory should be certified by one or more accreditation organizations such as CLIA

(Congress passed the Clinical Laboratory Improvement Amendments (CLIA) in 1988 establishing quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed. ) or the CAP (the College of American Pathologists), . Furthermore, either a genetic counselor or an expert in MH and MH-related disorders, should assist in test interpretation and advice on whom else in the family should be tested.

DNA testing holds great promise in detection and prevention of disease and abnormal drug reactions for the individual patient. Hence the term personalized medicine. However, although the technology of DNA analysis has advanced greatly such that the entire genetic makeup may be analyzed in detail for under $10,000, the problem now is the interpretation of the changes. This will require not only knowledge of the structure of a patient’s DNA, but also correlation of the DNA alteration with the disease states. This has lead to a rapidly expanding field called bioinformatics,” The use of computer science, mathematics, and information theory to model and analyze biological systems, especially systems involving genetic material.”( http://www.thefreedictionary.com/bioinformatics).

Over the next number of years, we anticipate, although cannot guarantee that the DNA testing will become more sensitive and perhaps in the future lead to a screening test for MH susceptibility. Such analysis will also show the linkage between MH and a variety of other disorders.

As the story evolves, we intend for MHAUS to be “the” source of accurate information about MH and related syndromes.

Help us realize that ambition by becoming a member or contributor to MHAUS.

Thanks. As always, your comments are appreciated.

The opinions and information expressed in this blog do not necessarily represent those of MHAUS or it’s Professional Advisory Council or other experts.

Revisions to a new In-Service Kit will be ready in Spring of 2012.

Purchase the current version at this clearance price and sign up to receive notification of new version availability.

Item: Video and Test Booklet and Pocket Card
Item code: InSvKit
Length: 26 minute
Description: Describes participant roles during a Malignant Hyperthermia emergency.
Suggestion: Review of MH in a classroom setting.

Click here to order and sign up now!

On January 5, 2012, an MH episode was portrayed on the popular TV program Grey’s Anatomy.

In the episode, the young patient undergoing emergency surgery develops elevated levels of carbon dioxide, increased heart rate and elevated temperature. The anesthesiologist recognizes the signs and informs the team of the problem. One of the OR personnel is dispatched to obtain ice and the anesthesiologist whips out a vial of dantrolene, injects it and waits for the signs of MH to respond. Interestingly the patient’s sibling is undergoing surgery in an adjacent OR and the team is astute enough to warn the other surgical team that the patient might develop MH also and modify the anesthetic regimen. While the writers of Grey’s Anatomy got the basic elements of MH diagnosis and treatment correct, they oversimplified the critical nature of the situation and omitted many important elements. (Here is the link to the episode: http://abc.go.com/watch/greys-anatomy/SH559058.)

For starters, when treating an MH episode with dantrolene, multiple vials (any where from 9 to 20) of the drug need to be obtained and reconstituted with sterile bacteriostatic water for injection. Secondly, a variety of blood studies need to be performed to gauge the extent of the physiologic changes and to measure the response to treatment. Thirdly, the patient needs to be treated post event in a critical care unit and further doses of dantrolene need to be administered until the patient is out of danger. Usually 36 hours. However, most importantly, what was not really emphasized is that treatment of MH requires a coordinated team approach. Some members of the team need to obtain the cart containing dantrolene (the medication is not kept in the medication cart next to the anesthesia provider), and then at least one or two people need to work on reconstituting the drug and handing it to the anesthesia provider. At the same time other team members need to obtain blood specimens for analysis of acid base balance, electrolytes such as sodium and potassium, and coagulation studies. It was curious how the team just sat there waiting for the dantrolene to work; while in the actual situation, either the patient responds immediately to dantrolene, or if not additional drug needs to be administered. It would have been icing on the cake if the team had called the MH hotline. On the positive side the episode emphasized the critical role of the anesthesia provider in directing the treatment of the MH episode and the fact that MH could appear unexpectedly during surgery in an apparently healthy patient. It would have been nice to have the discussion of what happens once the syndrome is under control. The impression was from the program that once the episode is done, nothing further needs to be done.

Although, there was a gross oversimplification of MH, I applaud the team for recognizing that MH is a life threatening disorder that requires prompt diagnosis and treatment. If this episode alerts the public and health care providers to some of the essential elements of diagnosis and treatment of MH that is of benefit. I certainly could not expect a program on prime time to go into ryanodine receptor variants, DNA versus muscle biopsy testing, association with other disorders and reference to resources such as MHAUS to assist in diagnosis and management. After the program aired, I was contacted by someone who has a web site that posts questions and comments as to the authenticity of the medical condition depicted in such programs. There is a web site for everything!

Shortly after the Grey’s Anatomy episode the public was made aware of a fascinating study examining the effect of a medication known to enhance athletic performance on the response to MH triggered by heat exposure in genetically susceptible mice. (reference 1) As I have mentioned previously, investigators at a variety of very well known universities, such as University of Rochester, Baylor Medical School and Harvard Medical School have developed an animal model to study MH by incorporating a known DNA change in the ryanodine receptor into mice.

These mice will develop MH on exposure to anesthetic trigger agents, as well as high environmental heat. Male mice are more at risk than female mice for reasons not well understood. In the study that was published recently, the investigators demonstrated that the drug, AICAR, acts in these animals to block release of calcium into the cell. This is also the basic defect in Malignant Hyperthermia, but curiously the drug does not block anesthesia induced MH. (AICAR works in a complex manner to reduce muscle fatigue and increase muscle endurance.) The connection between heat stroke and malignant hyperthermia has been demonstrated in some patients as I have described in several of my previous blogs. In general though the treatment of heat stroke has been limited to symptomatic treatment, namely cooling the patient with ice or infusion of cold solution. Nevertheless the mortality from heat stroke is quite significant. AICAR represents a possible means to block or prevent heat stroke in those susceptible to this syndrome. The study shows clearly that at least one ryanodine receptor genetic change that predisposes to anesthesia induced MH also predisposes, at least in the animal model of MH, to heat induced MH.

The study also shows that drugs other than dantrolene may be efficacious in anesthesia induced MH as well. For example, perhaps if the investigators used a higher dose of the drug in their model of anesthesia induced MH it would have been effective in reversing the signs of MH. Perhaps in cases of MH related to other genetic changes, it might have also been of value. Obviously, much more work is needed to determine the utility of this drug in humans.

Other intriguing studies

The ryanodine receptor a calcium channel found in skeletal muscle (RYR-1) is known to be defective in most cases of MH. For a while investigators have shown that the channel is also located in other tissues, such as certain white blood cells and even in nerves. A recent study from U Mass and U of Toronto (ref 2) again using genetically engineered MH susceptible mice demonstrated that a mutation in the RYR-1 gene affects the function of certain nerve cells (neurons) in the brain. The effect on calcium release in the neurons was measured and was found to be identical to the change in calcium movements in skeletal muscle cells in MH. Hence the ryanodine receptor in these brain neurons is important for the normal function of the neurons and therefore may affect brain cell function. The overall effect on the body depends on the role of the neuron and is hard to measure in animals. This is the first demonstration that I know of, that mutations associated with MH may have an effect on nerve cells.

Speaking of neurons yet another investigative group at the U of Texas Southwestern (ref 3) has demonstrated abnormal calcium movements in neurons in the brain of genetically engineered mice that express the signs of Huntington’s disease. This fatal inherited neurodegenerative disorder comes on in early middle age in humans and is associated with uncontrolled and disabling muscle movement. The investigators demonstrated that dantrolene administration when administered to the diseased mice protects the neurons from ongoing damage and improves performance of complex tasks involving muscle coordination. Yet to be demonstrated though are specific ryanodine mutations, but all signs point to a defect in the ryanodine receptor as a key factor in some forms of Huntington’s disease.

So, it seems that scientists are beginning to understand how important the ryanodine receptor is to the proper function of many organs in the body, not just skeletal and cardiac muscle. The implication is that drugs such as dantrolene and AICAR may over time prove to reverse or compensate for abnormal cell function in a variety of organ systems just as it does in skeletal muscle. Naturally there is a long road to follow between the demonstration of effect in animals and or isolated cells to studies in humans, but there are now some key insights that may underpin and explain how dantrolene may turn out to be a very effective therapeutic agent in a variety of disorders and drug reactions not involving muscle tissue directly.

Much more to follow.

References:

1.Lanner JT, Georgiou DK, Dagnino-Acosta A,………Dirksen RT and Hamilton SL. AICAR prevents heat-induced sudden death in RYR-1 mutant mice independent of AMPK activation. Nature Medicine published on line 8January 2012;doi:10.1038/nm.2598

2. De Crescenzo V, Fogarty KE, Lefkowitz,JI, ….WalshJV. Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):610-5. Epub 2011 Dec 27.www.pnas.org/cgi/doi/10.1073/pnas.1115111108.

3. Chen X, Wu J, Lvovskaya S, Herndon E, Supnet C, Bezprozvanny I.

Dantrolene is neuroprotective in Huntington’s disease transgenic mouse model.

Mol Neurodegener. 2011 Nov 25;6:81.

http://www.hdsa.org/research/news/dantrolene.html