Some New and Interesting Developments

First, I would like to apologize for the somewhat technical blog I posted for October, 2010. I realize that not everyone would be familiar enough with the science of MH and cellular physiology to understand some of the information behind my reasoning. However, in basic terms what I was trying to do was separate MH into subcategories based on what is known of the molecular biology and biochemistry of the disorder.  I realize too that not everyone would agree with my reasoning, but that is what a blog is for, i.e., theorizing and proposing some new ways of looking at things. 

In this blog I would like to draw your attention to two new and interesting items related to MH. One of them is a promising test for MH susceptibility; the other is an aid for diagnosing and managing MH using the most modern technology. 

The study I am referring is one that was done by investigators associated with the MH Investigative Unit at the Uniformed Services University in Bethesda. This group is virtually the only one in the US that studies MH from the clinical presentation to biopsy testing to molecular genetic testing in both animals and humans. The center is a tribute to the hard work and vision of Dr. Sheila Muldoon.  Dr. Muldoon started her interest in MH when asked to develop the muscle biopsy contracture test for the military many years ago.  Starting from that beginning she recruited many physicians and scientists to join her in developing a first class MH investigative unit that has contributed a great deal to the understanding of MH and the clinical care of MH patients and their families.  She has also been a very valuable member of the Board of MHAUS for a long time. A recitation of the many contributions made by the group would take many pages. I will save that for another time perhaps. 

The aforementioned study by investigators at the MH unit may lead to a test for MH susceptibility that bridges the gap between the muscle biopsy contracture test and the molecular genetic test. The former test is very accurate in detecting those who are MH susceptibles (no false negatives) at the expense of mislabeling a few patients as MH susceptible who may not be. The drawback of the test is that it is invasive, i.e., requires a muscle biopsy, specialized equipment and personnel, a surgeon and is very expensive.   The other available test for MH is much less invasive. It only requires a blood sample for DNA analysis. The test is very specific; however it only detects about 30% of MH susceptibles with certainty. It is not as expensive as the contracture test. We have great hopes that, in time, the genetic test will be perfected such that we can determine MH susceptibility with certainty using DNA analysis. But considering that there are over 250 DNA changes or mutations in the one gene that is most associated with MH, there is much more work to do.  So, what is missing at present is a minimally invasive test (such as a blood test) that is easy to use, that will detect those who are MH susceptible and then have the susceptibility confirmed by the most specific test available, the DNA test.  Several such tests have been proposed in the past, but either they require very expensive complex equipment, require injection of drugs, much time to perform or were not very accurate.  

Dr. Saiid Bina and colleagues in the Department of Anesthesiology at Uniform Services University, home of the MH Investigative unit that Dr. Muldoon initiated, reflected on the underlying biochemical changes in MH and hypothesized that since calcium levels are abnormally elevated in MH susceptibles or at the least more easily released from storage organelles than in normals, there should be energy expended to reduce the calcium levels to more normal levels.  That energy derives from ATP (adenosine triphosphate) which is produced in the cell through metabolism.  If ATP is used at a higher rate than normal then one of the breakdown products of ATP, adenosine, might be elevated in cells.  It is possible to measure adenosine in the laboratory without problem, but what cells should be assayed?  The cell they chose was one of the white blood cells, the lymphocyte. This made perfect sense because several years ago, Dr. Yoshi Sei who had worked with Dr. Muldoon in the past) demonstrated that lymphocytes release calcium on exposure to such calcium releasing agents as caffeine and halothane. Further, other investigators had shown that certain types of lymphocytes contain ryanodine receptors, identical to the ones in skeletal muscle.  Whereas measuring calcium movements in cells over brief periods of time is a complicated affair (and not suitable to a relatively inexpensive clinical test), measuring adenosine levels is far simpler. 

Thus, Dr. Bina and collegues first chose MH susceptible pigs, sampling blood and isolating lymphocytes for the measurement of adenosine levels in cells with and without a drug similar to caffeine that releases calcium from storage organelles.  The researches compare results between known MH swine and know normal swine.  As predicted, they found elevated levels of adenosine in the lymphocytes from the MH pigs as compared to non-MH pigs, with no overlap in values between MH and non-MH animals.  

Please bear in mind that this was a preliminary study in animals and will need to be verified in humans in a large number of patients. Nevertheless it is a promising first step toward a test that bridges the gap between the muscle biopsy test and the genetic test. The study was published in Anesthesiology in October, 2010 (see full reference information below). 

Something else that I am excited to bring to your attention, because I had a hand in developing it, is an interactive “app” for the iPhone for diagnosis and treatment of MH. The person who did the lion’s share of the work on the app is Dr. Thierry Girard who is the director of the MH Investigative Unit in Basel Switzerland.  We felt that an app for MH would assist those dealing with a case of MH by reminding the clinician of the many steps needed to diagnose and treat MH. For example, when the clinician enters certain signs such as muscle rigidity and /or unexplained elevation of carbon dioxide levels, the app will prompt the clinician to discontinue the anesthetic agent and will, based on the patient’s weight, calculate both the dose and number of vials of dantrolene needed.  The app will also calculate the Clinical Grading Scale score used to assess the likelihood of MH. Furthermore a log of events during the episode will be created that can be saved or

emailed.  A touch of the screen will also place a call to the hotline.   The app is available on I tunes for $4.99. The proceeds will be shared between MHAUS and the European MH group.  Dr. Girard has already produced a version of the app in German and we hope to have it translated into other languages. We hope that try it and find it useful.  We welcome your feedback. 

These are some examples of the advances that are being made by those interested in improving care of MH patients and assisting clinicians in managing this complex disorder. 

Reference:Bina S, Capaccione J, Muldoon S, Bayarsaikhan M, Bunger R. Lymphocyte-based determination of susceptibility to malignant hyperthermia: a pilot study in swine. Anesthesiology 2010; 113:917-924.