Malignant hyperthermia

Definition

Malignant hyperthermia (MH) is a condition that causes a number of physical changes to occur among genetically susceptible individuals when they are exposed to a particular muscle relaxant or certain types of medications used for anesthesia. The changes may include increased rate of breathing, increased heart rate, muscle stiffness, and significantly increased body temperature (i.e. hyperthermia). Although MH can usually be treated successfully, it sometimes leads to long-term physical illness or death. Research has identified a number of genetic regions that may be linked to an increased MH susceptibility.

Description

Unusual response to anesthesia was first reported in a medical journal during the early 1960s, when physicians described a young man in need of urgent surgery for a serious injury. He was very nervous about exposure to anesthesia, since he had 10 close relatives who died during or just after surgeries that required anesthesia. The patient himself became very ill and developed a high temperature after he was given anesthesia. During the next decade, more cases of similar reactions to anesthesia were reported, and specialists began using the term malignant hyperthermia to describe the newly recognized condition. The word hyperthermia was used because people with this condition often rapidly develop a very high body temperature. The word malignant referred to the fact that the majority (70–80%) of affected individuals died. The high death rate in the 1960s occurred because the underlying cause of the condition was not understood, nor was there any known treatment (other than basically trying to cool the person's body with ice).

Increased awareness of malignant hyperthermia and scientific research during the following decades improved medical professionals' knowledge about what causes the condition, how it affects people, and how it should be treated. MH can be thought of as a chain reaction that is triggered when a person with MH susceptibility is exposed to specific drugs commonly used for anesthesia and muscle relaxation.

Triggering drugs that may lead to malignant hyperthermia include:

• halothane
• enflurane
• isoflurane
• sevoflurane
• desflurane
• methoxyflurane
• ether
• succinylcholine

Once an MH susceptible person is exposed to one or more of these anesthesia drugs, they can present with a variety of signs. One of the first clues that a person is susceptible to MH is often seen when they are given a muscle relaxant called succinyl choline. This drug generally causes some stiffness in the masseter (jaw) muscles in most people. However, individuals with MH susceptibility can develop a much more severe form of jaw stiffness called masseter spasm when they receive this drug. They may develop muscle stiffness in other parts of their bodies as well. When exposed to any of the trigger drugs listed above (inhalants for anesthesia), people with MH susceptibility can develop an increased rate of metabolism in the cells of their body, resulting in rapid breathing, rapid heartbeat, high body temperature (over 110°F), muscle stiffness, and muscle breakdown. If these signs are not recognized, treated, or able to be controlled, brain damage or death can occur due to internal bleeding, heart failure, or failure other organs.

The series of events that occur after exposure to trigger drugs is activated by an abnormally high amount of calcium inside muscle cells. This is due to changes in the chemical reactions that control muscle contraction and the production of energy. Calcium is normally stored in an area called the sarcoplasmic reticulum, which is a system of tiny tubes located inside muscle cells. This system of tubes allows muscles to contract (by releasing calcium) and to relax (by storing calcium) in muscle cells. Calcium also plays an important role in the production of energy inside cells (i.e. metabolism). There are at least three important proteins located in (or nearby) the sarcoplasmic reticulum that control how much calcium is released into muscle cells and thus help muscles contract. One of these proteins is a "calcium release channel" protein that has been named the ryanodine receptor protein, or RYR. This protein (as well as the gene that tells the body how to make it) has been an important area of research. For some reason, when people with MH susceptibility are exposed to a trigger drug, they can develop very high levels of calcium in their muscle cells. The trigger drugs presumably stimulate the proteins that control the release of calcium, causing them to create very high levels of calcium in muscle cells. This abnormally high calcium level then leads to increased metabolism, muscle stiffness, and the other symptoms of MH.

The amount of time that passes between the exposure to trigger drugs and the appearance of the first symptoms of MH varies between different people. Symptoms begin within 10 minutes for some individuals, although several hours may pass before symptoms appear in others. This means that some people do not show signs of MH until they have left the operating room and are recovering from surgery. In addition, some individuals who inherit MH susceptibility may be exposed to trigger drugs numerous times during multiple surgeries without any complications. However, they still have an increased risk to develop an MH episode during future exposures. This means that people who have an increased risk for MH susceptibility due to their family history cannot presume they are not at risk simply because they previously had successful surgeries. Although MH was frequently a fatal condition in the past, a drug called dantrolene sodium became available in 1979, which greatly decreased the rate of both death and disability.

Genetic profile

Susceptibility to MH is generally considered to be inherited as an autosomal dominant trait. "Autosomal" means that males and females are equally likely to be affected. "Dominant" refers to a specific type of inheritance in which only one copy of a person's gene pair needs to be changed in order for the susceptibility to be present. In this situation, an individual susceptible to MH receives a changed copy of the same gene from one parent (who is also susceptible to MH). This means that a person with MH susceptibility has one copy of the changed gene and one copy of the gene that works well. The chance that a parent with MH susceptibility will have a child who is also susceptible is 50% for each pregnancy. The same parent would also have a 50% chance to have a non-susceptible child with each pregnancy.

It is not unusual for people to not know they inherited a genetic change that causes MH susceptibility. This is because they typically do not show symptoms unless they are exposed to a specific muscle relaxant or certain anesthetics, which may not be needed by every person during his or her lifetime. In addition, people who inherit MH susceptibility do not always develop a reaction to trigger drugs, which means their susceptibility may not be recognized even if they do have one or more surgeries. Once MH susceptibility is diagnosed in an individual, however, it is important for his or her family members to know they also have a risk for MH susceptibility, since it is a dominant condition. This means that anyone with a family member who has MH susceptibility should tell their doctor about their family history. Since MH may go unrecognized, it is important that anyone who has had a close relative die from anesthesia notify the anesthesiologist before any type of surgery is planned. People with a family history of MH susceptibility may choose to meet with a genetic counselor to discuss the significance of their family history as well. In addition, relatives of an affected person may consider having a test to see if they also inherited MH susceptibility.

Although there are many people who have the same symptoms of MH when exposed to trigger drugs, genetic research has shown that there are probably many genes, located on different chromosomes , that can all lead to MH susceptibility. This indicates that there is genetic heterogeneity among different families with MH susceptibility, meaning that different genes can lead to the same or similar disease among different families. As of March 2001, researchers identified six different types of MH susceptibility. Although specific genes have been discovered for some of these types, others have been linked only to specific chromosomal regions.

Genetic classification of malignant hyperthermia:

• MHS1—Located on chromosome 19q13.1. Specific gene called RYR1. Gene creates the RYR protein.
• MHS2—Located on chromosome 17q11.2-24. Suspected gene called SCN4A.
• MHS3—Located on chromosome 7q21-22. Suspected gene called CACNA2DI. Gene creates part of the DHPR protein called the alpha 2/delta subunit.
• MHS4—Located on chromosome 3q13.1. Specific gene and protein unknown.
• MHS5—Located on chromosome 1q32. Specific gene called CACNA1S. Gene creates part of the DHPR protein called the alpha 1 subunit.
• MHS6—Located on chromosome 5p. Specific gene and protein unknown.

Over half of all families with MH susceptibility are believed to have MHS1 (i.e. have changes in the RYR1 gene), while the rest have MHS2, MHS3, MHS4, MHS5, or MHS6. However, as of January 2000, only 20% of all families tested had specific genetic changes identified in the RYR1 gene. This is because there are many different types of genetic changes in the gene that can all lead to MH susceptibility, and many families have changes that are unique. As a result, genetic testing of the RYR1 gene is complicated, time consuming, and often cannot locate all possible genetic changes. In addition, genetic testing for families may become more complex as knowledge about MH grows. This issue was discussed in an article published by researchers in July 2000. The authors explained that although MH susceptibility has typically been described as an autosomal dominant trait caused by a single gene that is passed from one generation to the next, they believe MH susceptibility may actually depend upon various genetic changes that occur in more than one gene. Further research may clarify this issue in the future.

While specific genes have been identified for some of the MH susceptibility types (i.e. RYR1 and DHPR alpha 1 subunit), not all changes in these genes lead specifically to MH susceptibility. For example, although at least 20 different genetic changes have been identified in the RYR1 gene that can lead to MH susceptibility, some people who have certain types of these changes actually have a different genetic condition that affects the muscles called central core disease (CCD). Infants with this autosomal dominant condition typically have very poor muscle tone (i.e. muscle tension) as well as an increased susceptibility to MH. Among families who have CCD, there are some individuals who do not have the typical muscle changes, but have MH susceptibility instead. Hopefully, future research will help scientists understand why the same genetic change in the RYR1 gene can cause different symptoms among people belonging to the same family.

Demographics

The exact number of individuals who are born with a genetic change that causes MH susceptibility is not known. Until genetic research and genetic testing improves, this number will likely remain unclear. However, it is estimated that internationally one in 50,000 people who are exposed to anesthesia develop an MH reaction. Among children, it is estimated that one in 5,000 to one in 15,000 develop MH symptoms when exposed to anesthesia. MH has been seen in many countries, although there are some geographic areas where it occurs more often in the local populations, including parts of Wisconsin, North Carolina, Austria, and Quebec.

Signs and symptoms

Although the specific symptoms of malignant hyperthermia can vary, the most common findings include:

• stiffness/spasms of jaw muscles and other muscles
• rapid breathing, causing decreased oxygen and increased carbon dioxide in the blood
• rapid or irregular heartbeat
• high body temperature (over 110°F)
• muscle breakdown (may cause dark or cola-colored urine)
• internal bleeding, kidney failure, brain damage, or death (if not treated successfully)

Diagnosis

The diagnosis of MH susceptibility can be made before or during a reaction to a triggering drug. Ideally, the diagnosis is made before a susceptible individual is exposed and/or develops a reaction. This is possible for people who learn they have an increased chance for MH because they have a relative with MH susceptibility. Testing these individuals requires a surgical procedure called a muscle biopsy, in which a piece of muscle tissue is removed from the body (usually from the thigh). Safe (i.e. non-triggering) anesthetics are used during the procedure. The muscle is taken to a laboratory and is exposed to halothane (a triggering anesthetic) and caffeine, both of which cause any muscle tissue to contract, or tighten. Thus the test is called the caffeine halothane contracture test (CHCT). Muscle tissue taken from individuals with MH susceptibility is more sensitive to caffeine and halothane, causing it to contract more strongly than normal muscle tissue from non-susceptible people. This type of test is a very accurate way to predict whether a person has MH susceptibility or not. However, the test does require surgery, time to recover (typically three days), and it is expensive (approximately $2,500). In the United States, many insurance companies will pay for the testing if it is needed. Although the test is not available in every state or country, there are at least 40 medical centers worldwide that can perform the test.

Unfortunately, not all MH susceptible people will learn from their family histories that they have an increased risk for MH before they are exposed to a trigger drug. For these individuals, the diagnosis of MH susceptibility is often made during surgery by the anesthesiologist (a physician specializing in anesthesia) who is providing the anesthesia medications. Other health care specialists also may notice symptoms of MH during or after surgery. Symptoms such as rapid breathing, rapid heart rate, and high body temperature can usually be detected with various machines or devices that examine basic body functions during surgery. Muscle stiffness of the jaw, arms, legs, stomach and chest may be noticed as well. These symptoms may happen during surgery or even several hours later. If the diagnosis is made during or after surgery, immediate treatment is needed to prevent damage to various parts of the body or death. If a person has a suspicious reaction to anesthesia, he or she may undergo a muscle biopsy to confirm MH susceptibility at a later date.

In spite of the fact that a number of important genes and genetic regions associated with MH susceptibility have been identified, testing a person's DNA for all of the possible changes that may cause this condition is not easily done for affected individuals and their families. As of March 2001, existing genetic testing identifies some changes that have been seen among families with MHS1 and MHS6. Research studies may provide information for families with MHS2, MHS3, MHS4, and MHS5 as well. Sometimes the testing requires DNA from only one affected person, but in other cases, many samples are needed from a variety of family members. However, until genetic technology improves, the contracture test that is done on muscle tissue will likely remain the "gold standard" for diagnosis of MH susceptibility.

Treatment and management

The early identification of an MH episode allows for immediate treatment with an "antidote" called dantrolene sodium. This medication prevents the release of calcium from the sarcoplasmic reticulum, which decreases muscle stiffness and energy production in the cells. If hyperthermia develops, the person's body can be cooled with ice. In addition, the anesthesiologist will change the anesthetic from a trigger drug to a non-trigger drug. Immediate treatment is necessary to prevent serious illness and/or death.

Once a person with definite or suspected MH susceptibility is diagnosed (by an MH episode, muscle biopsy, or family history), prevention of an MH episode is possible. There are many types of non-triggering anesthetic drugs and muscle relaxants that can be used during surgical procedures. The important first step in this process is for people with known or suspected MH susceptibility to talk with their doctors before any surgery, so that only nontriggering drugs are used. People with definite or suspected MH susceptibility should always carry some form of medical identification that describes their diagnosis in case emergency surgery is needed. The Malignant Hyperthermia Association of the United States provides wallet-sized emergency medical ID cards for its members.

Prognosis

Early diagnosis and treatment of MH episodes with dantrolene sodium has dramatically improved the prognosis for people who develop MH during or just after surgery. When the condition was first recognized in the 1960s, no real treatment (other than cooling the person's body) was available, and only 20–30% of people who developed MH survived. When the antidote (dantrolene sodium) became available in 1979, the survival rate increased to 70–80%. However, 5–10% of people who develop MH after exposure to a trigger drug still may die even with proper medication and care. Among those who do survive, some are disabled due to kidney, muscle, or brain damage. The best prognosis exists for people with definite or suspected MH susceptibility who are able to prevent exposures to trigger drugs by discussing their history with their doctors. Improved genetic testing in the future may help identify most or all people with inherited MH susceptibility, so they too may prevent exposures that could trigger MH episodes.

Resources

BOOKS

Hopkins, Philip M., and F. Richard Ellis, eds. Hyperthermic and Hypermetabolic Disorders: Exertional Heat Stroke, Malignant Hyperthermia and Related Syndromes. Port Chester, NY: Cambridge University Press, 1996.

Morio, Michio, Haruhiko Kikuchi, and O. Yuge, eds. Malignant Hyperthermia: Proceedings of the 3rd International Symposium on Malignant Hyperthermia, 1994. Secaucus, NJ: Springer-Verlag, 1996.

Ohnishi, S. Tsuyoshi, and Tomoko Ohnishi, eds. Malignant Hyperthermia: A Genetic Membrane Disease. Boca Raton, FL: CRC Press, 1994.

PERIODICALS

Denborough, Michael. "Malignant hyperthermia." The Lancet 352, no. 9134 (October 1998): 1131–36.

Hopkins, P.M. "Malignant Hyperthermia: Advances in clinical management and diagnosis." British Journal of Anesthesia 85, no. 1 (2000): 118–28.

Jurkat-Rott, Karin, Tommie McCarthy, and Frank Lehmann-Horn. "Genetics and Pathogenesis of Malignant Hyperthermia." Muscle & Nerve 23 (January 2000): 4–17.

ORGANIZATIONS

Malignant Hyperthermia Association of the United States. PO Box 1069, 39 East State St., Sherburne, NY 13460. (800) 98-MHAUS. <http://www.mhaus.org>.

WEBSITES

Larach, Marilyn Green, MD, FAAP. "Making anesthesia safer: Unraveling the malignant hyperthermia puzzle." Federation of American Societies for Experimental Biology (FASEB).<http://www.faseb.org/opar/mh/>.

"Malignant hyperthermia." UCLA Department of Anesthesiology.<http://www.anes.ucla.edu/dept/mh.html>.

Pamela J. Nutting, MS, CGC