Last Updated: 10/1/2005
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Is the muscle contracture test, the "gold standard," for you?
One of the important steps in our understanding of malignant hyperthermia (MH) was the discovery that certain breeds of pigs develop MH and have proven to be the most reliable animal models. From them we have learned a great deal about the causes and treatment of the disorder. There are, however, some distinct differences between humans and swine in terms of MH triggering and treatment response. These differences will probably be ultimately understood when the complete mystery of malignant hyperthermia is unraveled.
What is the "gold standard" test for malignant hyperthermia?
The Caffeine Halothane Contracture Test (CHCT), a test performed on freshly biopsied muscle, is the “gold standard” for diagnosis of MH. It can be performed only in roughly 30 centers worldwide, eight of which are located in the United States and Canada. The patient must travel to one of these sites for the test because the test must be completed within hours after muscle is removed.
Following administration of a non-triggering anesthetic, the CHCT will require the removal of approximately two grams of muscle (less than one-tenth of an ounce, about the size of a dime), through a two- to three-inch incision usually from the thigh. The force response of the muscle after exposure to caffeine and separately to halothane in the laboratory is characterized and recorded electronically. Comparison of the strength of contracture (sustained muscle tension) with previously established standards allows determination of MH susceptibility. Muscle from MH susceptibles (MHS) is more sensitive and elicits contractures at lower levels to the administered trigger agents.
Why have the muscle biopsy test?
MH is life threatening when susceptible individuals receive triggering anesthetics. An MH episode can present an extremely rapid occurring chain of events triggered by all general volatile anesthetics, e.g. desflurane, sevoflurane and isoflurane and halothane (halothane is less used in North America, but is still used worldwide) and the muscle relaxant succinylcholine. Left untreated, the mortality of an induced MH episode is high. While the antidote drug, dantrolene, has greatly reduced this mortality, early diagnosis and treatment of MH are absolute prerequisites for a satisfactory outcome. Identification of MH susceptibility in affected families is important in order to subsequently deliver as safe an anesthetic as possible.
Who should be tested?
The CHCT test should be considered for all those judged to be at significant risk for MH, either through family history, or by elicitation of signs of an episode of MH, or if there had been any previous uncharacterized adverse reaction to a general anesthetic. Experts from the Malignant Hyperthermia Association of the United States (MHAUS) welcome consultation to assist in determining which patients are at significant risk and should be tested. Importantly, patients found to be MHS can have surgery if anesthetized with non-triggering agents and are carefully monitored during the procedure. A negative (or normal) response to the CHCT is the only way to prove a patient is NOT MH susceptible. A significant number of people who experienced adverse events that look like MH were found NOT to be MH susceptible. They can receive the most frequently given anesthetics, which makes treatment easier in emergencies.
What other factors should be taken into account if testing for MH susceptibility is being considered?
- COST: In the U.S., charges for the contracture test is typically greater than $5000 but is covered by most insurance companies. In order to avoid any confusion about coverage, the U.S. patient should contact his/her insurance carrier before the biopsy procedure. In Canada, the charges are covered entirely by each Provincial health plan for Canadian residents. In both the U.S. and Canada, contracture testing is routinely provided as an outpatient procedure.
- COMPLICATIONS: After undergoing the test, patients should avoid strenuous activities for at least three days. Like similar surgical procedures, the biopsy carries with it a small chance of bleeding, infection, or numbness.
- ALTERNATIVES: The molecular genetic test is available for those who meet the criteria. Otherwise, one should be considered as MH susceptible on the basis of personal or family history and avoid the MH-triggering agents.
Muscle biopsy test accuracy and results
The muscle biopsy contracture test is the most sensitive and specific diagnostic test for MH. However, because it is a biologic test and because of the inherent variability in the syndrome process itself, questions are sometimes raised as to its accuracy.
If the muscle biopsy result is negative, then researchers are very confident that you are not susceptible to MH. Because of the outstanding reliability of a negative biopsy result, most experts agree that MH precautions are not necessary.
If the biopsy result is positive, you must take appropriate precautions. When undergoing surgery, non-triggering general anesthetic agents, or local or regional anesthesia, must be used.
Where is the Caffeine Halothane Contracture Test (CHCT) done?
The CHCT diagnostic test for MH can be performed at eight sites in North America. Click here for the directory.
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IS MH MOLECULAR GENETIC TESTING FOR YOU
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What is molecular genetic testing?
Molecular genetic testing is a form of analysis of a person’s DNA to determine if he/she harbors specific mutations that have been associated with a disease. A change in a gene, known as a mutation, can cause that gene not to work properly. One virtue of genetic testing is that DNA can be extracted from cells that are found in a blood sample. Expensive and invasive techniques need not be used to obtain a DNA sample.
All of the constituents of a person’s body are determined by DNA, which is contained within the chromosomes of every cell and is passed on from parents to children. Genes are sections of the DNA that are the basic units of heredity and occur in pairs. One member of each pair is inherited from each parent.
Minor variations in the thousands of genes that make up a person determine the individual characteristics of that person, e.g. eye color or hair color. For some genes the function is known with certainty and for others it is not.
What is malignant hyperthermia (MH)?
MH is an inherited, pharmacogenetic muscle disorder that manifests when susceptible patients are exposed to certain anesthetic agents. It is not an allergy. Most people who are at risk for MH have no outward signs. However, when given potent gas anesthetics such as desflurane, sevoflurane, isoflurane, and halothane (halothane is less used in North America, but is still used worldwide) or succinylcholine (a drug to induce temporary paralysis), they can develop muscle rigidity, acidosis, elevations of potassium level, cardiac rhythm disturbance, muscle breakdown and high fever. If not recognized and treated promptly, mortality will be high. MH susceptibles should NOT receive agents that trigger MH; other anesthetics can be used safely.
Why consider molecular genetic testing?
If a person is known to be MH susceptible (MHS) and a DNA change (mutation) known to be causative for MH is found, then relatives may be diagnosed as MHS through the DNA test, and they do not, therefore, have to undergo the muscle biopsy test for confirmation. However, the absence of the mutation does NOT mean that they are NOT at risk for MH.
The person known to be at risk to developing MH would not be given one of the agents that triggers MH. Other anesthetics can be used instead. These other anesthetics may be slightly less convenient for the patient (more chance of nausea, slower awakening after surgery, etc.), but they are safe.
How does molecular genetic testing apply to MH?
MH is inherited in an autosomal dominant fashion, meaning only one mutated gene will lead to the disorder and it may come from either parent.
MH has been associated with at least 23 mutations. One particular gene, called the RYR1 gene (ryanodine receptor of skeletal muscle) is associated with the majority of cases of MH. There are other genes that may cause MH as well.
However, only about 30% of all known patients are found to have one of the mutations that has been described. This means that there are many other variations in the DNA that are yet to be discovered. When one of those 23 mutations is identified, however, the patient is considered to be MHS.
What is the alternative to molecular genetic diagnostic testing?
The Caffeine Halothane Contracture Test that has been used for many years involves taking a piece of muscle from the thigh and testing it for responsiveness to anesthetics and caffeine.
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Molecular genetic testing requires The doctor ordering the test will receive the results and |
What is the value of molecular genetic testing?
Molecular genetic testing is less expensive and less invasive than the muscle contracture test because DNA can be extracted from cells that are found in a blood sample .
When a mutation is found, the value of molecular genetic testing is that family members with the same mutation are considered susceptible to MH and can avoid the muscle contracture test.
Even though the genetic test is not highly sensitive (25%-30%), it is very specific, meaning that detection of a known mutation confirms that the patient is at risk for MH.
What is the importance of the MH Registry?
In order to advance our understanding of MH and the role of genetics it is important to correlate the results of the test with the patient’s clinical history.
We urge medical professionals to contact the North American MH Registry of MHAUS to report the details of the patient’s history for the MH Registry database.
The Registry conforms to requirements for protection of patient privacy. If you or a family member has had a biopsy test done for MH we suggest that you contact the biopsy center director for guidance.
North American MH Registry of MHAUS
Barbara W. Brandom, MD, Director
Univ. of Pittsburgh Children’s Hospital
Anesthesiology Dept., Room 7446
3705 Fifth Ave at DeSoto Street
Pittsburgh, PA 15213-2583
888-274-7899 or 412-692-5464
www.mhreg.orgIf you or one of your close blood relatives have had an episode of MH during anesthesia, had a diagnostic muscle contracture test for MH1 or were found to have a mutation that is known to cause MH2, consider joining MHAUS as a member and contacting the MH Registry (www.mhreg.org).
1 See the list of Diagnostic MH Biopsy Centers
2 Visit www.emhg.org for the list of mutations that are known to be causative of MH.
Who can benefit from MH molecular genetic testing?
1) Those who have tested positive by the muscle contracture test.
2) Relatives of those who have been tested positive by the contracture test.
3) Those who have been found to have a mutation causative for MH under
a research protocol.
4) Relatives of those with a known mutation for malignant hyperthermia.
5) Those with a very high likelihood of having experienced an MH episode.
Testing must be ordered by a physician or genetic counselor.
- MHAUS advises patients and physicians to consult with an MH biopsy center director prior to having the molecular genetic test performed. A listing of biopsy center directors may be found on the other side of this brochure or at www.mhaus.org.
- It is essential that medical history and records be reviewed prior to ordering genetic testing. The biopsy center director and/or a genetics counselor should be consulted for test interpretation as well.
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Molecular genetic testing does NOT Failure to identify a RYR1 mutation does NOT |
Where are the sites and contact information for the molecular genetic testing?
Two CLIA-licensed laboratories are prepared for the molecular genetic testing. Click here for information.
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