April 1997
Volume 61 |
Number 4
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| Current Diagnostic
Testing for Malignant Hyperthermia |
Thomas E. Nelson, Ph.D.
Molecular genetic screening for malignant hyperthermia (MH) susceptibility
is not an option today. The gene coding for the ryanodine receptor
calcium release channel (Ry1) is on chromosome 19 and, at the
present time, 15 different mutations in Ry1 have been linked to
MH susceptibility. However, about 50 percent of susceptible families
do not have linkage of MH to chromosome 19. What is evident at
this stage of our understanding is that MH is genetically heterogeneous
and that simple genetic screening will not be complete for several
years.
Contracture Testing
Consequently, the current method of diagnosing MH by contracture
testing will remain the only means for detecting susceptibility.
The contracture test is invasive, expensive and requires that
the patient go to one of the few diagnostic centers so that the
test can be performed on freshly biopsied tissue. The vastus lateralis
is the muscle of choice, but if the patient is having another
surgical procedure (e.g., abdominal), then other muscle such as
rectus abdominis can be tested.
Approximately 2-3g of carefully dissected muscle is required
to perform the three pharmacologic tests, each in triplicate.
One test exposes the muscle to halothane, 3 percent bubbled through
the muscle bath and a contracture tension 0.5-0.7g indicates an
MH positive response.
The second test exposes the muscle to increasing concentrations
of caffeine so that a caffeine dose versus tension response curve
is obtained. Muscle that produces contracture at 2 mM caffeine
0.2-0.3g indicates an MH positive response. Normal muscle usually
starts developing tension at 4 mM caffeine.
A third test, not used by all centers, combines halothane and
caffeine, and the tension response to caffeine in both MH and
normal muscle is much greater when halothane is present.
Based on guidelines established by the North American MH Registry,
these tests provide diagnostic sensitivity of 97 percent and specificity
of 78 percent. (Exact cutoff values may vary among diagnostic
centers, based upon each center's control values.)
Muscle Biopsy Test Candidates
Who should and who should not have a muscle biopsy for the diagnosis
of MH, and what is the value of this diagnostic test? The answers
to these questions are related to expectations of the surgeon,
the anesthesiologist, the patient and the patient's family.
Some surgeons may refuse to perform elective procedures until
the MH diagnosis is established. Some anesthesiologists also choose
to defer elective procedures until muscle contracture testing
is done. One argument against these approaches is whether or not
the test results will alter the surgical and anesthetic management
of the patient, in any manner, in the future.
If the biopsy test results are negative, will the patient
have triggering anesthetics administered? This question and
the issues surrounding it are relevant to arguments regarding
the value of MH muscle testing, but it is not the most important
issue. If we assume that muscle testing does not alter patient
management, then compelling reasons remain for performing the
muscle test. Those reasons include determining susceptibility
of the proband and, when MH is found, determining which parent
of the proband carries the MH gene. Unless muscle testing for
MH is carried out to this extent, a significant population of
individuals (proband relatives) will be given a false diagnosis
of MH susceptibility.
The consequences of having an MH positive diagnosis can be significant:
it will prevent enlistment into armed forces, may affect employment
and insurability, and certainly will alter medical management.
The uncertain diagnosis of MH may be unacceptable to the individual
patient or to the patient's relatives. Thus, a patient who develops
masseter muscle rigidity (MMR) only during induction and is labeled
"possibly MH susceptible" has a 50-percent chance of
not being susceptible to MH. The identification of susceptible
and not susceptible probands can be of great benefit to family
members as well as the individual patient.
Muscle contracture testing of all MH probands is strongly
recommended. Another important reason for continuing
muscle contracture testing for MH diagnosis is to advance our
understanding about the molecular genetic bases (basis) for this
disease and to bring us closer to a simple diagnostic screening
test. The molecular geneticists who are investigating MH are totally
dependent on muscle contracture phenotyping for the identification
of MH susceptible families. Without this information, genetic
research cannot go forward.
The following are ordinary reasons for which patients are referred
to MH diagnostic centers, including several case examples:
1. Either or both the surgeon and anesthesiologist are not willing
to proceed with an elective procedure until diagnostic testing
is completed.
2. The individual patient (or the minor patient's parents) wish
to have the test performed. There are a variety of reasons why
individuals request to have testing done:
a) A grandparent with MH family history knows that if they
have the muscle biopsy and test negative, their children and
grandchildren have no greater chance of being MH susceptible
than any other person in the population. There is little to
no benefit to the grandparent but great benefit to other family
members if the test result is negative.
b) Parents of a clinically and biopsy-confirmed MH proband
have no information to determine which parent contributed the
MH gene to the child. Both parents have several siblings with
children and the MH diagnosis has affected them as well. By
determining which parent is the MH gene carrier, the other parent's
relatives become relieved from the MH-susceptible label.
c) A young person with family history wishes to enlist into
the armed services but has an unproved MH diagnosis. A negative
MH test result will remove this concern.
d) A 7-year-old child develops MMR after halothane induction
and the administration of succinylcholine I.V. for a tonsillectomy.
The surgery is postponed; the CK level increases to 20,000 and
a small amount of myoglobin is detected in the urine. After
being informed about MH and the 50-percent chance of it being
in the family, the parents elect to have the child tested to
confirm or deny the diagnosis because of the impact it will
have on other members of the family.
Current Muscle Biopsy Procedure
Currently, there are 10 muscle biopsy centers operating in the
United States. The pharmacologic testing of freshly biopsied muscle
requires specialized training and equipment and is very nonroutine.
Most centers do the muscle biopsy as an outpatient procedure using
either general or regional anesthesia. Surgeons are selected to
do the biopsy, which must be done without damage to the tissue,
and the dissection must produce fascicles that can be electrically
stimulated to contract (i.e., "twitch viable"). The
vastus lateralis is identified and the biopsy is obtained along
the muscle fascicle lines. The vastus fascicles, ca. 2 mm diameter
and 2-2.5 cm long, are dissected from the biopsied muscle and
mounted in temperature (37°C) controlled muscle contraction
chambers containing Krebs-Ringer solution equilibrated with 95
percent O2, 5 percent CO2. Maximally stimulated,
each fascicle is stretched to optimal length for twitch tension
and then treated either with halothane or caffeine.
Patients are discharged to return home, and the biopsy results
are available within 24 hours of testing.
Thomas E. Nelson, Ph.D., is Professor of
Anesthesia, Bowman Gray School of Medicine of Wake Forest University,
Winston-Salem, North Carolina. He is also a member of the Professional
Advisory Council of the Malignant Hyperthermia Association of
the United States as well as the director of a diagnostic test
center for malignant hyperthermia.
E-mail the author.
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