SEMINARS I N NEUKOLOGY-VOLUME

1 1, N O . 3

SEPTEMBER 1 991

Malignant Hyperthermia

Malignant hyperthermia (MH) is an anesthetic-induced hypermetabolic syndrome characterized by acidosis, hyperthermia, muscle rigidity, and rhabdomyolysis. Its neurologic interest derives from the primary role of skeletal muscle in the pathogenesis of the syndrome and the association of MH with other specific neuromuscular diseases.

CLINICAL PRESENTATION Malignant hypertherniia is a syndrome in which there is a genetically induced susceptibility to a pharmacologic agent (an anesthetic), which can cause muscular rigidity, temperature elevations of greater than 'Lo to 4OC/hr, and metabolic acidosis, with an increase in end-tidal partial carbon dioxide tension (PCO,) and lactic acidosis.' Although the earliest descriptions of MH probably date back to 1900, when postoperative heatstroke , ~ syndrome was first clearly rewas d e s ~ r i b e d the ported in 1960 by Denborough and Lovell.These authors presented a family in which 10 patients had died while undergoing anesthesia. Subsequent reports established that there was an inherited basis to the syndrome, and in at least some families, an autosomal dominant inheritance pattern was evident"for review see Britt"). However, with the advent of in vitro testing for MH susceptibility (see later), family members unexposed to anesthesia could be evaluated and a spectrum of susceptibility was demonstrated.Family studies indicated that in at least some families two different nonallelic genes may be present, whereas in other families inheritance is m~ltifBctoria1.~-' Finally, based on assumption that the inheritance is autosomal dominant, chromosonlal linkage studies have recently been reported in MH kindred. These studies have localized the MH susceptibility locus in at least

some kindreds to human chromosome 19 q1213.2.' The association of a myopathy with MH was first described in 1970 when elevated creatine kinase (CK) was noted to follow an autosomal dominant pattern in a family in which three patients had MH episodes." Subsequent reports verified this and indicated a spectrum of neuromuscular disorders in which MH may occur (see later). MH is estimated to occur in 1 in 15,000 pediatric and 1 in 50,000 to 100,000 adult anesthetic procedures.'.k1"-" The events are more common in males.'."' MH is triggered by potent inhalation agents, as well as depolarizing muscle relaxants5 (Table 1). Furthermore, MH events can follow previous uneventful anesthetic procedures in up to half of' susceptible patients."'The reasons for this may relate to the duration of the anesthesia, the type of premedication, the use of succinylcholine with a potent inhalation agent, or the state of the sympathetic nervous system prior to the anesthetic.Vurthermore, an MH event may be delayed in appearance or recrudesce after apparent control. 'rhe earliest event in an MH episode is a rise in end-tidal carbon dioxide caused by increased carbon dioxide production, a byproduct of the hypermetabolic state that has been initiated. There is central venous desaturation with elevation of the end-tidal PCO, and both metabolic and respiratory acidosis. 'I'he early evolution of the syndrome niay include Sailure to relax to succinylchol~nefollowed by tachycardia and tachypnea. If the event goes unrecognized, there will be cyanosis despite a high inspired oxygen and adequate ventilation. Acidosis develops along with rhabdomyolysis and frequent muscle rigidity. Temperature elevation, which may be delayed, occurs in only one third of patients. Arrhythmias and hypertension are often present,

T h o m a s J e f f e r s o n University, Department of Neurology, Philadelphia, Pennsylvania Reprint requests: Dr. Heirnan-Patterson, Department of Neurology, Thomas Jefferson University, 1025 Walnut Street, Suite 51 1, Philadelphia, PA 19107.5083 Copyright 0 1991 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

Downloaded by: Universite Laval. Copyrighted material.

Terry D. Heiman-Patterson, M .D.

Halothane

Enflurane

lsoflurane

Methoxyflurane

Trichlorethylene

Chloroform

Diethyl ether

Cyclopropane

Succinylcholine

Ketarnine

and death during the anesthetic often results from ventricular arrhythmia. During the event, there is an increase in serum CK and myoglobinuria. Late complications include seizures, disseminated intravascular coagulopathy, acute renal failure, and acute pulmonary and cerebral edema. With early recognition and aggressive treatment with dantrolene sodium (Dantrium) (see "'li-eatment"), the mortality has been reduced from 65% to as low as 7%. MH was so named because there is a marked rise in temperature, as well as a high mortality untreated (65%). However, fever is a late occurrence in the clinical evolution of MH, and often episodes are aborted before any elevation in temperature occurs. Thus, M H may be a misnomer.

LABORATORY EVALUATION FOR SUSCEPTIBILITY Diagnosis of an anesthetic event as MH relies on the clinical picture and is supported by the presence of a metabolic and respiratory acidosis. The earliest signs include elevation of the end-tidal pCO, and tachycardia. Other signs include tachypnea, hypertension, and muscle rigidity. T h e patients demonstrate a lactic acidosis along with hyperkalernia, hyperphosphatemia, elevations of CK, and myoglobinuria. Many tests have been suggested for identifying MH-susceptible individuals. These procedures can be applied to relatives of a proband with a clearly documented event as well as patients who have had suspicious events. Additional indications for MH testing are controversial but include patients with neuromuscular disease, osteogenesis irnperfecta, or rleuroleptic malignant syndrome. Several noninvasive tests have been suggested but are of limited value. Serum CK elevations have frequently been used to screen families of MH patients since elevated CK was demonstrated in 50% of subjects in a large kindred in which MH had occurred.VThis suggested an autosomal dominant inheritance and the possibility that CK might provide a noninvasive screen. However, in a large study that examined the relationship of elevated C K to contracture test results (see later) there was no predictive value in CK l e v e l s . l ~ n a c c e p t a b l e

false-positive and false-negative results were obtained. Furthermore, elevated CK levels were more likely to be associated with patients who had neuromuscular disorders and had experienced anesthetic events.lg Similarly, other noninvasive blood tests that have been proposed, including halothane-induced calcium uptake into lymphocytes, platelet aggregation with nucleotide depletion in the presence of halothane, and red cell fragility, have proven unreliable.14-'" Electromyographic testing has been reported to show abnormalities of motor units and altered response of the ulnar nerve when stimulated in the presence of succinylcholine in MH-susceptible individuals. However, this has not been verified.lLl7 Finally, nuclear magnetic resonance imaging techniques show an increased ratio of inorganic phosphate to phosphocreatine at rest as well as abnormalities of the high-energy phosphate recovery curve following exercise.lx Although no false-negative results were identified when compared with in vitro contracture testing responses, there was an overlap between some normal patients and MHsusceptible patients. Furthermore, similar changes may be seen in a variety of neuromuscular disorders. Invasive procedures utilizing biopsied skeletal muscle for in vitro contracture testing remain the most reliable method to predict MH susceptibility.~w~.20Other investigations using biopsied muscle have not been proven to be reliable. For instance, histologic changes are frequent in susceptible individuals but are nonspe~ific.~'-'~ (See later for discussion of histopathology.) To date, the most sensitive contracture test is the halothane-caffeine test.'"'"."'.2"-2X This test, first suggested by Kalow et aI,'%onsists of immersing thin strips (1 cm x 1 mm) of skeletal muscle into Krebs-Ringer solution at 37"C, bubbled with 95% oxygen and 5% carbon dioxide. T h e strips are stimulated electrically to achieve a supramaximal response. Once equilibration is obtained, strips are exposed to 3% halothane and the amount of contracture is recorded. Subsequently, additional muscle strips are exposed to an incremental caffeine dose (0.5 to 32 mM) and the contracture response to 2 mM caffeine as well as the concentration of caffeine that causes a 1 g contracture response are recorded. According to the North American protocol, a contracture of 0.7 g to 35% halothane, a contracture more than 0.2 g to 2 mmol caffeine, or a contracture of 1 g at less than 4 mmol caffeine is considered to indicate MH susceptibility. Studies confirm the usefulness of contracture tests in identifying susceptible individuals, but also demonstrate that the test is problematic, since 5 to 15%of tests demonstrate ambiguous r e ~ u l t s . ' " ~ l ~ ~22~1~ ' " ~

Downloaded by: Universite Laval. Copyrighted material.

Table 1. Trigger Agents for Malignant Hyperthermia

T h e ambiguity may relate to the variability of the biologic test, the variability in the pathophysiology of the MH syndrome, o r the nonspecificity of the test. Unfortunately, since all biopsied patients cannot be exposed to anesthetic challenge to verify results, the true predictive value, sensitivity, and specificity of the test cannot be a~certained.~!'."' Similar contracture testing procedures can be carried out on muscle fibers subjected to a "skinning" solution."" T h e advantage ofthis is that biopsied muscle can be shipped from outside hospitals to the testing laboratory in skinning solution. Results of skinned fiber testing are comparable to standard contracture testing.:"' Other tests performed with biopsied skeletal muscle that can be frozen and shipped have included myophosphorylase measurement arid calciunl uptake into skeletal muscle slices o r homogenate~.'""~."'Unfortunately, these procedures could not be validated when compared with contracture test resuhs.'"

ASSOCIATED DISORDERS MH has been associated with many rnusculoskeletal abnormalities (Table 2), which occur in u p to two thirds of all M H patients and one third of first-degree relatives."I'he musculoskeletal findings that are most common include kyphosis, scoliosis, pectus excavatum, strabismus, ptosis, dislocated patella, poor dentition with crowded teeth, cryptorchidism, hernias, and cramps. T h e King-Denborough syndrome (KDS) is characterized by multiple dysmorphic features, myopathy, arid MH.""-:" It occurs predominantly in young boys with short stature who demonstrate a constellation of dysmorphic features, including cryptorchidism, webbed neck, kyphosis, lordosis, pectus excavatum, low-set ears, micrognathia, winged scapula, and an antirnongoloid slant of

Table 2.

Histopathology in 102 MH-Positive Patients

Normal

50

Fiber size variation

34

Angular fibers

17

Possibly denervated

16

Motheaten-targetoid

11

Internal nuclei

222

6

Type II atrophy

8

Type I predominance

7

Scattered necrotic fibers

4

Fiber splitting

3

Central core disease

3

VOLUME: I I . N U M H E K 3

St.;l'7'1:"2/IUER 1991

the palpebral f'iss~res.:~:'-:'~ Muscle biopsies in these children have shown nonspecific rnyopathic changes, including variation in f'iber size, increased central nuclei, regeneration and degeneration, poor fiber type clifferentiation and type I hypertrOphy,:$I . Y ~ . : ~We x performed halothane contracture testing for MH susceptibility in a young boy with KDS and also in other family members."% positive contracture test was found in the boy as well as his mother, who had only tnild scoliosis and a history of' three anesthesias without incident. These results have several possible explanations. First, KDS may be part of autosornal dominantly inherited MH syndrome, the disparate number of dvsmorphisrns between the boy arid his mother eniphasizing the phenotypic heterogeneity o f t h e MH syndrorne. A second possibility is that MH and KDS may be closely linked and inherited together. Finally, the association of MH and KDS may be coincicleiital. Other disorders have also been associated with MH-like anesthetic events arid positive testing for MH susceptibility. 'These include several specific neurornuscular disorders (see later), osteogenesis ilnperfecta, myelomeningocele, and sudden infant death syndrome. 'x-" Other disorders such as heat stroke, thyrotoxicosis, pheochromocytolna, and sepsis can be confused with MH."

ASSOCIATION WITH NEUROMUSCULAR DISORDERS MH has been associated with neurornuscular clisorders since 1970 when Isaacs and Karlow tiescribed an MH kindred with elevated CK in an autosotnal dominant pattern.",-" They postulated that a subclinical nlyopathy existed in MH. Many nonspecific abnormalities have been described on histopathologic examination of biopsied muscle f'rorn patients with malignant hyperthermia,"-'"also indicating underlying muscle involvemenl. T h e most frequently described changes include \,ariation in fiber size, increased internal nuclei, and architectural changes on staining for reduced nicotinamitle-adenine dinucleotide. 'l'here may also he small angulated fibers and type I1 atrophy. Other changes such as necrosis arid regenel-ation have also been reported. We studied histopathologic findings in 102 patients in whom contracture testing was positive and 104 family members in whom testing was negative. Almost 50% of contracturepositive patients had no pathologic changes, while this was true of' 88% of contracture-negative patients (Tables 2,3). T h e most frequent abnorrnalities in o u r patients were variation in fiber size, angulated fibers, type I1 atrophy, and architectural

Downloaded by: Universite Laval. Copyrighted material.

SEMINAKS I N NE:UKOI,O(;Y

Normal

89

Type I predominance Type II atrophy

4

Angular fibers Fiber size variation Internal nuclei

1

Fiber splitting

1

Motheaten

1

Scattered necrotic fibers

1

changes. Three patients had central core disease. Thus, o u r f'indings are similar to those in the literature and indicate that although there are frequently abnormalities of muscle in biopsies, the changes are nonspecific and not consistently present. Furthermore, although they were less frequent, various similar abnormalities were present in biopsies of contracture-negative patients. Finally, boys with KDS associated with MH also have a nonspecific myopathy;'i:'-:ix further indicating muscle involvement in MH. Subsequently, several specific neuromuscular disorders were identified in patients who experienced anesthetic episodes that were similar, if not identical, to MH. In 1973, an aunt of the original proband described by 1)enborough and 1.ovell was found to have central core disease."' Several additional reports documenting this association appeared in the literature.""."' Anesthetic events have also heen reported in patients with other neuromuscular disorders, including nlyotonia congenits, l i - . i l rnyotonic dystrophy,"!' Duchenne nluscular dystrophy (I)MI)),"-" and congenital nluscular ciystrophv.""rn only a few of these patients were anesthetic events followed u p by in vitro contract ~ ~ tests r e to determine if the skeletal muscle from patients behaved similarly to MH rnuscle in vitro. In order- to assess the possible anesthetic risk in the ~leurornuscularpopulation, we performed contracture testing o n 25 consecutive patients during diagnostic eval~~ation.~!' We found positive halothane contracture tests in 7 of 18 patients with tnyopathic disorders and three of seven with neurogenic disorders."" Similar results have been reported using caffeine contracture testing for MH susceptibility in skinned muscle fibers from 21 patients with rnyopathic disorders and four patients with neurogenic disorder^."^' These authors reported positive test results in a variety of disorders, including DMI), adult-onset muscular dystrophy, infantile hypotonia, congenital muscular dystrophy, central core disease, and polyradiculitis. We

fhund positive halothane contracture tests in similar groups of patients as well as in spinal muscle atrophy, facioscapulohumeral dystrophy, limb girdle dystrophy, and Becker's muscular dystrophy. 'Ihus, both halothane testing of fiber bundles and caffeine skinned fiber contracture testing have shown an abnormal response in various neuromuscular disorders. T h e presence of abnormal contracture tests in several neuromuscular disorders suggests that they may share pathogenetic mechanisms with MH, resulting in the development of muscle contracture on exposure of' biopsied skeletal muscle to halothane. O n e possible shared abnormality is elevated myoplasrnic calcium concentration. It has been postulated that in MH, when the intracellular calcium concentration surpasses a critical threshold, a chain of biochemical events may be triggered that lead to the development of the malignant hypertherrnia syndrome'' (see "Pathogenesis", later). An elevated myoplasrnic calcium concentration has been demonstrated by using ionized intracellular electrodes in MH n~uscle." T h e pathway leading to this elevation is unclear but may involve defects of either- the sarcolemrna o r sarcoplasmic reticulun,," I-":' Kecently, the gene for the ryanodine receptor of the sarcoplasrnic reticulum has been suggested as a candidate for MH ~usceptibility.~~ Elevated calcium levels have also been reported in DM11 as well as other myopathies, neurogenic disorders, and experinlerital denervation."-" Halothane exposure induces an efnux of calcium from the sarcoplasrnic reticulurri in skeletal muscle. If intracellular calciurn concentration is already increased in these disorclers, a critical threshold may be reached, leading to the initiation of a cascade of biochemical reactions that result in a positive contracture test in vitro o r an anesthetic event in vivo. T h e presence of abnormal contracture response in the n e ~ ~ r o n ~ u s c u population larmight alternatively suggest that the test is nonspecific and the abnormal response is due to diseased skeletal muscle. However, results of contracture testing did not correlate with the clinical severity of disease."!' Furthermore, the halothane contracture test is the most specific test of MH susceptibility, both in huInan M H I ~ , Y O , Y ! ) and in susceptible swine."' Finally, suspicious anesthetic episodes have been reported in patients with a variety of neuromuscular disorders (see before) and have also occurred in two of our patients with positive coritracture 'I'hus, oul- patients with positive contracture tests may be at higher risk for the development of MHlike episodes, and care should be exercised during anesthesia. It further follows that until the significance of a positive halothane contracture test and the mechanisms of MH are better understood, the

223

Downloaded by: Universite Laval. Copyrighted material.

Table 3. Histopathology in 104 MH-~egativepatients

SEMINARS I N NEUKO1,OGY

VOLUME 1 1 , NUMBER 3

SEPTEMBER I W I

stance, there are data implicating an increase in phospholipase A, activity that can lead to increases in mitochondria1 free fatty acids (FFA) and stimulate calcium release.'"-x Furtherrnorc., there are a1)normalities of FFA that indicate an increased release of FFA primarily derived from triglycerides in homogenates of MH muscle. These changes, PATHOGENESIS which can increase sarcoplasmic release of C a - + ' ~ led some investiStudies of MH pathogenesis have fbcused pri- and decrease r e ~ p t a k e , ~ "have marily on swine rnodels of MH with subsequent gators to propose hormone-sensitive lipase as a verification of results in humans. T h e swine possible gene candidate, since this hormone is mumodels closely resetnble the human disorder both cia1 to the mobilization of' FFA and its gene is loclinically and biochemically. T h e most suggestive cated on chromosome 19 in a region flanked by the abnormalities are related to control of calcium. El- same markers as the MH gene." This possibility is evated levels of myoplasmic calcium have been re- strengthened by linkage data indicating that in at . ported."' These appear to be d u e to an abnorn~al- least two recently studied kindreds MH did not ity of the sarcoplasnlic reticulum C a + + release cosegregate with the ryanodine receptor, irnplicatmechanisms."-7" T h e changes in calcium levels ing alternative gene abnormalities in at least these may be associated with the ryanodine receptor, kintlreds.'' Therefore a number of' genetic defects since abnormalities in receptor function have been may underlie the MH syndrome by sharing comidentified in the swine mode1.77-xVurthermore, mon pathogenetic abnormalities; and, as pointed linkage of MH to the ryanodine receptor gene on out earlier, other diseases such as DMD, which also chromosome 19 has been accomplished in some share these abnormalities (that is, elevated C a + ) can manifest MH-like episodes under appropriate MH kindreds.'."" Elevated rnyoplasrnic calcium has been postu- conditions. It is for these reasons that MH is conlated to set off a cascade of biochemical events re- sidered a syndrome and not a specific disease. sulting in increased heat production, acidosis, muscle rigidity, and energy crisis-in other words, the MH syndrorne.'O~""First, the presence of elevated

Malignant hyperthermia.

SEMINARS I N NEUKOLOGY-VOLUME 1 1, N O . 3 SEPTEMBER 1 991 Malignant Hyperthermia Malignant hyperthermia (MH) is an anesthetic-induced hypermetabo...
744KB Sizes 0 Downloads 0 Views