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Pediatric Anesthesiology: Medical Intelligence Article

The Myotonias and Susceptibility to Malignant Hyperthermia

Parness, Jerome MD, PhD*†; Bandschapp, Oliver MD; Girard, Thierry MD

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doi: 10.1213/ane.0b013e3181a7c8e5
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Malignant hyperthermia (MH) is a pharmacogenetic disorder in which volatile anesthetics trigger a sustained increase in intramyoplasmic Ca2+ via release from sarcoplasmic reticulum (SR) and, possibly, entry from the extracellular milieu that leads to hypermetabolism, muscle rigidity, rhabdomyolysis, and death.1,2 Treatment is both supportive and specific, the latter consisting of rapid IV therapy with the drug, dantrolene, an intracellularly acting skeletal muscle relaxant that suppresses the pathologic increase in intramyoplasmic Ca2+ during an MH episode. Late recognition of a MH episode and delay in treatment can result in severe morbidity or death. Although easy and rapid preoperative recognition of potential MH susceptibility is the desired goal, it is not easily achieved. Preoperative diagnosis of MH susceptibility can sometimes be achieved by history, especially if the patient had a definitive previous episode. The potential for susceptibility to MH is not lessened because a patient had previous noneventful anesthetics, since MH, although transmitted by autosomal dominant inheritance, is characterized by incomplete penetrance and variable expressivity. Incomplete penetrance indicates that while one may have the requisite genetic mutation for MH susceptibility, it does not mean that MH will express itself during the first or even subsequent exposure to a volatile anesthetic. Variable expressivity signifies that the expression of clinical symptoms varies from indolent to fulminant likely depending on a number of physiological and pharmacological variables (i.e., genetic background, the degree of body hypothermia, and the use of depolarizing muscle relaxants, such as succinylcholine).

MH susceptibility may be suspected if a first degree family member had an episode. Definitive scientific diagnosis is achieved with a genetic test for known mutations in the gene Type 1 ryanodine receptor (RYR1) for the skeletal muscle intracellular Ca2+ release channel, the RYR1, the most common site of mutations conferring MH susceptibility, or by a positive live muscle biopsy caffeine-halothane contracture test (CHCT) in North America, or the in vitro contracture test (IVCT) in Europe. It is not yet feasible to screen the entire population for RYR1 mutations because more than 170 variants,3 of which 29 are known causative mutations,* have been described. Furthermore, there are at least three other described genetic loci that are associated with MH susceptibility and for which no genetic test is available. The CHCT/IVCT is expensive, painful and requires a specialized testing center of which there are only six in North America, three in Australia, one in New Zealand, and a fairly comprehensive coverage of Europe. It would be informative to the preoperative evaluation of patients if we knew there were positive associations between other disease states and likelihood of developing MH. Patients with a variety of neuromuscular disorders are sporadically reported to have developed one or more of the clinical features of MH (fever, tachycardia, hypercapnia, and/or hyperkalemia) in the perioperative period. It is important to determine whether these signs and symptoms represent true MH or whether any one or combination of these develop for other reasons, relating either to the particular myopathy in question or peculiar pathophysiological states that have nothing to do with MH. For example, a septic patient with underlying chronic obstructive pulmonary disease, along with early acute renal failure, having an emergent appendectomy under general anesthesia with a volatile anesthetic may exhibit fever, tachycardia, hypercapnia, and hyperkalemia. MH may not be the most likely diagnosis in such a patient, yet the diagnosis of MH is not excluded by the presence of a set of potentially confounding conditions. The importance of making the correct diagnosis is imperative because different underlying pathophysiological mechanisms require different treatments and have different implications for the management of future anesthetics for the patient and family.

Myotonias are a class of inherited skeletal muscle diseases characterized by impaired relaxation after sudden, voluntary muscle contraction, and result from skeletal muscle membrane hyperexcitability, inappropriate firing, delay in muscle relaxation, and resultant contracture states of varying severity and duration. Other myopathies, such as the periodic paralyses, central core disease, nemaline rod myopathy, and multiminicore disease have very different pathologies, but all have muscle weakness as a primary phenomenon. All these entities have a variety of causes and modes of inheritance, and to understand them we must first review the basics of the known physiology of skeletal muscle excitability and excitation-contraction coupling (ECC) (for more extensive treatment of this subject see the following reviews.4,5

Skeletal Muscle ECC

Skeletal muscle excitation is initiated by motor neuron stimulation of skeletal muscle at the neuromuscular junction. This generates an action potential, detected as membrane depolarization, which travels down the length of the skeletal muscle membrane and into the interior of the muscle cell by invaginations of the muscle membrane known as transverse tubules (TT) (Fig. 1). The TT are found at regular intervals at right angles to the long axis of the muscle fiber, thereby insuring simultaneous distribution of the action potential along the long and short axes of the muscle membrane and resulting in coordinated skeletal muscle contraction. The upstroke of the depolarizing action potential results from influx of Na+ into the muscle cell and is mediated by rapid activation of the skeletal muscle voltage-gated sodium channel (Nav1.4) encoded by the SCNA4 gene and its accessory β-subunit by the SCNA1B gene. Repolarization of the skeletal muscle membrane is mediated by fast inactivation of this sodium channel, and the opening of potassium channels, encoded by the KCNC4 and the accessory subunit KCNE3 genes, generating an outwardly rectifying K+ current. Potentially dysfunctional after-potentials are buffered by high conductance, homodimeric Cl channels encoded by the CLCN1 gene.

Figure 1.
Figure 1.:
A, Schematic of the elements of skeletal muscle excitation-Ca2+ release coupling that functions in normal excitation-contraction coupling. After stimulation of the neuromuscular junction by release of acetylcholine from the motor nerve terminal (not shown), the skeletal muscle sodium channel, Nav1.4, opens to allow Na+ into the cell, thereby depolarizing the sarcolemma. The change in voltage is sensed by a voltage-dependent calcium channel in the T-tubule membrane, the dihydropyridine receptor (DHPR), which undergoes a conformational change and directly contacts the Type 1 ryanodine receptor (RyR) in the sarcoplasmic reticulum membrane (SR). RyR1 then opens to release the Ca2+ stored in the SR (small blue circles), primarily bound to the calcium binding protein, calsequestrin (CSQ), and now becomes available for stimulation of the contractile apparatus (not depicted). If the requirements for myoplasmic Ca2+ increase above that which can be provided via RyR1, this is somehow signaled to the Store-Operated Ca2+ (SOC) entry channels in the T-tubule via the SR membrane protein, STIM1, to allow more Ca2+ into the cell. See text and reviews referenced therein for more detail. B, Sites of mutation in the excitation-contraction coupling schema that result in malignant hyperthermia (MH), the myotonias, and hypokalemic periodic paralysis. Channels are as depicted in (A). In MH, the presence of volatile anesthetics (VA) ± pharmacological depolarization by succinylcholine will result in a massive release of Ca2+ either from the sarcoplasmic (SR) via mutated type 1 ryanodine receptor (RyR1), or as the presumed result of enhanced activation of RyR1 by a mutated DHPRα1 subunit, or as a result of mutations in unknown genes in at least three other unidentified genetic loci, all augmented by enhanced Ca2+ entry via SOC entry channels (SOC) and/or ECCE channels (not depicted). The site of dantrolene activity is on RyR1, and its coupling to the SOCE/ECCE channels to suppress Ca2+ entry and possibly release. MH = malignant hyperthermia; PC = paramyotonia congenita; MC = myotonia congenita; DM = myotonic dystrophy; HypoPP = hypokalemic periodic paralysis; HyperPP = hyperkalemic periodic paralysis; SR = sarcoplasmic reticulum; CSQ = calsequestrin. Detailed descriptions of the myopathies and references are denoted in the text.

ECC is mediated by specialized TT groupings of skeletal muscle-specific, L-type voltage-dependent Ca2+ channels, also known as the skeletal muscle type dihydropyridine receptors (DHPR), and encoded by the CACNA1S gene, along with accessory proteins encoded by the CACNA2D1, CACNG1, and CACNB1 genes (Fig. 1). The DHPRs overlie corresponding groupings of the homotetrameric, SR Ca2+ release channels known as the RyR1 encoded by the RYR1 gene. Depolarization of the TT membrane is sensed by the DHPR, which undergoes a conformational change while experiencing intra-TT membrane charge movement, causing the intracellular loop between transmembrane segments II and III of its α-1s subunit to contact the apposed RyR1. This contact causes RyR1 to open and release Ca2+, which, in turn, stimulates the contractile apparatus and results in skeletal muscle shortening. Skeletal muscle relaxation normally occurs with the timely reuptake of Ca2+ into the SR via the energy requiring Ca2+-ATPase found in the SR membrane.

Two other processes that may also contribute to the Ca2+ transient in skeletal muscle underlie Ca2+ entry into the cell, rather than Ca2+ release from SR. These are Store-Operated Ca2+ Entry (SOCE) and Excitation-Coupled Ca2+ Entry (ECCE).6,7 SOCE is classically characterized by slow Ca2+ entry into the cell after depletion of the SR or endoplasmic reticulum Ca2+ store that is sensed by an SR/endoplasmic reticulum resident transmembrane protein, STIM1, containing the EF-hand Ca2+ binding motif, which then binds to the plasma membrane proteins, Orai1 and TRPC1, that presumably make up the Ca2+ entry channel.8,9 ECCE, however, does not require store depletion, but is activated after trains of tetanic stimuli to the muscle cell surface membrane10 and does not involve the molecular machinery of SOCE, making these physiological properties of skeletal muscle mechanistically distinct.11 The roles of SOCE and ECCE in the normal functioning of skeletal muscle are unknown at present, but it must be noted that dantrolene and azumolene have been shown to inhibit both these processes.2,6,12 Indeed, it has been directly demonstrated that the dantrolene analog, azumolene, had no effect on Ca2+ release from SR, but dramatically reduced RyR1-coupled SOCE.6 Furthermore, there is enhanced ECCE in mouse myotubes taken from MH-susceptible muscle.2 Taken together, and contrary to common wisdom, these results suggest that MH may result as much from aberrant RyR1-coupled Ca2+ entry as from exaggerated Ca2+ release.

Molecular diseases are theoretically possible with mutations in any of the channels described above, in any of their regulatory proteins, or in channels and regulatory components not yet described. As we will see with the myotonic dystrophies, channelopathies are also possible without any mutations in the channel genes that underlie the disease state. No myopathies have yet been described with disruption of function of SOCE or ECCE, but it is clear that STIM1-controlled SOCE is required for the development and contractile function of skeletal muscle.13 Description of myopathies with mutations in the molecular machinery of SOCE and ECCE is probably only a matter of time.


The myotonias are generally classed into two large subgroups: the dystrophic and nondystrophic (dystrophic: defective nutrition14), and the descriptions cited below are taken largely from the following critical reviews: Jurkat-Rott et al.,4 Heatwole et al.,15 and Ryan et al.16

Nondystrophic Myotonias

Chloride Channelopathies

Myotonia Congenita.

This myotonia falls into two subtypes of inheritance, autosomal dominant (Thomsen's Disease) and autosomal recessive (Becker's Disease), and both are linked to mutations in CLCN1, the skeletal muscle chloride channel that suppress muscle membrane after potentials (Table 1 and Fig. 1B). Under normal conditions, influx of chloride stabilizes the membrane potential after a depolarization of the muscle fiber membrane. In Thomsen's and Becker's myotonia, however, the reduced chloride conductance of the mutated chloride channels leads to hyperexcitability of the muscle fiber membrane leading to bursts of aberrant action potentials. The clinical picture is characterized by slowed relaxation after forceful voluntary contractions (myotonic stiffness). As of 2007, more than 80 mutations in the CLCN1 gene have been reported, though it is not clear how many of them are actually causative. Moreover, the same disease-associated mutation has been reported to be inherited in a dominant fashion in one family, yet be recessive in another. No real explanation for this disease-related inheritance anomaly has yet emerged. Moreover, even with the same mutation within a family, there can be marked phenotypic variation in presentation and progression of disease, implying multigenic and/or epigenetic modulation of these myotonic phenotypes. Significantly, both forms of myotonia tend to improve with exercise, the so-called “warm-up” phenomenon.

Table 1
Table 1:
Tabular List of Myotonias, Genes Encoding Associated Channels and Estimated Risk of Malignant Hyperthermia (MH) (in the Absence of a Family History of MH)

In Thomsen's disease, symptoms tend to present in early childhood, and although the myotonia is generalized, it tends to be more severe in the upper limbs, often with marked muscular hypertrophy. Symptoms are predominantly painless, transient muscle stiffness in the upper extremities and facial muscles and are characteristically initiated by muscle use after rest. The prognosis is good, with no reduction in life expectancy. Because of their muscle hypertrophy, children with Thomsen's disease often appear stronger than their counterparts and tend to be more involved in sports than others of their age.

Becker's disease, however, tends to present sometime during the second decade of life, progressing slowly into the third and fourth decades. Symptoms earlier in life are often insidious, only diagnosed with electrical testing. The symptoms of this form of myotonia are more severe than in Thomsen's and tend to involve the lower limbs first. It is sometimes accompanied by a slowly progressive weakness, hypertrophy of lower limb muscles, and by peculiar transient episodes of proximal weakness, especially involving the hands and arm muscles. Some Becker myotonia patients show permanent weakness in some muscle groups, distal muscle atrophy, and unusually high serum creatine kinase levels making the differentiation from myotonic dystrophies difficult.17

Two other rarer forms of myotonia congenita are described with mutations that are also in the CLCN1 gene: myotonia levior and fluctuating myotonia congenita. There is disagreement whether these are distinct entities or variants of Thomsen's, autosomal dominant, myotonia. The constellation of symptoms in myotonia levior consists of stiffness, particularly of the grip, that is provoked by prolonged rest. In contradistinction to Thomsen's disease, myotonia levior is later in onset, has milder symptoms, and is not associated with muscle hypertrophy. Fluctuating myotonia congenita, also an autosomal dominant entity, is characterized by stiffness, primarily of the lower extremities that is initiated by movement after rest, pregnancy, fasting, cold exposure, or emotional stress and is associated with lower extremity pain. It can affect the upper extremities as well and has varying effects on ocular and masticatory muscles. This form of myotonia temporally fluctuates in severity (hence, its name), and there can be long periods with no symptoms at all. Muscle hypertrophy is not a characteristic of this entity.

Anesthetic Implications and Susceptibility to MH.

These chloride channel myotonias are sensitive to succinylcholine, administration of which can result in sustained total body rigidity and difficulty in intubation or mask ventilation.18 Indeed, depolarizing muscle relaxants induce prolonged contractures in myotonic human skeletal muscle.19 There is one report of a family with myotonia congenita referred for live muscle biopsy and halothane contracture testing after two sisters both developed rigidity under anesthesia.20 Another report of a nondystrophic myotonic family and an identified mutation in the SCN4A gene of the α subunit of the skeletal muscle sodium channel correlated the presence of masseter muscle rigidity and an IVCT positive for MH susceptibility.21 The validity of assigning MH susceptibility on the basis of contracture testing in patients with skeletal muscle channelopathies has yet to be validated and is likely fraught with confounding physiological variables that can result in contracture tests that are factitiously assigned to MH. Two reports of fatal hyperthermia and acidosis (not definitive MH) during a general anesthetic in patients with myotonia have been found: one in a girl anesthetized with halothane/ether,22 and one in a boy with Thomsen's disease pretreated with oral dantrolene and anesthetized with a nontriggering anesthetic (thiopental/dextroramide§/nitrous oxide).23 Although these case reports are widely quoted, the assignment of MH susceptibility in this disease on one case report in which a triggering anesthetic was used and one in which a nontriggering anesthetic was used is suspect. Indeed, in the latter case, one could just as easily assign the cause to side effects of the little-studied dextroramide. Furthermore, one study in a goat model of myotonia congenita failed to induce MH with 1% halothane and a single injection of succinylcholine,24 and the results of IVCT in control and myotonic (arrested development of righting response) mice did not differ (W. Klingler, Ulm, Germany, unpublished data). Indeed, the rarity of clinical reports of MH-like responses to volatile anesthetics in myotonic patients allows for the suggestion that a myotonic patient who experiences a true MH crisis could easily have the misfortune of having mutations at two distinct genetic loci, one for myotonia and one for MH susceptibility. We conclude that it is highly unlikely that patients with any of the chloride channel myotonias have a risk of developing MH above that of the general population.

Despite the generalized myotonia induced by succinylcholine, nondepolarizing muscle relaxants seem to behave normally in myotonic patients, but will not counteract a myotonic response caused by succinylcholine. Nevertheless, in the myotonic conditions in which muscle wasting can develop (i.e., Becker's disease), an exaggerated response may occur.25 Ideally, a short-acting nondepolarizing muscle relaxant should be used, as anticholinesterase drugs to antagonize the effects of the nondepolarizing neuromuscular blocking drugs have been reported to precipitate myotonia.26 The use of propofol, in conjunction with epidural anesthesia, was reported to be safe in a patient with myotonia congenita (Becker type).27

Sodium Channelopathies

Paramyotonia Congenita.

This entity, eponymously known as Eulenberg's disease, is the result of autosomally dominant transmitted mutations in the SCN4A gene of the skeletal muscle sodium channel, Nav1.4, and has high penetrance (Table 1 and Fig. 1B). The exact physiological mechanism of the induction of symptoms is unknown, but this subunit is also the site of mutations that produce hyperkalemic periodic paralysis with myotonia. Symptoms, often beginning in the first decade of life, are characterized by cold- or exercise-induced stiffness of the facial, lingual, neck, and hand muscles. These symptoms can last from minutes to hours. Frozen or slow tongue is often reported by affected individuals after eating ice cream or ices, and a frozen smile-like appearance is noted after facial exposure to cold temperatures. Interepisode periods may be characterized by residual stiffness of the facial, eyelid, and pharyngeal muscles. Unlike most other myotonias, symptoms of paramyotonia congenita paradoxically worsen with repeated movement of affected muscles, hence, paramyotonia, the opposite of the warm-up phenomenon. Symptoms are most common in the ocular and hand muscles. Indeed, the classical physical finding in paramyotonia congenita is the inability to open the eyelids after a bout of repeated, sustained eyelid closures. Later in life, episodes of myotonia may be followed by periods of flaccid paralysis of the affected muscle. At this point in time, weakness is sometimes precipitated when rest is followed by exercise, after the ingestion of potassium-containing compounds and prolonged fasting.

Several variants of paramyotonia congenita are known; among them is hyperkalemic periodic paralysis (HyperPP) with myotonia (see below), which is characterized less by cold-induced symptoms than by potassium ingestion or exercise. Similar to HyperPP, weakness is more common in the early hours of the day and is often accompanied by elevated serum potassium levels. Significant to anesthetic practice is that respiratory muscles are usually spared.28 Dysrhythmias due to ictal hyperkalemia have been reported, but are rare.29,30

Anesthetic Implications and Susceptibility to MH.

There are no case reports of MH index cases with general anesthesia in patients with paramyotonia congenita, and there is one in which an infant was anesthetized with sevoflurane without untoward incidents.31 One patient had an IVCT performed after masseter spasm during anesthesia induction. The IVCT was negative, and the patient was later diagnosed as having paramyotonia congenita (T. Girard, unpublished data). Risk of MH in this entity is considered to be that of the general population (Table 1).

Potassium-Aggravated Myotonias (PAM).

This rubric describes three similar entities of somewhat overlapping phenotypes all caused by mutations in the skeletal muscle sodium channel: myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia. Symptoms in all of these are aggravated by potassium ingestion. In contrast to paramyotonia congenita, they do not worsen after cold exposure, and, unlike hyperkalemic periodic paralysis, they do not present with significant weakness.

Myotonia Fluctuans.

This entity is transmitted by autosomal dominant inheritance, and symptoms, which include extraocular, bulbar, and limb stiffness exacerbated by potassium ingestion or exercise, begin in the first or second decade. There are five classic symptoms of this myotonia: fluctuating myotonia of variable severity, the presence of the warm-up phenomenon, the absence of periodic weakness or cold-induced myotonia, and the exacerbation of myotonia after potassium ingestion or exercise. Curiously, the exercise-induced stiffness is particularly severe, even resulting in immobilization, when the exercise is performed after a narrow window of rest, typically 20–40 min after a previous period of exercise. The variability of clinical myotonia is the result of episodic periods of myotonia lasting from 30 to 120 min and separated from each other by prolonged periods of normal muscle function. With this entity creatine phosphokinase (CPK) levels can be 2–3 times normal. Rigidity and rhabdomyolysis may occur during surgery, but an association with MH is not a feature of myotonia fluctuans.

Myotonia Permanens.

This myotonia is also dominantly inherited, extremely rare, and a very severe form of nondystrophic myotonia whose symptoms include persistent myotonia predominantly of facial, limb, and respiratory muscles and often begins within the first decade of life. Myotonia may worsen with exercise or potassium ingestion, but the effects of cold exposure are variable. Hypertrophy of the neck and shoulder muscles is common, and severe stiffness of the intercostal muscles can result in respiratory compromise. CPK levels are elevated in this entity as well.

Acetazolamide-Responsive Myotonia.

This is another autosomal dominant, sodium channelopathy that is characterized by generalized myotonia after potassium ingestion, cold exposure, or fasting. Symptoms progress during childhood, involve the extraocular muscles, muscles of mastication, and those of the proximal limbs, and do not involve episodes of weakness or paralysis. Episodes are often painful, mildly affected by exercise and, in contrast to other myopathies, unusually responsive to the therapeutic effects of acetazolamide. CPK levels are normal to mildly elevated. Close monitoring during surgery is recommended for the development of rigidity and rhabdomyolysis.

Anesthetic Implications and Susceptibility to MH.

No reports of MH susceptibility were found for any of the PAMs, and the risk is estimated to be that of the general population (Table 1).

HyperPP With (or Without) Myotonia.

This is an autosomal dominant sodium channelopathy with nearly complete penetrance, also known as adynamia episodica hereditaria, which results in episodic attacks of weakness, the result of hyperkalemia-induced electrical inexcitability (Table 1 and Fig. 1B). In some individuals, this entity is accompanied by clinical and electrical myotonia. Symptoms begin in early childhood with attacks of weakness brought about by resting after exercise, cold exposure, fasting, emotional stress, or potassium ingestion. The clinical myotonia, when it occurs, can be reduced with repeated exercise, i.e., the warm-up phenomenon. Curiously, the attacks of weakness can be generalized or localized to a single limb, but usually spare the facial and respiratory muscles. The ingestion of glucose is therapeutic.

Almost all mutated sodium channels have an impaired fast-inactivation leading to increased sensitivity to elevated potassium or reduced temperature.30 In HyperPP, there is a gain of function leading to excessive depolarization followed by inactivation. A milder depolarization maintains the channel in a noninactivated state and sustained inward sodium current leads to repetitive firing.32,33 As a result, small differences in the extent of depolarization are responsible for symptoms of weakness or myotonia.34 During an attack, potassium is shifted from the intracellular to the extracellular space, causing serum potassium to increase. This relative hyperkalemia depolarizes the muscle membrane sufficiently to prevent activation of the normal sodium channels (50% of the population in patients) and, thereafter, the propagation of the action potential.

Anesthetic Implications and Susceptibility to MH.

Despite the above, the administration of potassium-releasing drugs, such as succinylcholine, should be avoided.35 Indeed, a prolonged episode of muscle weakness for 4 days after a general anesthetic that included succinylcholine has been described.36 Furthermore, succinylcholine may induce severe muscle spasms in these patients.37,38 Several reports document the safe use of nondepolarizing muscle relaxants.35,39 A number of case reports have shown an uneventful course of anesthesia when volatile anesthetics were administered to patients with HyperPP35,39 and have suggested using inhaled induction of anesthesia in these patients.40 IVCT of muscle biopsies from patients with HyperPP did not reveal MH susceptibility.41 In contrast, a genetic linkage was suggested between mutations in SCN4A for HyperPP and MH, but in this pedigree the only person tested by IVCT had an abnormal response to caffeine only, making him MH-equivocal by European Malignant Hyperthermia Group criteria and MH-normal by North American criteria.42 Depolarizing drugs, such as succinylcholine or anticholinesterases, worsen myotonia and should therefore be avoided.43 Propofol, as a voltage gated sodium channel inhibitor, seems theoretically advantageous in these patients, and there are reports of its safe use.44–46 The perioperative management of these patients should include preoperative potassium depletion by diuretics,35 continuous electrocardiogram monitoring, administration of glucose to avoid carbohydrate depletion during the fasting period, and temperature monitoring with emphasis on maintaining normothermia.25

Of the various types of PAM, the incidence of adverse anesthetic events seems to be most frequent in families with myotonia fluctuans.43 This most likely relates to the frequent absence of clinical signs before surgery, and, thus, the anesthesiologist is unaware of the condition. With other types of myotonia, patients often report that they have myotonic episodes or attacks of weakness. Depolarizing drugs should be avoided, thereby decreasing the risk of an adverse event. Paramyotonia congenita patients may be paralyzed for several hours upon awakening from general anesthesia. Both preventive therapy before surgery and maintaining a normal body temperature will help to prevent such attacks.

In contrast to the muscle contractures in MH that respond well to dantrolene,47 myotonic contractions are generally relieved by lidocaine (a sodium channel blocker) rather than by dantrolene because they result from bursts of action potentials. Dantrolene would reduce the contractile force and thus the complication-inducing stiffness of the myotonia, but not the primary hyperexcitability of the membrane.43

Given the above, and because no reports of MH susceptibility have been found, we do not consider this population of patients with sodium channelopathies to be at increased risk for MH (Table 1).

Dystrophic Myotonias

In contrast to the nondystrophic myotonias, the two major myotonic dystrophies are primary, autosomally dominant inherited, multisystem disorders that have significant neuromuscular findings that prominently involve the presence of myotonia and weakness, but do not involve mutations in ion channels. Rather startlingly, they result from expanded repeats in the 3′ untranslated regions of specific genes and join a growing number of unrelated diseases (>20) whose common pathophysiological base is that of heritable, unstable nucleotide repeats48 (Table 1 and Fig. 2). In Type 1 myotonic dystrophy (DM1), the more common entity, the expanded trinucleotide repeat, CTG, is expanded from 50 to 200 times in the 3′ untranslated region of the myotonic dystrophy protein kinase gene. In DM2, the less common form, there is an expansion (80–11,000 times) of a tetranucleotide repeat of CCTG in the first intron of the zinc finger protein 9 (ZNF9) gene. As it turns out, the disease mechanisms have nothing to do with either the dystrophy protein kinase or the ZNF9 proteins or their expression. Rather, the long RNA repeats that result from the translation of these expanded repeats fold into an unusual pathological hairpin structure that results in their accumulation in the nucleus and disruption of normal alternative splicing of messenger RNA. As a result, many normal proteins are dysregulated and, in our cases, result in wasting myotonias with multisystem involvement. The severity of clinical symptoms in both DM1 and DM2 are roughly correlated with the length of triplet or tetranucleotide repeats. The descriptions of DM1 and DM2 below are taken from the following critical reviews.49–54

Figure 2.
Figure 2.:
Schematic depicting the splicing abnormalities caused by CTG expansion repeats and their reversal in a mouse model of myotonic dystrophy. Myotonic dystrophy (DM) is caused by CTG repeats within a noncoding region of the Dmpk gene. It is also caused by the expansion of a four-base motif CCTG in a noncoding region of the Znf9 gene (not shown). Transcribed RNA repeats fold into a long, misshapen hairpin, and the RNA is retained in the nucleus, where it alters the ratio of CUG RNA-binding proteins, such as CUG-BP1 and MBNL1. These proteins are mutually antagonistic mediators of a subgroup of alternative splicing events that are disrupted in myotonic dystrophy, in which “embryonic” forms of some proteins, that is, isoforms typically expressed in the developing embryo and fetus, predominate. A primary result of this dysregulation in both forms of DM is dysfunctional splicing of the embryonic form of ClC1 into the adult form, resulting in lack of buffering of sarcolemmal after-potentials and the induction of sustained contractures, i.e., myotonia. A recent study showed that increasing the expression of MBNL1 in a mouse model of DM restored the adult splicing pattern of the ClC-1 protein and reversed the myotonia associated with ClC-1 dysregulated splicing. Figure and modified legend reprinted with permission from ref. 54 (Cooper TA. A reversal of misfortune for myotonic dystrophy? N Engl J Med 2006;355:1825–7). Copyright © 2006 Massachusetts Medical Society. All rights reserved.

Clinical features common to both DM1 and DM2 include: myotonia, muscle weakness, and atrophy (face, neck, fingers, and limbs), cardiac conduction defects, cognitive dysfunction, cataracts, hypersomnia, insulin resistance, testicular atrophy, frontal balding in males, hypogammaglobulinemia, and muscle pain. The myotonia, muscle weakness and atrophy, cardiac conduction defects, and hypersomnia are clinically more significant and can present at an earlier age in DM1. In both DM1 and DM2, and like myotonia congenita, there is a defect in the skeletal muscle chloride channel, but this is due to loss of appropriate splicing and resultant retention of the embryonic form of the channel, thereby inhibiting its replacement by the adult form appropriate to postnatal function. This gives rise to the myotonic symptoms, and, in contradistinction to the nondystrophic myotonias, there is early and progressive muscle weakness. Similarly, there is inappropriate splicing of the insulin receptor, giving rise to insulin resistance.


DM1, also known as Steinert's Disease, is the most common form of myotonic dystrophy and is a dominantly inherited multisystem disorder that usually results in death from skeletal muscle wasting and cardiac conduction defects. Clinical symptoms specific for DM1 include distal muscle weakness with muscle atrophy at onset, learning and speech disabilities, hypotonia, facial diplegia, and sometimes gastrointestinal problems. DM1 is associated with the phenomenon of generational anticipation, by which the disease has an earlier onset and more severe course in subsequent generations. There are four subsets of DM1 related to the age of onset: congenital, childhood onset, adult-onset, and late onset/asymptomatic. This is roughly correlated with the size of CTG expansion repeats.


DM2, previously known as proximal myotonic dystrophy or proximal myotonic myopathy, before this entity was identified as a member of the expansion nucleotide repeat family of myotonias, is also a dominantly inherited disorder. Though there is some evidence of generational anticipation in this disease, there is no congenital form yet identified, and the earliest age of onset is approximately 13 yr. Symptoms specific to this entity are proximal muscle weakness and atrophy at onset and hypertrophy of calf muscles.

Anesthetic Implications and Susceptibility to MH.

There are no case reports in the literature directly linking the myotonic dystrophies to MH. The IVCT of 44 patients with myotonias, including the myotonic dystrophies, resulted in four positive results, 10 equivocal results, and 30 negative results.41 The four positive results all came from DM patients, but 12 of these patients were negative. There is one report of a patient with DM2 who developed muscle stiffness, oculogyric cramps, and elevated creatine kinase levels after treatment with neuroleptics and had a positive IVCT with halothane.55 Undoubtedly, the IVCT cannot be used to diagnose MH susceptibility in a patient population with membrane channelopathies without worrying about false positives.56 Succinylcholine will induce generalized skeletal muscle rigidity in these patients, raising the specter of MH susceptibility, but the latter seems unlikely to occur in the absence of a second genetic change specifically causative for MH.

Our assessment of the triplet expansion myopathies is that susceptibility to MH is that of the background population. IVCT/CHCT results in these patients are likely misleading even if contractures reach the threshold we have set for MH susceptibility. One should avoid the use of succinylcholine in these patients. Given the intrinsic weakness of these patients, we recommend the judicious use of nondepolarizing drugs, along with careful attention to respiratory status.

Calcium Channelopathies

Hypokalemic Periodic Paralysis (HypoPP)

HypoPP is a rare, autosomal dominant, skeletal muscle disorder with episodes of muscle weakness.57 Affected patients first exhibit episodes of asymmetrical muscle paralysis associated with low potassium levels in the second decade of life. The muscle weakness affects mainly the proximal muscles, sparing the diaphragm, and muscles supplied by the cranial nerves.58 In most patients the disorder is caused by mutations in the skeletal muscle voltage-gated calcium channel encoded by CACNA1S (HypoPP Type 1), although it is less frequently associated with mutations in the SCN4A gene (HypoPP Type 2)43 (Fig. 1B). All HypoPP mutations are situated in the so-called voltage sensors of the channels.43 These mutations result in pore currents with reduced amplitude and shifted voltage-dependence, i.e., findings that cannot explain the disease pathogenesis.59 The exact mechanisms leading to hypokalemic paralysis are unclear.28,43

Anesthetic Implications and Susceptibility to MH.

Several authors have described the uneventful use of inhaled anesthetics and succinylcholine in patients with HypoPP.60,61 However, there are case reports of intraoperative hypermetabolic crises after administration of MH trigger drugs to patients with HypoPP,57,62,63 and one group also described contracture-like responses to succinylcholine.64 In one of these case reports, a positive IVCT was obtained in one of the two patients with clinically suspected MH.63 Genetic investigations in this same patient excluded known mutations in CACNA1S and SCN4A, whereas a novel mutation (Asn2342Ser, subsequently found in other MH susceptible families) was identified in the RYR1 gene, which was likely the source of that patient's MH susceptibility. Myotonia in this patient must have arisen from a mutation in CACNA1S or SCN4A that was not tested for, or from a new, unidentified locus. This illustrates the possibility that “lightning does strike twice,” i.e., it is possible to have two separate genetic mutations that predispose to two separate conditions in the same patient, and may underlie the rare confluence of myotonia and MH susceptibility.

As noted above, mutations in specific regions of CACNA1S confer susceptibility to HypoPP. A few mutations in another region of this gene have been associated with MH.65 There is a similar situation for central core disease and MH in which both conditions are linked to mutations in RYR1, and the incomplete clinical overlap between the two seems to correlate with the region of the protein in which the mutations are found (for more complete treatment of this, see the reviews by Refs. 66, 67). Because there are a few MH patients known to have mutations in another region of CACNA1S, a theoretical association between MH and HypoPP in this small subset of patients has been made, but never been confirmed. Moreover, there is a lack of evidence for MH susceptibility that is generalizable to all HypoPP patients, and it is unclear that all of the few reports of anesthetic-associated reactions suspected of being MH were really MH. Indeed, the patient with the highest MH clinical grading score (33, “somewhat > than likely” vs 18, “somewhat < likely”68) reported above,63 and retrospectively determined by the authors of this manuscript, had a normal IVCT. It would seem, therefore, that not all “hypermetabolic” responses of anesthetized patients with neuromuscular disease are MH. However, anesthesiologists must have a heightened suspicion for hypermetabolic reactions when caring for these patients because, should volatile anesthetics be used, the reaction might be MH. As noted above, one can have the misfortune of having mutations in two separate genes resulting in both an unrelated channelopathy and susceptibility to MH.

Depolarizing neuromuscular blocking drugs should not be administered to patients with HypoPP, and their anesthetic management should focus on the prevention of perioperative episodes of muscle weakness. This includes avoiding large glucose and salt loads, maintaining normothermia, keeping serum potassium levels in the upper part of the normal range, and reducing the patients' anxiety, because all these factors are associated with increased occurrence of postoperative paralytic episodes.40 If nondepolarizing muscle relaxants are required, drugs with a relatively short duration of action are best69,70; neuromuscular function must be monitored if neuromuscular blocking drugs are given. Because there are no definitive reports of MH in patients with HypoPP, we conclude that the likelihood of HypoPP patients being susceptible to MH is that of the general population. However, the mutational locus linked to HypoPP is the DHPR α1s gene, the same gene that is also a locus of a few MH mutations. There is the theoretical likelihood, therefore, that susceptibility to MH may overlap with that of HypoPP, despite the fact that the mutations for the two entities segregate to separate parts of the gene. Our present state of knowledge does not allow definitive recommendations. We leave it to the discretion of the clinician as to whether to use volatile anesthetics in these patients but, if they do, they should be extra vigilant.


The care of myopathic patients is often difficult enough without having to worry about their often-touted, potential susceptibility to MH. We hope the above review and recommendations clarifies that, for the channelopathies reviewed above, the risk of MH is that of the general population. Only for HypoPP can we not yet definitively say that risk of MH is that of the general population for the reasons explained above, despite the fact that there are no reports of MH occurring in patients with this entity. Readers are cautioned, however, that it is not impossible for patients to have the genetic disposition toward two separate entities, MH and another of the myopathies that has no genetic relation to MH, no matter how unlikely. Clinicians should act on the side of caution if perioperative signs and symptoms of MH present themselves in someone with one of the above myopathies and treat the event as a potential MH episode. There is no significant downside to treatment with dantrolene in suspected but not true MH. Potential disaster awaits if true MH is undiagnosed and left untreated.


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*Maintained as an up-to-date list by the European Malignant Hyperthermia Group at
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†See the list at the Malignant Hyperthermia Association of the United States website
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§Electronic search of the literature does not show a listing for dextroramide, but it does for dextromoramide, an analgesic structurally related to methadone and in limited use in Europe to treat severe pain. It has been recommended not to give this drug to patients taking MAO inhibitors, though no reports of hyperthermic crises or serious drug interactions have been found in electronic search of the literature.
Cited Here

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