Malignant Hyperthermia and the Muscular Dystrophies
Amanda Brown, MD, Harshad Gurnaney, MD, Ronald S. Litman, DO
The Children’s Hospital of Philadelphia
The muscular dystrophies (MD) encompass a diverse group of disorders with varying modes of inheritance and pathophysiological characteristics. The most common are the X-linked recessive, Duchenne’s muscular dystrophy (DMD) and Becker’s dystrophy (BD). In this lecture, we will summarize the existing literature with regard to the anesthetic concerns in patients with MD, with an emphasis on proving or disproving a link between MD and malignant hyperthermia (MH) susceptibility.
For the purposes of this discussion, we broadly identified 4 different categories of anesthetic complications in MD patients: 1) intraoperative heart failure; 2) rhabdomyolysis with inhalational anesthetic agents without succinylcholine; 3) rhabdomyolysis and life-threatening hyperkalemia immediately following succinylcholine administration; and 4) true malignant hyperthermia.
Intraoperative heart failure
A number of retrospective reviews attest to the safety of anesthetizing DMD patients using inhalational halogenated agents without succinylcholine.1-7We identified several published reports of intraoperative heart failure attributable to ventricular insufficiency in patients with known DMD during correction of spinal scoliosis.8-13 Characteristic of each was the sudden onset of a nonviable tachyarrhythmia and/or hypotension. The eventual contribution of the general anesthetic agents to the cause of the event cannot be ascertained as events occurred during intravenous and inhalational anesthetic exposures, without succinylcholine. Gross perturbations of serum electrolytes were not found, however ongoing volume resuscitation was generally an aspect of each scoliosis correction. In most, markers of adequate volume status just prior to the onset of the event were identified, but the case reports fail to identify whether the volume administered was transiently insufficient in light of ongoing losses or if the volume loss overstressed an already compromised left ventricular dysfunction. Transesophageal echocardiography and pulmonary artery catheters generally were not utilized in these cases prior to the cardiac events, although arterial and central venous pressure monitoring were frequently utilized.
Given the prevalence of DMD and the number of operative procedures performed on this patient population, it is surprising that acute cardiac insufficiency superimposed on chronic cardiomyopathy is not more frequent. The surgical stress of scoliosis correction for these patients is severe, with hemodynamic alterations imposed by prone positioning, positive pressure ventilation, anesthetic exposure, and hypovolemia from blood loss. A preoperative echocardiographic assessment of cardiac function and the employment of invasive monitoring are critical to the successful management of these patients. The anesthetic utilized in these case reports, whether inhalational or intravenous, was not observed to be protective against these cardiovascular events, but not clearly precipitant either. The full recoveries achieved in some acute events serve to contrast with historical reports detailing respiratory failure precipitating or contributing to catastrophic cardiac arrest following both minor and major operative procedures in DMD patients ranging in age from 9 – 17years.7;14 These event types evolved from muscular insufficiency that progressively worsened in the recovery period. Current improved outcomes are likely the result of prescreening surgical candidates and multi-specialty involvement that maximizes pulmonary and cardiovascular function prior to surgery.
Rhabdomyolysis with inhalational anesthetic agents without succinylcholine
The abnormal skeletal muscle cell of dystrophic disease is particularly susceptible to volatile and neuromuscular agents. Alterations in the sarcolemma architecture disrupt regulation of neurotransmitter-mediated contraction and result in proliferation of abnormal extra-junctional receptors. An exacerbated release of potassium stores can lead to rhabdomyolysis, hyperkalemia, and cardiac depolarization abnormalities.
Intraoperative and postoperative cardiac arrest in muscular dystrophy patients occurs in the absence of succinylcholine administration, and is almost always associated with acute rhabdomyolysis and hyperkalemia as the precipitating factor.15-31
Identified events have occurred in younger DMD patients, and the muscular dystrophy status is often occult. Variable time of onset of a clinically significant cardiac arrhythmia after anesthetic induction is seen, with bradycardia and tachycardia both observed to precede complete cardiovascular collapse. Initial serum potassium levels exceeded 8mEq/dL. Resuscitations persisted in excess of 60 min, with full recoveries obtained in some. Dantrolene was often employed empirically following documented concomitant metabolic and respiratory acidosis, with or without modest temperature increases. These cases would suggest a predisposition to rhabdomyolysis on exposure to volatile anesthetic agents regardless of surgical stress. The components of an effective resuscitation are difficult to discern but reduction of the serum potassium appears critical.
Rhabdomyolysis and life-threatening hyperkalemia immediately following succinylcholine administration
When succinylcholine binds to the normal nicotinic acetylcholine receptor, it causes a pharmacologically prolonged depolarization of the membrane, and results in the passage of sodium into the cell, and potassium out of the cell and into the circulation. This usually results in a clinically insignificant rise of serum potassium on the order of 0.5 to 1 mmol/L. However, succinylcholine-induced life-threatening hyperkalemia may result in a number of preexisting patient disease states. This has been extensively reviewed by Gronert32 and Martyn.33
There are two general mechanisms underlying succinylcholine-induced hyperkalemia: (1) excess potassium release as a result of up-regulation of abnormal extrajunctional acetylcholine receptors (e.g., burns, denervation atrophy, etc.) and, (2) development of hyperkalemia as a result of rhabdomyolysis that occurs in patients with certain clinically evident as well as subclinical myopathic disease states such as DMD.
The exact mechanism by which succinylcholine muscle depolarization results in rhabdomyolysis that is severe enough to cause life-threatening hyperkalemia is unknown. It is known however, that the absence of dystrophin that characterizes DMD results in a number of intracellular pathophysiological changes that result in destabilization of the cytoskeletal components of muscle cells and propensity toward destruction when exposed to succinylcholine as well as inhalational anesthetic agents.34
From the literature, there are at least 23 known patients with DMD that developed succinylcholine-induced fatal and near-fatal hyperkalemia. The majority of these patients did not manifest clinical signs or symptoms of a myopathy at the time of the succinylcholine administration, and therefore, the adverse event led to the eventual diagnosis of a myopathy. In many cases, retrospective analysis revealed subtle, subclinical motor milestone delays, such as inability to begin walking until age 2.
True association of MD with MH susceptibility
Clinical MH has been reported in patients with DMD. However, the rhabdomyolysis and other clinical characteristic that result from administration of succinylcholine and volatile anesthetics to DMD patients is similar to those arising from a true MH episode; thus the two entities are difficult to distinguish. It seems unlikely that a true genetic association exists between DMD (X-linked mutation) and MH because the genetic mutation associated with DMD is located on the X chromosome, and the mutations associated with MH susceptibility are usually found on chromosome 19. Nevertheless, some patients with DMD have demonstrated a positive CHCT indicating MH susceptibility.23;35-37 However, in all these “clinical MH” cases, the patients suffered acute rhabdomyolysis with hyperkalemia following succinylcholine, without classic signs and symptoms of MH.
Is it possible that DMD muscle demonstrates a positive CHCT without true MH susceptibility? In other words, does muscle tissue from DMD patients give a false positive CHCT?35;38;39 The answer is not known.
Summary of Recommendations
1. Succinylcholine is absolutely contraindicated in patients with known DMD or Becker’s dystrophy, unless required for a life-threatening airway emergency. All children presenting for administration of general anesthesia or sedation should be screened for motor milestones. Inability to walk until past 15 months of age or other signs of motor delay should prompt suspicion of a subclinical myopathy and should warrant neurological evaluation prior to elective surgery.
2. In patients with known or suspected MD, exposure to volatile agents should be minimized and used only when absolutely necessary for safe administration of general anesthesia.
3. DMD patients without a known positive CHCT should not be considered to be MH susceptible.
References
1. Can.J Anaesth. 1992; 39:1117
2. Anaesthesia and Intensive Care 1972; 1:150
3. Anaesthesist 2000; 49:187
4. Can.J Anaesth 1989; 36:418
5. Med.Klin.(Munich) 1996; 91 Suppl 2:34
6. Ugeskr.Laeger 1996; 158:6274
7. Can.Anaesth Soc.J 1982; 29:250
8. Acta Anaesthesiol.Scand. 2005; 49:267
9. Anaesth.Intensive Care 1995; 23:626
10. Br.J Anaesth. 2003; 90:800
11. Anaesthesia 1999; 54:364
12. Muscle Nerve 1992; 15:604
13. Anesthesiology 1988; 68:462
14. Br.J Anaesth. 1985; 57:1113
15. Can.Anaesth.Soc.J. 1986; 33:799
16. J Child Neurol. 1987; 2:160
17. Neuromuscul.Disord. 1991; 1:201
18. Arch.Surg. 1982; 117:349
19. Paediatr.Anaesth. 2006; 16:170
20. Anesthesia and Analgesia 2005; 100:672
21. Anesthesiology 2000; 93:1535
22. Anaesthesia 1990; 45:22
23. Pediatrics 1983; 71:118
24. J Pediatr.Surg. 1970; 5:71
25. Masui 2002; 51:190
26. Acta Paediatr. 1992; 81:716
27. Can.J Anaesth. 1999; 46:564
28. Eur.J Pediatr. 2001; 160:579
29. Can.Anaesth Soc.J 1983; 30:295
30. Anesthesiology 1987; 67:856
31. Kyobu Geka 2005; 58:201
32. Anesthesiology 2001; 94:523
33. Anesthesiology 2006; 104:158
34. Paediatr.Anaesth 2008; 18:100
35. Anesthesiology 1983; 59:362
36. Anesthesiology 1983; 58:180
37. Can.Anaesth.Soc.J. 1982; 29:627
38. Pediatr.Neurol. 1986; 2:356
39. Muscle Nerve 1988; 11:453
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Congenital Myopathies
Thierry Girard, MD
There is an important difference between malignant hyperthermia episodes caused by increased Ca2+ release from the sarcoplasmatic reticulum and other hypermetabolic states due to different etiologies. Volatile anesthetics act agonistic on the skeletal muscle type ryanodine receptor and lead to an increased Ca2+ release from the sarcoplasmic reticulum. In myopathies where the dihydropyridine and/or the ryanodine receptor are known to have an increased sensitivity, volatile anesthetics should be avoided, as they have the potential to trigger a hypermetabolic state, such as malignant hyperthermia. Besides being triggering agents for malignant hyperthermia, volatile anesthetics have many medical and economic advantages. Hypermetabolic reactions and muscular rigidity can occur during administration of volatile anesthetics to patients with neuromuscular diseases. These might be due to myotonic reactions unrelated to ‘true’ malignant hyperthermia. In neuromuscular diseases, where neither pathophysiological mechanisms nor clinical episodes unequivocally link to malignant hyperthermia we refrain from generally discouraging the use of volatile anesthetics. Myopathies share common clinical pictures and the underlying molecular mechanism is frequently not unequivocally identified through clinical evaluation. The anesthetist must not content with a clinical diagnosis of a certain myopathy, but collect information about the underlying molecular mechanism, i.e. underlying mutated channel, in order to decide in favor or against volatile anesthetics. We recommend to cautiously consider pros and cons of volatile anesthetics in a specific patient and to watch carefully for signs of hypermetabolism, should volatile anesthetics be chosen. Usage of depolarizing muscle relaxants should be generally discouraged in patients with neuromuscular diseases. Adverse effects are exaggerated in patients with extrajunctional acetylcholine receptors, increased proportion of the fetal gamma-isoform and those susceptible for myotonic reactions.
Channelopathies
Chloride: Myotonia congenita
Myotonia congenita (MC) is caused by mutations in the skeletal muscle chloride channel gene (CLCN1) and can be inherited either as an autosomal dominant (Thomsen’s myotonia) or autosomal recessive (Becker’s myotonia) trait. The reduced chloride conductance of the mutated chloride channels leads to hyperexcitability of the muscle membranes leading to burts of action potential. The association of MC and malignant hyperthermia (MH) is controversial [1-4]. In animal experiments malignant hyperthermia could not be induced in myotonic goats [5] and in-vitro contracture testing in control and myotonic mice did not differ. The use of propofol was reported to be safe in a patient with MC (Becker type) [6]. An unambiguous linkage between MC and MH is lacking and there is no evidence to generally avoid volatile anesthetics in these patients.
Sodium: Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis (HyperPP) is a rare autosomal dominant condition caused by gene mutations of the sodium channel alpha-subunit gene (SCN4A) causing periodic hypotonia when associated with increases in serum potassium levels [7, 8]. Potassium aggravated myotonia and paramyotonia congenita are also associated with mutations in SCN4A. As these myotonias share a similar pathogenesis with HyperPP [9], anesthetic recommendations do not differ. A number of case reports have shown an uneventful course of inhalational anesthesia in patients with HyperPP [10, 11] even suggesting inhalational induction [12]. In-vitro contracture testing of muscle biopsies from patients with HyperPP did not reveal malignant hyperthermia susceptibility [4]. In contrast a genetic linkage was suggested between mutations in SCN4A and malignant hyperthermia, but in this pedigree the only person tested by IVCT had an abnormal response to caffeine [13]. Propofol, as a voltage gated sodium channel inhibitor, seems theoretically.
Calcium: Hypokalemic periodic paralysis
Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant skeletal muscle disorder in which episodes of muscle weakness occur [14]. In most patients the disorder is associated with mutations in the skeletal muscle voltage-gated calcium channel encoded by CACNA1S (HypoPP type 1), while it is less frequently associated with mutations in the SCN4A gene (HypoPP type 2) [9]. Several authors described the uneventful use of inhalational anesthetic agents and succinylcholine in patients with HypoPP [15, 16]. Mutations in CACNA1S have been associated with malignant hyperthermia [17]. These reports suggest an association between MH and HypoPP in some patients, but there is lack of evidence for general MH susceptibility of HypoPP patients.
Central core disease
Central core disease (CCD) is a rare hereditary myopathy, which presents with weakness of variable degree and central cores in the muscle biopsy.
Histological findings are characterized by demarcated cores, which lack oxidative enzyme activity. The cores are only found in the predominant type I fibres. Disease causing mutations in or linkage to RyR1 have been shown for the majority of cases. There is an overlap of CCD to other myopathies (e.g. nemaline myopathy) [18]. The current understanding of CCD suggests a strong link between the subcellular Ca2+ metabolism and the pathomechanism of the disease [19, 20]. This is corrobated by clinical evidence of MH-susceptibility of CCD-patients and pathological contractures in the MHdiagnostic caffeine-halothane contracture test (IVCT). Every CCD patient should be regarded as MHsusceptible and therefore receive non-triggering anesthesia.
Multiminicore disease
Multiminicore disease (MmD) is usually considered a recessively inherited congenital myopathy with a pattern of weakness that differs from central core disease in that there is often severe axial involvement, respiratory and bulbar involvement and the extra-ocular muscles are commonly involved. MmD is characterized by cores lacking oxidative enzyme activity on histochemical analysis.
The moderate form with hand involvement is most often associated with mutations in RYR1 [20, 21]. The classical predominant form of MmD is, however, most frequently associated with mutations in the selenoprotein N gene (SEPN1) [22]. This is the same gene that is responsible for congenital muscular dystrophy with rigid spine (RSMD) [23]. Mutations in patients with core myopathies have also been described in the alpha-actine gene (ACTA1) [24].
There are no reports of patients with multiminicore disease developing clinical malignant hyperthermia during general anaesthesia. There is, however, a report of a large MH kindred in whom the majority of MH susceptible individuals have histopathological features of multiminicore disease but have no clinical myopathy [25]. A time related change in the morphology from minicores to cores has been described [26]. It may, therefore, be a pragmatic approach, at least in respect of the association of core myopathies with MH, to consider MH risk to be associated with an RYR1 aetiology rather than a core histology aetiology. However, at this stage there is probably insufficient evidence to conclude that patients with multiminicore disease and a non-RYR1 aetiology are at low risk for malignant hyperthermia.
Nemaline rod myopathy
Nemaline rod myopathy (NM) is a rare congenital myopathy which appears in a considerable clinical and genetic heterogeneity [27-29]. The cardinal features of all nemaline subtypes are muscle weakness and the presence of nemaline bodies (rod-shaped structures) in the muscle fibres [30, 31]. Most cases of NM have a sporadic onset (~63%). Familial forms are observed in about one third of cases (24% autosomalrecessive, 13% autosomal-dominant) [29]. In the majority of cases NM is caused by mutations in the nebuline (NEB) gene [32], followed by mutations in the ACTA1 gene [33]. In few cases mutations in RYR1 have also been associated with nemaline bodies. However, these nemaline bodies appeared together with central cores, indicating a mixed muscle disorder core-rod myopathy [34-36].
There is a possible association with MH is more likely in patients who exhibit the histological feature of cores and rods in the same muscle biopsy. The latter can possibly be put down to two different myopathies: Central Core Disease (CCD) and/or NM. Clinically it is difficult to distinguish between these two myopathies since they are related to significantly overlapping phenotypes [37].
A tight assocation between typical NM and MH can probably be excluded. “NM”-patients should be considered with particular caution, if the histological feature of the muscle biopsy is characterised by both cores and rods, if NM is transmitted in an autosomal-dominant manner or if genetic linkage to the RYR1 gene can be demonstrated. In these cases an increased risk for MH must be taken into account and all triggering substances of MH (volatile anaesthetics, depolarizing muscle relaxants) should not be administered during general anaesthesia (table).
Table of Myopathy, associated genes and estimated risk of MH (given there is no particular MH history in family)
| Disease | Gene | MH risk |
| Myotonia congenital Becker or Thomson | CLCN1 | low |
| Hyperkalemic periodic paralysis | SCN4A | low |
| SCN4A | low | |
| CACNA1S | moderate | |
| Central Core Disease (CCD) | RYR1 | high |
| Multiminicore disease | SEPN1 | unclear |
| ACTA1 | unclear | |
| RYR1 | high | |
| Nemaline rod myopathy | NEB, TPM3, TNNT1, | low |
| TPM2, ACTA1 | ||
| RYR1 | high |
Abbreviations stand for the genes of the following proteins: CLCN1 = skeletal muscle chloride channel, SCN4A = sodium channel alpha-subunit gene, CACNA1S = Alpha1 subunit of voltage-dependent L-type calcium channel, RYR1 = Ryanodinereceptor Type 1, SEPN1 = selenoprotein N, ACTA1 = alpha-actine, NEB = Nebuline, TPM3 = Tropomyosin 3, TNNT1 = troponin T1, TPM2 = beta-tropomyosin,
References
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[2] Russell SH, Hirsch NP. Anaesthesia and myotonia. Br J Anaesth. 1994 Feb;72(2):210-6.
[3] Brownell AK. Malignant hyperthermia: relationship to other diseases. Br J Anaesth. 1988 Feb;60(3):303-8.
[4] Lehmann-Horn F, Iaizzo PA, Franke C, Hatt H, Spaans F. Schwartz-Jampel syndrome: II. Na+ channel defect causes myotonia. Muscle Nerve. 1990 Jun;13(6):528-35.
[5] Newberg LA, Lambert EH, Gronert GA. Failure to induce malignant hyperthermia in myotonic goats. Br J Anaesth. 1983 Jan;55(1):57-60.
[6] Hayashida S, Yanagi F, Tashiro M, Terasaki H. [Anesthetic managements of a patient with congenital myotonia (Becker type)]. Masui. 2004 Nov;53(11):1293-6.
[7] Ptacek LJ, Tyler F, Trimmer JS, Agnew WS, Leppert M. Analysis in a large hyperkalemic periodic paralysis pedigree supports tight linkage to a sodium channel locus. American journal of human genetics. 1991 Aug;49(2):378-82.
[8] Fontaine B, Khurana TS, Hoffman EP, Bruns GA, Haines JL, Trofatter JA, et al. Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science. 1990 Nov 16;250(4983):1000-2.
[9] Lehmann-Horn F, Rüdel R, Jurkat-Rott K. Nondystrophic myotonias and periodic paralyses. In: Engel A, Franzini-Armstrong C, eds. Myology: basic and clinical. 3rd ed. New York: McGraw-Hill 2004:1257-300.
[10] Aarons JJ, Moon RE, Camporesi EM. General anesthesia and hyperkalemic periodic paralysis. Anesthesiology. 1989 Aug;71(2):303-4.
[11] Ashwood EM, Russell WJ, Burrow DD. Hyperkalaemic periodic paralysis and anaesthesia. Anaesthesia. 1992 Jul;47(7):579-84.
[12] Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord. 2005 Mar;15(3):195-206.
[13] Moslehi R, Langlois S, Yam I, Friedman JM. Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. American journal of medical genetics. 1998 Feb 26;76(1):21-7.
[14] Lambert C, Blanloeil Y, Horber RK, Berard L, Reyford H, Pinaud M. Malignant hyperthermia in a patient with hypokalemic periodic paralysis. Anesth Analg. 1994 Nov;79(5):1012-4.
[15] Bashford AC. Case report: anaesthesia in familial hypokalaemic periodic paralysis. Anaesthesia and intensive care. 1977 Feb;5(1):74-5.
[16] Siler JN, Discavage WJ. Anesthetic management of hypokalemic periodic paralysis. Anesthesiology. 1975 Oct;43(4):489-90.
[17] Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. American journal of human genetics. 1997 Jun;60(6):1316-25.
[18] Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006 Jun;129(Pt 6):1470-80.
[19] Avila G, Dirksen RT. Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol. 2001 Sep;118(3):277-90.
[20] Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89.
[21] Jungbluth H, Zhou H, Hartley L, Halliger-Keller B, Messina S, Longman C, et al. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology. 2005 Dec 27;65(12):1930-5.
[22] Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. American journal of human genetics. 2002 Oct;71(4):739-49.
[23] Okamoto Y, Takashima H, Higuchi I, Matsuyama W, Suehara M, Nishihira Y, et al. Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene. Neurogenetics. 2006 Jul;7(3):175-83.
[24] Kaindl AM, Ruschendorf F, Krause S, Goebel HH, Koehler K, Becker C, et al. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet. 2004 Nov;41(11):842-8.
[25] Guis S, Figarella-Branger D, Monnier N, Bendahan D, Kozak-Ribbens G, Mattei JP, et al. Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol. 2004 Jan;61(1):106-13.
[26] Ferreiro A, Monnier N, Romero NB, Leroy JP, Bonnemann C, Haenggeli CA, et al. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol. 2002 Jun;51(6):750-9.
[27] Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, et al. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology. 2003 Feb 25;60(4):665-73.
[28] Sanoudou D, Beggs AH. Clinical and genetic heterogeneity in nemaline myopathy--a disease of skeletal muscle thin filaments. Trends Mol Med. 2001 Aug;7(8):362-8.
[29] Wallgren-Pettersson C, Pelin K, Hilpela P, Donner K, Porfirio B, Graziano C, et al. Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord. 1999 Dec;9(8):564-72.
[30] Shy GM, Engel WK, Somers JE, Wanko T. Nemaline Myopathy. a New Congenital Myopathy. Brain. 1963 Dec;86:793-810.
[31] Yamaguchi M, Robson RM, Stromer MH, Dahl DS, Oda T. Nemaline myopathy rod bodies. Structure and composition. Journal of the neurological sciences. 1982 Oct;56(1):35-56.
[32] Wallgren-Pettersson C, Donner K, Sewry C, Bijlsma E, Lammens M, Bushby K, et al. Mutations in the nebulin gene can cause severe congenital nemaline myopathy. Neuromuscul Disord. 2002 Oct;12(7-8):674-9.
[33] Sparrow JC, Nowak KJ, Durling HJ, Beggs AH, Wallgren-Pettersson C, Romero N, et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord. 2003 Sep;13(7-8):519-31.
[34] Monnier N, Romero NB, Lerale J, Nivoche Y, Qi D, MacLennan DH, et al. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet. 2000 Nov 1;9(18):2599-608.
[35] Pallagi E, Molnar M, Molnar P, Dioszeghy P. Central core and nemaline rods in the same patient. Acta Neuropathol. 1998 Aug;96(2):211-4.
[36] Scacheri PC, Hoffman EP, Fratkin JD, Semino-Mora C, Senchak A, Davis MR, et al. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology. 2000 Dec 12;55(11):1689-96.
[37] Thomas C. Nemaline rod and central core disease: a coexisting Z-band myopathy. Muscle Nerve. 1997 Jul;20(7):893-6.
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The Myotonias and Susceptibility to Malignant Hyperthermia
Jerome Parness, M.D. Ph.D. Professor
Department of Anesthesiology
Children’s Hospital of Pittsburgh
University of Pittsburgh Medical Center
3705 Fifth Avenue
Pittsburgh, PA 15213
We concern ourselves with the question whether the Myotonias, as a class of myopathy, are susceptible to Malignant Hyperthermia.
Introduction
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. They have a variety of causes and modes of inheritance, and to understand them we must first review the basic physiology of skeletal muscle excitability and excitation-contraction coupling (ECC) [1,2].
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). 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 ß-subunit by the SCNA1B gene. Repolarization of the skeletal muscle membrane is mediated by fast inactivation of this sodium channel, as well as 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.
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. The DHPRs overlie corresponding groupings of the homotetrameric, sarcoplasmic reticulum Ca2+ release channels known as the Ryanodine Receptor, type I, (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 alpha-1s subunit to contact the apposed RyR1. This contact causes RyR1 to open, and release Ca2+, which stimulates the contractile apparatus and results in skeletal muscle shortening. Skeletal muscle relaxation normally occurs with the timely re-uptake of Ca2+ into the SR via the energy requiring Ca2+-ATPase found in the SR membrane.
Molecular diseases are theoretically possible with mutations in any of the channels described above, in any of their regulatory proteins, or in channels not yet described. As we will see with the myotonic dystrophies, channelopathies are possible without any mutations in the channel genes that underlie the disease state.
The Myotonias
The myotonias are generally classed into two large subgroups: the dystrophic and nondystrophic (dystrophic: defective nutrition[3]), and the descriptions cited below are taken from the following critical reviews[1,4,5].
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. As of 2007, over 80 mutations in the CLCN1 gene have been reported, though it is not clear as to 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. Both forms of myotonia tend to improve with exercise - the socalled ‘warm-up’ phenomenon.
In Thomsen’s disease, symptoms tend to present in early childhood, and while 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. 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 their age.
Becker’s disease, on the other hand, 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 transient episodes of proximal weakness.
Two other rarer forms of myotonia congenita are described with mutations 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 [6]. Indeed, it long has been known that depolarizing muscle relaxants induce prolonged contractures in human skeletal muscle [7]. 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 [8]. Another report of a nondystrophic myotonic family and an identified mutation in the SCN4A gene of the alpha subunit of the skeletal muscle sodium channel correlated the presence of masseter muscle rigidity and an IVCT positive for MH susceptibility [9]. 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. Two reports of fatal hyperthermia and acidosis during a general anesthetic in patients with myotonia have been found - one in a girl anesthetized with halothane/ether [10], and one in a boy with Thomsen’s disease pretreated with oral dantrolene and anesthetized with a non-triggering anesthetic (thiopental/dextroramide*/nitrous oxide) [11]. While these case reports are widely quoted, the assignment of MH susceptibility in this disease based on one case report of a triggering anesthetic and one in which a non-triggering 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, even though this has not been reported in the literature. Furthermore, one study in a goat model of myotonia congenita failed to induce MH with 1% halothane and a single injection of succinylcholine [12]. The rarity of these reports also lends itself to the theory that myotonic patients experiencing an MH crisis could easily have the misfortune of having two mutations – one for myotonia and one for MH susceptibility. This author concludes that it is highly unlikely that the any of chloride channel myotonias are susceptible to MH.
*
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.Sodium Channelopathies
Paramyotonia Congenita: This entity, eponymously known as Eulenberg’s disease, is the result of autosomally dominant transmitted mutations in the alpha-1 subunit (SCN4A) of the skeletal muscle sodium channel, Nav1.4, and has high penetrance. 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. Inter-episode 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 with myotonia, which is characterized less by coldinduced symptoms than by potassium ingestion or exercise. Similar to hyperkalemic periodic paralysis, weakness is more common in the early hours of the day and is often accompanied by elevated serum potassium levels.
Anesthetic Implications and Susceptibility to MH: There are no case reports of MH index cases with general anesthesia, and there is one in which an infant was anesthetized with sevoflurane without untoward incidents [13].
Potassium-aggravated myotonias: 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 minutes after a previous period of exercise. The variability of clinical myotonia is the result of episodic periods of myotonia lasting from 30 to 120 minutes and separated from each other by prolonged periods of normal muscle function. With this entity 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.
Anesthetic Implications and Susceptibility to MH: No reports of MH susceptibility found.
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 muscles in the face, limbs and respiratory muscles that often begin 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.
Anesthetic Implications and Susceptibility to MH: No reports of MH susceptibility found.
Acetazolamide-responsive myotonia: This is another autosomal dominant, sodium channelopathy that is characterized by generalized myotonia following 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 found.
Hyperkalemic Periodic Paralysis 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, and, in some individuals, 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 – 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, and the ingestion of glucose is therapeutic.
Anesthetic Implications and Susceptibility to MH: No reports of MH susceptibility found.
Our assessment is that none of the sodium channelopathies should be considered MH susceptible.
Dystrophic Myotonias
In contrast to the non-dystrophic 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 repeats[14]. In type 1 myotonic dystrophy (DM1), the more common entity, the expanded trinucleotide repeat, CTG, is expanded from 50-200 times in the 3’ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. In DM2, the less common form, there is a 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 DMPK 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 [15-20].
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, rather than its replacement by the adult form appropriate to post-natal 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.
Type 1 Myotonic Dystrophy (DM1): 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, and learning and speech disabilities, hypotonia, facial diplegia, and sometimes gastrointestinal problems. DM1 is associated with the phenomenon of 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.
Type 2 Myotonic Dystrophy (DM2): DM2, previously known as proximal myotonic dystrophy (PDM), or proximal myotonic myopathy (PROMM), 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 disease anticipation, there is no congential form yet identified, and the earliest age of onset is ~ 13 years. Symptoms specific to this entity is 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 4 positive results, 10 equivocal results and 30 negative results [21]. 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 postivie IVCT with halothane [22]. Undoubtedly, the IVCT cannot be used to diagnose MH susceptibility in a patient population with membrane channelopathies without worrying about false positives [23]. Succinylcholine will induce generalized skeletal muscle rigidity in these patients, raising the specter of MH susceptibility, but the latter is unlikely to occur in the absence of a second genetic change specifically causative for MH.
References
[1] Jurkat-Rott, K., Lerche, H., and Lehmann-Horn, F.: Skeletal muscle channelopathies. J.Neurol. 2002; 249(11):1493-1502.
[2] Cannon, S. C.: Physiologic principles underlying ion channelopathies. Neurotherapeutics. 2007; 4(2):174-183.
[3] Stedman's Medical Dictionary. 23rd. 1976. Baltimore, MD, Williams & Wilkins. Ref Type: Book, Whole
[4] Heatwole, C. R. and Moxley, R. T., III: The nondystrophic myotonias. Neurotherapeutics. 2007; 4(2):238-251.
[5] Ryan, A. M., Matthews, E., and Hanna, M. G.: Skeletal-muscle channelopathies: periodic paralysis and nondystrophic myotonias. Current Opinion in Neurology 2007; 20(5):558-563.
[6] Farbu, E., Softeland, E., and Bindoff, L. A.: Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Acta Anaesthesiologica Scandinavica 2003; 47(5):630-634.
[7] Orndahl, G.: Myotonic human musculature: stimulation with depolarizing agents. II. A clinico-pharmacological study. Acta Med.Scand. 1962; 172:753-65.:753-765.
[8] Heiman-Patterson, T., Martino, C., Rosenberg, H., Fletcher, J., and Tahmoush, A.: Malignant hyperthermia in myotonia congenita. Neurology. 1988;38(5):810-812.
[9] Vita, G. M., Olckers, A., Jedlicka, A. E., George, A. L., Heiman-Patterson, T., Rosenberg, H., Fletcher, J. E., and Levitt, R. C.: Masseter muscle rigidity associated with glycine1306-to- alanine mutation in the adult muscle sodium channel a-subunit gene. Anesthesiology 1995; 82:1097-1103.
[10] SAIDMAN, L. J., HAVARD, E. S., and EGER, E. I.: Hyperthermia during anesthesia. JAMA. 12-21-1964; 190:1029-32.:1029-1032.
[11] Haberer, J. P., Fabre, F., and Rose, E.: Malignant hyperthermia and myotonia congenita (Thomsen's disease). Anaesthesia. 1989; 44(2):166.
[12] Newberg, L. A., Lambert, E. H., and Gronert, G. A.: Failure to induce malignant hyperthermia in myotonic goats. British Journal of Anaesthesia 1983;55(1):57-60.
[13] Ay, B., Gercek, A., Dogan, V. I., Kiyan, G., and Gogus, Y. F.: Pyloromyotomy in a patient with paramyotonia congenita. Anesthesia and Analgesia 2004;98(1):68-9, table.
[14] Gatchel, J. R. and Zoghbi, H. Y.: Diseases of unstable repeat expansion: mechanisms and common principles. Nat.Rev.Genet. 2005; 6(10):743-755.
[15] Cho, D. H. and Tapscott, S. J.: Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim.Biophys.Acta. 2007; 1772(2):195-204.
[16] Day, J. W. and Ranum, L. P.: RNA pathogenesis of the myotonic dystrophies. Neuromuscul.Disord. 2005; 15(1):5-16.
[17] Schara, U. and Schoser, B. G.: Myotonic dystrophies type 1 and 2: a summary on current aspects. Semin.Pediatr.Neurol. 2006; 13(2):71-79.
[18] Machuca-Tzili, L., Brook, D., and Hilton-Jones, D.: Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve. 2005; 32(1):1-18.
[19] Kuyumcu-Martinez, N. M. and Cooper, T. A.: Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy. Prog.Mol.Subcell.Biol. 2006;44:133-59.:133-159.
[20] Cooper, T. A.: A reversal of misfortune for myotonic dystrophy? N.Engl.J.Med. 10-26-2006; 355(17):1825-1827.
[21] Lehmann-Horn, F. and Iaizzo, P. A.: Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? British Journal of Anaesthesia 1990; 65(5):692-697.
[22] Schneider, C., Pedrosa, Gil F., Schneider, M., Anetseder, M., Kress, W., and Muller, C. R.: Intolerance to neuroleptics and susceptibility for malignant hyperthermia in a patient with proximal myotonic myopathy (PROMM) and schizophrenia. Neuromuscul.Disord. 2002; 12(1):31-35.
[23] Iaizzo, P. A. and Lehmann-Horn, F.: Anesthetic complications in muscle disorders. Anesthesiology 1995; 82:1093-1096.
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Heat & Exercise-Related Rhabdomyolysis
John Capacchione, MD
Heat- and/or exercise-induced rhabdomyolysis (HER) is a problem that plagues military recruits in basic training, physically-fit well-conditioned career military service members, and the physicians called upon to treat them. Similarly, HER occurs not infrequently among well-trained, seasoned athletes. It is clear that under extreme physical and environmental conditions anyone may develop rhabdomyolysis. What are less clear is who is predisposed, who will develop sequelae and who will have recurrence. It is not surprising when rhabdomyolysis occurs in poorly conditioned, un-acclimated individuals asked to perform extreme physical activity in extreme heat. What are more vexing are the sudden and unexplained cases of rhabdomyolysis in the physically-fit, well-conditioned and acclimated who have been exercising all their lives without previous problems. At the Uniformed Services University of the Health Sciences (USUHS), neurologists, sports medicine specialists, geneticists, and anesthesiologists have collaborated to address this problem in a variety of clinical and laboratory protocols.
The associations between unexplained exercise-induced rhabdomyolysis, asymptomatic hyperCKemia and Malignant Hyperthermia (MH) are strongly suggested by the literature.1-3 Wappler et al performed the in vitro contracture test (IVCT), the only validated European diagnostic test for MH susceptibility, on muscle biopsies from 12 unrelated patients with exercise-induced rhabdomyolysis and no prior personal or family histories of MH. Ten of these 12 had positive contracture tests, and 3 of those 10 were found to have mutations in the ryanodine type 1 receptor gene (RYR1),2 the gene most likely associated with MH susceptibility.4 For many years, the protocol for evaluation of rhabdomyolysis at the Walter Reed Army Medical Center has included consultations with neurologists or rheumatologists with muscle biopsy for standard histology and histochemistry. However, the results of these biopsies were frequently normal or showed non-specific changes. These results were a stimulus for a new protocol to investigate the link between MH and rhabdomyolysis in a more systematic manner. Since 2006, nine healthy, physically-fit career service members without family or personal histories of MH symptoms developed repeated unexplained episodes of exercise-induced rhabdomyolysis and were referred to USUHS for the Caffeine Halothane Contracture Test (CHCT), the North American equivalent to the IVCT. Five were CHCT positive by North American MH standards. Thus far, RYR1 gene variants have been found in two of those five. Molecular genetic screening of the entire RYR1 gene for mutations causative for MH and screening of genes for the metabolic myopathies commonly associated with rhabdomyolysis, namely carnitine palmitoyltransferase deficiency, adenosine monophosphate deaminase deficiency, and muscle glycogen phosphorylase deficiency, are on-going.
The CHCT was developed and validated as a diagnostic test for MH following a clinical event suspicious for MH. In that development process the sensitivity was 97%, but the specificity was only 78%,5 indicating a 22% false positive rate. Since clinical correlation of MH was used to validate the CHCT, it is difficult to know if patients with HER and positive CHCT are truly MH susceptible or false positives. While there may be a commonality of a ryanodine receptor mechanism for both disease processes since some people with prior clinical episodes of MH are at increased risk of developing heat and exercise-related problems in their futures,6 it is also important to make the distinction that the vast majority of heat stroke and exertional rhabdomyolysis cases are not related to MH susceptibility.
While mutations in the RYR1 gene are the most likely causative mutations associated with MH susceptibility, there are a multitude of other candidate genes that are being explored with regard to HER. In previous studies, RYR1 mutations were found in only 22-25% of people who were CHCT positive7,8 when screening for the North American panel of the most common mutations.9 The current strategy, based on results from Japan and several European centers, recommends screening the entire RYR1 gene, the approach now employed at USUHS. Experts have agreed that complete RYR1 gene sequencing is required for all CHCT positive patients, a complex task given the gene’s size at more than 159,000 nucleotides.
Although the incidence of MH is rare, estimated at 1 in 50,000 adults undergoing general anesthesia,10 two recent epidemiologic studies estimate the incidence of RYR1 variants at 1 in 2000 in the general population.11,12 The fact that MH susceptible people do not develop detectable signs and symptoms each and every time they are exposed to anesthetic triggering agents may be due to MH being a subclinical myopathy that is not manifest more often because of “variable expression.” This raises the possibility that unknown MH susceptible people are developing other signs and symptoms, namely those manifested as HER. Since the defect in MH occurs at the level of skeletal muscle calcium regulation,13 compensatory homeostatic mechanisms occurring at the cellular level likely prevent detection by insensitive clinical monitors measuring global physiologic responses. Detection by standard anesthesia monitors likely occurs only after cellular decompensation takes place. Because of the possible link between HER and MH, it may be prudent to administer non-MH-triggering agents to patients with histories of HER.
Other environmental factors have been implicated as precipitators of HER, to include the ingestion of dietary supplements such as creatine monophosphate, ephedrine-based products, and anabolic steroids.14-16 Still, people develop HER when denying use of these products. Regardless of HER etiology or precipitators, the question remains, are people with histories of HER and positive CHCT truly MH susceptible? All previous reports drawing an association between HER and MH have relied on IVCT, CHCT or RYR1 mutations for diagnoses, but not upon actual clinical MH event. However, we now have an unpublished case of an individual who developed exercise-induced rhabdomyolysis requiring bilateral lower extremity fasciotomies. During a second surgical procedure under inhalational anesthesia, the patient developed MH-like symptoms requiring dantrolene treatment. Subsequent CHCT was positive, and genetic analysis revealed an RYR1 variant. This is the first documented case showing a direct link between an episode of HER followed by a clinical episode of MH while undergoing treatment for HER, with subsequent confirmatory positive CHCT and RYR1 variant.
Classifying HER individuals as MH susceptible can have huge personal and professional ramifications. Military physicians are faced with the problem of what to do with service members who develop recurrent HER, positive CHCT, or clinical MH events. Service members are required to be world-wide deployable and combat ready. This means being stressed with extreme physical labor in desert climates such as Iraq. Department of Defense regulation 6130.4 states that MH is a disqualifying condition for appointment or enlistment into the armed services. However, retention of service members identified as MH susceptible is often left to the discretion of the individual service branches. There are multiple justifications for military discharge, to include nonavailability of dantrolene in forward deployed units, insufficient resources to treat an MH crisis during a mass casualty, and the unpredictability of environmental exposures triggering an MH crisis. Service members may also be discharged at the discretion of the individual branches for rhabdomyolysis, myoglobinuria, or heat stroke regardless of any connection to MH or CHCT results. These decisions are based or the severity of the illness and the impact on the performance of duties.
Presently, discharged service members with diagnoses of MH susceptibility receive no medical disability compensation because the military considers it an inherited preexisting medical condition prior to enlistment and not a military service-related injury. However, the Department of Veterans’ Affairs has been known to award disability benefits, but the service members had to apply for them. Furthermore, the respective service branches do not apply the rules equally; some service members are retained while others are discharged.
References:
1. Poels PJE, Joosten EMG, Sengers RCA, Stadhouders AM, Veerkamp JH, Benders AAGM: In vitro contraction test for malignant hyperthermia in patients with unexplained recurrent rhabdomyolysis. J Neurol Sci 1991; 105:67-72
2. Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte am Esch J: Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001;94:95-100
3. Weglinski MR, Wedel DJ, Engel AG: Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg 1997;84:1038-41
4. MacLennan DH, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk RG, Frodis W, Britt A, Worton RG: Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 1990;343:559-61
5. Allen GC, Larach MG, Kunselman AR: The sensitivity and specificity of the caffeinehalothane contracture test: a report from the North American malignant hyperthermia registry. Anesthesiology 1998; 88:579-88
6. Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N: Malignant hyperthermia and apparent heat stroke. JAMA 2001;286:168-9
7. Brandt A, Schleithoff L, Jurkat-Rott K, Klinger W, Baur C, Lehmann-Horn F: Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: Novel mutations and concordance with the in vitro contracture test. Hum Mol Genet 1999;8:2055-62
8. Sambuughin N, Sei Y, Gallagher KL, Wyre HW, Madsen D, Nelson TE, Fletcher JE, Rosenberg H, Muldoon SM: North American malignant hyperthermia population: Screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology 2001; 95:594-9
9. Sei Y, Sambuughin N, Muldoon S: Malignant hyperthermia genetic testing in North America working group meeting. Anesthesiology 2004; 100:464-5
10. Britt BA, Kalow W: Malignant hyperthermia. A statistical review. Can Anaesth J 1970; 17:293-315
11. Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J: Presence of two different genetic traits in malignant hyperthermia families. Anesthesiology 2002; 97:1067-74
12. Ibarra CA, Wu S, Murayama K, Minami N, Ichihara Y, Kikuchi H, Noguchi S, Hayashi Y, Ochiai R, Nishino I: Malignant hyperthermia in Japan. Anesthesiology 2006;104:1146-54
13. Nelson TE. Malignant hyperthermia: a pharmacogenetic disease of Ca++ regulating proteins. Curr Mol Med 2002; 2:347-69
14. Sheth NP, Sennett B, Berns JS: Rhabdomyolysis and acute renal failure following arthroscopic knee surgery in a college football player taking creatine supplements. Clin Nephrol 2006; 65:134-7
15. De Cock KJS, Delbeke FT, Van Eenoo P, Desmet N, Roels K, De Backer P: Detection and determination of anabolic steroids in nutritional supplements. J Pharm Biomed Anal 2001; 25:843-52
16. Stahl CE, Borlongan CV, Szerlip H, Szerlip M: No pain, no gain – exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra. Med Sci Monit 2006; 12:CS81-4
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Review of MH association with OI, Arthrogryposis, McArdles, CPT-2, Noonan syndrome, and myoadenylate deficiency
Joan Benca MD
Kirk Hogan MD
1.Osteogenesis Imperfecta
Case reports of MH: one
Rampton AJ, Kelly DA, Shanahan EC, Ingram GS. Occurrence of malignant hyperthermia in a patient with osteogenesis imperfecta. Br J Anaesth 1984;56:1443-6.
Report quality: convincing, but no IVCT done (patient refused)
Reports of positive IVCT in OI: one, but no case report of anesthetic misadventure Rosenberg H. Clinical presentation of malignant hyperthermia. Br J Anaesth 1988;60:268-73.
Relevant literature:
Porsborg P, Astrup G, Bendixen D et al. Osteogenesis imperfecta and malignant hyperthermia. Is there a relationship? Anaesthesia 1996; 51(9):863-5.
A hyperthermic, hypermetabolic reaction to anesthesia in OI patients has been reported by multiple sources… “and they seem to have a uniform pattern with high temperature and metabolic and respiratory acidosis. In contrast to fulminant malignant hyperthermia the increase in metabolism seems to be self-limiting and generalized rigidity is not seen.”
Ryan CA, Al-Ghamdi AS, Gayle M and Finer NN. Osteogenesis imperfecta and hyperthermia. Anesthesia and Analgesia 1989; 68: 811-4.
Masuda Y, Harada Y, Honma E, Ichimya T Namiki A. Anesthetic management of a patient with osteogenesis imperfecta congenital. Masui 1990; 39: 383-7.
Sadat-Ali M, Sankaran-Kutty M, Adu-Gymafi Y. Metabolic acidosis in osteogenesis imperfecta. European Journal of Pediatrics 1986; 145: 582-3.
Karabiyik L, Capan Z. Osteogenesis imperfecta:different anaesthetic approaches to two paediatric cases(Letter). Paeditr Anaesth 2004;14:524-5.
Clemens K, Leonhardt A and Hinnerk W. Lactic acidosis after short-term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta. Pediatr Anaesth 2003;13:823-826.
Conclusion:
No obvious association between osteogenesis imperfecta and malignant hyperthermia. The case reports of hypermetabolic state during anesthesia in this group of patients are concerning, but in all cases resolved with active cooling measures and symptomatic treatment. I would not criticize anyone for administering dantrolene to those patients in that setting, but in the absence of convincing case reports and muscle biopsy data, I would not make the association. I would avoid succinylcholine. The last letter discusses use of TIVA in 2 cases, with no hypermetabolism, but that isn’t anything that would make me change my practice.
2. Noonan syndrome (Many texts discuss this as being the same as King syndrome, I do not agree. It is a different syndrome)
Case reports: one
Lee CK, Chang BS, Hong YM, et al. Spinal deformities in Noonan syndrome: a clinical review of sixty cases. J Bone Joint Surg 2001;83-A:1495-1502.
“Surgery was postponed in another patient (case 18) because malignant hyperthermia developed during the induction of anesthesia. The preoperative serum creatinine phosphokinase level in this patient was 224 U/L (normal range, 20 to 270 U/L). During induction of anesthesia, the patient was noted to have generalized muscle rigidity and a rapidly rising body temperature to 40 degrees Centigrade with a severe metabolic acidosis (pH 7.18).” No further information on anesthetic technique, hospital course or laboratory data. No report of IVCT.
Quality: concerning, but questionable
IVCT data: none
Other relevant literature:
Mendez HM, Opitz JM. Noonan syndrome: a review. Am J Med Genet 1985; 21:493-506.
I’m waiting for a copy of this article, but other authors have stated that the patients also had myopathies and were more likely King syndrome, not Noonan syndrome.
Conclusion: MH association unclear. I would avoid succinylcholine.
3. Arthrogryposis
AMC is a clinical diagnosis consisting of multiple joint contractures and can result from primary neurogenic or myopathic processes or oligohydramnios causing decreased fetal movement.
Case report: one with 2 cases of club foot repair The anesthetic technique is not described Froster-Iskenius UG, Weterson JR, Hall JG. A recessive form of congenital contractures and torticollis associated with malignant hyperthermia. J Med Genet 1988;25:102-112.
I’m waiting for a full-text version of this article, so I can’t comment further on the quality of the evidence.
Positive IVCT report: none
Relevant literature:
Martin S and Tobias J D. Perioperative care of the child with arthrogryposis. 2005;16:31-37.
Arthrogryposis patients may become hyperthermic, but it is distinct from MH.
Hopkins PM, Ellis FR, Halsall PJ. Hypermetabolism in arthrogryposis multiplex congenital. Anaesthesia. 1991;46(5):374-5.
Hypermetabolic reaction to anesthesia is not MH.
Baines DB, Douglas ID, Overton JH. Anaesthesia for patients with arthrogryposis multiplex congenital: what is the risk of malignant hyperthermia? Anaesth Intensive Care. 1986;14(4):370-372.
A review of the 32 year experience at Royal Alexandra Hospital for Children was negative for MH.
Conclusion: Not MH associated, but I would avoid succinylcholine.
4. Myoadenylate Deaminase Deficiency
Some people would not even describe this as a “stand-alone” disease because it is the most common enzyme deficiency disease of muscle. There is no clear association with MH, and a few families are described in the literature, that clearly have a separate pattern of inheritance of MAD deficiency and MH.
Case reports: none with isolated MAD deficiency.
IVCT: none with isolated MAD deficiency.
Relevant literature:
Brownell AKW: Malignant hyperthermia: Relationship to other diseases. Br J Anaesth 1988;57:1113.
Fricker R, Raffelsberger T, Rauch-Shorny S et al. Positive Malignant hyperthermia susceptibility in vitro test in a patient with mitochondrial myopathy and myoadenylate deaminase deficiency. Anesthesiology. 2002;97(6):1635-1637.
Fishbein WN, Muldoon SM, Deuster PA, Armbrustmacher VW. Myoadenylate deficiency and malignant hyperthermia susceptibility: is there a relationship? Biochem Med. 1985;34(3):344-54.
Conclusion: Probably not MH associated. I would avoid succinylcholine.
5. CPT-2 Deficiency
Case reports of MH: one case diagnosed by clinical course, one case of elevated CPK, rhabdomyolysis and acute renal failure
Sugiyama N, Sugiura A, Wada Y, Kobayashi M, Ando T, Suzuki S, Nonaka I: Metabolic myopathy complicated by malignant hyperthermia—A case report of carnitine palmitoyltransferase deficiency. J Jpn pediatr Soc 86:342-349, 1982.
IVCT: none
Relevant literature:
Katsuya H, Misumi M, Ohtani Y, et al. Postanesthetic acute renal failure due to carnitine palmitoyl transferase deficiency. Anesthesiology 68:945, 1988.
Vladutiu GD, Hogan K, Saponara I, Tassini L, Conroy J. Carnitine palmitoyl transferase deficiency in malignant hyperthermia. Muscle Nerve. 1993;16(5):485-91.
El-Hayek R, Valdivia C, Valdivia HH, et al. Activation of the CA2+ Release Channel of Skeletal Muscle Sarcoplasmic Reticulum by Palmitoyl Carnitine. Biophysical Journal. 1993;65:779-789.
DiPaola J, Schwartz PH, Anas N., et al. Obesity, diabetic ketoacidosis, malignant hyperthermia and rhabdomyolysis: A new phenotype of carnitine palmitoyl transferase type II deficiency? Am J of Human Genetics. 1999;65(4):1302.
Zierz S, Schmitt U. Inhibition of carnitine palmitoyltransferase by malonyl-CoA in human muscle is influenced by anesthesia(Letter). Anesthesiology. 1989;68:945-948.
Schaer H, Steinmann B, Jerusalem S, et al. Rhabdomyolysis induced by anaesthesia with intraoperative cardiac arrest. Br J of Anaesth. 1977;49:495-499.
Conclusion: Because a feature of this disease is rhabdomyolysis, I would avoid trigger agents.
6. McArdle’s
Case reports: one
Isaacs H, Badenhorst ME, Du Sautoy C: Myophosphorylase B deficiency and malignant hyperthermia. Muscle Nerve 1989;12:203-205.
IVCT: five
Relevant literature:
Lobato EB, Janelle GM, Urdaneta F and Malias MA. Noncardiogenic Pulmonary Edema and Rhabdomyolysis after Protamine Administration in a Patient with Unrecognized McArdle’s Disease. Anesthesiology.1999;91:303-5.
Bollig G, Mohr S, and Reder J. McArdle’s disease and anaesthesia: Case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand. 2005;49:1077-83.
Poels PJE, Braakhekke JP, Joosten EMG, et al. Dantrolene sodium does influence the 2nd wind phenomenon in McArdles disease. J of the Neurological Sciences.1990;100(1-2):108-112.
Aquaron R, Berge-Lefranc JL, Pellissier JF, et al. Molecular characterization of myophosphorylase deficiency (McArdle disease) in 34 patients from Southern France: Identification of 10 new mutations. Absence of genotype-phenotype correlation. Neuromuscular Disorders. 2007;17:235-41.
Conclusion: No trigger drugs.
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Society for Pediatric Anesthesia
Anesthesia for the Hypotonic Infant presenting for Muscle Biopsy
Barbara W. Brandom, M.D.
Professor of Anesthesiology, Children’s Hospital of Pittsburgh
One of the challenges of providing anesthesia for pediatric patients is that the patient may have an occult disease which has not yet produced sufficient physiologic impairment to have been diagnosed. How can the anesthesia provider guess when such a situation exists and predict which of the many stresses inherent in the delivery of anesthesia will be the least damaging to the infant? Certainly there have been wonderful advances in biologic science that allow some of us to understand intricacies of human physiology and adverse drug effects which were not imaginable 20 years ago . But such understanding is not easy to apply to the daily practice of pediatric anesthesia.
What are the goals of the anesthetic? What are the potential complications that the anesthetic should be designed to avoid? Critical incidents are much more common in infants than in older children during anesthesia.1 Airway management is of the utmost importance in normal infants.2,3 Active airway reflexes in young infants are most easily managed with endotracheal intubation unless surgery is very short in duration, the head of the patient is next to the anesthetist and the airway management skills of the anesthetist are excellent due to frequent practice with infants. Therefore, in planning anesthesia for a simple muscle biopsy, full preparations for mask ventilation, endotracheal intubation and use of laryngeal mask ventilation4 should be made. Cardiovascular stability is a desirable anesthetic goal. Hypotension is a frequent finding in pediatric anesthetics, but usually is readily reversible when the cardiac rhythm remains relatively normal. An intravenous catheter should be placed to provide a means of delivering fluid and vasoactive drugs as well as titratable intravenous anesthetics5 and adjuvants.6,7 Minimal response to painful stimuli intra-operatively and postoperative behavior demonstrating the presence of analgesia are goals of anesthesia. Rapid awakening and return to normal feeding habits are highly valued elements of the ideal pediatric anesthetic.
Regional anesthesia, such as spinal anesthesia,8 may meet all the anesthetic goals. But optimal application of regional techniques requires teamwork and frequent practice. Both caudal epidural analgesia and femoral nerve blocks have been applied successfully for muscle biopsy in hypotonic infants.9,10,11,12
Whatever specialized needs may be associated with the underlying cause of hypotonia the patient should be anesthetized with as little stress as possible. Comprehensive pre-operative evaluation should be conducted to assess neurologic status including general muscle tone and pharyngeal reflexes, cardiovascular status and hepatic dimensions. If physical findings or chest x ray suggest the presence of cardiomyopathy, the electrocardiogram and echocardiography should be evaluated. Pre-operative nasal continuous positive airway pressure, diuretics and intravenous drugs to improve cardiac contractility and reduce afterload may be adviseable.9 If specialized nutritional needs have been identified preoperatively these nutrients should be supplied on the day of surgery also. If there is a genetic test that can confirm a highly suspected diagnosis, such as spinal muscular atrophy, genetic testing should be considered because open muscle biopsy may not be necessary.13
I have given mask inhalation anesthesia with nitrous oxide, oxygen and halothane to infants presenting for muscle biopsy. An intravenous catheter was placed after induction. Local anesthetic was placed after surgery. Rectal acetaminophen was administered as guided by age and weight.14 If I performed an anesthetic for this procedure next week, for an infant who is NOT in heart failure, I would give 50% nitrous oxide15 only until loss of lash reflex, followed by sevoflurane in oxygen and nitrogen while starting an intravenous catheter. Then if reassessment of ventilation and gastric distention suggests that endotracheal intubation will be useful I would give 0.1 mg atropine (This is particularly useful if there is any doubt about the function of the intravenous catheter, because administration of atropine usually is followed within one minute by an increase in heart rate.), 0.1 mg/kg of cisatracurium, 1 to 3 mcg/kg of fentanyl and intubate the trachea. Administration of this neuromuscular blocker allows placement of the endotracheal tube with minimal movement and oxygen desaturation, in my experience, with lower doses of inhalation agent.16 After securing airway and intravenous access, regional anesthesia can be applied. In a small infant I would probably not apply regional anesthesia unless a large amount of muscle were to be excised or the Pediatric Anesthesia Pain Service were immediately available to perform an expeditious femoral nerve block.12 I choose to minimize intravenous drug administration because recovery from propofol17 may be prolonged in young infants. Similarly the duration of action of ketamine may be prolonged and the effects of alpha 2 agonists uncertain. But others have administered ketamine for muscle biopsy in floppy infants.18
No process in medicine or anesthesia is guaranteed. Vigilance is a good motto, especially for the practice of pediatric anesthesia. But it is noteworthy that airway complications, such as laryngospasm, are common complications especially in the recovery room.19 Is there any evidence to support my choice of anesthetic? Case series suggest that in pediatric patients inhalation anesthetics can be used safely for surgical muscle biopsies, especially when the underlying diagnosis is known.20,21,22 There is one study suggesting that creatine kinase increases are less following diagnostic muscle biopsies in children if ketamine or local