Rhabdomyolysis is a relatively common condition characterized by the breakdown of skeletal muscle and the leakage of cellular constituents into the intra- and extravascular spaces after injury. A variety of factors including some prescription medications and drugs of abuse may precipitate skeletal muscle injury. Rhabdomyolysis is responsible for up to 7% of all cases of acute renal failure.1 Exertional rhabdomyolysis (ER) occurs in response to exercise when mechanical or metabolic stress damages skeletal muscle.2 Under extreme physical and environmental conditions, anyone can develop ER.1 However, some individuals appear more susceptible, suggesting an underlying metabolic myopathy or genetic abnormality.2 Malignant hyperthermia (MH) is a potentially lethal, inherited, subclinical myopathy identified by an unexpected hypermetabolic reaction during and after exposure to particular anesthetic-related medications. One clinical feature of MH is rhabdomyolysis. Both ER and MH are characterized by an uncontrolled increase in intracellular skeletal muscle calcium, leading to oxidative, chemical, and mechanical stress with irreversible muscle breakdown.1 Mutations in the protein structure of the ryanodine receptor type I (RyR1) fast release calcium channel of skeletal muscle sarcoplasmic reticulum have been identified as the defect most strongly associated with MH susceptibility (MHS).3 Thus, RyR1 gene (RYR1) analysis has become an invaluable diagnostic test for individuals and families with suspected MHS.
The association between MH and nonanesthesia-related ER has been a topic of debate for many years. Despite growing literature to suggest otherwise,4–11 the concept of awake MH manifestations has been controversial and slow to gain acceptance among clinicians and scientists with MH expertise.12 The traditional definition of MH as a pharmacogenetic disorder of skeletal muscle calcium regulation triggered by potent volatile anesthetics and/or succinylcholine13 may describe only a portion of the clinical presentations caused by this myopathy. More accurately, MH is a subclinical metabolic myopathy that may lead to a hypermetabolic crisis on exposure to potent volatile anesthetics and/or succinylcholine,14 and in some individuals on exposure to heat and exercise.4–11,15–21
Whereas unrecognized anesthetic-induced MH events that go untreated with IV dantrolene may result in >70% mortality,22 the full extent of the awake manifestations of the syndrome are not well appreciated. RYR1 changes typical of MH may be expressed as ER, and lack of recognition of this connection may lead to patient morbidity and delay in appropriate treatment. As experts in the treatment and understanding of MH, anesthesiologists will be called on to educate and advise other caregivers in the recognition and treatment of associated myopathies having clinical manifestations similar to those of MH. In this case report, we describe the association between a RYR1 MH-causative mutation and recurrent rhabdomyolysis with and without exercise in identical male twins. Furthermore, their history demonstrates that nonanesthesiologists also require education concerning the relationship between MHS and rhabdomyolysis.
All patients described in this case report gave their consent for publication.
A 30-year-old African American man presented to the Emergency Department (ED) with a complaint of chest pain after working outside on a hot summer day. The medical evaluation was significant only for a creatine kinase (CK) of 3900 U/L (normal <200 U/L). Rhabdomyolysis was diagnosed, and the patient was treated with IV hydration and discharged home. His CK levels remained increased (>2000 U/L) for 2 months before gradually decreasing to the 1000 U/L range. After this episode, the patient developed persistent exercise intolerance, reporting severe muscle cramps with only moderate exertion. His symptoms progressed to include jaw and face cramps at rest and a complete inability to exercise. Of note, he had undergone 2 uncomplicated surgical procedures with general anesthesia as a child, and he denied a personal or family history of MH. The patient was referred for evaluation of myopathic disorders, including MH, under an IRB-approved protocol.
The patient underwent a complete physical examination, including electromyography, nerve conduction studies, serial CKs, plasma and urine myoglobin, urinalysis, standard chemistries, lipid panel, thyroid panel, metanephrines panel, erythrocyte sedimentation rate, antinuclear antibodies, rheumatoid factor, rapid plasma reagin, and testing for human immunodeficiency virus. An Exercise Intolerance Mutation Profile was performed to screen for the most common genetic causes of metabolic myopathies (carnitine palmitoyltransferase 2 deficiency, CPT2: S113L, 413delAG, P50H, R503C, G549D, R631C; myoadenylate deaminase deficiency, AMPD1: Q12X, P48L; myophosphorylase deficiency, PYGM: R49X, G204S). All tests were within normal limits.
The patient was referred to a MH diagnostic center for a muscle biopsy. The histology/histochemistry findings were nonspecific, and a myoglobinuria panel was negative. The caffeine halothane contracture test (CHCT) was positive for MH, with muscle contracture increases from baseline twitch tension in 3 separate muscle strips of 6.1, 2.4, and 3.8 g, respectively, to 3% halothane (positive ≥0.7 g). Another 3 separate muscle strips had contracture increases from baseline twitch tension of 0.4, 0.9, and 0.5 g, respectively, to 2 mM caffeine (positive ≥0.3 g). Targeted gene sequencing of CACNA1S and RYR1 (the 2 genes most strongly associated with MH) was performed. The CACNA1S evaluation was negative, but the RYR1 was positive for an Arg2454Cys mutation, a mutation reported as functionally causative for MH.23
Two months after completion of the genetic analysis, the same MH testing center was contacted by a surgeon who was planning an elective surgery on the patient’s identical twin brother, which we denote as twin B. Preoperative genetic analysis identified the same Arg2454Cys RYR1 mutation in twin B. Furthermore, twin B also reported a history of 2 episodes of unexplained ER with CKs >18,000 U/L. He also gave a history of 2 episodes of “cardiac arrest” in association with anesthesia as a child while undergoing bilateral ptosis surgery, although no anesthetic records were available for review. He and his family were never told that these episodes might be MH related. Genetic analysis of the parents revealed the same RYR1 mutation in the mother, who also reported a history of muscle cramping. After genetic testing, oral dantrolene (100 mg 3 times per day) was prescribed for each brother for treatment of their debilitating muscle cramping and fatigue. However, while their complaints of muscle cramping, pain, and fatigue were decreased while receiving this dantrolene regimen, neither brother was able to tolerate even moderate exercise.
Both brothers moved to another state and were treated by a primary care provider who discontinued their oral dantrolene due to his unfamiliarity with their disorder and the treatment regimen. Shortly after stopping their dantrolene therapy, the brothers developed recurrent rhabdomyolysis associated with simple routine physical activity. Twin B reported to an ED with a complaint of incapacitating spontaneous muscle pain without exercise. His CK was measured at 2500 U/L, and he received IV hydration and was sent home. When his symptoms continued, he returned to the ED the next day, where his CK was measured at 5000 U/L. He was admitted for IV hydration and given an oral nonsteroidal anti-inflammatory medication and opioids for pain. His pain continued, and by hospital day 2, his CK had increased to 10,000 U/L. He informed the hospitalist in charge of his care that he was MHS and had a RYR1 mutation. The hospitalist was unfamiliar with this condition, and a MH testing center director and Malignant Hyperthermia Association of the United States (MHAUS) hotline consultant were independently contacted for advice.
Both the MH testing center director and MHAUS hotline consultant gave the same advice: admit the patient to the intensive care unit (ICU), monitor hemodynamics, administer IV dantrolene 2.5 mg/kg, and check arterial blood gases and CK every 6 hours. The hospitalist was instructed to retreat with IV dantrolene 1 mg/kg if the CK did not decrease after 6 hours, and to consult the hospital’s anesthesiologists and pharmacy for assistance with the dantrolene preparation. Neither the anesthesiologist nor pharmacist was familiar with rhabdomyolysis occurring in an awake MHS patient with RYR1 mutations. Because he was uncomfortable providing treatment, the hospitalist transferred the patient to a larger city hospital with an ICU for higher acuity patients. He did not contact or inform the MH testing center director or hotline consultant of this transfer, nor did the physician at the receiving hospital contact them for advice. After 2 days at the city hospital, the new hospitalist sought advice from the MH testing center director and received the same advice regarding dantrolene therapy. However, this advice was never followed, and the patient was discharged home still in pain with a CK of 3800 U/L after a total of 5 hospital days wherein he received only IV hydration and opioid therapy.
Two weeks later, twin B presented to the hospital ED again, stating that his muscle pain never resolved after the last hospital admission. His CK was 3500 U/L. A new hospitalist contacted the MH testing center director and followed the recommended advice of ICU admission with dantrolene therapy (2.5 mg/kg IV). After 1 dosage of dantrolene and 1 day in the ICU, his CK decreased to 900 U/L. His pain level decreased, and he was discharged home with some residual weakness.
Based on a positive CHCT24 and the presence of a MH-causative RYR1 mutation,3 twin A was diagnosed as MHS. The patient’s mother and twin B were likewise diagnosed as MHS based on the presence of the same mutation. Among the >400 RYR1 variants associated with MH,25 Arg2454Cys is one of only 31 functionally characterized MH-causative gene mutations.23 In this case report, 3 people have been diagnosed as being as MHS, but none is reported to have experienced anesthesia-related MH episodes, including the index case. Although twin B did give a history of cardiac complications in association with general anesthesia as a child, old hospital records were not available for review, and he was never diagnosed with or treated for MH. Furthermore, none of his family members reported a similar history when questioned independently.
Despite advances in molecular genetics, the CHCT remains the only validated diagnostic test for MH and has several limitations. The CHCT was validated by comparing muscle biopsy tissue from patients with documented histories of anesthesia-related MH to muscle biopsy tissue from patients without such a history.24 Since the MH syndrome is characterized by variable expression and penetrance, it is difficult to know how many subjects in the control population were really MHS. With a specificity of 78%, the CHCT erroneously diagnoses 22% of the population as MHS.26 However, more problematic is using the CHCT to diagnose people as MHS who present with ER, given that the CHCT was not developed or validated to evaluate patients with ER.
It is important to note that the CHCT was never validated regarding various ethnic groups. Most patients involved in the validation process were Caucasian. The African American population has baseline CK levels higher than those of Caucasians,27 and these 2 populations have separate and distinct variations in RYR1.9 Given the differences in baseline CK measurements and RYR1 expression between the African American and Caucasian populations, CHCT results should be interpreted with caution. The African American patient evaluated in this case was diagnosed as MHS based on CHCT thresholds validated in a Caucasian population. However, based on the patient’s strong CHCT contractures and Arg2454Cys RYR1 mutation, MHS is a logical diagnosis. The danger with using this methodology potentially arises when a MHS diagnosis is made for an ER patient whose muscle contractures barely reach the positive CHCT criteria, and in whom no MH-causative gene mutation is identified.
Regardless of the impact of ethnicity on RYR1 expression and CHCT thresholds, or the validity of using the CHCT to diagnose patients with ER, it remains undeniable that these twin brothers have a MH-related RYR1 myopathy that responds favorably to oral dantrolene. This is not the typical MH presentation with which most anesthesiologists are familiar, nor is the administration of oral dantrolene a well-recognized therapy for the management of muscle pain in patients who are MHS. Conversely, most ED physicians, hospitalists, and intensivists do not associate ER with MH. Thus, consideration of RYR1 myopathies in the differential diagnosis of ER may be easily overlooked. Although the incidence of fulminant MH during anesthesia is relatively rare, with estimates between 1 in 4200 and 250,000,28 2 independent studies estimate the incidence of RYR1 mutations in the general population at 1 in 2000.29,30 This implies that there is a cohort of MHS patients that does not develop MH during general anesthesia. Furthermore, exome sequencing performed on 870 volunteers without medical or family histories for MHS identified 3 with RYR1 variants predicted to predispose to MH.31
Despite the growing clinical evidence describing nonanesthesia-associated MH-related RYR1 myopathies,4–11,15–21 the lack of human laboratory studies linking MH, ER, and heat stroke has led some investigators to argue against a relationship.12 However, heat and/or exercise stress triggers nonanesthesia-related MH-like reactions in genetically engineered mice that express RYR1 causal mutations,32,33 and in some strains of swine with RYR1 mutations.34 Furthermore, a recent study in humans suggests that RYR1 mutations may account for more than one-third of all unexplained cases of rhabdomyolysis.11 While no randomized controlled human trials have been conducted to prove that MH, ER, and heat stroke are caused by the same RYR1 mutations, it is unlikely that such a study will ever occur. The incidence of MH or RYR1-related ER and heat stroke will require collaboration among epidemiologists and clinicians expert in sports medicine, neurology, and anesthesiology. Case reports such as this one will hopefully stimulate others to look more deeply into the underlying causes of ER and heat stroke.
Perhaps the most important feature of this case report is the suggestion of a new mission for anesthesiologists to extend their expertise beyond the operating room and share it with primary care providers and ED physicians treating patients with RYR1 myopathies. Likewise, the physicians and scientists associated with MHAUS must broaden their mission and disseminate information to all clinicians regardless of specialty.
1. O’Connor F, Deuster P.Drazen J Rhabdomyolysis, Cecil Medicine, 23rd ed. In:. 2008 Philadelphia, PA Saunders Elsevier:798–802
2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002;25:332–47
3. MacLennan DH, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk RG, Frodis W, Britt BA, Worton RG. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature. 1990;343:559–61
4. Poels PJ, Joosten EM, Sengers RC, Stadhouders AM, Veerkamp JH, Benders AA. In vitro
contraction test for malignant hyperthermia in patients with unexplained recurrent rhabdomyolysis. J Neurol Sci. 1991;105:67–72
5. Hackl W, Winkler M, Mauritz W, Sporn P, Steinbereithner K. Muscle biopsy for diagnosis of malignant hyperthermia susceptibility in two patients with severe exercise-induced myolysis. Br J Anesth. 1991;66:138–40
6. Köchling A, Wappler F, Winkler G, Schulte am Esch JS. Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anesth Intensive Care. 1998;26:315–8
7. 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
8. Davis M, Brown R, Dickson A, Horton H, James D, Laing N, Marston R, Norgate M, Perlman D, Pollock N, Stowell K. Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anesth. 2002;88:508–15
9. Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet. 2009;76:564–8
10. Capacchione JF, Sambuughin N, Bina S, Mulligan LP, Lawson TD, Muldoon SM. Exertional rhabdomyolysis and malignant hyperthermia in a patient with ryanodine receptor type 1 gene, L-type calcium channel alpha-1 subunit gene, and calsequestrin-1 gene polymorphisms. Anesthesiology. 2010;112:239–44
11. Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, Quinlivan R, Snoeck M, Norwood F, Radunovic A, Straub V, Roberts M, Vrancken AF, van der Pol WL, de Coo RI, Manzur AY, Yau S, Abbs S, King A, Lammens M, Hopkins PM, Mohammed S, Treves S, Muntoni F, Wraige E, Davis MR, van Engelen B, Jungbluth H. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord. 2013;23:540–8
12. Maclennan DH, Zvaritch E. Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum. Biochim Biophys Acta. 2011;1813:948–64
13. Nelson TE. Malignant hyperthermia: a pharmacogenetic disease of Ca++ regulating proteins. Curr Mol Med. 2002;2:347–69
14. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498–507
15. Gronert GA, Thompson RL, Onofrio BM. Human malignant hyperthermia: awake episodes and correction by dantrolene. Anesth Analg. 1980;59:377–8
16. Hopkins PM, Ellis FR, Halsall PJ. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet. 1991;338:1491–2
17. Ryan JF, Tedeschi LG. Sudden unexplained death in a patient with a family history of malignant hyperthermia. J Clin Anesth. 1997;9:66–8
18. Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA. 2001;286:168–9
19. Loke J, Kraeva N, MacLennan D, Mutations. in RYR1 gene associated with malignant hyperthermia and a non-anaesthetic phenotype. Can J Anesth. 2007;54:44609
20. Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee HS, Qiu X, Sambuughin N, Dirksen RT. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology. 2011;115:938–45
21. Lavezzi WA, Capacchione JF, Muldoon SM, Sambuughin N, Bina S, Steele D, Brandom BW. Case report: death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old. Anesth Analg. 2013;116:420–3
22. Wilson RD, Dent TE, Traber DL, McCoy NR, Allen CR. Malignant hyperpyrexia with anesthesia. JAMA. 1967;202:183–6
24. Larach MG. Standardization of the caffeine halothane muscle contracture test. North American Malignant Hyperthermia Group. Anesth Analg. 1989;69:511–5
26. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS. Anesthesiology. 1998;88:579–88
27. Brewster LM, Mairuhu G, Sturk A, van Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J. 2007;154:655–61
28. Ording H. Incidence of malignant hyperthermia in Denmark. Anesth Analg. 1985;64:700–4
29. 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: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97:1067–74
30. Ibarra M CA, Wu S, Murayama K, Minami N, Ichihara Y, Kikuchi H, Noguchi S, Hayashi YK, Ochiai R, Nishino I. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006;104:1146–54
31. Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LGNISC Comparative Sequencing Program. . Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013;119:1043–53
32. Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell. 2008;133:53–65
33. Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J. 2006;20:329–30
34. Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, O’Brien PJ, MacLennan DH. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253:448–51