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  • Exertional rhabdomyolysis:physiological response or manifestationof an underlying myopathy?

    Renata S Scalco,1 Marc Snoeck,2 Ros Quinlivan,1 Susan Treves,3,4

    Pascal Lafort,5 Heinz Jungbluth,6,7,8 Nicol C Voermans9

    To cite: Scalco RS,Snoeck M, Quinlivan R, et al.Exertional rhabdomyolysis:physiological response ormanifestation of anunderlying myopathy?BMJ Open Sport Exerc Med2016;2:e000151.doi:10.1136/bmjsem-2016-000151

    Prepublication history forthis paper is available online.To view these files pleasevisit the journal online(http://dx.doi.org/10.1136/bmjsem-2016-000151).

    HJ and NCV shared seniorauthorship.

    Accepted 1 August 2016

    For numbered affiliations seeend of article.

    Correspondence toDr Renata Scalco; r.scalco@ucl.ac.uk

    ABSTRACTExertional rhabdomyolysis is characterised by musclebreakdown associated with strenuous exercise ornormal exercise under extreme circumstances. Keyfeatures are severe muscle pain and sudden transientelevation of serum creatine kinase (CK) levels with orwithout associated myoglobinuria. Mild cases mayremain unnoticed or undiagnosed. Exertionalrhabdomyolysis is well described among athletes andmilitary personnel, but may occur in anybody exposedto unaccustomed exercise. In contrast, exertionalrhabdomyolysis may be the first manifestation of agenetic muscle disease that lowers the exercisethreshold for developing muscle breakdown. Repeatedepisodes of exertional rhabdomyolysis should raise thesuspicion of such an underlying disorder, in particularin individuals in whom the severity of therhabdomyolysis episodes exceeds the expectedresponse to the exercise performed. The present reviewaims to provide a practical guideline for the acutemanagement and postepisode counselling of patientswith exertional rhabdomyolysis, with a particularemphasis on when to suspect an underlying geneticdisorder. The pathophysiology and its clinical featuresare reviewed, emphasising four main stepwiseapproaches: (1) the clinical significance of an acuteepisode, (2) risks of renal impairment, (3) clinicalindicators of an underlying genetic disorders and (4)when and how to recommence sport activity followingan acute episode of rhabdomyolysis. Geneticbackgrounds that appear to be associated with bothenhanced athletic performance and increasedrhabdomyolysis risk are briefly reviewed.

    INTRODUCTIONExertional rhabdomyolysis (ERM) is thegeneral term for muscle breakdown asso-ciated with strenuous exercise and is welldescribed among athletes and military per-sonnel. Although there is no universallyaccepted definition, ERM is often defined asa clinical syndrome associated with severemuscle pain, sudden elevation (and subse-quent fall) of serum creatine kinase (CK)levels with or without myoglobinuria.Individuals experiencing ERM present to a

    variety of physicians, in particular to generalpractitioners and physicians working insports medicine, emergency and internalmedicine, neurology and the neuromuscularfield, and for the military. As a result of thediversity of medical personnel having to dealwith ERM, most physicians will have experi-ence with some but not necessarily allaspects of this important condition.ERM results in the entry of skeletal muscle

    contents, in particular CK and myoglobin,into the systemic circulation. In most cases,the condition has a mild course charac-terised by postexertional myalgia withmild-to-moderate CK increases, mild pigmen-turia, and will often not even come tomedical attention. However, in a minority ofpatients the clinical course can be severe,resulting in marked hyperCKaemia, compart-ment syndrome, acute renal injury, dissemi-nated intravascular coagulation, cardiacarrhythmias secondary to electrolyte imbal-ances, and even cardiac arrest if leftuntreated. The annual rhabdomyolysis

    What are the new findings

    Exertional rhabdomyolysis (ERM) may be thefirst manifestation of a genetic muscle diseasethat lowers the exercise threshold for developingmuscle breakdown.

    Consider a genetic cause of the ERM in case ofrecurrent episodes; high creatine kinase (CK)levels (>50upper limit of normal) or persistinghyperCKaemia; absence of unaccustomed exer-cise; absence of (recreational or medical) drugs;or a positive family history of rhabdomyolysis orother exertional symptoms.

    Type 1 ryanodine receptor (RYR1) mutationshave been recently recognised to account for asubstantial proportion of patients presenting withERM.

    Participants with a genetic predisposition toERM need specific guidance when they recom-mence exercise and sporting activities.

    Scalco RS, et al. BMJ Open Sport Exerc Med 2016;2:e000151. doi:10.1136/bmjsem-2016-000151 1

    Open Access Reviewcopyright.

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  • prevalence has been reported as 26 000 cases in theUSA, with 47% meeting the diagnostic criteria of ERM.1

    In other studies, a lower percentage of ERM has beensuggested,2 a discrepancy which reflects differences inthe cohorts studied.ERM most often represents a physiological response

    to extreme physical exercise or to normal exercise underextreme circumstances. In contrast, ERM might also bethe first manifestation of a genetic muscle disease, whichlowers the exercise threshold for developing musclebreakdown. A genetic cause should always be consideredin individuals with repeated episodes of ERM and inthose in whom the severity of rhabdomyolysis exceedsthe expected response to the exercise performed.The recognition of a patient with an underlying

    genetic disorder is essential for acute management aswell as (and most importantly) for counselling after-wards. First, in type 1 ryanodine receptor (RYR1)-relatedcases of ERM,3 the specific RyR1 antagonist dantrolenecould be administered to limit further muscle break-down and CK increases and more severe, potentially life-threatening downstream medical complications. Patientswith RYR1-related ERM will have a higher recurrencerisk and will have to be specifically advised with regardto subsequent sporting activities. The same patients arealso at increased risk of malignant hyperthermia suscep-tibility (MHS), a pharmacogenetic response to volatileanaesthetics and/or the depolarising muscle relaxantsuccinylcholine, with important consequences foraffected individuals but possibly also for their relativescarrying the same RYR1 variants. Furthermore, certaingenetic myopathies carrying an increased rhabdomyoly-sis risk may also be associated with cardiac or other sys-temic symptoms that will have to be screened for. Finally,certain medications may be relatively contraindicatedand exercise advice should be individually adapted incase of an underlying genetic cause.The present review therefore aims to provide a prac-

    tical guideline for the acute management and postepi-sode counselling of patients with ERM. The vast majorityof the relevant literature until now has focused either onthe physiological circumstances of ERM (particularly inpublications with an emphasis on sports or militarymedicine),4 5 on general causes of rhabdomyolysis,6 oron genetic myopathies which may predispose to rhabdo-myolysis (particularly in publications with an emphasison emergency medicine, genetics, neurology and neuro-muscular medicine).79 As a result, physicians workingin sports or military and emergency medicine are wellupdated on the symptoms and management of ERM,but may find it difficult to decide when to consider anunderlying genetic disorder. On the other hand, a neur-ologist may perform unnecessary muscle biopsies inhealthy individuals who have suffered from a singleepisode of ERM after extreme unaccustomed exercise.Therefore, a combined approach is necessary to recog-nise individuals who are at risk for recurrent rhabdo-myolysis and to advise patients with certain genetic

    disorders on when and how to recommence exerciseand sporting activities.We will first discuss the pathophysiology of ERM and

    its typical clinical features, and provide examples oftypical physiological ERM. Next, we will propose a struc-tured approach to patients with ERM, based on the fol-lowing four key questions: (1) is the ERM clinicallysignificant, requiring hospital admission and intravenousfluids administration? (2) What is the risk of developingacute renal failure (ARF)? (3) Is the ERM the (first)manifestation of a genetic disorder? And (4) when andhow to restart exercise and sporting activities? We expectthat such an approach will be of benefit for a widerange of physicians facing this severe and challengingcondition in different medical settings.

    WHAT IS ERM?BackgroundIn muscle tissue, the process of neuronal signal transduc-tion leading to muscle contraction is called excitation-contraction coupling (ECC). During ECC, presynapticacetylcholine release induces postsynaptic depolarisationof the sarcolemma, resulting in activation of the voltage-gated L-type calcium channels (also known as dihydro-pyridine receptors (DHPRs)). Unlike in cardiac muscle,it is not this calcium influx itself but rather the directinteraction between DHPRs and RyR1s that causes theopening of RyR1 Ca2+ channels, leading to a rapidrelease of Ca2+ from the intracellular sarcoplasmic reticu-lum (SR) stores. The increased myoplasmic Ca2+ (fromabout 10-7 to 10-5 M) induces the effective interactionbetween thick and thin filaments by binding to troponinC, and this ultimately leads to


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