toxic myopathies · 2020. 10. 22. · toxic myopathies andrew l. mammen, md, phd abstract purpose:...

Toxic MyopathiesAndrew L. Mammen, MD, PhD

ABSTRACTPurpose: This article reviews the most important muscle toxins, many of which arewidely prescribed medications. Particular emphasis is placed on statins, which causemuscle symptoms in a relatively large proportion of the patients who take them.Recent Findings: As with other toxic myopathies, most cases of statin-associatedmyotoxicity are self-limited and subside with discontinuation of the offendingagent. Importantly, about 2% of the population is homozygous for a singlenucleotide polymorphism, and these individuals have a dramatically increased riskof self-limited statin myopathy. Much more rarely, statins trigger a progressiveautoimmune myopathy characterized by a necrotizing muscle biopsy and autoan-tibodies recognizing hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, thepharmacologic target of statins.Summary: In most cases, toxic myopathies resolve after the toxic agent is stopped.Recognizing that statins can cause an autoimmune necrotizing myopathy isimportant because patients with this form of statin-triggered muscle disease usuallyrequire immunosuppressive therapy.

Continuum (Minneap Minn) 2013;19(6):1634–1649.

INTRODUCTIONExposures to numerous exogenoussubstances have been reported tocause muscle damage. Many of theseare commonly prescribed medica-tions. Table 6-11 provides a compre-hensive list of such substances,including some for which only a fewcase reports exist. This review willfocus on the most important and well-established myotoxic substances, orga-nizing them based on their histologicfeatures and/or presumed pathogenicmechanisms according to a schemeadapted from Amato and Russell.2 Thereview will begin with a detailed dis-cussion of statins, the most commonlyprescribed class of potentially myotoxicmedication, emphasizing the recentdiscovery that these drugs can triggeran autoimmune necrotizing myopathy.

NECROTIZING MYOPATHIESThe following section highlights sev-eral classes of medications that are

associated predominantly with myo-fiber necrosis on muscle biopsy. Al-though the pathogenic mechanismsare poorly understood, it is thoughtthat some of these medications maydestabilize the lipophilic muscle mem-brane and thereby cause myofiberdegeneration. As a consequence ofmyofiber necrosis, patients typicallyhave creatine kinase (CK) elevationsand features of an irritable myopathyon EMG. Fortunately, discontinuationof the offending agent usually leads toresolution of the myopathic processand restoration of muscle strength. Animportant exception is the case ofstatin-associated immune-mediatednecrotizing myopathy, which requiresimmunosuppressive treatment to haltand reverse the disease process.

Statin-Associated MyopathySelf-limited statin-associatedmyopathy.Statins decrease serum cholesterollevels and thereby reduce the risk of

Address correspondence toDr Andrew L. Mammen, JohnsHopkins Myositis Center,Johns Hopkins BayviewMedical Center, Mason F. LordCenter Tower, Suite 4500,5200 Eastern Avenue,Baltimore, MD, 21224,[email protected].

Relationship Disclosure:Dr Mammen serves on themedical advisory boards ofaTyr Pharma and Biogen Idecand has licensed a patent foran antiYHMG-CoA reductasetest to INOVA Diagnostics.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Mammen discusses theunlabeled use of therapies fortoxic myopathies.

* 2013, American Academyof Neurology.

1634 www.ContinuumJournal.com December 2013

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

cardiovascular events by inhibitinghydroxymethylglutaryl coenzyme A(HMG-CoA) reductase, the enzyme cat-alyzing the rate-limiting step of cho-lesterol biosynthesis (Figure 6-13).Although they are generally well toler-ated, mild statin-associated musculo-skeletal side effects, such as myalgia orcramps, occur in as many as 20% ofstatin users,4 which may represent a1.5-fold to 10-fold increase comparedto those not on statins.5Y7 However,severe myotoxicity in the form ofrhabdomyolysis is much more rareand only occurs at a rate of 0.44 per10,000 patient-years.8 Nonetheless, be-cause close to 30 million Americans arecurrently prescribed a statin medica-tion, patients with significant statinmyotoxicity are regularly encounteredin clinical practice. Fortunately, in mostcases, both mild and severe side effectsare self-limiting, with discontinuationof the offending medication resultingin resolution of symptoms after anaverage of 2 months (range 1 week to14 months).9

Several factors appear to increase therisk of statin-triggered myopathy. Forinstance, older age, hypothyroidism,obesity, and preexisting liver diseaseall increase the risk of side effects.

KEY POINTS

h As many as 20% ofstatin users experiencemyalgias or cramps.

h Statin-associatedrhabdomyolysis is rare,occurring at a rate of0.44 per 10,000patient-years.

h Self-limited statinmyopathy typicallyresolves 1 week to14 months afterstopping the drug.

TABLE 6-1 Potentially MyotoxicSubstancesa

b Adalimumab

b (-Aminocaproic acid

b Alcohol

b Amiodarone

b Apamin (bee venom)

b Barium

b Chlorophenoxy herbicides

b Chloroquine

b Ciguatoxin

b Clofibrate

b Colchicine

b Corticosteroids

b Crotamine

b Crotoxin

b Cyclosporine

b Daptomycin

b 20,25-Diazacholesterol

b Emetine

b Ethanol

b Fibrates

b Gemcitabine

b Germanium

b Gold

b Gossypol

b Interferon-"

b Ipecac

b Isotretinoin

b Labetalol

b Lithium

b Minocycline

b Mojave toxin

b Nucleoside reverse-transcriptaseinhibitors (eg, azidothymidine[AZT])

b Penicillamine

b Pentaborane

b Procainamide

b Propofol

b Snake venom

b Statins

b Tacrolimus

TABLE 6-1 Continued

b Taipoxin

b Tumor necrosis factor "antagonists

b Spanish toxic oil (myotoxiccomponent not clearlyidentified)

b L-Tryptophan

b Valproate

b Vecuronium bromide

b Vinca alkaloids

a Data from Pestronk A, NeuromuscularDisease Center.1

1635Continuum (Minneap Minn) 2013;19(6):1634–1649 www.ContinuumJournal.com


Different statin medications appear tohave different risks of toxicity; for ex-ample, fluvastatin and pravastatin mayhave significantly higher rates of myop-athy compared to rosuvastatin.7 Impor-tantly, higher statin doses also appearto increase the risk of statin myopathy.For example, 98 out of 6031 (1.6%)subjects taking simvastatin at a dose of80 mg/d developed myopathy, com-pared to just 8 out of 6033 (0.1%) ofsubjects who were taking 20 mg/d.10

Because of the dose-dependent natureof statin toxicity, the coadministrationof medications that increase serumlevels of statins can increase the riskof myopathy. Since atorvastatin, lova-statin, and simvastatin are metabolized

by the cytochrome P450 (CYP) 3A4isoenzyme, other drugs that aremetabolized by this enzyme can in-crease the risk of statin myopathy.Many prescribed drugs belong to thiscategory, including calcium channelblockers, antibiotics, antifungals,antiretrovirals, antidepressants, andimmunosuppressants (Table 6-2).Pravastatin and rosuvastatin are notmetabolized by the CYP3A4 system andtherefore are not susceptible to theseinteractions.

Recently, a genome-wide associa-tion study identified a polymorphismwithin the SLCO1B1 gene as a signifi-cant genetic risk factor for developingstatin-associated myopathy.10 Thisgene encodes a protein responsiblefor the hepatic uptake of statins, andpeople who are homozygous for thispolymorphism most likely have higherserum levels of statins, thus accountingfor the increased risk. Around 2% of thegeneral population fall into this cate-gory, and the best evidence suggeststhat around 15% of these patientswould develop a myopathy withinthe first year of treatment with simva-statin at a dose of 80 mg/d. Althoughother genetic risk factors for develop-ing statin myopathy have been pro-posed (eg, mutations in genesencoding carnitine palmitoyltransferase2 and myoadenylate deaminase), evi-dence to support these associations isless robust.

Proposed mechanisms of self-limited statin-myopathy. Statins re-duce cholesterol levels by inhibitingHMG-CoA reductase and thereby de-creasing levels of mevalonate, a prin-cipal cholesterol precursor. While ithas been proposed that decreasedcholesterol levels might cause myo-toxicity by disrupting the integrity ofthe muscle fiber membrane, a reduc-tion in other downstream products ofmevalonate could also conceivably lead

KEY POINTS

h Higher statin doses areassociated with anincreased risk of toxicity.

h Atorvastatin, lovastatin,and simvastatin aremetabolized by theCYP3A4 P450 system.Coadministration ofother drugs metabolizedby this enzyme canincrease the risk ofstatin myopathy.

FIGURE 6-1 The mevalonate pathway. HMG-CoAreductase catalyzes the rate-limiting step inthe production of cholesterol, CoQ10, and

isoprenylated proteins from the precursors acetyl-CoA andacetoacetyl-CoA. Inhibition of HMG-CoA by statins results indecreased levels of cholesterol and the other downstreamproducts of this pathway. Decreased levels of cholesterolcause compensatory increased levels of HMG-CoA; thismay provoke an immune response against the enzyme inimmunogenetically susceptible individuals.

CoA = coenzyme A; HMG-CoA = hydroxymethylglutarylcoenzyme A; PP = pyrophosphate; tRNA = transfer RNA;CoQ10 = coenzyme Q10.

Reprinted with permission from Greenberg SA, Amato AA, Continuum(Minneap Minn).3 B 2006, American Academy of Neurology. journals.lww.com/continuum/Fulltext/2006/06000/Statin_Myopathies.8.aspx.


Toxic Myopathies


journals.lww.com/continuum/Fulltext/2006/06000/Statin_Myopathies.8.aspxjournals.lww.com/continuum/Fulltext/2006/06000/Statin_Myopathies.8.aspx

to muscle damage (Figure 6-1). Forexample, mevalonate is required forproduction of farnesyl pyrophosphateand geranylgeranyl pyrophosphate,which in turn are required for proteinprenylation, an important posttransla-

tional modification. The production ofubiquinone (ie, coenzyme Q10), a keycomponent of the mitochondrial elec-tron transport chain, also depends onprotein prenylation. Other prenylatedproteins include Rho and Rab, smallguanosine triphosphatases (GTPases)that promote cell survival; inhibitingproduction of these proteins couldconceivably lead to cell death. Further-more, prenylation is required for theprocess of N-glycosylation, a criticalposttranslational modification, the inhi-bition of which could be damaging tomuscle cells. While some observationaland experimental evidence supportseach of these mechanisms in mediat-ing self-limited statin myopathy,11 theactual mechanisms underlying muscledamage in humans taking statins re-main unknown.

Statin-triggered immune-mediatednecrotizing myopathy. In most sub-jects with statin-associated musculo-skeletal side effects, discontinuingthe offending medication will halt thepathophysiologic process, and thesubsequent regeneration of myofiberswill restore muscle function. However,recent evidence suggests that statinscan also trigger an autoimmune my-opathy that progresses even after thestatin is discontinued.12Y14 After pe-riods of statin exposure ranging fromweeks to years, these patients developproximal muscle weakness, markedlyelevated CK levels (mean is approxi-mately 10,000 IU/L), an irritable my-opathy on needle EMG, and muscleMRI demonstrating edema. Musclebiopsies typically reveal a necrotizingmyopathy with minimal inflammatorycell infiltrates (Figure 6-2). Whenpresent, infiltrating lymphocytes oc-cur most typically in a perivasculardistribution. Immunostaining revealsthat the sarcolemmal surface of manyspecimens from these patients ispositive for major histocompatibility

KEY POINTS

h About 2% of thepopulation arehomozygous for asingle nucleotidepolymorphism withinthe SLCO1B1 gene andconsequently have anincreased risk ofdeveloping self-limitedstatin myopathy.

h The mechanisms ofstatin toxicity areunknown but areprobably related todecreased productionof mevalonate and itsdownstream products,including cholesteroland isoprenylatedproteins such asubiquinone andsmall guanosinetriphosphatases.

TABLE 6-2 InhibitorsandInducersof the CYP3A4 P450Enzymatic Pathway

b Inhibitors

Ketoconazole

Itraconazole

Fluconazole

Erythromycin

Clarithromycin

Tricyclic antidepressants

Nefazodone

Venlafaxine

Fluvoxamine

Fluoxetine

Sertraline

Cyclosporine A

Tacrolimus

Mibefradil

Diltiazem

Verapamil

Protease inhibitors

Midazolam

Corticosteroids

Grapefruit juice

Tamoxifen

Amiodarone

Warfarin

b Inducers

Phenytoin

Phenobarbital

Barbiturates

Rifampin

Dexamethasone

Cyclophosphamide

Carbamazepine

Omeprazole

Pioglitazone



complex (MHC)YI, as seen in otherforms of autoimmune myopathy. Somespecimens also show membrane attackcomplex on the surface of nonnecroticmuscle fibers.

Many, if not all, patients with statin-triggered autoimmune myopathydevelop antibodies recognizing HMG-CoA reductase, the pharmacologictarget of statins.15 These antibodiesappear to be specific for patients withan autoimmune process and have notbeen found in other statin-treatedsubjects, including those with mildself-limited muscle symptoms.16

Therefore, when testing for the pres-ence of these antibodies becomescommercially available, this shouldhelp clinicians differentiate those withimmune-mediated myopathyVwhorequire treatmentVfrom those withself-limited statin toxicity.

Patients with statin-associated auto-immune myopathy do not have anincreased prevalence of the SLCO1B1single nucleotide polymorphism thatis associated with a susceptibility toself-limited statin toxicity. However, as

in other systemic autoimmune diseases,immunogenetic factors can protect orpredispose individuals to developingantiYHMG-CoA reductase-positive my-opathy.17 For example, the class IIhuman leukocyte antigen (HLA) allelesDQA1 and DQB6 are negatively associ-ated with developing this form ofautoimmune muscle disease. In con-trast, the odds ratios for developingantiYHMG-CoA reductase myopathyare 24.5 (P=3.2 � 10j10) in whitepatients and 56.5 (P=3.1 � 10j6) inblack patients who have the class IIHLA allele DRB1*11:01 compared tothose without this allele. It should benoted, however, that testing for theDRB1*11:01 allele is not useful inclinical practice because the vast ma-jority of those with this allele mostlikely tolerate statins without develop-ing an autoimmune myopathy.

Importantly, patients with statin-associated immune-mediated necrotizingmyopathy often require aggressiveimmunosuppressive therapy. To date,optimal treatment strategies have notbeen validated in trials. However, basedon the author’s clinical experience andthat of others, optimal results are achievedin patients with moderate to severeweakness when they are initiated on‘‘triple therapy’’ with high-dose oralprednisone, IV immunoglobulin(IVIg), and another steroid-sparingagent (eg, azathioprine, methotrexate,or mycophenolate mofetil) (Case 6-1).In treated statin-exposed antiYHMG-CoA reductase myopathy patientsfollowed for an average of over 2years, CK levels declined from anaverage of 4835 IU to 878 IU, andproximal muscle strength improvedfrom an average of approximately 3/5to 4+/5 on the Medical ResearchCouncil scale.18

An approach to the patient withmuscle symptoms after statin expo-sure. In statin-treated patients who

KEY POINTS

h In some instances,statins can trigger anautoimmune myopathycharacterized byproximal muscleweakness, very highcreatine kinase levels,a necrotizing musclebiopsy, andautoantibodiesrecognizinghydroxymethylglutarylcoenzymeA (HMG-CoA)reductase.

h AntiYHMG-CoAreductaseautoantibodiesappear to be specificfor those with anautoimmune myopathyand have not beenfound in patients withself-limited statinmyopathy.

FIGURE 6-2 A muscle biopsy from a patient withstatin-associated immune-mediated necrotizingmyopathy shows myofiber degeneration,

necrosis, myophagocytosis, and regeneration without prominentlymphocytic infiltrates (hematoxylin and eosin stain).


Toxic Myopathies


present with muscle symptoms,strength should be assessed and se-rum muscle enzyme levels should bemeasured. Those with normal muscleenzymes and strength most likely havea mild process that may or may not berelated to the statin. If possible, thestatin should be discontinued to seewhether the muscle symptoms spon-taneously resolve over weeks tomonths. If muscle symptoms do notresolve or become worse, then other

causes of these symptoms should beconsidered. However, if the symptomsdo resolve, then rechallenging thepatient with a different statin at aninitially low dose can be considered.For example, the majority of patientswho experienced myalgia on anotherstatin were able to tolerate rosuvastatindosed at 5 mg every other day with anadequate reduction in low-density li-poprotein (LDL) cholesterol levels(Case 6-2).19

KEY POINTS

h Patients withstatin-associatedautoimmune myopathyoften require aggressiveimmunosuppressivetherapy to reverse thedisease process.

h Many patients withself-limited statinmyopathy toleratelow-dose rosuvastatintherapy with adequatereduction in cholesterollevels.

Case 6-1A 64-year-old man with hypercholesterolemia had been on atorvastatinfor 3 years when he developed progressive bilateral quadriceps musclepain. After 3 weeks of myalgia, he saw his primary care doctor, who foundthat the patient’s creatine kinase (CK) was elevated to 1047 IU/L andsubsequently discontinued the statin medication. Four weeks later, themuscle pain had not diminished, and the patient noticed that he washaving increasing difficulty climbing stairs. His CK was 2216 IU/L, and hisphysician now noted moderate hip flexor weakness on examination. Norash was present. Two weeks later, the patient underwent EMG thatrevealed an irritable myopathy. A muscle biopsy performed the next weekshowed many degenerating and regenerating myofibers with a fewperivascular inflammatory cells. He was diagnosed with probablestatin-associated immune-mediated necrotizing myopathy, andprednisone was initiated at 60 mg/d, at which time his CK was 5231 IU/Land he was experiencing difficulty with proximal arm weakness as well asincreasing difficulty walking even on flat surfaces. After 4 weeks ofhigh-dose oral steroids, his CK decreased to 3742 IU/L, but his weaknesshad not improved. Oral methotrexate was started, but 6 weeks later his CKremained markedly elevated and he was no stronger. IV immunoglobulin(IVIg) was initiated at a dose of 0.4 g/kg/d for 5 days each month. After3 months of high-dose steroids, methotrexate, and IVIg, his CK hadnormalized, and he was back to near normal strength. Over the next 6months, the steroids were tapered off and the IVIg was discontinuedwithout relapse; however, when the methotrexate was stopped, hedeveloped recurrent muscle pain with a CK elevation to 631 IU/L.Methotrexate was restarted, and he underwent a short course of oralprednisone therapy with resolution of the symptoms and the elevatedmuscle enzymes. He required continued methotrexate therapy to keep themuscle disease in remission.

Comment. Patients with statin-associated immune-mediated necrotizingmyopathy develop weakness in the context of statin exposure thatcontinues to progress despite discontinuation of the statin. These patientstypically require aggressive immunosuppressive therapy, often with multipleagents, in order to control the disease. Some patients require long-termimmunosuppressive therapy. In the author’s experience, reexposure tolipid-lowering medications may precipitate relapse of the myopathy.



Most patients with elevated muscleenzymes and muscle weakness due tostatins also have a self-limited process,and a similar approach can be taken.However, if muscle strength continuesto worsen (or fails to improve) or CKlevels do not begin to drop within afew weeks of statin discontinuation, itmay be that the patient has a statin-triggered autoimmune process. Amuscle biopsy should be consideredto look for other potential causes ofsevere myopathy. If the patient has anecrotizing muscle biopsy with nolikely alternative diagnosis, immuno-suppressive therapy may be instituted.If, in the future, a commercially avail-able test for antiYHMG-CoA reductaseantibodies becomes available, this mayallow for the earlier recognition andtreatment of statin-triggered autoim-mune myopathy.

The role of dietary supplementsin treating statin-related musclesymptoms. In addition to decreasing

cholesterol levels, statins decrease theproduction and serum concentration ofcoenzymeQ10, an essential componentof the mitochondrial respiratory chain.It has been hypothesized that self-limited statin-induced myopathy mayresult from coenzyme Q10 depletionand the subsequent disruption ofmitochondrial function. It has alsobeen suggested that statins may causemyopathy by disrupting selenoproteinsynthesis. To determine whethercoenzyme Q10 and se len iumsupplementation ameliorate statin-induced myopathy, 43 patients withatorvastatin-induced myopathy wererandomized to receive either 400 mgcoenzyme Q10 and 200 2g seleniumper day or placebo for 12 weeks.20

Despite increasing serum coenzymeQ10 and selenium concentrations inthose taking the supplements, no dif-ferences in muscle symptoms or mea-sures of muscle function were foundbetween the two groups. Similar studies

Case 6-2A 59-year-old man with hypercholesterolemia and a strong family historyof coronary artery disease was started on simvastatin at a dose of 40 mg/d.After several months, he began to experience muscle pain withoutweakness, and the dose of statin was reduced to 20 mg/d. He continued tohave muscle pain after 2 weeks on the lower dose. His creatine kinase levelwas checked and found to be normal at 187 IU/L. The simvastatin wasdiscontinued, and he was started on atorvastatin at a dose of 20 mg/d.After 4 weeks, the myalgias persisted and were particularly troublesomeafter exercise. On repeat testing, serum muscle enzyme levels remainedwithin normal limits. The atorvastatin was stopped, and his musclesymptoms only resolved after 4 months without statin treatment. Given hiscardiovascular risk factors, he was started on rosuvastatin at a dose of5 mg once per week. After he tolerated this well for a month, the dosewas increased to 5 mg every other day. He was able to tolerate increasingthe dose to 10 mg every other day and reached his target goal for lipidreduction without adverse effects.

Comment. Patients with statin intolerancemay experience disablingmusclepain any time after starting statin medications without overt weakness orelevations in muscle enzymes. It may take weeks to months (in some cases aslong as a year) for myalgias to resolve after the statin is discontinued.Fortunately, a majority of statin-intolerant patients can tolerate low-dose,every-other-day rosuvastatin treatmentwith adequate reductions in lipid levels.


Toxic Myopathies


investigating the effect of coenzymeQ10 supplementation have yieldedmixed results.21Y23 Therefore, specificrecommendations about coenzymeQ10 and selenium supplementation inthose with statin intolerance will have towait until more definitive studies areconducted.

Some evidence exists that low vitaminD levels may be associated with statinmyopathy,24 but this association has notbeen consistently reproduced.25 Al-though one unblinded trial suggestedthat vitamin D supplementation mayimprove statin-associated myalgias,26

placebo-controlled trials will be re-quired to determine whether patientswith statin-associated myopathy andnormal vitamin D levels benefit fromvitamin D supplementation. In themeantime, it can only be recommendedthat those with documented vitamin Ddeficiency (lower than 32 ng/mL) be pro-vided with vitamin D supplementation.

Cholesterol-Lowering Drugs(Excluding Statins)Fibric acid derivatives (eg, fenofibrateand gemfibrozil), niacin, and ezetimibeare also prescribed to control hyperlip-idemia. Although monotherapy witheach of these has been reported to causea myopathy, the link between drug ex-posure and development of myopathyis best established for gemfibrozil. Witheach agent, the risk of myopathy appearsto be highest in patients who are alsotaking statins. Again, this is particularlywell-established for gemfibrozil, whichinterferes with statin metabolism, in-creases statin plasma concentrations,and is associated with a 15-fold in-creased risk of rhabdomyolysis comparedto fenofibrate when coadministeredwith a statin.27

As with patients who take statins,those who are exposed to nonstatinlipid-lowering drugs have been reportedto develop CK elevations, myalgias, or

weakness within weeks of starting themedications. However, these manifesta-tions of muscle injury more commonlydevelop several months after drug initia-tion. In some cases, patientsmay toleratethese cholesterol-lowering agents wellfor years before developing an overtmyopathy. Interestingly, patients whohave developed rhabdomyolysis afterstatin exposure may be at risk forrecurrence of rhabdomyolysis follow-ing use of a different class of lipid-lowering agent as monotherapy.28

ImmunophilinsCyclosporine and tacrolimus are po-tent immunosuppressive medicationsused in many patients to prevent therejection of transplanted organs, andused in some patients with autoim-mune disease. In rare cases, these drugshave been associated with myalgias, CKelevations, or muscle weakness in themonths after they are initiated. A car-diomyopathy has also been reported insome patients taking tacrolimus. Inone comprehensive review including34 patients who developed myopathyon cyclosporine, only 2 received cy-closporine monotherapy.29 In theremaining cases, cyclosporine was ad-ministered along with other potentialmyotoxins such as a statin or colchicine.This makes it difficult to determinewhether cyclosporine alone can cause amyopathy. In addition to myofiber ne-crosis, muscle biopsies sometimes re-vealed evidence of mitochondrialdamage including ragged red fibersand lipid vacuoles.

Other Agents Associated WithNecrotizing MyopathyThe antihypertensive agent labetaloland the anesthetic propofol haverarely been associated with a necrotiz-ing myopathy characterized by weak-ness, high CK levels, and an irritablemyopathy on EMG.

KEY POINTS

h It is unclear whethercoenzyme Q10supplementation has arole in preventing ortreating statinmyopathy.

h Vitamin D deficiencymay predispose patientsto statin myopathy andshould be repleted inthosewith a documenteddeficiency.

h When coadministeredwith a statin, gemfibrozildramatically increases theprobability of developinga myopathy.

h Cyclosporine, especiallywhen taken incombination with astatin or colchicine,may cause a necrotizingmyopathy.



Snake VenomsSnake venom includes numerous com-pounds, some of which are potentmyotoxins. For example, venom fromthe South American rattlesnake con-tains crotamine and other peptidesthat interact with sodium channels inthe sarcolemma and T tubules. Thisresults in increased sodium influx withresulting myofiber necrosis. Othersnake venoms, such as that producedby the cobra, include peptides withphospholipase A2 activity, which cancause rapidmuscle-fiber necrosis withina few hours of injection. Snake-venompoisoning often involves multiple organsystems and is a medical emergencyrequiring consultation with experts whocan be contacted at a regional poisoncontrol center.30

AMPHIPHILICDRUGMYOPATHIESAmphiphilic medications include bothhydrophobic and hydrophilic domains,thus allowing them to interact with anddisrupt cellular membranes. Thesedrugs can be myopathic, causing highCK levels and proximal weakness. Theymay also cause neuropathy, withresulting distal weakness and sensoryloss. In addition to features of anirritable myopathy seen on EMG, mo-tor and sensory nerve conduction stud-ies may reveal decreased amplitudesand slow velocities. Weakness is typi-cally more severe in the legs thanthe arms.

Chloroquine andHydroxychloroquineThese medications are used in thetreatment and prevention of malariabecause of their ability to accumulatein the parasite’s food vacuole, disruptthe metabolism of heme, and ulti-mately kill the parasite. Chloroquineand hydroxychloroquine are also usedin several rheumatic diseases, wherethey exert immunomodulatory effects

by inhibiting intracellular toll-likereceptors. In one 3-year longitudinalstudy of patients with rheumatic diseasestaking antimalarials, the prevalence ofmyopathy was 9.2%, and the annualincidence of myopathy was 1.2%; in allcases, the myopathy resolved withdiscontinuation of the antimalarialagent.31 In this and other studies, elec-tron microscopy of muscle biopsiesrevealed myeloid bodies and curvi-linear bodies due to lipid deposition;in some cases, light microscopy re-vealed a vacuolar myopathy. Of note,cardiac muscle may also be vulnerableto chloroquine-induced toxicity, result-ing in a vacuolar cardiomyopathy.

AmiodaroneThis antiarrhythmic medication maycause tremor or ataxia along with aneuromyopathy, especially in patientswith renal insufficiency. The myotoxiceffects of amiodarone may be exacer-bated in those who also developamiodarone-induced hypothyroidism.Muscle biopsies reveal a vacuolar myop-athy, and nerve biopsies typically showlysosomal inclusions.32 In most cases,the neuropathy and myopathy resolveafter the medication is discontinued orthe dose is reduced, although this cantake from 1 to 6 months. It should benoted that concurrent use of amio-darone and statin medications in-creases the risk of statin myopathy.

ANTIMICROTUBULARDRUG MYOPATHIESMedications that disrupt the assemblyof microtubules, such as colchicine andvincristine, may interfere with theintracellular trafficking of lysosomes,thereby causing the accumulation ofautophagic vacuoles. In addition to aproximal myopathy, these drugs cancause an axonal sensorimotor poly-neuropathy resulting in distal sensoryloss or weakness. Both myogenic and

KEY POINTS

h Antimalarialmedications are usedto treat patients withrheumatic diseases andcan cause myopathy atan annual rate of 1.2%.

h Amiodarone andcolchicine can causeneuropathy as well as avacuolar myopathy.


Toxic Myopathies


neurogenic motor units may be seenon EMG. Nerve conduction studiesshow reduced amplitudes and slightlyreduced conduction velocities.

ColchicineColchicine is used to prevent and treatgout flares as well as in the manage-ment of familial Mediterranean fever.Patients can develop a myopathy andneuropathy leading to gradually pro-gressive weakness, markedly elevatedCK levels, and an irritable myopathyon EMG.33 As illustrated in Case 6-3,this may occur in the context of renalfailure, which causes increased serumcolchicine levels. Muscle biopsies re-veal the accumulation of lysosomesand autophagic vacuoles (Figure 6-3).Discontinuation of colchicine usuallyresults in resolution of weakness with-in 3 to 4 weeks.

VincristineThis chemotherapeutic agent predom-inantly causes a dose-limiting poly-neuropathy but has also rarely beenassociated with proximal muscleweakness in the absence of elevatedserum muscle enzymes. Muscle biop-sies have demonstrated necrotic mus-cle fibers with disarray of the normalmyofibrillar architecture, but not auto-phagic vacuoles.34

DRUGS TOXIC TOMITOCHONDRIANucleoside Reverse-TranscriptaseInhibitorsNucleoside reverse-transcriptase in-hibitors (NRTIs) were the first classof antiretroviral drugs to be devel-oped; they interfere with replicationof the HIV virus through their inhibi-tion of the viral reverse transcriptase.However, these medications also in-hibit mitochondrial DNA polymerase,resulting in mitochondrial dysfunc-tion. It has been hypothesized thatmitochondrial dysfunction underlies

the muscle weakness seen in patientsusing NRTIs.

Azidothymidine (AZT), an analog ofthymidine, is the NRTI most tightlylinked to development of a myopa-thy.35 Patients with AZT myopathytypically present with myalgias, slowlyprogressive weakness, modestly ele-vated CK levels, and an irritable my-opathy on EMG. These features maynot distinguish AZT myopathy fromother HIV-related myopathies such aspolymyositis and inclusion body myosi-tis; however, muscle biopsies in pa-tients with AZT myopathy are uniquebecause of the presence of ragged redfibers on modified Gomori one-steptrichrome stain, reflecting the subsar-colemmal accumulation of abnormalmitochondria. In contrast to those withHIV-associated polymyositis or in-clusion body myositis, inflammatorycells are not found in muscle biopsiesof patients with AZT myopathy. Thus,muscle biopsy may be helpful in differ-entiating AZT myopathy from otherHIV-associated myopathies, whichmay require immunosuppressive ther-apy. In those with AZT myopathy,discontinuation of the drug results inclinical improvement and resolution ofthe mitochondrial abnormalities seenon muscle biopsy.

Other NRTIs (eg, lamivudine, zal-citabine, stavudine, and didanosine)may also damage mitochondria. How-ever, the risk of myopathy with theseappears to be less compared to thatseen in patients exposed to AZT.

INFLAMMATORYDRUG-INDUCED MYOPATHIESA number of medications, includingcimetidine, levodopa, and imatinibmesylate, have been reported to causean inflammatory myopathy. However,the apparent associations are basedon very few cases (in some instances,only a single patient), and so the

KEY POINT

h Azidothymidine (AZT)myopathy can bedistinguished fromHIV-associated myositison muscle biopsy bythe absence ofinflammation andthe presence ofmitochondrialabnormalities such asragged red fibers.



relationship between drug exposureand the development of myopathy isunclear. If these medications do causemyopathy, this is most likely a veryrare event.

The evidence is stronger thatinterferon-" exposure may trigger au-toimmune muscle disease in a smallminority of patients who take thismedication for viral hepatitis or to treatsome cancers. Similarly, a dermato-myositislike illness has been reportedin patients taking adalimumab, a tumornecrosis factor inhibitor, for rheuma-toid arthritis.36 However, this reactionhas not been reported in patients taking

adalimumab for other conditions, suchas Crohn disease, so it is unclearwhether development of the inflamma-tory myopathy is related to the medica-tion or the underlying rheumatoidarthritis.

The occurrence of inflammatorymyopathy in patients with rheumatoidarthritis treated with D-penicillaminehas been well documented.37 Similarly,procainamide can be associated withmyalgias, weakness, CK elevations,and an inflammatory muscle biopsy.In both cases, withdrawal of the medi-cation should lead to resolution of themyopathy.

KEY POINT

h Interferon-", tumornecrosis factor inhibitors,and D-penicillaminehave been reportedto precipitate aninflammatory myopathy.

Case 6-3A 73-year-old woman with hypertension, diabetes mellitus, and goutdeveloped worsening renal function over the course of a year. She thenbegan to experience painless proximal muscle weakness, with increasingdifficulty walking up stairs and brushing her hair. On examination, herphysician noted proximal muscle weakness and a creatine kinase (CK) levelof 2532 IU/L. EMG showed an irritable myopathy. She was started onprednisone 40 mg/d for a presumptive diagnosis of polymyositis. Herdiabetes mellitus and hypertension worsened, and her weakness failed toimprove after 2 months of prednisone treatment. She also began toexperience paresthesia in her feet and some mild but persistent nausea.A muscle biopsy was performed, which showed variation in fiber size,disrupted internal architecture on NADH staining, and prominentnonrimmed vacuoles on Gomori one-step trichrome stain; noaccumulations of lymphocytes were evident, and no perifascicularatrophy was noted. Review of the patient’s medication list revealed thatshe had been taking colchicine to control her gout for many years. Theprednisone and colchicine were both discontinued, and her musclestrength and CK levels returned to normal within a month. She alsoexperienced resolution of her sensory and gastrointestinal symptoms.

Comment. Colchicine binds to tubulin, prevents the formation ofmicrotubules, and disrupts the intracellular movement of vesicles andlysosomes. With high serum concentrations, colchicine can be myotoxic,with muscle biopsy revealing a distinctive vacuolar myopathy. Sinceclearance of colchicine depends on adequate renal function, those whohave tolerated the medication previously can develop toxicity in thecontext of a declining glomerular filtration rate. Of note, colchicinetoxicity may also result in an axonal neuropathy, cardiac toxicity, andgastrointestinal symptoms such as nausea, vomiting, and abdominal pain.This case also highlights the importance of obtaining a muscle biopsy torule out other causes of myopathy when a diagnosis of polymyositis issuspected. Ideally, when polymyositis is suspected, muscle biopsy shouldbe performed before initiating immunosuppressive treatment.


Toxic Myopathies


CRITICAL ILLNESS MYOPATHYPatients exposed to high-dose IV ste-roids and nondepolarizing neuromus-cular blocking agents in the intensivecare unit (ICU) setting are at increasedrisk for developing critical illness my-opathy, critical illness neuropathy, orprolonged neuromuscular blockade.One large case series suggests thatamong those with weakness in theICU setting, critical illness myopathy isapproximately 3 times more commonthan critical illness neuropathy, andthat prolonged neuromuscular block-ade is a relatively rare phenomenon.38

The rate of critical illness myopathy inthe ICU is unknown but may be lessthan in previous years because ofphysicians’ heightened awareness ofthe risk factors, which has led them tolimit the use of high-dose steroids andlong-term neuromuscular blockade incritically ill patients.

A patient’s inability to be weanedfrom the ventilator is commonly thefirst noticed manifestation of criticalillness myopathy. On examination,these patients have weakness of thetrunk and proximal limbs. CK levels

may be normal or moderately ele-vated. In those without neuropathy,sensory nerve action potential (SNAP)amplitudes are normal, whereas com-pound muscle action potential(CMAP) amplitudes are dramaticallyreduced. EMG may reveal an irritableor nonirritable myopathy. However, insevere cases, patients may not be ableto recruit any motor units. Musclebiopsies reveal type 1 fiber atrophy,necrotic muscle fibers, and/or loss ofmyosin thick filaments as visualized onthe adenosine triphosphatase (ATPase)stain (Figure 6-4). To date, the mech-anism of muscle injury is poorly un-derstood. Although mortality is as highas 30% due to sepsis and organ failurein these critically ill patients, muscleweakness can be expected to improveover months in those who are dis-charged from the ICU.

STEROID MYOPATHYChronic exposure to high-dose oralsteroids (30 mg of prednisone per dayor the equivalent) confers the greatestrisk of developing steroid myopathy.2

However, steroid myopathy may

KEY POINTS

h Critical illness myopathyis probably a morecommon cause ofweakness in theintensive care unitthan critical illnessneuropathy orprolonged neuromuscularblockade.

h Loss of myosinthick filaments is adistinguishing musclebiopsy feature in criticalillness myopathy.

FIGURE 6-3 This muscle biopsy from a patient withcolchicine myopathy shows autophagicvacuoles (Gomori one-step trichrome stain).

Courtesy of Andrea M. Corse, MD.



occur after just a few weeks of treat-ment. Triamcinolone, betamethasone,dexamethasone, and other fluorinatedsteroids are more likely to causesteroid myopathy than prednisone orhydrocortisone, which are nonfluo-rinated. For unclear reasons, womenare more likely to develop steroid myop-athy then men.

Patients with steroid myopathy typ-ically present with progressive proxi-mal muscle weakness in the context ofnormal CK levels. EMG may either benormal or reveal a nonirritable myop-athy. Although not routinely per-formed when steroid myopathy issuspected, muscle biopsies reveal type2 fiber atrophy and lipid accumula-tion in type 1 fibers (Figure 6-5). Themechanism or mechanisms wherebysteroids disrupt muscle function arenot clearly understood.

Because steroids are frequently usedto treat weakness associated with auto-immune neuromuscular disorders, itmay be difficult to distinguish steroidmyopathy from an exacerbation of theunderlying disease. In myositis patients

treated with steroids, a normal CK leveland nonirritable myopathy may besuggestive of steroid myopathy ratherthan flaring of the autoimmune dis-ease. When the role of steroids incausing weakness is unclear, a trial ofsteroid tapering may be considered. Inpatients with steroid myopathy, thisshould result in improved strength. Incontrast, clinical worsening with ste-roid tapering suggests that more ag-gressive immunosuppressive therapymay be required to treat the underlyingdisease.

MALIGNANT HYPERTHERMIADepolarizing muscle relaxants (eg,succinylcholine) and inhalationalanesthetic agents (eg, halothane,sevoflurane, and desflurane) maycause a potentially fatal malignanthyperthermia to develop during orshortly after surgery in geneticallysusceptible individuals. Patients pres-ent with muscle rigidity, fever, andcardiac arrhythmias. Laboratory stud-ies may reveal high CK levels,hyperkalemia, and acidosis. Numeroussusceptibility loci have been identifiedand are associated with mutations ofthe ryanodine receptor, sodium chan-nels, calcium channels, and other pro-teins (Table 6-3). In addition togenetic testing, the halothane contrac-ture test or caffeine contracture testcan be used to screen for suscep-tibility to malignant hyperthermia.However, these tests are often onlyavailable at specialized centers. De-polarizing muscle relaxants and inha-lational anesthetic agents should beavoided in subjects with known sus-ceptibility factors. In those who de-velop malignant hyperthermia, theanesthetic agent must be stoppedand aggressive cooling measures mustbe instituted. In addition to providingother measures of supportive care,dantrolene may be delivered by rapid

KEY POINTS

h Fluorinated steroids (eg,dexamethasone) aremore likely to causesteroid myopathy thannonfluorinated steroids(eg, prednisone).

h Type 2 muscle fiberatrophy is characteristicof steroid myopathy butcan be seen in othercontexts, such as disuseatrophy.

h Steroid myopathy doesnot cause an elevationin serum muscle enzymelevels and should notresult in an irritablemyopathy on EMG.

h Malignant hyperthermiacan occur in patientswith susceptibilitymutations in theryanodine receptor,sodium channels, andcalcium channels.

FIGURE 6-4 An area of central clearing resulting from theloss of myosin thick filaments in a musclebiopsy from a patient with critical illnessmyopathy (adenosine triphosphatase [ATPase]stain).



Toxic Myopathies


IV injection at a dose of 2 mg/kg to3 mg/kg every 5 minutes for a totalcumulative dose of 10 mg/kg.

ALCOHOLPatients who engage in binge drinkingmay developmyalgias, muscle cramping,and weakness.39 These symptoms areassociated with high CK levels, an irrita-ble myopathy on EMG, and, in severecases, acute renal failure. CK levels andmuscle symptoms resolve over severalweeks but may recur with repeated ex-

posure to alcohol in those who are sus-ceptible to this form of toxic myopathy.

CONCLUSIONMany exogenous substances have thepotential to cause myotoxicity, includ-ing commonly prescribed medications(eg, statins and steroids), snake venom,and alcohol. Fortunately, muscle cellshave the capacity to regenerate so thatdamage can usually be reversed by rec-ognizing and discontinuing the offend-ing agent. An important exception

KEY POINTS

h Dantrolene at a dose of2 mg/kg to 3 mg/kgevery 5 minutes for atotal cumulative doseof 10 mg/kg may behelpful in treatingpatients with malignanthyperthermia.

h Binge alcohol drinkingcan cause a myopathy.

TABLE 6-3 Malignant Hyperthermia

Susceptibility Genes Inheritance Patterns

Ryanodine receptor Autosomal dominant

SCN4A sodium channel Autosomal dominant

CACNL2A calcium channel Autosomal dominant

CACNA1S calcium channel Autosomal dominant

Carnitine palmitoyltransferase II Autosomal dominant

Dystrophin X-linked recessive

Myotonin protein kinase Autosomal dominant

CLCN1 chloride channel Autosomal dominant

Perclan Autosomal recessive

FIGURE 6-5 Profound atrophy of type 2 fibers (staineddark) in muscle biopsy from a patient withsteroid myopathy (adenosine triphosphatase[ATPase] stain at pH 9.4).




includes patients who develop animmune-mediated necrotizing myopa-thy in the context of statin exposure.Recognizing this entity is essential be-cause, unlike patients with self-limitedstatin myopathy, those with statin-associated autoimmune myopathy re-quire immunosuppressive therapy tocontrol the disease process. Whentesting for these becomes commerciallyavailable, the presence of antiYHMG-CoA reductase antibodies should helpphysicians identify this rare but impor-tant population of patients.

REFERENCES1. Pestronk A. Neuromuscular Disease Center.

Toxic myopathies. neuromuscular.wustl.edu/mother/myotox.htm. Accessed August 22,2013.

2. Amato AA, Russell JA. Neuromusculardisorders. In: Anonymous NeuromuscularDisorders. China: McGraw Hill Companies,Inc, 2008:597.

3. Greenberg SA, Amato AA. Statinmyopathies. Continuum (Minneap Minn)2006;12(3):169Y184.

4. Franc S, Dejager S, Bruckert E, et al. Acomprehensive description of musclesymptoms associated with lipid-loweringdrugs. Cardiovasc Drugs Ther 2003;17(5Y6):459Y465.

5. Buettner C, Davis RB, Leveille SG, et al.Prevalence of musculoskeletal pain andstatin use. J Gen Intern Med 2008;23(8):1182Y1186.

6. Nichols GA, Koro CE. Does statin therapyinitiation increase the risk for myopathy? Anobservational study of 32,225 diabetic andnondiabetic patients. Clin Ther 2007;29(8):1761Y1770.

7. Molokhia M, McKeigue P, Curcin V, MajeedA. Statin induced myopathy and myalgia:time trend analysis and comparison of riskassociated with statin class from 1991Y2006.PLoS One 2008;3(6):e2522.

8. Garcia-Rodriguez LA, Gonzalez-Perez A,Stang MR, et al. The safety of rosuvastatin incomparison with other statins in over 25,000statin users in the Saskatchewan HealthDatabases. Pharmacoepidemiol Drug Saf2008;17(10):953Y961.

9. Hansen KE, Hildebrand JP, Ferguson EE,Stein JH. Outcomes in 45 patients with

statin-associated myopathy. Arch InternMed 2005;165(22):2671Y2676.

10. SEARCH Collaborative Group, Link E, ParishS, Armitage J, et al. SLCO1B1 variantsand statin-induced myopathyVa genomewidestudy. N Engl J Med 2008;359(8):789Y799.

11. Mammen AL, Amato AA. Statin myopathy:a review of recent progress. Curr OpinRheumatol 2010;22(6):644Y650.

12. Needham M, Fabian V, Knezevic W, et al.Progressive myopathy with up-regulation ofMHC-I associated with statin therapy.Neuromuscul Disord 2007;17(2):194Y200.

13. Grable-Esposito P, Katzberg HD, GreenbergSA, et al. Immune-mediated necrotizingmyopathy associated with statins. MuscleNerve 2010;41(2):185Y190.

14. Christopher-Stine L, Casciola-Rosen LA,Hong G, et al. A novel autoantibodyrecognizing 200-kd and 100-kd proteinsis associated with an immune-mediatednecrotizing myopathy. Arthritis Rheum2010;62(9):2757Y2766.

15. Mammen AL, Chung T, Christopher-Stine L,et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase inpatients with statin-associated autoimmunemyopathy. Arthritis Rheum 2011;63(3):713Y721.

16. Mammen AL, Pak K, Williams EK, et al.Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statinusers, including those with self-limitedmusculoskeletal side effects. Arthritis CareRes (Hoboken) 2012;64(2):269Y272.

17. Mammen AL, Gaudet D, Brisson D, et al.Increased frequency of DRB1*11:01 inanti-hydroxymethylglutaryl-coenzyme Areductase-associated autoimmunemyopathy. Arthritis Care Res (Hoboken)2012;64(8):1233Y1237.

18. Werner JL, Christopher-Stine L, GhazarianSR, et al. Antibody levels correlate withcreatine kinase levels and strength inanti-3-hydroxy-3-methylglutaryl-coenzymeA reductase-associated autoimmunemyopathy. Arthritis Rheum 2012;64(12):4087Y4093.

19. Backes JM, Venero CV, Gibson CA, et al.Effectiveness and tolerability ofevery-other-day rosuvastatin dosing inpatients with prior statin intolerance. AnnPharmacother 2008;42(3):341Y346.

20. Bogsrud MP, Langslet G, Ose L, et al. Noeffect of combined coenzyme Q10 andselenium supplementation on atorvastatin-induced myopathy. Scand Cardiovasc J2013;47(2):80Y87.


Toxic Myopathies


neuromuscular.wustl.edu/mother/myotox.htmneuromuscular.wustl.edu/mother/myotox.htm

21. Bookstaver DA, Burkhalter NA,Hatzigeorgiou C. Effect of coenzymeQ10 supplementation on statin-inducedmyalgias. Am J Cardiol 2012;110(4):526Y529.

22. Caso G, Kelly P, McNurlan MA, Lawson WE.Effect of coenzyme q10 on myopathicsymptoms in patients treated with statins.Am J Cardiol 2007;99(10):1409Y1412.

23. Young JM, Florkowski CM, Molyneux SL,et al. Effect of coenzyme Q(10)supplementation on simvastatin-inducedmyalgia. Am J Cardiol 2007;100(9):1400Y1403.

24. Gupta A, Thompson PD. The relationship ofvitamin D deficiency to statin myopathy.Atherosclerosis 2011;215(1):23Y29.

25. Backes JM, Barnes BJ, Ruisinger JF, MoriartyPM. A comparison of 25-hydroxyvitamin Dserum levels among those with or withoutstatin-associated myalgias. Atherosclerosis2011;218(1):247Y249.

26. Ahmed W, Khan N, Glueck CJ, et al. Lowserum 25 (OH) vitamin D levels (G32 ng/mL)are associated with reversiblemyositis-myalgia in statin-treated patients.Transl Res 2009;153(1):11Y16.

27. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk ofadverse events with fibrates. Am J Cardiol2004;94(7):935Y938.

28. Crespo-Leiro MG, Paniagua MJ, Marzoa R,et al. The efficacy and safety of ezetimibefor treatment of dyslipidemia after hearttransplantation. Transplant Proc 2008;40(9):3060Y3062.

29. Breil M, Chariot P. Muscle disordersassociated with cyclosporine treatment.Muscle Nerve 1999;22(12):1631Y1636.

30. Gold BS, Dart RC, Barish RA. Bites ofvenomous snakes. N Engl J Med 2002;347(5):347Y356.

31. Casado E, Gratacos J, Tolosa C, et al.Antimalarial myopathy: an underdiagnosedcomplication? Prospective longitudinalstudy of 119 patients. Ann Rheum Dis2006;65(3):385Y390.

32. Pulipaka U, Lacomis D, Omalu B.Amiodarone-induced neuromyopathy: threecases and a review of the literature. J ClinNeuromuscul Dis 2002;3(3):97Y105.

33. Kuncl RW, Duncan G, Watson D, et al.Colchicine myopathy and neuropathy.N Engl J Med 1987;316(25):1562Y1568.

34. Bradley WG, Lassman LP, Pearce GW,Walton JN. The neuromyopathy ofvincristine in man. Clinical, electrophysiologicaland pathological studies. J Neurol Sci 1970;10(2):107Y131.

35. Scruggs ER, Dirks Naylor AJ. Mechanisms ofzidovudine-induced mitochondrial toxicityand myopathy. Pharmacology 2008;82(2):83Y88.

36. Brunasso AM, Scocco GL, Massone C.Dermatomyositis during adalimumabtherapy for rheumatoid arthritis.J Rheumatol 2010;37(7):1549Y1550.

37. Chappel R, Willems J. D-penicillamine-induced myositis in rheumatoid arthritis.Clin Rheumatol 1996;15(1):86Y87.

38. Lacomis D, Petrella JT, Giuliani MJ.Causes of neuromuscular weakness in theintensive care unit: a study of ninety-twopatients. Muscle Nerve 1998;21(5):610Y617.

39. Urbano-Marquez A, Fernandez-Sola J.Effects of alcohol on skeletal and cardiacmuscle. Muscle Nerve 2004;30(6):689Y707.



toxic myopathies · 2020. 10. 22. · toxic myopathies andrew l. mammen, md, phd abstract purpose:...

Documents