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Ростовский Государственный Медицинский Университет

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Theperimysiumsurroundsacollectionofmusclefibers,groupingthemintobundles;theendomysium surroundseachfiberandliesdeeperwithinthemuscle.

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Thedifferingpathologiesofpolymyositisanddermatomyositisonmusclebiopsy.

Treatment.Initialtherapywithcorticosteroidsisusuallyeffective.Otherimmunosuppressivedrugsare usedwhenthediseaseisresistanttosteroidtherapy.The10-yearsurvivalrateisnowover80%with currenttherapeuticregimens.

InclusionBodyMyositis.Inclusionbodymyositispresentswithbothproximalanddistalmuscle weakness.Thedistalweaknesscanbeasymmetricandmaybedetectedonexaminationbyfindingsubtle

weaknessinthepatient’sgriporinthefingerflexors.Thisisaninsidiousdiseasethatprogressesslowly. Thediagnosisisgenerallymademanyyearsaftertheinitialcomplaintofweakness.

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Typicalfindingsonmusclebiopsyinpatientswithinclusionbodymyositis,includingendomysial inflammation,vacuolatedfibers,andmitochondrialabnormalities.

Thereareseveralwaysinwhichinclusionbodymyositisdiffersfrompolymyositisand dermatomyositis:

It is more commoninmen, and the averageageofonsetisolder (60 years, ascompared with 45 years). Itaffectsbothproximalanddistalmuscles(nearly95%ofpatientswillhavesomedegreeofdistal fingerflexorweaknessonexamination). The CKmayor may not be elevated, but almostneverashighasthe levels that canbeseenwith polymyositis. Inflammatorymarkers,ESRandCRP,arenotelevated. Muscle biopsyis distinct, revealing endomysial inflammation, rimmed bubble-likevacuoles, and, underelectronmicroscopy,inclusionbodies.

Drugtherapyhasnotbeensuccessful;thediseasedoesnotrespondtosteroids.Patientsslowlybecome disabledoveracourseofmanyyears.

Immune-MediatedNecrotizingMyopathy.Thisistheleastcommonoftheinflammatorymyopathies.It canoccuraseitheraparaneoplasticdisorderorinassociationwithcertaindrugs—mostoften,statins.

Immune-mediatednecrotizingmyopathy(IMNM)canbeassociatedwithanti-SRPantibodiesor,when statin-associated,anti-HMGCRantibodies.Histologyshowsonlyscatterednecroticmusclefibers withoutthesignificantperimysialorendomysialinflammationseenwiththeotherinflammatory myopathies.Whenstatinassociated,symptomsdonotimprovewithdiscontinuationofthestatin(see discussionbelow).Despitethelackofasignificantinflammatoryinfiltrateonmusclebiopsy,IMNMoften respondstoimmunosuppressivetherapies.

https://t.me/med1917

NoninflammatoryMyopathies

Drug-InducedMyopathies.Numerousdrugscanbedirectlytoxictothemuscles.Amongthemare alcohol,glucocorticoids,interferons,amiodarone,antimalarialdrugs,andanti-HIVagents.Others,such asdiuretics,cancauseweaknessbycausinghypokalemia.

Oneofthemostcommondrug-inducedmyopathiesisthatproducedbytheHMG-CoAreductase inhibitors(akathestatins)thatareusedtotreathyperlipidemia.

StatinMyopathy.Statinsareamongthemostcommonlyprescribeddrugs,soitisimportanttounderstand theirpotentialsideeffects.Thereareseveralwaysinwhichthesedrugscancausemyopathy.Wecan organizetheseintofourdistinctclinicalscenarios:

1.  Mild myalgias. This mildformof statin-induced muscle toxicity occurs in 10% to 20% of patients on statin therapy. Patients will describemuscleachesandsoreness,buttherewillbenoobjectiveweaknessonexamination.CKcanbenormalormildlyelevated.It’s not always necessary tostopthe statin, buttemporarydiscontinuation, especially inthe setting of moderate tosevere pain, is often helpful.Manypatientscanthenrestartthesamedrugoradifferentstatinwithoutrecurrenceoftheirmyalgias.

2. Toxin-relatedmyopathy.Thisisthestatin-inducednoninflammatorymyopathy thattrulybelongsinthissectionofthebook.Patients complain ofmild pain that’s associated with proximal muscle weak ness,distinguishing it from the more common clinicalscenario above.TheCKiselevated.Patientscanalmostalwaysbesuccessfullymanagedbystoppingthedrugand eitherswitchingtoanother statinorcontinuingthesameoneatalowerdoseorgivenlessfrequently(e.g.,twiceaweekinsteadofdaily).Improvementisusually seenwithinafewweeksofstoppingtheinitialstatin.

3.  Immune-mediated necrotizing myopathy.Rarely, statins cancause a type ofinflammatory myopathy,as mentionedin the section above,thoughttobemediatedbyantibodiesagainstHMG-CoAreductase.Clinically,thiscanappearindistinguishablefromtoxin-related myopathy,butunliketoxin-relatedmyopathy,symptomsdonotimprovewhenthestatinisstopped.Immunosuppressivetherapyisoften necessary.

4.  Rhabdomyolysis. Those very rare patients who develop signs of possible rhabdomyolysis (see Box 12.11 page 326) with severe musclesymptoms,darkurine,andaserumCKmorethan10timesnormalmuststoptheirstatinimmediately;treatmenttopreventrenal damagemustbeundertakenatonce.

Statinshavemanydrug–druginteractions,andsomeofthesemayinhibitstatinmetabolismandincrease statinlevelsintheblood,therebyincreasingtheriskoftoxicity.Thedrugsmostoftenimplicatedarethe macrolideantibiotics,primarilybecausetheyaresowidelyprescribed,andgemfibrozil,whichisusedto lowertriglyceridesandthereforeisfrequentlycombinedwithstatinsinpatientswithhyperlipidemia.The riskofmyopathyisgreaterwithlipophilicstatins(e.g.,simvastatin)thanwithhydrophilicstatins(e.g., rosuvastatin).

RoutinemonitoringofCKisnotrecommendedforpatientsonastatin,butifyouhappentodiscoveran elevatedCKinapatientwhoisasymptomatic,thedrugdoesnothavetobestoppedaslongastheCKis lessthan10timesnormal.

SteroidMyopathy.Corticosteroidsareanothercommoncauseofdrug-relatedmyopathy.Steroid myopathytypicallydevelopsgradually,anywherefromseveralweekstoseveralmonthsaftersteroid therapyisbegun.Thehigherthedoseofsteroids,thegreatertherisk.

Patientsreportprogressiveproximalmuscleweaknesswithoutmyalgiasortenderness.Thediagnosis islargelyoneofexclusion:muscleenzymesarenormal,EMGisnormal(or,lesscommonly,canshow low-amplitudemotorunitpotentials),andmusclebiopsyshowsnonspecifictypeIIfiberatrophy.Patients canimprovewithin3to4weeksofdiscontinuingthesteroid,butsome,dependingonthedegreeof weakness,maytakesignificantlylonger.Physicaltherapyisoftenhelpful.

https://t.me/med1917

EndocrineMyopathies.Manyendocrinedisorderscancausemyopathy,butmostofthetimeyouwill alreadyknowthatthepatienthasanendocrinopathy,sodeterminingthecauseofthepatient’sweakness shouldnotbeachallenge.Examplesinclude:

Hypo-andhyperthyroidism Hypo-andhypercortisolism(thelatteroftenfromexogenoussteroids) Hyperparathyroidism Acromegaly(excessgrowthhormoneintheadult)

Exceptforhypothyroidism,theCKisusuallynormal,andEMGmayeitherbenormalorshow myopathicchanges.Thekeytodiagnosis,ifyoudon’talreadyknowthatthepatienthasanendocrine disorder,istorecognizeothersymptomssuggestiveofanendocrinopathyandordertheappropriate hormonaltests.Treatmentinvolvestreatingtheunderlyingendocrinedisorder.

MyopathiesCausedbyViralandBacterialIllness.Manyviral(includinginfluenza,HIV,andSARSCoV-2)andbacterial(Lymedisease)infectionscancausemyopathy,withsymptomsrangingfrombenign myalgiastomuscletenderness,weakness,and,rarely,rhabdomyolysis.Inmostcases,thehistoryofa precedinginfectionisenoughtomakethediagnosis.ACKandurinalysisshouldbecheckedtoruleout rhabdomyolysisinseverecases.Musclebiopsyisrarelynecessarybutissometimesdonetoexclude othercausesofmyopathy,includinginflammatoryandgeneticdiseases.Almostallcasesareself-limited.

InheritedMyopathies.Thesediseasescanbedividedintothemusculardystrophiesandmetabolic myopathies.Themusculardystrophiesareagroupofhereditarydisorderscharacterizedbyprogressive weaknessandwastingofmuscles.Themetabolicmyopathiesresultfromgeneticdefectsinmuscleenergy metabolism.

MuscularDystrophies

DuchenneMuscularDystrophy(DMD).Duchennemusculardystrophyisthemostcommonmuscular dystrophythatcausessignificantdisabilityandearlydeath.ItistheresultofanX-linkedrecessivegene mutationthatcodesfordystrophin,aproteinthatiscriticalformaintainingtheintegrityofthecytoskeleton ofmusclefibers.ChorionicvillussamplingcandetectDMDby12weeks’gestation.Thediseasecanbe familialortheresultofasporadicmutation.

Presentation.Patientspresentinchildhood(usuallybetween2and3yearsold)withdelayedmotor milestonesandmildhypotonia.Parentsmaynotethattheirchildisunabletokeepupwithhispeerswith runningandjumping.Byage5years,mostpatientswillhaveclear-cutproximalweakness,andthe musclesofthecalves,shoulders,andbuttocksmayappearenlargedasmuscletissueisgraduallyreplaced byconnectiveandfattytissue,aprocesstermedpseudohypertrophy.Bytheonsetoftheirteenageyears, patientswillhavedifficultywalkingwithoutassistance.Thediseaseisaccompaniedbycognitivedeficits andlearningdifficulties.Dilatedcardiomyopathyoftenappearsintheteenageyearsandcancause arrhythmias,congestiveheartfailure,anddeath.

https://t.me/med1917

PseudohypertrophyofthelegsinapatientwithDuchennemusculardystrophy.

Diagnosis.Byage5years,astheproximalweaknessbecomesunmistakable,aCKshouldbechecked.If itiselevated,thepatientshouldundergoDNAanalysisormusclebiopsy(whichwillrevealabsentor abnormaldystrophin).BecauseDMDisX-linked,itoccursmostlyinmales,althoughfemalecarriersof themutationmayshowsomeweaknessandareatriskofdevelopingcardiomyopathy.

Treatment.Musclestrengthandfunctionaswellasmobilitycanbeimprovedwithdailyglucocorticoid therapy.Thereisalsoevidencethatcreatinesupplementationcanimprovemusclestrength.Angiotensin convertingenzymeinhibitorsarecardioprotectiveandimproveall-causemortality.Aneweragent, eteplirsen,isspecificallydesignedtotargettheinvolvedexontoallowproductionofatruncatedformof dystrophinandcanimprovemusclestrength.

Prognosis.DMDisrelentlesslyprogressive.Withcurrenttherapies,mostpatientstodaywillsurvive theirteenageyears.Almosthalfofpatientswillsurvivetoage25years,andsome,withassistive ventilation,canliveintotheirthirties.

https://t.me/med1917

Box12.10BeckerMuscularDystrophy

BeckermusculardystrophyissimilartoDuchennemusculardystrophy,buttheskeletal

muscularinvolvementtendstobemilder(thedystrophinmutationisincomplete,resultingin someremainingfunctionalprotein),theonsetofthediseaseislater,andcognitivedifficulties aresignificantlylesscommon.Mostpatientsremainambulatorywellintoadulthood. Cardiomyopathy,however,isevidentinmostpatientsusuallybytheteenageyears,leading tohigh-gradeconductionblocksandcongestiveheartfailure.

Therearemanyothermusculardystrophies,toomanytocoverinthistext.Here,though,aretwoyou shouldbefamiliarwith.

Fascioscapulohumeraldystrophy(FSHD).Isanautosomaldominantdisease.Itprogressesmoreslowly thanDMD,withsignificantsymptomsfirstappearinginadolescence.Characteristicsignsincludefacial weakness,scapularwinging,andabnormalitiesoftheshouldergirdle.Weaknessofthelowerabdominal musclescanresultinapositiveBeevorsign(notuniquetoFSHD,butoftenassociatedwithit),inwhich thereisupwardmovementoftheumbilicusuponneckflexionwhileinasupineposition.

(A)Scapularwingingand(B)BeevorsigninpatientswithFSHD.

Myotonicdystrophy.Comesintwomajortypes,DM1andthelesssevereDM2.Bothareautosomal dominant.Theformeristheresultofanexpandedcytosine-thymine-guanine(CTG)repeatinthemyotonic dystrophyproteinkinasegene,thelatterofanexpandedCCTGrepeatinazincfingerprotein.

Bothtypesofmyotonicdystrophyarecharacterizedbyprogressiveskeletalmuscleweaknessand myotonia,atermthatreferstoimpairedrelaxationofthemusclesfollowingcontraction.Onewaytotest thisistohavepatientsgripyourfingerandthentrytoreleasetheirgrip;therelaxationphasewillbe noticeablydelayed.AnEMGwillshowabnormal,spontaneousmyotonicdischarges(classically describedassoundinglikea“divebomber”)thatoccuratrestandafterrelaxationbegins.Other associatedfeaturesincludecataracts,cardiomyopathy,frontalbaldnessandvariousendocrinedisorders. EMGandDNAanalysiswillconfirmthediagnosis.

TohelpyoudistinguishbetweenDM1andDM2:

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DM1 is the more severe form. Weakness is typically distal rather than proximal and characteristicallyaffects thefacial muscles, intrinsic hand muscles, and footdorsiflexors, causing footdrop.Ptosis,impairedextraocularmovements,dysphagia,anddysarthriaarecommon. DM2 predominantly causes proximal weakness. Pain is more common, but cardiomyopathy and endocrineabnormalitiesarerare.

LifeexpectancycanbereducedforpatientswithsevereformsofDM1,butbothformscanbe compatiblewithlonglife.

MetabolicMyopathies

Theseraredisordersresultfromdefectsinenergymetabolism.If,foramoment,wecanaskyoutoreach backtoyourhalcyondaysinbiochemistryclass,youwillrecallthatATP,theprimarysourceofcellular energy,isgeneratedbythebreakdownofglycogen,glucose,andfreefattyacids.Whenaninherited mutationcompromisesoneoftheenzymesthatiscriticalforoneofthesepathways,theresultingenergy deficitcanleadtosignificantweakness.Somepatientsfirstpresentininfancy,someinadulthood.

Thinkofthesedisorderswhenyouhaveapatientwithunexplainedexerciseintolerance.Thereare threemaincategoriesofmetabolicmyopathytobefamiliarwith(manyofthesearediscussedfurtherin Chapter17).

1.  Disorders of glycogen metabolism. These are autosomal recessive disorders caused by impaired glycogen breakdown. The key featureisexerciseintolerance;bothisometricexerciseandsustainedaerobicactivitiesbringonfatigue,cramps,andmyalgias.TheCK is elevated evenat rest. Diagnosisrelies upon clinicalpresentation,familyhistory,laboratory abnormalities and, increasingly, genetic testing.Treatmentvaries,butoftencentersondietmodificationandenzymereplacementtherapy.

2.  Disorders of lipid metabolism. The most common of these are the result of various defects in the carnitine cycle, resulting in abnormalfattyacid oxidation.Themostcommoniscarnitine palmitoyltransferaseII deficiency.Theinfantile formisrapidly fatal, whereas the adult-onset form is less severe and presents with exercise intolerance and episodes of rhabdomyolysis. A high carbohydratedietcanpreventsymptomaticattacks.

3.  Mitochondrial myopathies. These disorders are due to mutations in mitochondrial DNA and can present with a wide range of symptoms.Themyopathycanbeisolatedorcanbejustonecomponentofanillnessthatimpactsmultipleorgansystems.Themyopathy itself can range from mild exercise intolerance presenting in adulthood tofatal infantile forms. Resting levels of lactate are almost alwayselevatedandkeytomakingthediagnosis.

Box12.11Rhabdomyolysis

Theacutebreakdownofmusclecellswiththeresultantreleaseoftheirintracellularcontents intothecirculationistermedrhabdomyolysis.CKlevelscangoskyhigh,andmyoglobinuriais present.Thereleaseofintracellularmusclecontentscanleadtosevereelectrolyte imbalancesandacuterenalfailure.Potentialtriggersarenumerousandinclude:

Manyofthedisorderswe’vediscussedinthischapter,includingbothinflammatory(rare) and noninflammatory (most common with the metabolic) myopathies; always consider statin-inducedrhabdomyolysisinanyonetakingoneofthesedrugs. Acutetrauma,suchascrushinjuriesandlightningstrikes Prolongedimmobilization Compartmentsyndrome Extremephysicalexertion(runningamarathoninhot,humidweather)

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Especiallycommoninuntrainedorundertrainedindividuals,butanyonecangetheatstrokewithrhabdomyolysis ifthestressisgreatenough

Neardrowning,probablyfromprolongedhypothermia Prolongedgeneralizedtonic-clonicseizures Deliriumtremens Overdosingondrugs,includingamphetaminesandcocaine Malignanthyperthermia Neurolepticmalignantsyndrome Hypokalemia Hypophosphatemia

Rhabdomyolosiscanoccurfromextremeexertion.

Inpatientswithtrauma,thenatureofthetraumawilldominatetheclinicalpicture,butinmost

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othersettingsthechiefcomplaintwillbemyalgias,andpatientsmaydescribepassingbright redurine.Muscleswillbetenderonexamination.

Laboratorytestingwillrevealelevatedmuscleenzymesandmyoglobinuria.TheCKtakes severalhoursbeforeitwillbeseentorise,peakingin1to3daysandthendecliningoverthe nextfewdays.Myoglobinhasahalf-lifeofonly2to3hours,soitmaynotbepresentbythe timeyouseethepatient.Justareminder—myoglobinwillbereadasbloodonaurine dipstick,butmicroscopywillrevealanabsenceofredbloodcells.Electrolytesshouldbe checked—inparticular,anticipatethepossibilityofhyperkalemia,whichcancauseserious cardiacarrhythmias.Themostfearedcomplicationofrhabdomyolosisisacuterenalfailure. Renalinjuryinrhabdomyolysiscanhavemanycauses,includingmyoglobinitself,whichis toxictothekidneys.

Intensivefluidreplacementisessentialtosuccessfulmanagement.Electrolytedisturbances shouldbemonitoredandtreatedifneeded.

CriticalIllnessMyopathy.Wecan’tleavethesubjectofmyopathywithoutbrieflydiscussingacommon sourceofweaknessseeninpatientswhoarecriticallyill.Theword“common”isactuallyan understatement:ithasbeenestimatedthatasmanyas11%ofpatientsdevelopsomedegreeofcritical illnessmyopathy(CIM)within1dayofbeingadmittedtoanintensivecareunit,anumberthatrisesto 67%forpatientswhoareonmechanicalventilationforatleast10days.

CIMtypicallypresentsasflaccidpredominantlyproximalmuscleweaknessofthelimbsand respiratorymuscles;thelattercanmakeitdifficulttoweanpatientsoffofmechanicalventilation.Critical illnesspolyneuropathy(CIP)canalsodevelop,characterizedbyadistal,symmetricstocking-glove sensory-motorpolyneuropathywithdiminisheddeeptendonreflexes.Somepatientsdevelopa combinationofthetwo.

Thepathogenesisisnotknown,buthypothesesabound,includinginflammation,immobilization, nutritionaldeficiencies,andthetoxiceffectsofmedicationsusedintheintensivecareunit(particularly corticosteroidsandneuromuscularblockingagents).Generally,thesickerthepatient(e.g.,thosewith sepsisormultiorganfailure),thegreatertheriskofdevelopingCIMorCIP.

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