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Ростовский Государственный Медицинский Университет

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12DiseasesoftheMusclesandthe NeuromuscularJunction

Inthischapter,youwilllearn:

1. Howtodistinguishbetweendisordersofthenerves,neuromuscularjunction,andmuscles

2. How to recognizeand treat diseases of theneuromuscular junction, such as myasthenia gravis

3. How to recognize and treat inflammatory myopathies (e.g., polymyositis) and noninflammatorymyopathies(e.g.,muscularcomplaintscausedbytheuseoflipid-lowering statins)

4. Howtodiagnoseandmanagepatientswithrhabdomyolysis

CASE12

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YourPatient:Carol,a33-year-oldlaboratorytechnician,comestoseeyouforseveral

episodesofdoublevisionanddroopyeyelidsoverthepastfewweeks.Shehasalsostarted toexperienceoccasionaltroubleswallowingandattheendofeachdaythinkshervoice soundsfunny—quieterthannormalandmorenasal-sounding.Despitetheseconcerns,her examinationinyourofficeisnormal.Whatisgoingon?

Ifyou’vebeenfollowingalongchapterbychapter,youmayhavenoticedthatwehavebeendescending throughthecentralnervoussystemandintotheperipheralnervoussystem.We’venowreachedtheouter provincesofneurology,theneuromuscularjunctionandthemusclesthemselves.

Asyouwouldexpect,thisisachapterlargelyaboutweakness,andweaknesshasaprettybroad differentialdiagnosis.We’vealreadyseenthatbothcentralandperipheralnervoussystemdisorderscan leadtoweakness,rangingfrommilddebilitytofullparalysis.How,then,arewetoknowwhenmuscular diseaseitself,asopposedtodiseaseofthecentralnervoussystem,peripheralnerves,orneuromuscular junction,istheculprit?

FiguringOuttheCauseofWeakness

Weaknesscanbecausedbydiseaseprocessesextendinganywherefromthecerebralcortextothe musculature.Itcanresultfromahostofgenetic,infectious,inflammatory,toxic,metabolic,andmalignant processes,inotherwords,diseasesthatarenotprimarilyneurologicatall.Thus,patientswitharthritis maydescribetheirjointsymptomsasweakness.Patientswiththeflu,chronicfatiguesyndrome,chronic lungdisease,orasleepdisordermaydescribetheirprimarysymptomasweakness,althoughcareful questioningmayrevealthatwhattheyreallymeanisfatigueorlackofenergy.And,ofcourse,weakness canbeacomplaintofpatientssufferingfromdepression,anxiety,orjustplainlackofmotivation.Howdo wesortoutallthesepossibilities?Thegoodnewsisthatifwerelyonourneurologictoolbox,wewill almostalwaysbeabletoarriveatthecorrectdiagnosiswithouttoomuchdelay.

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Weaknessisintheeye(andbody)ofthebeholder.

Thehistoryisalwayscritical.Oneofthewaystoseparateoutgeneralizedwearinessfromtruemuscle weaknessistoaskyourpatientsiftheyfeelweakallthetimeorjusthavedifficultywithspecificefforts (e.g.,climbingstairsorreachingoverheadtogetsomethingdownfromahighshelf).Theformeroften reflectsanunderlyingsystemicorpsychosocialcause,whereasthelatterismoresuggestiveofa neuromuscularissue.Certaincomplaintsshouldbeviewedasredflagsforanurgentevaluation:

Rapidlyprogressiveweakness(overoneorseveraldays) Compromisedabilitytowalk Shortnessofbreath Bulbar symptoms (meaning symptoms due to compromise of cranial nerves 9 to 12, such as dysphagia)

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Alteredbowelorbladderfunction

Thephysicalexaminationshouldalwaysincludestrengthtestingandcarefulassessmentforsignsof bothuppermotorneuronandlowermotorneuroncompromise(seepage20).Asageneralprinciple(and

animportantonetoremember!),mostprimarymusclediseases(myopathies)affecttheproximal musculature—theneck,back,deltoids,andhipflexors—whereasperipheralpolyneuropathies predominantlyaffectthedistalextremities,atleastatfirst(asyouwillsee,however,thismaximis

notwritteninstone).Mostmusculardiseasesaresymmetric,sofindingfocallesionsismoreindicativeof aneurologicprocess,forexample,carpaltunnelsyndromeorbrachialorlumbarplexopathy.

Laboratorytestingcanruleinoroutmanyofthepotentialcausesofweakness.Aprimarymuscular diseaseissuggestedwhenserummuscleenzymesareelevated;theseincludealdolase,creatinekinase, thetransaminases,andlactatedehydrogenase.Myoglobinuriaispresentwithrhabdomyolysis.Screensfor othercausesofweaknessincludeathyroidstimulatinghormonetest(TSH,forthyroiddisease),serum electrolytes(especiallylookingforhypokalemia,butalsohypo-orhypernatremiaanddisturbancesin calciumandphosphorusmetabolism),urinetoxicologyscreens,andtestingforconnectivetissue disorders(suchaspoly/dermatomyositisandvasculitis).Genetictestingisindicatedwhenyoususpect oneofthemusculardystrophiesorotherinheriteddisordersofthemuscle.Thisisnotacomprehensive list,andyourclinicaljudgmentshouldguideadditionaltesting.

Finally,nerveconductionstudies(NCS)andelectromyography(EMG)canhelppindownthetype andsiteoftheunderlyingdisorder.Imagingisrarelyuseful.Musclebiopsyofaninvolvedmusclecanbe helpfulwhenaninflammatorymyopathy,suchasdermatomyositis,issuspected.

CausesofWeakness—AnAnatomicApproach

AnatomicSite Example

Uppermotorneuron Braintumor Lowermotorneuron Guillain-Barre,diabeticneuropathy Upperandlowermotorneuron Amyotrophiclateralsclerosis Neuromuscularjunction Myastheniagravis Muscle Seecausesofmyopathybelow

CausesofMyopathy

(myopathywillbediscussedstartingonpage317)

GeneralClassification Examples

Inflammatory(seeBox12.1) Polymyositis(PM)

Dermatomyositis(DM) Inclusionbodymyositis(IBM) Immune-mediatednecrotizingmyopathy(IMNM)

Noninflammatory Drug-Related:statins,steroids,alcohol

Electrolytedisorders:hypokalemia,hypophosphatemia Infections:viral(HIV,influenza),bacterial(Lyme) Endocrinedisorders:hypo-orhyperthyroidism Dystrophies:Duchenne,myotonic Metabolic:Glycogenandlipidstoragediseases

Box12.1UpdatingtheWayWeThinkAbouttheInflammatoryMyopathies

Thereisarevisedclassificationsystemfortheinflammatorymyopathiesthatisbecoming increasinglypreferredbyexpertsinthefield.Traditionally,theinflammatorymyopathieshave

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beenclassifiedastheyareintheprecedingtable:polymyositis,dermatomyositis,inclusion bodymyositis,andimmune-mediatednecrotizingmyopathy.However,thesesyndromes, oncebelievedtorepresentuniqueanddistinctentities,turnouttohavesignificantoverlapin termsofclinicalphenotypeandassociatedantibodies.Amorerecentclassificationsystem hasproposednewdivisionsbasedonclinicalmanifestationsandmyositis-specificantibodies. Thisisnotjustanacademicexercise,butmayprovetohaverealclinicalutility.The diagnosticcategoriesthathaveemergedare:

Dermatomyositis (most often associated with anti-Mi 2, anti-MDA5, or anti-TIF1y antibodies) Inclusion body myositis (associated with vacuolated fibers and mitochondrial abnormalitiesonhistology) Immune-mediatednecrotizingmyopathy(associatedwithanti-SRPoranti-HMGCR) Antisynthetase syndrome (most often associated with anti-Jo1 or anti-PL7 antibodies; clinically this is verysimilar to dermatomyositisbut is associated withsignificantly less severemuscledeficits)

Ofinterest,patientswhohavetraditionallybeenclassifiedashavingpolymyositisdonot appeartorepresentadistinctsubgroupofpatients,andithasbeensuggestedthatthisterm oughttobediscontinued.Wehavechosentolettheoriginalcategoriesstand,becausemuch oftheworldstillthinksthisway,butit’simportanttobeawarethatthisnewclassification exists,andthat,inreality,polymyositisisamuchlesscommonsyndrome,ifitexistsatall, thanpreviouslybelieved.We’llgettoalltheimportantdetailsofthevariousmyopathiesina bit.

DiseasesoftheNeuromuscularJunction

MyastheniaGravis

ClinicalManifestations.Myastheniagravisstandsoutfromalltheothercausesofweaknessbecauseof onenotableclinicalfeature:fatigability.Whatdowemeanbythis?Simplythatmuscleweakness worsenswithrepeateduse.Nootherdisorder,noneuropathyormyopathy,causesthisphenomenon.You, theexaminer,canmissthisunlessyoulookspecificallyforit,becausetheweaknesstypicallyvaries throughouttheday;insomepatientsitcanappearanddisappearoveramatterofminutes.Theweakness isusuallyworseafterexerciseandlaterintheday.Themostcommonlyaffectedmusclesinclude:

 Ocular muscles. Almost all patients with myasthenia will have ocular muscle weakness, which typically presents as either ptosis or diplopia. Unlike limb muscle weakness, ocular muscle weakness is often asymmetric. A small percentage of patients with myasthenia experience only ocular symptoms (this entity is termed “ocular myasthenia”; interestingly, around 50% of these patientsareseronegativeforantibodiesagainsttheacetylcholinereceptor;seepage311).

Box12.2TheOcularMuscles

Theocularmusclesincludethosethatareresponsibleforeyemovement(thesuperior,inferior,medialandlateralrecti,

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and thesuperiorand inferior obliques), involvementofwhich cancausediplopia,and thelevator palpebrae, which is responsibleforsuperioreyelidopeningandwhichcancauseptosiswhen affected.Ocular myastheniacanalsoaffect theorbicularisoculimuscle,whichclosestheeyes,resultinginweakeyelidclosure.

Bulbarmuscles.Symptomsincludedysarthriaanddysphagia.Patientsoftenreportachangeinthe quality of their voice (often described as “nasal” sounding), difficulty drinking through a straw, inabilitytowhistle,asensationoffoodgettingstuckinthethroat,andjawmuscleweakness. Neckmuscles. Neckflexionisusually affected morethanextension,which canresultin“dropped head”syndrome,aninabilitytokeeptheheadupright,oftenmostapparentattheendoftheday. Limbmuscles.Aswithothermusclediseases,theproximalmusclesarepredominantlyaffected. Respiratorymuscles.Asyoucanimagine,involvementoftherespiratorymusclescanbedangerous. Severe respiratory muscle weakness resulting in respiratory failure that requires intubation and mechanicalventilationiscalled“myastheniccrisis”;moreonthisinabit.

Box12.3VitalCapacity,NegativeInspiratoryForce,andPositive ExpiratoryForce

Don’tworry,youhaven’taccidentlypickedupapulmonologytextbook.Butpermitusjusta quickwordontheseparameters,sincetheyarethebestwaytomonitorforimpending respiratoryfailureinpatientswithmyasthenia.Inspiratoryforceismeasuredbybothvital

capacity(VC)andnegativeinspiratoryforce(NIF);expiratoryforceismeasuredbypositive expiratoryforce(PEF).Myastheniacanaffectbothinspiratorymuscles(primarilythe

diaphragmandexternalintercostals)andexpiratorymuscles(primarilypassive,but abdominalandinternalintercostalscanberecruited).Asaresult,allpatientswhoare admittedtothehospitalwithamyasthenicflareshouldhavetheseparameterscheckedat leastonceifnottwooreventhreetimesaday,dependingontheseverityoftheir presentation.The20-30-40ruleisagoodonetoremember:VClessthan20mL/kg,anNIF lessthan30cmH2O,oraPEFlessthan40cmH2Ocanallindicateimpendingrespiratory

failureandshouldpromptimmediateevaluationforintubation.

Onexamination,neckflexorweaknessandsomethingcalledthesinglebreathtesthaveboth beenshowntobegoodsurrogatemarkersofrespiratoryfunction.Thesinglebreathtestis performedbyhavingpatientstakeadeepbreathinandthen,ontheexhale,countashighas possibleuntiltheyrunoutofbreath(theabilitytoreach50indicatesnormalrespiratory function).

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Testingneckflexorstrength.Thepatientshouldpushforwardintoyourhand,whileyouactivelypush againstthem.

Box12.4Ptosis

Ptosisoftheeyelid.

Thedifferentialdiagnosisfortheunderlyingcausesofptosisisagoodonetofileaway:it’s

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short,forone,andincludesrelativelycommondiagnosesthatareimportanttosortout.

Myastheniagravis.  Third cranial nerve palsy. This classically presents with a “down and out” eye, mydriasis, andptosis(often completeptosisinwhichtheeyeappearsfullyclosed)due to dysfunction of the levator palpebrae muscle. Patients most often report horizontal diplopia.WewilldiscussthisindepthinChapter18. Hornersyndrome.Thisischaracterizedbytheclassictriadofipsilateralptosis(usually incomplete),miosis,andfacialanhidrosis.Itcanbecausedbyalesionanywherealong thesympatheticpathway(seeBox12.5). Aponeurotic,orsenile,ptosis.Thisentityisquitecommonandiscausedmostoftenby changesin thelevator aponeurosis(part of the apparatus that elevates the eyelid) as weage.Theabsenceofanyotherneurologicfindingsinanolderpatientshouldsuggest thisdiagnosis.

Box12.5HornerSyndrome

Takealookattheanatomicaldrawingofthesympatheticnervoussystemthatpertainsto HornerSyndromebelow.Givesyoupause,no?ButtheanatomyunderlyingHornersyndrome isn’tascomplicatedasitlooks.It’sa3-steppathway.

The first-order neurons travel from the hypothalamus down into the brainstem and cervicalspinalcordandsynapseonthe: Second-orderneuronsinthelateralhornofthe spinalcord(attheciliospinal centerof budge, usually around C8–T2). The second-order (or preganglionic) neurons then exit thecord and loop back up through the brachial plexus, over the apex of the lung and underneaththe subclavianartery,to synapseon thethird-order neuronsin the superior cervicalganglion. The third-order (or postganglionic) neurons run on the surface of the common carotid artery andultimatelyseparateouttowardtheir specifictargets;these include the facial sweat glands, pupillarydilator muscle, and thesuperiortarsal muscle (Muller muscle), whichhelpstoelevatetheuppereyelid.

CommoncausesofHornersyndromeinclude:

1. Lesionsoffirst-orderneurons:brainstemstrokesortumors,spinalcordlesionsaboveT1

2. Lesionsofsecond-orderneurons:pancoasttumors(tumorsofthesuperiorpulmonarysulcus),thyroidcancer

3. Lesionsofthird-orderneurons:carotiddissection,cavernoussinusthrombosis

Finally,forthoseofyouwholovenothingmorethanadeepdiveintoneuroanatomy,youwill wanttonotethatthesympatheticsweatfiberssplitfromtheothersympatheticfibersnear thelevelofthecarotidbifurcation.Thefiberstravelingtowardthepupillarydilatormuscleand Mullermusclecontinuetorunontheinternalcarotidartery,whereasthoseheadedtoward

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thesweatglandsbranchofftorunontheexternalcarotidartery.Therefore,lesionsabove thispointwillpresentwithptosisandmiosisbutnotanhidrosis.

TheanatomyunderlyingHornersyndrome;thefirst-orderneuronisinred,thesecond-orderinorange, andthethird-orderinblue.

Pathogenesis.Acetylcholinebindstotwotypesofreceptors:thenicotinicreceptor(located-most importantly,forourpurposes-attheneuromuscularjunction),andthemuscarinicreceptor(locatedonthe parasympathetictargetend-organs).Myastheniagravisiscausedbyautoantibodiesthatblockthe postsynapticnicotinincacetylcholinereceptors(AChRs)attheneuromuscularjunction,therebyreducing neurochemicaltransmissionacrossthesynapse.Approximately80%ofcasesareassociatedwithAChR antibodies.IncasesthatarenotassociatedwithAChRantibodies,approximatelyone-thirdwillbefound tohavemuscle-specifictyrosinekinase(MuSK)antibodies,whicharethoughttomediateclusteringofthe acetylcholinereceptorsduringdevelopment.Stillotherpatientsareconsidered“seronegative”(although otherautoantibodies,includinganti-LRP4,anti-titin,andanti-ryanodinereceptorantibodieshavebeen

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