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This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Theimmune-mediatednatureofMGwassuspectedasearlyas1960whenSimpsonspeculatedthatitwasanautoimmunediseasewithantibodiesdirectedagainstthenicotinicskeletalmuscleAChR.Thishypothesiswascon-rmedinthe1970swhenLindstromandcolleaguesdevel-opedananimalmodelofexperimentalautoimmunemyastheniagravis(EAMG)byimmunizingrabbitsandratswithhighlypuriedAChRfromtheelectricorganoftheeel.AChRantibodieshavebeenshowntoreducethenumberoffunctionalAChRsbyseveralmechanisms:acceleratedturn-overbycross-linking,complement-dependentlysisofthepostsynapticmembrane,anddirectblockadeofacetylcho-line-bindingsites.Inlightoftherelativelywell-characterizedimmune-mediatednatureofMG,itisnotsurprisingthatimmunotherapyplaysakeyroleinitseffectivemanagement.OverviewofTreatmentThetreatmentofMGhasimproveddramaticallyoverthelastfewdecades,withintroductionofanincreasingnumberofimmunotherapies.Ingeneral,theobjectiveoftherapyistoreturnpatientstonormalfunctionasexpeditiouslyaspossi-ble,whilelimitingsideeffectsandcosts.Withoptimaltherapy,mostpatientscanreturntoproductivelives,andthereisessentiallynomortality.Treatmentfocusesonanticholinesterases,immunosuppressiveagents,thymecto-my,andshort-terminterventionsplasmaexchange(PEx)andintravenousimmunoglobulin(IVIg).Treatmentshouldbeindividualized,andthereisnosingleregimenthatisappro-priateforallpatients.Theaggressivenessofmanagementshouldbeweighedrelativetoseveralfactorsincludingdis-easeseverity,distributionofinvolvement,rateofprogression,degreeoffunctionalimpairment,lifestyleandcareerchoices,coexistingdisease,andpatientageandgender.Theprognosiswithtreatmentisgenerallyfavorable.Inarecentsurvey,only4%ofpatientsfollowedforatleast12monthshadmoderateorseveredisability,althoughamilddegreeofocularorgener-alizedweaknesspersistedinthemajority.AnticholinesteraseAgentsRationaltherapeuticuseofcholinesteraseinhibitorsdatesbacktothesecondhalfofthe19thcentury,whenCalabarbeanextractwasgivenasanantidoteforatropinepoisoningandphysostigminewasrstusedtotreatglaucoma.In1934,WalkerintroducedtheuseofanticholinesterasesinMGwhenshereportedthatphysostigminesalicylateinjectionsproduceddramatic,thoughtemporary,improvementina56-year-oldwoman.Today,thesyntheticquaternaryammo-niumcompoundpyridostigmineisthemainstayofanticho-linesterasetherapyinMGbecauseoflimitedcentralnervoussystem(CNS)toxicity.CholinesteraseinhibitorsareoftentheinitialinterventioninMG.TheseagentsinhibittheenzymatichydrolysisofAChbyacetylcholinesteraseatthesynapse,allowingtheneurotransmittertoaccumulateattheNMJ,prolongingitsactivity,andincreasingthenumberofneuro-transmitter-receptorinteractions.Aclinicalresponsetopyr-idostigminegenerallybeginsin15to30minutesandlastsupto3to4hours,althoughawearing-offeffectmayoccurbeforethen.Initialdosesof30to60mgevery4to6hoursaretypical.Dosescanbetitratedupwardto90120mgtomaximizetheclinicalresponse,butregimensexceeding120mgevery3hoursareunlikelytohaveaddedbeneandwilllikelyproducecholinergicsideeffects.DosingequivalentsforothercholinesteraseinhibitorsandpediatricdosesareshowninTable1.A60mg/5mlelixirofpyridos-tigmineand2mginjection(equivalentto60mgadminis-teredorally)arealsoavailable.MestinonTimespan(ValeantPharmaceuticalsInternational,MontrealQuebec,Canada),atimed-release180mgpyridostigminetablet,isoccas

ionallyprescribedatbedtimeforpatientswhoawakeninthemiddleofthenightorinthemorningwithmyasthenicsymptoms.However,absorptionofthetimed-releaseprep-arationisunpredictable,andmanyMGexpertsdonotrecommendit.Properdosingofpyridostigminerequiresindividualiza-tion.Patientsoftenlearntoself-adjustthedoseforoptimal Figure12Hzrepetitivenervestimulationofthemediannerve,demonstratingasignicantamplitudedecrementpeakingat25%onthefourthwaveformofthetrain.Notethatthegreatestabsolutedecrementof14%isobservedbetweentherstandsecondwaveforms,typicalforthedecrementalpatternseenonslowratesofrepetitivenervestimulation.SeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe benet.Forpatientswithpurelyoculardisease,ptosisoftenimproves,butdiplopiamaynotresolvecompletely.Insettingsofsevere,unilateralptosis,anticholinesteraseagentsmayunmaskdoublevisionbyraisingtheloweredlid,andthismayprovetobeevenmoredisabling.Overall,20to40%ofocularMGpatientsrespondsatisfactorilytoanticholinester-ases.MuSKMGpatientstendtorespondpoorlytothem.15,16Themostcommonadverseeffectsofthecholinesteraseinhibitorsaremuscarinicinnature,includinggastrointestinalcramps;diarrhea;nauseaandvomiting;increasedlacrimal,salivary,andbronchialsecretions;andsweating.Oralgly-copyrrolate(1mg),hyoscyaminesulfate(0.125mg),atropine(0.4mg),orover-the-counterloperamidecanbeprescribedonanas-neededbasisorprophylacticallywitheachpyridos-tigminedosetolimitthesesideeffects.Nicotinictoxicityincludesmusclecramping,fasciculations,andweakness.ThymectomyThymectomyhasbeenacomponentofMGmanagementforover70years.In1939,BlalocketalreportedimprovementofgeneralizedMGina21-year-oldwomanfollowingremovalofacysticthymictumor.InhissubsequentreportofsixMGpatientswithoutthymomawhounderwentthymectomy,onebecamesymptom-free,twosignicantlyimproved,twohadmildbenet,andoneexpired.Thepresenceofthymomaprovidesaclearindicationforthymectomy.ThereisageneralconsensusthatgeneralizednonthymomatousMGpatientsbetweenpubertyand60yearsofagewillalsobenetfromthymectomy.However,randomizedstudiesofthymectomythatcontrolformedicaltherapyhaveneverbeenperformed.Ina1977analysis,remissionratescompiledfromalargerseriesdidnotportrayasignicantdifferencebetweenthesurgicalandnonsurgicaltreatmentgroups.In2000,anevi-dence-basedpracticeparameterfromtheAmericanAcademyofNeurology(AAN)analyzedretrospective,controlled,non-randomizedstudiesofthymectomyinnonthymomatousMG.Atotalof28studiespublishedbetween1953and1998wereidentied.Theeffectofsurgerywasbroadlyfavorableinmostseries.However,thebenetofsurgerywasgenerallysmall.Forexample,themedianrelativeratefavoringsurgeryovernonsurgicaltreatmentforachievingremissionwas2.1,amodestgainwhenconsideringthatthemedianremissionrateinthenonthymectomizedgroupswas10%.Othermedianrelativerateswere1.6forasymptomaticstatus,1.7forimprovement,and1.1forsurvival.Patientsubgroupanalysisindicatedthatonlythosepatientswithmoderateweakness(Osserman2b)orgreatershowedasignicantimprovementfollowingthymectomycomparedwithcontrols.Importantly,themodestbenetsascribedtothymectomywereconfoundedbybaselinedifferencesbe-tweenthesurgicalandnonsurgicalgroups.Nostudyincludedblindedassessments.Inthosefewstudiesthatemployedamatcheddesignwithanattempttocontrolformultipleconfoundingvariables,aconsistentbenetfromthymectomywasnotobserved.TheAANpracticeparameterconcludedthatthymectomyshouldbeconsideredatreatmentoptionpatientswithoutthymoma.Toaddressthisuncertainty,aninternational,NIH-supported,prospective,single-blinded,randomizedtrialcontrollingformedicaltherapyhasbeenorganizedinnonthymomatousMGandbeganenrollingpatientsinlate2006.Intermsofextentofresection,transsternalthymectomyapproachesarestillroutinelyperformedbecausetheypermitgreaterthymictissueremoval.Recentevidence,however,suggeststhattranscervicalandinfraaxillaryvideo-assistedapproachesallowasimilarextentofremovalwithquickerrecoverytimesandshorterpostoperativehospitalstays.24,25Robotic-assistedsurgeryhasproventobeasafeandeffectivetechniqueandisassociatedwithshorterrecoverytimesandsimilarratesofimprovementcomparedwithtranssternalapproaches.26,27Nevertheless,thereremainsevidencetosupporttheviewthatthegreatertheresection,thebetterthelong-termresults.Usingamaximalthymectomyapproachthatincludesbothtranscervicalandtranssternalincisions,life-tableanalysesdemonstratedan81%remissionrateat7.5years.Comparativeremissionratesfortrans-cervicalapproacheshavebeeninthe30to45%rangeat7years,50%at6yearsusingeitheranextendedtranssternaloravideo-assistedthorascop

icprocedurethatincludesatransversecervicalincision.Inaretrospectivereviewof54patientswhounderwenttranssternalthymec-tomy,Takanamifoundthat67%ofpatientsdemonstratedimprovement(including9%incompleteremission),and33%ofpatientshadnochangeinsymptoms.Shorterdiseasedurationpriortosurgery(24months)andmoreadvancedMyastheniaGravisFoundationofAmerica(MGFA)classica-tionsstatusbeforesurgerywerethebestpredictorsoffavorableoutcome.Itshouldbenotedthatremissionratesinsurgicalseriesoftenareunexpectedlyhigh.Denitionsofremissionaswellastheirdurationvarybetweenstudies,and Table1EquivalentDosingofAcetylcholinesterase(AChE)InhibitorsAChEInhibitorOralDoseIMDoseIVDosePediatricOralDosePyridostigminebromide(Mestinon)60mg2.0mg0.7mg1.0mg/kg;upto7.0mg/kg/dindivideddosesNeostigmine15mg1.5mg(methylsulfate)0.5mg(methylsulfate)0.3mg/kg;upto2mg/kg/dindivideddoseschloride(Mytelase)7.5mg0.150.3mg/kg;upto1.5mg/kg/dindivideddosesIM,Intramuscular;IV,intravenous.SeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe 217 theretrospectivedeterminationoftheseoutcomesiscertain-lyopentobias.21,28Nomattertheapproach,thymectomyshouldnotbeperformedasanemergentprocedure.PExorIVIgcanbeusedtostabilizepatientswithmoreseverediseasepriortosurgery.BecausemostpatientswithMGhavenothymoma,howcanthepracticingneurologistcometotermswithuncertain-tiessurroundingtheroleofthymectomyandcommunicateeffectivelywithpatients?Atthispoint,itisreasonabletoadvisepatientsthatmorelikelythannottheywillimproveafterthymectomy.However,suchstatementsshouldbebalancedbyinformingthemthatpotentialbenetshavenotbeenestablishedinrigorousclinicalstudies,andthatremissionandimprovementareknowntooccurwithoutthymectomy.Furthermore,itwouldbemisleadingtoguar-anteeimprovementafterthymectomyorgiveaxedtimeta-bleforclinicalbeneThymectomyisgenerallynotarst-orsecond-lineap-proachinpatientswithpureocularMG.Oneretrospectivereviewof110patientswithocularmyastheniawhounder-wentextendedtranssternalthymectomy,however,demon-stratedthat84.6%patientsexperiencedsymptomaticimprovementaftermedianfollow-upof33.5months.Thy-mectomyisprobablylesseffectiveintheelderly,andmostMGexpertsdonotadvocateitsuseinthisgroup,withcutoffagesrangingbetween50and70years(median60years).Thymectomyhasbeenperformedwithfavorableresultsinchildhoodeveninpatientslessthan5yearsofage.35,36Itsuse,however,remainscontroversialintheyoungestchildren,withrecommendedloweragelimitsrangingfrom1yeartopuberty.CorticosteroidsCorticosteroids,therstimmunosuppressantstobewidelyusedinMG,producemarkedimprovementin80%ormoreofpatients.37,38Despitetheabsenceofcontrolled,randomizedstudies,corticosteroidsareconsideredbymanyMGexpertsasthemosteffectiveoralimmunosuppressiveagent.Inastudyof116patients,prednisoneproducedremissionin28%,markedimprovementin53%,moderateimprovementin15%,andnoimprovementinonly5%.Theclinicalresponseisrelativelyrapid,observedwithintherst2to4weeksondosingof1to1.5mg/kg/d(Table2).Ifapositiveresponseisapparentinthistimeframe,patientscanbeswitchedtoanalternatedayregimenof1to1.5mg/kg/dafter4weeks.Morerefractorypatientsrequiredailydosingfor2to3monthsbeforeasloweralternate-daytapercancommence.Themeanresponsetomaximumbenetis5to6months.Arecentstudyof35MGpatientsdemonstratedthatprednisonewassuperiortopyridostigmineinimprovingocularsymptomsandsigns.Completeresolutionofocularsymptomswasseeninonly29%ofpatientsonanticholin-esteraseagentsaloneversus70%ofthosetakingpredni-sone.Itisnoteworthythatarecentretrospectiveanalysissuggeststhatprednisonereducestheincidenceofdiseasegeneralizationat2yearsinpatientspresentingwithpureocularMG.Only7%ofocularMGpatientsreceivingprednisonedevelopedgeneralizeddisease,comparedwith36%receivingonlypyridostigmineornomedication.Nota-bly,anAmericanAcademyofNeurologyQualityStandardsSubcommitteeevidence-basedreviewfailedtouncoverhigh-qualitystudydataonwhichtobaserecommendationsforthepharmacologictreatmentofocularMG.ThereportalsoconcludedthatcorticosteroidsandazathioprineareofuncertainbenetinreducingtheriskofprogressiontogeneralizedMG.Alargemulticentertrialisplannedtoaddressthisquestion.Themainconcernwheninitiatingprednisoneathigherdosesisthetransientworseningthatmayoccur.Pascuzzietalobservedtransientworseningin8.6%ofpatientswhorequiredintubation.Thus,anadvisedpracticeistoadmitMGpatientstothehospitalfor5to7dayswheninitiatinghigh-doseprednisone.Acommonregimenusedtoavoidthesetransientexacerbationsistobeginwithlow-doseprednisoneonalternatedays,startingat10to25mg,increasingthedoseby10mgeveryf

ewdaystoapeakdoseof1.5mg/kgonalternatedays.ThisisausefulstrategyinpatientswithmilderdisabilityorpureocularMGwhereaslowerresponseisacceptable.Afterpatientshaveachievedsignicantimprovement,thereshouldnotbearushtotaperoffcorticosteroids.Prematureorrapidtaperingarecommonmanagementer-rors.Itisbesttotaperslowly,reducingthedosenofasterthan5mgevery2weeks.Onceadoseof20mgeveryotherdayhasbeenreached,taperingatevenslowerratesisadvisable.Otherimmunosuppressantstobediscussedlatercanbeaddedtoprednisoneassteroidsparerstoassistwithtaperingefforts.Priorthymectomydoesnotappeartouencethelikelihoodofasuccessfulprednisonetaper.SideeffectsofcorticosteroidsarecommonandsignicantTable2),occurringintwo-thirdsofpatients.Sideeffectscansubsideatdosesbelow20mgeveryotherday.TheAmericanCollegeofRheumatologyguidelinessuggestthatcalciumandvitaminDsupplementation,alongwithaweight-bearingexerciseprogramthatmaintainsadequatemusclemassaresuitabletherapiesforallpatientsonlong-termcorticosteroids.InthosepatientswhohaveestablishedosteoporosisbeforeinitiationofsteroidtherapyorwhohavedecliningbonemineraldensityvaluesonserialDEXAscans,bisphosphonatesorzoledronicacidshouldbestarted.Theside-effectsburdenhasledsometoquestionwhethercorticosteroidsareoverutilizedinMG.Still,thelowcostandcacyofsteroidsprovideastrongargumentfortheircontinueduse.AmulticenterJapanesesurveyindicatesthattheproportionofMGpatientstreatedwithcortico-steroidsactuallyincreasedfrom50%in1987to64%in19992000.OtherImmunotherapiesAzathioprineAzathioprineinhibitspurinemetabolismandblockscellproliferation,therebyaffectingrapidlydividingcellpopula-tionsincludinglymphocytes.Itremainsthemostestablishedsteroid-sparingagentinMG.InadditiontoitsuseinpatientswhohavehadarelapseduringacorticosteroidtaperSeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe Table2SummaryofimmunotherapiesforMyastheniaGravisAgent(TradeNames)InitialDoseMaintenanceDoseOnsetofActionMajorAdverseEventsLaboratorymonitoringCommentsPrednisone1520mgdaily,increasingby10mgevery21.5mg/kg/d,followedbyslowalternate-daytaper(taperby510mg/mo)4wkHTN,diabetes,weightgain,boneloss,cataracts,GIulcers,psychologicdisorders,glucoseeveryfewmonths;bonedensitymonitoringAdministerinsingledose;ifstartingwithhighdoses(1.5mg/kg)watchforearlyworseningseeninupto½ofpatientsAzathioprine50mgdailyIncreaseby50mgincrementsevery24weekstotargetof23mg/kg10moforinitialresponse.Upto24moforpeakFever,abdominalpain,n/v,anorexia,leukopenia,hepatotoxic,skinrashCBC,LFTs4timesinrstmonth,thenmonthly10%ofpatientscannottoleratebecauseofulikereaction;majordruginteractionwithallopurinolCyclosporin100mgtwicedailyIncreaseslowlyasneededto36mg/kgontwicedailyschedule3moHirsutism,tremor,gumhyperplasia,HTN,hepatotoxic,nephrotoxicCBC,LFTs,BUN/Crmonthly.FollowtroughdruglevelsBioequivalencediffersbetweenpreparations;avoidbrandswitchingwhenpossibleMycophenolatemofetil500mgtwicedaily1500mgtwicedaily212moDiarrhea,vomiting,leukopeniaCBCweeklyfor4wk,every2wkfor4wk,thenmonthlyDiarrheamayresolvebyswitchtothreetimesadaydosingCyclophos-phamide5mg/kg/dCanbeprecededbyIVpulse3mg/kg/d26moAlopecia,leukopenia,nauseaandvomiting,skindiscolor-ation,anorexiahemorrh-agiccystitis,malignancyCBC,chemistrypanel,urinalysisevery24wkIVpulsetherapymaybelesstoxicTacrolimus35mg/dor0.1mg/kg/dIncreaseupto5mg/dfollowingtroughlevels(seelastcolumn)3moHypergly-cemia,hypertension,headache,hyperkalemia,nephrotoxicity,diarrhea,nauseaandvomitingBUN/Cr,glucose,potassium,troughlevelseveryfewweeksinitially,thenlessregularlyInsulin-dependentdiabetesmellitusdevelopedin20%ofpostrenaltransplantpatients.Troughlevelsof89ng/mlhavebeeneffectiveinMGRituximab375mg/mIVevery12wkfor4wkNoneor375mg/mevery10wkforafewmonths3moPruritus,nausea,vomiting,dizziness,headache,angina,cardiacdysrhythmia,anemia,leukopenia,thrombocytopeniaCBCregularlyinmonthoftherapy,cardiacmonitoringinpatientswithpre-existingdiseaseTumorlysissyndromeshouldnotbeanissueintheMGpopulation;premedicatewithacetaminophenanddiphenhydra-mineEtanercept25mgSQtwiceweekly25mgSQtwiceweekly26moInjectionsitereactions,vomiting,rhinitis,upperrespiratorytractinfection,anemia,pancytopenia,vasculitis,centraldemyelinationCBCReactivationofhepatitisBandgranulomatousdisease(TB)isofconcern;avoidinpatientswithheartfailureIntravenousimmunoglobulin(IVIg)2g/kgover25d0.41g/kgevery4wk;canattempttodecreasefrequencyovertime2wkHeadache,asepticmeningitis,nephrotoxic,ischemicevents,uidoverloadBUN/CrAvoidinpatientswithrecentischemiaBUN,bloodureanitroge

n;CBC,completebloodcount;Cr,creatinine;HTN,hypertension;IV,intravenous;LFT,liverfunctiontests;MG,myastheniagravis;n/v,nausea/vomiting;SQ,subcutaneous;TB,tuberculosis.SeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe 219 orwhoareexperiencingadverseeventsfromchronicsteroiduse,azathioprinealsoisusedasarst-lineagent.Retro-spectivestudiesdemonstratethat70to90%ofMGpatientsimproveonazathioprine.51,52However,itsroleishamperedbyadelayedonsetofaction;benetmaybeginasearlyas2months,butmaynotbeseenfor10months,andamaximaleffectmaynotbereachedfor12to24months.Arandomizeddouble-blindtrialcomparedtheuseoforalprednisoloneplusazathioprine2.5mg/kg/dversusprednis-olonealone,providingusefulinsightintoitsroleinMG.Oncepatientsreachedremission,prednisolonewastaperedbyblindedpersonneltotheminimaldosethatmaintainedremission.Medianprednisolonedosingdidnotdifferbe-tweenthetwoarmsat12months,butwassignicantlylowerinthecombinedtherapygroupat24and36months,withasteroid-sparingeffectrstdiscernibleat15months.Patientsreceivingazathioprinehadfewerrelapses,longerremissions,andfewersideeffectswithlessweightgain.At3years,63%ofpatientsreceivingazathioprinehadbeencompletelytaperedoffofprednisolone,comparedwith20%whohadreceivedprednisolonealone.Inanotherstudy,relapsesoccurredinthemajorityofpatientswhodiscontinuedazathioprine.Thesepatientsdidrespondasfavorablyuponreinitiationofazathioprineastheydidwithinitialtreatment,althoughthetimecoursewasnotprovided.Initialresponsestoazathio-prinewereseenwithintherstyear,withcontinuedim-provementthrough3yearsoftherapy.Priortoinitiatingtreatmentwithazathioprine,allpatientsshouldbescreenedforthiomethylpurinetransferase(TPMT)ciency.PatientsthatareheterozygotesformutationsintheTPMTgenehavedifcultymetabolizingthedrugandshouldbeplacedonlowdoseswithclosemonitoringforbonemarrowsuppression.Thosethatarehomozygotesforthemutationshouldnotreceivethedrugatall.InitialandmaintenancedosingandadverseeventsforazathioprinearelistedinTable2MycophenolateMofetilMycophenolatemofetilenteredcommonuseinMGaftershowingpromiseinuncontrolledopenseriesdemonstratingfavorableresponsesintwo-thirdsofpatients.55,56Themostcommondosingregimenis1gtwicedaily.Mycophenolateblocksinosinemonophosphatedehydrogenase,resultinginselectiveinhibitionofB-andT-lymphocyteproliferationbyimpairingpurinesynthesis.Mainsideeffectsarediarrhea,vomiting,increasedriskforinfection,andrarelyleukopenia.Long-termsafetyformycophenolateisstillinquestion.Malignancyratesdonotappearhigherinthetransplantpopulation;however,therearerarereportsoflymphomaorlymphoproliferativedisordersdevelopinginMGpa-tients.57,58Resolutionisgenerallyobservedwithcessationofmycophenolateandappropriatetherapy.AlsoofconcernarerecentreportsfromtheFoodandDrugAdministrationofprogressivemultifocalencephalopathyinsolidorgantrans-plantrecipientsandinpatientswithsystemiclupuseryth-ematosuswhowerereceivingmycophenolicacid.Inaretrospectiveanalysisof85patientsthatemployedMGFApostinterventionclassications,73%achievedphar-macologicremission,minimalmanifestationstatus,orim-provementwithmycophenolate.Mycophenolatehadarelativelyrapidonsetofaction,withimprovementobservedatameanof9to11weeksandmaximalimprovementby6months.However,insomepatientstheinitialresponselaggedupto40weeks.Only6%ofpatientsdiscontinuedtherapybecauseofsideeffects.Unfortunately,tworandomizedcontrolledtrialsfailedtodemonstratethatmycophenolateplusprednisonewasmoresuccessfulthanprednisonealoneinreducingQMGscores,attainingminimalmanifestationstatus,orimprovingvari-oussecondaryoutcomemeasures.Severalexplanationshavebeenforwardedforthesenegativeresults:thegenerallymilddiseasestatusofpatients,thebetter-than-expectedresponsetorelativelylowdosesofprednisone,andthedurationofthestudies.Arecentretrospectivereviewof102AChRantibody-positivepatientstreatedwithmycophenolate(eithermono-therapyorinconjunctionwithprednisone)demonstratedthatMGFAminimalmanifestationstatusorbetterwasgen-erallyreachedafter6monthsoftreatment.Aclearsteroid-sparingeffectwasseenafter12monthsinthemajorityofpatients.CyclosporinCyclosporinpotentlyinhibitsT-cell-dependentimmunere-sponsesviadisruptionofcalcineurinsignaling,reducedpro-ductionandsecretionofcytokinessuchasinterleukin-2,andimpairedT-helper-cellactivation.Cyclosporinhasbeensub-jectedtorandomizeddouble-blinded,placebo-controlledtrialsinMG.Thirty-ninepatientswererandomizedinthelargerstudy,20tocyclosporin(5mg/kg/d)and19toplacebo.Anunblindedinvestigatoradjusteddosingtoachievemorningtroug

hlevelsof300to500nm/mLwithoutimpairingrenalfunction.By6months,patientsreceivingcyclosporindemonstratedsignicantlyimprovedstrength,reducedsymptoms,andgreaterreductioninAChRantibodiesthanpatientsonplacebo.Atrendtowardmoresuccessfulsteroidtaperinginpatientsreceivingtheactivedrugwasalsoobserved.Clinicalimprovementwithcyclosporinusuallyoccursbetween4and12weeksafterinitiation.Aprelimi-naryreportofadouble-blindtrialsuggestedthatazathio-prine2.5mg/kg/dandcyclosporin5mg/kg/dwereequallyeffective.Sideeffectsofhypertensionandnephrotoxicityarecom-monwithcyclosporin;clinicalexperiencesuggeststhedrugislesswelltoleratedthaneitherazathioprineormycophenolatemofetil.Overone-quarterofpatientswillhaveserumcreati-ninelevelsincreasebetween30to70%abovebaselinelevels.Intherandomizedtrial,at36-monthfollow-upof18patientsinitiallyrandomizedtocyclosporin,55%haddiscontinuedthemedicationduetosideeffects.Dosing,adverseevent,andlaboratorymonitoringinformationforcyclosporinarelistedinTable2.Currentdosingrecom-mendationsforongoingtherapyarelowerthanthe5to6mg/kg/dusedinearlierstudies.Long-termdiseasecontrolispossibleinmanypatientswithdosingat3mg/kg/dorTroughbloodlevelsof100to150g/Ltendtocorrelatewithclinicalimprovement.ItisimportantnottomixSeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe differentcyclosporinpreparationsasthedifferentbrandsarenotbioequivalent.Cyclosporinhasnumerousproblematicdruginteractions,includingaminoglycosides,vancomycin,amphotericinB,ketoconazole,trimethoprim/sulfamethoxa-zoleHblockers,colchicine,andseveralnonsteroidalantiin-ammatorydrugs.IntravenousImmunoglobulinIntravenousimmunoglobulin(IVIg)isfrequentlyusedforimmune-mediatedneuromusculardiseasesincludingMG.InananalysisofeightpublishedretrospectivestudiesinMG,a73%favorableresponseratetoIVIgwascalculated,withclinicalresponsesseenin4to5days.Theeffectcanpersistforseveralweekstoseveralmonths.Arandomizeddouble-blinded,placebo-controlledtrialofIVIgingeneral-izedMGwasinitiated,butwasterminatedbeforeanadequatenumberofpatientscouldbeenrolled.Intheopen-labelIVIgextension,favorabletrendsinquantitativestrengthandelectrophysiologicoutcomemeasureswereseeninpatientswhohadinitiallyreceivedplacebo,inlinewithqualitativeimprovementseeninpriorreports.Amorerecentrandomizeddouble-blinded,placebo-con-trolledtrialenrolled51patientsandfoundsignicantim-provementontheQMGscoreat14daysafterIVIg2g/kgversusplacebo.Thetreatmenteffectpersistedthroughday28,althoughthechangeinQMGbarelymissedstatisticalsignicance.Whenstratifyingpatients,itwasdeterminedthatonlythosewithmoreseverediseaseatentry(QMG11)benetedfromIVIg.TheauthorsconcludedthatpatientswithminorsymptomsorwithpureoculardiseaseareunlikelytobenetfromIVIg.Noseriousadverseeventswereobserved,although75%ofsubjectsrandomizedtoIVIgreportedheadache.IndicationsforIVIGaresimilartoPEx:reducingperiopera-tivemorbiditypriortothymectomy,inducingrapidimprove-mentinsettingsofcrisisorseveredisease,andchronicmanagementinselectedrefractorypatients.IVIgdemonstratedsimilarefcacytoplasmapheresisinMGexacerbations,al-thoughsomereportssuggestitislesseffectivethanPExintruecrisisscenarios.Inarecentstudyof84patientswithmoderateorsevereMG(QMG10.5),patientswererandomizedtoIVIg(1g/kg/d2days)andplasmapheresis(totalofveexchangeseveryotherday).Thepostinterventionstatusat14dayswassimilarinthetwogroups:69%ofpatientswhoreceivedIVIgand65%whoreceivedPExdemonstratedimprovementontheQMG.However,17.5%patientswhoreceivedIVIgworsenedcomparedwithonly2%whounderwentplasmapheresis.Ingeneral,complicationratestendtobelowerforIVIgthanforPEx.IVIgisaparticularlyattractivealternativetoPExinpatientswithpoorvenousaccess,hemodynamicinstability,orothercontra-indicationstoplasmapheresis.AveragecostforacourseofIVIgtendstobelessthanthatforPExinMGexacerbation.StandardIVIgregimensandadverseeventsarelistedinTable2PlasmaExchangePlasmaexchangewasrstusedinMGin1976,andisroutinelyemployedintheshort-term,acutemanagementofseverediseaseincludingcrisisandinpreparingweakpatientsforthymectomy.ArecentAANpracticeparameter,however,determinedthatthereisinsufcientevidencetosupportorrefutetheuseofplasmapheresisinMGbasedontheabsenceofrigorous,controlleddata.Nevertheless,mostMGexpertsagreethatplasmapheresisiseffectivetherapyforpatientsinmyastheniccrisis.Improvementisoftenseenwithin48hoursaftertherstorsecondexchange.Treatmentscanbeper-formeddailyoreveryotherdayintheacutesetting.Evidencesuggeststhatthebenetofplasmapheresisisgreaterifitisstartedwithin2daysfollowinghospi

taladmission.BecausetheresponsetoPExisshort-lived,high-dosecorticosteroidsareroutinelyadministeredincrisissettings.Long-termbi-monthlyormonthlyexchangesareusedinselectedrefractorypatientsaspartofachronictreatmentprogram.Plasmaexchangehasseverallimitations.Manyarerelatedtotheneedforlarge-boreduallumencentraldialysiscath-eters,includingpneumothorax,hypotension,lineinfectionandsepsis,andpulmonaryembolism.Plasmapheresisisexpensiveandunavailableinmanycommunityhospitalsettings.Theclinicalresponseisrelativelybriefwhennotcombinedwithimmunosuppressiveagents.CyclophosphamideTheuseofcyclophosphamide,anitrogenmustardalkylatingagentthatblockscellproliferation,ismainlyreservedforrefractoryMGpatients.Studiesarelimited.Perezetalreported42patientstreatedwithcyclophosphamide;33werealsoreceivingcorticosteroids.Atthetimeofretrospec-tiveanalysis,25(60%)wereasymptomaticand12wereincompleteremissionoffallmedications.Inarandomizeddouble-blinded,placebo-controlledstudy,monthlyintrave-nous(IV)pulsesofcyclophosphamide500mg/mweregivento23MGpatientswithsevere,refractorydiseaseorsteroid-relatedsideeffects.Atmonth12,thecyclophosphamidearmhadsignicantlyimprovedmusclestrengthonquantita-tiveMGscoring.Atboth6and12months,steroiddosesweresignicantlylowerinthecyclophosphamidegroup.Similarly,impressivetherapyresponseswereseeninthreerefractoryMGpatientswhoreceivedhigh-dose(50mg/kg)IVcyclo-phosphamidefor4daysfollowedbyrescuewithgranulo-cytecolonystimulatingfactor.Markedimprovementinstrengthwithoutdiseaserecurrenceoverseveralyearswasobserved.Ofnote,oneofthesepatientswasMuSKanti-body-positive.Thehighrateandseverityoftoxicityarethedrawbacksforcyclophosphamide:Alopeciacanoccurin75%,leukopeniain35%,andnauseaandvomitingin25%.Theincreasedriskofbladderandlymphoreticularmalignancywithprolongedadministrationofcyclophosphamideshouldbeofparticularconcern.Intravenous,pulsedcyclophosphamidemaybesaferthandailyoraldelivery,asaresultoflowertotalcumulativedoses(Table279,80NewerImmunotherapiesCasereportsandopentrialshavedemonstratedefcacyfortacrolimusasmonotherapyorwhenaddedtoSeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe 221 immunosuppressiveagents.Afavorableresponsetotacroli-muswasrecentlyconrmedinarandomized,butunblindedprednisolone-controlledstudy(maximumdose20mg/d)in36denovoMGpatients.Plasmaexchangeandhigh-doseIVmethylprednisolonewereaddedasneededfordiseasecon-trol.Patientsinbotharmsofthestudyimprovedsignicantly.ThenumberofPExandmethylprednisolonetreatmentswassignicantlylessinpatientstreatedwithtacrolimusbothinearlyphasesoftherapyandthrough1yearoffollow-up0.05).Likewise,prednisolonedosesweresignicantlylowerforpatientswhowereontacrolimusat1year0.05).Fourpatientsmaintainedminimalmanifestationstatusontacrolimusalone.Tacrolimuswaswelltolerated,withincreasedserumcreatininelevelsobservedinonlyonepatientwhoalsohadhypertension.Inthelargestreportof212patients,tacrolimuswasgivenatadosageof0.1mg/kgperdayintwodivideddoses,lateradjustedforplasmadrugconcentrationsbetween7and8mg/mL.Approximatelyhalfofthepatientswereonprednisoneorwerecyclosporindependent.Themeanfol-low-uptimewasnearly50months.Withtheadditionoftacrolimus,prednisonecouldbewithdrawnin95%ofpa-tients.QMGscoresfellsignicantlyfrom20.5atbaselinetolessthan1.0atthenalvisit,andmusclestrengthimprove-mentwasevidentasearlyas1monthaftertreatmentinitia-tion.Morethan85%ofpatientsachievedcompletestableremissionorpharmacologicremissionattheendoffollow-up.Another5%reachedminimalmanifestationstatus.Im-pressiveremissionresultswereobservedirrespectiveofwhetherpatientshadundergonethymectomyorhadthy-moma,althoughcompletestableremissionwaslesslikelyinthymomatousMG.Yoshikawaetalrecentlyperformeda28-weekdouble-blindplacebo-controlledstudytoevaluatethesteroid-sparingeffectandtolerabilityoftacrolimusinpatientsinminimalmanifestationsstatusonmaintenancedosesofprednisone(1020mg/d).Therewasnosignicantdifferencebetweengroupsintheprimaryendpoint(meandailysteroiddose),althoughtacrolimuswaswell-toleratedwithfewadverseevents.Possibleexplanationsforthelackofcacyseeninthisstudyincludetheselectionofrelativelystablepatients,theshortduration,andthemodestdoseoftacrolimus.Tacrolimusdosesof3to5mgadayor0.1mg/kg/dhavebeenusedinthevariousstudies.Tacrolimusisacalcineurininhibitor,thesameimmunosuppressantclassascyclosporin,hasasimilaronsetofaction,butmaybelessnephrotoxic.Hyperglycemiaisawell-recognizedcomplication(Table2RituximabRituximab,achimericmonoclonalantibodydirectedagainsttheB-cell-surface

membraneantigenCD20thatinducesdepletionofBlymphocytes,hasproducedclinicalimprove-mentwithin4weeksincasereportsofadultsandchil-dren.Nocomplicationsorsideeffectswereobserved.Sustainedimprovementforatleast1yearwasdemonstratedin14patientswithsevere,treatment-refractoryMG.anotherstudy,11of14patientswithsevere,treatment-refractorydiseaseshowedsignicantimprovementlastinganaverageof12months.RecoveryofB-lymphocytecountswascorrelatedwithclinicalworseninginthisstudy,suggest-ingthatmonitoringtheselevelsisusefulinguidingtheneedforrepeatinfusions.Effectivenessinanti-MuSKMGhasbeenseeninseveralseries.96,97InadditiontoadverseeventslistedTable2,rituximabhasbeenassociatedwiththedevelop-mentofprogressivemultifocalencephalopathyinthenonHodgkinslymphomapopulationforwhichitisindicated.EtanerceptThissoluble,recombinanttumornecrosisfactor-receptorblocker,wasstudiedinaprospectivepilottrialin11patientswithcorticosteroid-dependentMG.Eightpatientscompletedthe6-monthtrial,receiving25mgsubcutaneous-lytwiceaweek.Prednisonewastaperedaccordingtoastandardizedprotocol.Ofthethreepatientswhodidnotcompletethestudy,onewithdrewduetoageneralizedrashandtwoothersbecauseofdiseaseworsening.Oftheremain-ingeightpatients,veimprovedonQMGbyatleast3points,theprimarymeasureofefcacy.Ittookbetween2to6monthstoseesignicantimprovement.Atstudyexit,prednisonehadbeenreducedbyameanof80.4%.Inasatellitestudy,etanercepttreatmentraisedthelevelsofmostplasmacomplementandcytokinelevels,includingC3,interleukins(IL),andIFN-Patientswhorespondedbesttoetanercepthadeithersmallincreasesoractualdecreasesincytokinelevelsduringthepilotstudy.Theinvestigatorssurmisedthatinsomepatientsetanerceptmightworsendiseasecontrol,especiallyinsubjectswithhighbaselineIL-6andIFN-levels.ArecentcasereportdescribedapatientwhodevelopedMGwhiletakingetaner-ceptforrheumatoidarthritis.100Symptomsresolvedafteretanerceptwasdiscontinued.MethotrexateAlthoughmethotrexateisoftenusedinthetreatmentofotherneuromusculardisorders,mostnotablyinammatorymyop-athies,itsuseinMGislesscommon.Inasingle-blindedstudyof24patientswithrecentlydiagnosedgeneralizedMG,Heckmanndemonstratedsimilarsteroid-sparingefcacyformethotrexate(17.5mg/wk)andazathioprine(2.5mg/kg/d).Thesteroid-sparingeffectwasseenasearlyas10monthsafterinitiation.Methotrexatewasgenerallywell-tolerated.Alarge,multicenterdouble-blindedplacebo-controlledtrialofmetho-trexateinMGisunderway.NovelApproachesTerbutalineAlthoughadrenergicagonists,suchasephedrine,wereusedinthepasttotreatMG,theyarerarelyusedtoday.Catechol-aminesmayhavedirecteffectsonneuromusculartransmis-sionandmayalsoregulatelymphocyteproliferationandantibodysynthesis.Apilot,double-blindedplacebo-controlledcrossoverstudy(2-weektreatmentperiods)dem-onstratedthatterbutaline,a2agonist,producedatleasta3-pointimprovementontheQMGinveofeightpatients(63%).DecrementstorepetitivenervestimulationalsoSeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe improved.Nosuchbenetwasseenwithplacebo.Theterbutalinedoseof2.5mgthreetimesdailywaswelltolerat-ed.Thisstudywassmallandbrief;furtherinvestigationiswarrantedbeforesympathomimeticcompoundsareroutine-lyusedinMG.ComplementInhibitorsArecentstudyutilizingpassiveandactiverodentmodelsofexperimentalautoimmuneMGdemonstratedefcacyofacomplementinhibitor,rEV576.103Treatedratsdemonstratedasignicantreductioninweakness.Trialsofcomplementinhibitorsareunderwayinhumansubjects.ManagementofMyasthenicCrisisMyastheniccrisisreferstoanexacerbationsevereenoughtoendangerlife,generallyrelatedtorespiratoryfailurefromeitherdiaphragmaticorintercostalmuscleweaknessorairwaycompromiserelatedtobulbardysfunction.Itoccursin15to20%ofallpatientswithMG,primarilyintherst2yearsafterdiseaseonset.ManagementofMGcrisisshouldtakeplaceinanintensivecaresettingtoallowforclosemonitoring.Intercur-rentinfections,acommontrigger,shouldbemanagedaggres-sively.Patientswithmarkedbulbarweaknessorlowbaselinevitalcapacitiesof20to25ml/kgareespeciallyatriskforrespiratoryfailure.Paradoxicalbreathingordyspneainasupinepositionareotherwarningsigns.Becauseofitsrapidonsetofactionwithindays,PExisafavoredtreatmentforMGcrisis.Acourseofplasmapheresisconsistsof4to6exchangesinwhich50ml/kgofplasmaareremovedateachtreatment.However,itshouldbestressedthatthereisnoexactsciencetothenumberofexchangesortheamountremoved.Thetreatmentscanbedonedailyoreveryotherdayinthehospitalsothatthefullcourseiscompletedin7to10days.BecausetheresponsetoPExisshort-lived,high-dosecorticosteroidsareroutinelyadminis-teredi

ncrisissettings.AlthoughIVpyridostigmineisavail-able(2mgIV60mgorally),itisgenerallywithheldwhilepatientsareintubatedbecauseitcancomplicatemanage-mentofairwaysecretionsandisunlikelytoplayacontribut-ingroleinsuccessfulweaningfromtheventilator.IVIghasdemonstratedsimilarefcacytoplasmapheresisinMGex-acerbations,althoughsomereportssuggestitislesseffectivethanPExintruecrisisscenarios.70,71ComplicationratestendtobelowerforIVIgthanforPEx.TreatmentAlgorithmTakingintoaccountthecaveatthatMGtreatmentmustbeindividualized,Figure2depictsamanagementapproachsuitableformanypatientswithnonthymomatousgeneral-izedMG.Ingeneral,patientswithoculardiseaseshouldbestartedonpyridostigmineinitially.Ifthisisnotsuccessfulintreatingsymptoms,escalatingdosesofprednisonemaybe Initiate pyridostigmine after diagnosis confirmed;Adjust dose for maximal control steroid-sparing agent azathioprine as monotherapy, keeping in mind azathioprine's slow onset Continue pyridostigmine Follow disease course In remission Not in remission Not improved remission Initiate slow prednisonealternate-day taper withthat maintains improvedstatus. Steroid-sparingagents can be tapered slowly plasma exchange3) Plan on thymectomy when patient stable incremental increases inmedication that has beenlowered. High-dose steroidsmay need to be reinitiated. In case of relapse Improved improved Improved/in remission exchange or IVIG2) Cyclophosphamide3) Tacrolimus Figure2Algorithmfortreatmentofnonthymomatousgeneralizedmyastheniagravis.SeminarsinNeurologyVol.32No.3/2012 MyastheniaGravisSilvestri,Wolfe 223 used,slowlytaperingoncesymptomsarestabilized.Patientswithgeneralizeddiseasetypicallyrequirebothpyridostig-mineandprednisoneatthetimeofpresentation.Inpatientswithseverediseaseatonset,orinthosethatworsenonceaprednisonetaperhascommenced,initiationofasteroid-sparingagentsuchasazathioprineormycophenolatemofetilisstandard.Therearenoevidence-basedguidelinesastowhenitisappropriatetobegintotaperpyridostigmineorsteroid-sparingagents;however,itisreasonabletoattemptaweanofthesemedicationsifpatientsareasymptomaticorminimallysymptomaticonthesemedicationsforatleast1year.Ingeneral,taperingofsteroid-sparingagentsshouldproceednofasterthanadosechangeevery6monthstoreducetheriskofdiseaserecurrences.Incasesofthymom-atousMG,thymectomywouldbearequisitecomponentofearlyintervention.ReferencesMcGroganA,SneddonS,deVriesCS.Theincidenceofmyastheniagravis:asystematicliteraturereview.Neuroepidemiology2010;34(3):171183SimpsonJ.Myastheniagravis:anewhypothesis.ScottMedJ1960;5:419436LindstromJM,LennonVA,SeyboldME,WhittinghamS.Experi-mentalautoimmunemyastheniagravisandmyastheniagravis:biochemicalandimmunochemicalaspects.AnnNYAcadSci1976;274:254274VincentA,DrachmanDB.Myastheniagravis.In:PourmandR,HaratiY,eds.AdvancesinNeurology:NeuromuscularDisorders.Philadelphia,PA:LippincottWilliams&Wilkins;2002:159188KaminskiHJ.Myastheniagravis.In:KatirjiB,KaminskiHJ,PrestonDC,RuffRL,ShapiroBE,eds.NeuromuscularDisordersinClinicalPractice.Boston,MA:Butterworth-Heinemann;2002:916930KawaguchiN,KuwabaraS,NemotoY,etal;StudyGroupforMyastheniaGravisinJapan.Treatmentandoutcomeofmyasthe-niagravis:retrospectivemulti-centeranalysisof470Japanesepatients,1999-2000.JNeurolSci2004;224(12):43Kleinwächter.Beobachtungüberdiewirkungdescalabar-ex-tractsgegenatropin-vergiftung.BerlKlinWochensch1864;38:369371LaqueurL.Ueberatropinundphysostigminundihrewirkungaufdenintraocularendruck.Einbeitragzurtherapiedesglaucoms.GraefesArchClinExpOphthalmol1877;23:149176WalkerMB.Treatmentofmyastheniawithphysostigmine.Lancet1934;1:12001201WolfeGI,BarohnRJ,GalettaSL.Drugsforthediagnosisandtreatmentofmyastheniagravis.In:ZimmermanT,KoonerK,SharirM,FechtnerRD,eds.TextbookofOcularPharmacology.Philadelphia,PA:Lippincott-RavenPress;1997:837848DrachmanDB.Myastheniagravis.NEnglJMed1994;330(25):17971810ReynoldsJ,Ed.Martindale:TheExtraPharmacopoeia.30thed.London,UK:ThePharmaceuticalPress;1993SandersDB,ScoppettaC.Thetreatmentofpatientswithmyas-theniagravis.NeurolClin1994;12(2):343368SommerN,SiggB,MelmsA,etal.Ocularmyastheniagravis:responsetolong-termimmunosuppressivetreatment.JNeurolNeurosurgPsychiatry1997;62(2):156HatanakaY,HemmiS,MorganMB,etal.NonresponsivenesstoanticholinesteraseagentsinpatientswithMuSK-antibody-posi-tiveMG.Neurology2005;65(9):15081509PasnoorM,WolfeGI,NationsS,etal.ClinicalndingsinMuSK-antibodypositivemyastheniagravis:aU.S.experience.MuscleNerve201

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