神經(jīng)病學(xué)英文課件：03 Myasthenia Gravis

MyastheniaGravis重癥肌無(wú)力MyastheniaGravis重癥肌無(wú)力WhatisMyastheniaGravis?Myastheniagravis(MG)isachronicautoimmunedisorderofneuromuscular

transmission,whichcharacterizedby

fluctuating

weaknessandfatigabilityofstriatedskeletalmuscles.WhatisMyastheniaGravis?MyasEtiologyandPathogenesisEtiologyandPathogenesis神經(jīng)病學(xué)英文課件：03MyastheniaGravisNeuromuscularJunction(NMJ)inMGNeuromuscularJunction(NMJ)iThymusGlandandMGInpatientswithMG,thethymusglandisabnormal.10-15%developedthymoma60-70%withthymichyperplasiaItisbelievedthatthethymusglandmaygiveincorrectinstructionsabouttheproductionofAChR-Ab.ThymusGlandandMGInpatientsClinicalManifestationsPrevalence:

10-20/100,000

Annualincidence:1.5/100,000MGcanoccuratanyage.<50yearsprevalenceandincidenceremainedstableandwithaconstantfemalepreponderancetherehasbeenanincreaseofMGintheelderlypopulation,especiallyinmalesClinicalManifestationsPrevaleOnsetoftheDiseaseTheonsetisinsidious,sometimesinitiatedbyfatigue,anemotionalupset,infectionorpregnancyetc.Oncethediseasehasbegan,aslowprogressionfollows.OnsetoftheDiseaseTheonsetPresentingSymptomsPatientstypicallyhavefluctuatingweaknessandfatigueofthespecificmusclegroupsaffected.Theinitialinvolvedmuscleasfollowing:Ocularmuscles------->50%Extraocularmuscleweaknessorptosisispresentinitiallyin50%ofpatientsandoccursduringthecourseofillnessin90%.

Bulbarmuscles-------15%

Proximallimbmuscles-------<10%PresentingSymptomsPatientstyThenoticeablesymptomsincluding:OcularmanifestationsPtosis:droopingofoneorbotheyelidsDiplopia:blurredordoublevisionBulbarsymptomsDysphagia:difficultyinswallowingDysarthria:slurredspeech,soundsnasal,oflowintensity(hypophonic)prolongedchewing(fatigablechewing),frequentlyoccurshalf-waythroughamealThenoticeablesymptomsinclud神經(jīng)病學(xué)英文課件：03MyastheniaGravisPtosisPtosisStrabismusStrabismusNeckweaknessTheweightoftheheadmayovercometheextensors,producinga"droppedheadsyndrome"------unabletosupportthehead.Limbweaknessdifficultyinliftingarmsdifficultyinrunningandclimbing,unstableorwaddlinggaitInvolvementoftherespirationmuscles

difficultyinbreathingNeckweaknessFluctuation------cardinalfeatureofMG

Fluctuation

ofsymptomsWeaknessisincreasedbyexertionandalleviatedbyrest,atleastpartially.Theweaknessmayfluctuatethroughouttheday,butmostcommonlyworselaterinthedayorevening.Fluctuation------cardinalfeFluctuationofdiseasecourseEarlyinthedisorder,thesymptomsareoftentransientinmanypatients(withhours,days,orevenweeksfreeofsymptoms),whichmayevenremitspontaneouslyforweeksorlonger.Later,themanifestationstypicallyworsenandaremorepersistent.FluctuationofdiseasecourseClassificationOcualrmyasthenia---(15-20%)ocularsignsandsymptomsonly(aftermorethan2years)Generalizedmyasthenia

About87%ofpatientshavegeneralizeddiseasewithin13monthsafteronsetClassificationOcualrmyastheniMyasthenicCrisisArapiddeteriorationinweaknessofthemusclesthatcontrolbreathingbringsthepatienttorespiratoryfailure.MyasthenicCrisisArapiddeterLaboratoryTestsSerumantibodiestesting>80-90%AChR-Ab(+)in

generalizedMGabout40-55%AChR-Ab(+)inocularMG1–10%againstMuSK

(muscle-specifictyrosinekinase)andveryfewagainstLRP4(lowdensitylipoproteinreceptor-relatedprotein4)Thisisingeneralahighlyspecifictest

(upto100%).

LaboratoryTestsSerumantibodiElectrophysiologicalTestingRepetitivenervestimulation(RNS)6-10timesrepetitiveelectricalstimulationofmotorperipheralnerveat2-3Hzcouldevokesaprogressivedecline(>10%)intheamplitudeofcompoundmuscleactionpotentials(CMAP)------decrementalresponse(+)75%

ingeneralizedMG,50%inocularMG.ElectrophysiologicalTestingDecrementalResponseinRNSDecrementalResponseinRNSSingle-fiberelectromyography(SFEMG)(+)

92-99%

ofgeneralizedMG(+)85-95%ofocularMGChestCTscanthymusenlargementorthymomaSingle-fiberelectromyographyCTscanofthymomaCTscanofthymomaDiagnosisClinicalpresentationsymptomsandsignsareconsistentwithMGandnotanotherdisorder.PhysicalexaminationBedsidefatigueTestTheptosismayincreasewithsustainedupwardgazeLimbstrengthmaydecreasewithrepetitiveliftingorsquattingDiagnosisClinicalpresentationPharmacologictestsNeostigminemethylsulfate0.5-1.0mgi.m.,improvementoccursin10-15min,reachesitspeakat20min,andlast2-3hoursAtropinesulfate

0.3-0.5mg

shouldbeengiventocounteractmuscariniceffectsThesensitivityis80-90%.

LaboratoryTestsAChR-AbRNSandSFEMGPharmacologictestsDifferentialDiagnosisLambert-Eatonmyasthenicsyndrome(LEMS)>95%

patientswith

antibodiestopresynapticvoltage-gatedcalciumchannel(VGCC)(P/Q-type),whichcausesadeficientquantalreleaseofACh.Approximatelyhalfofpatientshavecancer,usuallysmallcelllungcancer.DifferentialDiagnosisLambert-NMJinLambert-Eatonsyndrome

NMJinLambert-EatonsyndromeDifferentiatefromMGmusclesofthetrunkandlimbsratherthanocularmusclesareinvolvedfrequentlyatemporaryincreaseinmusclepowerwithabriefexerciseandadecreasefollowingcontinuingcontractionRNSat20-50Hzevokesamarkedincrease(>200%)intheamplitudeofCMAP----incrementalresponse(+)poorresponsetoAChEinhibitorsDifferentiatefromMGIncrementalResponseinRNSIncrementalResponseinRNSBotulismIntoxicationusuallyiscausedbyingestionoffoodcontainingClostridiumbotulinumandinfectionviawoundsisveryuncommon.Botulismtoxinisametalloendopeptidase,whichcleavesspecificproteinsrequiredforneuroexocytosisandthereforeblockedthereleaseofACh.BotulismTypicalclinicalpresentationisadescendingflaccidparalysis.cranialmuscleparalysis----diplopia,ptosis,dilatedpupils,difficultyinswallowingandspeaking,andfacialparalysisparalysisofthelimbsandrespiratorymusclesbecomeapparentasthediseaseprogressesdysfunctionsoftheautonomicnervoussystem----reducedsalivationandlacrimation,nausea,vomitingandabdominalpainTypicalclinicalpresentationPolymyositisProgressivemuscleweaknessmainlyinproximallimbandocularmusclesarenotinvolvedingeneralNo

fluctuationinweaknessRNS----no

decrementingresponseIncreasingCKlevelinserumPolymyositisOculopharyngealdystrophyAprogressiveweaknessinmusclesofocularandpharyngealNo

fluctuationinweaknessChronicprogressiveexternalophthalmoplegia(CPEO)ThyroidophthalmopathyBrainstemandmotorcranialnervepathology

OculopharyngealdystrophyTreatmentTargetoftreatment:completelyclinicalremission---allsymptomsdisappear4basictherapiesforMGSymptomatictreatments------anticholinesterase(AChE)agentsChronicimmunomodulatingtreatments------corticosteroids

and

otherimmunosuppressivedrugs

Rapidimmunomodulatingtreatments------plasmaexchange

and

intravenousimmunoglobulin

Surgicaltreatment------thymectomyTreatmentTargetoftreatment:ThefactorsmaytriggerorworsenexacerbationsBrightsunlightSurgeryImmunizationEmotionalstressMenstruationIntercurrentillness(eg,viralinfection)Medication(eg,aminoglycosides,ciprofloxacin,chloroquine,procaine,lithium,phenytoin,beta-blockers,procainamide,statins)ThefactorsmaytriggerorworSymptomatictreatmentsAChEinhibitorsTheuseofAChEinhibitorsshouldbethefirst-linetreatmentforallformsofMG.pyridostigminebromide----60-120mgq8h-q6hp.o.relieveweaknessAChEinhibitorsprovideonlysymptomatictherapyandareusuallynotsufficient,especiallyingeneralizedMG.Nonetheless,insomepatientsthisistheonlytherapyeverneededforgoodcontrol,suchaspurelyocularMGandmildgeneralizedMGwithoutthymictumorSymptomatictreatmentsAChEinhChronicimmunomodulatingtreatmentsImmunosuppressiveagentsCorticosteroids(prednisoneorprednisolone)AzathioprineCyclosporineTacrolimusMycophenolatemofetilRituximabstarttoworkslowly(overweeks),offerlong-termbenefit(monthstoyears)

ChronicimmunomodulatingtreatCorticosteroidsOralprednisoneshouldbeafirstchoicewhenimmunosuppressivedrugsarenecessary.Beginningwith10-15mg/day,increasingthedosegraduallyuntiladailydoseof1mg/kg/disreach.Oncethemaximaleffectattained,thedosagecanbereducedslowlyovermonthstothelowestpointatwhichitisstilleffective.Azathioprineasasteroidsparingagentusedtogetherwithprednisonebeginwith1mg/kgandincreasegraduallyto2-3mg/kgCorticosteroidsAcombinationofcorticosteroidsandazathioprineremainsthefirst-choiceimmunosuppressivedrugalternativeformostMGpatients.Corticosteroidsinhighdosesusuallyhaverelevantlong-termsideeffects.Combiningazathioprinewitharelativelylowdoseofprednisoneisrecommended.Corticosteroidsactafterafewweeks,whereastheazathioprineeffectisdelayedforseveralmonthsanduptoayear.AcombinationofcorticosteroiFormilderMGnotrespondingtoprednisoneandazathioprine,mycophenolatemofetilshouldberegardedasanalternative.Itsadvantagesarefewsideeffects,easyadministrationandaclinicalresponsebeingevidentafterjustafewweeks.Cyclosporine

andTacrolimusarealternativeimmunosuppressivedrugswithaproveneffectongeneralizedMG.FormilderMGnotrespondingtForsevere,generalizedMGnotrespondingtoprednisoneandazathioprine,Rituximabshouldberegardedasanearlyalternative.RituximabisamonoclonalantibodywithadirecteffectonBcells.ThebindingofrituximabtoBcellsisspecific,buttheresultingimmunechangesarewidespreadandmuchlessspecific.Rituximabisregardedasespeciallyeffectiveinantibody-mediatedautoimmunedisorderssuchasMG.Forsevere,generalizedMGnotRapidimmunomodulatingtreatmentsPlasmaexchangeaprocedureinwhichabnormalantibodiesareremovedfromtheblood

Intravenousimmunoglobulin(IVIg)temporarilymodifiestheimmunesystemstarttoworkquickly(overdays),butofferonlyshort-termbenefit(weekstomonths)

RapidimmunomodulatingtreatmeUsedinthefollowingsituations:

MyastheniccrisisPreoperativelybeforethymectomyorothersurgeryAsa"bridge"tosloweractingimmunotherapiesPeriodicallytomaintainremissioninpatientswithMGthatisnotwellcontrolleddespitetheuseofchronicimmunomodulatingdrugsIVIgappearstobeabettertreatmentoptionfortheelderlyandthosewithcomplexcomorbiddiseases.UsedinthefollowingsituatioSurgicaltreatmentThymectomythymoma:indicatedthymichyperplasia:anelectiveprocedureisadvisableasafeandeffectivetreatmentwhichishelpfulininducingremissionSurgicaltreatmentThymectomyManagementOfMGCrisis

SupportivecareEndotrachealintubationandmechanicalventilationPlasmaexchange,?veexchangesonalternatingdays

utilizing2–4litresperexchange

/

IVIG0.4g/kgforfivedays

Corticosteroids(prednisone60-100mg/day)continuedforatleastfourweeksStopping

AChEinhibitorsforpatientsincrisis,reinstitutingthemorallywhenpatientsareabouttobeextubated.ManagementOfMGCrisisSupporSupplementaryTreatmentPhysicalactivityandphysicaltrainingoflowtomediumintensityisrecommended.WeightcontrolisofimportanceinMGPreventallinfectionswhichcantriggeranexacerbationinMGAvoidthedrugswhichmaycauseorworsenMGAntibiotics,anestheticsandsedativesshouldbeevaluatedinparticular.

SupplementaryTreatmentPhysicaThanks!Thanks!MyastheniaGravis重癥肌無(wú)力MyastheniaGravis重癥肌無(wú)力WhatisMyastheniaGravis?Myastheniagravis(MG)isachronicautoimmunedisorderofneuromuscular

transmission,whichcharacterizedby

fluctuating

weaknessandfatigabilityofstriatedskeletalmuscles.WhatisMyastheniaGravis?MyasEtiologyandPathogenesisEtiologyandPathogenesis神經(jīng)病學(xué)英文課件：03MyastheniaGravisNeuromuscularJunction(NMJ)inMGNeuromuscularJunction(NMJ)iThymusGlandandMGInpatientswithMG,thethymusglandisabnormal.10-15%developedthymoma60-70%withthymichyperplasiaItisbelievedthatthethymusglandmaygiveincorrectinstructionsabouttheproductionofAChR-Ab.ThymusGlandandMGInpatientsClinicalManifestationsPrevalence:

10-20/100,000

Annualincidence:1.5/100,000MGcanoccuratanyage.<50yearsprevalenceandincidenceremainedstableandwithaconstantfemalepreponderancetherehasbeenanincreaseofMGintheelderlypopulation,especiallyinmalesClinicalManifestationsPrevaleOnsetoftheDiseaseTheonsetisinsidious,sometimesinitiatedbyfatigue,anemotionalupset,infectionorpregnancyetc.Oncethediseasehasbegan,aslowprogressionfollows.OnsetoftheDiseaseTheonsetPresentingSymptomsPatientstypicallyhavefluctuatingweaknessandfatigueofthespecificmusclegroupsaffected.Theinitialinvolvedmuscleasfollowing:Ocularmuscles------->50%Extraocularmuscleweaknessorptosisispresentinitiallyin50%ofpatientsandoccursduringthecourseofillnessin90%.

Bulbarmuscles-------15%

Proximallimbmuscles-------<10%PresentingSymptomsPatientstyThenoticeablesymptomsincluding:OcularmanifestationsPtosis:droopingofoneorbotheyelidsDiplopia:blurredordoublevisionBulbarsymptomsDysphagia:difficultyinswallowingDysarthria:slurredspeech,soundsnasal,oflowintensity(hypophonic)prolongedchewing(fatigablechewing),frequentlyoccurshalf-waythroughamealThenoticeablesymptomsinclud神經(jīng)病學(xué)英文課件：03MyastheniaGravisPtosisPtosisStrabismusStrabismusNeckweaknessTheweightoftheheadmayovercometheextensors,producinga"droppedheadsyndrome"------unabletosupportthehead.Limbweaknessdifficultyinliftingarmsdifficultyinrunningandclimbing,unstableorwaddlinggaitInvolvementoftherespirationmuscles

difficultyinbreathingNeckweaknessFluctuation------cardinalfeatureofMG

Fluctuation

ofsymptomsWeaknessisincreasedbyexertionandalleviatedbyrest,atleastpartially.Theweaknessmayfluctuatethroughouttheday,butmostcommonlyworselaterinthedayorevening.Fluctuation------cardinalfeFluctuationofdiseasecourseEarlyinthedisorder,thesymptomsareoftentransientinmanypatients(withhours,days,orevenweeksfreeofsymptoms),whichmayevenremitspontaneouslyforweeksorlonger.Later,themanifestationstypicallyworsenandaremorepersistent.FluctuationofdiseasecourseClassificationOcualrmyasthenia---(15-20%)ocularsignsandsymptomsonly(aftermorethan2years)Generalizedmyasthenia

About87%ofpatientshavegeneralizeddiseasewithin13monthsafteronsetClassificationOcualrmyastheniMyasthenicCrisisArapiddeteriorationinweaknessofthemusclesthatcontrolbreathingbringsthepatienttorespiratoryfailure.MyasthenicCrisisArapiddeterLaboratoryTestsSerumantibodiestesting>80-90%AChR-Ab(+)in

generalizedMGabout40-55%AChR-Ab(+)inocularMG1–10%againstMuSK

(muscle-specifictyrosinekinase)andveryfewagainstLRP4(lowdensitylipoproteinreceptor-relatedprotein4)Thisisingeneralahighlyspecifictest

(upto100%).

LaboratoryTestsSerumantibodiElectrophysiologicalTestingRepetitivenervestimulation(RNS)6-10timesrepetitiveelectricalstimulationofmotorperipheralnerveat2-3Hzcouldevokesaprogressivedecline(>10%)intheamplitudeofcompoundmuscleactionpotentials(CMAP)------decrementalresponse(+)75%

ingeneralizedMG,50%inocularMG.ElectrophysiologicalTestingDecrementalResponseinRNSDecrementalResponseinRNSSingle-fiberelectromyography(SFEMG)(+)

92-99%

ofgeneralizedMG(+)85-95%ofocularMGChestCTscanthymusenlargementorthymomaSingle-fiberelectromyographyCTscanofthymomaCTscanofthymomaDiagnosisClinicalpresentationsymptomsandsignsareconsistentwithMGandnotanotherdisorder.PhysicalexaminationBedsidefatigueTestTheptosismayincreasewithsustainedupwardgazeLimbstrengthmaydecreasewithrepetitiveliftingorsquattingDiagnosisClinicalpresentationPharmacologictestsNeostigminemethylsulfate0.5-1.0mgi.m.,improvementoccursin10-15min,reachesitspeakat20min,andlast2-3hoursAtropinesulfate

0.3-0.5mg

shouldbeengiventocounteractmuscariniceffectsThesensitivityis80-90%.

LaboratoryTestsAChR-AbRNSandSFEMGPharmacologictestsDifferentialDiagnosisLambert-Eatonmyasthenicsyndrome(LEMS)>95%

patientswith

antibodiestopresynapticvoltage-gatedcalciumchannel(VGCC)(P/Q-type),whichcausesadeficientquantalreleaseofACh.Approximatelyhalfofpatientshavecancer,usuallysmallcelllungcancer.DifferentialDiagnosisLambert-NMJinLambert-Eatonsyndrome

NMJinLambert-EatonsyndromeDifferentiatefromMGmusclesofthetrunkandlimbsratherthanocularmusclesareinvolvedfrequentlyatemporaryincreaseinmusclepowerwithabriefexerciseandadecreasefollowingcontinuingcontractionRNSat20-50Hzevokesamarkedincrease(>200%)intheamplitudeofCMAP----incrementalresponse(+)poorresponsetoAChEinhibitorsDifferentiatefromMGIncrementalResponseinRNSIncrementalResponseinRNSBotulismIntoxicationusuallyiscausedbyingestionoffoodcontainingClostridiumbotulinumandinfectionviawoundsisveryuncommon.Botulismtoxinisametalloendopeptidase,whichcleavesspecificproteinsrequiredforneuroexocytosisandthereforeblockedthereleaseofACh.BotulismTypicalclinicalpresentationisadescendingflaccidparalysis.cranialmuscleparalysis----diplopia,ptosis,dilatedpupils,difficultyinswallowingandspeaking,andfacialparalysisparalysisofthelimbsandrespiratorymusclesbecomeapparentasthediseaseprogressesdysfunctionsoftheautonomicnervoussystem----reducedsalivationandlacrimation,nausea,vomitingandabdominalpainTypicalclinicalpresentationPolymyositisProgressivemuscleweaknessmainlyinproximallimbandocularmusclesarenotinvolvedingeneralNo

fluctuationinweaknessRNS----no

decrementingresponseIncreasingCKlevelinserumPolymyositisOculopharyngealdystrophyAprogressiveweaknessinmusclesofocularandpharyngealNo

fluctuationinweaknessChronicprogressiveexternalophthalmoplegia(CPEO)ThyroidophthalmopathyBrainstemandmotorcranialnervepathology

OculopharyngealdystrophyTreatmentTargetoftreatment:completelyclinicalremission---allsymptomsdisappear4basictherapiesforMGSymptomatictreatments------anticholinesterase(AChE)agentsChronicimmunomodulatingtreatments------corticosteroids

and

otherimmunosuppressivedrugs

Rapidimmunomodulatingtreatments------plasmaexchange

and

intravenousimmunoglobulin

Surgicaltreatment------thymectomyTreatmentTargetoftreatment:ThefactorsmaytriggerorworsenexacerbationsBrightsunlightSurgeryImmunizationEmotionalstressMenstruationIntercurrentillness(eg,viralinfection)Medication(eg,aminoglycosides,ciprofloxacin,chloroquine,procaine,lithium,phenytoin,beta-blockers,procainamide,statins)ThefactorsmaytriggerorworSymptomatictreatmentsAChEinhibitorsTheuseofAChEinhibitorsshouldbethefirst-linetreatmentforallformsofMG.pyridostigminebromide----60-120mgq8h-q6hp.o.relieveweaknessAChEinhibitorsprovideonlysymptomatictherapyandareusuallynotsufficient,especiallyingeneralizedMG.Nonetheless,insomepatientsthisistheonlytherapyeverneededforgoodcontrol,suchaspurelyocularMGandmildgeneralizedMGwithoutthymictumorSymptomatictreatmentsAChEinhChronicimmunomodulatingtreatmentsImmunosuppressiveagentsCorticosteroids(prednisoneorprednisolone)AzathioprineCyclosporineTacrolimusMycophenolatemofetilRituximabstarttoworkslowly(overweeks),offerlong-termbenefit(monthstoyears)

ChronicimmunomodulatingtreatCorticosteroidsOralprednisoneshouldbeafirstchoicewhenimmunosuppressivedrugsarenecessary.Beginningwith10-15mg/day,increasingthedosegraduallyuntiladailydoseof1mg/kg/disreach.Oncethemaximaleffectattained,thedosagecanbereducedslowlyovermonthstothelowestpointatwhichitisstilleffective.Azathioprineasasteroidsparingagentusedtogetherwithprednisonebeginwith1mg/kgandincreasegraduallyto2-3mg/kgCorticosteroidsAcombinationofcorticosteroidsandazathioprineremainsthefirst-choiceimmunosuppressivedrugalternativeformostMGpatients.Corticosteroidsinhighdosesusuallyhaverelevantlong-termsideeffects.Combiningazathioprinewitharelativelylowdoseofprednisoneisrecommended.Corticosteroidsactafterafewweeks,whereastheazathioprineeffectisdelayedforseveralmonthsanduptoayear.AcombinationofcorticosteroiFormilderMGnotrespondingtoprednisoneandazathioprine,mycophenolatemofetilshouldberegardedasanalternative.Itsadvantagesarefewsideeffects,easyadministrationandacli