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MyastheniaGravis重症肌无力MyastheniaGravis重症肌无力WhatisMyastheniaGravis?Myastheniagravis(MG)isachronicautoimmunedisorderofneuromuscular
transmission,whichcharacterizedby
fluctuating
weaknessandfatigabilityofstriatedskeletalmuscles.WhatisMyastheniaGravis?MyasEtiologyandPathogenesisEtiologyandPathogenesis神经病学英文课件：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神经病学英文课件：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,fiveexchangesonalternatingdays
utilizing2–4litresperexchange
/
IVIG0.4g/kgforfivedays
Corticosteroids(prednisone60-100mg/day)continuedforatleastfourweeksStopping
AChEinhibitorsforpatientsincrisis,reinstitutingthemorallywhenpatientsareabouttobeextubated.ManagementOfMGCrisisSupporSupplementaryTreatmentPhysicalactivityandphysicaltrainingoflowtomediumintensityisrecommended.WeightcontrolisofimportanceinMGPreventallinfectionswhichcantriggeranexacerbationinMGAvoidthedrugswhichmaycauseorworsenMGAntibiotics,anestheticsandsedativesshouldbeevaluatedinparticular.
SupplementaryTreatmentPhysicaThanks!Thanks!MyastheniaGravis重症肌无力MyastheniaGravis重症肌无力WhatisMyastheniaGravis?Myastheniagravis(MG)isachronicautoimmunedisorderofneuromuscular
transmission,whichcharacterizedby
fluctuating
weaknessandfatigabilityofstriatedskeletalmuscles.WhatisMyastheniaGravis?MyasEtiologyandPathogenesisEtiologyandPathogenesis神经病学英文课件：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神经病学英文课件：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
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