神经肌接头病-重症肌无力Lambert-Eaton综合征.ppt

神经肌接头病 Disordersofneuromusculartransmission 重症肌无力Lambert Eaton综合征 Dep ofNeurologyThe2ndHospitalHarbinMedicalUniversity NeuromuscularDisordersDefinition Thediseasesofneuromuscularjunction NMJ describesasetsofdiseasecausedbycirculatingfactorssuchasneurotoxinsorautoantibodieswhichbindwithhighaffinitytospecificproteinsattheNMJanddisturbtheneuromusculartransmission NeuromusuclarJunction NMJ Physiology thenerveAPreachesthenerveterminalwhichinflatedandwithoutmyelinandleadstotheopeningofcalciumchannelandreleaseofAChintothesynapticcleftbyexocytosis NeuromusuclarJunction NMJ Physiology 1 3oftheAChdiffusesrapidlytothepostsynapticmembraneandbindstotheAChRs leadingtoopeningoftheAChR associatedcationchannelanddepolarizationcalledtheend platepotential EPP IftheEPPexceedscertainthreshold voltagegatedsodiumchannelatthepostsynapticmembraneareopened Thisgeneratesthemuscleactionpotential CMAP thatpropagatesalongthemusclefiberandactivatescontraction NeuromusuclarJunction NMJ Physiology Another1 3oftheAChishydrolyzedbycholinesterase ChE Theremaining1 3oftheAChisrecapturedbythepresynapticmembrane 重症肌无力 MyastheniaGravis MG 概念病因及发病机制病理临床表现诊断及鉴别诊断治疗 Myastheniagravis MG Definition MGwasoriginatedfromLatin meaningverysevereweakness acquiredMGisanantibodyandcomplement mediated Tcell dependentautoimmunediseaseleadingtoadefectinneuromusculartransmission Myastheniagravis MG Epidemiology Itistheprototypicneuromusculardisorderswithanincidenceof80 200permillionandprevalenceabout500permillion InChina itisestimatedthat0 6millionpeoplewerediagnosedasMGandmostofthemlivesintheSouthofChina Ithadbeenalife threateningdiseasebefore1970 s thoughnowadaystheincidenceofdeathhasbeengreatlyreducedtoabout0 2 MyastheniaGravis MG Etiology TheautoimmuneoriginofMGisproposedlongbeforeitwasestablishedin1973bythedirectevidenceprovidedbyPatrickandLindstrom whohaveimmunizedrabbitwithaffinity purifiedTorpedoAChRwithCFAandreproducedtheanimalmodelsrepresentinghumanMG EAMG TheAChRistheautoantigen MyastheniaGravis MG Etiology Thepresenceofanti AChRAbscanbedemonstratedin80 90 ofMGpatients Thereisa3 1female maleratioforpatientswhodevelopMGinearlyadultlife Overall theabovemakesMGfulfillsthecriteriaforautoimmunediseases MyastheniaGravis MG Etiology MostofthepatientswithMGhaveabnormalitiesinthethymus e g thymichyperplasticorthymoma Althoughtheprimaryantiselfeventbeingunclear thymusappearstobetheplacewhereitinitiates ThegeneralopinionisthatvirusinfectionorothernonspecificfactorsinvadesthethymusingeneticallypredisposedindividualsleadingtothedevelopmentofMG MyastheniaGravis MG Pathology Lymphoidfolliculuscanbeseeninthymus About10 ofMGpatientshasthymomaofepitheliatype Lymphorage definedbyaggregatedlymphoidcellsaroundthebloodvessels issometimesseeninotherwisenormalmusculatureinMGpatients MyastheniaGravis MG Pathology AttheNMJ grosslysimplifiedpostsynapticfoldswithdepositionofimmune complexandtheanti AChRAbsisdemonstratedbyimmunochemicalstudies Thereisalsoconsiderabledebriswithinthewidenedsynapticcleft NormalNMJ NMJinMGpatients 示意图 电镜 MyastheniaGravis MG ClinicalManifestations MGcanariseatanyage althoughyoungfemalesandoldmalesaremorevulnerabletoit Precipitatingfactors concurrentinfection stress weariness menses pregnancyorparturition Thediseaseinitiatesinsidiousandfollowsaslowlyprogressivecourse MyastheniaGravis MG ClinicalManifestations Clinically MGfeatureswithfluctuatedmuscularweaknessinintensityduringthedayandeasyfatigability Typically theweaknessvariesindistributionandseverityfromdaytoday Characterizedbyabnormalweakness whichbeingworseattheendofthedayorafterexertionandtendstoimproveafterrestorAChEtreatment MyastheniaGravis MG ClinicalManifestations Theweaknessoftenbeginswiththelateralorbilateralextra ocularmuscles leadingtoasymmetricocularpalsies e g diplopia strabismic andptosis Pupillaryresponsesarenotaffected MyastheniaGravis MG ClinicalManifestations Thepatientsmaypresentwithlesswrinkles amimia difficultyinclosingtheeyesordisclosingtooth difficultyinchewingorswallowing nasalspeech weaknessoftheneckortheproximalupperlimbs MyastheniaGravis MG Crisis definition Crisisdescribesarapidlydevelopedweaknessinthebulbarmusclesandrespiratoryinsufficiencythatnecessitatesassistedventilation ItistheleadingcauseofdeathinpatientswithMG MyastheniaGravis MG Crisis classification Myastheniccrisis abletoreacttoAChEdrugsandbeinghypersensitivetothecurare Cholinergiccrisis 1 overmedicationcanleadtoincreasedweakness which unlikemyasthenicweakness isunaffectedorenhancedbyintravenousedrophonium 2 Itmaybeaccompaniedbypallor sweating nausea vomiting salivation colic anddiarrhea muscarinicsyndrome Brittiecrisis unresponsivetoAChE MyastheniaGravis MG OssermanClassification Fivesubgroupscanbedefinedamongpatientswithmyasthenia I OcularIIa MildgeneralizedIIb ModerategeneralizedIII ProgressivelysevereIV latesevere MyastheniaGravis MG Otherclassification MGcanalsobesubdividedintoadolescentandadulttype neonatalMG congenitalmyasthenia D Penicillamineinducedmyasthenia asimilardisorderinpatientsreceivingpenicillamineforrheumatoidarthritisfrequentlyremitswhenthedrugisdiscontinued MyastheniaGravis MG Investigation Routineexaminationontheblood ureaandCSFarenormal X raysandCTscansofthechestmayrevealacoexistingthymomainpatientsover40years MyastheniaGravis MG Investigation EMG increaseddecrement 10 oftheevokedCMAPuponrepeatedstimuliat3or5Hz SinglefibermyographyshowsreducedamplitudeofMEPPandincreasedvariability jitter ormoreblockadeofimpulses MyastheniaGravis MG Investigation Theanti AChRAbspresentin85 90 ofpatientswithgeneralizedMGandin50 ofpatientswithocularMG butnotpresentinhealthyindividuals Whentheanti AChRAbsareidentified thediagnosisisestablished autoantibodiesagainststriatedmuscles MyastheniaGravis MG Diagnosis 疲劳试验 Jolly试验 抗胆碱酯酶药物试验1 腾喜龙 tensilon 试验2 新斯的明 neostigmine 试验重复神经电刺激AChR抗体滴度测定 特征性意义 MyastheniaGravis MG Diagnosis edrophoniumin2 3dose totally10mg giveni v givearapid within2 butshort lived lessthan5 improvementinstrengthinmostpatientswithMG neostigmineof1 5mggiveni m improvesmusclestrengthwithin30 andlastsfor2hs false positiveandfalse negativeresultscanoccur thereisasmallriskofcardiorespiratorycollapse MyastheniaGravis MG Diagnosis Oncethediagnosishasbeenmade CTorMRIofthechestshouldbedonetoexcludeanassociatedthymoma ThyroidfunctionandthyroidAbsshouldbemeasured becauseoftheincreasedfrequencyofthyroiddisease MyastheniaGravis MG Differentialdiagnosis ThedifferentialdiagnosisofMGiswide AcquiredMGv s congenitalMGandneurotoxinse g botulism venoms OcularMG ofwhomabout50 areAChRAb negative v s ocularmusculardystrophyandmitochodrialcytopathy Bulbarmyastheniav s brainstemstrokeandmotor neurondisease e g ALS MyastheniaGravis MG Differentialdiagnosis patientswithgeneralizedweaknessbutarenegativeforAChRAbsv s neuropathiesandmyopathies myasthenicsyndromes otherdisordersoftheNMJwhichneurophysiologicalstudiesmightshowchangessimilartothoseofMG MyastheniaGravis MG Treatment AChEdrugsprovidessymptomaticbenefitwithoutinfluencingthecourseoftheunderlyingdisease pyridostigmine atdosesindividuallydeterminedbutusuallybetween60and180mgq q d Smalldosesofatropinemayattenuatesideeffectssuchasdiarrhea MyastheniaGravis MG Treatment thymectomyshouldbeperformedinpatientsunder60yearsofage usuallyleadstosymptomaticbenefitorremissionHowever itsbeneficialeffectmaynotbeevidentimmediately MyastheniaGravis MG Treatment corticosteriodsareindicatedforpatientswhohaverespondedpoorlytoAChEandhavealreadyunderthymectomy Treatmentsareinitiatedwiththepatientinhospital sinceweaknessmayinitiallybeexacerbated Aninitialhighdoseofpredinisone 60 80mg dorally cangraduallybetaperedtoarelativelylowmaintenancelevel 10 20mg d asimprovementoccurs MyastheniaGravis MG Treatment Immunosuppressant e g azathioprine isusedassteriod sparingagent Itcanalsobegiveninplaceofcorticosteroidstopatientswhoshownosustainedbenefitwithlowdoses Theusualdoseis1 3mg kg d increasedfromalowerinitialdose MyastheniaGravis MG Treatment plasmapheresis PE maybeusedduringanacuteexacerbation myastheniccrisis orundercertainspecialcircumstances e g priortosurgery intravenousimmunoglobulins IVIG havebeenusedtoprovidetemporarybenefitincircumstancessimilartothoseinwhichPEisused MyastheniaGravis MG Treatment Crisis respiratoryandbulbarcomplicationsrequireappropriatesupportivemeasures e g assistedventilationand ornasogastricfeeding PEandIVIGareneeded Lambert EatonSyndrome LEMS 概念病因及发病机制临床表现诊断及鉴别诊断治疗 Lambert EatonSyndrome LEMS Definition Intheparaneoplasticdisorder Absagainsttumorantigenscross reactwithvoltage gatedcalciumchannelsinvolvedinacetylcholinerelease leadingtoadisturbanceofNMT Lambert EatonSyndrome LEMS Etiology In1957 LambertandEatondescribedamyasthenicsyndromethatwaselectrophysiologicallydistinctfromMG anarchetypalparaneoplasticneurologicdisorder frequentlyassociatedwithSCLC occasionallyassociatedwithperniciousanemia Lambert EatonSyndrome LEMS ClinicalManifestations LEMSismorecomm