Anti-NMDAR encephalitis

Anti-NMDA receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis (AE), which is associated with autoantibodies against ... Skiptomaincontent Share January2020;7(1)ArticleOpenAccess Anti-NMDARencephalitisAsingle-center,longitudinalstudyinChina XiaoluXu,QiangLu,YanHuang,SiyuanFan,LixinZhou,ViewORCIDProfileJingYuan,XunzheYang,HaitaoRen,DaweiSun,YiDai,HuadongZhu,YinanJiang,YichengZhu,BinPeng,LiyingCui,HongzhiGuan FirstpublishedOctober16,2019,DOI:https://doi.org/10.1212/NXI.0000000000000633 XiaoluXuFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite QiangLuFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite YanHuangFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite SiyuanFanFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite LixinZhouFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite JingYuanFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite ORCIDrecordforJingYuan XunzheYangFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite HaitaoRenFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite DaweiSunFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite YiDaiFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite HuadongZhuFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite YinanJiangFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite YichengZhuFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite BinPengFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite LiyingCuiFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite HongzhiGuanFromtheDepartmentofNeurology(X.X.,Q.L.,Y.H.,S.F.,L.Z.,J.Y.,X.Y.,H.R.,Y.Z.,B.P.,L.C.,H.G.),DepartmentofGynecologyandObstetrics(D.S.,Y.D.),DepartmentofEmergency(H.Z.),andDepartmentofPsychology(Y.J.),PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China;andCenterofNeuroscience(L.C.),ChineseAcademyofMedicalSciences.FindthisauthoronGoogleScholar FindthisauthoronPubMed Searchforthisauthoronthissite FullPDF Citation Anti-NMDARencephalitisAsingle-center,longitudinalstudyinChina XiaoluXu,QiangLu,YanHuang,SiyuanFan,LixinZhou,JingYuan,XunzheYang,HaitaoRen,DaweiSun,YiDai,HuadongZhu,YinanJiang,YichengZhu,BinPeng,LiyingCui,HongzhiGuan NeurolNeuroimmunolNeuroinflammJan2020,7(1)e633;DOI:10.1212/NXI.0000000000000633 CitationManagerFormats BibTeX Bookends EasyBib EndNote(tagged) EndNote8(xml) Medlars Mendeley Papers RefWorksTagged RefManager RIS Zotero Permissions MakeComment SeeComments Downloads2616 Share Article Figures&Data 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AbstractObjectiveTodescribethedetailedclinicalcharacteristics,immunotherapy,andlong-termoutcomesofpatientswithanti-NMDAreceptor(NMDAR)encephalitisinChina.MethodsAsingle-center,prospectivestudy.Patientswhometthediagnosticcriteriawereenrolledfrom2011to2017andfollowedup.Theclinicalfeatures,treatment,andlong-termoutcomeswerecollectedprospectively.Factorsaffectingthelong-termprognosiswereanalyzed.ResultsThestudyincluded220patients.Themostcommonclinicalpresentationswerepsychosis(82.7%)andseizures(80.9%).Ofthepatients,19.5%hadanunderlyingneoplasm;ofwhichovarianteratomawas100%oftumorsinfemalesandonlyonemalehadlungcancer.Mostpatients(99.5%)receivedfirst-linetherapy(glucocorticoids,IVimmunoglobulin,orplasmapheresisaloneorcombined),andonly7.3%receivedsecond-lineimmunotherapy(rituximab,cyclophosphamidealone,orcombined).Long-termimmunotherapy(mycophenolatemofetilorazathioprine>1year)wasadministeredto53.2%ofpatients.Duringthefirst12months,207(94.1%)patientsexperiencedimprovement,and5(2.3%)died,whereas38(17.3%)experiencedrelapses.At12-monthfollow-up,92.7%hadfavorableclinicaloutcomes(modifiedRankinScalescore≤2).ConclusionsPatientsinChinapresentwithpsychosisandseizurefrequentlybuthavealowpercentageofunderlyingneoplasms.Re-enforcedfirst-lineimmunotherapyiseffectiveinmanaginganti-NMDARencephalitisintheacutephase.Althoughrelapseisrelativelycommon,withcombinedfirst-lineandlong-termimmunotherapy,mostpatientsreachedfavorableoutcomes.GlossaryAE=autoimmuneencephalitis;AQP4=aquaporin-4;AZA=azathioprine;CTX=cyclophosphamide;HSV=herpessimplexvirus;ICU=intensivecareunit;IQR=interquartilerange;IVIG=IVimmunoglobulin;MMF=mycophenolatemofetil;MOG=myelinoligodendrocyteglycoprotein;mRS=modifiedRankinScale;MTX=methotrexate;NMDAR=NMDAreceptor;PE=plasmapheresis;PUMCH=PekingUnionMedicalCollegeHospital;RTX=rituximabAnti-NMDAreceptor(NMDAR)encephalitisisthemostcommontypeofautoimmuneencephalitis(AE),whichisassociatedwithautoantibodiesagainstneurosurfaceorsynapticantigens.1,–,3Sinceitsfirstreportin2007,1withtheproposedclinicalapproach,3increasingnumbersofanti-NMDARencephalitiscaseswereidentified.Differencesinclinicalcharacteristicsandtreatmentstrategiesofanti-NMDARencephalitiswerereportedamongracesandcountries.4,–,10MainbarrierstoAEmanagementinChinaconsistoftheavailabilityofreferralcenters,thetimelinessofcorrectdiagnosis,andfinancialconcerns.11In2017,ChinaproposedadomesticconsensusonthemanagementofAE,aimingtoincreaseawarenessofthediseaseanddeterminetheoptimaltreatmentforChinesepatients.12However,limiteddataofclinicalcharacteristicsandlong-termprognosisofChineseanti-NMDARpatientsareavailableowingtofewreportswithsmallsamplesize.9,11,13,14TakingtheadvantageofPekingUnionMedicalCollegeHospital(PUMCH)asthenationalreferralcenterforcomplicateddisease,aprospectiveanti-NMDARencephalitisdiseasecohortwasestablishedtodescribetheclinicalcharacteristics,treatmentregimen,andlong-termoutcomesofpatientswithanti-NMDARencephalitisinChina.MethodsStudydesignandpopulationInthisstudy,patientswithanti-NMDARencephalitiswereenrolledconsecutivelyatPUMCHbetweenMay2011andDecember2017.Theinclusioncriteriawereasfollows:(1)acuteonsetof1ormoreofthe8majorgroupsofmanifestations:psychosis,memorydeficit,speechdisturbance,seizures,movementdisorder,lossofconsciousness,autonomicdysfunction,andcentralhypoventilation;(2)CSFtestedpositiveforNMDARantibodies(cell-basedassay[EUROIMMUN,Lübeck,Germany]);and(3)reasonableexclusionofotherdisorders.Tobetterunderstandtheclinicalcharacteristics,wealsorecordedtheco-occurrenceoffever,headache,arrhythmia,intensivecareunit(ICU)admission,andotheratypicalsymptoms.Becauseoflimitedresourcesofthehospitalandfinancialconcernsthepatients,theabsoluteindicationsforICUadmissionincludedsevereanti-NMDARencephalitiswithovarianteratomarequiringsurgicaloperation,statusepilepticus,mechanicalventilationrequirement,andhemodynamicinstability.Demographicdataandancillarytestsresultswererecorded,includingageatonset,sex,diseasecourse,CSFtestsresults,MRI,andEEGresults.Allpatientswerescreenedatleastonceforsystemictumorsatonset.Patientswithtumorsunderwenttumorremoval.Immunotherapyincludedfirst-line(corticosteroids,IVimmunoglobulin[IVIG],orplasmapheresis[PE]aloneorcombined)andsecond-line(rituximab[RTX]andcyclophosphamide[CTX]aloneorcombined)immunotherapies.6,7Long-termimmunotherapy(mycophenolatemofetil[MMF]orazathioprine[AZA]>1year)andotherimmunotherapy(intrathecalmethotrexate[MTX])werealsoadministered.15,16PatientswerefollowedregularlyinlocalhospitalsorPUMCHneurologyclinics.Treatmenteffectsandlong-termoutcomeswereassessedusingthemodifiedRankinScale(mRS).ApoorresponsewasdefinedasnoimprovementinthemRSscoreorasanmRSscore≥4for4weeks;clinicalimprovementwasdefinedasadecreaseinthemRSscore≥1pointfromthatatthepreviousvisit;relapsewasdefinedasanexacerbationofprevioussymptomsortheoccurrenceofnewsymptomsafterbeingstablefor2months.Long-termfavorableoutcomewasdefinedasanmRSscore≤2,andpooroutcomewasdefinedasanmRSscore>2attheendoffollow-up.StatisticalanalysisStatisticalanalyseswereperformedusingSPSSIBM20.0.GraphPadPrism6.0wasusedtogeneratefigures.Quantitativedatawithnormaldistributionsarepresentedasmean±SD,otherwiseasmedianswiththeinterquartilerange(IQR).ThemRSscoresbeforeandaftertreatmentwerecomparedusingtheWilcoxontest.Symptomsanddemographicdatawereanalyzedusingtheχ2testorFisherexacttestforcategoricalvariablesandMann-WhitneyUtestforcontinuousvariables.Factorsaffectingoutcomewereassessedusingbinarylogisticregressionanalysis.Kaplan-Meiercurveswithlog-rankwereusedtoanalyzerelapsefrequency.p<0.05wasconsideredsignificant.Standardprotocolapprovals,registrations,andpatientconsentsThisstudywasapprovedbytheEthicsCommitteeofPUMCH(JS-891),andinformedconsentwasobtainedfromeachpatient.Allthedataanalyzedinthestudywerestrictlyanonymous.DataavailabilityAnonymizeddatanotpublishedwithinthisarticlewillbemadeavailablebyrequestfromanyqualifiedinvestigator.ResultsClinicalcharacteristicsAtotalof220patientswereenrolled,andallweretestedforanti-NMDARantibodywithpairedCSFandserum.Allpatients(100%)werepositiveforanti-NMDARantibodiesinCSF,and157(71.4%)werepositiveinserum.ReviewoftheenrolledpatientsindicatedthatallpatientsmetthediagnosticcriteriaproposedbyGrausetal.3Themedianageatonsetwas21(range5–72)years,with69(31.4%)ofthepatientsyoungerthan18years.Overall,143(65.0%)patientswerefemales,and77(35.0%)weremales.Tumorswerefoundin43(19.5%)patients:42femaleswithovarianteratomasand1malewithlungcancer.Allthefemalepatientswithovarianteratomasunderwenttumorremoval,whereasthepatientwithlungcancerwastreatedwithpalliativetherapybyaninternistandlaterdiedofcancer.Inaddition,8patientswerefoundtohaveprominentmolesonthebodysurface,whichwerelaterresected.Pathologically,themoleswerecompoundorintradermalnevi.17,18Themostcommonclinicalmanifestationsoftheanti-NMDARencephalitiswerepsychosis(182,82.7%)andseizures(178,80.9%).Movementdisorderpresentedmoreofteninpatientsyoungerthan18yearsthanadultpatients(38/69,55.1%vs56/151,37.1%,p=0.01).Table1describesthepatients'clinicalcharacteristicsindetail.Viewthistable:Viewinline Viewpopup Downloadpowerpoint Table1Clinicalcharacteristicsofpatientswithanti-NMDAreceptorencephalitisFigure1showsthedistributionoffemalepatientsaccordingtoageandpresencevsabsenceoftumor;thepeakco-occurrenceofovarianteratomawasbetween19to24years.Downloadfigure Openinnewtab Downloadpowerpoint Figure1DistributionoffemalepatientsbyageandpresenceorabsenceofovarianteratomaAncillarytestresultsAllpatientsunderwentbrainMRIatonset,and79(35.9%)hadabnormalfluid-attenuatedinversionrecoverysequencesignals,including31(14.1%)inthemedialtemporallobe.Otherinvolvedareasincludedthefrontal,parietal,andoccipitalcortices,diencephalon,cerebellum,andbrainstem.Eleven(5.0%)patientshaddemyelinatinglesions,ofwhom4werepositiveforaquaporin-4(AQP4)antibodyand5formyelinoligodendrocyteglycoprotein(MOG)antibody.AbnormalEEGfindingswereseenin113(51.4%)patients:102(46.4%)hadslowactivityand14(6.4%)epilepticdischarges.However,asmostpatientsreceivedshort-durationEEGinsteadofvideoEEGof24hoursorlonger,thepercentageofdelta-brushabnormalitywasunabletoassess.Repeatedlumbarpunctureswereperformedfordiagnosisandevaluation,andtheCSFresultsatonsetbeforeimmunotherapywerecollectedandanalyzed.Theanalysisshowedamedianopeningpressureof170(IQR150–280)mmH2O.Ofnote,81.3%ofthepatientshadpleocytosis,themedianwhitebloodcellcountwas14.0(IQR7.0–22.5)×106/L,and90.9%wereofmononuclearcells(i.e.,lymphocyteandmonocytes).Theproteinlevelwaselevatedin29.7%ofthepatients.Table2summarizesthemainancillarytestsofthepatients.Viewthistable:Viewinline Viewpopup Downloadpowerpoint Table2SummaryofthemainancillarytestsresultsImprovementsindiagnosisaccuracyandgeneralhospitalizationstatusUnderrecognitionandmisdiagnosiswereinevitableinthepast,occurringattheinitialvisittoalocalphysicianoradmissiontoourhospital.In2011,4patientswereidentified,takingamediandurationof9(IQR1–36)monthsbeforediagnosiswasmade.Themisdiagnosisratethenwas75.0%,withmostcasesmisdiagnosedasviralencephalitis.WithincreasedawarenessofAE,screeningforanti-NMDARantibodiesatadmissionisnowrequiredforallcaseswithsuspectedencephalitis.By2017,themisdiagnosisratehaddecreasedto15.4%.Overall,30patientsweremisdiagnosedwithviralencephalitis,10withschizophrenia,2withepilepsy,and1eachwithcerebralangiitis,cerebralvascularevents,andtuberculosis.Thepercentagesofcorrectdiagnosisattheinitialhospitalvisitovermisdiagnosisbycalendaryearwereshowninfigure2,indicatingagrowingnumberofreferredpatientsandincreasedcorrectdiagnosisidentifiedovertheyears.Downloadfigure Openinnewtab Downloadpowerpoint Figure2NumberofpatientsofcorrectdiagnosisovermisdiagnosisattheinitialhospitalvisitbycalendaryearThemediandurationfromonsettodiagnosiswas2(IQR1–4)weeks.Immunotherapywasinitiatedthesamedaydiagnosiswasmadeandsometimesevenbeforediagnosisatlocalhospitalsasempiricaltreatment.Themedianlengthofhospitalizationwas26(IQR14–42)days.However,severepatientswhorequiredintensivecarestayedinthehospitalforupto117days.TreatmentoutcomesOverall,219(99.5%)patientsreceivedfirst-lineimmunotherapy,inmostcasesacombinedregimenofrepeatedsteroidsandIVIG.Atotalof208(94.5%)patientsreceivedsteroids,ofwhom103(46.8%)receivedpulsedIVmethylprednisolone.IVIGwasadministeredto199(90.5%)patients,and7(3.2%)patientsunderwentPE.Second-lineimmunotherapywasadministeredtoonlyasmallproportionofthepatients,usuallybecauseoftheoff-labeluseofRTXinAE,cost,IVandhospitalizationrequirements,andconcernsaboutsideeffects.Twelve(5.5%)patientsreceivedRTX,and4(1.8%)receivedCTX.Long-termimmunotherapywasadministeredmainlyinpatientswhowereenrolledlater,asanadd-ontherapyforsevereorrefractorypatientsintheacutephase,orasmaintenancetherapytopreventandmanagerelapses.Ingeneral,MMFwasadministeredin109(49.5%)patients,55ofwhomatonsetand54afterrelapse,andAZAwasadministeredin8(3.6%)patients.Inaddition,intrathecalMTXwasgivento8(3.6%)severepatients.Duringthefirst12months,207(94.1%)patientsexperiencedimprovement,8(3.6%)werestable,and5(2.3%)patientsdied.Allsurvivalpatientswerefollowedforatleastayear(range12–72months).At12-monthfollow-up,204(92.7%)patientshadattainedsatisfactoryneurologicfunction(mRSscoreof0,1,and2in144,47,and13patients,respectively)comparedwith23(10.5%)patientswithanmRSscore≤2atonset,asshowninfigure3.ThemedianmRSscoreatthelastfollow-upwas0(IQR0–1),whichwassignificantlylowerthanthescoreof4(IQR3–5)atonset(Z=−12.67,p<0.0001).Downloadfigure Openinnewtab Downloadpowerpoint Figure3DistributionofmRSscoresatonsetandlastfollow-upmRS=modifiedRankinScale.Table3summarizesthecomparisonsbetweenpatientswithfavorableandpoorclinicaloutcomes.Ofinterest,morepatientswithspeechdisturbancewereidentifiedinthefavorableoutcomegroup(p=0.03).Furtheranalysisindicatedthatpatientswithspeechdisturbancepresentedtotheneurologistearlierthanthosewithout(20days[IQR12–34days]vs31days[IQR19–58days],p=0.008,Z=−2.665).However,ageatonset,theratesofdecreasedconsciousnesslevel,centralhypoventilation,ICUadmission,mechanicalventilation,ovarianteratoma,andrelapsewerehigherinthepooroutcomesubgroup,althoughnoneofthesedifferencesreachedsignificance.Viewthistable:Viewinline Viewpopup Downloadpowerpoint Table3Comparisonsofclinicaldataofpatientswithanti-NMDAreceptorencephalitisRelapseDuringthefirst12months,38(17.3%)patientsexperiencedafirstrelapse.Theirmedianagewas21(IQR16–37)years,andthemediandurationfromonsettothefirstrelapsewas7(IQR5–10)months.Oftherelapsedpatients,25(65.8%)werefemale,and5hadovarianteratomasatdiseaseonset.Thoroughclinicalandlaboratoryexaminationswereconductedtoruleoutotheretiologiesandtovalidatethediagnosis.Twopatientsweretreatedatlocalhospitalsbeforeantibodiesweretested,whereas10/36(27.8%)patientsshowedelevatedantibodytiteratrelapseduringserialserumantibodymonitoring.Ofthe17patientswhounderwentlumbarpuncture,CSFantibodiesweredetectedin15(88.2%)patients.MRIwasabnormalin8(21.1%)patients,andanovarianteratomawasdetectedinonly1(2.6%)patientatrelapse.Adelayintreatmentwasassociatedwithrelapse(p<0.01).However,neithertumorstatus(p=0.58)nortreatmentregimen(p=0.34)wasstatisticallyassociatedwithrelapsefrequency(figuree-1,links.lww.com/NXI/A157).Allrelapsedpatientsunderwentreinitiationofthefirst-lineimmunotherapy,and18patientswerealsogivenlong-termMMF.Subsequently,12(31.6%)patientsexperiencedfurtherrelapses(range2–4episodes).TherewasnosignificantdifferenceintheoccurrenceofsubsequentrelapsebetweenMMF-treatedpatientsandotherpatients(4/18,22.2%vs8/20,40.0%,p=0.31).Subsequentrelapsesweresimilarto,orworsethan,theinitialepisodesinonly3(7.9%)patients.Theinitialhospitalizationdurationwas25(IQR14–43)days,andthesubsequenthospitalizationswereallshorterthan14days.Between2011and2017,80(36.4%)patientsexperiencedrelapse,and21(26.3%)experiencedmultiplerelapses(range2–4episodes).Mostpatientshadafirstrelapseduringthefirst24months(64/80,80.0%).However,relapsesupto6yearsafteronsetwerealsoreportedinourcohort.DiscussionToourknowledge,thisisthelargestChineseanti-NMDARencephalitiscohorttodate.Inourstudy,anti-NMDARencephalitisispredominantlyfoundinfemales(65.0%)withthemedianageatonsetof21years.Mostpatientspresentedwithpsychiatricsymptomsandseizures,andyoungerpatientspresentedmoreoftenwithmovementdisorders,whichareconsistentwithpreviousstudies.6,7However,ourstudyreportedalowICUadmissionrate.ThelargecohortstudyofTitulaeretal.7reportedthat75%(435/563)ofpatientswithmRSscore≥4wereadmittedtotheICU.Inourstudy,becauseoflimitedavailabilityofmedicalrecoursesandconcernofexpenses,only68/133(51.1%)oftheseverepatients(mRSscore≥4)wereadmittedtotheICU.Theprevalenceofanunderlyingneoplasmvariedamongstudies.Titulaeretal.7reportedthat38%ofthepatientshadatumor,andAsianpatientsweremorelikely(45%)tohaveateratoma.However,only19.5%ofthepatientsinourcohorthadatumor,with29.4%ofthefemaleshadanovarianteratoma.OtherstudiesofChineseorAsianpatientshavealsoreportedlowprevalenceoftumors(Limetal.,22.7%;Wangetal.,8%;Liuetal.,6.7%;andZhangetal.,8.1%).8,11,13,14Theheterogeneityamongreportsmaybeduetosamplesizesandselectionbiasorotherfactorsincludinggeneticbackgroundsandepidemiologicreasons,andfuturestudiesarerequired.Intumor-negativepatients,herpessimplexvirus(HSV)infectionhasbeenreportedtobethepossibletrigger.However,asthegoldstandardfortheinfectionisPCRtesting,whichisexpensiveandtimeconsuming,mostpatientsreceivedempiricaltreatmentbeforeorevenwithoutadefinitediagnosisofHSVencephalitis.Thuspost-HSVanti-NMDARencephalitiswasunabletoassessinourcurrentstudy.BrainMRIfindingsprovidefurtherevidencethatanti-NMDARencephalitisisa“diffuseencephalopathy.”6Abnormalsignalswerereportedin35.9%ofthepatients,predominantlyinthemedialtemporallobe.Signalsinotherareasofthecortex,diencephalon,brainstem,andcerebellumwerealsoreported.Notably,“overlappingsyndrome”wasidentifiedin11(5.0%)patientswithbothMRIdemyelinatinglesionsandanti-AQP4oranti-MOGantibodies.19Studieshavesuggestedmoreintenseimmunotherapyrequirementsandmoreresidualdeficitsinthesepatients.19,20Inourseries,allthesepatientsreceivedlong-termimmunotherapywithMMF,and10(90.9%)hadfavorableclinicaloutcomes.Inthemanagementofanti-NMDARencephalitis,repeatedfirst-lineimmunotherapywasfrequentlyusedinourcohort,whereassecond-lineimmunotherapywasadministeredinasmallportionofpatientsowingtotheoff-labeluseofRTXforAEinChina,cost,hospitalizationrequirements,andconcernsaboutsideeffect.9,11,14,15However,long-termimmunotherapywasadministeredto117(53.2%)patients,includingMMFto109(49.5%).Withcombinedtherapyofre-enforcedfirst-linetherapyandlong-termimmunotherapy,204(92.7%)patientsreachedfavorableclinicaloutcomes,andthemedianmRSscoredecreasedsignificantlyfrom4to0atafollow-upof12months.Comparedwithotherreports(Dalmauetal.,77%;Tituaeretal.,79%;Wangetal.,80.4%;Liuetal.,64%;andZhangetal.,89.2%),6,7,11,13,14weobservedmoresatisfactoryclinicaloutcomes.Speechdisturbancewasfoundtobemorefrequentinthegroupwithfavorableoutcome.Furtheranalysisindicatedthatpatientswithspeechdistancewerediagnosedearlier.Thus,thiscouldbeaconfounderreflectingbetterrecognitionandthereforequickertreatment.Relapseswererelativelycommoninourcohort.Thedefinitionofrelapseinourstudy,alongwithotherproposeddefinitions,7,21,22isbasedmoreonobservationsanddescriptionsofclinicalsymptoms.Nevertheless,thoroughexaminationsareneededtoruleoutotherdisordersandvalidatethediagnosis.Whenmonitoringandevaluatingtherelapses,MRIwasfrequentlyunremarkable.Theserumantibodytiterdidnotcorrelatewiththeclinicalseverityperfectly,andsomerelapsedantibodiesweredetectedonlyintheCSF,aspreviouslyreported.6,22However,serialCSFmonitoringmaybeimpracticalduringfollow-up,andbetterindicatorsshouldbeidentifiedinfuturestudies.Neithertumorstatusnortreatmentregimenwasassociatedwithrelapsefrequencystatistically,possiblyduetothelowprevalenceoftumorandvarietyinthetreatmentregimensusedinourcohort.Long-termMMFdidnotpreventfurtherrelapses,possiblybecauseoftherelativelysmallsamplesize,andtheroleoflong-termimmunotherapywarrantsfurtherinvestigation.Althoughmostpatientsexperiencedafirstrelapsewithin24months,relapse6yearsafteronsetwasalsoreported.OtherreportsalsosuggestedthatAErelapsecouldoccuryearsaftertheinitialepisode.21,23,24Therefore,extendedfollow-upisessential.Ourstudyhasseverallimitations.Asthenationalreferralcenterforcomplicateddisease,ourcohortmaybebiasedbymorerefractorycases.Theanalysisforeachindividualtreatment,particularlyforlong-termimmunotherapy,andtheassessmentofrelapseswarrantsfurtherstudy.ParametersotherthanthemRSscorearerequiredtodescribefullytheoutcomesofanti-NMDARencephalitis,especiallyinevaluatingthecognitiveorbehavioralfunction,whichusuallyremainslastinthesepatients.Despitetheselimitations,ourstudyaddstothepresentknowledgeofanti-NMDARencephalitis,andactsasaprecursorforfuturemulticenterstudieswithmorecomprehensiveevaluations,andstudiestofurtherevaluatetheefficacyofeachindividualtreatment.Wedescribetheclinicalcharacteristics,immunotherapyregimens,andlong-termoutcomesofpatientswithanti-NMDARencephalitisinChina.Repeatedfirst-linetherapyiseffectiveinmanagingacutephaseencephalitis,andtheefficacyoflong-termimmunotherapywarrantsfurtherstudy.Althoughrelapsesarerelativelycommon,mostpatientsreachedfavorableoutcomes.Furthermulticenterstudieswithmoreadvancedstudydesign,moredetailedevaluation,andextendedfollow-uparerequired.StudyfundingThestudywassupportedby(1)NationalKeyResearchandDevelopmentProgramofChina(Grantno.2016YFC0901500);(2)CenterforRareDiseasesResearch,ChineseAcademyofMedicalSciences,Beijing,China(Grantno.2016ZX310174-4);and(3)BeijingMunicipalScienceandTechnologyFoundation(Grantno.Z161100000516094).DisclosureTheauthorsreportnodisclosures.GotoNeurology.org/NNforfulldisclosures.AcknowledgmentTheauthorsthankProf.JianmingWangofPekingUnionMedicalCollegeHospitalandProf.JiaweiWangofBeijingTongrenHospitalAffiliatedtoCapitalMedicalUniversityforprovidingadviceforthearticle.TheyalsothankDr.YanZhangofXuanwuHospitalAffiliatedtoCapitalMedicalUniversity,Dr.YongqiangHuofBeijingFengtaiYouanmenHospital,andBeijingEncephalitisGroupforcontributingparticipants.AppendixAuthorsFootnotesGotoNeurology.org/NNforfulldisclosures.Fundinginformationisprovidedattheendofthearticle.↵*Theseauthorscontributedequallytothemanuscript.TheArticleProcessingChargewasfundedbyNationalKeyResearchandDevelopmentProgramofChina(Grantno.2016YFC0901500);CenterforRareDiseasesResearch,ChineseAcademyofMedicalSciences,Beijing,China(Grantno.2016ZX310174-4);andBeijingMunicipalScienceandTechnologyFoundation(Grantno.Z161100000516094).ReceivedApril21,2019.AcceptedinfinalformSeptember12,2019.Copyright©2019TheAuthor(s).PublishedbyWoltersKluwerHealth,Inc.onbehalfoftheAmericanAcademyofNeurology.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivativesLicense4.0(CCBY-NC-ND),whichpermitsdownloadingandsharingtheworkprovideditisproperlycited.Theworkcannotbechangedinanywayorusedcommerciallywithoutpermissionfromthejournal.References1.↵DalmauJ,TuzunE,WuHY,etal.Paraneoplasticanti-N-methyl-D-aspartatereceptorencephalitisassociatedwithovarianteratoma.AnnNeurol2007;61:25–36.OpenUrlCrossRefPubMed2.↵DalmauJ,GleichmanAJ,HughesEG,etal.Anti-NMDA-receptorencephalitis:caseseriesandanalysisoftheeffectsofantibodies.LancetNeurol2008;7:1091–1098.OpenUrlCrossRefPubMed3.↵GrausF,TitulaerMJ,BaluR,etal.Aclinicalapproachtodiagnosisofautoimmuneencephalitis.LancetNeurol2016;15:391–404.OpenUrlCrossRefPubMed4.↵IizukaT,SakaiF,IdeT,etal.Anti-NMDAreceptorencephalitisinJapan:long-termoutcomewithouttumorremoval.Neurology2008;70:504–511.OpenUrlCrossRefPubMed5.↵IraniSR,BeraK,WatersP,etal.N-methyl-D-aspartateantibodyencephalitis:temporalprogressionofclinicalandparaclinicalobservationsinapredominantlynon-paraneoplasticdisorderofbothsexes.Brain2010;133:1655–1667.OpenUrlCrossRefPubMed6.↵DalmauJ,LancasterE,Martinez-HernandezE,RosenfeldMR,Balice-GordonR.Clinicalexperienceandlaboratoryinvestigationsinpatientswithanti-NMDARencephalitis.LancetNeurol2011;10:63–74.OpenUrlCrossRefPubMed7.↵TitulaerMJ,McCrackenL,GabilondoI,etal.Treatmentandprognosticfactorsforlong-termoutcomeinpatientswithanti-NMDAreceptorencephalitis:anobservationalcohortstudy.LancetNeurol2013;12:157–165.OpenUrlCrossRefPubMed8.↵LimJA,LeeST,JungKH,etal.Anti-N-methyl-d-aspartatereceptorencephalitisinKorea:clinicalfeatures,treatment,andoutcome.JClinNeurol2014;10:157–161.OpenUrlPubMed9.↵YuanJ,PengB,GuanH,etal.Immunotherapystrategyfor35casesofsevereanti-N-methyl-D-aspartatereceptorencephalitis.NatlMedJChina2016;96:1035–1039.OpenUrl10.↵BartoliniL,MuscalE.Differencesintreatmentofanti-NMDAreceptorencephalitis:resultsofaworldwidesurvey.JNeurol2017;264:647–653.OpenUrl11.↵WangW,LiJM,HuFY,etal.Anti-NMDAreceptorencephalitis:clinicalcharacteristics,predictorsofoutcomeandtheknowledgegapinsouthwestChina.EurJNeurol2016;23:621–629.OpenUrl12.↵AssociationNBoCM.Chineseexpertconsensusonthediagnosisandmanagementofautoimmuneencephalitis.ChinJNeurol2017;50:91–98.OpenUrl13.↵LiuL,SongZH,GuoJ,etal.Clinicalanalysisof45Chinesepatientswithanti-N-methyl-D-aspartatereceptorencephalitis.ChinJNeurol2014;47:474–481.OpenUrl14.↵ZhangY,LiuG,JiangM,ChenW,HeY,SuY.Clinicalcharacteristicsandprognosisofsevereanti-N-methyl-D-aspartatereceptorencephalitispatients.NeurocritCare2018;29:264–272.OpenUrl15.↵GuanHZ,XuXL,ZhuYC,etal.Clinicalandimmunologicalanalysisofmycophenolatemofetiltreatmentinanti-leucine-richglioma-inactivated1encephalitis.ChinJNeurol2018;51:281–287.OpenUrl16.↵YangXZ,CuiLY,RenHT,QuT,GuanHZ.Anti-NMDARencephalitisafterresectionofmelanocyticnevi:reportoftwocases.BMCNeurol2015;15:165.OpenUrl17.↵YangXZ,ZhuHD,RenHT,etal.Utilityandsafetyofintrathecalmethotrexatetreatmentinsevereanti-N-methyl-D-aspartatereceptorencephalitis:apilotstudy.ChinMedJ(Engl)2018;131:156–160.OpenUrl18.↵YinH,ZhuC,RenH,etal.Resectionofmelanocyticneviasapotentialtreatmentofanti-NMDARencephalitispatientswithouttumor:reportofthreecases.NeurolSci2018;39:165–167.OpenUrl19.↵TitulaerMJ,HoftbergerR,IizukaT,etal.Overlappingdemyelinatingsyndromesandanti-N-methyl-D-aspartatereceptorencephalitis.AnnNeurol2014;75:411–428.OpenUrlCrossRefPubMed20.↵FanS,XuY,RenH,etal.Comparisonofmyelinoligodendrocyteglycoprotein(MOG)-antibodydiseaseandAQP4-IgG-positiveneuromyelitisopticaspectrumdisorder(NMOSD)whentheyco-existwithanti-NMDA(N-methyl-D-aspartate)receptorencephalitis.MultSclerRelatDisord2018;20:144–152.OpenUrl21.↵GabilondoI,SaizA,GalanL,etal.Analysisofrelapsesinanti-NMDARencephalitis.Neurology2011;77:996–999.OpenUrlCrossRefPubMed22.↵Gresa-ArribasN,TitulaerMJ,TorrentsA,etal.Antibodytitresatdiagnosisandduringfollow-upofanti-NMDAreceptorencephalitis:aretrospectivestudy.LancetNeurol2014;13:167–177.OpenUrlCrossRefPubMed23.↵ArinoH,ArmangueT,Petit-PedrolM,etal.Anti-LGI1-associatedcognitiveimpairment:presentationandlong-termoutcome.Neurology2016;87:759–765.OpenUrl24.↵vanSonderenA,ThijsRD,CoendersEC,etal.Anti-LGI1encephalitis:clinicalsyndromeandlong-termfollow-up.Neurology2016;87:1449–1456.OpenUrl 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