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AntiNmethylDaspartatereceptorencephalitis:Acasereportandreviewoftheliterature

JPediatrNeurosci.2014MayAug9(2):145147.

PMCID:PMC4166838

doi:10.4103/18171745.139322

AntiNmethylDaspartatereceptorencephalitis:Acasereportandreviewof
theliterature
SatnamKaur,MonicaJuneja,DevendraMishra,andSilkyJain
DepartmentofPediatrics,MaulanaAzadMedicalCollege,LokNayakHospital,NewDelhi,India
Addressforcorrespondence:Dr.SatnamKaur,DepartmentofPediatrics,MaulanaAzadMedicalCollege,LokNayakHospital,NewDelhi
110002,India.Email:sk_doc@yahoo.co.in
Copyright:JournalofPediatricNeurosciences
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract
AntiNmethylDaspartatereceptorencephalitisisawellcharacterizedimmunemediatedencephalitis.Itis
increasinglybeingrecognizedasoneofthecommoncausesofencephalitis,butisfrequentlymisdiagnosed
especiallyinresourceconstrainedsettings.Withasimpletestavailabletodiagnosethedisorderand
prospectsofgoodrecoveryfollowingearlyimmunotherapy,thedisordershouldbekeptasadifferential
diagnosisinpatientspresentingwithunexplainedbehavioral/psychiatricsymptomsandprogressive
encephalopathywithmovementdisorders.
Keywords:Encephalitis,immunemediatedencephalitis,NmethylDaspartatereceptors
Introduction
Encephalitishasnumerousandvariedcauses,butinresourceconstrainedsettings,mostcasesareassumedto
beinfectiousinetiology.Despiteinfectionsbeingacommoncause,immunemediatedencephalitisis
increasinglybeingrecognizedasasignificantcontributortoencephalitiscases(2030%).[1,2]Apartfrom
acutedisseminatedencephalomyelitis(ADEM)(immunemediatedencephalitispredominantlyaffecting
whitematter),anumberofaimmunemediatedencephalitispredominantlyaffectingthegreymatterhave
beendescribedrecently.Infact,anumberofcasespreviouslylabeledasencephalitisofunknowncause
havebeenfoundtohaveimmunemediatedetiology.[2,3]
Here,wereportacaseofantiNmethylDaspartatereceptorencephalitis(antiNMDARencephalitis),
followedbydiscussionofonimmunemediatedencephalitis.Themainpurposeofourcasereportisto
increaseawarenessregardingtheimmunemediatedencephalitis,especiallyantiNMDARencephalitis.
CaseReport
A9yearolddevelopmentallynormalgirlchildwasadmittedwithahistoryofabnormalbehaviorfor3days
andinabilitytosleepfor2days.Shewasapparentlywell7daysbackwhenshehadaflulikeillnessthat
lasted4days.Followinganasymptomaticperiodof2days,shesuddenlystartedtalkingirrelevantlywith
periodsofnormalbehaviorinbetween.Overnext3days,shebecameincreasinglyrestless,agitatedand
anxious,anddidnotsleepfor2consecutivenightsbeforepresentingtothehospital.Shewashaving
hallucinations,delusionsandhyperreligiosity.Therewasnoinadvertentdrugintake,abdominalpain,dark
coloredurine,jaundice,dogbiteorstressfullifeevent.Atadmission,shewasorientedtoplaceandperson
butnottime.Shewashavinginappropriatespeechandwasrestlessandagitated.Restoftheexamination
(includingneurological)wasunremarkable.Liverfunctiontests,serumammonia,andlactatewerewithin
normallimits.Neuroimagingdoneonday3ofadmissionwasunremarkable.Cerebrospinalfluid(CSF)
examinationincludingherpessimplexvirusserologywasnormal.Overnext2days,childdevelopedfeatures
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ofcatatoniaintheformofecholalia,echopraxiaandkeepinglimbsinbizarrepostures,followedbygradually
decreasingverbaloutputthatprogressedtocompletemutismbyday6.Shestoppedinteractingwithparents
andindicatingherneeds.Onday6,shehadmultipleepisodesofleftsidedcomplexpartialseizures(interictal
electroencephalography(EEG)revealedaslowbackground).Nextday,shestartedhavingabnormal
movementsintheformoforofacialdyskinesias(grimacing,chewing,tonguethrusting,lipsmacking,
frowning),dystonias(progressingtothedystonicstorm)andchoreoathetoidmovementsoflimbsthatwere
difficulttocontrol.NoevidencewasfoundforWilson'sdisease.Repeatmagneticresonanceimaging(MRI)
doneonday10ofadmission[Figure1a]revealedT2hyperintensitiesinbilateralthalamusandcerebellar
hemisphere(left>right).Inviewofthepresentationwithpsychiatricsymptomsfollowedbydevelopmentof
catatonia,seizures,encephalopathy,abnormalmovementswithnormalCSFandnonspecificMRIfindings,
possibilityofautoimmuneencephalitiswaskept.TestingforserumantiNMDARantibodieswas
requisitioned(whichsubsequentlycamepositive),andmethylprednisolonewasstarted.CSFevaluationfor
antibodiescouldnotbedonebecauseoffinancialconstraints.Contrastenhancedcomputedtomography
abdomentolookforovarianteratomawasnormal.RepeatMRIbrain[Figure1b]showeddecreasedhyper
intensityascomparedtothepreviousscanwithsomecorticalatrophymainlyinthetemporalregion.
Subsequently,shereceivedtwocoursesofintravenousimmunoglobulin(IVIG).Afterthesecondcourseof
IVIG,involuntarymovementsdecreased,thoughshecontinuedtobeunresponsivetosurroundingswith
intermittentvisualfixationandfollowing.Shealsostartedhavingstereotypicmovements(pelvicthrusting,
floatingofhandsintotheair,writhingmovementsofextremities)andperiodsofhyperthermia.Inviewof
poorresponsetoIVIGandsteroids,shewasgiven4dosesofrituximabatweeklyintervals.Gradually,her
sensoriumimproved,abnormalmovementsabated,andshestartedfollowingsimplecommands.Followup
MRIonday63showeddiffusecerebralatrophy[Figure1c].Atlastfollowup,6monthsafteronset,shehas
rareabnormalmovements,noseizures,nearnormalspeechinresponsetoquestions(butreduced
spontaneousspeechoutput)andimprovedcognition.
Discussion
Immunemediatedencephalitis(predominantlyaffectingthegreymatter,thusexcludingADEM)canbe
broadlydividedintothreegroupsparaneoplasticencephalitisassociatedwithonconeuralantibodies
(paraneoplasticneurologicalsyndromes[PNS])autoimmuneencephalitisassociatedwithantibodiesto
neuronalcellsurfaceproteins(neuronalsurfaceantibodysyndrome[NSAS])encephalitisstronglysuspected
tobeimmunemediated,butimmunemechanismsstillnotfullyelucidated(e.g.,opsoclonusmyoclonus
syndrome,Rasmussenencephalitis,Hashimotoencephalopathy,etc.).[4,5]
Paraneoplasticneurologicalsyndromesarerare(overallaffect<1%ofpatientswithcancers),associatedwith
thepresenceofonconeuralantibodiesandusuallyprecedethediagnosisofcancer.Criteriafordiagnosisof
PNSwereestablishedbyPNSEuronetworkin2004.[6]NeuronalcelllossinPNSismediatedbycytotoxic
Tcellsthatareprobablydirectedagainstthetargetantigensofaccompanyingantibodies.Thus,onconeural
antibodiesarejustmarkersforimmunemediatedprocessandarenotpathogenic.Thesedisordersdonot
usuallyrespondtoimmunotherapy,thoughdiseaseprogressioncanbeslowedwitheffectivetumortherapy.
Neuronalsurfaceantibodysyndromeareassociatedwithantibodiestocellsurfaceproteinsexpressedin
neurons.Theseantibodiesarepathogenicandtargetreceptorsandcellsurfaceproteinsinvolvedinsynaptic
transmission,plasticityorneuronalexcitability.MainNSASdescribedareantiNMDARencephalitisand
limbicencephalitis.Though,thesedisorderscanbeassociatedwithtumors,theyarefrequently
nonparaneoplastic,especiallyinpediatricagegroup,andtheyrespondtoimmunotherapywithagood
chanceofsubstantialrecovery.ComparedwithPNS,thesedisordersarenotrare.Infact,inalongterm
study,frequencyofantiNMDARencephalitisexceededthatofanyindividualviralencephalitis.[2]
AntiNMDARencephalitisisawellcharacterizedsyndromeandismostfrequentofallthedisorders
discussedabove.InarecentpopulationbasedstudydoneinEngland,antiNMDARencephalitisconstituted
4%ofallthecasesofencephalitis.[1]Majorityofcasesoccurinfemales(about80%),anddisorderismore
frequentinyoungteenagersandchildren.[7]Frequencyoftumorassociation(mostlyteratoma)dependson
age,sexandethnicity,beingmorecommoninadultblackwomen.Tumordetectionislesslikelyinyounger
patientsandmen.Tumorsotherthanteratomaareuncommon(2%).[7,8]
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AntibodiesagainstNR1subunitofNMDARcauseareversibledecreaseinNMDARclusterdensityin
postsynapticdendritesintiterdependentfashionresultinginacharacteristicneuropsychiatricsyndromethat
evolvesinseveralstagesofillnessandrecovery.ThedecreaseinNMDARreceptordensityisreversible
uponremovalofantibodiesandexplainsgoodresponsetotumorremovalandimmunotherapyevenin
patientswithseveresymptoms.[9]Whattriggerstheimmuneresponseisnotclearbutageneticandracial
predispositiontoautoimmunityhasbeensuggested.
Illnessbeginswithaprodromalphaseoflowgradefever,andnonspecificfeaturesfollowed,usuallywithin2
weeks,byaprominentpsychiatricphasecharacterizedbyanxiety,insomnia,bizarrebehavior,delusions,
hyperreligiosity,mania,visual/auditoryhallucinations.Languageproblems,varyingfromreducedverbal
outputandecholaliatocompletemutism,arecommon.Shorttermmemorylossisfrequent,thoughdifficult
toassessbecauseofpsychiatricsymptomsandspeechproblems.Neurologicalphasefollowsthepsychiatric
phaseandischaracterizedbydecreasedresponsivenessthatmayalternatewithperiodsofagitationand
catatonia.Abnormalmovementsandautonomicinstabilitypredominateinthisphase.Orofacialdyskinesias
areparticularlystriking.Otherabnormalmovementsincludechoreoathetosis,complexandstereotypic
movements,dystonicposturing,episodicopisthotonus,oculogyriccrisis.Autonomicmanifestationsinclude
hyperthermia,tachycardia,hypersalivation,bradycardia,hypotension,andhypoventilation.Comparedto
adults,autonomicmanifestationsarelesssevereinchildren.[8]Seizuresarecommon.Recoveryoccursin
reverseorderofsymptompresentationandusuallythereiscompleteamnesiafortheentireevent.[9]
Cerebrospinalfluidisabnormal(lymphocyticpleocytosis,normalormildincreaseinproteins,oligoclonal
bands)inmostofthepatients.[7,8,9]EEGabnormalitiesarefoundinallthepatientsintheformof
nonspecificslowanddisorganizedactivity,sometimeswithelectrographicseizures.[7,8,9]BrainMRIis
unremarkablein50%patients.Inother50%,itmayshownonspecifichyperintensitiesincortical/subcortical
areasandcerebellum,sometimeswithcontrastenhancementintheaffectedareasormeninges.SerialMRIs
mayshowcerebralatrophy,butthisisatleastpartlyreversibleoveryears.[7]Definitivediagnosisis
establishedbydemonstratingantibodiesagainstNR1subunitofNMDARinCSF/seraofpatients.
ManagementofNMDARencephalitisincludesimmunotherapyanddetectionandremovalofteratoma,if
present.FirstlineimmunotherapyincludesIVIG,methylprednisoloneandplasmaexchange.Concurrentuse
ofIVIGandmethylprednisoloneasfirstlinetreatmentfollowedbyrituximab(4dosesatweeklyintervals)
withorwithoutcyclophosphamideincaseofpoorresponseatday10isthesuggestedtreatment.[7]
AdditionalcoursesofIVIG/methylprednisolone/plasmaexchangehavebeensuggestedtobeusefulifboth
CSFandserumantibodytitersremainhigh.[10]Chronicimmunosuppressionwithmycophenolatemoeftilor
azathioprinefor1yearisrecommendedforpatientswithoutteratomaandthoserequiringsecondline
immunotherapy.Methotrexatecanbeusedasanalternativeimmunosuppressantincaseofpoorresponseto
firstandsecondlinetreatment.Yearlysurveillanceforteratomaforatleast2yearsisrecommended.
Recoveryfromthisdiseaseisslow(monthsyears)but75%patientsshowcomplete/substantialrecovery.
[7,8,9]Outcomeisbetterwithearlydiagnosisandtreatment.[7,10]Relapsescanoccurin2025%patients
andaremorecommoninidiopathiccasesandwithdelayeddiagnosis.[7,8,9,10]
Toconclude,antiNMDARencephalitisisoneofthecommoncausesofencephalitis,hasdistinctiveclinical
featuresandispotentiallyreversibleifdiagnosedearlyandtreatedappropriately.
Footnotes
SourceofSupport:Nil
ConflictofInterest:Nonedeclared.

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FiguresandTables
Figure1

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AntiNmethylDaspartatereceptorencephalitis:Acasereportandreviewoftheliterature

Serialmagneticresonanceimagingbrainshowing(a)T2hyperintensitiesinbilateralcerebellarhemispheres(left>right)
(b)Mildcorticalatrophy,moreprominentintemporallobeswithdecreasedhyperintensitiesinbilateralcerebellar
hemispheres(c)Diffusecerebralatrophy
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