12/29/2016 OutbreaksofUnexplainedNeurologicIllnessMuzaffarpur,India,20132014

MorbidityandMortalityWeeklyReport(MMWR)

OutbreaksofUnexplainedNeurologicIllnessMuzaffarpur,
India,20132014
Weekly
January30,2015/64(03)4953

AakashShrivastava,MD1,PadminiSrikantiah,MD2,3,AnilKumar,MD1,GyanBhushan,MD4,Kapil
Goel,MD5,SatishKumar,MD5,TripurariKumar,MBBS5,RajuMohankumar,MBBS5,RajeshPandey,
MBBS5,ParvezPathan,MBBS5,YogitaTulsian,MBBS5,MohanPappanna,MD6,AchhelalPasi,MD6,
ArghyaPradhan,MBBS6,PankajSingh,MBBS6,D.Somashekar,MD6,AnoopVelayudhan,MBBS6,
RajeshYadav,MBBS6,MalaChhabra,MD1,VeenaMittal,MD1,ShashiKhare,MD1,JamesJSejvar,
MD7,MayankDwivedi,MD2,KaylaLaserson,ScD2,3,KennethC.Earhart,MD2,3,P.Sivaperumal,
PhD8,A.RameshKumar,PhD8,AmitChakrabarti,MD8,JerryThomas,MD9,JoshuaSchier,MD9,
RamSingh,PhD1,RaviShankarSingh,MD1,A.C.Dhariwal,MD10,L.S.Chauhan,MD1(Author
affiliationsatendoftext)
Outbreaksofanunexplainedacuteneurologicillnessaffectingyoungchildrenandassociatedwithhigh
casefatalityrateshavebeenreportedintheMuzaffarpurdistrictofBiharstateinIndiasince1995.The
outbreaksgenerallypeakinJuneanddeclineweekslaterwiththeonsetofmonsoonrains.Therehave
beenmultipleepidemiologicandlaboratoryinvestigationsofthissyndrome,leadingtoawidespectrum
ofproposedcausesfortheillness,includinginfectiousencephalitisandexposuretopesticides.An
associationbetweenillnessandlitchifruithasbeenpostulatedbecauseMuzaffarpurisalitchifruit
producingregion(Figure1).Tobettercharacterizeclinicalandepidemiologicfeaturesoftheillnessthat
mightsuggestitscauseandhowitcanbeprevented,theIndianNationalCentreforDiseaseControl
(NCDC)andCDCinvestigatedoutbreaksin2013and2014.Clinicalandlaboratoryfindingsin2013
suggestedanoninflammatoryencephalopathy,possiblycausedbyatoxin.Acommonlaboratoryfinding
waslowbloodglucose(<70mg/dL)onadmission,afindingassociatedwithapooreroutcome44%of
allcaseswerefatal.Anongoing2014investigationhasfoundnoevidenceofanyinfectiousetiologyand
supportsthepossibilitythatexposuretoatoxinmightbethecause.Theoutbreakperiodcoincideswith
themonthlonglitchiharvestingseasoninMuzaffarpur.Althoughaspecificetiologyhasnotyetbeen
determined,the2014investigationhasidentifiedtheillnessasahypoglycemicencephalopathyand
confirmedtheimportanceofongoinglaboratoryevaluationofenvironmentaltoxinstoidentifya
potentialcausativeagent,includingmarkersformethylenecyclopropylglycine(MCPG),acompound
foundinlitchiseedsknowntocausehypoglycemiainanimalstudies(13).Currentpublichealth
recommendationsarefocusedonreducingmortalitybyurgingaffectedfamiliestoseekpromptmedical
care,andensuringrapidassessmentandcorrectionofhypoglycemiainillchildren.

2013OutbreakInvestigation
DuringMay17July22,2013,atotalof133childrenwereadmittedtothetwomainreferralhospitalsin
Muzaffarpurwithillnessesthatmettheinvestigationcasedefinitionofacuteonsetseizuresoraltered
mentalstatuswithin7daysofadmissioninachildaged<15years.Ofthese,94(71%)patientswerefrom
Muzaffarpurotherpatientswerefromsixneighboringdistricts.Amongthe133patients,71%wereaged
15years,94%hadgeneralizedseizures,and93%hadalteredmentalstatus.Most(61%)wereafebrileat
admissionthecasefatalityratewas44%.Among56patientswithcerebrospinalfluid(CSF)examined,
31(55%)hadnormalcytology(whitebloodcell[WBC]count=<5/mm3)48of59(81%)hadCSF
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normalprotein(<45mg/dL),and46of61(75%)hadnormalCSFglucose(>45mg/dL)levels.At
admission,20(21%)of94patientshadhypoglycemia(bloodglucose<70mg/dL).
CSFsamplesweretestedatNCDCforselectedinfectiouspathogensknowntocauseencephalitisinthe
region.Of60CSFspecimenstestedforJapaneseencephalitisvirusbyimmunoglobulinM(IgM)capture
enzymelinkedimmunosorbentassay,33bypolymerasechainreaction,and33byvirusisolation,all
werenegative.Sixteenconvalescentserumspecimens,collected14daysafterillnessonset,alsowere
negativeforJapaneseencephalitisvirusbyIgMassay.ThirtyCSFspecimensexaminedbyreverse
transcriptionpolymerasechainreactionforflavivirusesand13examinedmorespecificallyforWest
Nilevirusalsowerenegative,aswere23evaluatedforChandipuravirus.FourteenCSFspecimens
evaluatedbypolymerasechainreactionandvirusisolationforenterovirusesdidnotdemonstrate
evidenceofinfection.
Analysisofriskfactorsfordeathamong94affectedchildrenshowedthatlowbloodglucoseatadmission
wasmorecommonamongthosewhodied(oddsratio=2.695%confidenceinterval[CI]=1.07.2).A
casecontrolstudyenrolled101casepatientsand202agematchedcontrols,101fromthehospitaland
101fromthecommunity.Illchildrenhadspentagreateramountoftimeinagriculturalfieldsor
orchards(matchedoddsratio=2.6CI=1.25.2)thancontrols.Anthropometricdataon24patents
suggestedthatyoungerpatients(thoseaged<5years)weremorelikelytohavewasting(>2standard
deviationsbelowthemedianweightforheightofthereferencepopulation)thancontrolsinthesameage
group(p=0.03).
Datacollectedduringthe2013investigationsuggestedthattheillnesswasmorelikelytobea
noninflammatoryencephalopathythananinfectiousencephalitis,andraisedconcernforthepossibility
ofatoxinmediatedillness.Althoughthe2013investigationdidnotidentifyaspecificetiology,key
recommendationssharedwithstateanddistricthealthofficialsfocusedonreductionofmortality,
includingprovisionofglucometersforhospitalsandperipheralhealthfacilitiesandrapidassessment
andtreatmentofhypoglycemiainchildrenwithsuspectedillness.

2014OutbreakInvestigation
Buildingonthe2013findings,NCDCandCDCagaininvestigatedthissyndromein2014,using1)
facilitybasedclinicalsurveillance,2)epidemiologiccasecontrolandenvironmentalstudiestoexamine
riskfactorsforillness,includingtoxinexposuresandnutritionalindices,and3)comprehensive
laboratoryevaluationofpatientspecimensandenvironmentalsamplestosearchforinfectious
pathogensaswellasselectedpesticides,heavymetals,andnaturallyoccurringplantorfruittoxins.
Suspectedpatientswerepromptlytestedforhypoglycemiaonarrivalatthehospital,beforebeinggiven
anytreatment.Patientsadmittedwiththesuspectedoutbreakillnesswererecommendedtoreceive
immediateintravenousdextrosetherapy.
DuringMay26July17,2014,atotalof390patientsadmittedtothetworeferralhospitalsin
Muzaffarpurwithillnessesthatmetthesamecasedefinitionusedin2013wereevaluatedbythe
NCDC/CDCinvestigationteam.Amongthepatients,213(55%)weremale,themedianagewas4years
(range=6months14years),and280(72%)wereaged15years.MostpatientswerefromMuzaffarpur
district(70%),althoughpatientsalsowerereportedfromsixsurroundingdistricts.Asinpreviousyears,
clusteringofcaseswasnotobservedtheillnessofeachaffectedchildappearedtobeanisolatedcasein
variousvillages(approximatepopulationpervillage=1,000).TheoutbreakpeakedinmidJune,with
147casesreportedduringJune814,2014.Thenumberofcasesdeclinedsignificantlyaftertheonsetof
monsoonrainsonJune21,2014(Figure2).
Caregiversreportedthataffectedchildrenwerepreviouslyhealthyandexperiencedanacuteonsetof
convulsions,oftenbetween4:00a.m.and8:00a.m.,frequentlyfollowedbyadecreasedlevelof
consciousness.Of345patientswithrecordeddata,324(94%)hadseizuresonadmission,and267(77%)

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hadalteredmentalstatus.Of357patientswithbodytemperaturemeasuredonadmission,219(61%)
wereafebrile(99.5F[37.5C]).Thecasefatalityratewas31%.
Detailedclinicalevaluationof52patientswithin12hoursofadmissionelicitedahistoryofgeneralized
tonicortonicclonicseizuresin100%.Uppermotorneuronfindingsofgeneralizedhypertoniaand
Babinksi'ssignwereobservedinapproximatelyonethirdofpatientsfocalneurologicdeficitswererare.
Brainmagneticresonanceimagingof16patientsselectedatrandomrevealednofocalabnormalitiesor
changessuggestiveofinflammationeightpatients(50%)showedmildtomoderatecerebraledema.
Electroencephalographyin30casesdemonstratedfindingsconsistentwithgeneralizedencephalopathy
in22(73%)sevendemonstratedepileptiformdischarges.Overall,neurologicfindingssuggesteda
diffuseencephalopathywithseizuresandcerebraledema.
Of62patientswithCSFcollectedforanalysis,52(84%)hadnormalWBCcounts,58(94%)hadnormal
protein,and49(79%)hadnormalglucoselevels.Of327patientswithbloodglucosemeasurementon
admission,themedianbloodglucoselevelwas48mg/dL,and171(52%)and204(62%)patientshad
glucoselevelsof50mg/dLand70mg/dL,respectively.Laboratorydiagnostictestingof17CSF
specimensforJapaneseencephalitisvirusandWestNilevirusbypolymerasechainreactionwas
negative.Additionally,evaluationof12CSFspecimenswithamultiplexpolymerasechainreaction
platformassaywiththecapacitytodetect11viruses*alsowasnegative.

Discussion
The2013and2014Muzaffarpurinvestigationsindicatethatthisoutbreakillnessisanacute
noninflammatoryencephalopathy.Thisissupportedbyclinicalandlaboratoryfindings,inclusiveof
negativediagnosticresultsforthemostcommonpathogensthatcauseinfectiousencephalitisinthis
region.Laboratorydataindicatethatsignificanthypoglycemiaisanimportantpresentingfeatureof
illness.Furthermore,theimplementationofthe2013recommendationsforrapidassessmentand
correctionofhypoglycemiamight,inpart,havehelpedtoreducemortality(44%in2013versus31%in
2014).
Althoughtheunderlyingcauseofthisillnessremainsunknown,initialclinicalandlaboratoryresultsof
the2014investigationconfirmtheimportanceofsystematicallyevaluatingtoxinsandagentswiththe
potentialtocauseacuteencephalopathy.Furthermore,theconsistentfindingofhypoglycemiaamong
affectedchildrenunderscorestheimportanceofexaminingthepossibleroleofcompoundsthatmight
acutelyresultinlowbloodsugar,seizures,andencephalopathy,includingthepossibleroleofMCPGin
litchis.OutbreaksofsimilaracuteneurologicillnessesoccurringinlitchigrowingregionsofBangladesh
andVietnamhavebeenreported(4,5)raisingfurtherinterestinapossibleassociationbetweenlitchis
andthisillness.TheinvestigationinBangladeshfocusedprimarilyonthepossibilitythatpesticidesused
seasonallyinlitchiorchardsmightbeinvolved,butnospecificpesticidewasimplicated.The
investigationinVietnamfocusedprimarilyonpossibleinfectiousagentsthatmightbepresent
seasonallynearlitchifruitplantationsbutfoundnonetoexplaintheoutbreak.InMuzaffarpur,MCPGis
hypothesizedtocauseacutehypoglycemiaandillnessthroughasimilarmechanismtohypoglycinA,a
toxinthathasbeenreportedtocauseacuteencephalopathyintheWestIndiesandWestAfricaafter
consumptionofunripeackee,afruitinthesamebotanicalfamilyaslitchi(69).
Aspartofthecollaborativeinvestigation,bloodandurinespecimensofaffectedchildrenarebeing
systematicallyassayedbytheIndianNationalInstituteforOccupationalHealthandCDCforpesticide
metabolites,heavymetals,andmarkersforMCPGanditsmetabolites.Litchifruitscollectedfrom
orchardsthatborderthehomesofaffectedchildrenarebeingexaminedforMCPGmarkers,and
environmentalsamples(localvegetation,foodgrains,andwater)collectedfromhomesofpatientsand
controlsarebeingevaluatedforpesticideresidues.Additionally,analysisofepidemiologicdatacollected
inthe2014casecontrolstudy,includingdetailedhistoriesregardingconsumptionoflitchisorexposure
topesticides,mightelucidatepotentialriskfactorsforillnessamongthesechildren.

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Analysisofnutritionalindicesandotherhostfactorsisplannedtosearchforanexplanationforthelack
ofclusteringofcasesintheseoutbreaks.Untilanetiologyforthisillnessisidentified,currentpublic
healthandclinicalrecommendationsarefocusedonreducingmortalitybyensuringfamilieswith
affectedchildrenrapidlyaccessmedicalattention,andhealthcareproviderspromptlyassessforand
correcthypoglycemia.
1NationalCentreforDiseaseControl,DirectorateGeneralofHealthServices,MinistryofHealthand
FamilyWelfare,GovernmentofIndia,NewDelhi,India2GlobalDiseaseDetectionProgram,CDC,New
Delhi,India3DivisionofGlobalHealthProtection,CenterforGlobalHealth,CDC4Muzaffarpur
DistrictHealthDepartment,GovernmentofBihar,Muzaffarpur,India5IndiaEpidemicIntelligence
ServiceCohort1,NationalCentreforDiseaseControl,NewDelhi,India,6IndiaEpidemicIntelligence
ServiceCohort2,NationalCentreforDiseaseControl,NewDelhi,India7NationalCenterforEnteric
andZoonoticDiseases,CDC8NationalInstituteofOccupationalHealth,IndianCouncilofMedical
Research,Ahmedabad,India9NationalCenterforEnvironmentalHealth,CDC10NationalVector
BorneDiseaseControlProgramme,DirectorateGeneralofHealthServices,MinistryofHealthand
FamilyWelfare,GovernmentofIndia,NewDelhi,India(Correspondingauthors:PadminiSrikantiah,
pks6@cdc.gov,+911124198876,AakashShrivastava,a.shrivastava@ncdc.gov.in,+911123909242)

Acknowledgments
P.K.Sen,MD,R.Jaiswal,MD,andotherofficialsoftheNationalVectorBorneDiseaseControl
Programme,India.B.Mohan,MD,A.Kumar,MD,G.S.Sahni,MD,RajivaKumarMD,andother
pediatriciansatparticipatinghospitals.

References
1.GrayDO,FowdenL.alpha(methylenecyclopropyl)glycinefromlitchiseeds.BiochemJ
196282:3859.
2.MeldeK,JacksonS,BartlettK,SherrattHS,GhislaS.Metabolicconsequencesof
methylenecyclopropylglycinepoisoninginrats.BiochemJ1991274:395400.
3.MeldeK,BuettnerH,BoschertW,WolfHP,GhislaS.Mechanismofhypoglycaemicactionof
methylenecyclopropylglycine.BiochemJ1989259:9214.
4.PaireauJ,TuanNH,LefrancoisR,etal.Litchiassociatedacuteencephalitisinchildren,Northern
Vietnam,20042009.EmergInfectDis201218:181724.
5.BiswasSK.Outbreakofillnessanddeathsamongchildrenlivingnearlycheeorchardsinnorthern
Bangladesh.InternationalCentreforDiarrhoealDiseasesResearch,BangladeshICDDRBHealth
SciBull201210:1522.
6.GaillardY,CarlierJ,BerschtM,etal.Fatalintoxicationduetoackee(Blighiasapida)inSuriname
andFrenchGuyana.GCMSdetectionandquantificationofhypoglycinA.ForensicSciInt
2011206:e1037.
7.CDC.ToxichypoglycemicsyndromeJamaica,19891991.MMWRMorbMortalWklyRep
199241:535.
8.JoskowR,BelsonM,VesperH,BackerL,RubinC.Ackeefruitpoisoning:anoutbreak
investigationinHaiti20002001,andreviewoftheliterature.ClinToxicol(Phila)200644:267
73.
9.MedaHA,DialloB,BuchetJP,etal.Epidemicoffatalencephalopathyinpreschoolchildrenin
BurkinaFasoandconsumptionofunripeackee(Blighiasapida)fruit.Lancet1999353:53640.

*Herpessimplexviruses1and2,humanherpesviruses6and7,cytomegalovirus,varicellazostervirus,
EpsteinBarrvirus,parechovirus,adenovirus,enteroviruses,andparvovirusB19.

Whatisalreadyknownonthistopic?

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Seasonaloutbreaksofanunexplainedacuteneurologicillnessaffectingyoungchildrenandassociated
withhighcasefatalityhavebeenreportedfromMuzaffarpur,India,since1995.Multiplepotential
etiologieshavebeenproposed,includinginfectiousencephalitisandpesticideexposure,butnot
systematicallyassessed.
Whatisaddedbythisreport?
Outbreakinvestigationsin2013and2014helpedtoclassifythisillnessasanoninflammatory
encephalopathy.Approximately60%ofpatientshadlowbloodglucose(<70mg/dL)onadmission,
whichwasassociatedwithpooreroutcomesandpromptedrecommendationsforrapidassessmentand
treatmentoflowbloodglucose.Thelowbloodglucoseraisedthepossibilitythatexposuretoatoxin
couldresultinlowbloodglucose,seizures,andencephalopathy.Onespecifichypothesiswasthat
exposuretoMCPG,atoxininlitchis,mightcauseacutehypoglycemiaandencephalopathyinsome
children.Laboratoryinvestigationstoassessthispossibilityandunderstandwhyonlysomechildrenare
affectedareongoing.
Whataretheimplicationsforpublichealthpractice?
Acollaborative,multidisciplinarysystematicinvestigationofthisoutbreakhasbeenessentialto
correctlyclassifythisillnessandfocusanalyticeffortsonevaluationoftestabledatadrivenhypotheses
toidentifyapotentialetiology.Theimplementationofthe2013recommendationsforrapidassessment
andcorrectionofhypoglycemiamight,inpart,havehelpedtoreducemortality(44%in2013compared
with31%in2014).Publichealthrecommendationsarefocusedonadvisingaffectedfamiliestoseek
promptmedicalattention,andadvisinghealthcareproviderstorapidlyassessandcorrecthypoglycemia
inillchildren.

FIGURE1.Litchifruitorchardshavebeenafocusoftheinvestigationintooutbreaksof
unexplainedneurologicillnessamongchildrenMuzaffarpur,India,20132014

AlternateText:ThefigureaboveisaphotographoflitchifruitinMuzaffarpur,India.Anassociation
betweenunexplainedneurologicillnessandlitchifruithasbeenpostulatedbecauseMuzaffarpurisa
litchifruitproducingregion.

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FIGURE2.Numberofpatientsadmittedtotworeferralhospitalswithunexplainedacute
neurologicillness,bydateofadmissionMuzaffarpur,India,May26July17,2014

AlternateText:Thefigureaboveisanepidemiologiccurveshowingthenumberofpatientsadmitted
totworeferralhospitalswithunexplainedacuteneurologicillness,bydateofadmission,inMuzaffarpur,
IndiaduringMay26July172014.

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Pagelastreviewed:January30,2015
Pagelastupdated:January30,2015
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