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Acuteviralencephalitisinchildrenandadolescents:Pathogenesisandetiology

OfficialreprintfromUpToDate
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Acuteviralencephalitisinchildrenandadolescents:Pathogenesisandetiology
Author
HordurSHardarson,MD

SectionEditor
MorvenSEdwards,MD

DeputyEditor
CarrieArmsby,MD,MPH

Disclosures:HordurSHardarson,MDNothingtodisclose.MorvenSEdwards,MDConsultant/AdvisoryBoards:Novartis
Vaccines[GroupBstreptococcus].CarrieArmsby,MD,MPHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Apr23,2015.
INTRODUCTIONViralinfectionofthecentralnervoussystem(CNS)mostoftenleadstomeningitis,
meningoencephalitis,orencephalitis,indescendingorderoffrequency[1].Encephalitisimpliesinflammationof
thebrainandstrictlyspeakingisapathologicaldiagnosis.However,inpractice,mostpatientswith
encephalitisarediagnosedbasedonclinicalmanifestationsofbraindysfunctionandlaboratoryorimaging
evidenceofinflammation(ie,whitebloodcellsinthecerebrospinalfluidand/orinflammationonbrainimaging).
Encephalitisisanacute,lifethreateningemergency,requiringpromptintervention.Althoughdiscussed
separately,theassessmentandmanagementoftenareperformedsimultaneously(table1).
Thepathogenesis,epidemiology,andetiologyofviralencephalitisinchildrenandadolescentswillbe
discussedhere.Theclinicalmanifestations,differentialdiagnosis,evaluation,treatment,andpreventionofviral
encephalitisinchildrenandadolescentsandviralencephalitisinadultsarediscussedseparately.(See"Acute
viralencephalitisinchildrenandadolescents:Clinicalmanifestationsanddiagnosis"and"Acuteviral
encephalitisinchildrenandadolescents:Treatmentandprevention"and"Viralencephalitisinadults".)
TERMINOLOGYViralinfectionofthecentralnervoussystem(CNS)caninvolvethemeninges(meningitis),
thebrain(encephalitis),thebrainstem(rhombencephalitis),thespinalcord(myelitis),spinalroots(radiculitis),or
combinationofsites(meningoencephalitis,encephalomyelitis,ormyeloradiculitis).
Certainvirusesusuallycauseisolatedencephalitisorisolatedmeningitis(table2).Otherscauselessdiscrete
manifestationsofCNSinfection,describedasmeningoencephalitisorencephalomyelitis[2].
EncephalitisEncephalitisisinflammationofthebrainparenchyma,manifestedbyneurologicdysfunction
(eg,alteredmentalstatus,behavior,orpersonalitymotororsensorydeficitsspeechormovementdisorders
hemiparesisandparesthesias)[3,4].Thepresenceorabsenceofneurologicdysfunctiondistinguishes
encephalitisfrommeningitis.However,thedistinctionbetweenmeningitisandencephalitisissometimes
blurred(eg,meningoencephalitis).
Encephalitismayoccurduringorafteraviralinfection(acuteviralencephalitisandpostinfectiousencephalitis,
respectively).Chronicencephalitismaybecausedbyanumberofviruses(JCvirus,BKvirus,Simianvirus
40,HIV)andpriondiseases[3].(See"ClinicalmanifestationsanddiagnosisofJC,BK,andotherpolyomavirus
infections"and"Diseasesofthecentralnervoussystemcausedbyprions".)
EncephalopathyEncephalopathyisadisruptionofbrainfunctionintheabsenceofadirectinflammatory
processinbrainparenchyma(eg,causedbymetabolicdisturbance,hypoxia,ischemia,drugs,intoxications,
organdysfunction,systemicinfection)[5].(See"Acutetoxicmetabolicencephalopathyinchildren"and
"Clinicalfeatures,diagnosis,andtreatmentofneonatalencephalopathy".)
PATHOGENESISTherearetwomainwaysinwhichvirusescauseneurologicmanifestations:
Theycandirectlyinvadebraintissue,asinacuteviralencephalitis.Insuchcases,theviruscanbe
culturedfromthebrain,orevidenceoftheviruscanbefoundonhistologicexamination.Directinvasion
mayoccurasanextensionofviralmeningitis,secondarytoviremia,orviaretrogradespreadthroughthe
peripheralnerves(eg,rabies,herpessimplexvirus[HSV])[3,6].
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Theinnateimmunesystem,inparticularthepatternrecognitionreceptor,tolllikereceptor3(TLR3),plays
akeyroleinprotectingthecentralnervoussystemfrominfectionwithHSVtype1.Patientswith
autosomalrecessiveandautosomaldominantTLR3deficiencyanddeficiencyinotherTLR3pathways
havebeenfoundtobepredisposedtoHSVtype1encephalitis[7].(See"Herpessimplexvirustype1
encephalitis",sectionon'Hostsusceptibility'.)
Theyalsocancausepostinfectiousencephalitisbyprovokinganautoimmuneresponse,leadingtoacute
disseminatedencephalomyelitis(ADEM).Inpostinfectiousencephalitis,aviruscannotbedetectedor
recoveredfromthebrain,butthereisoftenhistoryofillnessorvaccinationtwotofourweekspriortothe
onsetofsymptomsandsigns.(See"Acutedisseminatedencephalomyelitisinchildren:Pathogenesis,
clinicalfeatures,anddiagnosis".)
Itcanbedifficulttodifferentiateviralencephalitisfrompostinfectiousencephalitiswithoutneuroimaging.(See
"Acuteviralencephalitisinchildrenandadolescents:Clinicalmanifestationsanddiagnosis",sectionon
'Differentialdiagnosis'and"Acutedisseminatedencephalomyelitisinchildren:Pathogenesis,clinicalfeatures,
anddiagnosis".)
EPIDEMIOLOGYDatafromtheNationalHospitalDischargeSurveyintheUnitedStates(1988to1997)
indicatethatviralencephalitisaccountsforapproximately19,000hospitaladmissionsand1400deathsperyear
[8].Encephalitisoccurspredominantlyamongchildren,theelderly,immunocompromisedhosts,andindividuals
whoareexposedtoarthropodvectorsthroughresidence,travel,recreationalactivity,oroccupation.
Theuseoftumornecrosisfactoralpha(TNFalpha)inhibitors(eg,infliximab,adalimumab,etanercept)totreat
rheumatologicandotherinflammatorydisorderscanincreasetheriskofvariousinfectionsincludingHSV
encephalitis[9].(See"Tumornecrosisfactoralphainhibitors:Riskofbacterial,viral,andfungalinfections".)
ETIOLOGY
OverviewVirusesarethemostfrequentlydiagnosedcauseofencephalitis[10].Bacteria,fungi,and
parasitesalsocauseencephalitis,butlesscommonlythanviruses(table3).Inmanycasesofencephalitis,the
etiologyremainsunknown[5,1012].
IntheCaliforniaEncephalitisProject,whichprospectivelyenrolled1570patientsofallages(medianage23
years)from1998to2005andperformedanextensivemicrobiologicevaluation,noetiologywasidentifiedin63
percentofcases[10].Aconfirmedorprobableinfectiousetiologywasidentifiedin16percent(69percentviral,
20percentbacterial,7percentprion,3percentparasitic,1percentfungal),apossibleinfectiousetiologywas
identifiedin13percent,andanoninfectiousetiologyin8percent.Themostcommonlyisolatedviruseswere
enterovirusandherpessimplexvirustype1.
Inprospectiveseriesofencephalitisthatwerelimitedtochildren,confirmedorprobableinfectiousetiologies
wereidentifiedinapproximately40to60percentofcases,andpossibleinfectiousetiologiesinapproximately
25percent[1114].
ViralpathogensAwidevarietyofvirusescancauseencephalitis(table3).Amongthosemostcommonly
isolatedareenteroviruses(eg,poliovirus,echovirus,enterovirus,coxsackievirusAandB),parechoviruses,
herpessimplexvirus(HSV)type1and2,otherHerpesviridae(eg,EpsteinBarr,varicellazoster,
cytomegalovirus,humanherpesvirus6),andarboviruses(eg,LaCrosse,WestNile,St.Louis,Easternand
Westernequineencephalitisvirus,Coloradotickfever,andyellowfever).(Seeappropriatetopicreviews).
Lesscommonviralcausesofencephalitisincludeinfluenza,Nipahvirus,rabiesvirus,andJapanese
encephalitisvirus,dependingongeographiclocale(table4).(See"NipahandHendraviralencephalitis"and
"Clinicalmanifestationsanddiagnosisofrabies".)
EnterovirusesNonpolioenterovirusesandparechovirusesareamajorcauseofencephalitisinchildren
[15,16].Enteroviruseshaveaclearseasonality,with78percentofcasesintheUnitedStatesoccurringfrom
JunethroughOctober[17].(See"Epidemiology,pathogenesis,treatment,andpreventionofenterovirusand
parechovirusinfections".)
HerpessimplexvirusApproximately5percentofcasesofchildhoodencephalitisarecausedbyherpes
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simplexvirus(HSV)[18,19].ClinicalfeaturesofHSVencephalitisinclude[18]:

Cerebrospinalfluid(CSF)pleocytosis(94percent)
ElevatedCSFprotein(50percent)
Electroencephalographic(EEG)changes(94percent)
Imagingabnormalities(88percent)

HSVtype1encephalitisoccursinallagegroups[15].Itisthemostcommonconfirmedcauseofsporadicfatal
encephalitis[20],withanincidenceofapproximately2.2casespermillionpopulationperyear[20,21].
HSVtype2isthepredominantcauseofneonatalHSVinfection.Inaretrospectivereviewof5817neonates
evaluatedintheemergencydepartmentandadmittedtoatertiarycarechildren's'hospitaloverfiveyears,10
patientshadconfirmedHSVinfection,aprevalenceof0.2percent,whichwasnotstatisticallydifferentthan
thatforbacterialmeningitis[22].(See"Neonatalherpessimplexvirusinfection:Clinicalfeaturesand
diagnosis",sectionon'Epidemiologyandtransmission'.)
EpsteinBarrvirusEpsteinBarrvirus(EBV)causedapproximately10percentof216casesofchildhood
encephalitisinaprospectiveregistryfromasingleinstitution(1994to2003)[23].EncephalitiscausedbyEBV
presentedwithneurologicmanifestationsitdidnotfollowaninfectiousmononucleosislikeillness.Diagnosis
wasbasedonEBVserologyand/orEBVpolymerasechainreaction(PCR)testingofthecerebrospinalfluid
(CSF)[23].(See"Infectiousmononucleosisinadultsandadolescents",sectionon'Diagnosis'.)
Arboviruses
LaCrosseencephalitisAmongthearboviruses,LaCrossevirusisthemostcommoncauseofCNS
infectioninchildreninNorthAmerica.LaCrosseencephalitisvirushasbeenreportedinmorethanone
halfofstates.LaCrossevirushasaclearseasonaloccurrence(JulythroughSeptember).
LaCrosseencephalitisismostcommoninchildrenfivetonineyearsold[24,25].Itusuallypresentswith
mildmeningoencephalitis,butsubsequentneurologicdeteriorationmayoccur.About50percentof
childrenpresentwithseizures.TheEEGmayshowfocalactivity.Redbloodcells(RBC)maybepresent
intheCSF,afindingoftenassociatedwithHSVcentralnervoussysteminfections.(See"Arthropod
borneencephalitides",sectionon'LaCrosseencephalitisvirus'.)
WestNilevirusWestNilevirus(WNV),mainlytransmittedbymosquitobites,isfoundacrossthe
UnitedStates.WNVCNSdiseaseoccursin<1percentofinfectedpersons,mainlyadults[2630].WNV
encephalitisoccursinchildrenbutisrare.(See"EpidemiologyandpathogenesisofWestNilevirus
infection"and"ClinicalmanifestationsanddiagnosisofWestNilevirusinfection".)
OtherarbovirusesOtherarboviralcausesofencephalopathymustbeconsideredinspecificgeographic
locations(eg,ColoradotickvirusinthewesternUnitedStatesandJapaneseencephalitisvirusinAsia)
(table5).(See"Arthropodborneencephalitides".)
InfluenzavirusInfluenzavirusiswellrecognizedinJapanandcausedapproximately5percentof311
casesofchildhoodencephalitisinaprospectiveregistryfromasingleinstitution(1994to2005),whichisthe
sameastheproportionofcasescausedbyHSV[31,32].Themajorityofcasesoccurinchildrenyoungerthan
fiveyearsofage.Anacute,ratherthanpostinfectious,processwassuggested[32].Thepathogenesisof
influenzaassociatedCNSdiseaseinunknown.(See"Seasonalinfluenzainchildren:Clinicalfeaturesand
diagnosis",sectionon'Neurologic'.)
OthervirusesMeasles,mumps,andrubellaencephalitisarerareincountriesthatvaccinateagainst
thesediseases[15].Humanmetapneumovirusencephalitishasbeenreportedrarelyinchildren.(See"Human
metapneumovirusinfections",sectionon'Children'.)
SUMMARY
Encephalitisimpliesinflammationofthebrainparenchyma.Itismanifestclinicallybyneurologic
dysfunction.Encephalitismayoccurduringorafteraviralinfection.(See'Encephalitis'above.)
Encephalitisoccurspredominantlyamongchildren,theelderly,immunocompromisedhosts,and
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individualswhoareexposedtoarthropodvectors(table5).(See'Epidemiology'above.)
Inmanycasesofencephalitis,theetiologyremainsunknowndespiteextensiveevaluation.Virusesare
themostcommonlydiagnosedcauseofencephalitis.Otherinfectiouscausesincludebacteria,fungi,and
parasites(table3).(See'Etiology'above.)
Thelistofpotentialinfectiouspathogensmaybenarrowedaccordingtoclinicalclues(table2),location
(ortravelhistory)(table4),andexposuretoarthropodvectors(table5).(See'Viralpathogens'aboveand
"Acuteviralencephalitisinchildrenandadolescents:Clinicalmanifestationsanddiagnosis".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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