Febrile Seizures - Clinical Practice Guideline For The Long-Term Management of The Child With Simple Febrile Seizures - FROM The AMERICAN ACADEMY of PEDIATRICS - Pediatrics

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Revised 103(6):1307
Pediatrics
June2008,VOLUME121/ISSUE6
FebrileSeizures:ClinicalPracticeGuidelinefortheLongterm
ManagementoftheChildWithSimpleFebrileSeizures
SteeringCommitteeonQualityImprovementandManagement,SubcommitteeonFebrile
Seizures
Article Figures&Data Info&Metrics Comments
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Abstract
Febrileseizuresarethemostcommonseizuredisorderinchildhood,affecting2%to5%ofchildrenbetweentheagesof6and60months.
Simplefebrileseizuresaredefinedasbrief(<15minute)generalizedseizuresthatoccuronceduringa24hourperiodinafebrilechildwho
doesnothaveanintracranialinfection,metabolicdisturbance,orhistoryofafebrileseizures.Thisguideline(arevisionofthe1999American
AcademyofPediatricspracticeparameter[nowtermedclinicalpracticeguideline]TheLongtermTreatmentoftheChildWithSimple
FebrileSeizures)addressestherisksandbenefitsofbothcontinuousandintermittentanticonvulsanttherapyaswellastheuseof
antipyreticsinchildrenwithsimplefebrileseizures.Itisdesignedtoassistpediatriciansbyprovidingananalyticframeworkfordecisions
regardingpossibletherapeuticinterventionsinthispatientpopulation.Itisnotintendedtoreplaceclinicaljudgmentortoestablishaprotocol
forallpatientswiththisdisorder.Rarelywilltheseguidelinesbetheonlyapproachtothisproblem.
fever
Theexpectedoutcomesofthispracticeguidelineinclude:
1.optimizingpractitionerunderstandingofthescientificbasisforusingoravoidingvariousproposedtreatmentsforchildrenwith
simplefebrileseizures
2.improvingthehealthofchildrenwithsimplefebrileseizuresbyavoidingtherapieswithhighpotentialforadverseeffectsandno
demonstratedabilitytoimprovechildren'slongtermoutcomes
http://pediatrics.aappublications.org/content/121/6/1281
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3.reducingcostsbyavoidingtherapiesthatwillnotdemonstrablyimprovechildren'slongtermoutcomesand
4.helpingthepractitionereducatecaregiversaboutthelowrisksassociatedwithsimplefebrileseizures.
Thecommitteedeterminedthatwiththeexceptionofahighrateofrecurrence,nolongtermeffectsofsimplefebrileseizureshavebeen
identified.Theriskofdevelopingepilepsyinthesepatientsisextremelylow,althoughslightlyhigherthanthatinthegeneralpopulation.No
data,however,suggestthatprophylactictreatmentofchildrenwithsimplefebrileseizureswouldreducetherisk,becauseepilepsylikelyis
theresultofgeneticpredispositionratherthanstructuraldamagetothebraincausedbyrecurrentsimplefebrileseizures.Although
antipyreticshavebeenshowntobeineffectiveinpreventingrecurrentfebrileseizures,thereisevidencethatcontinuousanticonvulsant
therapywithphenobarbital,primidone,orvalproicacidandintermittenttherapywithdiazepamareeffectiveinreducingfebrileseizure
recurrence.Thepotentialtoxicitiesassociatedwiththeseagents,however,outweightherelativelyminorrisksassociatedwithsimplefebrile
seizures.Assuch,thecommitteeconcludedthat,onthebasisoftherisksandbenefitsoftheeffectivetherapies,neithercontinuousnor
intermittentanticonvulsanttherapyisrecommendedforchildrenwith1ormoresimplefebrileseizures.
INTRODUCTION
Febrileseizuresareseizuresthatoccurinfebrilechildrenbetweentheagesof6and60monthswhodonothaveanintracranialinfection,
metabolicdisturbance,orhistoryofafebrileseizures.Febrileseizuresaresubdividedinto2categories:simpleandcomplex.Simplefebrile
seizureslastforlessthan15minutes,aregeneralized(withoutafocalcomponent),andoccuronceina24hourperiod,whereascomplex
febrileseizuresareprolonged(>15minutes),arefocal,oroccurmorethanoncein24hours. 1Despitethefrequencyoffebrileseizures(2%
5%),thereisnounanimityofopinionaboutmanagementoptions.Thisclinicalpracticeguidelineaddressespotentialtherapeutic
interventionsinneurologicallynormalchildrenwithsimplefebrileseizures.Itisnotintendedforpatientswithcomplexfebrileseizuresand
doesnotpertaintochildrenwithpreviousneurologicinsults,knowncentralnervoussystemabnormalities,orahistoryofafebrileseizures.
Thisclinicalpracticeguidelineisarevisionofa1999AmericanAcademyofPediatrics(AAP)clinicalpracticeparameter,TheLongterm
TreatmentoftheChildWithSimpleFebrileSeizures.2
Forachildwhohasexperiencedasimplefebrileseizure,therearepotentially4adverseoutcomesthattheoreticallymaybealteredbyan
effectivetherapeuticagent:(1)declineinIQ(2)increasedriskofepilepsy(3)riskofrecurrentfebrileseizuresand(4)death.Neithera
declineinIQ,academicperformanceorneurocognitiveinattentionnorbehavioralabnormalitieshavebeenshowntobeaconsequenceof
recurrentsimplefebrileseizures. 3EllenbergandNelson4studied431childrenwhoexperiencedfebrileseizuresandobservednosignificant
differenceintheirlearningcomparedwithsiblingcontrols.InasimilarstudybyVerityetal, 5303childrenwithfebrileseizureswere
comparedwithcontrolchildren.Nodifferenceinlearningwasidentified,exceptinthosechildrenwhohadneurologicabnormalitiesbefore
theirfirstseizure.
Thesecondconcern,increasedriskofepilepsy,ismorecomplex.Childrenwithsimplefebrileseizureshaveapproximatelythesameriskof
developingepilepsybytheageof7yearsasdoesthegeneralpopulation(ie,1%). 6However,childrenwhohavehadmultiplesimplefebrile
seizures,areyoungerthan12monthsatthetimeoftheirfirstfebrileseizure,andhaveafamilyhistoryofepilepsyareathigherrisk,with
generalizedafebrileseizuresdevelopingby25yearsofagein2.4%. 7Despitethisfact,nostudyhasdemonstratedthatsuccessfultreatmentof
simplefebrileseizurescanpreventthislaterdevelopmentofepilepsy,andtherecurrentlyisnoevidencethatsimplefebrileseizurescause
structuraldamagetothebrain.Indeed,itismostlikelythattheincreasedriskofepilepsyinthispopulationistheresultofgenetic
predisposition.
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Incontrasttotheslightlyincreasedriskofdevelopingepilepsy,childrenwithsimplefebrileseizureshaveahighrateofrecurrence.Therisk
varieswithage.Childrenyoungerthan12monthsatthetimeoftheirfirstsimplefebrileseizurehaveanapproximately50%probabilityof
havingrecurrentfebrileseizures.Childrenolderthan12monthsatthetimeoftheirfirsteventhaveanapproximately30%probabilityofa
secondfebrileseizureofthosewhodohaveasecondfebrileseizure,50%haveachanceofhavingatleast1additionalrecurrence. 8
Finally,thereisatheoreticalriskofachilddyingduringasimplefebrileseizureasaresultofdocumentedinjury,aspiration,orcardiac
arrhythmia,buttothecommittee'sknowledge,ithasneverbeenreported.
Insummary,withtheexceptionofahighrateofrecurrence,nolongtermadverseeffectsofsimplefebrileseizureshavebeenidentified.
Becausetherisksassociatedwithsimplefebrileseizures,otherthanrecurrence,aresolowandbecausethenumberofchildrenwhohave
febrileseizuresinthefirstfewyearsoflifeissohigh,tobecommensurate,aproposedtherapywouldneedtobeexceedinglylowinrisks
andadverseeffects,inexpensive,andhighlyeffective.
METHODS
Toupdatetheclinicalpracticeguidelineonthetreatmentofchildrenwithsimplefebrileseizures,theAAPreconvenedtheSubcommitteeon
FebrileSeizures.Thecommitteewaschairedbyachildneurologistandconsistedofaneuroepidemiologist,2additionalchildneurologists,
andapracticingpediatrician.AllpanelmembersreviewedandsignedtheAAPvoluntarydisclosureandconflictofinterestform.The
guidelinewasreviewedbymembersoftheAAPSteeringCommitteeonQualityImprovementandManagementmembersoftheAAP
SectionsonNeurology,PediatricEmergencyMedicine,DevelopmentalandBehavioralPediatrics,andEpidemiologymembersoftheAAP
CommitteesonPediatricEmergencyMedicineandMedicalLiabilityandRiskManagementmembersoftheAAPCouncilsonChildrenWith
DisabilitiesandCommunityPediatricsandmembersofoutsideorganizationsincludingtheChildNeurologySocietyandtheAmerican
AcademyofNeurology.
Acomprehensivereviewoftheevidencebasedliteraturepublishedsince1998wasconductedwiththeaimofaddressingpossibletherapeutic
interventionsinthemanagementofchildrenwithsimplefebrileseizures.Thereviewfocusedonboththeefficacyandpotentialadverse
effectsoftheproposedtreatments.Decisionsweremadeonthebasisofasystematicgradingofthequalityofevidenceandstrengthof
recommendations.
TheAAPestablishedapartnershipwiththeUniversityofKentucky(Lexington,KY)todevelopanevidencereport,whichservedasamajor
sourceofinformationforthesepracticeguidelinerecommendations.Thespecificissuesaddressedwere(1)effectivenessofcontinuous
anticonvulsanttherapyinpreventingrecurrentfebrileseizures,(2)effectivenessofintermittentanticonvulsanttherapyinpreventing
recurrentfebrileseizures,(3)effectivenessofantipyreticsinpreventingrecurrentfebrileseizures,and(4)adverseeffectsofeither
continuousorintermittentanticonvulsanttherapy.
Intheoriginalpracticeparameter,morethan300medicaljournalarticlesreportingstudiesofthenaturalhistoryofsimplefebrileseizuresor
thetherapyoftheseseizureswerereviewedandabstracted. 2Anadditional65articleswerereviewedandabstractedfortheupdate.Emphasis
wasplacedonarticlesthatdifferentiatedsimplefebrileseizuresfromothertypesofseizures,thatcarefullymatchedtreatmentandcontrol
groups,andthatdescribedadherencetothedrugregimen.Tableswereconstructedfromthe65articlesthatbestfitthesecriteria.Amore
comprehensivereviewoftheliteratureonwhichthisreportisbasedcanbefoundinaforthcomingtechnicalreport(theinitialtechnical
reportcanbeaccessedathttp://aappolicy.aappublications.org/cgi/content/full/pediatrics103/6/e86).Thetechnicalreportalsowillcontain
dosinginformation.
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Theevidencebasedapproachtoguidelinedevelopmentrequiresthattheevidenceinsupportofarecommendationbeidentified,appraised,
andsummarizedandthatanexplicitlinkbetweenevidenceandrecommendationsbedefined.Evidencebasedrecommendationsreflectthe
qualityofevidenceandthebalanceofbenefitandharmthatisanticipatedwhentherecommendationisfollowed.TheAAPpolicystatement
ClassifyingRecommendationsforClinicalPracticeGuidelines9wasfollowedindesignatinglevelsofrecommendations(seeFig1and
Table1).
FIGURE1
Downloadfigure Openinnewtab Downloadpowerpoint
Integratingevidencequalityappraisalwithanassessmentoftheanticipatedbalancebetweenbenefitsandharmsifapolicyisconductedleadstodesignationofa
policyasastrongrecommendation,recommendation,option,ornorecommendation.RCTindicatesrandomized,controlledtrial.
TABLE1
Viewinline
GuidelineDefinitionsforEvidenceBasedStatements
RECOMMENDATION
Onthebasisoftherisksandbenefitsoftheeffectivetherapies,neithercontinuousnorintermittentanticonvulsanttherapyisrecommended
forchildrenwith1ormoresimplefebrileseizures.
Aggregateevidencequality:B(randomized,controlledtrialsand
diagnosticstudieswithminorlimitations).
Benefit:preventionofrecurrentfebrileseizures,whicharenot
harmfulanddonotsignificantlyincreasetheriskfordevelopmentof
futureepilepsy.
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Harm:adverseeffectsincludingrarefatalhepatotoxicity(especiallyin
childrenyoungerthan2yearswhoarealsoatgreatestriskoffebrile
seizures),thrombocytopenia,weightlossandgain,gastrointestinal
disturbances,andpancreatitiswithvalproicacidandhyperactivity,
irritability,lethargy,sleepdisturbances,andhypersensitivityreactions
withphenobarbitallethargy,drowsiness,andataxiaforintermittent
diazepamaswellastheriskofmaskinganevolvingcentralnervous
systeminfection.
Benefits/harmsassessment:preponderanceofharmoverbenefit.
Policylevel:recommendation.
BENEFITSANDRISKSOFCONTINUOUSANTICONVULSANT
THERAPY
Phenobarbital
Phenobarbitaliseffectiveinpreventingtherecurrenceofsimplefebrileseizures. 10Inacontrolleddoubleblindstudy,dailytherapywith
phenobarbitalreducedtherateofsubsequentfebrileseizuresfrom25per100subjectsperyearto5per100subjectsperyear. 11Fortheagent
tobeeffective,however,itmustbegivendailyandmaintainedinthetherapeuticrange.InastudybyFarwelletal, 12forexample,children
whosephenobarbitallevelswereinthetherapeuticrangehadareductioninrecurrentseizures,butbecausenoncompliancewassohigh,an
overallbenefitwithphenobarbitaltherapywasnotidentified.
Theadverseeffectsofphenobarbitalincludehyperactivity,irritability,lethargy,sleepdisturbances,andhypersensitivityreactions.The
behavioraladverseeffectsmayoccurinupto20%to40%ofpatientsandmaybesevereenoughtonecessitatediscontinuationofthe
drug. 1316
Primidone
Primidone,indosesof15to20mg/kgperday,hasalsobeenshowntoreducetherecurrencerateoffebrileseizures. 17,18Itisofinterestthat
thederivedphenobarbitallevelinaMinigawaandMiurastudy17wasbelowtherapeutic(16g/mL)in29ofthe32children,suggestingthat
primidoneitselfmaybeactiveinpreventingseizurerecurrence.Aswithphenobarbital,adverseeffectsincludebehavioraldisturbances,
irritability,andsleepdisturbances. 18
ValproicAcid
Inrandomized,controlledstudies,only4%ofchildrentakingvalproicacid,asopposedto35%ofcontrolsubjects,hadasubsequentfebrile
seizure.Therefore,valproicacidseemstobeatleastaseffectiveinpreventingrecurrentsimplefebrileseizuresasphenobarbitaland
significantlymoreeffectivethanplacebo. 1921
Drawbackstotherapywithvalproicacidincludeitsrareassociationwithfatalhepatotoxicity(especiallyinchildrenyoungerthan2years,
whoarealsoatgreatestriskoffebrileseizures),thrombocytopenia,weightlossandgain,gastrointestinaldisturbances,andpancreatitis.In
studiesinwhichchildrenreceivedvalproicacidtopreventrecurrenceoffebrileseizures,nocasesoffatalhepatotoxicitywerereported. 15
Carbamazepine
13
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Carbamazepinehasnotbeenshowntobeeffectiveinpreventingtherecurrenceofsimplefebrileseizures.AntonyandHawke 13compared
childrenwhohadbeentreatedwiththerapeuticlevelsofeitherphenobarbitalorcarbamazepine,and47%ofthechildreninthe
carbamazepinetreatedgrouphadrecurrentseizurescomparedwithonly10%ofthoseinthephenobarbitalgroup.Inanotherstudy,Camfield
etal22treatedchildren(whoseconditionsfailedtoimprovewithphenobarbitaltherapy)withcarbamazepine.Despitegoodcompliance,13of
the16childrentreatedwithcarbamazepinehadarecurrentfebrileseizurewithin18months.Itistheoreticallypossiblethattheseexcessively
highratesofrecurrencesmighthavebeenattributabletoadverseeffectsofcarbamazepine.
Phenytoin
Phenytoinhasnotbeenshowntobeeffectiveinpreventingtherecurrenceofsimplefebrileseizures,evenwhentheagentisinthe
therapeuticrange. 23,24Otheranticonvulsantshavenotbeenstudiedforthecontinuoustreatmentofsimplefebrileseizures.
BENEFITSANDRISKSOFINTERMITTENTANTICONVULSANT
THERAPY
Diazepam
Adoubleblindcontrolledstudyofpatientswithahistoryoffebrileseizuresdemonstratedthatadministrationoforaldiazepam(givenatthe
timeoffever)couldreducetherecurrenceoffebrileseizures.Childrenwithahistoryoffebrileseizuresweregiveneitheroraldiazepam
(0.33mg/kg,every8hoursfor48hours)oraplaceboatthetimeoffever.Theriskoffebrileseizuresperpersonyearwasdecreased44%
withdiazepam. 25Inamorerecentstudy,childrenwithahistoryoffebrileseizuresweregivenoraldiazepamatthetimeoffeverandthen
comparedwithchildreninanuntreatedcontrolgroup.Intheoraldiazepamgroup,therewasan11%recurrenceratecomparedwitha30%
recurrencerateinthecontrolgroup. 26Itshouldbenotedthatallchildrenforwhomdiazepamwasconsideredafailurehadbeen
noncompliantwithdrugadministration,inpartbecauseofadverseeffectsofthemedication.
Thereisalsoliteraturethatdemonstratesthefeasibilityandsafetyofinterruptingasimplefebrileseizurelastinglessthan5minuteswith
rectaldiazepamandwithbothintranasalandbuccalmidazolam. 27,28Althoughtheseagentsareeffectiveinterminatingtheseizure,itis
questionablewhethertheyhaveanylongterminfluenceonoutcome.InastudybyKnudsenetal, 29childrenweregiveneitherrectal
diazepamatthetimeoffeveroronlyattheonsetofseizure.Twelveyearfollowupfoundthatthelongtermprognosisofthechildreninthe
2groupsdidnotdifferregardlessofwhethertreatmentwasaimedatpreventingseizuresortreatingthem.
Apotentialdrawbacktointermittentmedicationisthataseizurecouldoccurbeforeafeverisnoticed.Indeed,inseveralofthesestudies,
recurrentseizureswerelikelyattributabletofailureofmethodratherthanfailureoftheagent.
Adverseeffectsoforalandrectaldiazepam26andbothintranasalandbuccalmidazolamincludelethargy,drowsiness,andataxia.Respiratory
depressionisextremelyrare,evenwhengivenbytherectalroute. 28,30Sedationcausedbyanyofthebenzodiazepines,whetheradministered
bytheoral,rectal,nasal,orbuccalroute,havethepotentialofmaskinganevolvingcentralnervoussysteminfection.Ifused,thechild's
healthcareprofessionalshouldbecontacted.
BENEFITSANDRISKSOFINTERMITTENTANTIPYRETICS
Nostudieshavedemonstratedthatantipyretics,intheabsenceofanticonvulsants,reducetherecurrenceriskofsimplefebrileseizures.
Camfieldetal11treated79childrenwhohadhadafirstfebrileseizurewitheitheraplaceboplusantipyreticinstruction(eitheraspirinor
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acetaminophen)versusdailyphenobarbitalplusantipyreticinstruction(eitheraspirinoracetaminophen).Recurrenceriskwassignificantly
lowerinthephenobarbitaltreatedgroup,suggestingthatantipyreticinstruction,includingtheuseofantipyretics,isineffectiveinpreventing
febrileseizurerecurrence.
Whetherantipyreticsaregivenregularly(every4hours)orsporadically(contingentonaspecificbodytemperatureelevation)doesnot
influenceoutcome.Acetaminophenwaseithergivenevery4hoursoronlyfortemperatureelevationsofmorethan37.9Cin104children.
Theincidenceoffebrileepisodesdidnotdiffersignificantlybetweenthe2groups,nordidtheearlyrecurrenceoffebrileseizures.The
authorsdeterminedthatadministeringprophylacticacetaminophenduringfebrileepisodeswasineffectiveinpreventingorreducingfever
andinpreventingfebrileseizurerecurrence. 31
Inarandomizeddoubleblindplacebocontrolledtrial,acetaminophenwasadministeredalongwithlowdoseoraldiazepam. 32Febrileseizure
recurrencewasnotreduced,comparedwithcontrolgroups.Aswithacetaminophen,ibuprofenalsohasbeenshowntobeineffectivein
preventingrecurrenceoffebrileseizures. 3335
Ingeneral,acetaminophenandibuprofenareconsideredtobesafeandeffectiveantipyreticsforchildren.However,hepatotoxicity(with
acetaminophen)andrespiratoryfailure,metabolicacidosis,renalfailure,andcoma(withibuprofen)havebeenreportedinchildrenafter
overdoseorinthepresenceofriskfactors. 36,37
CONCLUSIONS
Thesubcommitteehasdeterminedthatasimplefebrileseizureisabenignandcommoneventinchildrenbetweentheagesof6and60
months.Nearlyallchildrenhaveanexcellentprognosis.Thecommitteeconcludedthatalthoughthereisevidencethatbothcontinuous
antiepileptictherapywithphenobarbital,primidone,orvalproicacidandintermittenttherapywithoraldiazepamareeffectiveinreducing
theriskofrecurrence,thepotentialtoxicitiesassociatedwithantiepilepticdrugsoutweightherelativelyminorrisksassociatedwithsimple
febrileseizures.Assuch,longtermtherapyisnotrecommended.Insituationsinwhichparentalanxietyassociatedwithfebrileseizuresis
severe,intermittentoraldiazepamattheonsetoffebrileillnessmaybeeffectiveinpreventingrecurrence.Althoughantipyreticsmay
improvethecomfortofthechild,theywillnotpreventfebrileseizures.
SUBCOMMITTEEONFEBRILESEIZURES,20022008
PatriciaK.Duffner,MD,Chairperson
RobertJ.Baumann,MD,Methodologist
PeterBerman,MD
JohnL.Green,MD
SanfordSchneider,MD
STEERINGCOMMITTEEONQUALITYIMPROVEMENTAND
MANAGEMENT,20072008
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ElizabethS.Hodgson,MD,Chairperson
GordonB.Glade,MD
NormanChipHarbaugh,Jr,MD
ThomasK.McInerny,MD
MarleneR.Miller,MD,MSc
VirginiaA.Moyer,MD,MPH
XavierD.Sevilla,MD
LisaSimpson,MB,BCh,MPH
GlennS.Takata,MD
LIAISONS
DeniseDougherty,PhD
AgencyforHealthcareResearchandQuality
DanielR.Neuspiel,MD
SectiononEpidemiology
EllenSchwalenstocker,MBA
NationalAssociationofChildren'sHospitalsandRelatedInstitutions
STAFF
CarynDavidson,MA
Footnotes
AllclinicalreportsfromtheAmericanAcademyofPediatricsautomaticallyexpire5yearsafterpublicationunlessreaffirmed,
revised,orretiredatorbeforethattime.
Theguidanceinthisreportdoesnotindicateanexclusivecourseoftreatmentorserveasastandardofmedicalcare.Variations,
takingintoaccountindividualcircumstances,maybeappropriate.
AAPAmericanAcademyofPediatrics
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Febrile Seizures - Clinical Practice Guideline For The Long-Term Management of The Child With Simple Febrile Seizures - FROM The AMERICAN ACADEMY of PEDIATRICS - Pediatrics

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