Controversies in the Treatment of Neonatal Seizures Lecture 2017 … · 2017-09-04 · § Concerns...

NeonatalSeizures

TreatmentControversiesandOptionsAclinicalperspective

K.S.Krishnamoorthy MDPediatricNeurologyDivisionMassGeneralHospital

NeonatalSeizures

MostcommonforaconsultinthenewbornICUItcanbedramaticandanxietyprovokingIncidencevaries:1- 3.5/1000livebirthsinterminfantsHigherreportedinpremiesFamiliesconcernedaboutconsequencesandlaterepilepsy

NeonatalSeizures1970- 2017

Milestones

§ HIEwasthemostcommonetiologyandPhenobarbitalwasthefirstlinedrugused

§ Physiology:GABAisinhibitory(1970’s)GABAisexcitatory(2000’s)

§ Braininjury- moststudiesarestillbasedonanimalmodels§ ExtentofbraininjuryinhumanneonatesisnowdefinedbyMRI/MRS§ StandardsnapshotEEGisreplacedbyuseLTM-EEGtechnologyintertiarycenters§ Emphasisonaggressivetreatmentofelectographic seizures§ Etiologyofseizuresbetteridentifiedby4majortools:

MRI/MRSNeurometabolicstudiesEpilepsygeneticpanelsPlacentalPathology

NeonatalSeizures1970- 2017

MajorMilestones2017

HIE(perinatalencephalopathy)stillremainsthemostcommonetiology

*Phenobarbitalslightlydeclinedinusestillremainsthefirstlinedrug(96%)

*Useofphenytoinhassignificantlydeclined

*UseofLevetiracetam(Keppra)hasincreasedten-fold

*AhmadKJPerinatol2016;El-DibMohamedSeminFet&NeonatMed2017

NeonatalSeizures

Whataboutcontroversies……....?

NeonatalSeizuresControversies

ControversiesconcerningNeonatalSeizures.Scher,MS andPainterMJ/Pediatr ClinicsofNorthAmerica1989;36:281

ControversiesinthediagnosisandmanagementofNeonatalSeizures.LowPS.JSingaporePaediatr Soc 1991;33:6-10

Controversies intreatmentofNeonatal Seizures.HahnJS.Pediatr Neurol 1993; 9:330-1

ControversiesintreatmentofNeonatalSeizuresYoungRSKPediatr Neurol 1993; 9:331-2

Neonatalseizures:DiagnosticandTherapeuticControversiesLegido A.RevNeurol 1996;24:694-700

NeonatalSeizuresControversies

Neonatalseizures:DiagnosticandTherapeuticControversiesLegido A.RevNeurol 1996;24:694-700

Currentcontroversiesindiagnosisandmanagementofneonatalseizures.Laroia Laroia N.IndianPediatr.2000 37:367-72

Controversiesinneonatalseizuremanagement.Glass HC,Wirrell E.JChildNeurol.2009 May;24(5):591-9.

Seizures:controversiesandchallengesintranslatingnewtherapiesfromthelabtotheisolette.ChapmanKE,Raol YH,Brooks-Kayal A.Eur JNeurosci.2012 Jun;35(12):1857-65.

NeonatalSeizures

Areasofcontroversy

Whatisthebestwaytoto detectandmonitorneonatalseizures?

Areclinicalonlyorelectrographiconlyeventstrulyseizures?

Doneonatalseizurescausebraininjury?

Howaggressivelyshouldneonatalseizuresbetreated?

Roleolderdrugsversusnewerdrugsinthetreatmentofneonatalsz ?

Howlongdoyoutreatinfantswithneonatalseizures?GlassHJCN2009

NeonatalSeizuresTreatment

WhyControversies

§ Moststudiesonbraininjuryarefromstudiesonanimalmodels

§ NoevidencebasedguidelinestotreatNS

§ Noclearpolicytotreatacuteclinicalsz (eg:1st choice;2nd choiceetc)

§ Nouniformprotocolstotreatelectrographicseizures

§ Norandomizedcontrolledstudiescomparingdifferentdrugs

§ Concernsaboutthelongtermsideeffectsofolddrugs(phenobarb)

§ Limitedpharmacokineticdataaboutnewerdrugs

NeonatalSeizuresControversiesinTreatment

Objectives

Whytreatneonatalseizures?Whynottotreatneonatalseizures?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewerdrugsHowlongtotreat?

NeonatalSeizures

WhyTreatConcernsaboutBrainInjury

Thereiscompellingevidencepredominantlyfromanimalstudies (Sankar 1998)

Thereisa55-70foldincreaseriskforCP;5foldincreaseforIDand18foldincreaseriskforlaterepilepsy(Holden1982)

BothclinicalandEEGseizurescausesevereneurologicalsequelaeinhumansneonates(Legido A;Pediatrics2001)

HIEwithseizureswasassociatedwithworseoutcomethanwithoutseizures(GlassHJofPediatrics2009)

Seizuresmayexacerbateunderlyingbraininjuryinthesettingofhypoxicischemicencephalopathy(Dzhala V2000;Wirrel 2001)

NeonatalSeizuresWhyTreat

BrainInjuryVOLPE2012

NeonatalSeizuresWhytreat

Volpe JJ 2012

Brain Injury

NeonatalSeizures

WhyTreatRiskofPostNeonatalEpilepsy

§ Riskofpostneonatalepilepsyvariesfrom15- 35%(Scher1993)

§ Treatmentofearlyseizuresmaypreventlaterepilepsy.*In2observationalstudiestreatingsubclinicalsz(EEG)wereassociatedwithlowerincidenceofpostnatalepilepsy8.3- 9.4%

(*(HellstromWestas1995;*Toet2005)

§ EarlyMRIpatternsmaypredictlaterepilepsy(JungDE2015)

NeonatalSeizures

Objectives

Whytreatneonatalseizures?Whynottotreatneonatalseizures?Whattotreat?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewdrugsHowlongtotreat?

NeonatalSeizuresWhynottotreat

§ Mostseizuresarerelatedtoacutereversibletransientcauses

§ Mostseizuresmayresolveinamatteroffewdays

§ Earlytreatmentmaynotpreventlaterepilepsy

§ Riskofpostneonatalepilepsyismostlybasedonetiologyofneonatalseizures

§ Dataofacuteandlongtermconsequencesaremostlyfromanimalmodels(seizuresinanimalmodelsareinducedbychemicals;neuronallossshownintheseexperimentalmodelsmaynotberelevantinhumaninfant)

§ Adverseeffectsoftheanticonvulsantsusedareofconcern

§ Noclearhumandatatosupportthenotionthataggressivetherapyofneonatalseizuresimproveslongtermoutcome.(epileptogenesis andlaterepilepsy)

*Guillet etalfoundthatrecurrencewasindependentofpheonobarb prophylaxisin146children:30%withRxvs23%withoutRx

NeonatalSeizures

Objectives

Whytreatneonatalseizures?Whynottreatneonatalseizures?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewerdrugsHowlongtotreat?

NeonatalSeizuresHowaggressivelytotreat?

Electroclinicaldissociation

OverestimationClinicallyevidentseizurelikebehaviormaynothaveEEGcorrelation

UnderestimationElectrographicseizuresmaynothaveclinicalorbehaviorcorrelation

*MizrahiE1987;ClancyR1995

NeonatalSeizuresHowAggressivelytoTreat

ClinicaleventswithoutEEGchanges

§ Manyneonatalbehaviorsmayresembleseizureseg:jitteriness

§ Neonatalbehaviours maybebrainstem“releasephenomenon

§ Neonatalseizuresmayoriginateinsubcortical/brainstemregions

eg:inferiorcolliculiinratsmaygeneratepaddlingortreadingmovts

NeonatalSeizuresHowaggressivelytotreat

EEGchangeswithoutclinicalevents

Oftenseeninneonateswithveryfrequentelectrographicseizures

*Clancyetal*reportedthatonly21%ofEEGseizureshadclinicalcorrelation*Epilepsia1988

**Wietstocketalreported24%withEEGseizureshadnoclinicalcorrelates**JChildNeurol2016

***BuraniqiEetalreported23%ofpremies(MeanGA32.8wks)withelectrographicseizureshadnoclinicalcorrelates

***JChildNeurol2017Lackofclinicalcorrelatesmostcommonlyseenafterloadingdosesofanticonvulsants

NeonatalSeizuresHowAggressivelytotreat?

Electroclinical Dissociation

Clinicalonly:thereissomedebateifclinicalonlyevents(noEEGcorrelates)shouldbeaggressivelytreatedornot.SomeclinicaleventsmayhaveseizurefocuswhichmaynotberecordedbyscalpEEG.DuetopotentialsideeffectsoftheAEDmanymaynotpursuewithtreatingtheseeventsandcarefulmonitoringisreasonable.Isolatedclinicaleventsmaynotbedetrimentalbutrecurrenteventsmayneedacarefulre-looktoconsidertreatment.

Electrographicseizures:Mostclinicianswillopttotreatelectrographicseizures.

Doseizurespredictoutcome?

Van Rooji Pediatrics 2010

NeonatalSeizuresSurvey

*Areelectrographicneonatalseizuresharmful?

YesDon’knowPediatricNeurologists38%47%Neonatalogists 34%43%

*Wouldyoutreatelectrographicseizures?YesNoDon’tknow

PediatricNeurologists40% 30% remainingNeonatologists38%35%remaining

*Basan HPed Neurol 2008

NeonatalSeizures

HowaggressivelyshouldNSbetreated?

Goalistoeliminatebothclinicalandelectrographicseizures

Totreatonlyclinicaleventswithoutelectrographiccorrelatesisdebatable

NeonatalSeizuresaEEG (AmplitudeIntegratedEEG)

aEEG iswidelyusedinEuorpe andinmanyUStertiarycenters

aEEG :easeapplication;interpretationatbedsidebytrainednurses/MD’s

*aEEG isconsideredlowaccuracyforseizuredetection

*aEEG actualsensitivityforindividualseizuredetection12- 38%

ConventionalLTMEEGwithconcurrentvideoisstillgoldstandard

**ACNSadvocatesuseofcontinuousLTMinthediagnosisofNS

*Snelhass RAClin Neurophysiol 2007;**2011

NeonatalSeizures

Beware:Themisuseoftechnologyandthelawofunintendedconsequences:*FreemanJM:JAmSocietyofExp NeuroTherapeutics2007

“Whetherseizuresorsubclinicalseizuresthemselvescauseharmtothedevelopingbrainisunclear.Theeffectivenessofmedicationsfortreatmentofseizuresinthenewbornhasnotbeenwellestablished.ThereforetheconsequencesofautomatedEEGforthedetectionofsubclincal neonatalseizuresarelikelytobesimilartotheintroductionofelectronicfetalmonitoring:creationofanotherpseudodiseasefollowedbyunwarrantedinterventionandincreasedlegalliability”

*LateProfJohnFreemanfromJohnsHopkins

NeonatalSeizures

Objectives

Whytreatneonatalseizures?Whattotreat?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewdrugsHowlongtotreat?

NeonatalSeizures

WhattoTreatWith§ Firstlineandsecondlinedrugshaveremainedthesameoverdecades§ Noevidencebasedclinicalguidelinesarestillavailable§ Verylittleevidencetosupporttheuseofonedrugovertheother

§ IncreasingrecognitionofneuronalapoptosisrelatedtoolderAED’ssuchasphenobarbital;phenytoin;VPAanddiazepam

§ Poorefficacyofphenobarb anddiazepammayberelatedtoexcitatorynatureofGABAreceptorsinthenewborn(animals)

§ Lackofrandomizedplacebocontrolledtrialsmakesitdifficulttoknowtheabsoluteefficacyofvariousoldandnewanticonvulsants

§ Manypublishedstudiesarenot basedonLTMEEG’s.

§ Limitedpharmacokineticstudiesandsafetydataonnewerdrugs

NeonatalSeizuresAntiConvulsantDrugTherapy

“thereislittleevidencetosupporttheuseofanyoftheanticonvulsantscurrentlyusedintheneonatalperiod”

BoothD.CochraneDatabase2004

NeonatalSeizuresAntiConvulantDrugTherapy

ThereisconcernandconcensusthatcurrentlyusedAEDsareoftenineffectivefortreatmentofneonatalseizures.

SankarR,PainterMJ.Neurology2005

NeonatalSeizuresAntiConvulantDrugTherapy

*WHOevidenceguidelinesonneonatalseizuresemphasizethelackofevidenceforthemanagementofneonatalseizures.

*WHOGuidelinesonneonatalseizures,Geneva2011

NeonatalSeizuresAnticonvulsantDrugTherapy

Wearenotalone!

Thereareothertypesofseizuredisordersandepilepsythathavenowellstudiedrandomizedcontroldrugtrials:

Lennox-GastautsyndromeInfantilespasmsESES(electricalstatusepilepsticusinsleep)EarlyInfantileandEarlyMyoclonicEncephalopathy(EIEE/EMEE)

NeonatalSeizuresAnticonvulsantDrugtherapy

OldDrugs

Phenobarbital

Phenytoin(fosphenytoin)

NeonatalSeizuresAnticonvulsantDrugTherapy

WhyusePhenobarbital?

Useasfirstlinedrugfordecadesforneonatalseizures

AvailabilityworldwideCheapPharmacokineticswellstudiedandpredictableLonghalf-lifeespeciallyinHIEbabies(>120hrs).CrossestheBBBinlessthan30minutesLessproteinbinding(33%)Useasmaintenanceorallyisfeasible

NeonatalSeizuresAnticonvulantDrugTherapy

PainterandScher NEJM1999

(PhenobarbitalvsPhenytoin)AdoubleblindplacebocontrolledstudySeizuresweremonitoredoncontinuousLTMEEG

DrugIVrouteResponsePhenobarb 43%+Phenytoin 57%

Phenytoin 45%+Phenobarb 62%

Conclusion:Overallresponsewitheitherdrug<50%Nosignificantdifferencesbetweenthese2drugsincontrollingelectrographicseizures

NeonatalSeizuresTreatmentJChildNeurol2009:24;148

NeonatalSeizuresHellstrom-WestasL.ActaPaedrica2015

Hellstrom-Westas,L

NeonatalSeizures

ConcernsaboutPhenobarbitalExperimentaldataemerged3decadesagoaboutphenobarbitalexposurehadadverseeffectsonsurvivial andmorphologyofculturedneuronsoffetalmousetissueandraisedconcernsaboutitsuseinthetreatmentofneonatalseizure

(BergeyGK1991SerranoEE1988)

Recentevidencethatevenbrieftreatmentwithconventionalanticonvulsantssuchasphenobarbital,diazepam,phenytoinandvalproate allincreaseapoptoticneuronaldeathinnormalimmaturerodentmodelsincortexthalamusbasalganglia

Bittigau P.ProcNatlAcad Sci2002

Neuronalapoptosisinratneuronsatserumconcentrationlevel25-35mc/mlBiitigau P.AnnNYAcad Sci2003

NeonatalSeizuresAnticonvulsantDrugTherapy

WhyusePhenytoin/Fosphenytoin?

Anotheroldwithwellstudiedpharmacokineticsanduses

Wellestablishedashighlyeffectivedrugforstatusepilepticus

LesscardiovascularsideeffectsCrossesBBBin<20minutesConvertedtophenytoinbyphosphatasesin<8minutesIVEffectiveinneonatalseizuresabolishingclinicalandEEGseizures

Combinedwithphenobarbitaliseffectivein65%

NeonatalSeizuresAnticonvulsantDrugTherapy

ConcernsaboutPhenytoin

*Inratneuronstriggersneuronalapoptosisatadoseof20mg/kg

(ie:Plasmaconcentrationof10- 15mc/ml)

Reducedproteinbindingandlikelytoincreasefreephenytoinlevels

Maydisplacefreebilirubinandincreasesriskforkernicterus

Lastlyphenytoinisnotideallyusedorallyasamaintenancedrugforneonatalseizures

*BittigauP.AnnNYAcadSc2003

NeonatalSeizures

OldDrugs

Despiteproblemsandlessefficacybothphenobarbitalandfosphenytoinstillremainmainstayintheinitialdrugtherapyforneonatalseizures

NeonatalSeizures

Objectives

Whytreatneonatalseizures?Whattotreat?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewerdrugsHowlongtotreat?

NeonatalSeizures

NewerAntiepilepticDrugs(AED)

LevetiracetamTopiramateBumetanideFlupirtine(potassiumchannelopenertestedinrats)

NeonatalSeizures

NewerAED’s

MostnewerAED’sarecurrentlyofflabelreportedascaseseries

Clinicaluseanddataareinsufficienttorecommendthemasfirstline.

Levetiracetamandtopiramatehavefavorablepharmacokineticprofiles.

Topiramateandlevetiracetamdonotcauseneuronalapoptosisordisruptsynapticdevelopmentinanimalmodels(KimJJ2007)

TopiramateandLevmayhaveneuroprotectiveproperties.(Kim,J.2007)

Experiencewithnewerdrugsisreportedonlyascaseseries.

NeonatalSeizuresLevetiracetam

AnimalDataNoneurotoxiceffectsin7dayoldratsatdosesupto100mg/kg( Manthley DExp Neurol 2005)

- LEVgivenprophylacticallytoHIEinducedratsreducedclinicalandelectricalseizures- (Talos DMPediatr Res2013)

- LEVappearedtoexertadiseasemodifyingeffectonHIEinducedseizures)- Giler CExp Nneurol 2004)

LEVsignificantlyreducedthenumberofapoptoticcellsinthehippocampus,cerebralcortexandthalami(Kilicdag HEarlyHumDev2013)

- LEVsupressed acuteseizuresinducedbyperinatalhypoxiaand- diminshed laterlifeseizuresusceptibilityandseizureinducedneuronal- injuryinrodentneonatalseizuremodel.(JensenFEPediatr Res2011)-

- LEVandTopiramatehavenoeffectsonapoptosisinthedevelopingbrain.- (Talos DMPediatr Res2013)

-

NeonatalSeizuresLevetiracetam

ClinicalData(Total144cases)Allcaseseries

*AbendNS;JChildNeurol 2011*Ramantani G;Eur JPediatr Neurol 2011*KhanO;PediNeurol 2011*KhanO;PediNeurol 2013*Rakshabhuvankar A;JClic Neurosci 2013*Neininiger MP:Neuropediatrics 2015*Lo-YeeYau M;WorldJClin Pedi2015

(Doserange10- 55MG/KGResponserate35- 100%(overall90%)

Surveyshaveindicatedlevetiracetam beingusedassecondline(SilversteinF2008)

AdoubleblindrandomizedcontrolledtrialofIVLevetiracetam iscurrentlyinprogressinChildren’sHospital,SanDiego,Ca.

AnobservationalstudycomparingLevandPhenobarbitalasfirstlineiscurrentlyinprogressatUniv ofCincinnati

NeonatalSeizuresLevetiracetam

ClinicalStudy

RamantaniGetalEurJPedNeurol2011

AprospectivestudyusingLEVasfirstlinedrugN38pretermandterminfantsDoserange10mg/kgloadtomax60mg/kgSomeneededphenobarbitalIVforpersistentseizures30/38infantsbecameseizurefreeinoneweekEEGmarkedlyimprovedin24infantsin4weeks.

NeonatalSeizuresLevetiracetam

ClinicalStudyFalsaperlaRJPediatrNeurosci2017

AprospectivestudyusingLEVasfirstlinedrugN=16neonates(12termand4preterm)LEVinitialdose10mg/kgBIDMaintenanceDoseupto40mg/kgBIDAllrespondedtoLEVmonotherapyResponsewithin24- hoursto15days(mean96hrs)

NeonatalSeizuresLevetiracetam

LEViscurrentlyoftenusedassecondorthirdlinetreatmentforneonatalseizures

AvailabilityofIVpreparationhasenableditsuseofflabel

MechanismisactioninunknownbutsuggestiveofinteractionwithSVP2A(synapticvesicleprotein)

Itisnotlinkedtoplasmaproteins-sonoriskofdisplacementofotherproteinboundsubstancesMinimalhepaticmetabolisminvolved

ItisnotmetabolizedbycytochromeP450system

Meanhalflifeinneonatesrangefrom9to18hoursQ8hourlydosemaybepreferable

SeveralanimalstudieshavesuggestedLEV’ssafetyinthenewborninfants(doesnotcauseapoptoticdegeneration)

APhase2randomizedstudyasfirstlinedrugbeingconductedatUniv ofCaatSanDiego

NeonatalSeizuresLevetiracetam

HumanStudiesinNeonatalSeizures

Studiesaboutitsusepublishedaresmallretrospectiveseries

MostofthemreceivedLEVassecondorthirdlinedrugtreatment

Methodologicalissuesmakethemdifficulttointerprettheresults

Manyoftheneonateshavealreadyreceivedotherdrugs

UnclearifseizurecessationisLEVefficacyornaturalresolution

CurrentevidencesuggeststhatLEVworksbestin30%ofneonates

El-DibM.andSoulJ.SemFetal&NeonatalMed2017

NeonatalSeizuresLevetiracetam

CurrentUse

AsfirstlinedrugforneonatalseizuresisstillnotprevalentStudiesareunderwayofLEVasfirstlinedrugforneonatalseizures

Assecondlineiswidelycatchingup.AlmosteveryoneusesLEVasthirdlineforneonatalseizures

NeonatalSeizuresAnticonvulsantDrugTherapyNewerDrugsTopiramate(AMPAModulator)

TPMhasmultiplemechanismsofaction(Koh&JensenAnnNeurol 2001)

InanimalsmodelswithcerebralischemiaTPMreducedseverityofbraininjuryaloneorwithhypothermia.(Scubert S.2005;BrainRes)

Inanimalsmodelsnotshowntohaveanyharmfuleffectsondevelopingbrain

Neuroprotective effectshavebeendescribedinratsrelatedtoAMPAmediatedeffectsandkainate receptorinhibition(Koh&JensenAnnNeurol 2001)

Nocleardataonhumanneonates/noIVformulationlimitsuse.

Susceptibletodruginteractionsandeffectsofhypothermia(CP450)(PedNeurol 2011;2012)

Lowriskforapoptosis(Sem Fetal&NeonatalMed2017)

TrialasadjuvantwithhypothermiainHIEcurrentlyinprogressinUSAandItaly

NeonatalSeizuresAnticonvulsantDrugTherapyNewerDrugs

*Bumetanide(NKCC1transporterinhibitor)

§ Aloopdiureticwidelyusedfordecadesinneonatesasadiuretic

§ InhibitsNKCCL(Cl-cotransporter)thatishighlyexpressedinimmatureneurons

§ BlockadeofNKCCLdecreasesneuronalCl levelsandrestoresGABAinhibition

§ CombiningwithphenobarbitalaugmentsGABAinhibitionandmaycontrolseizuresnotcontrolledbyphenobarbitalalone

§ **AugmentsneuroprotectiveeffectsofphenobarbitalinHIEmodelswithhypothermia

§ AlargedoubleblindmulticenterRCTstudycompletedatHarvard(SoulJ,StaleyKJetal).

*Dzhazla V,StaleyKAnnNeurol **LiuYPedRes2012

NeonatalSeizures

NeonatalSeizures

GABA acts excitatory in immature neurons due to over expression ofNKCC1 and under expression of KCC2 resulting in increased intraneural Cl ions and depolarization ( excitation)

Mature neurons have over expression of KCC2 and low intraneuronal Cl ions concentration resulting in GABA induced hyperpolarization(inhibition) Mruk AL 2015

NeonatalSeizuresAnticonvulsantDrugTherapyNewerDrugs

Flupirtine(Potassiumchanelopeners)

*Arecentstudyinratshasshownexcellentefficacy

In5minutescompletelyabolishedelectrographicandclinicalsz

PotentialuseinhumansinKCNQ2andKCNQ3epilepsies

RaolYHetalAnnNeurol2009

NeonatalSeizuresAnticonvulsantDrugTherapy

*AED’sadministeredforNeonatalSeziures

(N- 420)(from8tertiarycarecenters)

DrugN%Phenobarbital387(92%)Levetiracetam130(31%)Fosphenytoin116(27%)

Benzodiazepine81(19%)Midazolaminfusion34(8%)Vitamins(B6etc)32(8%)

*GlassHetalJournalofChildNeurology2016

NeonatalSeizuresAntiConvulsantDrug Therapy

*Informalpersonalpollofneonatalneurologistsfrom4majortertiarycenters:

1. Everyoneusesphenobarbital asthefirstchoice2. SecondchoiceisstillFosphenytoin in2/4centers

3. SecondchoiceisLevetiracetam in2/4centers4. SecondchoiceofIVMidazolam in1/4ifEEGshowsstatus5. AllagreethatpracticesvaryaccordingtotheAttendings6. UseofTopomax isstillnotcommonbecausenoIVform.

7. NooneusesPentobarbitalcomaintheneonates

NeonatalSeizuresPretermBabies

92 preterm infants ( < 28 weeks to 37 weeks)Phenobarbital was initial drug used in majority of infants HIE and ICH most common causes. More subclinical seizure detected in preterm ( 24% ) than term(14% ) Mortality was twice ( 35% ) in preterm than term ( 15%)Recommending routine LTM EEG monitoring in preterm infants

NeonatalSeizures

HypothermiaTherapeutichypothermiaisstandardofcareinneonatalHIE

*Hypothermiaislikelytoreduceseizureburden

**Hypothermiamightaffectbiotransformationofdrugsviahepatic

cytochromeenzymesP450(CYP450)

**EffectofhypothermiaisexaggeratedinHIEhinderingdrugmetabolism

andelimination

Bothphenobarbandphenytoinmetabolismbutlevetiracetamisnot

depressedbyhypothermia

*JPediatr**CritCareMed200**ExpertopinDrugMetabToxicol2011

NeonatalSeizuresAEDTherapy

PersistentElectrographicSz

§ Mostelectrographicsz respondtooptimaldosesphenobarb/fosphenytoin

§ Usuallyresponseseenin24– 72hours

§ MaytryIVlorazepam0.05MG/kgbolusx1-2doses

§ IVLevetiracetamisgainingaroleasanexcellentoption

§ IVMidazolamcontinuousinfusionisusedinselectedcases

§ IVPentobarb infusionisonlyveryrarelyusedintheneonates

§ IVLidocaineisusedinEuropecommonlybutnotinUSA

§ TrialofPyridoxine(B6)iswarrantedinallintractablecases

NeonatalSeizures

Midazolam

AnticonvulsanteffectatGABAreceptors

Apoptosishasnotbeenwellstudied

Concernsaresedation,mortalityandlengthyhospitalstayetc

Efficacyas2nd or3rd lineforrefractoryNShasbeenpublishedascaseseries

Smallsamplesizeandmethodologicalissueshamperinterpretation

UseofmidazolammaybeconsideredforrefractoryNS

NeonatalSeizuresDrugTherapy

VitaminTherapyUseinselectedintractablecases

Pyridoxine(Vit B6)100- 200mgIVwithconcurrentEEG

Biotin5-15mgtid (PO)

Folinic acid4mg/kg/IV/PO/tid

Pyridoxal4Phosphate30mg/kg/dayPOdividedTID

NeonatalSeizuresFuture DrugTherapy

MikatiMSemPedNeurol2016

NeonatalSeizuresAcuteDrugTherapy

UsualStrategy

LoadwithPhenobarb 20mg/kg-maygoup

with5mg/kgincrementsto30mg/kg-40mg/KgBepreparedtointubateinthosewith40mg/Kg

IfnoresponseAddIVFosphenyoin 20mg/kgIfnoresponse

Maytryanotherdose5mg/kgIVIfnoresponse

GiveIVLevetiracetam20mg/KgMaytrydosesupto40- 50MG/KGIV

IfnoresponseConsiderIVMidazolaminfusion

NeonatalSeizuresAcuteDrugTherapy

ModifiedStrategy

LoadwithPhenobarb 20mg/kg-maygoupwith5mg/kgincrementsto30mg/kg-40mg/Kgbepreparedtointubateinthosewith40mg/Kg

IfnoresponseLoadIVLevetiracetam40-60mg/kg(highdose)

IfnoresponseLoadIVFosphenytoin 20mg/kg

IfnoresponseTryPyridoxine100-200mgIV

IfnoresponseConsiderIVMidazolaminfusion

NeonatalSeizures

Objectives

Whytreatneonatalseizures?Whattotreat?Howaggressivelytotreat?Whattotreatwith?OlddrugsNewdrugsHowlongtotreat?

NeonatalSeizures

HowLongtoTreatThereislittleagreementonthisissue/noclearpolicy/guidelinesexistTherearenorandomizedcontrolledstudiescomparingtheeffectsofAEDtreatmentvs notreatmentonshortandlongtermoutcome.*SurveyshaveindicateddurationofRxdaystoyears–nouniformity**Neonatologiststendadvocateshorterdurationthanneurologists

*Massingale TWJPerinatol 1993;Bartha AIPediNeurol 2007;Basan H2008**Basan H2008;Wickerstrom RPediNeurol 2013

Ingeneral,infantswithsevereHIEbraininjury;corticalmalformations,largebleedsandgeneticepilepsiesmayneedlongerdurationoftreatment.

NeonatalSeizuresDrugTherapy

CriteriatostopAEDtherapy

§ 80%-85%ofneonateswillneedonlyshorttermmaintenence therapy(weeks)§ *Mayconsidertodiscontinueiffollowingcriteriaaremet:

NoseizurerecurrenceNormalfollowup EEGNormalNeurologicalExamination

*VolpeJJPediatrics1989

§ ThosewhoneedlongtermAEDtherapy(15-20%)haveconsequencesofsevereHIE/malformations/metabolic/genetic/meningoencephalitis

NeonatalSeizuresConclusionsofControversies

CurrentstateoftreatmentforneonatalseizuresThereisnoevidencebasedstudiestosupportcurrentAEDuse

Currentmanagementislargelybasedonoldtradition;caseseriesandclinicalexperience

Clinicaltrialsinneonateshavelogisticalandethicalproblems

AED’sbasedonagespecificmechanismsmightholdpromiseuseofnewerdrugs

Trialsoflevetiracetam,topiramateandbumetanidearebeingconductedmethodicallyandmayalterfuturedrugtreatmentofneonatalseizures

Thereisastrongneedformoreevidencebasedstudiesanddataforthemanagementofneonatalseizures.

ControversiesinNeonatalSeizures

KeyReferencesChapmanKE.European JournalofNeuroscience;2012:1857-65Pressler RM.Seminars inFetal&NeonatalMedicine;2013:216-223Spagnoli C.ItalianJournalofPediatrics;2013:37-39

ShettyJ.DevelopMed&ChildNeurol ;2015:40- 43Wietstock SO.JChildNeurol 2016:328-332GlassHC.JournalofChildNeurol 2009:591-99El-Dib,M.SeminarsinFetal&NeonatalMedicine2017;1-7

Mruk AL.JPediatr Pharmacol Ther 2015:76-89

ControversiesinNeonatalSeizures

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