Epilepsia 2012

PharmacologicalUpdateofClinicalGuideline20
TheEpilepsies
Thediagnosisandmanagementoftheepilepsiesin
adultsandchildreninprimaryandsecondarycare
November2013:Afootnotehasbeenaddedtorecommendation81inthisguidelinehighlightingnewadviceissuedbythe
MHRAaboutoralantiepilepticdrugs(AEDs)andswitchingbetweendifferentmanufacturersproductsofaparticulardrug.
SeetheMHRAadviceformoreinformationatwww.mhra.gov.uk.Thecorrespondingchangehasbeenmadeto
recommendation1.9.1.4intheNICEguidelineandontheNICEepilepsypathway.
Final
Methods,evidenceandrecommendations
January2012
CommissionedbytheNationalInstitutefor
HealthandClinicalExcellence
TheEpilepsies
Preface
PartialPharmacologicalUpdateofClinicalGuideline20
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Preface
DrRichardRoberts
ConsultantNeurologist,NinewellsHospital,Dundee
Chairman,SIGN70Diagnosisandmanagementofepilepsyinadults(2003)
Theinadequaciesthathaveexistedintheservices,careandtreatmentforpeoplewithepilepsyare
wellrecognised.Importantissuesincludemisdiagnosis,inappropriateorinadequatetreatment,
suddenunexpecteddeaththatmighthavebeenprevented,adviceaboutpregnancyand
contraceptionandmanagementofstatusepilepticus.Serviceprovisionforpeoplewithepilepsyhas
beenpatchyandsometimespoorbothinprimaryandsecondarycare.Thisisnowchanging.The
newGeneralMedicalServices(GMS)contractincludestargetsforepilepsy.Thenumberof
specialistswithexpertiseinepilepsyisincreasing.Therehasbeenagreatincreaseinthenumberof
epilepsyspecialistnurses,andstructuredservicesforepilepsyacrossprimaryandsecondarycareare
emerging.Atthesametimeanumberofnewantiepilepticdrugshavebeenlicensed.
Thisguidelineispublished,therefore,atatimewhenitislikelytohaveamajorimpact.The
recommendationsonserviceprovision,suchaswaitingtimestoseespecialistsandforinvestigations,
willbechallengingfortheserviceproviders,astheyhavebeeninScotlandfollowingsimilar
recommendations(SIGNGuideline70).Theguidanceontheuseofthenewerantiepilepticdrugs
confirmstheirimportantroleinthetreatmentofepilepsy.Clearguidanceisgiveninvariousspecific
areassuchaspregnancyandcontraception,learningdisability,youngpeople,repeatedseizuresin
thecommunityandstatusepilepticus.Theimportanceoftheprovisionofinformationforpeople
withepilepsyandtheircarersisstressed.Ifthereissuccessfulimplementationofthe
recommendations,therewillbeagreatimprovementinthecareofpeoplewithepilepsy.
DrNickKosky
ConsultantPsychiatrist,PrisonMentalHealthInreachTeamandMedicalDirector,Dorset
CommunityHealthServices
Chairman,Theepilepsiesguideline2012
ThefirstNICEguidelineonthemanagementofepilepsyinchildrenandadultswaspublishedin2004.
TheEpilepsies
PublishedbytheNationalClinicalGuidelineCentreat
TheRoyalCollegeofPhysicians,11StAndrewsPlace,RegentsPark,London,NW14BT
Firstpublished2004
NationalClinicalGuidelineCentreJanuary2012
Apartfromanyfairdealingforthepurposesofresearchorprivatestudy,criticismorreview,as
permittedundertheCopyright,DesignsandPatentsAct,1988,nopartofthispublicationmaybe
reproduced,storedortransmittedinanyformorbyanymeans,withoutthepriorwrittenpermissionof
thepublisheror,inthecaseofreprographicreproduction,inaccordancewiththetermsoflicences
issuedbytheCopyrightLicensingAgencyintheUK.Enquiriesconcerningreproductionoutsidethe
termsstatedhereshouldbesenttothepublisherattheUKaddressprintedonthispage.
Theuseofregisterednames,trademarks,etc.inthispublicationdoesnotimply,evenintheabsenceof
aspecificstatement,thatsuchnamesareexemptfromtherelevantlawsandregulationsandtherefore
forgeneraluse.
TherightsofNationalClinicalGuidelineCentretobeidentifiedasAuthorofthisworkhavebeen
assertedbytheminaccordancewiththeCopyright,DesignsandPatentsAct,1988.
TheEpilepsies
Preface
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Theguidelinehighlightedtheinadequaciesthatexistedintheservices,careandtreatmentfor
peoplewithepilepsy,andmadegreatprogressinaddressingrelevantimportantissues
misdiagnosis,inappropriateorinadequatetreatment,suddenunexpecteddeaththatmighthave
beenprevented,adviceaboutpregnancyandcontraceptionandmanagementofstatusepilepticus.
Revisitingthisguidelineistimely.TheNHSisfacingmajorfinancialchallenges,anditisvitalthata
spotlightiskeptontheneedtofurtherdevelopthestillvariableservicesforpeoplewithepilepsy.
Theplaceofnewlylicenseddrugsforepilepsyalsoneedscarefulconsideration.
Theupdatedguidelineremindsthereaderoftheneedforproperlyresourcedservices,offering
appropriatelevelsofexpertise,whichallowtimelyaccesstoassessmentandtreatmentforpeople
withepilepsy.Theprimaryscopeoftheguidelineswastoconsidertheroleofantiepilepticdrugs,
especiallygiventheimpactofimportant,realworldstudiessuchasSANAD.Theroleofestablished
andnewlylicenseddrugshasbeenconsideredusingnovelstatisticalmethodsallowingcomparison
ofcosteffectivenessaprocessthathasbeenmuchaided,asalways,byarobuststakeholder
reviewprocess.
Peoplewithepilepsyremainatthecentreofthisguideline,andtheneedforservicestoconsiderthe
needsofeachindividual,tonotdiscriminateinprovisionandtoworkinpartnershipwithpeoplewith
epilepsyandtheircarersisunderlined.
Attentionhasbeenpaidtoensurethattherecommendationsarewritteninclearlanguageandare
accessible,and,wehope,usefultoall.Supportingthewrittenversionisanonlinecarepathway,and
qualitystandardsaresoontobepublished.Weremaincommittedtothecareofpeoplewith
epilepsyandcommendtheseguidelinestoyouinthatlight.
TheEpilepsies
Foreword
Foreword
DrMayurLakhani
ChairmanElect,RoyalCollegeofGeneralPractitionersuntil2006
FoundingChairmanoftheNationalCollaboratingCentreforPrimaryCare(20012004)
Itgivesmegreatpleasuretoseethepublicationofthefirstmajorclinicalpracticeguidelinefromthe
NationalCollaboratingCentreforPrimaryCare,hostedbytheRoyalCollegeofGeneralPractitioners.
AsapractisingGP,Iamwellawareofthechallengesfacedwhendealingwithpatientswithepilepsy.
Itiswellrecognisedthatthecareofpatientswithepilepsyissuboptimalandmoreneedstobedone
toimproveclinicalstandards.GPsarefacedwithacomplexsetofissuesonaregularbasisincluding
givingadvicetopatientsaboutepilepsyanddriving,planningapregnancyandthethornyissueof
withdrawalofantiepilepticmedication.Intheseandotherareas,practicalrecommendationsare
essential:ItisthereforewelcometohavethisclearguidancewhichwillsupportGPstoimplement
theQualityandOutcomesFrameworkofthenewGeneralMedicalServicescontract.Inadditionthe
guidelinecontainsimportantrecommendationsaboutserviceforpatientswithepilepsyandthe
organisationofcare.
TheRoyalCollegeofGeneralPractitionersexiststopromotethehighestpossiblestandardsof
generalmedicalcareanditiscommittedtoincreasingsupportforGPstoenablethemtodoso.I
commendtheseguidelinestothehealthcommunityasawholeandurgecommissionerstosupport
itsimplementation.IwouldliketoacknowledgetheexcellentworkofthestaffofNational
CollaboratingCentreforPrimaryCareandcolleaguesattheUniversityofLeicesterinproducingthis
guideline.
TheEpilepsies
Contents
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Contents
Guidelinedevelopmentgroupmembers.......................................................................................15
Acknowledgements......................................................................................................................20
1 Introduction..........................................................................................................................21
1.1 Definitionofepilepsy..........................................................................................................21
1.2 Clinicalaspects....................................................................................................................21
1.3 Epidemiology.......................................................................................................................22
1.4 Costofepilepsy...................................................................................................................23
1.5 HealthServicesforpeoplewithepilepsy............................................................................24
1.5.1 Primarycare.........................................................................................................24
1.5.2 Secondarycare....................................................................................................25
1.6 TheSANADtrial...................................................................................................................25
1.7 Guidelineaims.....................................................................................................................26
1.8 Principlesunderlyingtheguidelinedevelopment..............................................................26
1.9 Whoshouldusethisguideline?..........................................................................................27
1.10 Structureofguidelinedocumentation................................................................................27
1.11 Guidelinelimitations...........................................................................................................28
1.12 Plansforupdatingtheguideline.........................................................................................28
2 Methods................................................................................................................................30
2.1 Introduction........................................................................................................................30
2.2 Thedevelopers....................................................................................................................30
2.2.1 TheNationalCollaboratingCentreforPrimaryCare...........................................30
2.2.2 TheNationalClinicalGuidelinesCentre..............................................................30
2.2.3 Themethodologyteam.......................................................................................30
2.2.4 TheGuidelineDevelopmentGroup.....................................................................31
2.3 Developingkeyclinicalquestions(KCQs)............................................................................32
2.4 Identifyingtheevidence......................................................................................................32
2.4.1 Literaturesearchstrategies.................................................................................32
2.4.2 Healtheconomics................................................................................................34
2.5 Reviewingandgradingtheevidence..................................................................................35
2.5.1 Methodsfor2004Guideline................................................................................35
2.5.2 Methodsfor2012Guideline................................................................................36
2.6 Methodsofcombiningstudies(2012)................................................................................37
2.7 Protocolforguidelineevidencereviewsforthepartialupdate(2012)..............................37
Typesofstudies.............................................................................................................................37
Typesofparticipants.....................................................................................................................38
Typesofinterventions...................................................................................................................39
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Durationofstudies........................................................................................................................39
Posology........................................................................................................................................39
Typesofoutcomemeasuresanddefinitions................................................................................39
Typeofanalysis.............................................................................................................................41
Useofunpublisheddataintheguideline.....................................................................................41
2.8 Gradingofqualityofevidenceforoutcomes(2012)..........................................................41
Inconsistency.................................................................................................................................42
Indirectness...................................................................................................................................42
Imprecision....................................................................................................................................42
2.8.1 Healtheconomicsmethods.................................................................................44
2.8.2 Literaturereviewforhealtheconomics..............................................................45
2.9 Developingrecommendations............................................................................................46
2.10 ResearchRecommendations...............................................................................................48
2.10.1 Newlydiagnosedseizures(focalandgeneralised)monotherapy....................48
2.10.2 Epilepsysyndromes.............................................................................................48
2.10.3 Infantilespasms...................................................................................................49
2.10.4 Treatmentofconvulsivestatusepilepticus(i.e.notjustrefractory)..................49
2.10.5 AEDsandpregnancy............................................................................................50
2.10.6 Ketogenicdietinadults.......................................................................................50
2.11 Prioritisationofrecommendationsforimplementation....................................................51
2.12 TherelationshipbetweentheguidelineandtheTechnologyAppraisalsforthenewer
antiepilepticdrugs(AEDs)...................................................................................................51
2.13 TherelationshipbetweentheguidelineandNationalServiceFrameworks......................52
2.14 TherelationshipbetweentheguidelineandtheScottishIntercollegiateGuidelines
Networkguidelinesonepilepsy..........................................................................................52
2.15 Externalreview...................................................................................................................53
2.16 Levelofevidencetable.......................................................................................................53
3 Keyprioritiesforimplementation..........................................................................................55
4 Guidance...............................................................................................................................57
4.1.1 Outlineepilepsycarealgorithms.........................................................................82
5 AuditCriteria.........................................................................................................................85
6 Principleofdecisionmaking..................................................................................................86
6.1 Whoshouldbeinvolvedinthedecisionmakingprocessforadultsandchildrenwith
epilepsy?.............................................................................................................................86
7 Diagnosis...............................................................................................................................87
7.1 Introduction........................................................................................................................87
7.2 Establishingthediagnosisofepilepsy.................................................................................87
7.3 Keyfeaturesofthehistoryandexaminationthatallowepilepsytobedifferentiated
fromotherdiagnosesinadultsandchildren......................................................................88
7.4 Whatarethekeyfeaturesofthehistoryandexaminationthatallowanepileptic
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seizuretobedifferentiatedfromothercausesofattackdisorderinadults?....................91
7.5 Theroleofattack/seizurediariesindiagnosisinadults&children...................................91
7.6 Theroleofhomevideorecordinginmakingthediagnosisofepilepsyinadultsand
children?..............................................................................................................................91
8 Investigations........................................................................................................................93
8.1 Introduction........................................................................................................................93
8.2 TheroleofEEGinmakingadiagnosisofepilepsy..............................................................93
8.2.1 HowgoodisthestandardEEGatdifferentiatingbetweenindividualswho
havehadanepilepticseizureandthosewhohavehadanonepileptic
seizure?................................................................................................................93
8.2.2 HowgoodistheEEGatdifferentiatingbetweenindividualswhohave
differentepilepsyseizuretypesandepilepsysyndromes?.................................98
8.2.3 HowcanthediagnosticyieldofthestandardinterictalEEGbeimproved?.......98
8.2.4 WhataretherolesoflongtermvideoEEGandambulatoryEEG?...................102
8.2.5 Whatistheroleofprovocationtechniquesandinductionprotocols?.............103
8.2.6 DoesanabnormalEEGpredictseizurerecurrence?.........................................105
8.3 Theroleofneuroimaginginthediagnosisofepilepsy.....................................................107
8.4 Theroleofprolactinlevelsandotherbloodtestsasanaidtodiagnosis.........................114
8.5 Cardiovasculartestsasanaidtodiagnosis.......................................................................116
8.6 Whatistheroleofneuropsychologicalassessmentinthediagnosisandmanagement
ofepilepsy?.......................................................................................................................116
9 Classificationofseizuresandepilepsysyndromes...............................................................119
9.1 Introduction......................................................................................................................119
9.2 Classificationoftheepilepsies..........................................................................................119
9.3 Whatistheroleofclassificationinadultsandchildrenwithepilepsy?...........................129
10 Pharmacologicaltreatmentofepilepsy...............................................................................130
10.1 Introduction......................................................................................................................130
Pharmacologicaltreatmentofepilepsy......................................................................................131
10.2 Howmanytimesshouldmonotherapybetriedbeforecombinationtherapyis
considered?.......................................................................................................................131
10.2.1 WhenshouldAEDtreatmentinadultsandchildrenbestarted?......................132
10.2.2 WhoshouldstartAEDtreatmentinadultsandchildren?.................................136
10.2.3 InadultsandchildrenwithepilepsyonAEDsdoesmanagementof
continuingdrugtherapybyageneralistasopposedtoaspecialistleadto
differentclinicaloutcomes?..............................................................................136
10.2.4 Whatistheroleofmonitoringinadultsandchildrenwithepilepsy?..............137
10.2.5 WhatinfluencesAEDtreatmentconcordanceinadultsandchildren?............140
10.2.6 WhenandhowshouldAEDtreatmentbediscontinuedinadultsand
children?............................................................................................................141
10.2.7 Inadults/childrenwithepilepsyonAEDsdoesmanagementofdrug
withdrawalbyageneralistasopposedtoaspecialistleadtodifferent
TheEpilepsies
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outcomes?.........................................................................................................147
10.2.8 Newrecommendationsandlinktoevidence....................................................148
10.3 MonotherapyfornewlydiagnosedFocalSeizures...........................................................156
10.3.1 Introduction.......................................................................................................156
10.3.2 Methodsoftheevidencereview.......................................................................156
10.3.3 Matrixoftheevidenceforadults......................................................................156
10.3.4 Monotherapyforadultswithnewlydiagnosedfocalseizures..........................159
10.3.5 Individualpatientdatanetworkmetaanalysisasmonotherapyforfocal
epilepsy..............................................................................................................199
10.3.6 HealtheconomicevidenceofAEDsusedasmonotherapyforadultswith
newlydiagnosedfocalepilepsy.........................................................................200
10.3.7 Monotherapyforchildrenwithnewlydiagnosedfocalepilepsy......................206
10.3.8 HealtheconomicevidenceofAEDsusedasmonotherapyforchildrenwith
newlydiagnosedfocalepilepsy.........................................................................209
10.3.10 Newresearchrecommendations(forfulllistseesection2.11)........................221
10.4 Therapyforrefractoryfocalseizures................................................................................222
10.4.1 Introduction.......................................................................................................222
10.4.3 Matrixoftheevidence.......................................................................................222
10.4.4 SingleAEDtherapyforrefractoryfocalseizures...............................................226
10.4.5 HealthEconomicEvidenceforsingleAEDtherapyforrefractoryfocal
seizures..............................................................................................................228
10.4.6 Adjunctivetherapyinchildren,youngpeopleandadultswithrefractory
focalseizures.....................................................................................................229
10.4.7 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforadults
withrefractoryfocalepilepsy............................................................................268
10.4.8 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildren
withrefractoryfocalepilepsy............................................................................273
10.4.10 ResearchRecommendations(forfulllistseesection2.11)..............................283
10.5 GeneralisedTonicClonicSeizures(GTCS).........................................................................284
10.5.1 Introduction.......................................................................................................284
10.5.4 Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresin
adults.................................................................................................................287
10.5.5 Individualpatientdatanetworkmetaanalysisasmonotherapyfor
generalisedtonicclonicepilepsy.......................................................................308
10.5.6 Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresin
children..............................................................................................................310
TheEpilepsies
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10.5.7 Adjunctivetherapyforthetreatmentofgeneralisedtonicclonicseizures......310
10.5.8 HealtheconomicevidenceforAEDsusedasadjunctivetherapyinadults
withrefractorygeneralisedtonicclonicseizures..............................................315
10.6 AbsenceSeizures...............................................................................................................322
10.6.1 Introduction.......................................................................................................322
10.6.4 AEDsforthetreatmentofabsenceseizures.....................................................323
10.7 MyoclonicSeizures............................................................................................................329
10.7.1 Introduction.......................................................................................................329
10.7.4 Monotherapyforthetreatmentofmyoclonicseizures....................................330
10.7.5 Adjunctivetherapyforthetreatmentofmyoclonicseizures...........................331
10.8 Tonicoratonicseizures.....................................................................................................340
10.8.1 Introduction.......................................................................................................340
10.9 InfantileSpasms(Westsyndrome)...................................................................................345
10.9.1 Introduction.......................................................................................................345
10.9.3 Matrixoftheevidenceforadjunctivetherapy..................................................345
10.10 Dravetsyndrome(SMEI)...................................................................................................357
10.10.1 Introduction.......................................................................................................357
10.10.4 AdjunctivetreatmentofDravetSyndrome(SMEI)............................................358
10.11 LennoxGastautSyndrome................................................................................................363
10.11.1 Introduction.......................................................................................................363
TheEpilepsies
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10.11.4 AdjunctivetreatmentforLennoxGastautsyndrome.......................................364
10.11.5 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildren
withLennoxGastautsyndrome........................................................................369
10.12 Benignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeandlate
onsetchildhoodoccipitalepilepsy(Gastauttype)............................................................376
10.12.1 Introduction.......................................................................................................376
10.12.4 MonotherapyforthetreatmentofadultsandchildrenwithBECTS,
Panayiotopoulossyndromeandlateonsetchildhoodoccipitalepilepsy
(Gastauttype)....................................................................................................377
10.13 IdiopathicGeneralisedEpilepsy(IGE)...............................................................................397
10.13.1 Introduction.......................................................................................................397
10.13.2 MethodsoftheevidencereviewofIGE............................................................397
Matrixoftheevidenceforchildhoodabsenceepilepsy,juvenileabsenceepilepsyand
otherabsenceepilepsysyndromes...................................................................400
10.13.4 MonotherapyforthetreatmentofIGEinnewlydiagnosedpatients...............401
10.13.5 Adjunctivetherapyinchildren,youngpeopleandadultswithIGE..................405
10.13.6 HealtheconomicevidenceforAEDsusedasmonotherapyinthetreatment
ofpatientswithnewlydiagnosedIGE...............................................................406
10.13.7 Monotherapyforthetreatmentofchildhoodabsenceepilepsy,juvenile
absenceepilepsyandotherabsenceepilepsysyndromes................................409
10.13.8 Adjunctivetherapyforthetreatmentofchildhoodabsenceepilepsy,
juvenileabsenceepilepsyandotherabsenceepilepsysyndromes..................415
10.13.9 MonotherapyforthetreatmentofJuvenileMyoclonicEpilepsy(JME)............415
10.13.10 Monotherapy/adjunctivetherapyforthetreatmentofjuvenilemyoclonic
epilepsy(JME)....................................................................................................417
10.13.11 AdjunctivetreatmentforforthetreatmentofofJuvenileMyoclonic
Epilepsy(JME)....................................................................................................418
10.13.12 AEDsforthetreatmentofepilepsywithgeneralisedtonicclonicseizures
only....................................................................................................................419
10.13.13 Introduction.......................................................................................................419
10.13.16 Newrecommendationsandlinktoevidence...................................................419
10.14 Otherepilepsysyndromes................................................................................................443
10.14.1 Introduction.......................................................................................................443
TheEpilepsies
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10.15 Prolongedseizuresandconvulsivestatusepilepticus......................................................444
10.15.1 Introduction.......................................................................................................444
10.15.4 AEDsforthetreatmentofprolongedseizuresandconvulsivestatus
epilepticusinthecommunity............................................................................448
10.15.5 Treatmentofprolongedseizuresandconvulsivestatusepilepticusin
children(community)........................................................................................450
10.15.6 Treatmentofacuterepetitiveseizures(childrenandadults)...........................452
10.15.7 Treatmentofconvulsivestatusepilepticusinadultsinhospitals.....................452
10.15.8 Treatmentofconvulsivestatusepilepticusinchildren.....................................458
10.15.9 Treatmentofrefractorystatusepilepticus........................................................462
10.16 Nonconvulsivestatusepilepticus....................................................................................476
10.16.1 Introduction.......................................................................................................476
10.16.3 AEDsforthetreatmentofnonconvulsiveStatusEpilepticus(observational
study).................................................................................................................477
10.16.5 Genericprescribing............................................................................................477
10.17 Whenshouldanindividualwithepilepsybereferredforassessmentinatertiary
centre?..............................................................................................................................477
10.17.1 Introduction.......................................................................................................477
11 Theroleofnondrugtreatmentsinthemanagementoftheepilepsies................................481
11.1 Introduction......................................................................................................................481
11.2 Doesthetreatmentofepilepsyinadultsorchildrenwithpsychologicalmethodslead
toareductioninseizurefrequencyand/orabetterqualityoflife?................................481
11.3 KetogenicDiet...................................................................................................................482
11.3.1 Introduction.......................................................................................................482
11.3.6 Ketogenicdietinadults.....................................................................................488
11.4 Inpeoplewithdrugresistantepilepsy,isvagusnervestimulation(VNS)effectiveas
anadjunctivetreatment?..................................................................................................488
12 Informationneedsofindividuals,families,andcarers.........................................................493
12.1 Introduction......................................................................................................................493
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12.2 Informationneedsoftheindividualwithepilepsy,thefamily,thecarer,andspecial
groups...............................................................................................................................493
12.3 Whatinformationisrequiredatdifferentstagesofthecarepathway............................496
12.4 WhatistheriskofSUDEPinindividualswithepilepsy.....................................................501
13 Womenofchildbearingagewithepilepsy...........................................................................504
13.1 Introduction......................................................................................................................504
13.2 Whatinformationandcounsellingshouldbegivenandwhen?......................................504
13.3 Whatissuesshouldbeconsideredinwomenwhomaybecomepregnantorwhoare
breastfeeding?.................................................................................................................507
13.4 Increasedriskofseizuresduringpregnancyorwhilstbreastfeeding...............................508
13.5 TeratogeniceffectsofAEDswhilstpregnant....................................................................511
13.5.1 Introduction.......................................................................................................511
13.5.3 Comparisonbetweenspecificmonotherapiesondevelopmental/cognitive
outcomes...........................................................................................................516
13.5.4 Anymonotherapyexposureversusnoexposureingeneralpopulation..........519
13.6 DoAEDsinteractwithcontraceptives?.............................................................................533
13.7 Doesepilepsyincreasetheriskofcomplicationsinpregnancy?......................................537
13.7.1 Arewomenwithepilepsyatincreasedriskofcomplicationsduringthe
pregnancyandlabour?......................................................................................538
13.7.2 Whenshouldscreeningforstructuralfetalanomaliesbeperformedin
pregnantwomenwithepilepsy?.......................................................................538
13.8 Whenshouldfolicacidbestarted?...................................................................................539
13.9 Whatarethedangersofseizuresinwomenwhoarepregnantorpostnatal?...............539
13.10 Whatistheroleofdrugmonitoringinpregnantwomenwithepilepsy?........................541
13.11 ShouldoralorparenteralvitaminKbeused?..................................................................542
13.12 Whatistheriskofofinheritingepilepsy?........................................................................542
13.13 Whatistheroleofjointepilepsyandobstetricclinicsinthecareofwomenwith
epilepsywhoarepregnant?..............................................................................................543
14 Children,youngpeopleandadultswithlearningdisabilitiesandepilepsy...........................544
14.1 Introduction......................................................................................................................544
14.2 Whoshouldmanageandtreatepilepsyinchildren,youngpeopleandadultswith
learningdisabilities?..........................................................................................................544
14.2.1 Dopeoplewithlearningdisabilitiesandepilepsywhoreceivecarefroma
specialistinlearningdisabilitiesandepilepsycomparedwithcarefroma
nonspecialisthavedifferencesinprocessesandoutcomesofcare?..............544
14.3 Ismakingadiagnosismoredifficultinpeoplewithlearningdisabilities?........................545
14.3.1 Aretheratesofmisdiagnosishigherforpeoplewithlearningdisabilitiesand
epilepsywhencomparedwithpeoplewithepilepsywhodonothave
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learningdisabilities?..........................................................................................545
14.3.2 Whatarethepracticaldifficultiesinestablishingthediagnosisinthisgroup? 545
14.4 Aretheredifficultiesindoinginvestigationsinthisgroup?.............................................546
14.4.1 Aretherea)difficultiesinconductinginvestigations(EEG;neuroimaging);b)
difficultiesininterpretinginvestigations(EEG;neuroimaging)inpeoplewith
learningdisabilityandepilepsywhencomparedwithpeoplewithepilepsy
whodonothavelearningdisabilities?..............................................................546
14.5 Whatarethemainfactorstoassesswhenmakingacareplanforanindividualwith
learningdisabilitiesandepilepsy?....................................................................................547
14.6 Pharmacologicalmanagementofpeoplewithepilepsyandlearningdisabilities............547
14.6.1 Introduction.......................................................................................................547
14.6.5 Isepilepsymoredifficulttotreatinpeoplewithlearningdisabilities?............554
14.6.6 Likelihoodofremissionofseizures....................................................................554
14.7 Whataretheadditionalmanagementissuesinpeoplewithlearningdisabilities?.........555
14.7.1 Isthereincreasedmortalityinpeoplewithlearningdisabilitiesand
epilepsy?............................................................................................................556
14.7.2 Whatmanagementissuesinpeoplewithlearningdisabilitiesdohealthcare
practitionersandcarersviewasimportant?.....................................................557
15 Youngpeoplewithepilepsy.................................................................................................558
15.1 Introduction......................................................................................................................558
15.2 Isadifferentapproachtomanagementrequiredinadolescence?..................................558
15.3 Whatarethefactorsthataffectadherencetotreatmentinadolescentswith
epilepsy?...........................................................................................................................558
15.4 Isthereanyevidenceofeffectivenessforanygivenstrategiesproposedtoimprove
outcomesforadolescents?...............................................................................................559
15.5 Whatarethespecialneedsorinformationrequirementsofthisgroup?........................559
15.6 Shouldthediagnosisofepilepsyberevisitedinthisgroup?............................................561
16 Olderpeople.......................................................................................................................563
16.1 Pharmacologicalmanagementofepilepsyinolderpeople..............................................563
16.1.1 Introduction.......................................................................................................563
17 Peoplefromblackandminorityethnicgroups.....................................................................572
17.1 Introduction......................................................................................................................572
17.2 Whataretheinformationandserviceprovisionneedsofpeoplefromblackand
minorityethnicgroups?....................................................................................................572
18 Thecareprocessforpeoplewithepilepsy...........................................................................574
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18.1 Introduction......................................................................................................................574
18.2 Whatfeaturesofthecareprocessinprimarycare/sharedcareleadtoimproved
healthoutcomesforadultsandchildrenwithepilepsy?..................................................574
18.2.1 Whatevidenceisthereregardingthequalityofcarecurrentlyprovidedin
primarycare?.....................................................................................................575
18.2.2 Whatprocessofcarehasbeenproposedtoimproveoutcomesforadults
andchildrenwithepilepsyinprimarycare?.....................................................576
18.3 Whatfeaturesofthecareprocessinsecondaryandtertiarycareleadtoimproved
healthoutcomesforadultsandchildrenwithepilepsy?..................................................577
18.3.1 Whatevidenceisthereofthequalityofcarecurrentlyprovidedin
secondary/tertiarycare?...................................................................................578
andchildrenwithepilepsyinsecondary/tertiarycare?....................................581
18.4 WhatfeaturesofthecareprocessinA&Eleadtoimprovedhealthoutcomesfor
adultsandchildrenwithepilepsy?...................................................................................583
18.4.1 Qualityofcarecurrentlyprovidedinandaccidentandemergency
departments(A&E)............................................................................................583
andchildrenwithepilepsyinA&E?...................................................................585
18.5 Howeffectiveareindividual/selfmanagementplansinadultsandchildrenwith
epilepsy?...........................................................................................................................585
18.5.1 Introduction.......................................................................................................585
18.5.2 Doadultsandchildrenwithepilepsywhoareeducatedinselfmanagement,
whencomparedwiththosewhodonot,havebetterhealthoutcomes?.........586
19 Glossary..............................................................................................................................588
20 Referencelist......................................................................................................................606
TheEpilepsies
Guidelinedevelopmentgroupmembers
15
GuidelineDevelopmentGroup(GDG)members(2004)
MsKathyBairstow,nominatedbyEpilepsyAction(BritishEpilepsyAssociation)
PatientRepresentative,Leeds
MsBernieConcannon,nominatedbytheRoyalCollegeofNursing
ClinicalNurseSpecialist(PaediatricEpilepsy),BirminghamChildrensHospital
MrIanCostello,nominatedbytheNeonatal&PaediatricPharmacistsGroup
ChiefPharmacist,CentreforPaediatricResearch,SchoolofPharmacy,London
DrHelenCross,nominatedbytheRoyalCollegeofPaediatrics&ChildHealth
SeniorLecturer&HonoraryConsultantinPaediatricNeurology,InstituteofChildHealthandGreat
OrmondStreetHospitalforChildren,London
ProfessorJohnDuncan,nominatedbytheRoyalCollegeofPhysicians
ProfessorofNeurology,TheNationalHospitalforNeurologyandNeurosurgery,London
DrAmandaFreeman,nominatedbytheRoyalCollegeofPaediatricsandChildHealth
ConsultantPaediatrician,StMarysHospital,Portsmouth
MsSallyGomersall,nominatedbytheNationalSocietyforEpilepsy
PatientRepresentative,Newark
MsJaneHanna,nominatedbyEpilepsyBereaved
PatientRepresentative,Wantage
MrWilliamHarkness,nominatedbytheSocietyofBritishNeurologicalSurgeons
ConsultantNeurologicalSurgeon,GreatOrmondStreetHospitalforChildren,London
DrPeterHumphrey,nominatedbytheAssociationofBritishNeurologists
ConsultantNeurologist,TheWaltonCentreforNeurology&Neurosurgery,Liverpool
DrTanzeemRaza,nominatedbytheRoyalCollegeofPhysicians
ConsultantPhysician,RoyalBournemouthHospital
MrPeterRogan,nominatedbytheJointEpilepsyCouncil
PatientRepresentative,Ormskirk
DrHenrySmithson,nominatedbytheRoyalCollegeofGeneralPractitioners
GuidelineDevelopmentGroupLead
GeneralPractitioner,YorkandHonoraryClinicalSeniorLecturer,HullYorkMedicalSchool
TheEpilepsies
16
GuidelineDevelopmentGroup(GDG)members(2012)
DrAmandaFreeman
ConsultantPaediatrician,DepartmentofPaediatrics,QueenAlexandraHospital,Portsmouth.
MrsDianeFlower
LeadChildren'sEpilepsySpecialistNurse,RoyalGwentHospital,Newport,SouthWales,and
Children'sEpilepsySpecialistNurse,BristolRoyalHospitalforChildren,Bristol.
DrGregRogers
GPandGeneralPractitionerwithaSpecialInterestinEpilepsy[GPwSI]EasternandCoastalKentPCT
ProfessorHelenCross
ThePrinceofWales'sChairofChildhoodEpilepsy,UCLInstituteofChildHealth,GreatOrmondStreet
HospitalforChildren&NationalCentreforYoungPeoplewithEpilepsy.HeadofNeurosciencesUnit,
UCLInstituteofChildHealth,London.
ProfessorIanChiKeiWong
DirectorandProfessorofPaediatricMedicinesResearch,CentreforPaediatricPharmacyResearch,
TheSchoolofPharmacy,TheUniversityofLondon,UCLInstituteofChildHealth,GreatOrmond
StreetHospitalNHSTrustforChildren(UntilAugust2011).DepartmentofPharmacologyand
Pharmacy,LiKaShingFacultyofMedicine,UniversityofHongKong.
ProfessorJohnDuncan
ProfessorofNeurology,DepartmentofClinicalandExperimentalEpilepsy,UCLInstituteof
Neurology,London.ConsultantNeurologist,NationalHospitalforNeurologyandNeurosurgery.
MedicalDirector,TheEpilepsySociety
DrMargaretJackson
ConsultantNeurologist,NewcastleUponTyneHospitalsNHSTrust
MrMichaelHarnor
Patientmember.Retireduniversityacademic.Neurologicalcharitiestrustee
DrNickKosky(chair)
ConsultantPsychiatrist,PrisonMentalHealthInreachTeam,MedicalDirector
DorsetCommunityHealthServices,NHSDorset
DrRichardAppleton
ConsultantPaediatricNeurologist.TheRoaldDahlEEGDepartmentPaediatricNeurosciences
Foundation.AlderHeyChildren'sNHSFoundationTrust,Liverpool.
MrsSallyGomersall
Patientmember.EpilepsySocietyTrusteeandEpilepsyBereavedEducation&AwarenessManager
MrSeanMackey(untilMarch2010)
IndependentPharmacistconsultant.Dalton
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MrsTraceyTruscott
HeadofEpilepsyNursingService,NHSEasternandCoastalKentCommunityservices
GuidelineDevelopmentGroup(GDG)cooptees(2004)
ProfessorGusBaker,nominatedbytheBritishPsychologicalSociety
ProfessorofNeuropsychology,UniversityofLiverpool
ProfessorFrankBesag,nominatedbytheRoyalCollegeofPsychiatrists
ConsultantPsychiatrist,Bedfordshire&LutonCommunityNHSTrustandVisitingProfessorof
Neuropsychiatry,UniversityofLuton
ProfessorShoumitroDeb,nominatedbytheRoyalCollegeofPsychiatrists
ProfessorofNeuropsychiatryandIntellectualDisability,UniversityofBirmingham
DrDavidFinnigan,nominatedbyPRODIGY
GeneralPractitioner,SowerbyCentreforHealthInformatics,UniversityofNewcastle
MrAndrewGreen,nominatedbytheCollegeofOccupationalTherapists
OccupationalTherapist,FrenchayHospital,Bristol
DrJoJarosz,nominatedbytheRoyalCollegeofRadiologists
ConsultantNeuroradiologist,KingsCollegeHospital,London
DrAndrewLloydEvans,nominatedbytheRoyalCollegeofPaediatricsandChildHealth
ConsultantPaediatrician,RoyalFreeHospital,London
DrDavidMcCormick,nominatedbytheInternationalLeagueAgainstEpilepsy(ILAE)
ConsultantPaediatrician,EastKentHospitalsNHSTrust,Kent
MrJamesOates,nominatedbytheRoyalCollegeofNursing
EpilepsyLiaisonNurse(Adult),HullRoyalInfirmary
DrGillianPenney,nominatedbytheRoyalCollegeofObstetriciansandGynaecologists
SeniorLecturer,ScottishProgrammeforClinicalEffectivenessinReproductiveHealth,Universityof
Aberdeen
MsLindaPerry,nominatedbytheNationalCentreforYoungPeoplewithEpilepsy(NCYPE)
DirectorofMedicalServices,NCYPE,StPiersLane,Lingfield
MrMartinShalley,nominatedbytheBritishAssociationforAccident&EmergencyMedicine
ConsultantinA&EMedicine,BirminghamHeartlandsHospital
ProfessorRaymondTallis,nominatedbytheBritishGeriatricsSociety
ProfessorofGeriatricMedicine,UniversityofManchester
GuidelineDevelopmentGroup(GDG)cooptees(2012)
ProfessorFrankBesag
TheEpilepsies
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ConsultantNeuropsychiatristChildrensLearningDisabilityService.TwinwoodsHealthResource
Centre,Bedford.
DrMichaelMarsh
ConsultantinObstetricsandGynaecology,King'sCollegeHospital,London
DrAzaJJAbdulla
ConsultantPhysicianandGeriatrician.DepartmentofElderlyMedicine,SouthLondonHealthcare
NHSTrust.PrincessRoyalUniversityHospital.Kent
ProfessorTonyMarson(ExternalPeerReviewer)
ProfessorofNeurology.UniversityofLiverpoolandCoordinatingEditorCochraneEpilepsyGroup
DrCatrinTudurSmith(ExternalPeerReviewer)
SeniorLecturerinBiostatistics.UniversityofLiverpoolandStatisticalEditorCochraneEpilepsyGroup
DrGPSinha(ExternalPeerReviewer)
ConsultantPaediatrician.WalsallHealthcareNHSTrust,ManorHospital
NationalCollaboratingCentreforPrimaryCare(NCCPC)ProjectTeam(2004)
ProfessorRichardBaker,Director,NCCPC
Director,DepartmentofHealthSciences,UniversityofLeicester
MsJanetteCamossoStefinovic,InformationLibrarian,NCCPC
InformationLibrarian,DepartmentofHealthSciences,UniversityofLeicester
MsNicolaCostin,SystematicReviewer,NCCPC(January2004onwards)
ResearchAssociate,DepartmentofHealthSciences,UniversityofLeicester
MsAriadnaJuarezGarcia,HealthEconomist,NCCPC(May2003toJuly2004)
ResearchAssociate,DepartmentofHealthSciences,UniversityofLeicester
MsElizabethShaw,SeniorSystematicReviewer,NCCPC
ResearchFellow,DepartmentofHealthSciences,UniversityofLeicester
DrTimStokes,DeputyDirector,NationalCollaboratingCentreforPrimaryCare,Leicester(NCCPC)
ProjectLead
SeniorLecturerinGeneralPractice,DepartmentofHealthSciences,UniversityofLeicester
DrAllanWailoo,HealthEconomist,NCCPC(untilMay2003)
LecturerinHealthEconomics,SchoolofHealthandRelatedResearch,UniversityofSheffield
NationalClinicalGuidelineCentreProjectteam(2012)
DrJenniferHill(untilMarch2011)
GuidelinesOperationsDirector
MsSusanLatchem(fromApril2011)
TheEpilepsies
19
GuidelinesOperationsDirector
MsVanessaDelgadoNunes
SeniorResearchFellowandProjectManager
MsJulieNeilson
SeniorResearchFellow
MsLauraSawyer
SeniorHealthEconomist
DrGrammatiSarri
SeniorResearchFellow
MrCarlosSharpin
SeniorInformationScientistandResearchFellow
TheEpilepsies
Acknowledgements
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Acknowledgements
2004
TheGuidelineDevelopmentGroupwouldliketothankNancyTurnbullandCharmaineLarmentofthe
NationalCollaboratingCentreforPrimaryCare,RoyalCollegeofGeneralPractitionersforalltheir
hardworkinarrangingGDGmeetingsandsupportingtheguidelinedevelopmentprocess.
TheProjectTeamwouldliketothankMsVickiCluley,UniversityofLeicester,forsecretarialsupport
andDrAliAlGhorrandDrMorayNairn,ScottishIntercollegiateGuidelinesNetwork,Edinburghfor
theirhelpinsharingrelevantsearchesandevidencereviewsontheepilepsiesinadultsandchildren.
TheteamwouldalsoliketothankDrAllanWailloo,UniversityofSheffieldforhisinitialhealth
economicinputandMsNicolaCostinforherhelpwiththeseconddraft.
2012
TheGuidelineDevelopmentGroupandprojectteamwouldliketothankDrLeeYeeChong,Ms
KatrinaSparrow,MrsFulviaRonchi,MsAbigailJones,MrDavidWonderling,MrTimReason,Ms
ElisabettaFenu,MrsLizAvital,MsHatiZorbaandDrNormaOFlynnforalltheirhelpandsupport
throughouttheguidelinedevelopmentprocess.TheprojectteamwouldalsoliketothankProfessor
TonyMarsonandDrCatrinTudurSmithforprovidingfurtherdatafortheevidenceanalysesandfor
actingasexpertpeerreviewerstotheguidelineupdate.
TheEpilepsies
Introduction
21
1 Introduction
1.1 Definitionofepilepsy
2004
Anepilepsyisdefinedasaneurologicalconditioncharacterisedbyrecurrentepilepticseizures
unprovokedbyanyimmediatelyidentifiablecause.Anepilepticseizureistheclinicalmanifestation
ofanabnormalandexcessivedischargeofasetofneuronsinthebrain
1
.
Epilepsyshouldbeviewedasasymptomofanunderlyingneurologicaldisorderandnotasasingle
diseaseentity.Thetermepilepsiesisusedinthetitleoftheguidelinetoreflectthis.
1.2 Clinicalaspects
2004
Theclinicalpresentationdependsonanumberoffactors,chiefly:thepartsofthebrainaffected,the
patternofspreadofepilepticdischargesthroughthebrain,thecauseoftheepilepsyandtheageof
theindividual.
2
Theclassificationoftheepilepsiesiscontroversialandhastendedtofocusonboth
theclinicalpresentation(typeofepilepticseizure)andontheunderlyingneurologicaldisorder
(epilepsiesandepilepsysyndromes).
3
Epilepsyisprimarilyaclinicaldiagnosisbasedonadetaileddescriptionoftheeventsbefore,during
andafteraseizuregivenbythepersonand/orwitness.Electroencephalogram(EEG),magnetic
resonanceimaging(MRI)andcomputedtomography(CT)areusedtoinvestigateindividualswith
knownandsuspectedepilepsy.Thediagnosisofepilepsyrequiresthatseizuretype,epilepsy
syndromeandanyunderlyingcausearedetermined.
4
Itcanbedifficulttomakeadiagnosisof
epilepsyandmisdiagnosisiscommon.
5
TheUKNationalGeneralPracticeStudyofEpilepsyfoundthat60%ofpeoplewithepilepsyhave
convulsiveseizures,ofwhichtwothirdshavefocalepilepsiesandsecondarilygeneralisedseizures
andtheotherthirdwillhavegeneralisedtonicclonicseizures.
1,6,7
Aboutonethirdofcaseshaveless
thanoneseizureayear,onethirdhavebetweenoneand12seizuresperyearandtheremainder
havemorethanoneseizurepermonth.
8
Inadultsandchildrenwithepilepsy,most(70%)willenterremission(beingseizurefreeforfiveyears
onorofftreatment)but30%developchronicepilepsy.
9
Thenumberofseizuresinthe6months
afterfirstpresentationisanimportantpredictivefactorforbothearlyandlongtermremissionof
seizures.
10
TheUKNationalGeneralPracticeStudyofEpilepsyfoundthatthemajority(60%)ofpeoplewith
newlydiagnosedorsuspectedepilepticseizureshadepilepsywithnoidentifiableaetiology.Vascular
diseasewastheaetiologyin15%andtumourin6%.Amongoldersubjectstheproportionwithan
identifiablecausewasmuchhigher:49%wereduetovasculardiseaseand11%totumours.
6
Themainstayoftreatmentforepilepsyisantiepilepticdrugs(AEDs)takendailytopreventthe
recurrenceofepilepticseizures.SincethedevelopmentofMRItherehasbeenanincreaseinthe
numberofpeopleidentifiedwithepilepsywhocouldbenefitfromsurgery.Thereisalsoaneedto
ensureprovisionofappropriateinformationtopeoplewithepilepsyandtheircarers.IntheUKthe
voluntarysectorhasanimportantroleinhelpingpeoplewithepilepsy.
11
TheEpilepsies
Introduction
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Since2004,discussionwithregardtotheclassificationoftheepilepsieshascontinued.With
advancesintechnology,particularlyimagingandgenetics,someoftheoldertermininologyeg
idiopathic/symptomatic/cryptogenic,hasbecomeredundantingeneraluse.Furthermore,although
seizuresmaybefocalorgeneralisedinonset,suchterminologycannotbeappliedtosyndromes.The
termspartial,complexandsimplearealsoreplacedsimplybyfocal.
Ensuringanaccuratediagnosisisimportantforplanningmanagement.Althoughtheprimaryaimis
todiagnosearecognisableelectroclinicalsyndrome,itisrecognisedthismaynotbepossibleinanot
insignificantnumberofindividuals.Theexactsyndromediagnosismaynotbereadilyapparentat
presentation.Moreover,insome,thecausemaybeofequalimportance.Amoredescriptive
approachhasbeenrecommended,retainingtheelectroclinicalsyndromeswherepossiblebutwhere
underlyingaetiologyistakenintoaccount
12
.Thishasimplicationsfortreatmentinanincreasing
numberofsituations.
1.3 Epidemiology
2004
TheepilepsiescomprisethemostcommonseriousneurologicaldisordersintheUK.Itaffects
between260,000and416,000peopleinEnglandandWales(AppendixG).
13
Theincidenceofepilepsyisabout50per100,000perannum.
14
Theincidenceishighinchildhood,
decreasesinadulthoodandrisesagaininolderpeople.
6
Theusualprevalencefiguregivenforactive
epilepsyintheUKis510casesper1,000.
11
Epidemiologicalstudiesconsistentlyreportastandardisedmortalityrate(SMR)of24for
epilepsy.
15,16
Innewlydiagnosedepilepsy,deathislargelyattributabletotheunderlyingdisease(for
example,vasculardisease,tumour).Inchronicepilepsy,however,themaincauseofexcessmortality
isdeathduringaseizure:suddenunexpecteddeathinepilepsy(SUDEP).
17
SUDEPisestimatedto
accountfor500deathsayearintheUKandhasbeenthesubjectofarecentNationalSentinel
ClinicalAudit.
18
Epilepsyisnotalwaysassociatedwithsignificantmorbidity.Manypeoplewithepilepsycontinueto
havehighlyproductiveandfruitfullives,inwhichtheepilepsydoesnotinterferetoagreatextent.
However,thereisanassociatedmorbiditywhichmaybesignificantinsomeindividuals,andmaybe
duetotheeffectsofseizures,theirunderlyingcauseand/ortreatment.Epilepsymaysometimes
resultinsignificantdisability,socialexclusionandstigmatisation.Peoplewithepilepsycommonly
encounterproblemsinthefollowingareas:education;employment;driving;personaldevelopment;
psychiatricandpsychologicalaspectsandsocialandpersonalrelationships.
11
Inaddition,itis
importanttorecognisethatpeoplewithepilepsymayhavecomorbidities.Forexample,children
withepilepsymayhaveattentionaldifficultiesorlearningdifficulties.
19
2012
AnalysisofdatafromtheQualityandOutcomesFramework(QOF)epilepsydiagnosticcodessuggest
aprevalenceofdiagnosedepilepsyinpeopleaged18andoverof1.15%.Theuseofdatafrom
administrativedatabasessuchastheQOF,however,whichincorporatenonvalidatedepilepsy
diagnosticcodesfortheestimationofprevalenceratesisfraughtwithdifficultyandthereisa
tendencyforsuchdatabasestooverestimateprevalence.Therearenodirectestimatesofthe
epilepsyprevalenceforEngland.Someexistingdatausingvalidatedmethods,suggesttheprevalence
TheEpilepsies
Introduction
23
tobebetween0.7to0.8%forthewholepopulation
*
BasedonapopulationinEnglandof
51,810,000in2009(<http://www.statistics.gov.uk/downloads/theme_population/mid09ukeng
walesscotnorthernireland240610.zip)thiswouldsuggesttherearebetween362,000and
415,000peoplewithepilepsyinEngland.Inaddition,therewillbeindividuals,estimatedtobea
further530%,soamountingtouptoanother124,500,whohavebeendiagnosedwithepilepsy,but
inwhomthediagnosisisincorrect
.Therateoflearningdisabilityintheepilepsypopulationremains
high;inparticularchildrenwithearlyonsetepilepsyarehighlylikelytoexperience
neurodevelopmentalcompromise
20
.Eveninthosewithlateronset,numberswithanydegreeof
learningdisabilityarethoughttobeunderestimated.Theprevalenceofbehaviourdisorderin
childrenwithepilepsyalsoremainshigh.TheBritishchildandadolescentmentalhealthsurvey,
questioning10,438childrenintheUKage515years,foundaprevalenceofbehaviourdisorderin
childrenwithpureepilepsytobeuptothreetimesthatofanotherchronicdisorder(diabetes,
10.2%)orthegeneralpopulation(9.3%)andinepilepsyplus,almostsixtimes(56%)
21
.Bothmaybe
compoundedbymedicationandmustthereforebetakenintoconsiderationwhendiscussing
medicationtouse.
Anincreasingpopulationistheelderly,inwhomtheincidenceofnewonsetepilepsyisincreasing,
althoughthepossibilityofmisdiagnosisalsoremainshigh
22
.Specialconsiderationneedstobegiven
whenprescribinganymedicationwithinthispopulation,notleastbecauseofdruginteractionand
pharmacokineticissues,andthissimilarlyappliestoantiepilepticmedication.Increasinginformation
isalsobeinggatheredontheeffectofantiepilepticdrugstakenbyamotherontheunbornchild;
furtherdatahavetobeaccumulatedtoensureaccurateinformationontreatmentanditspossible
effectsaregiventoawomanpriortoconceptionsosheisabletomakechoices
23
.
1.4 Costofepilepsy
2004
ThemedicalcosttotheNHSin1992/1993ofnewlydiagnosedepilepsyinthefirstyearofdiagnosis
wascalculatedas18millionandthetotalannualcostofestablishedepilepsyestimatedat2billion
(directandindirectcosts),over69%ofwhichwasduetoindirectcosts(unemploymentandexcess
mortality).
24
Thecostsoftreatingepilepsyarelikelytoincreasegiventhenewtrendsinprescribingpatterns
towardsnewerandmoreexpensiveAEDs.Oneofthelateststudiesintheliterature
25
estimatedthat
thecostsofprescribingcostsinthecommunityhasrisenthreefoldinthelast10years,from26
millionto86million,ayearlyincreasefivetimestherateofinflation.Theauthorconcludedthat
thiswaslargelyexplainedbyarapidincreaseintheprescribingofnewerAEDs.Overtheperiod1991
to1999,thenumberofAEDprescriptionitemsinEnglandroseby33%,and42%ofthisincreasewas
accountedforbyincreasedprescribingofnewAEDs.ThevolumeofolderAEDsprescribedincreased
from4.8millionprescriptionitemsin1991to5.7millionin1999,comparedwithmorethana
hundredfoldincreaseinprescribingofnewAEDsfrom5,400to721,000overthesameperiod.
25
*
MacDonaldBK,CockerellOC,SanderJW,ShorvonSD.Theincidenceandprevalenceofneurologicaldisorders
inaprospectivecommunitybasedstudyintheUnitedKingdom.Brain2000;123:665676
PurcellB,GaitatzisA,SanderJW,MajeedA.EpilepsyprevalenceandprescribingpatternsinEnglandand
Wales.HealthStatistics2002;15:2331.
ChowdhuryFA,NashefL,ElwesRD.Misdiagnosisinepilepsy:areviewandrecognitionofdiagnostic
uncertainty.EurJNeurol.2008Oct;15(10):103442.
TheEpilepsies
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Since2004,afurtherfiveAEDshavebecomelicensedforuseintheUKforthetreatmentofepilepsy.
AmorerecentcostanalysisestimatedthetotalcostofepilepsyinEuropein2004was15.5billion
Euros;thecostofantiepilepticdrugusebeing400,000
26
.Economiccosthoweverisonlyoneaspect
tobeconsideredwhendiscussingthecostofepilepsytotheindividual.Lostemployment,hospital
visitsandoveralllifedisruption/qualityoflifeneedtobecarefullyconsidered.Studiesreviewing
qualityoflifeofindividualswithepilepsyhighlightimportantdeterminantstobeseizurefreedom
andmedicationsideeffectsamongstothers
27
.Seizurefreedomshouldbestrivedforineach
individualwhopresentswithepilepsy,althoughnotattheexpenseofexcessivesideeffects.Choices
ofantiepilepticmedicationthereforehavetomeasuredandtailoredtotheindividual,informedby
dataavailablefromtheexistingevidencebase.
1.5 HealthServicesforpeoplewithepilepsy
2004
Since1953sixmajorreports
11,18,2831
havemaderecommendationstoimproveservicesforpeople
withepilepsyintheUK,buttheseservicesremainpatchyandfragmented.
13
TheDepartmentof
Healthhasrecentlypublishedanactionplan
32
toimproveservicesforpeoplewithepilepsyin
responsetotheNationalSentinelClinicalAudit(SUDEPreport).
18
Akeyaimoftheauditwastoestablishwhetherdeficienciesinthestandardofclinicalmanagement
oroverallpackageofhealthcarecouldhavecontributedtodeaths.TheissuesraisedbytheSUDEP
reportastheyrelatetoprimaryandsecondarycarearesummarisedhere.
2012
Since2004,theclinicalguidelinerecommendationshaveprovidedaframeworkbywhichepilepsy
servicescanbeimproved.Howeverservicesremainpatchy;afurtherreportin2008bytheAllParty
ParliamentaryGrouponepilepsy(wastedmoney,wastedlives)recognisedthatinsomeareasmany
oftherecommendationsaspublishedin2004hadnotbeenimplemented,andthatanearlyreview
wasrequiredastotheprogressofimplementationoftheNICEguidelinesinEngland&Wales.
Furthermore,thewiderneedfortrainingwasalsorecognised.CurrentlyHQIPincollaborationwith
theBritishPaediatricNeurologyAssociationandtheRoyalCollegeofPaediatricsandChildHealth
haveinitiatedanationalauditofchildrensservices(Epilepsy12),measuredagainstvarious
performancemeasuresasdefinedbythe2004guideline,duetopublishin2014.
1.5.1 Primarycare
2004
Generalpractitioners(GPs)haveacentralroleintheprovisionofmedicalcaretoadultswith
epilepsy.ThenewGPcontractincludesqualitymarkers,andhencefinancialincentive,forthe
managementofepilepsyinprimarycare.Theyalsohaveanimportant,althoughmorelimited,role
inthemanagementofepilepsyinchildren.AGPwhohasalistof2,000peoplecanexpecttocarefor
between10to20peoplewithepilepsywhoareontreatmentandtoseeonetotwonewcasesper
year.
11
TheSUDEPreportfoundthatthemainproblemsinprimarycareforpeoplewithepilepsywere:lack
oftimelyaccesstoskilledspecialists;sparseevidenceofstructuredcareplans;triggersforreferral
weresometimesmissed,andtherewerefailuresofcommunicationbetweenprimaryandsecondary
care.
18
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Whotakesprimaryresponsibilityforindividualswithepilepsymaydependonlocalnetworksofcare.
Inchildren,responsibilityremainsprimarilywithinsecondarycare.Traininghasbeenstandardised
withcoursesthroughtheBritishPaediatricNeurologyAssociationandothers.Transitionofcareinto
adulthoodmayproveproblematichowever,asdifferinggroupsofindividualadultsmayfallwithin
theremitofdifferingprofessionalgroupsandteamsegadultswithlearningdisability,andthe
elderly.SomePrimaryCareTrustshavedevelopedtheroleoftheGPwithaspecialinterestinthe
epilepsies(GPSIES)whoareresponsibleforindividualswithepilepsy.Definedcarepathwaysfor
individualspresentingwithseizuresarerecommended,frominitialdiagnosistocomplexcare(NICE
2004).
1.5.2 Secondarycare
2004
Themajorityofpeoplewithepilepsyreceivemostoftheirinitialcareinsecondarycareandthose
whoseseizuresarenotwellcontrolledcontinuetoreceiveongoingcareinsecondarycare.The
SUDEPreportidentifieddeficienciesincareprovidedtobothadultsandchildreninsecondarycare.
18
Amajorityofadults(54%,84/158)hadinadequatecare,whichledtotheconclusionthat39%of
adultdeathswereconsideredpotentiallyorprobablyavoidable.Themaindeficienciesidentified
were(indescendingorderoffrequency):inadequateaccesstospecialistcare,inadequatedrug
management,lackofappropriateinvestigations,noevidenceofapackageofcare,inadequate
recordingofhistories,adultswithlearningdifficultieslostintransferfromchildtoadultservices,
andoneormoremajorclinicalmanagementerrors.
Amajorityofchildren(77%,17/22)hadinadequatecare,whichledtotheconclusionthat59%of
deathsinchildrenwereconsideredpotentiallyorprobablyavoidable.Themaindeficiencies
identifiedwere(indescendingorderoffrequency):inadequatedrugmanagement,inadequate
accesstospecialistcare,andinadequateinvestigations.
Therewasconcernthatdocumentationwaspoorinbothprimaryandsecondarycare;only1%of
hospitalrecordsforadultsshowedthatSUDEPhadbeendiscussed.
2012
Criteriabywhichindividualsshouldbereferredintotertiarycarewereincludedinthe2004
guideline.Careofindividualswithepilepsywillbeoptimisedwheretheseguidelinesarefollowedand
carepathwaysareinplace.Auditofcareisyettobeundertakenhowever;HQIPincollaborationwith
BritishPaediatricNeurologyAssociationandtheRoyalCollegeofPaediatricsandChildHealthhave
initiatedanauditof12outcomesfromtheNICEguidelinetobeconductedthroughouttheUKin
children(Epilepsy12)tobecompleteby2014.
1.6 TheSANADtrial
TheSANADtrialwasapragmatic,randomised,unblinded,parallelgroupclinicaltrialcomprisingtwo
arms(onecomparingnewAEDswithcarbamazepineandtheothercomparingnewerAEDswith
sodiumvalproate).ItwascommissionedandsponsoredbytheNHSR&DHealthTechnology
AssessmentProgramme,butalsosupportedbythepharmaceuticalcompanieswithAEDsincludedin
thestudy,whocontributedapproximately20%ofthetotalcostsofthestudy.Itreceivedappropriate
multicentreandlocalethicsandresearchcommitteeapprovals,andpatientsgaveinformedconsent
toinclusionandtolongtermfollowup.Italsoachievedtheinvolvementofalargenumberof
TheEpilepsies
Introduction
26
physiciansforalongtermcollaboration.Themethodologyofthestudyinvolvedphysiciansdeciding
ondiagnosisofanindividualwithepilepsy,andwhethertheirdrugofchoicewouldbesodium
valproateorcarbamazepine.Ifthechoicewassodiumvalproate,individualswererandomisedto
receivesodiumvalproate,lamotigineortopiramate(ArmA);ifthechoicewascarbamazepinethen
theindividualwouldberandomisedtocarbamazepine,gabapentin,lamotrigine,oxcarbazepineor
topiramate.(ArmB).
Atotalof1721patientswererecruitedtoArmAand716toArmB.ArmArecruited88%ofpatients
withsymptomaticorcryptogenicpartialepilepsiesand10%withunclassifiedepilepsy.ArmB
recruited63%ofpatientswithidiopathicgeneralisedepilepsiesand25%withunclassifiedepilepsy.
Thestudyprovidesevidencethatlamotriginemaybeaclinicalandcosteffectivealternativetothe
existingstandarddrugtreatmentforfocalseizures,carbamazepine.Some88%ofpatientsinArmA
werediagnosedashavingfocalseizures,soconclusionsareapplicabletopatientswiththeseepilepsy
syndromes.ForpatientsinArmBwithidiopathicgeneralisedepilepsiesordifficulttoclassify
epilepsy,sodiumvalproateremainedtheclinicallymosteffectivedrug,althoughtopiramatemaybe
acosteffectivealternativeforsomepatients.
TheauthorsofSANADchallengepreviousRCTsonAEDmonotherapyefficacythatfailtoinform
clinicalpracticeofpolicy,anddespitesomeoftheperceivedmethodologicallimitationsitisavery
importanttrialoffirstAEDtherapy.
Theresultssuggestthatsodiumvalproateshouldbethedrugofchoiceingeneralisedand
unclassifiableepilepsies,andlamotrigineinfocalepilepsies.Itwasthereforeconsiderednecessaryto
reviewnewevidenceregardingantiepilepticdrugswithinanupdateoftheNICEclinicalguideline.
ForfurtherdetailsonthequalityassessmentoftheSANADtrial,pleaserefertotherelevantseizure
type/syndromechapters.
1.7 Guidelineaims
Clinicalguidelinesaredefinedassystematicallydevelopedstatementstoassistpractitionerand
patientdecisionsaboutappropriatehealthcareforspecificclinicalcircumstances.
33
Thisguidelineisapartialupdateofthe2004guidelineandoffersbestpracticeadviceonthe
treatmentandmanagementoftheepilepsiesinchildrenandadults.
1.8 Principlesunderlyingtheguidelinedevelopment
Thekeyprinciplesbehindthedevelopmentofthisguidelinewerethatitshould:
consideralltheissuesthatareimportantinthediagnosis,treatmentandmanagementofepilepsy
inchildrenandadults
basetherecommendationsonthepublishedevidencethatsupportsthem,withexplicitlinksto
theevidence
beusefulandusablebyallhealthcareprofessionalsdealingwithpeoplewithepilepsy
takefullaccountoftheperspectiveofthepersonwithepilepsyandtheirfamilyand/orcarers
Indicateareasofuncertaintyrequiringfurtherresearch.
TheEpilepsies
Introduction
27
1.9 Whoshouldusethisguideline?
Theguidelineisintendedforusebyindividualhealthcareprofessionals,peoplewithepilepsyand
theircarersandhealthcarecommissioningorganisationsandproviderorganisations.
Separateshortformdocumentsforpeoplewithepilepsyandhealthcareprofessionalsareavailable
withoutdetailsofthesupportingevidence.TheseareavailablefromtheInstituteswebsite
(www.nice.org.uk).
1.10 Structureofguidelinedocumentation
2004
Theguidelineisdividedintosectionswhichcoverindetailspecifictopicsrelatingtothediagnosis,
investigationandmanagementofpeoplewithepilepsy.Foreachtopicthelayoutissimilar.
Thebackgroundtothetopicisprovidedinoneortwoparagraphsthatsettherecommendationsin
context.
Therecommendationsarepresentedinboththeexecutivesummaryandeachsection.Theseare
gradedtoindicatethestrengthoftheevidencebehindtherecommendation.
Theevidencestatementsarepresentedthatsummarisetheevidence.Theseevidencestatements
providethebasisonwhichtheguidelinedevelopmentgroupmadetheirrecommendations.The
evidencestatementsaregradedaccordingtothestrengthoftheavailableevidence.Anevidence
statementbasedontheavailablehealtheconomicevidenceisprovidedwhereappropriate.
Anarrativereviewofthesecondaryandprimaryevidence,andhealtheconomicevidencewhere
appropriate,thatwasusedtoproducetheevidencestatementsfollows.Importantgeneral
methodologicalissuesareflaggedupasappropriate.Whereappropriate,fulldetailsofthepapers
reviewedarepresentedintheevidencetables(seeAppendixF).
2012
Theguidelineisdividedintosectionswhichcoverindetailspecifictopicsrelatingtothetreatment
andmanagementofpeoplewithepilepsy.Foreachtopicthelayoutissimilar.
Theintroductionofthetopicisgivenatthebeginningofthesectionthatputstherecommendations
incontext.
Amatrixofevidencepresentsthecomparisonsoftreatmentsforwhichevidencewasidentified.
Whentheboxisleftempty,thennoevidencewasfound.Inthiscase,nosectiononthiscomparison
oftreatmentisincludedinthechapter.Allthecomparisonsarepresentedindividuallyand,when
applicable,thecomparisonsarelistedseparatelyforadultsandchildren.Theclinicalevidenceis
summarisedinGradeprofiletables(PleaseseeAppendixN).Foreachcomparison,thefirstsetof
tablespresentsasummaryofclinicalstudycharacteristicsandthesecondsetoftablespresentsa
summaryofclinicalfindiings(AppendixN).Furtherexplanationsonqualityassessmentdecisionsare
giveninfootnotes.
Theevidencestatementspresentedsummarisetheevidence.Theseevidencestatementsare
groupedinfivemainsections;thefirstfoursectionsfollowthemainfourcategoriesofoutcome
measures(efficacy,adverseevents,qualityoflifeandcognitiveoutcomes)andthefifthsection
presentsanyeconomicconsiderations.Allevidencestatementsaregradedaccordingtothestrength
ofavailableevidence.Thelastsectionofevidencestatementsreferstooutcomesforwhichno
TheEpilepsies
Introduction
28
evidencewasretrieved.Theseevidencestatementsprovidethebasisonwhichtheguideline
developmentgroupmadetheirrecommendations.
Therecommendationsarepresentedinboththeexecutivesummaryandinthelastsectionineach
evidencereview.Forthepurposesoftheguidelineupdate,the[2004]recommendationswillbeina
blueshadedboxatthestartofanewsection,whilstthenewrecommendations[2012]and[New
2012]willbeattheendofeachsectionwiththerelevantevidencetorecommendations.
Foreachrecommendation,thefollowingpointsaretakenintoconsideration;relativevalueplacedon
theoutcomesconsidered,tradeoffbetweenclinicalbenefitsandharms,economicconsiderations,
qualityofevidenceonwhichthisrecommendationwasbasedandanyotherconsiderationmade
underthatrecommendation.
Labellingofrecommendations
Newrecommendationsaredefinedaseitheranadditionalareafortheguidelineorchanged
becauseofanupdatedevidencereview.Newrecommendationsarelabelledbyadding
[NEW2012]totheendoftherecommendation.
Unchangedrecommendationswheretheevidencehasbeenreviewedforthe2012update
arelabelledas[2012].Theserecommendationscouldberewordedtomatchnewstyle
recommendationsbutthedeveloperscheckedwiththeGDGthatrewordinghasntchanged
themeaning.
Unchangedrecommendationsfrom2004,wheretheevidencehasnotbeenformally
reviewedforthe2011update,arelabelledas[2004].
Whereevidencehasnotbeenreviewed,buttherehavebeenminorchangesin2012tothe
wordingofa2004recommendationthatdonotaffectthemeaning,forspecificreasonssuch
asinterminologyoravailabilityofdrugs,thesearelabelledas[2004,amended2012].
Deletedrecommendationsfromthe2004guidelinecanbeviewedinAppendixX
1.11 Guidelinelimitations
Theguidelinedocumentationandrecommendationsaresubjecttovariouslimitations.TheNational
InstituteforHealthandClinicalExcellence(NICE),thecommissionerofthiswork,isprimarily
concernedwiththeNationalHealthServiceinEnglandandWalesandisnotabletomake
recommendationsforpracticeoutsidetheNHS.Itisimportanttostressthatsocialservices,
educationalservicesandthevoluntarysectorhaveanimportantroletoplayinthecareofpeople
withepilepsyandthisguidelineishighlyrelevanttotheseagencies.Themethodologicallimitations
oftheguidelinearediscussedinchapter2.
1.12 Plansforupdatingtheguideline
2004
Theprocessofreviewingtheevidenceisexpectedtobegin4yearsafterthedateofissueofthis
guideline.Reviewingmaybeginearlierthan4yearsifsignificantevidencethataffectstheguideline
recommendationsisidentifiedsooner.Theupdatedguidelinewillbeavailablewithin2yearsofthe
startofthereviewprocess.
TheEpilepsies
Introduction
29
2012
ThisguidelineisapartialupdateofTheepilepsies:thediagnosisandmanagementoftheepilepsies
inadultsandchildreninprimaryandsecondarycare(NICEclinicalguideline20,2004).Itupdates
thepharmacologicalmanagementsectionsofthe2004guidelineandalsoincludestheuseofthe
ketogenicdiet.
Threeyearsafterpublicationoftheclinicalguideline,theNCGCandNICEwilldeterminewhetheran
updateiswarranted.
TheEpilepsies
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2 Methods
2.1 Introduction
Thischaptersetsoutindetailthemethodsusedtogeneratetherecommendationsforclinical
practicethatarepresentedinthesubsequentchaptersofthisguideline.Themethodsarein
accordancewiththosesetoutbytheNationalInstituteforHealthandClinicalExcellence(the
Institute)inTheGuidelineDevelopmentProcessInformationforNationalCollaboratingCentres
andGuidelineDevelopmentGroups(availableat:http://www.nice.org.uk).
2.2 Thedevelopers
2.2.1 TheNationalCollaboratingCentreforPrimaryCare
The2004editionofthisguidelinewasdevelopedbytheNationalCollaboratingCentreforPrimary
Care(NCCPC).TheNCCPCwasbasedattheRoyalCollegeofGeneralPractitioners(RCGP),and
involvedthefollowingpartners:RoyalCollegeofGeneralPractitioners,RoyalPharmaceuticalSociety
ofGreatBritain,CommunityPractitionersandHealthVisitorsAssociation,andtheClinical
GovernanceResearchandDevelopmentUnit(CGRDU),DivisionofGeneralPracticeandPrimary
Healthcare,DepartmentofHealthSciences,UniversityofLeicester.TheCollaboratingCentrewasset
upin2000,toundertakecommissionsfromtheNationalInstituteforClinicalExcellencetodevelop
clinicalguidelinesfortheNationalHealthServiceinEnglandandWales.
The2004guidelinewasdevelopedbytheClinicalGovernanceResearchandDevelopmentUnit
(CGRDU),DivisionofGeneralPracticeandPrimaryHealthcare,DepartmentofHealthSciences,
UniversityofLeicester.
2.2.2 TheNationalClinicalGuidelinesCentre
NICEcommissionedthe2011guidelinetobedevelopedbytheNCCPC.On1stApril2009theNCCPC
mergedwith3othercollaboratingcentrestoformtheNationalClinicalGuidelinesCentre(NCGC).
ThedevelopmentofthisguidelinewasthereforestartedattheNCCPCandcompletedattheNCGC.
ThecentreisoneoffourcentresfundedbyNICEandcomprisesapartnershipbetweenavarietyof
academic,professionalandpatientbasedorganisations.Asamultidisciplinarycentrewedrawupon
theexpertiseofthehealthcareprofessionalsandacademicsandensuretheinvolvementofpatients
inourwork.
2.2.3 Themethodologyteam
2004
ThemethodologyteamwasledbytheDeputyDirectoroftheNCCPCLeicester,aSeniorLecturerin
GeneralPractice(theprojectlead).Othermembersoftheteamwereasystematicreviewer,an
informationlibrarian,ahealtheconomist,andtheDirectoroftheNCCPCLeicester.Where
appropriate,theadviceandopinionoftheChiefExecutiveoftheNCCPC,theappointedChairofthe
GuidelinesDevelopmentGroup(GDG,seebelow)andmembersandcoopteesoftheGDGwas
sought.
Editorialresponsibilityfortheguidelinerestedsolelywiththemethodologyteam.
TheEpilepsies
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ThemethodologyteamwasledbytheGuidelinesOperationsDirectoroftheNationalClinical
GuidelinesCentre(NCGC),andcomprised:aseniorresearchfellowwhoactedalsoasproject
manager,twosystematicreviewers,onehealtheconomistandtwoinformationscientists.Advice
andguidancewasalsosoughtfromtheclinicaladvisor(ProfessorHelenCross),theappointedChair
oftheGuidelinesDevelopmentGroup(DrNickKosky),andmembersandcoopteesoftheGDG.
2.2.4 TheGuidelineDevelopmentGroup
2004
Nominationsforgroupmemberswereinvitedfromvariousstakeholderorganisationswhowere
selectedtoensureanappropriatemixofhealthcareprofessionalsanddelegatesofpatientgroups.
Inviewofthenumberoforganisationswhoneededtocontributetotheguidelineitwasdecidedthat
thereshouldbetwogroups:membersoftheGuidelineDevelopmentGroupandcooptees.Each
nomineewasexpectedtoserveasanindividualexpertintheirownrightandnotasarepresentative
oftheirparentorganisation,althoughtheywereencouragedtokeeptheirnominatingorganisation
informedoftheprocess.Coopteescontributedtoaspectsoftheguidelinedevelopmentbutdidnot
sitontheguidelinedevelopmentgroupandwerenotinvolvedinthefinalwordingofthe
recommendations.Groupmembershipandcoopteedetailscanbefoundintheprefacetothe
guideline.
TheGDGmetatsixweeklyintervalsfor16monthstoreviewtheevidenceidentifiedbythe
methodologyteam,tocommentonitsqualityandcompletenessandtodeveloprecommendations
forclinicalpracticebasedontheavailableevidence.Inordertogenerateseparaterecommendations
foradultsandchildrentheGDGwasdividedintoadultandchildsubgroups.Eachsubgroupmetto
discusstheevidencereviewsandtomakepreliminaryrecommendations.Thefinal
recommendationswereagreedbythefullGDG.
AllGDGmembersmadeaformalDeclarationofInterestsatthestartoftheguidelinedevelopment
andprovidedupdatesthroughoutthedevelopmentprocess.
2012
AChairwasappointedforthegroupandhisprimaryrolewastofacilitateandchairtheGDG
meetings.
TheGDGconsistedofadiversemultidisciplinarygroupwithaninterestand/orexpertiseinthe
pharmacologicalmanagementoftheepilepsies.
Theprofessionalrepresentativesonthegroupwerechosenaccordingtoasetprocess.TheNCCPC
projectteamdecidedonthenecessaryprofessionalrepresentationrequiredfortheGDG,basedon
thescopeoftheguideline.Professionalregisteredstakeholderorganisationswerewrittentoto
notifythemoftheadvertisementandrecruitmentprocess.Oncealloftheapplicationswere
received,theNCCPCClinicalDirector,chairmanandtheprojectleadselectedtheindividual
members,onthebasisoftheirCVs,supportingstatements,andagainstaselectioncriteriaadapted
fromthepersonspecificationandjobdescription.
Forthepatientmembers,thePPIPatNICEsubmittedthereceivedapplications,fromwhichtheNCC
PCClinicalDirector,chairmanandtheprojectleadchosetwoaspatientmembersbasedontheaim
(aswiththeprofessionalhealthcareapplicants)ofincludingaswidearangeaspossibleofexpertise,
experience,andgeographicrepresentationfromacrossEnglandandWales.
InaccordancewithguidancefromNICE,allGDGmembersandthechairdeclaredinwritinginterests
thatcoveredconsultancies,feepaidwork,shareholdings,fellowships,andsupportfromthe
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healthcareindustryandtheseweremadeavailableinthepublicdomain.Detailsofthesecanbeseen
inAppendixU.DeclarationofinterestswereupdatedatthestartofeachGDGmeeting.Arecordof
updateddeclarationsofinterestwasrecordedintheNCGCsdatabaseandminutesofeachmeeting
wereproduced.TheminutesoftheGDGmeetingswerepublishedontheNICEwebsitewithin10
weeksofbeingagreedbytheGDG.
2.3 Developingkeyclinicalquestions(KCQs)
Thefirststepinthedevelopmentoftheguidelinewastorefinetheguidelinescope(seeappendixB)
intoaseriesofkeyclinicalquestions(KCQs)whichreflectedtheclinicalcarepathwayforadultsand
childrenwithepilepsy.TheseKCQsformedthestartingpointforthesubsequentsystematicreview
andasaguidetofacilitatethedevelopmentofrecommendationsbytheGDG.
TheKCQsweredevelopedbytheGDG,withinputasappropriatefromcoopteesandwithassistance
fromthemethodologyteam.TheKCQswererefinedintospecificevidencebasedquestions(EBQs)
bythemethodologyteamandtheseEBQsformedthebasisoftheliteraturesearching,appraisaland
synthesis
34
.
2004
Atotalof72KCQswereidentified,ofwhich52hadseparatechildandadultstems(seeAppendixE).
ThemethodologyteamandtheGDGagreedthatafullliteraturesearchandcriticalappraisalcould
notbeundertakenforalloftheseKCQsduetothetimeandresourcelimitationswithintheguideline
developmentprocess.Themethodologyteam,inliaisonwiththeGDG,identifiedthoseKCQswhere
afullliteraturesearchandcriticalappraisalwereessential.Reasonsforthisincludedawarenessthat
theevidencewasconflictingorthattherewasaparticularneedforevidencebasedguidanceinthat
area.
2012
Atotalof22newKCQswereidentified;
SeventeenkeyclinicalquestionsfocusedontheeffectivenessandcosteffectivenessofAEDsand
hadcommonstemsforchildrenandadults;
Threekeyclinicalquestionsspecificallyaddressedchildren;twoofthesekeyclinicalquestions
adressedtheeffectivenessandcosteffectivenessofAEDsintreatingchildrenwithchildhood
absenceepilepsyandchildrenwithinfantilespasms.Thethirdkeyclinicalquestionassessedthe
clinicaleffectivenessandcosteffectivenessoftreatingchildrenwiththeketogenicdiet;
Onekeyclinicalquestionfocusedontheclinicaleffectiveness,costeffectivenessofAEDsandthe
safetyoftheiruseinpregnantwomenandwomencurrentlybreastfeeding;
OnekeyclinicalquestionaddressedwhichAEDsarethemostwelltoleratedforolderpeople,
who,forthepurposesofthisguideline,weredefinedasthoseaged65yearsandover.
Fullliteraturesearches,criticalappraisalsandevidencereviewswerecompletedforallthespecified
clinicalquestions,withtheexceptionofonesubgroupfortheclinicalquestion:WhichAEDsare
clinicallyeffective,costeffectiveandsafestforuseinpregnancy?Thesubgroupaddressedwomen
whowerecurrentlybreastfeeding.
2.4 Identifyingtheevidence
2.4.1 Literaturesearchstrategies
2004
TheEpilepsies
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33
Theaimoftheliteraturereviewwastoidentifyallavailable,relevantpublishedevidenceinrelation
tothekeyclinicalquestionsgeneratedbytheGDG.TheprioritisedKCQswereturnedintoEBQsby
theprojectleadandsystematicreviewer.Literaturesearcheswereconductedusinggenericsearch
filtersandmodifiedfilters,designedtobestaddressthespecificquestionbeinginvestigated.
Searchesincludedbothmedicalsubjectheadings(MeSHterms)andfreetextterms.Detailsofall
literaturesearchesareavailablefromtheNCCPC,UniversityofLeicester.
Theinformationlibrariandevelopedasearchstrategyforeachquestionwiththeassistanceofthe
systematicreviewerandtheprojectlead.Searcheswerererunattheendoftheguideline
developmentprocess,thusincludingevidencepublisheduptotheendofDecember2003.
Dependingontheclinicalarea,someorallofthefollowingdatabasesweresearched:Cochrane
Library(uptoIssue3,2003)wassearchedtoidentifyanyrelevantsystematicreviews,andfor
reportsofrandomisedcontrolledtrials,MEDLINE(fortheperiodJanuary1966toNovember2003,on
theOVIDinterface),EMBASE(fortheperiodJanuary1980toNovember2003,ontheOVID
interface),theCumulativeIndexofNursingandAlliedHealthLiterature(fortheperiodJanuary1982
toNovember2003,ontheDialogDataStarinterface),PsycINFO(fortheperiod1887toSeptember
2003,ontheOVIDandtheDialogDataStarinterfaces),theHealthManagementInformation
Consortiumdatabase(HMIC),theBritishNursingIndex(BNI),andtheAlliedandComplementary
MedicineDatabase(AMED).Searchesfornonsystematicreviewsoftheliteraturewerelimitedto
1997November2003.Thiswasapragmaticdecisionthatdrawsonthesearchstrategiesusedby
theNorthOfEnglandEvidenceBasedGuidelineDevelopmentProject.
35
Nosystematicattemptwas
madetosearchgreyliterature(suchasconferenceproceedings,abstracts,unpublishedreportsor
trials,etc.).
Existingsystematicreviewsandmetaanalysesrelatingtoepilepsywereidentified.Recent(last6
years)highqualityreviewsoftheepilepsyliteraturewerealsoidentified.Newsearches,including
identificationofrelevantrandomisedcontrolledtrials(RCTs),wereconductedinareasofimportance
totheguidelinedevelopmentprocess,forwhichexistingsystematicreviewswereunabletoprovide
validoruptodateanswers.Thesearchstrategywasdictatedbytheexactevidencebasedquestion
(EBQ)theGDGwishedtoanswer.Expertknowledgeofgroupmemberswasalsodrawnuponto
corroboratethesearchstrategy.
TheNationalResearchRegister(NRR),NationalGuidelinesClearinghouse(NGC),NewZealand
GuidelinesGroup(NZGG)andtheGuidelinesInternationalNetwork(GIN)weresearchedtoidentify
anyexistingrelevantguidelinesproducedbyotherorganisations.Thereferencelistsinthese
guidelineswerecheckedagainstthemethodologyteamssearchresultstoidentifyanymissing
evidence.
ThetitlesandabstractsofrecordsretrievedbythesearcheswerescannedforrelevancetotheGDGs
clinicalquestions.Anypotentiallyrelevantpublicationswereobtainedinfulltext.Thesewere
assessedagainsttheinclusioncriteriaandthereferencelistswerescannedforanyarticlesnot
previouslyidentified.FurtherreferenceswerealsosuggestedbytheGDG.Evidencesubmittedby
stakeholderorganisationsthatwasrelevanttotheGDGsKCQs,andwasofatleastthesamelevelof
evidenceasthatidentifiedbytheliteraturesearches,wasalsoincluded.
2012
Theaimoftheliteraturesearchwastoupdatetherelevantevidencefromthe2004guidelineandto
identifynewevidencewithinthepublishedliterature,toanswertheclinicalreviewquestionsasper
TheNICEGuidelinesManual(2009)
36
.Clinicaldatabasesweresearchedusingrelevantmedical
subjectheadings,freetexttermsandstudytypefilterswhereappropriate.NonEnglishstudieswere
notreviewedandwerethereforeexcludedfromsearches.Wherepossible,searcheswererestricted
toarticlespublishedinEnglishlanguage.Allsearcheswereconductedoncoredatabases,Medline,
Embase,CinahlandTheCochraneLibrary.Initialsearchesforeachsectionwereperformedwhenthe
TheEpilepsies
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34
literaturewasneededforthereview.Eachsearchwasupdated3monthsand6weeksbeforethe
endofguidelinedevelopmentperiod.Nopapersindexedinthedatabasesafterthisdatewere
considered.
Searchstrategieswerecheckedbylookingatreferencelistsofrelevantkeypapers,checkingsearch
strategiesinothersystematicreviewsandaskingtheGDGforknownstudies.Thesearchstrategies
alongwiththedatabasessearchedandtheyearscoveredcanbefoundinAppendixJ.
Duringthescopingstage,asearchwasconductedforguidelinesandreportsonthewebsiteslisted
belowandonorganisationsrelevanttothetopic.Searchingforgreyliteratureorunpublished
literaturewasnotsystematicallyundertaken.Allreferencessentbystakeholderswereconsidered.
ConstituentwebsitesoftheGuidelinesInternationalNetworkdatabase(www.gin.net)
NationalGuidelineClearingHouse(www.guideline.gov/)
NationalInstituteforHealthandClinicalExcellence(NICE)(www.nice.org.uk)
NationalInstitutesofHealthConsensusDevelopmentProgram(consensus.nih.gov/)
NationalLibraryforHealth(www.library.nhs.uk/)
2.4.2 Healtheconomics
2004
Aseparatesystematicliteraturereviewwasconductedtoassessthestateoftheeconomicevidence,
giventhatinthemainsearchesthisevidencewaslimited.Thesystematicreviewerandthehealth
economistcarriedoutthesesearchesforhealtheconomicsevidence.Economicsearchfilterswere
usedincludingtheonedevelopedbytheCentreforReviewsandDisseminationinthefollowing
bibliographicelectronicdatabasesMEDLINE,PreMEDLINE,EMBASE,PsycINFO,CINAHL,theCochrane
DatabaseofSystematicReviews(CDSR),theDatabaseofAbstractsofReviewofEffectiveness(DARE),
theCochraneControlledTrialsRegister(CCTR)andtheNHSR&DHealthTechnologyAssessment
ProgrammeandspecialhealtheconomicdatabasesOfficeofHealthEconomicsOHEHealth
EconomicEvaluationsDatabase(HEED)andNHSEconomicEvaluationDatabase(NHSEED)were
searched.Thedetailsoftheelectronicsearch(interfaces,dates)willbereportedintheguideline.
Giventhelimitedeconomicevidenceintheareaitwasdecidedtoperformabroadsearchfor
evidencethatwasdesignedtoidentifyinformationaboutthecostsorresourcesusedinprovidinga
serviceorinterventionand/orthebenefitsthatcouldbeattributedtoit.Nocriteriaforstudydesign
wereimposedapriori.InthiswaythesearcheswerenotconstrainedtoRCTsorformaleconomic
evaluations.PapersincludedwerelimitedtopaperswritteninEnglishandhealtheconomic
informationthatcouldbegeneralizedtoUKstudiesonepilepsypublishedafter1990.
2012
Literaturesearcheswerealsoundertakentoidentifyhealtheconomicevidencewithinpublished
literaturerelevanttothereviewquestions.Theevidencewasidentifiedbyconductingabroadsearch
relatingtotheguidelinepopulationintheNHSeconomicevaluationdatabase(NHSEED),theHealth
EconomicEvaluationsDatabase(HEED)andhealthtechnologyassessment(HTA)databaseswithno
daterestrictions.Additionally,thesearchwasrunonMEDLINEandEmbase,withaspecificeconomic
filter.StudiespublishedinlanguagesotherthanEnglishwerenotreviewed.Wherepossible,searches
wererestrictedtoarticlespublishedinEnglishlanguage.
ThesearchstrategiesforhealtheconomicsareincludedinAppendixJ.Allsearcheswereupdatedon
priortoconsultation.Nopaperspublishedindexedinthedatabasesafterthisdatewereconsidered.
TheEpilepsies
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2.5 Reviewingandgradingtheevidence
2.5.1 Methodsfor2004Guideline
Thestudiesidentifiedfollowingtheliteraturesearchwerereviewedtoidentifythemostappropriate
evidencetohelpanswertheKCQsandtoensurethattherecommendationswerebasedonthebest
availableevidence.Thisprocessrequiredfourmaintasks:selectionofrelevantstudies;assessment
ofstudyquality;synthesisoftheresultsandgradingoftheevidence.
Thesearcheswerefirstsiftedbytheinformationlibrarianandsystematicreviewertoexcludepapers
thatdidnotrelatetothescopeoftheguideline.Theabstractsoftheremainingpaperswere
scrutinisedforrelevancetotheEBQunderconsideration.Initiallyboththesystematicreviewerand
projectleadreviewedtheabstractsindependently.Thisprovedimpracticalastheguideline
progressedandthetaskwasdelegatedtothesystematicreviewer.Theprojectleadwasaskedto
reviewtheabstractsincasesofuncertainty.
Thepaperschosenforinclusionwereobtainedandassessedfortheirmethodologicalrigouragainsta
numberofcriteriathatdeterminethevalidityoftheresults.Thesecriteriadifferedaccoringtostudy
typeandwerebasedonthechecklistsdevelopedbytheScottishIntercollegiateGuidelinesNetwork
(SIGN).
37
Criticalappraisalwascarriedoutbythesystematicreviewer.Tominimisebiasinthe
assessment,asampleofpaperswasindependentlyappraisedbytheprojectlead.Furtherappraisal
wasprovidedbytheGDGmembersattherelevantGDGmeeting.
Thedatawereextractedtoastandardtemplateonanevidencetable.Thefindingswere
summarisedbythesystematicreviewerintoaseriesofevidencestatementsandanaccompanying
narrativereview.Theprojectleadindependentlyassessedtheaccuracyofthederivedevidence
statements.NoneoftheEBQsrequiredthepreparationofaquantitativesynthesis(metaanalysis)
bytheprojectteam.
Theevidencestatementsweregradedbythesystematicrevieweraccordingtotheestablished
hierarchyofevidencetablepresentedinsection11ofthischapter.Thissystemreflectsthe
susceptibilitytobiasinherenceinparticularstudydesigns.Theprojectleadindependentlyassessed
theaccuracyofthegrading.
ThetypeofEBQdictatesthehighestlevelofevidencethatmaybesought.Forquestionsrelatingto
therapy/treatmentthehighestpossiblelevelofevidenceisasystematicreviewormetaanalysisof
RCTs(evidencelevelIa)oranindividualRCT(evidencelevelIb).Forquestionsrelatingtoprognosis,
thehighestpossiblelevelofevidenceisacohortstudy(evidencelevelIIb).Fordiagnostictests,the
highestpossiblelevelofevidenceisatestevaluationstudyusingaquasiexperimentaldesignthat
usesablindcomparisonofthetestwithavalidatedreferencestandardappliedtoasampleof
individualswhoarerepresentativeofthepopulationtowhomthetestwouldapply(evidencelevel
IIb).Forquestionsrelatingtoinformationneedsandsupport,thehighestpossiblelevelofevidence
isadescriptivestudyusingeitherquestionnairesurveyorqualitativemethods(III).
Foreachclinicalquestion,thehighestlevelofevidencewasselected.Ifasystematicreview,meta
analysisorRCTexistedinrelationtoanEBQ,studiesofaweakerdesignwereignored.
Summaryresultsanddataarepresentedintheguidelinetext.Moredetailedresultsanddataare
presentedintheevidencetables(AppendixF).
AnumberofKCQscouldnotbeappropriatelyansweredusingasystematicreview,forexample,
wheretheevidencebasewasverylimited.Thesequestionswereaddressedbytheidentificationof
publishedexpertnarrativereviewsbytheprojectteamand/orGDGwhichformedthebasisof
discussionpaperswritteneitherbytheprojectleadoramemberoftheGDG.
TheEpilepsies
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2.5.2 Methodsfor2012Guideline
2.5.2.1 Qualityassessementforinterventionstudies
Foreachclinicalquestionthehighestlevelofevidencewassought.Weincludedonlyrandomised
controlledtrialsastheyareconsideredthemostrobusttypeofastudydesignthatcouldproducean
unbiasedestimateoftheinterventioneffects.Whereanappropriaterandomised(doubleblinded,
singleblindedorunblinded)controlledtrialwasidentified,wedidnotsearchforstudiesofaweaker
design.ThequalityassessmentcriteriaaslistedintheNICEGuidelinesManual2009
36
wereusedto
assesssystematicreviews,metaanalysis,andrandomisedcontrolledtrials.
Forrandomisedcontrolledtrials,themaincriteriaconsideredwere:
Anappropriateandclearlyfocusedquestionwasaddressed
Appropriaterandomisation,allocationandconcealmentmethodswereused
Subjects,investigatorsandoutcomesassessorsweremaskedabouttreatmentallocation
Theinterventionandcontrolgroupsaresimilaratbaseline
Theonlydifferencebetweengroupisthetypeofinterventionreceived
Alloutcomesaremeasuredinastandardandreliablemethod
Dropoutrateswerereportedandareacceptable,andallparticipantsareanalysedinthegroups
towhichtheywererandomlyallocatedthetreatment
Formulticentredtrials,resultsarecomparablebetweensites
2.5.2.2 GRADE(GradingofRecommendationsAssessment,DevelopmentandEvaluation)
Theevidenceforoutcomesfromstudieswhichpassedthequalityassessmentwereevaluatedand
presentedusinganadaptationoftheGradingofRecommendationsAssessment,Developmentand
Evaluation(GRADE)toolboxdevelopedbytheinternationalGRADEworkinggroup
(http://www.gradeworkinggroup.org/).Thesoftware(GRADEpro)developedbytheGRADEworking
groupwasusedtoassesspooledoutcomedatausingindividualstudyqualityassessmentsandresults
frommetaanalysis.
Thesummaryoffindingsforeachclinicalquestionwaspresentedastwoseparatetablesinthis
guideline.TheClinicalStudyCharacteristicstableincludesdetailsofthequalityassessmentwhile
theClinicalSummaryofFindingstableincludespooledoutcomedata,anabsolutemeasureof
interventioneffectcalculatedandthesummaryofqualityofevidenceforthatoutcome.Inthistable,
thecolumnsforinterventionandcontrolindicatepooledsamplesizeforcontinuousoutcomes.For
binaryoutcomessuchasnumberofpatientswithanadverseevent,theeventrates(n/N)areshown
withpercentages.Reportingorpublicationbiaswasconsideredinthequalityassessmentbutnot
includedintheClinicalStudyCharacteristicstablebecausethiswasararereasonfordowngradingan
outcomeinthisguideline.
Eachoutcomewasexaminedseparatelyforthequalityelementslistedandeachgradedusingthe
qualitylevelslistedinSection2.9.Themaincriteriaconsideredintheratingoftheseelementsare
discussedintheliteraturereviewingprocess(seesection2.9GradingofEvidence).Footnoteswere
usedtodescribereasonsforgradingaqualityelementashavingseriousorveryseriousproblems.
TheGRADEtoolboxiscurrentlydesignedonlyforrandomisedcontrolledtrialsandobservational
studies.
TheEpilepsies
Methods
37
2.6 Methodsofcombiningstudies(2012)
Wherepossibleandappropriate,metaanalyseswereconductedtocombinetheresultsofstudiesfor
eachclinicalquestionusingCochraneReviewManager(RevMan5)software.Fixedeffects(Mantel
Haenszel)techniqueswereusedtocalculateriskratios(relativerisk)forthebinaryoutcomesandthe
continuousoutcomeswereanalysedusinganinversevariancemethodforpoolingweightedmean
differences.Statisticalheterogeneitywasassessedbyconsideringthechisquaredtestfor
significanceatp<0.05oranIsquaredinconsistencystatisticof>50%toindicatesignificant
heterogeneity.
Whereappropriate,sensitivityanalysesbasedonthequalityofstudieswerecarriedouttoexplore
theimpactofincludingcrossoverandunblindedstudies,andtheirfindingsinformedtheevidence
reviewandGDGconsiderationsoftheevidence.
Timetoeventdataweresummarizedusingmethodsofsurvivalanalysis.Theinterventioneffectwas
expressedasahazardratio(HR)followingtheproportionalhazardsassumption(anassumptionthat
hazardratioisconstantacrossthefollowupperiod).Whereappropriate,hazardratiosandvariances
fortimetoeventoutcomeswerepooledaccordingtotheinverseofvariancemethodwiththeuseof
ReviewManagersoftware.
2.7 Protocolforguidelineevidencereviewsforthepartialupdate
(2012)
The2012versionoftheguidelinewasapartialupdateofthe2004versionandcentredonanupdate
ofthepharmacologicalmanagement(alsoapplicabletopeoplewithlearningdisabilities,older
peopleandpregnantwomen)andthesectiononketogenicdiet.Theevidencereviewsconductedas
partoftheguidelinedevelopmentfollowedtheagreedreviewingprotocoloutlinedbelow:
Typesofstudies
Doubleblinded,singleblindedandunblinded,parallelandcrossoverrandomisedcontrolledtrials
(RCTswereincludedintheevidencereviewsconductedforthepartialupdate(2011).Crossover
trialsthatdidnotreporttheplaceboarmdatawereexcluded.
Weincludedrandomisedcontrolledtrials,astheyareconsideredthemostrobusttypeofastudy
designthatcouldproduceanunbiasedestimateoftheinterventioneffects.However,thereare
somelimitationsofthisapproachthatneedtobehighlighted;regulatorytrialsinepilepsyusually
haveonlyalimitedperiodoffollowup,andcansometimesusedosingregimensthatarenot
entirelyinlinewithsubsequentclinicalpractice.Therefore,thestudydosageshavealwaysbeen
checkedforaccordancewiththetherapeuticrangeslistedintheBNF.
StudydesignsotherthanRCTweresoughtwhennoRCTdatawasavailableforcertainclinical
questionsdeemedtobehighprioritybytheGDG(e.gevidencereviewonteratogenicityofAEDsin
pregnancy).However,astimewaslimited,itwasnotpossibletodothisforallquestionswherethere
wasnoRCTevidence.ForexamplewedidnotsearchnonRCTevidencefortheefficacyofAEDsin
CSWS,LandauKleffnersyndromeormyoclonicastaticepilepsy(MAE)eventhoughnoRCTevidence
hadbeenfound.
Onehighqualityindividualpatientdatanetworkmetaanalysis
38
wasidentifiedduringstakeholder
consultation.TheGDGagreedthatthiswasahighqualitystudythatshouldbeincorporatedintothe
evidencereivew.Theindividualpatientdatafor6418patientsfrom20randomisedcontrolledtrials
wasincorporatedintomonotherapyfornewlydiagnosedfocalandgeneralisedtonicclonicseizures
TheEpilepsies
Methods
38
evidencereviewstocomplementthefindingsofthepairwisemetaanalysesandassisttheGDGin
termsoftheirdecisionmakingandrecommendationdevelopment.
Weincludednoninferiority,equivalenceandsuperioritystudiesbutdidnotincludesinglearmnon
comparativetrials.Doseresponsetrialswithoutacomparativedrugorplaceboarmweretherefore
excluded.Wedidnotincluderesponseselectedtrialswherebyonlyparticipantswhorespondedtoa
drugwereincludedinthetrial.Theresultsofthesestudieswouldhavebeenbiasedtowardsthe
drugastheparticipanthadalreadyrespondedtoit.
Forthecomparisonsforwhichblindedtrialswerenotavailable,theGDGdowngradedthelevelof
qualityduetothehigherriskofbias.However,thedifficultyofblindinginthesetrialsandthetrade
offbetweenpossiblehigherbiasinunblindedstudiesagainstthewiderclinicalapplicabilitywas
notedbytheGDG.
Crossovertrialswereincludedinthemetaanalysisandanalysedasparalleltrialsbytreatingthe
resultsfromthefirstperiodasiftheycamefromonegroupofpatientsandresultsfromthesecond
periodasiftheycamefromadifferentgroupofpatients.Althoughthisapproachcanincreaseaunit
ofanalysiserror,itisconsideredtobeaconservativeanalysis,inthatstudiesareunderweighted
ratherthatoverweighted.
Originally,weaimedtotakeintoconsiderationthepaireddesignofthecrossovertrialsby
estimatingtheappropriatestandarderrorsfortwoperiodcrossovertrialsusingamethoddeveloped
byBeckerandBalagtas(asreportedinthepaperbyElbourneetal,2002
39
).However,nocrossover
trialincludedintheevidencereviewsprovidedthedatafortheestimationofstandarderrorsand
duetotimeconstraints,authorswerenotcontactedregardingtheindividualparticipantdataofthe
trials.Therefore,thedecisionwasmadetoanalyzecrossovertrialsasiftheywereparallelstudies.
TheCochraneReviewslistedintheCochranelibrarywhichincludeddrugsforbroadpopulations;
drugsforspecificseizuretypes;andspecificsyndromeswerecrossreferencedasqualityassurance
forthesearchstrategies.Forfurtherdetailsonthesereviews,pleasereferto
http://www.thecochranelibrary.com/view/0/index.html.
Typesofparticipants
Adultsandchildrenwereincludedintheevidencereviews.Theywereanalysedandpresentedin
separateevidencereviewsunlessthedatawerenotstratifiedinthetrials.Forthepurposesofthe
guidelinerecommendations,childrenweredefinedinthisguidelineasrangingfrom28daysto11
years,youngpeoplefrom12to17yearsandadults18yearsandolder.Forthepurposesofthe
analyses,childrenrangedfrom28daysto17years,andadultsweredefinedasaged18yearsand
older.
Themeanageatbaselineineachtrialarmwasusedtodeterminewhetheratrialwouldbeincluded
inadultorchildrenevidencereview.However,recentEMAdecisionsregardinglicensingofAEDSfor
useinchildrenindicatethatforfocalepilepsiesespeciallycryptogenicandsymptomatic,and
idiopathicgeneralisedepilepsies,withabsences,myoclonicand/orgeneralisedconvulsiveseizures,
theefficacyofAEDsseemstobecomparableinchildhoodandadulthood.Focalepilepsiesinchildren
olderthan4yearsoldhaveasimilarclinicalexpressiontofocalepilepsiesinadolescentsandadults.
Inrefractoryfocalepilepsies,theresultsofefficacytrialsperformedinadultscouldtosomeextent
beextrapolatedtochildrenprovidedthedoseisestablished.Asaresultofthis,andwiththe
agreementoftheGDG,dataforadultsandchildrenwascombinedinrefractoryfocalseizures.
TheGDGassertedthatstructuringtheguidelineaccordingtoepilepsyseizuretypeorsyndrome
wouldbethemostusefultopracticingclinicians,andmostclinicallymeaningful.Itwouldalsoallow
forthepotentialforagivenAEDtobetherapeuticforaspecificseizuretype(orsyndromeor
population)tobeestablished.Inclinicalpractice,choiceofAEDatpresentationshouldbebyepilepsy
TheEpilepsies
Methods
39
syndromewherepossible,butwhereunclear,seizuretype(ormostlikelyepilepsysyndromebyage
ofonset)providesaguidetotreatmentinthefirstinstance.
However,manystudiesdonotspecifyaparticularepilepsyseizuretypeorsyndromeintheir
inclusioncriteria,nordotheystratifytheirresultsaccordingtotheseseizuretypesandsyndromes.
Thiscontaminationoftheseizuretypeofinterestmeantthatmanyofthepatientscouldnotbe
categorised.Thiswasparticularlycommoninnewlydiagnosedconditionsastheseizuretypemay
nothavebeenestablished.Consequently,theGDGdecidedtouseacontaminationcutoffpoint
fortheminimumproportionoftrialparticipantswiththerelevantseizuretypethatwouldbeallowed
withinagivenstudy.ThiscutoffpointwassetbytheGDGtobeaminimumof80%forfocal
seizuresandaminimumof60%forgeneralisedseizures(bothprimarygeneralisedtonicclonic
seizuresandidiopathicgeneralisedepilepsy)atbaseline.Thiswasusedfortheclinicalquestionson
theeffectivenessofAEDsintreatingfocalseizureswithorwithoutsecondarygeneralisation;
generalisedtonicclonicseizures;andidiopathicgeneralisedepilepsy.TheGDGacceptedthatthese
thresholds,whilstarbitrary,reflectthedegreeofimprecisioninclinicalpracticeandlikelyinclusion
error.Studieswereexcludedwheretheproportionofpatientswiththeseizuretypeofinterestwas
lessthanthecutoffpointforbothfocalandprimarygeneralisedseizures.
Typesofinterventions
Weincludedstudiesthatcomparedpharmacologicalinterventions(aslistedunderourclinical
questions)eitherasmonotherapyoradjunctivetreatmentfortheepilepsysyndromesandseizure
typeslistedunderourclinicalquestions.Placebocontrolledtrialsandtrialscomparingdrugswere
included.Noncomparativetrialswerenotincluded.
Thescopeofthepartialupdateoftheepilepsiesguidelineincludedonlypharmacological
interventionsbecausenewevidencehademergedinthisareasincethepreviouspublishedepilepsies
guideline.Aslistedinourclinicalquestions,theGDGincludedallAEDsthatwereconsideredtobe
stillclinicallyrelevant.ThisincludedallAEDsincludedinthepreviousguidelineandHealth
TechnologyAppraisalsandfurthernewdrugsaslistedinthescopeoftheupdateguideline(appendix
I).
Durationofstudies
Noparticulartimedurationwasspecifiedforourinclusioncriteria.
Posology
Thedosesgivenwithinthestudieswerecheckedaccordingtotheusualdosesrangesspecifiedinthe
BritishNationalFormulary,andthemaximumandminimumdosesspecifiedinthesummaryof
productcharacteristics(SPC).Anytrialdoseoutsidetheserangeswasnotincludedinthemeta
analysis.Ifastudyassesseddifferentdoses(e.g.morethantwostudyarms)withintheusual
therapeuticrange,thenthesewereamalgamatedforthepurposesofthemetaanalysis.TheGDG
thoughtitimportanttolookforAEDsandthedoseswhichwereappropriateinaclinicalsetting
ratherthanjustinatrialsetting.Mostoftheexclusionswereparticulararmsofthetrialwherethe
dosagewasoutsideoftheadvisedrange.Weincludedtheotherarmsofthetrial(ifwithinrange)in
themetaanalyses.Fivetrialarmswerecompletelyexcludedduetodosage.
Typesofoutcomemeasuresanddefinitions
Weextracteddataonthefollowingoutcomesfromthetrials:
TheEpilepsies
Methods
40
Theproportionofseizurefreeparticipants:participantsseizurefreeonanintentiontotreat(ITT)
analysisoveradefinedperiodduringmaintenance.
Theproportionofparticipantsexperiencingatleasta50%reductioninseizurefrequency(i.e.
responders):thoseexperiencinga>50%reductioninseizuresoveradefinedendofmaintenance
periodcomparedtobaselineonITTanalysis.
Theproportionofparticipantshavingtreatmentwithdrawn:theproportionofparticipantsonITT
analysiswhowerewithdrawnfromthestudypriortothepredefinedtimeperiodofmaintenance
treatment.
Timetoexit/withdrawalofallocatedtreatment(retentiontime):Periodoftimefrom
randomizationtoexitfromtreatment(withdrawalfromtreatment),eitherforlackofefficacy
seizuresoradverseevents.
Timetofirstseizure:Timefromrandomisationtofirstseizure
Timeto12monthremission:Timefromrandomisationtotheachievementofa12monthperiod
withoutseizures
Incidenceofadverseevents(10%orabove):incidenceofreportedadverseeventatanytime
duringstudyperiod,asreportedwithinthestudyasaproportionofthetotalrandomised,(>10%
takenassignificantforreporting).
Anyoutcomesrelatingtocognitiveeffects.
Anyoutcomesrelatingtoqualityoflife.
Whentheproportionofparticipantswhowithdrewfromtreatmentduetoadverseeventswas
reportedforthewholesampleandnotperseizuretype,explanatoryfootnoteswereaddedinthe
tables.Weanalysedonlyvalidatedmeasuresofcognitiveeffectandqualityoflifeinthisreview.
TheoutcomeschosenwerethesameasthosereportedintheHTAsClinicaleffectiveness,
tolerabilityandcosteffectivenessofnewerdrugsforepilepsyinadults:asystematicreviewand
economicevaluation
40
,Theclinicaleffectivenessandcosteffectivenessofnewerdrugsforchildren
withepilepsyandthepreviousguidelineandthesereflectedmanyoftheoutcomeswithinvarious
epilepsyCochranereviews.Fortheprimaryoutcomemeasuresofstudiesreviewingefficacyof
medicationinthetreatmentofepilepsy,theGDGchoseseizurefreedomasthemostimportant
outcomemeasure,(mostreliablyassessedastimeto12monthsremission),andthereafter,for
adjunctivetherapy,thosewithmorethan50%reductionofseizuresfrombaseline.Theaimofall
antiepileptictreatmentisfortheindividualtoachieveseizurefreedomwithminimalifanyside
effects.Wheninitialdrugshavefailedandadjunctivetreatmentisusedseizurereductionislikelyto
betheaim.SeizurefreedomwasdefinedasparticipantsbeingseizurefreeonanITTanalysisovera
predefinedperiodduringmaintenance.Morethan50%reductioninseizurefrequencywasdefined
asthoseexperiencinga>50%reductioninseizuresoveradefinedendofmaintenanceperiod
comparedtobaseline,onanintentiontotreatanalysis.
TheGDGrecognisedthatmanyofthestudieswereperformedoverarelativelyshortperiodoftime,
andthatthemajorityusedthesemeasuresastheprimaryoutcomevariables.TheGDGalsoagreed
nottorestrictthetimeperiodformeasurementoftheproportionofseizurefreeparticipants,
proportionofparticipantsexperiencingatleasta50%reductioninseizurefrequency,andproportion
ofparticipantshavingtreatmentwithdrawn.Themostidealmeasureofeffectwouldappeartobe
timetoexitfromstudy,whetherduetolackofefficacyoradverseeventsasameasureofretention
onthemedication.Limitedstudiesappeartohavereportedthesedata.Whereavailablethiswas
utilised.TheGDGrecognisedthatthemostreliablemeasureofefficacy(seizurefreedom)and
retentionwaslikelytobetimeto12monthsremission.
Mostincludedtrialsreportedincidenceofarangeofadverseevents.TheGDGagreedonusingan
arbitrarycutoffofpointofaboveanincidenceof10%toprioritisethelistofadverseevents
TheEpilepsies
Methods
41
retrievedfromthetrials,astheyconsideredthat10%wasawellestablishedproportionforan
adverseevent.
Typeofanalysis
EstimatesofeffectfromindividualtrialsarebasedonITTdata,thatis,allparticipantsincludedinthe
randomizationprocessareconsideredinthefinalanalysisbasedonthetreatmentgroupstowhich
theywereoriginallyassigned.Insomecases,thesedatawerenotreportedinthestudiesandwhere
ITTdatawerepresented,atrueITTpopulationwassometimesnotreported.Inordertoallowforthe
inclusionofallofthestudies,regardlessofthetypeofthedatatheypresentedandtobeconsidered
inanequivalentmanner,alldataconsideredinthisreviewwerebasedontrueITTpopulations.Thus
inseveralcases,weneededtorecalculatethedatareportedinthestudiesbasedthatonthe
assumptionthatparticipantswhoweremissedoutdidnotexperiencetheeventofinterest.Similarly
theHTAusedITTanalysisandwhereatrueITTwasnotreportedtheyassumedmissingdatahada
negativeoutcome.Furtherexplanationsweregivenasfootnotesinthetables.
ItisimportanttonotethatITTanalysestendtobiastheresultstowardsnodifference.Theymaynot
bethemostappropriateanalysiswhenattemptingtoestablishequivalenceornoninferiorityofa
treatment.Becauseofthisasensitivityanalysiswasperfomedwheretherewasdifferentialdropout
greaterthan20%toassesswhetherthisaffectedtherecommendation.Thissensitivityanalysiswas
notrunwheredatawasavailablefromtheIndividualPatientData(IPD)networkmetaanalysesasit
wasfeltthatthishadalreadybeentakenintoaccountbytheIPD.Wehaveusedaconservative
approachtoanalysethedata,andthereforeacknowledgethattheeffectmaybesmallerthanin
reality.
Useofunpublisheddataintheguideline
Alargemulticentretrial(SANAD)hasbeenpublished,sincethepublicationofthe2004guidelineas
wellasthenewerAEDhealthtechnologyappraisals,whichevaluatedtheefficacyofAEDsagainst
standardtreatment,dependentonwhethercarbamazepineorsodiumvalproatewouldbedrugof
choice(Marson2007)
41
.ArmBofthepublishedSANADdocumentcollectedandreportedas
baselinedatasyndromedatabutdidnotprovideanalysesstratifiedpersyndromesorcertainseizure
typesandthereforethedatadidnotfollowthesamestratificationthatwasusedintheguideline
evidencereviews.Becauseoftherelativeimportanceofthistrial,wecontactedtheleadauthorto
determinewhetherfurthersubgroupanalysesaccordingtothesyndromes,seizuretypes,and
outcomesofinteresttotheguidelineevidencereviewshadbeenconducted.Unpublisheddataon
thefollowingsubgroupswasprovidedbytheauthors:juvenilemyoclonicepilepsy,absenceseizures
andepilepsywithgeneralisedtonicclonicseizuresonly.Theoutcomesincludedtimeto12month
remission,timetotreatmentfailure,timetofirstseizureandincidenceofadverseevents.When
unpublishedSANADdatahasbeenusedwithintheanalyses,thishasbeenreferencedasworkin
progressintherelevantGRADEprofiletables.ItisalsoincludedwithintheIPDnetworkmeta
analysis
38
.
2.8 Gradingofqualityofevidenceforoutcomes(2012)
Afterresultswerepooled,theoverallqualityofevidenceforeachoutcomewasconsideredusingthe
GRADEsystem.ThefollowingistheprocedureadoptedwhenusingGRADE
1. TheevidenceforalloutcomesstartwithaHIGHqualityratingasonlyRCTswereconsidered.
2. Theratingwasthendowngradedforthespecifiedcriteria:Studylimitations,inconsistency,
indirectness,imprecisionandreportingbias.Thesecriteriaaredetailedbelow.
3. Thedowngrademarksarethensummed.Eachqualityelementbeingconsideredashaving
seriousorveryseriousriskofbiaswererateddown1or2pointsrespectively.Allstudies
TheEpilepsies
Methods
42
startedasHIGHandthequalitybecameMODERATE,LOWorVERYLOWwhen1,2or3points
weredeductedrespectively.
4. Thereasonsorcriteriausedfordowngradingwerespecifiedinthefootnoteswheneverpossible.
Thedetailsofcriteriausedforeachofthemainqualityelementarediscussedbelow:
Inconsistency
Inconsistencyreferstoanunexplainedheterogeneityofresults.Whenestimatesofthetreatment
effectacrossstudiesdifferwidely(i.e.heterogeneityorvariabilityinresults),thissuggeststrue
differencesinunderlyingtreatmenteffect.Whenheterogeneityexists(Chisquarep<0.05orIsquare
50%),butnoplausibleexplanationcanbefound,thequalityofevidencewasdowngradedbyoneor
twolevels,dependingontheextentofuncertaintytotheresultscontributedbytheinconsistencyin
theresults.OntopoftheIsquareandChisquarevaluesthedecisionfordowngradingwasalso
dependentonfactorssuchaswhethertheinterventionisassociatedwithbenefitinallother
outcomesorwhethertheuncertaintyaboutthemagnitudeofbenefit(orharm)oftheoutcome
showingheterogeneitywouldinfluencetheoveralljudgmentaboutnetbenefitorharm(acrossall
outcomes).
Indirectness
Directnessreferstotheextenttowhichthepopulations,intervention,comparisonsandoutcome
measuresaresimilartothosedefinedintheinclusioncriteriaforthereviews.Indirectnessis
importantwhenthesedifferencesareexpectedtocontributetoadifferenceineffectsize,ormay
affectthebalanceofharmsandbenefitsconsideredforanintervention.
Imprecision
Thesamplesize,eventratesandtheresultingwidthofconfidenceintervalswerethemaincriteria
considered.Thecriteriaappliedforimprecisionarebasedontheconfidenceintervalsforpooled
outcomesasillustratedinFigure2.1andoutlinedinTable2.
Figure1: Illustrationofpreciseandimpreciseoutcomesbasedontheconfidenceintervalof
outcomesinaforestplot
TheEpilepsies
Methods
43
MID=minimalimportantdifferencedeterminedforeachoutcome.TheMIDsarethethresholdfor
appreciablebenefitsandharms.Theconfidenceintervalsofthetopthreepointsofthediagramwere
consideredprecisebecausetheupperandlowerlimitsdidnotcrosstheMID.Conversely,thebottom
threepointsofthediagramwereconsideredimprecisebecauseallofthemcrossedtheMIDand
reducedourcertaintyoftheresults.FigureadaptedfromGRADEProsoftware.
Table21:Criteriaappliedtodetermineprecision
Criteriafordowngradinganoutcomeforimprecision
TheGDGdecidedthedifferencethatislikelytobeconsideredclinicallyimportant
withinepilepsyis5%.
TheGDGdiscussedtheissueofimprecisionandtheminimalimportantdifference
atlengthafteritwasraisedbythestakeholderconsultation.AsstatedintheILAE
guidelines "Forinitialmonotherapytrials,a1998guidelineproducedbytheILAE
CommissiononAntiepilepticDrugsestimatedat20%(notstatedwhetherabsolute
orrelativedifference)theminimumoutcomedifferencethatshouldberegardedas
clinicallyimportant.
Afterextensivediscussion,itwasagreedthatanyrelativedifference>20%in
primaryoutcome(effectivenessorefficacy)versusthecomparatorsarm(asdefined
inthestudyprotocol)shouldberegardedasclinicallysignificant").TheGDGsview
isthatsinceseizuresareaseriousevent,a5%riskreductionorriskincrease,whilst
arbitrary,isaclinicallysignificantdifferenceintermsoftheabilityofthestudiesto
detectadifferenceinoutcomeinepilepsy.
Table22: DescriptionofqualityelementsforeconomicevidenceinNICEeconomicprofile
Qualityelement Description
Limitations Thiscriterionrelatestothemethodologicalqualityofcost,costeffectivenessor
netbenefitestimates.
Applicability Thiscriterionrelatestotherelevanceofthestudytothespecificguideline
questionandNICEReferenceCase.
Table23: LevelsforlimitationsforeconomicevidenceinNICEeconomicprofile
Level Description
Minor
limitations
Thestudymeetsallqualitycriteria,orthestudyfailstomeetoneormorequality
criteria,butthisisunlikelytochangetheconclusionsaboutcosteffectiveness.
Serious
limitations
Thestudyfailstomeetoneormorequalitycriteria,andthiscouldchangethe
conclusionaboutcosteffectiveness
TheEpilepsies
Methods
44
Veryserious
limitations
Thestudyfailstomeetoneormorequalitycriteriaandthisisverylikelytochange
theconclusionsaboutcosteffectiveness.Studieswithveryseriouslimitationswould
usuallybeexcludedfromtheeconomicprofiletable.
Table24: LevelsforapplicabilityforeconomicevidenceinNICEeconomicprofile
Level Description
Directly
applicable
Theapplicabilitycriteriaaremet,oroneormorecriteriaarenotmetbutthisis
notlikelytochangethecosteffectivenessconclusions.
Partially
applicable
Oneormoreoftheapplicabilitycriteriaarenotmet,andthismightpossibly
changethecosteffectivenessconclusions.
Notapplicable Oneormoreoftheapplicabilitycriteriaarenotmet,andthisislikelytochange
thecosteffectivenessconclusions.
Anoverallscoreoftheevidenceisnotgivenasitisnotclearhowthequalityelementscouldbe
summarisedintoasinglequalityrating.
Alimitednumberofpublishedeconomicevaluationswereidentifiedforinclusion,andmost
simultaneouslycomparedmultipledrugoptions.Insteadofdisaggregatingthecompleteincremental
analysisfromeachstudytopresentallpossiblepairwisecomparisonsalongwiththedirectevidence,
studyresultswerepresentedasawholeattheendofagivenevidencereview.Ahealtheconomic
evidencesectionandevidencestatementaccompanieseachpairwisecomparisonanddirects
readerstothecompleteeconomicresultsattheendofthereview.There,atablesummarisingthe
studycharacteristicsofallincludedstudiesispresentedandfollowedbyincrementalanalysisresults
tablesforeachstudywithasummaryofanalysisuncertainty.Finally,eachstudyisfollowedbya
seriesofsummaryevidencestatements.
2.8.1 Healtheconomicsmethods
2004
Identifiedtitlesandabstractsfromtheeconomicssearcheswerereviewedbythehealtheconomist
andfullpapersobtainedasappropriate.Thefullpaperswerecriticallyappraisalbythehealth
economistusingastandardvalidatedchecklist.
42
.Ageneraldescriptiveoverviewofthestudies,their
qualities,andconclusionswaspresentedandsummarizedintheformofashortnarrativereview.
Theeconomicevidencewasnotsummarizedintheformofmetaanalysesgiventhelimitedevidence
found.
TheGDGidentifiedtheissueofthecostsofmisdiagnosisinepilepsyasanimportantareaforfurther
economicanalysis.Thischoicewasmadeonthegroundsthatthemisdiagnosisofepilepsyis
commonandislikelytoleadtosignificantdirectcoststotheNHS,andtosocietyasawhole.At
presentthecostsofmisdiagnosistotheNHSareuncertain.Theresultsofthisanalysisarepresented
inAppendixG.
TheEpilepsies
Methods
45
2012
Itisimportanttoinvestigatewhetherhealthservicesarecosteffective(thatis,valueformoney).Ifa
particulartreatmentstrategywerefoundtoyieldlittlehealthgainrelativetotheresourcesused,
thenitwouldbeadvantageoustoredeployresourcestootheractivitiesthatyieldgreaterhealth
gain.
InaccordancewiththeNICEsocialvaluejudgementspaper
,theprimarycriteriaappliedforan
interventiontobeconsideredcosteffectivewereeither:
a) Theinterventiondominatedotherrelevantstrategies(thatis,itisbothlesscostlyintermsof
resourceuseandmoreclinicallyeffectivecomparedwithalltheotherrelevantalternative
strategies),or
b) Theinterventioncostlessthan20,000perqualityadjustedlifeyear(QALY)gained
comparedwiththenextbeststrategy.
Thefulleconomicevaluationofanystrategyhastobeincomparisonwithanotherstrategy.Hence
wereferto:
incrementalcost:themeancostofonestrategyminusthemeancostofacomparatorstudy
QALYsgained:themeanQALYsassociatedonestrategyminusthemeanQALYsofacomparator
study
incrementalcosteffectivenessratio:theincrementalcostdividedbytherespectiveQALYsgained
incrementalnetbenefit(INB):the(monetary)valueofastrategycomparedwithanalternative
strategyforagivencosteffectivenessthreshold(Forexample:20,000perQALYgained).
Inourowncosteffectivenessanalysis,weusethefollowingformulatoestimatetheINBofeach
strategy:
INB=(QALYsgainedcomparedwithabaselinedrugx20,000)minustheincrementalcost
comparedwithabaselinedrug.
Thisindicatesthatwewillinvestupto20,000togainoneadditionalQALY.Thestrategythathasthe
highestINBistheoptimal(thatis,mostcosteffective)strategy.StrategiesthathaveanegativeINB
arenotcosteffectiveevencomparedwiththebaselinedrug.
2.8.2 Literaturereviewforhealtheconomics
Ahealtheconomistreviewedtheabstracts.Relevantreferencesinthebibliographiesofreviewed
paperswerealsoidentifiedandreviewed.
Fulleconomicevaluations(costeffectiveness,costutility,costbenefitandcostconsequence
analyses)andcomparativecostingstudiesthataddressedthereviewquestionintherelevant
populationwereconsideredpotentiallyapplicableaseconomicevidence.Thesamepopulationand
interventioncriteriawereappliedasintheclinicalreview.
Studiesthatonlyreportedaveragecosteffectivenesswithoutdisaggregatedcostsandeffects,were
excluded.Abstracts,posters,reviews,letters/editorial,foreignlanguagepublicationsand
unpublishedstudieswereexcluded.Studiesjudgedtohaveanapplicabilityratingofnotapplicable
wereexcluded(thisincludedstudiesthattooktheperspectiveofanonOECDcountry).Studiesthat
werereviewpreviouslyaspartofTA76orTA79werealsoexcludedfromthisreview.
http://www.nice.org.uk/aboutnice/howwework/socialvaluejudgements/socialvaluejudgements.jsp
TheEpilepsies
Methods
46
RemainingstudieswereprioritisedforinclusionbasedontheirrelativeapplicabilitytothecurrentUK
NHSsituationanddevelopmentofthisguideline,andthestudylimitations.Forexample,ifahigh
quality,directlyapplicableUKanalysisisavailableotherlessrelevantstudiesmaynotbeincluded.
Whereexclusionsoccurredonthisbasis,thisisnotedintherelevantevidencesection.
Includedpaperswerecriticallyappraisedbyahealtheconomistusingthequalityandapplicability
checklistoutlinedintheNICEguidelinesmanual2009
36
.Ifapaperwasincluded,costs,outcomes
andadescriptionofitsqualityandapplicabilitywerepresentedintheeconomicevidencetablewith
abriefdescription.EconomicevidencetablesforincludedstudiesarepresentedinAppendixM.
Eachstudywascategorisedasoneofthefollowing:costanalysis,costeffectivenessanalysis,cost
utilityanalysis(thatis,costeffectivenessanalysiswitheffectivenessmeasuredintermsofQALYs),or
costconsequencesanalysis.Wedidnotfindanycostbenefitanalyses(studiesthatputamonetary
valueonhealthgain).
Modelsareanalogoustosystematicreviewsastheyarepoolingevidencefromanumberofdifferent
studiesandthereforeifwellconductedtheyshouldoutrankstudiesbasedonasingleRCT.
Statisticalsignificanceisnotusuallyapplicabletomodelsanduncertaintyisexploredusingsensitivity
analysisinstead.Hencetheresultsreportedinoureconomicsevidencetablesandwriteupmaynot
necessarilyimplystatisticalsignificance.
Westatethatcosteffectivenessisindeterminableincaseswhereoutcomesareexpressedonlyin
termsofseizuresavoidedorpercentofsuccessfullytreatmentpatientsratherthanoverallhealth
outcomesandwhereoneinterventionisbothmorecostlyandmoreeffective.
2.8.2.1 Costeffectivenessmodelling
Fiveeconomicmodelsweredevelopedaspartoftheguidelinedevelopment,oneforeachofthe
followingclinicalareas:
a) Monotherapyforadultswithnewlydiagnosedfocalepilepsy
b) Adjunctivetherapyforadultswithrefractoryfocalepilepsy
c) Monotherapyforchildrenwithnewlydiagnosedfocalepilepsy
d) Adjunctivetherapyforchildrenwithrefractoryfocalepilepsy
e) Adjunctivetherapyforadultswithrefractorygeneralisedtonicclonicseizures
Thefollowinggeneralprincipleswereadheredto:
TheGDGwasconsultedduringtheconstructionandinterpretationofthemodel.
Themodelwasbasedonthesystematicreviewofclinicalevidence.
Modelassumptionswerereportedfullyandtransparently.
Theresultsweresubjecttothoroughsensitivityanalysisandlimitationsdiscussed.
Costswerecalculatedfromahealthservicesperspective.
Effectsweremeasuredintermsofqualityadjustedlifeyears.
Thedetailsofthemethods,assumptions,resultsandlimitationsofeacheconomicmodelare
describedinAppendicesPthroughS.
2.9 Developingrecommendations
2004
TheEpilepsies
Methods
47
Foreachkeyclinicalquestion(KCQ),therecommendationswerederivedfromtheevidence
statementspresentedtotheGDG.Thelinkbetweentheevidencestatementandrecommendation
wasmadeexplicit.TheGDGwereabletoreachtheiragreedrecommendationsthroughaprocessof
informalconsensus.
Eachrecommendationwasgradedaccordingtothelevelofevidenceuponwhichitwasbasedusing
theestablishedgradingofrecommendationstablepresentedinsection12ofthischapter.For
questionsrelatingtotherapy/treatment,thebestpossiblelevelofevidence(asystematicreviewor
metaanalysisoranindividualRCT)wouldequatetoagradeArecommendation.Forquestions
relatingtoprognosisanddiagnostictests,thebestpossiblelevelofevidence(acohortstudy)would
equatetoagradeBrecommendation.Forquestionsrelatingtoinformationneedsandsupport,the
bestpossiblelevelofevidence(descriptivestudy)wouldequatetoagradeCrecommendation.Itis
importantthatthegradinginsuchareasisnottreatedasinferiortothoseoftherapyasitrepresents
thehighestlevelofrelevantevidence.
2012
FourmainareaswereconsideredintheGDGdiscussionsrelatingtointerpretingevidencetomake
recommendations.Thesewere:relativevalueplacedontheoutcomesconsideredimportantfor
decisionmaking;balancingtheclinicalbenefitsandharmsofanintervention;includingcost
effectiveness(economicconsiderations)andassessingthequalityofevidence(potentialbiasand
uncertaintyintheclinicalandeconomicevidence).Lastly,theGDGhadtheobligationtoinclude
otherconsiderationsinrelationtotheirresponsibilitiesunderequalitieslegislationandNICEs
equalityscheme(www.nice.org.uk/aboutnice/howwework/NICEEqualityScheme.jsp).
Overthecourseoftheguidelinedevelopmentprocess,theGDGwaspresentedwiththefollowing:
Evidencetablesoftheclinicalandeconomicevidencereviewed.Allevidencetablesarein
appendixL.
Summaryofclinicalevidenceandquality(aspresentedinevidencereviewsectionin
appendixN.
Adescriptionofthemethodsandresultsofthecosteffectivenessanalysis(appendicesPS)
Recommendationsweredraftedonthebasisofthisevidencewheneveritwasavailable.When
clinicalandeconomicevidencewaspoororabsent,theGDGdraftedrecommendationsbasedon
theirclinicalexpertise.TheGDGaddedsupportingrecommendationswheneveritwasnecessaryin
ordertoimproveclinicalpractice.Thesupportingrecommendationswerenotderivedfromclinical
questionsandwerebasedonGDGexpertopinion.Thedevelopmentoftherecommendations
requiredseveralsteps:
Wheneverpossible,apreliminarydraftrecommendationwaspresentedbyNCGCstaffafter
eachsummaryofevidencepresentationduringGDGmeetings.Thisdraftwasdiscussedand
modifiedbythegrouptoformthefirstdraftrecommendation.
Wherenecessary,NCGCstaffsuggestedmodificationstothedraftrecommendationsasa
resultofthediscussionandinthelightofNICEguidanceonwritingrecommendations.
Towardstheendoftheguidelinedevelopmentprocess,alistofallthedraft
recommendationswassenttotheGDGmembers.TheGDGmembersindependently
completedaconsensusexercisetofeedbackcommentsandlevelofagreementoneach
recommendation.ThisprocedureallowedtheNCGCtoverifythelevelofagreement
betweentheGDGmembers.
TheEpilepsies
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48
AllGDGfeedbackwascollatedandcirculatedagaintotheGDG.Therecommendationswhich
didnothaveunanimousagreementwerediscussedagainduringaGDGmeetingbeforebeing
finalised.
Duringthewritingupphaseoftheguideline,theGDGcouldfurtherrefineeach
recommendationworkinginsubgroupsoneachchapter.
NCGCstaffverifiedtheconsistencyofallrecommendationsacrosstheguideline.
2.10 ResearchRecommendations
2.10.1 Newlydiagnosedseizures(focalandgeneralised)monotherapy
HowdothenewerAEDscompareinefficacytothestandardAEDsinthetreatmentofnewly
diagnosedepilepsy?
Focalseizures:carbamazepine,eslicarbazepineacetate,lacosamide,lamotrigine,
levetiracetam,pregabalinandzonisamide.
Generalisedseizures:lamotrigine,levetiracetam,sodiumvalproateandzonisamide.
Whythisisimportant
LevetiracetamandotherAEDslicensedforthetreatmentoffocalandgeneralisedseizuressince
publicationoftheoriginalguidelineTheepilepsies(NICEclinicalguideline20)in2004havenotbeen
evaluatedasfirstlinemonotherapy.
Theresearchshouldinclude:
aprospectiverandomisedcontrolledtrial
allagegroups
subgroupanalysesonseizuretypesandsyndromes
primaryoutcomeofseizurefreedom
secondaryoutcomes,includingseizurereduction,qualityoflifeandcognitiveoutcome
anattempttoobtaindataonpharmacoresistance.
2.10.2 Epilepsysyndromes
WhataretheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswith
onsetinchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome?
Whythisisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidenceonthemost
appropriateinitialoraddonAEDsinthetreatmentoftherarerepilepsies.
multicentrerandomisedcontrolledcomparativetrialswithcentralisednationaldata
collection
theketogenicdietasoneoftherandomisedtreatments
TheEpilepsies
Methods
49
anattempttoobtaindataonpharmacoresistance
thepossibilityofincludingallchildrenwithspecificepilepsysyndromesforconsiderationin
thetrial.
2.10.3 Infantilespasms
Doestreatmentresponserelatetocauseininfantilespasms?Doesearlytreatmentsuccessinseizure
controlandresolutionofthehypsarrhythmicEEGinfluencethelongtermdevelopmentaland
cognitiveoutcomesmorethantheunderlyingcauseofthespasms?
Whythisisimportant
TheUKInfantileSpasmsStudy(UKISS)demonstrated14dayoutcomeefficacyofsteroidsover
vigabatrin,althoughthisexcludedchildrenwithtuberoussclerosis.Thisstudyprovidednospecific
subgroupanalysisbasedonthecauseofthespasms.Therewasalsonoanalysisontheeffectof
treatmentlag(delay)onthestudyfindings.Furtherdataareavailableonbehaviouraloutcomeswith
differenttreatmentsat14monthsand4yearsbutwithnoanalysisbasedoncauseortreatmentlag.
Furtherdevelopmentalandcognitiveoutcomeswouldbeuseful,includingresponsebyspecificcause
andbytreatmentlag.
prospectiverandomiseddesign,includingsubgroupanalysesbasedonbothcauseand
treatmentlag;thiswouldrequirelargenumbersofpatientsandwouldneedtobe
multicentre,possiblyinvolvingWesternEurope
EEGoutcomes
developmentalstatusatpresentation,andatfollowup
2.10.4 Treatmentofconvulsivestatusepilepticus(i.e.notjustrefractory)
WhatisthemosteffectiveandsafestAEDtotreat:
established(usuallylastinglongerthan30minutes)convulsivestatusepilepticus
refractoryconvulsivestatusepilepticus?
Whythisisimportant
Convulsivestatusepilepticus(CSE)shouldbetreatedasanemergency.Themostimportantaspectof
treatmentistotrytostoptheseizure.Prompt,successfultreatmentofCSEavoidstheneedfor
admissiontoanintensivecareunit(ICU).Themostcommonlyusedmedicationisphenytoin.This
shouldbeusedwithcareandclosemonitoringbecauseoftheriskofhypotensionandcardiac
arrhythmia.Sodiumvalproateandlevetiracetamarepotentiallyaseffectiveandsaferalternatives
butthereareverylimitedcomparativedata.
CSEthatisrefractorytofirstlinetreatment(RCSE)israreandoftencomplicatedbyirreversible
neurologicalandintellectualsequelae,includingdeath.Reasonsforthesecomplicationsincludethe
underlyingcauseofRCSE,itsdurationandmanagement.Themajority,ifnotallpatientswithRCSE
aremanagedinanICU.TherearenoagreeddrugsortreatmentprotocolsfortreatingRCSE.The
threemostcommonlyusedanticonvulsantsarethiopentalsodium,midazolamandpropofol
(propofolisrarelyusedinchildren).Dataontreatmentinchildren,youngpeopleandadultsare
TheEpilepsies
Methods
50
limitedandanecdotal.Arecentlycompleted2yearauditofeveryoneyoungerthan16yearswith
RCSEtreatedinanICUinEngland,WalesandScotlandwillprovideuniqueepidemiologicaldataon
paediatricRCSE,itscausesandcurrentmanagement.Thesedatacouldbeusedtodesigna
randomisedcontrolledtrial(RCT)ofspecificdrugtreatmentsandprotocols.
amulticentrerandomisedcomparativetrialofintravenouslevetiracetam,sodiumvalproateand
phenytoinininitialtreatmentofstatusepilepticus
amulticentreRCToftreatmentofrefractorystatusepilepticusinICUs,includingmidazolamand
thiopentalsodium(andpropofolinadults)
primaryoutcomeofcessationofCSE
secondaryoutcomesincludingrecurrencewithinadesignatedperiod(probably12hours),
mortalityandmorbidity
costdataincludingtreatmentcostsanddaysinintensivecare.
2.10.5 AEDsandpregnancy
Whatisthemalformationrateandlongertermneurodevelopmentaloutcomeofchildrenbornto
motherswhohavetakenAEDsduringpregnancy?
Whythisisimportant
PregnancyregistersareincreasingthedatathatareavailableonestablishedAEDs;however,these
registersmaygivemalformationratesbutdonotprovidecontrolledlongtermdataon
neurodevelopmentaloutcome.
measuresofmaternaloutcome,includingseizurefrequencyandqualityoflife
majorandminorratesofcongenitalmalformations
prospectiveneurodevelopmental(includingcognitive)andbehaviouraloutcomesinchildren
borntowomenandgirlswithepilepsy(theseshouldbeundertakenonalongtermbasisand
ideallyusingacohortstudy,followedfrombirthuntiladultlife).
2.10.6 Ketogenicdietinadults
Whatistheeffectivenessandtolerabilityoftheketogenicdietinadultswithepilepsy?
Whyisthisimportant?
Therearenodataontheuseoftheketogenicdietinadults.Thismayreflectthefactthatthediet
hasbeenshowntobeineffectiveandtheresultsunpublished,or,asismorelikely,thatthediethas
neverbeenusedinthisagegroup.Inviewofthenumerousanecdotalandrandomisedcontrolled
datademonstratingitseffectivenessandthatthenumberofantiepilepticdrugsprescribedmaybe
reducedasaresultofthisdietaryapproachinthepaediatricepilepsies,itisappropriatetoundertake
arandomisedcontrolledtrialofketogenicdietinadultpatientswithdrugresistantepilepsy.
aninitialpilotstudyofthefeasibilityandacceptabilityoftheketogenicdietinadultswhoare
independentinactivitiesofdailylivingandwhohavenolearningdifficulties
TheEpilepsies
Methods
51
ifthepilotstudyindicatesthattheketogenicdietisfeasibleandacceptable,amulticentre
randomisedcontrolledstudyshouldbedesigned;thiscouldevaluateoneormorevariantsof
thedietversusanormaldiet
primaryoutcomewouldbereductioninseizurefrequency
secondaryoutcomeswouldincludequalityoflifeandreductionofantiepilepticdrugburden
costdatashouldincludethetotalcostofthediet(includingdieteticsupport),reduceddrug
costsandreducedadmissions
2.11 Prioritisationofrecommendationsforimplementation
2012
Toassistusersoftheguidelineindecidingtheorderinwhichtoimplementtherecommendations,
theGDGidentifiedtenkeyprioritiesforimplementation.Thedecisionwasmadeafterdiscussionand
votingbytheGDG.Theyselectedrecommendationsthatwoulddoatleastoneofthefollowing
actions:
haveahighimpactonoutcomesthatareimportanttopatients
haveahighimpactonreducingvariationincareandoutcomes
leadtoamoreefficientuseofNHSresources
promotepatientchoice
promoteequalities
IndoingthistheGDGalsoconsideredwhichrecommendationswereparticularlylikelytobenefit
fromimplementationsupport.Theyconsideredwhetherarecommendation:
relatestoaninterventionthatisnotpartofroutinecare
requireschangesinservicedelivery
requiresretrainingstafforthedevelopmentofnewskillsandcompetencies
highlightstheneedforpracticetochange
affectsandneedstobeimplementedacrossvariousagenciesorsettings(complex
interactions)
maybeviewedaspotentialcontentious,ordifficulttoimprementforotherreasons.
2.12 TherelationshipbetweentheguidelineandtheTechnology
Appraisalsforthenewerantiepilepticdrugs(AEDs)
2004
Theguidelinewasdevelopedinparallelwithtwotechnologyappraisalswhoseremitwastoestablish
theclinicalandcosteffectivenessofnewerdrugsforadultsandchildrenwithepilepsyandtoprovide
guidancetotheNHSinEnglandandWales
43
(www.nice.org.uk).
Theprojectleadoftheguidelineworkedwiththetechnicalleadonthetechnologyappraisalsto
ensurethatthereleaseofthefinalappraisaldeterminationcoincidedwiththecompletionofthefirst
draftoftheguidelineandthattherewasappropriateexchangeofinformationduringthe
TheEpilepsies
Methods
52
developmentprocess.Inparticular,itwasimportanttoensurethattherewasnoconflictbetween
therecommendationsoftheguidelineandthetechnologyappraisals.
Theappraisalrecommendations,astheyrelatetothetechnologyunderreview,havebeen
reproducedunchangedinthemostappropriatesectionwithintheguideline,asrequiredbythe
Institute.TheyhavebeengradedA(NICE)asthisreflectsthecomprehensiveevidencebaseand
rigorousevaluationonwhichtheInstitutesappraisalrecommendationswerebased.Theevidence
statementstakenfromtherelevantappraisalhavealsobeenpresentedintherelevantchapter.
Wheretheappraisalsmadeadditionalrecommendationsinareasthatwerecoveredindetailbythe
scopeoftheguideline,theprojectleadnegotiatedwiththeInstitutethattheGDGs
recommendations,andnotthoseofthetechnologyappraisal,appearedinthepublishedguideline.
2012
The2012guidelinepartiallyupdatedthe2004guidelineandthetwotechnologyappraisalslisted
above.ThisupdatehasreviewedadditionalpublishedevidenceontheAEDSincludedinthe2004
guidelinetechnologyappraisals.Therefore,the2012recommendationssupersedethosecontained
intheappraisalspublishedin2003.FurthernewerAEDswerealsoincludedinthe2012guideline.
2.13 TherelationshipbetweentheguidelineandNationalService
Frameworks
2004
ThisguidelinewasdevelopedatthesametimeastworelevantNationalServiceFrameworks(NSFs):
thoseforlongtermconditions(focusingonneurologicalconditions)andchildren.NSFshavea
differentremitthanclinicalguidelines.Aclinicalguidelineaimstoassistpractitionerandpatient
decisionsaboutappropriatehealthcareforspecificclinicalcircumstances,
44
whereasanNSFis
primarilyconcernedaboutservicedelivery.Thus,NSFssetnationalstandardsandidentifykey
interventionsforadefinedserviceorcaregroup;putinplacestrategiestosupportimplementation;
establishwaystoensureprogresswithinanagreedtimescaleandformoneofarangeofmeasures
toraisequalityanddecreasevariationsinservice.
Itisthereforeoutsidethescopeofthisguidelinetoconsiderissuesofservicedeliveryandthe
emphasisisonprovidingaprocessofcarenecessaryfortheindividualwithepilepsytoachievethe
bestpossiblehealthoutcomes.
2.14 TherelationshipbetweentheguidelineandtheScottish
IntercollegiateGuidelinesNetworkguidelinesonepilepsy
2004
TheInstitutereceivedtheremittodevelopaclinicalguidelineonepilepsyfortheNHSinEnglandand
WalesfromtheDepartmentofHealthandNationalAssemblyforWalesinJuly2001aspartofits6th
waveprogrammeofwork.Concurrentlywiththiscommission,theScottishIntercollegiateGuidelines
Network(SIGN)wereintheprocessofupdatingclinicalguidelinesonthediagnosisand
managementofepilepsyinadults(publishedApril2003)anddevelopingguidelinesforthediagnosis
andmanagementofepilepsyinchildrenandyoungpeople(publicationdate2004).
AspartofapolicyofjointworkingbetweentheInstituteandSIGN,aworkingrelationshipwas
establishedbetweentheprojectleadandhisrespectivecolleaguesinSIGN.Itwasagreedthatthe
NCCPCandSIGNteamswouldsharerelevantsearchesandevidencereviewsbutwouldeachmake
theirownseparateguidelinerecommendationsasrequiredbytheirrespectiveguideline
TheEpilepsies
Methods
53
methodologies.Itwashopedthisprocesswouldminimisetheriskoftwonationalgroupsmaking
conflictingrecommendationsforclinicalpracticeinthesameclinicalarea.
2.15 Externalreview
2004
TheguidelinehasbeendevelopedinaccordancewiththeInstitutesguidelinedevelopmentprocess.
Thishasincludedallowingregisteredstakeholderstheopportunitytocommentonthescopeofthe
guideline,thefirstdraftofthefullandshortformguidelineandthefinaldraftoftheguideline.In
addition,thefirstdraftwasreviewedbynominatedindividualswithaninterestinepilepsyandan
independentGuidelineReviewPanel(GRP)establishedbytheInstitute.
Thecommentsmadebythestakeholders,peerreviewersandtheGRPwerecollatedandpresented
anonymouslyforconsiderationbytheGDG.Allcommentswereconsideredsystematicallybythe
GDGandtheprojectteamrecordedtheagreedresponses.
2012
Theexternalreviewprocessforthisguidelineremainsasperthe2004guideline.The2012guideline
developmentprocesshasfollowedtheguidancecontainedwithintheNICEGuidelinesManual
(2009).
Inaddition,thefinaldraftoftheguidelinewasreviewedbyexpertpeerreviewersandan
independentGuidelineReviewPanel(GRP)establishedbytheInstitute.Afurtherstepwasadded
followingtheGRPreview:anexternalprepublicationconsultationprocesswasundertakentoallow
forfactualinaccuraciestobecorrectedpriortopublication
Thecommentsmadebythestakeholders,peerreviewersandtheGRPwerecollatedandpresented
anonymouslyforconsiderationbytheGDG.Allcommentswereconsideredsystematicallybythe
GDGandtheprojectteamrecordedtheagreedresponses
2.16 Levelofevidencetable
2004
Table2.5Levelofevidencetable
Hierarchyofevidence
IaSystematicreviewormetaanalysisofrandomisedcontrolledtrials
IbAtleastonerandomisedcontrolledtrial
IIaAtleastonewelldesignedcontrolledstudywithoutrandomisation
IIbAtleastonewelldesignedquasiexperimentalstudy,suchasacohortstudy
IIIWelldesignednonexperimentaldescriptivestudies,casecontrolstudies,and
TheEpilepsies
Methods
54
caseseries
IVExpertcommitteereports,opinionsand/orclinicalexperienceofrespectedauthorities
NICEguidelinesorHealthTechnologyAppraisalprogramme
TheEpilepsies
Keyprioritiesforimplementation
55
3 Keyprioritiesforimplementation
Diagnosis
Allchildren,youngpeopleandadultswitharecentonsetsuspectedseizureshouldbeseen
urgently
**
byaspecialist
.Thisistoensurepreciseandearlydiagnosisandinitiationoftherapyas
appropriatetotheirneeds.[2004]
Management
Healthcareprofessionalsshouldadoptaconsultingstylethatenablesthechild,youngperson
oradultwithepilepsy,andtheirfamilyand/orcarersasappropriate,toparticipateaspartnersinall
decisionsabouttheirhealthcare,andtakefullyintoaccounttheirrace,cultureandanyspecific
needs.[2004]
Allchildren,youngpeopleandadultswithepilepsyshouldhaveacomprehensivecareplan
thatisagreedbetweentheperson,theirfamilyand/orcarersasappropriate,andprimaryand
secondarycareproviders.[2004]
TheAED(antiepilepticdrug)treatmentstrategyshouldbeindividualisedaccordingtothe
seizuretype,epilepsysyndrome,comedicationandcomorbidity,thechild,youngpersonoradults
lifestyle,andthepreferencesoftheperson,theirfamilyand/orcarersasappropriate.[2004]
Prolongedorrepeatedseizuresandconvulsivestatusepilepticus
Administerbuccalmidazolamasfirstlinetreatmentinchildren,youngpeopleandadults
withprolongedorrepeatedseizures.Administerrectaldiazepam
g
ifpreferredorifbuccalmidazolam
isnotavailable.Ifintravenousaccessisalreadyestablishedandresuscitationfacilitiesareavailable,
administerintravenouslorazepam.[new2012]
Onlyprescribebuccalmidazolam
orrectaldiazepam
g
foruseinthecommunityforchildren,
youngpeopleandadultswhohavehadapreviousepisodeofprolongedorserialconvulsiveseizures.
[new2012]
Specialconsiderationsforwomenandgirlsofchildbearingpotential
Womenandgirlswithepilepsyandtheirpartners,asappropriate,mustbegivenaccurate
informationandcounsellingaboutcontraception,conception,pregnancy,caringforchildren,
breastfeedingandmenopause.[2004]
Reviewandreferral
Allchildren,youngpeopleandadultswithepilepsyshouldhavearegularstructuredreview.
Inchildrenandyoungpeople,thisreviewshouldbecarriedoutatleastyearly(butmaybebetween3
and12monthsbyarrangement)byaspecialist.Inadults,thisreviewshouldbecarriedoutatleast
yearlybyeitherageneralistorspecialist,dependingonhowwelltheepilepsyiscontrolledand/or
thepresenceofspecificlifestyleissues.[2004]
Atthereview,children,youngpeopleandadultsshouldhaveaccessto:writtenandvisual
information;counsellingservices;informationaboutvoluntaryorganisations;epilepsyspecialist
**
TheGuidelineDevelopmentGroupconsideredthaturgentlymeantbeingseenwithin2weeks.
Foradults,aspecialistisdefinedthroughoutasamedicalpractitionerwithtrainingandexpertiseinepilepsy.Forchildren
andyoungpeople,aspecialistisdefinedthroughoutasapaediatricianwithtrainingandexpertiseinepilepsy
TheEpilepsies
Keyprioritiesforimplementation
56
nurses;timelyandappropriateinvestigations;referraltotertiaryservices,includingsurgeryif
appropriate.[2004]
Ifseizuresarenotcontrolledand/orthereisdiagnosticuncertaintyortreatmentfailure,
children,youngpeopleandadultsshouldbereferredtotertiaryservicessoon
forfurther
assessment.[2004]
TheGuidelineDevelopmentGroupconsideredthatsoonmeantbeingseenwithin4weeks.
TheEpilepsies
Guidance
57
4 Guidance
Note:seeappendixKforfurtherdetailsofpharmacologicaltreatment.
Therecommendationsmadeforpharmacologicaltreatmenthavebeenplacedtogetherhereinthis
summaryofrecommendations.Therecommendationsforeachseizuretypeandepilepsysyndrome
differandshouldbereadinconjunctionwiththerelevantsectionoftheguidelineforclarity
TheGDGisawareofthecontraindicationstoprescribingcarbamazepinetosomepeopleofHan
ChineseorThaiorigin.Recommendationsinthissectionofferalternatives,andsonospecific
recommendationsaremadeforthesegroups.
TheGDGisalsoawareofspecificissueswithprescribingsodiumvalproatetogirlsandwomenof
childbearingage.Recommendationsinthissectionofferalternativeprescribingoptionsforthis
group.Recommendations65,73,83,207and212alsoprovideadditionalspecificinformationof
relevancewhenconsideringprescribingAEDstowomenofchildbearingage.
NICEhasalsoissuedguidanceontheuseofretigabineasanoptionfortheadjunctivetreatmentof
partial(thetermfocalhasbeenusedinthisguideline)onsetseizureswithorwithoutsecondary
generalisationinadultsaged18yearsandolderwithepilepsyinRetigabinefortheadjunctive
treatmentofpartialonsetseizuresinepilepsy(NICEtechnologyappraisalguidance232).
Generalrecommendations
1. Healthcareprofessionalsshouldadoptaconsultingstylethatenablesthechild,youngpersonor
adultwithepilepsy,andtheirfamilyand/orcarersasappropriate,toparticipateaspartnersinall
decisionsabouttheirhealthcare,andtakefullyintoaccounttheirrace,cultureandanyspecific
needs.[2004]
2. Thediagnosisofepilepsyinadultsshouldbeestablishedbyaspecialistmedicalpractitionerwith
trainingandexpertiseinepilepsy.[2004]
3. Thediagnosisofepilepsyinchildrenandyoungpeopleshouldbeestablishedbyaspecialist
paediatricianwithtrainingandexpertiseinepilepsy.[2004]
4. Itisrecommendedthatalladultshavingafirstseizureshouldbeseenassoonaspossible
bya
specialistinthemanagementoftheepilepsiestoensurepreciseandearlydiagnosisandinitiation
oftherapyasappropriatetotheirneeds.[2004]
5. Itisrecommendedthatallchildrenandyoungpeoplewhohavehadafirstnonfebrileseizure
shouldbeseenassoonaspossible
byaspecialistinthemanagementoftheepilepsiestoensure
preciseandearlydiagnosisandinitiationoftherapyasappropriatetotheirneeds.[2004]
6. Adetailedhistoryshouldbetakenfromthechild,youngpersonoradultandaneyewitnesstothe
attack,wherepossible,todeterminewhetherornotanepilepticseizureislikelytohaveoccurred.
[2004]
7. Theclinicaldecisionastowhetheranepilepticseizurehasoccurredshouldthenbebasedonthe
combinationofthedescriptionoftheattackanddifferentsymptoms.Diagnosisshouldnotbe
basedonthepresenceorabsenceofsinglefeatures.[2004]
8. Theinformationthatshouldbeobtainedfromtheadultand/orfamilyorcarerafterasuspected
seizureiscontainedinAppendixA.[2004]
TheGuidelineDevelopmentGroupconsideredthatwitharecentonsetsuspectedseizure,referralsshouldbeurgent,
meaningthatpatientsshouldbeseenwithin2weeks.
TheEpilepsies
Guidance
58
9. Theinformationthatshouldbeobtainedfromthechildoryoungpersonand/orparentorcarer
afterasuspectedseizureiscontainedinAppendixA.[2004]
10.Inachild,youngpersonoradultpresentingwithanattack,aphysicalexaminationshouldbe
carriedout.Thisshouldaddresstheircardiac,neurologicalandmentalstatus,andshouldinclude
adevelopmentalassessmentwhereappropriate.[2004]
11.Itmaynotbepossibletomakeadefinitediagnosisofepilepsy.Ifthediagnosiscannotbeclearly
established,furtherinvestigations(seesection8)and/orreferraltoatertiaryepilepsyspecialist
(seerecommendation170)shouldbeconsidered.Followupshouldalwaysbearranged.[2004]
12.Wherenonepilepticattackdisorderissuspected,suitablereferralshouldbemadeto
psychologicalorpsychiatricservicesforfurtherinvestigationandtreatment.[2004]
13.Prospectiverecordingofevents,includingvideorecordingandwrittendescriptions,canbevery
helpfulinreachingadiagnosis.[2004]
14.AnEEGshouldbeperformedonlytosupportadiagnosisofepilepsyinadultsinwhomtheclinical
historysuggeststhattheseizureislikelytobeepilepticinorigin.[2004]
15.AnEEGshouldbeperformedonlytosupportadiagnosisofepilepsyinchildrenandyoungpeople.
IfanEEGisconsiderednecessary,itshouldbeperformedafterthesecondepilepticseizurebut
may,incertaincircumstances,asevaluatedbythespecialist,beconsideredafterafirstepileptic
seizure.[2004]
16.AnEEGshouldnotbeperformedinthecaseofprobablesyncopebecauseofthepossibilityofa
falsepositiveresult.[2004]
17.TheEEGshouldnotbeusedtoexcludeadiagnosisofepilepsyinachild,youngpersonoradultin
whomtheclinicalpresentationsupportsadiagnosisofanonepilepticevent.[2004]
18.TheEEGshouldnotbeusedinisolationtomakeadiagnosisofepilepsy.[2004]
19.Children,youngpeopleandadultsrequiringanEEGshouldhavethetestperformedsoon
afterit
hasbeenrequested.[2004]
20.AnEEGmaybeusedtohelpdetermineseizuretypeandepilepsysyndromeinchildren,young
peopleandadultsinwhomepilepsyissuspected.Thisenablesthemtobegiventhecorrect
prognosis.[2004]
21.Forchildren,youngpeopleandadultsinwhomepilepsyissuspected,butwhopresentdiagnostic
difficulties,specialistinvestigationsshouldbeavailable.[2004]
22.RepeatedstandardEEGsmaybehelpfulwhenthediagnosisoftheepilepsyorthesyndromeis
unclear.However,ifthediagnosishasbeenestablished,repeatEEGsarenotlikelytobehelpful.
[2004]
23.RepeatedstandardEEGsshouldnotbeusedinpreferencetosleeporsleepdeprivedEEGs.[2004]
24.WhenastandardEEGhasnotcontributedtodiagnosisorclassification,asleepEEGshouldbe
performed.[2004]
25.Inchildrenandyoungpeople,asleepEEGisbestachievedthroughsleepdeprivationortheuseof
melatonin
.[2004,amended2012]
Inthisrecommendation,centrehasbeenreplacedwithspecialistforconsistencyacrossrecommendations.
TheEpilepsies
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26.LongtermvideoorambulatoryEEGmaybeusedintheassessmentofchildren,youngpeopleand
adultswhopresentdiagnosticdifficultiesafterclinicalassessmentandstandardEEG.[2004]
27.Provocationbysuggestionmaybeusedintheevaluationofnonepilepticattackdisorder.
However,ithasalimitedroleandmayleadtofalsepositiveresultsinsomepeople.[2004]
28.PhoticstimulationandhyperventilationshouldremainpartofstandardEEGassessment.The
child,youngpersonoradultandfamilyand/orcarershouldbemadeawarethatsuchactivation
proceduresmayinduceaseizureandtheyhavearighttorefuse.[2004]
29.Inchildren,youngpeopleandadultspresentingwithafirstunprovokedseizure,unequivocal
epileptiformactivityshownonEEGcanbeusedtoassesstheriskofseizurerecurrence.[2004]
30.Neuroimagingshouldbeusedtoidentifystructuralabnormalitiesthatcausecertainepilepsies.
[2004]
31.MRIshouldbetheimaginginvestigationofchoiceinchildren,youngpeopleandadultswith
epilepsy.[2004]
32.MRIisparticularlyimportantinthose:
whodevelopepilepsybeforetheageof2yearsorinadulthood
whohaveanysuggestionofafocalonsetonhistory,examinationorEEG(unlessclearevidence
ofbenignfocalepilepsy)
inwhomseizurescontinueinspiteoffirstlinemedication.[2004]
33.Neuroimagingshouldnotberoutinelyrequestedwhenadiagnosisofidiopathicgeneralised
epilepsyhasbeenmade.[2004]
34.CTshouldbeusedtoidentifyunderlyinggrosspathologyifMRIisnotavailableoris
contraindicated,andforchildrenandyoungpeopleinwhomageneralanaestheticorsedation
wouldberequiredforMRIbutnotCT.[2004]
35.Inanacutesituation,CTmaybeusedtodeterminewhetheraseizurehasbeencausedbyan
acuteneurologicallesionorillness.[2004]
36.Children,youngpeopleandadultsrequiringMRIshouldhavethetestperformedsoon
.[2004]
37.Measurementofserumprolactinisnotrecommendedforthediagnosisofepilepsy.[2004]
38.Inadults,appropriatebloodtests(forexample,plasmaelectrolytes,glucose,calcium)toidentify
potentialcausesand/ortoidentifyanysignificantcomorbidityshouldbeconsidered.[2004]
39.Inchildrenandyoungpeople,otherinvestigations,includingbloodandurinebiochemistry,should
beundertakenatthediscretionofthespecialisttoexcludeotherdiagnoses,andtodeterminean
underlyingcauseoftheepilepsy.[2004]
40.Allinvestigationsforchildrenshouldbeperformedinachildcentredenvironment.[2004]
41.A12leadECGshouldbeperformedinadultswithsuspectedepilepsy.[2004]
42.Inchildrenandyoungpeople,a12leadECGshouldbeconsideredincasesofdiagnostic
uncertainty.[2004]
43.Incasesofdiagnosticuncertainty,areferraltoacardiologistshouldbeconsidered.[2004]
ThelicenceforuseofmelatoninintheUKhaschangedsincetherecommendationwaspublishedin2004.The
recommendationhasbeenupdatedaccordinglyandthefootnotethatcontainedtheoldinformationhasbeendeleted.
TheEpilepsies
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44.Neuropsychologicalassessmentshouldbeconsideredinchildren,youngpeopleandadultsin
whomitisimportanttoevaluatelearningdisabilitiesandcognitivedysfunction,particularlyin
regardtolanguageandmemory.[2004]
45.Referralforaneuropsychologicalassessmentisindicated:
whenachild,youngpersonoradultwithepilepsyishavingeducationaloroccupational
difficulties
whenanMRIhasidentifiedabnormalitiesincognitivelyimportantbrainregions
whenachild,youngpersonoradultcomplainsofmemoryorothercognitivedeficitsand/or
cognitivedecline.[2004]
46.Epilepticseizuresandepilepsysyndromesinchildren,youngpeopleandadultsshouldbe
classifiedusingamultiaxialdiagnosticscheme.Theaxesthatshouldbeconsideredare:
descriptionofseizure(ictalphenomenology);seizuretype;syndromeandaetiology.[2004]
47.Theseizuretype(s)andepilepsysyndrome,aetiology,andcomorbidityshouldbedetermined,
becausefailuretoclassifytheepilepsysyndromecorrectlycanleadtoinappropriatetreatment
andpersistenceofseizures.[2004]
48.Children,youngpeopleandadultswithepilepsyshouldbegiveninformationabouttheirseizure
type(s)andepilepsysyndrome,andthelikelyprognosis.[2004]
49.TheAEDtreatmentstrategyshouldbeindividualisedaccordingtotheseizuretype,epilepsy
syndrome,comedicationandcomorbidity,thechild,youngpersonoradultslifestyle,andthe
preferencesofthepersonandtheirfamilyand/orcarersasappropriate(seeAppendixK).[2004]
50.Thediagnosisofepilepsyneedstobecriticallyevaluatedifeventscontinuedespiteanoptimal
doseofafirstlineAED.[2004]
51.Itisrecommendedthatchildren,youngpeopleandadultsshouldbetreatedwithasingleAED
(monotherapy)whereverpossible.Iftheinitialtreatmentisunsuccessful,thenmonotherapy
usinganotherdrugcanbetried.Cautionisneededduringthechangeoverperiod.[2004]
52.Itisrecommendedthatcombinationtherapy(adjunctiveoraddontherapy)shouldonlybe
consideredwhenattemptsatmonotherapywithAEDshavenotresultedinseizurefreedom.If
trialsofcombinationtherapydonotbringaboutworthwhilebenefits,treatmentshouldrevertto
theregimen(monotherapyorcombinationtherapy)thathasprovedmostacceptabletothechild,
youngpersonoradult,intermsofprovidingthebestbalancebetweeneffectivenessinreducing
seizurefrequencyandtolerabilityofsideeffects.[2004]
53.IfanAEDhasfailedbecauseofadverseeffectsorcontinuedseizures,aseconddrugshouldbe
started(whichmaybeanalternativefirstlineorsecondlinedrug)andbuiltuptoanadequateor
maximumtolerateddoseandthenthefirstdrugshouldbetaperedoffslowly.[2004]
54.Iftheseconddrugisunhelpful,eitherthefirstorseconddrugmaybetapered,dependingon
relativeefficacy,sideeffectsandhowwellthedrugsaretoleratedbeforestartinganotherdrug.
[2004]
55.TreatmentwithAEDtherapyisgenerallyrecommendedafterasecondepilepticseizure.[2004]
56.ThedecisiontoinitiateAEDtherapyshouldbetakenbetweenthechild,youngpersonoradult,
theirfamilyand/orcarers(asappropriate)andthespecialistafterafulldiscussionoftherisksand
benefitsoftreatment.Thisdiscussionshouldtakeintoaccountdetailsofthepersonsepilepsy
syndrome,prognosisandlifestyle.[2004]
TheEpilepsies
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61
57.AEDtherapyshouldbeconsideredanddiscussedwithchildren,youngpeopleandadultsand
theirfamilyand/orcarersasappropriateafterafirstunprovokedseizureif:
thechild,youngpersonoradulthasaneurologicaldeficit
theEEGshowsunequivocalepilepticactivity
thechild,youngpersonoradultand/ortheirfamilyand/orcarersconsidertheriskofhavinga
furtherseizureunacceptable
brainimagingshowsastructuralabnormality.[2004]
58.Itshouldberecognisedthatsomechildren,youngpeopleandadults(throughtheirfamilies
and/orcarers,insomeinstances)maychoosenottotakeAEDtherapyfollowingafulldiscussion
oftherisksandbenefits.[2004]
59.AEDtherapyshouldbeinitiatedinadultsontherecommendationofaspecialist.[2004]
60.AEDtherapyinchildrenandyoungpeopleshouldbeinitiatedbyaspecialist.[2004]
61.AEDtherapyshouldonlybestartedoncethediagnosisofepilepsyisconfirmed,exceptin
exceptionalcircumstancesthatrequirediscussionandagreementbetweentheprescriber,the
specialistandthechild,youngpersonoradultandtheirfamilyand/orcarersasappropriate.
[2004]
62.ContinuingAEDtherapyshouldbeplannedbythespecialist.Itshouldbepartofthechild,young
personoradult'sagreedtreatmentplan,whichshouldincludedetailsofhowspecificdrugchoices
weremade,drugdosage,possiblesideeffects,andactiontotakeifseizurespersist.[2004]
63.Ifmanagementisstraightforward,continuingAEDtherapycanbeprescribedinprimarycareif
localcircumstancesand/orlicensingallow.[2004]
64.Theneedsofthechild,youngpersonoradultandtheirfamilyand/orcarersasappropriateshould
betakenintoaccountwhenhealthcareprofessionalstakeontheresponsibilityofcontinuing
prescribing.[2004]
65.Theprescribermustensurethatthechild,youngpersonoradultandtheirfamilyand/orcarersas
appropriatearefullyinformedabouttreatmentincludingactiontobetakenafteramisseddose
orafteragastrointestinalupset.[2004]
66.Regularbloodtestmonitoringinadultsisnotrecommendedasroutine,andshouldbedoneonly
ifclinicallyindicated.[2004]
67.Regularbloodtestmonitoringinchildrenandyoungpeopleisnotrecommendedasroutine,and
shouldbedoneonlyifclinicallyindicatedandrecommendedbythespecialist.[2004]
68.Examplesofbloodtestsinclude:
beforesurgeryclottingstudiesinthoseonsodiumvalproate
fullbloodcount,electrolytes,liverenzymes,vitaminDlevels,andothertestsofbone
metabolism(forexample,serumcalciumandalkalinephosphatase)every25yearsforadults
takingenzymeinducingdrugs.[2004]
69.Asymptomaticminorabnormalitiesintestresultsarenotnecessarilyanindicationforchangesin
medication.[2004]
70.Annualreviewshouldincludeanenquiryaboutsideeffectsandadiscussionofthetreatmentplan
toensureconcordanceandadherencetomedication.[2004]
Pleasenotethatvalproatehasbeenchangedtosodiumvalproatetobeconsistentwiththeterminologyusedinthis
update.
TheEpilepsies
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62
71.Treatmentshouldbereviewedatregularintervalstoensurethatchildren,youngpeopleand
adultswithepilepsyarenotmaintainedforlongperiodsontreatmentthatisineffectiveorpoorly
toleratedandthatconcordancewithprescribedmedicationismaintained.[2004]
72.Adherencetotreatmentcanbeoptimisedwiththefollowing:
educatingchildren,youngpeopleandadultsandtheirfamiliesand/orcarersinthe
understandingoftheirconditionandtherationaleoftreatment
reducingthestigmaassociatedwiththecondition(seealsosection18.5)
usingsimplemedicationregimens
positiverelationshipsbetweenhealthcareprofessionals,thechild,youngpersonoradultwith
epilepsy,andtheirfamilyand/orcarers.[2004]
73.Healthcareprofessionalshavearesponsibilitytoeducateothersaboutepilepsysoastoreduce
thestigmaassociatedwithit.Theyshouldprovideinformationaboutepilepsytoallpeoplewho
comeintocontactwithchildren,youngpeopleandadultswithepilepsy,includingschoolstaff,
socialcareprofessionalsandothers.[2004]
74.TherisksandbenefitsofcontinuingorwithdrawingAEDtherapyshouldbediscussedwith
children,youngpeopleandadults,andtheirfamiliesand/orcarersasappropriate,whohavebeen
seizurefreeforatleast2years(seeAppendixH
).[2004]
75.Thedecisiontocontinueorwithdrawmedicationshouldbetakenbythechild,youngpersonor
adult,theirfamilyand/orcarersasappropriate,andthespecialistafterafulldiscussionofthe
risksandbenefitsofwithdrawal.Attheendofthediscussionchildren,youngpeopleandadults,
andtheirfamilyand/orcarersasappropriate,shouldunderstandtheirriskofseizurerecurrence
onandofftreatment.Thisdiscussionshouldtakeintoaccountdetailsofthechild,youngperson
oradult'sepilepsysyndrome,prognosisandlifestyle.[2004]
76.WhenAEDtreatmentisbeingdiscontinuedinachild,youngpersonoradultwhohasbeenseizure
free,itshouldbecarriedoutslowly(atleast23months)andonedrugshouldbewithdrawnata
time.[2004]
77.Particularcareshouldbetakenwhenwithdrawingbenzodiazepinesandbarbiturates(maytake
upto6monthsorlonger)becauseofthepossibilityofdrugrelatedwithdrawalsymptomsand/or
seizurerecurrence.[2004]
78.Thereshouldbeafailsafeplanagreedwithchildren,youngpeopleandadultsandtheirfamilies
and/orcarersasappropriate,wherebyifseizuresrecur,thelastdosereductionisreversedand
medicaladviceissought.[2004]
79.WithdrawalofAEDsmustbemanagedby,orbeundertheguidanceof,thespecialist.[2004]
80.Whenpossible,choosewhichAEDtoofferonthebasisofthepresentingepilepsysyndrome.If
theepilepsysyndromeisnotclearatpresentation,basethedecisiononthepresentingseizure
type(s).[new2012]
81.Consistentsupplytothechild,youngpersonoradultwithepilepsyofaparticularmanufacturers
AEDpreparationisrecommended,unlesstheprescriber,inconsultationwiththechild,young
personoradult,considersthatthisisnotaconcern.Inthecaseofachildoryoungpersonthis
discussionmayinvolvetheparentorcareraswell.DifferentpreparationsofsomeAEDsmayvary
inbioavailabilityorpharmacokineticprofilesandcareneedstobetakentoavoidreducedeffect
orexcessivesideeffects.Consultthesummaryofproductcharacteristics(SPC)andBritish
nationalformulary(BNF;availableathttp://bnf.org.uk)onthebioavailabilityand
AppendixHofthefullguidelineprovidestablesfortheprognosisforremissionofseizuresinadults.
TheEpilepsies
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63
pharmacokineticprofilesofindividualAEDs,butnotethatthesedonotgiveinformationon
comparingbioavailabilityofdifferentgenericpreparations
.[new2012]
82.Ifusingcarbamazepine,offercontrolledreleasecarbamazepinepreparations.[new2012]
83.Whenprescribingsodiumvalproatetowomenandgirlsofpresentandfuturechildbearing
potential,discussthepossibleriskofmalformationandneurodevelopmentalimpairmentsinan
unbornchild,particularlywithhighdosesofthisAEDorwhenusingaspartofpolytherapy.[new
2012]
84.Maintainahighlevelofvigilancefortreatmentemergentadverseeffects(forexample,bone
healthissuesandneuropsychiatricissues
)[new2012]
Pharmacologicalmanagementoffocalseizures
85.Offercarbamazepineorlamotrigineasfirstlinetreatmenttochildren,youngpeopleandadults
withnewlydiagnosedfocalseizures.[new2012]
86.LevetiracetamisnotcosteffectiveatJune2011unitcosts
.Offerlevetiracetam,oxcarbazepineor
sodiumvalproate(providedtheacquisitioncostoflevetiracetamfallstoatleast50%ofJune2011
valuedocumentedintheNationalHealthServiceDrugTariffforEnglandandWales)if
carbamazepineandlamotrigineareunsuitableornottolerated.IfthefirstAEDtriedis
ineffective,offeranalternativefromthesefiveAEDs.Beawareoftheteratogenicrisksofsodium
valproate(seerecommendation83).[new2012]
87.ConsideradjunctivetreatmentifasecondwelltoleratedAEDisineffective(seerecommendations
85and86).[new2012]
88.Offercarbamazepine,clobazam
,gabapentin
,lamotrigine,levetiracetam,oxcarbazepine,
sodiumvalproateortopiramateasadjunctivetreatmenttochildren,youngpeopleandadults
withfocalseizuresiffirstlinetreatments(seerecommendations85and86)areineffectiveornot
tolerated.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation83).[new
2012]
89.Ifadjunctivetreatment(seerecommendation88)isineffectiveornottolerated,discusswith,or
referto,atertiaryepilepsyspecialist.OtherAEDsthatmaybeconsideredbythetertiaryepilepsy
specialistareeslicarbazepineacetate,lacosamide,phenobarbital,phenytoin,pregabalin,
tiagabine,vigabatrinandzonisamide.Carefullyconsidertheriskbenefitratiowhenusing
vigabatrinbecauseoftheriskofanirreversibleeffectonvisualfields.[new2012]
Pharmacologicalmanagementofnewlydiagnosedgeneralisedtonicclonicseizures
Recommendations1,182,184,191and283describetheprinciplesofdecisionmakingandbestpracticeinrelationto
effectiveandappropriateconsultationbetweenhealthcareprofessionalsandchildren,youngpeopleandadultswith
epilepsy.
InNovember2013,theMHRAissuednewadviceaboutoralantiepilepticdrugs(AEDs)andswitchingbetweendifferent
manufacturersproductsofaparticulardrug.Followingareviewoftheavailableevidence,theCommissiononHuman
Medicines(CHM)hasclassifiedAEDsinto3categoriesdependingonthelevelofpotentialconcernsrelatedtoswitching
betweendifferentmanufacturersproducts.ConsulttheMHRAadviceformoreinformation.
TreatmentwithAEDsisassociatedwithasmallriskofsuicidalthoughtsandbehaviour;availabledatasuggestthatthe
increasedriskappliestoallAEDsandmaybeseenasearlyas1weekafterstartingtreatment.Availablefrom:
www.mhra.gov.uk/PrintPreview/DefaultSplashPP/CON019574?DynamicListQuery=&DynamicListSortBy=xCreationDate
&DynamicListSortOrder=Desc&DynamicListTitle=&PageNumber=1&Title=Antiepileptics%20&ResultCount=10
Estimatedcostofa1500mgdailydosewas2.74atJune2011.CosttakenfromtheNationalHealthServiceDrugTarifffor
EnglandandWales,availableatwww.ppa.org.uk/ppa/edt_intro.htm
Atthetimeofpublication(January2012),thisdrugdidnothaveUKmarketingauthorisationforthisindicationand/or
population(seeappendixKfordetails).Informedconsentshouldbeobtainedanddocumented.
TheEpilepsies
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64
90.Offersodiumvalproateasfirstlinetreatmenttochildren,youngpeopleandadultswithnewly
diagnosedGTCseizures.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation
83).[new2012]
91.Offerlamotrigineifsodiumvalproateisunsuitable.Ifthepersonhasmyoclonicseizuresoris
suspectedofhavingjuvenilemyoclonicepilepsy(JME),beawarethatlamotriginemayexacerbate
myoclonicseizures.[new2012]
92.Considercarbamazepineandoxcarbazepine
butbeawareoftheriskofexacerbatingmyoclonic
orabsenceseizures.[new2012]
93.Offerclobazam
,lamotrigine,levetiracetam,sodiumvalproateortopiramateasadjunctive
treatmenttochildren,youngpeopleandadultswithGTCseizuresiffirstlinetreatments(see
recommendations90,91and92)areineffectiveornottolerated.Beawareofteratogenicrisksof
sodiumvalproate(seerecommendation83).[new2012]
94.Ifthereareabsenceormyoclonicseizures,orifJMEissuspected,donotoffercarbamazepine,
gabapentin,oxcarbazepine,phenytoin,pregabalin,tiagabineorvigabatrin.[new2012]
Pharmacologicalmanagementofabsenceseizures
95.Offerethosuximideorsodiumvalproateasfirstlinetreatmenttochildren,youngpeopleand
adultswithabsenceseizures.IfthereisahighriskofGTCseizures,offersodiumvalproatefirst,
unlessitisunsuitable.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation
83).[new2012]
96.Offerlamotrigine
ifethosuximideandsodiumvalproateareunsuitable,ineffectiveornot
tolerated.[new2012]
97.IftwofirstlineAEDs(seerecommendations95and96)areineffectiveinchildren,youngpeople
andadultswithabsenceseizures,consideracombinationoftwoofthesethreeAEDsas
adjunctivetreatment:ethosuximide,lamotrigine
orsodiumvalproate.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new2012]
98.Ifadjunctivetreatment(seerecommendation97)isineffectiveornottolerated,discusswith,or
referto,atertiaryepilepsyspecialistandconsiderclobazam
,clonazepam,levetiracetam
,
topiramate
orzonisamide
.[new2012]
99.Donotoffercarbamazepine,gabapentin,oxcarbazepine,phenytoin,pregabalin,tiagabineor
vigabatrin.[new2012]
Pharmacologicalmanagementofmyoclonicseizures
100. Offersodiumvalproateasfirstlinetreatmenttochildren,youngpeopleandadultswith
newlydiagnosedmyoclonicseizures,unlessitisunsuitable.Beawareofteratogenicrisksof
TheEpilepsies
Guidance
65
101. Considerlevetiracetam
ortopiramate
ifsodiumvalproateisunsuitableornottolerated.
Beawarethattopiramatehasalessfavourablesideeffectprofilethanlevetiracetamandsodium
valproate.[new2012]
102. Offerlevetiracetam,sodiumvalproateortopiramate
asadjunctivetreatmenttochildren,
youngpeopleandadultswithmyoclonicseizuresiffirstlinetreatments(seerecommendations
100and101)areineffectiveornottolerated.Beawareofteratogenicrisksofsodiumvalproate
(seerecommendation83).[new2012]
103. Ifadjunctivetreatment(seerecommendation102)isineffectiveornottolerated,discuss
with,orreferto,atertiaryepilepsyspecialistandconsiderclobazam
,clonazepam,piracetamor
zonisamide
.[new2012]
104. Donotoffercarbamazepine,gabapentin,oxcarbazepine,phenytoin,pregabalin,tiagabine
orvigabatrin.[new2012]
Pharmacologicalmanagementoftonicclonicseizures
tonicoratonicseizures.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation
83).[new2012]
106. Offerlamotrigine
asadjunctivetreatmenttochildren,youngpeopleandadultswith
tonicoratonicseizuresiffirstlinetreatmentwithsodiumvalproateisineffectiveornottolerated.
[new2012]
107. Discusswithatertiaryepilepsyspecialistifadjunctivetreatment(seerecommendation
106)isineffectiveornottolerated.OtherAEDsthatmaybeconsideredbythetertiaryepilepsy
specialistarerufinamide
andtopiramate
.[new2012]
108. Donotoffercarbamazepine,gabapentin,oxcarbazepine,pregabalin,tiagabineor
Pharmacologicalmanagementofinfantilespasms
109. Discusswith,orreferto,atertiarypaediatricepilepsyspecialistwhenaninfantpresents
withinfantilespasms.[new2012]
110. Offerasteroid(prednisoloneortetracosactide
)orvigabatrinasfirstlinetreatmentto
infantswithinfantilespasmsthatarenotduetotuberoussclerosis.Carefullyconsiderthe
riskbenetraowhenusingvigabatrinorsteroids.[new2012]
111. Offervigabatrinasfirstlinetreatmenttoinfantswithinfantilespasmsduetotuberous
sclerosis.Ifvigabatrinisineffective,offerasteroid(prednisoloneortetracosactide
).Carefully
considertheriskbenetraowhenusingvigabatrinorsteroids.[new2012]
PharmacologicalmanagementofDravetsyndrome
TheEpilepsies
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66
112. Discusswith,orreferto,atertiarypaediatricepilepsyspecialistwhenachildpresents
withsuspectedDravetsyndrome.[new2012]
113. Considersodiumvalproateortopiramate
asfirstlinetreatmentinchildrenwithDravet
syndrome.[new2012]
114. Discusswithatertiaryepilepsyspecialistiffirstlinetreatments(seerecommendation
113)inchildren,youngpeopleandadultswithDravetsyndromeareineffectiveornottolerated,
andconsiderclobazam
orstiripentolasadjunctivetreatment.[new2012]
115. Donotoffercarbamazepine,gabapentin,lamotrigine,oxcarbazepine,phenytoin,
pregabalin,tiagabineorvigabatrin.[new2012]
PharmacologicalmanagementofLennoxGastautsyndrome
116. Discusswith,orreferto,atertiarypaediatricepilepsyspecialistwhenachildpresents
withsuspectedLennoxGastautsyndrome.[new2012]
117. OffersodiumvalproateasfirstlinetreatmenttochildrenwithLennoxGastautsyndrome.
Beawareofteratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
118. Offerlamotrigineasadjunctivetreatmenttochildren,youngpeopleandadultswith
LennoxGastautsyndromeiffirstlinetreatmentwithsodiumvalproateisineffectiveornot
tolerated.[new2012]
119. Discusswithatertiaryepilepsyspecialistifadjunctivetreatment(seerecommendation
118)isineffectiveornottolerated.OtherAEDsthatmaybeconsideredbythetertiaryepilepsy
specialistarerufinamideandtopiramate.[new2012]
120. Donotoffercarbamazepine,gabapentin,oxcarbazepine,pregabalin,tiagabineor
121. Onlyofferfelbamate
incentresprovidingtertiaryepilepsyspecialistcareandwhen
treatmentwithalloftheAEDslistedinrecommendations119and120hasprovedineffectiveor
nottolerated.[new2012]
Pharmacologicalmanagementofbenignepilepsywithcentrotemporalspikes,Panayiotopoulos
syndromeorlateonsetchildhoodoccipitalepilepsy(Gastauttype)
122. Discusswiththechildoryoungperson,andtheirfamilyand/orcarers,whetherAED
treatmentforbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlate
onsetchildhoodoccipitalepilepsy(Gastauttype)isindicated.[new2012]
123. Offercarbamazepine
orlamotrigine
asfirstlinetreatmenttochildrenandyoung
peoplewithbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlateonset
childhoodoccipitalepilepsy(Gastauttype).[new2012]
124. LevetiracetamisnotcosteffectiveatJune2011unitcosts
.Offerlevetiracetam
,
oxcarbazepine
,orsodiumvalproate(providedtheacquisitioncostoflevetiracetamfallstoat
Estimatedcostofa1500mgdailydosewas2.74atJune2011.CosttakenfromtheNationalHealthServiceDrugTariff
forEnglandandWales,availableatwww.ppa.org.uk/ppa/edt_intro.htm
TheEpilepsies
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67
least50%ofJune2011valuedocumentedintheNationalHealthServiceDrugTariffforEngland
andWales)ifcarbamazepineandlamotrigineareunsuitableornottolerated.IfthefirstAEDtried
isineffective,offeranalternativefromthesefiveAEDs.Beawarethatcarbamazepineand
oxcarbazepinemayexacerbateorunmaskcontinuousspikeandwaveduringslowsleep,which
mayoccurinsomechildrenwithbenignepilepsywithcentrotemporalspikes.Beawareof
teratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
125. ConsideradjunctivetreatmentifasecondwelltoleratedAEDisineffective(see
recommendations123and124).[new2012]
,clobazam
,gabapentin
,lamotrigine
,levetiracetam
,
oxcarbazepine,sodiumvalproateortopiramateasadjunctivetreatmenttochildrenandyoung
peoplewithbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlateonset
childhoodoccipitalepilepsy(Gastauttype)iffirstlinetreatments(seerecommendations123and
124)areineffectiveornottolerated.Beawareofteratogenicrisksofsodiumvalproate(see
recommendation83).[new2012]
with,orreferto,atertiaryepilepsyspecialist.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistareeslicarbazepineacetate
,lacosamide
,phenobarbital,phenytoin,
pregabalin
,tiagabine
,vigabatrin
andzonisamide
.Carefullyconsidertheriskbenefitratio
whenusingvigabatrinbecauseoftheriskofanirreversibleeffectonvisualfields.[new2012]
Pharmacologicalmanagementofidiopathicgeneralisedepilepsy
newlydiagnosedIGE,particularlyifthereisaphotoparoxysmalresponseonEEG.Beawareof
ifsodiumvalproateisunsuitableornottolerated.Beawarethat
lamotriginecanexacerbatemyoclonicseizures.IfJMEissuspectedseerecommendations134and
135.[new2012]
130. Considertopiramate
butbeawarethatithasalessfavourablesideeffectprofilethan
sodiumvalproateandlamotrigine
.[new2012]
,levetiracetam
,sodiumvalproateortopiramate
asadjunctive
treatmenttochildren,youngpeopleandadultswithIGEiffirstlinetreatments(see
TheEpilepsies
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68
recommendations128,129and130)areineffectiveornottolerated.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new2012]
,clonazepamor
zonisamide
.[new2012]
Pharmacologicalmanagementofjuvenilemyoclonicepilepsy
newlydiagnosedJME,unlessitisunsuitable.Beawareofteratogenicrisksofsodiumvalproate
135. Considerlamotrigine
,levetiracetam
,ortopiramate
ifsodiumvalproateisunsuitableor
nottolerated.Beawarethattopiramatehasalessfavourablesideeffectprofilethanlamotrigine,
levetiracetamandsodiumvalproate,andthatlamotriginemayexacerbatemyoclonicseizures.
[new2012]
,levetiracetam,sodiumvalproateortopiramate
asadjunctive
treatmenttochildren,youngpeopleandadultswithJMEiffirstlinetreatments(see
recommendations134and135)areineffectiveornottolerated.Beawareofteratogenicrisksof
,clonazepamor
zonisamide
.[new2012]
Pharmacologicalmanagementofgeneralisedtonicclonicseizuresonly
139. Offerlamotrigineorsodiumvalproateasfirstlinetreatmenttochildren,youngpeople
andadultswithepilepsywithGTCseizuresonly.Iftheyhavesuspectedmyoclonicseizures,orare
suspectedofhavingJME,offersodiumvalproatefirst,unlessitisunsuitable.Beawareof
140. Considercarbamazepineandoxcarbazepine
butbeawareoftheriskofexacerbating
myoclonicorabsenceseizures.[new2012]
141. Offerclobazam
,lamotrigine,levetiracetam,sodiumvalproateortopiramateas
adjunctivetreatmenttochildren,youngpeopleandadultswithepilepsywithGTCseizuresonly,if
TheEpilepsies
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69
firstlinetreatments(seerecommendation139and140)areineffectiveornottolerated.Be
awareofteratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
Pharmacologicalmanagementofchildhoodabsenceepilepsy,juvenileabsenceepilepsyandother
absencesyndromes
142. Offerethosuximideorsodiumvalproateasfirstlinetreatmenttochildren,youngpeople
andadultswithabsencesyndromes.IfthereisahighriskofGTCseizures,offersodiumvalproate
first,unlessitisunsuitable.Beawareofteratogenicrisksofsodiumvalproate(see
ifethosuximideandsodiumvalproateareunsuitable,ineffectiveornot
tolerated.[new2012]
144. IftwofirstlineAEDs(seerecommendations142and143)areineffectiveinchildren,
youngpeopleandadultswithabsenceepilepsysyndromes,consideracombinationoftwoof
thesethreeAEDsasadjunctivetreatment:ethosuximide,lamotrigine
orsodiumvalproate.Be
awareoftheteratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
,clonazepam,
levetiracetam
,topiramate
orzonisamide
.[new2012]
Pharmacologicalmanagementofotherepilepsysydromes
147. Refertoatertiarypaediatricepilepsyspecialistallchildrenandyoungpeoplewith
continuousspikeandwaveduringslowsleep,LandauKleffnersyndromeormyoclonicastatic
epilepsy.[new2012]
Generalrecommendationscontinued
148. Caremustbetakentosecurethechild,youngpersonoradultsairwayandassesshisor
herrespiratoryandcardiacfunction.[2004]
149. Treatmentshouldbeadministeredbytrainedclinicalpersonnelor,ifspecifiedbyan
individuallyagreedprotocoldrawnupwiththespecialist,byfamilymembersorcarerswith
appropriatetraining.[2004]
150. RegularAEDsshouldbecontinuedatoptimaldosesandthereasonsforstatusepilepticus
shouldbeinvestigated.[2004]
151. Asthetreatmentpathwayprogresses,theexpertiseofananaesthetist/intensivistshould
besought.[2004]
152. Ifeitherthewholeprotocolorintensivecareisrequiredthetertiaryserviceshouldbe
consulted.[2004]
153. Anindividualtreatmentpathwayshouldbeformulatedforchildren,youngpeopleand
adultswhohaverecurrentconvulsivestatusepilepticus.[2004]
TheEpilepsies
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70
154. Giveimmediateemergencycareandtreatmenttochildren,youngpeopleandadultswho
haveprolonged(lasting5minutesormore)orrepeated(threeormoreinanhour)convulsive
seizuresinthecommunity.[2012]
155. Onlyprescribebuccalmidazolamorrectaldiazepam
foruseinthecommunityfor
children,youngpeopleandadultswhohavehadapreviousepisodeofprolongedorserial
convulsiveseizures.[new2012]
156. Administerbuccalmidazolamasfirstlinetreatmentinchildren,youngpeopleandadults
withprolongedorrepeatedseizuresinthecommunity.Administerrectaldiazepam
ifpreferred
orifbuccalmidazolamisnotavailable.Ifintravenousaccessisalreadyestablishedand
resuscitationfacilitiesareavailable,administerintravenouslorazepam.[new2012]
157. Dependingonresponsetotreatment,thepersonssituationandanypersonalisedcare
plan,callanambulance,particularlyif:
theseizureiscontinuing5minutesaftertheemergencymedicationhasbeenadministered
thepersonhasahistoryoffrequentepisodesofserialseizuresorhasconvulsivestatus
epilepticus,orthisisthefirstepisoderequiringemergencytreatmentor
thereareconcernsordifficultiesmonitoringthepersonsairway,breathing,circulationor
othervitalsigns.[new2012]
158. Forchildren,youngpeopleandadultswithongoinggeneralisedtonicclonicseizures
(convulsivestatusepilepticus)whoareinhospital,immediately:
secureairway
givehighconcentrationoxygen
assesscardiacandrespiratoryfunction
checkbloodglucoselevelsand
secureintravenousaccessinalargevein.
SeealsothesuggestedprotocolsinappendixK.[new2012]
159. Administerintravenouslorazepamasfirstlinetreatmentinhospitalinchildren,young
peopleandadultswithongoinggeneralisedtonicclonicseizures(convulsivestatusepilepticus).
Administerintravenousdiazepamifintravenouslorazepamisunavailable,orusebuccal
midazolamifunabletosecureimmediateintravenousaccess.Administeramaximumoftwo
dosesofthefirstlinetreatment(includingprehospitaltreatment).Seealsothesuggested
protocolsinappendixK.[new2012]
160. Ifseizurescontinue,administerintravenousphenobarbitalorphenytoinassecondline
treatmentinhospitalinchildren,youngpeopleandadultswithongoinggeneralisedtonicclonic
seizures(convulsivestatusepilepticus).SeealsothesuggestedprotocolsinappendixK.[new
2012]
161. FollowthesuggestedprotocolsinappendixKfortreatingrefractoryconvulsivestatus
epilepticusinsecondarycare.[2012]
162. Administerintravenousmidazolam
,propofol
orthiopentalsodium
totreatadultswith
refractoryconvulsivestatusepilepticus.Adequatemonitoring,includingbloodlevelsofAEDs,and
TheEpilepsies
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71
criticallifesystemssupportarerequired.SeealsothesuggestedprotocolsinappendixK.[new
2012]
orthiopentalsodium
totreatchildrenandyoung
peoplewithrefractoryconvulsivestatusepilepticus.Adequatemonitoring,includingbloodlevels
ofAEDs,andcriticallifesystemssupportarerequired.Seealsothesuggestedprotocolsin
appendixK.[2012]
164. Nonconvulsivestatusepilepticusisuncommonandmanagementislessurgent.A
suggestedguidelinecanbefoundinappendixK.[2004]
165. Allchildren,youngpeopleandadultswithepilepsyshouldhaveaccessviatheirspecialist
toatertiaryservicewhencircumstancesrequire.[2004]
166. Thetertiaryserviceshouldincludeamultidisciplinaryteam,experiencedinthe
assessmentofchildren,youngpeopleandadultswithcomplexepilepsy,andhaveadequate
accesstoinvestigationsandtreatmentbybothmedicalandsurgicalmeans.[2004]
167. Theexpertiseofmultidisciplinaryteamsinvolvedinmanagingcomplexepilepsyshould
includepsychology,psychiatry,socialwork,occupationaltherapy,counselling,neuroradiology,
clinicalnursespecialists,neurophysiology,neurology,neurosurgeryandneuroanaesthesia.
TeamsshouldhaveMRIandvideotelemetryfacilitiesavailabletothem.[2004]
168. Theneurosurgeoninthemultidisciplinaryteamshouldhavespecialistexperienceof
and/ortraininginepilepsysurgeryandhaveaccesstoinvasiveEEGrecordingfacilities.[2004]
169. Ifseizuresarenotcontrolledand/orthereisdiagnosticuncertaintyortreatmentfailure,
forfurther
assessment.Referralshouldbeconsideredwhenoneormoreofthefollowingcriteriaare
present:
theepilepsyisnotcontrolledwithmedicationwithin2years
managementisunsuccessfulaftertwodrugs
thechildisagedunder2years
achild,youngpersonoradultexperiences,orisatriskof,unacceptablesideeffectsfrom
medication
thereisaunilateralstructurallesion
thereispsychologicaland/orpsychiatriccomorbidity
thereisdiagnosticdoubtastothenatureoftheseizuresand/orseizuresyndrome.[2004]
170. Inchildren,thediagnosisandmanagementofepilepsywithinthefirstfewyearsoflife
maybeextremelychallenging.Forthisreason,childrenwithsuspectedepilepsyshouldbe
referredtotertiaryservicesearly,becauseoftheprofounddevelopmental,behaviouraland
psychologicaleffectsthatmaybeassociatedwithcontinuingseizures.[2004]
171. Behaviouralordevelopmentalregressionorinabilitytoidentifytheepilepsysyndromein
achild,youngpersonoradultshouldresultinimmediatereferraltotertiaryservices.[2004]
172. Children,youngpeopleandadultswithspecificsyndromessuchasSturgeWeber
syndrome,thehemisphericsyndromes,Rasmussensencephalitisandhypothalamichamartoma
shouldbereferredtoatertiaryepilepsyservice.[2004]
TheEpilepsies
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72
173. Psychiatriccomorbidityand/ornegativebaselineinvestigationsshouldnotbea
contraindicationforreferraltoatertiaryservice
.[2004]
174. Psychologicalinterventionsmaybeusedasadjunctivetherapy.Theyhavenotbeen
proventoaffectseizurefrequencyandarenotanalternativetopharmacologicaltreatment.
[2004]
175. Psychologicalinterventions(relaxation,cognitivebehaviourtherapy,biofeedback)maybe
usedinconjunctionwithAEDtherapyinadultswhereeitherthepersonorthespecialistconsiders
seizurecontroltobeinadequatewithoptimalAEDtherapy.Thisapproachmaybeassociatedwith
animprovedqualityoflifeinsomepeople.[2004]
176. Psychologicalinterventions(relaxation,cognitivebehaviourtherapy)maybeusedin
childrenandyoungpeoplewithdrugresistantfocalepilepsy.[2004]
177. Referchildrenandyoungpeoplewithepilepsywhoseseizureshavenotrespondedto
appropriateAEDstoatertiarypaediatricepilepsyspecialistforconsiderationoftheuseofa
ketogenicdiet.[new2012]
178. Vagusnervestimulationisindicatedforuseasanadjunctivetherapyinreducingthe
frequencyofseizuresinadultswhoarerefractorytoantiepilepticmedicationbutwhoarenot
suitableforresectivesurgery.Thisincludesadultswhoseepilepticdisorderisdominatedbyfocal
seizures
(withorwithoutsecondarygeneralisation)orgeneralisedseizures.[2004,amended
2012]
frequencyofseizuresinchildrenandyoungpeoplewhoarerefractorytoantiepilepticmedication
butwhoarenotsuitableforresectivesurgery.Thisincludeschildrenandyoungpeoplewhose
epilepticdisorderisdominatedbyfocalseizures
(withorwithoutsecondarygeneralisation)or
generalisedseizures
.[2004,amended2012]
180. Children,youngpeopleandadultswithepilepsyandtheirfamiliesand/orcarersshould
begiven,andhaveaccesstosourcesof,informationabout(whereappropriate):
epilepsyingeneral
diagnosisandtreatmentoptions
medicationandsideeffects
seizuretype(s),triggersandseizurecontrol
managementandselfcare
riskmanagement
firstaid,safetyandinjurypreventionathomeandatschoolorwork
psychologicalissues
socialsecuritybenefitsandsocialservices
insuranceissues
educationandhealthcareatschool
employmentandindependentlivingforadults
Inthisrecommendation,centrehasbeenreplacedwithserviceforconsistencyacrossrecommendations.
Inthisrecommendation,partialseizureshasbeenreplacedwithfocalseizurestoreflectachangeinterminologysince
theoriginalguidelinewaspublishedin2004.
EvidencefromVagusnervestimulationforrefractoryepilepsyinchildren,NICEinterventionalprocedureguidance50
(2004).
TheEpilepsies
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73
importanceofdisclosingepilepsyatwork,ifrelevant(iffurtherinformationorclarificationis
needed,voluntaryorganisationsshouldbecontacted).
roadsafetyanddriving
prognosis
suddendeathinepilepsy(SUDEP)
statusepilepticus
lifestyle,leisureandsocialissues(includingrecreationaldrugs,alcohol,sexualactivityand
sleepdeprivation)
familyplanningandpregnancy
voluntaryorganisations,suchassupportgroupsandcharitableorganisations,andhowto
contactthem.[2004]
181. Thetimeatwhichthisinformationshouldbegivenwilldependonthecertaintyofthe
diagnosis,andtheneedforconfirmatoryinvestigations.[2004]
182. Informationshouldbeprovidedinformats,languagesandwaysthataresuitedtothe
child,youngpersonoradultsrequirements.Considerationshouldbegiventodevelopmental
age,gender,cultureandstageoflifeoftheperson.[2004]
183. Ifchildren,youngpeopleandadults,andfamiliesand/orcarershavenotalreadyfound
highqualityinformationfromvoluntaryorganisationsandothersources,healthcareprofessionals
shouldinformthemofdifferentsources(usingtheInternet,ifappropriate:see,forexample,the
websiteoftheJointEpilepsyCounciloftheUKandIreland,www.jointepilepsycouncil.org.uk).
[2004]
184. Adequatetimeshouldbesetasideintheconsultationtoprovideinformation,which
shouldberevisitedonsubsequentconsultations.[2004]
185. Checklistsshouldbeusedtoremindchildren,youngpeopleandadults,andhealthcare
professionals,aboutinformationthatshouldbediscussedduringconsultations.[2004]
186. Everyoneprovidingcareortreatmentforchildren,youngpeopleandadultswithepilepsy
shouldbeabletoprovideessentialinformation.[2004]
187. Thechild,youngpersonoradultwithepilepsyandtheirfamilyand/orcarersas
appropriateshouldknowhowtocontactanamedindividualwheninformationisneeded.This
namedindividualshouldbeamemberofthehealthcareteamandberesponsibleforensuring
thattheinformationneedsofthechild,youngpersonoradultand/ortheirfamilyand/orcarers
aremet.[2004]
188. Thepossibilityofhavingseizuresshouldbediscussed,andinformationonepilepsyshould
beprovidedbeforeseizuresoccur,forchildren,youngpeopleandadultsathighriskofdeveloping
seizures(suchasafterseverebraininjury),withalearningdisability,orwhohaveastrongfamily
historyofepilepsy.[2004]
189. Essentialinformationonhowtorecogniseaseizure,firstaid,andtheimportanceof
reportingfurtherattacksshouldbeprovidedtoachild,youngpersonoradultwhohas
experiencedapossiblefirstseizure,andtheirfamily/carer/parentasappropriate.This
informationshouldbeprovidedwhilethechild,youngpersonoradultisawaitingadiagnosisand
shouldalsobeprovidedtotheirfamilyand/orcarers.[2004]
190. Informationshouldbeprovidedtochildren,youngpeopleandadultsandfamiliesand/or
carersasappropriateonthereasonsfortests,theirresultsandmeaning,therequirementsof
specificinvestigations,andthelogisticsofobtainingthem.[2004]
TheEpilepsies
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74
191. Children,youngpeopleandadultswithepilepsyshouldbegivenappropriateinformation
beforetheymakeimportantdecisions(forexample,regardingpregnancyoremployment).[2004]
192. Children,youngpeopleandadultsandtheirfamiliesand/orcarersshouldbegivenan
opportunitytodiscussthediagnosiswithanappropriatehealthcareprofessional.[2004]
193. InformationonSUDEPshouldbeincludedinliteratureonepilepsytoshowwhy
preventingseizuresisimportant.TailoredinformationonthepersonsrelativeriskofSUDEP
shouldbepartofthecounsellingchecklistforchildren,youngpeopleandadultswithepilepsyand
theirfamiliesand/orcarers.[2004]
194. TheriskofSUDEPcanbeminimisedby:
optimisingseizurecontrol
beingawareofthepotentialconsequencesofnocturnalseizures.[2004]
195. Tailoredinformationanddiscussionbetweenthechild,youngpersonoradultwith
epilepsy,theirfamilyand/orcarers(asappropriate)andhealthcareprofessionalsshouldtake
accountofthesmallbutdefiniteriskofSUDEP.[2004]
196. Wherefamiliesand/orcarershavebeenaffectedbySUDEP,healthcareprofessionals
shouldcontactfamiliesand/orcarerstooffertheircondolences,invitethemtodiscussthedeath,
andofferreferraltobereavementcounsellingandaSUDEPsupportgroup.[2004]
197. Informationthatisprovidedaboutantiepilepticdrugs(AEDs)needstobeinthecontext
ofthatprovidedbythemanufacturer,forexample,indications,sideeffectsandlicencestatus.
[2004]
carersasappropriateaboutthereasonsforconsideringsurgery.Thebenefitsandrisksofthe
surgicalprocedureunderconsiderationshouldbefullyexplainedbeforeinformedconsentis
obtained.[2004]
199. Inordertoenableinformeddecisionsandchoice,andtoreducemisunderstandings,
womenandgirlswithepilepsyandtheirpartners,asappropriate,mustbegivenaccurate
informationandcounsellingaboutcontraception,conception,pregnancy,caringforchildrenand
breastfeeding,andmenopause.[2004]
200. Informationaboutcontraception,conception,pregnancy,ormenopauseshouldbegiven
towomenandgirlsinadvanceofsexualactivity,pregnancyormenopause,andtheinformation
shouldbetailoredtotheirindividualneeds.Thisinformationshouldalsobegiven,asneeded,to
peoplewhoarecloselyinvolvedwithwomenandgirlswithepilepsy.Thesemayincludeher
familyand/orcarers.[2004]
201. Allhealthcareprofessionalswhotreat,carefor,orsupportwomenandgirlswithepilepsy
shouldbefamiliarwithrelevantinformationandtheavailabilityofcounselling.[2004]
202. Womenandgirlsshouldbereassuredthatanincreaseinseizurefrequencyisgenerally
unlikelyinpregnancyorinthefirstfewmonthsafterbirth.[2004]
203. Theclinicianshoulddiscusswiththewomanandgirltherelativebenefitsandrisksof
adjustingmedicationtoenablehertomakeaninformeddecision.Whereappropriate,the
womanorgirlsspecialistshouldbeconsulted.[2004]
204. Generally,womenandgirlsmaybereassuredthattheriskofatonicclonicseizureduring
thelabourandthe24hoursafterbirthislow(14%).[2004]
TheEpilepsies
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75
205. Allwomenandgirlswithepilepsyshouldbeencouragedtobreastfeed,exceptinveryrare
circumstances.BreastfeedingformostwomenandgirlstakingAEDsisgenerallysafeandshould
beencouraged.However,eachmotherneedstobesupportedinthechoiceoffeedingmethod
thatbestssuitsherandherfamily.[2004]
206. PrescribersshouldconsultindividualdrugadviceintheSPCandtheBNF(availableat
http://bnf.org)
whenprescribingAEDsforwomenandgirlswhoarebreastfeeding.Thedecision
regardingAEDtherapyandbreastfeedingshouldbemadebetweenthewomanorgirlandthe
prescriber,andbebasedontherisksandbenefitsofbreastfeedingagainstthepotentialrisksof
thedrugaffectingthechild.[2004,amended2012]
207. Discusswithwomenandgirlsofchildbearingpotential(includingyounggirlswhoare
likelytoneedtreatmentintotheirchildbearingyears),andtheirparentsand/orcarersif
appropriate,theriskofAEDscausingmalformationsandpossibleneurodevelopmental
impairmentsinanunbornchild.Assesstherisksandbenefitsoftreatmentwithindividualdrugs.
Therearelimiteddataonriskstotheunbornchildassociatedwithnewerdrugs.Specifically
discusstheriskofcontinueduseofsodiumvalproatetotheunbornchild,beingawarethathigher
dosesofsodiumvalproate(morethan800mg/day)andpolytherapy,particularlywithsodium
valproate,areassociatedwithgreaterrisk.[new2012]
208. BeawareofthelatestdataontheriskstotheunbornchildassociatedwithAEDtherapy
whenprescribingforwomenandgirlsofpresentandfuturechildbearingpotential.[2012]
209. Aimforseizurefreedombeforeconceptionandduringpregnancy(particularlyforwomen
andgirlswithgeneralisedtonicclonicseizures)butconsidertheriskofadverseeectsofAEDs
andusethelowesteffectivedoseofeachAED,avoidingpolytherapyifpossible.[new2012]
210. Discusswithwomenandgirlswhoaretakinglamotriginethatthesimultaneoususeofany
oestrogenbasedcontraceptivecanresultinasignificantreductionoflamotriginelevelsandlead
tolossofseizurecontrol.Whenawomanorgirlstartsorstopstakingthesecontraceptives,the
doseoflamotriginemayneedtobeadjusted.[new2012]
211. DonotroutinelymonitorAEDlevelsduringpregnancy.Ifseizuresincreaseorarelikelyto
increase,monitoringAEDlevels(particularlylevelsoflamotrigineandphenytoin,whichmaybe
particularlyaffectedinpregnancy)maybeusefulwhenmakingdoseadjustments.[new2012]
212. IndicationsformonitoringofAEDbloodlevelsare:
detectionofnonadherencetotheprescribedmedication
suspectedtoxicity
adjustmentofphenytoindose
managementofpharmacokineticinteractions(forexample,changesinbioavailability,changes
inelimination,andcomedicationwithinteractingdrugs)
specificclinicalconditions,forexample,statusepilepticus,organfailureandcertainsituations
inpregnancy(seerecommendation211)[2012]
213. RefertotheSPCandBNF(availableathttp://www.bnf.org)forindividualdrugadviceon
theinteractionsbetweenAEDsandhormonalreplacementandcontraception.[new2012]
214. Inwomenofchildbearingpotential,thepossibilityofinteractionwithoralcontraceptives
shouldbediscussedandanassessmentmadeastotherisksandbenefitsoftreatmentwith
individualdrugs.[2004]
Inthisrecommendation,theoriginalreferraltoappendix5oftheBNFhasbeenremovedandreplacedwithmoreupto
datesourcereferencematerialbecausethisappendixnolongerexistsandhasthereforebecomeobsoletesincethe
originalguidelinewaspublishedin2004.
TheEpilepsies
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76
215. Ingirlsofchildbearingpotential,includingyounggirlswhoarelikelytoneedtreatment
intotheirchildbearingyears,thepossibilityofinteractionwithoralcontraceptivesshouldbe
discussedwiththechildand/orhercarer,andanassessmentmadeastotherisksandbenefitsof
treatmentwithindividualdrugs.[2004]
216. Inwomenandgirlsofchildbearingpotential,therisksandbenefitsofdifferent
contraceptivemethods,includinghormonereleasingIUDs,shouldbediscussed.[2004]
217. IfawomanorgirltakingenzymeinducingAEDschoosestotakethecombinedoral
contraceptivepill,guidanceaboutdosageshouldbesoughtfromtheSPCandcurrenteditionof
theBNF(availableathttp://bnf.org).[2004,amended2012]
218. Theprogestogen
onlypillisnotrecommendedasreliablecontraceptioninwomenand
girlstakingenzymeinducingAEDs.[2004,amended2012]
219. Theprogestogen
implantisnotrecommendedinwomenandgirlstakingenzyme
inducingAEDs.[2004,amended2012]
220. Theuseofadditionalbarriermethodsshouldbediscussedwithwomenandgirlstaking
enzymeinducingAEDsandoralcontraceptionorhavingdepotinjectionsofprogestogen.[2004,
amended2012]
221. IfemergencycontraceptionisrequiredforwomenandgirlstakingenzymeinducingAEDs,
thetypeanddoseofemergencycontraceptionshouldbeinlinewiththeSPCandcurrentedition
oftheBNF(availableathttp://bnf.org).[2004,amended2012]
222. Womenandgirlswithepilepsyshouldbeinformedthatalthoughtheyarelikelytohave
healthypregnancies,theirriskofcomplicationsduringpregnancyandlabourishigherthanfor
womenandgirlswithoutepilepsy.[2004]
223. Careofpregnantwomenandgirlsshouldbesharedbetweentheobstetricianandthe
specialist.[2004]
224. PregnantwomenandgirlswhoaretakingAEDsshouldbeofferedahighresolution
ultrasoundscantoscreenforstructuralanomalies.Thisscanshouldbeperformedat1820
weeksgestationbyanappropriatelytrainedultrasonographer,butearlierscanningmayallow
majormalformationstobedetectedsooner.[2004]
225. Allpregnantwomenandgirlswithepilepsyshouldbeencouragedtonotifytheir
pregnancy,orallowtheircliniciantonotifythepregnancy,totheUKEpilepsyandPregnancy
Register(www.epilepsyandpregnancy.co.uk).[2004]
226. AllwomenandgirlsonAEDsshouldbeoffered5mgperdayoffolicacidbeforeany
possibilityofpregnancy.[2004]
227. Womenandgirlswithepilepsyneedaccurateinformationduringpregnancy,andthe
possibilityofstatusepilepticusandSUDEPshouldbediscussedwithallwomenandgirlswhoplan
tostopAEDtherapy(seesection10.2.6).[2004]
228. Womenandgirlswithgeneralisedtonicclonicseizuresshouldbeinformedthatthefetus
maybeatrelativelyhigherriskofharmduringaseizure,althoughtheabsoluteriskremainsvery
low,andthelevelofriskmaydependonseizurefrequency.[2004]
Inthisrecommendation,progesteronehasbeenreplacedwithprogestogentoreflectachangeinterminologysincethe
TheEpilepsies
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77
229. Womenandgirlsshouldbereassuredthatthereisnoevidencethatfocal
,absenceand
myoclonicseizuresaffectthepregnancyordevelopingfetusadverselyunlesstheyfallandsustain
aninjury.[2004,amended2012]
230. Theriskofseizuresduringlabourislow,butitissufficienttowarrantthe
recommendationthatdeliveryshouldtakeplaceinanobstetricunitwithfacilitiesformaternal
andneonatalresuscitationandtreatingmaternalseizures.[2004]
231. Advancedplanning,includingthedevelopmentoflocalprotocolsforcare,shouldbe
implementedinobstetricunitsthatdeliverbabiesofwomenandgirlswithepilepsy.[2004]
232. Parentsshouldbereassuredthattheriskofinjurytotheinfantcausedbymaternal
seizureislow.[2004]
233. Parentsofnewbabiesoryoungchildrenshouldbeinformedthatintroducingafewsimple
safetyprecautionsmaysignificantlyreducetheriskofaccidentsandminimiseanxiety.An
approachingbirthcanbeanidealopportunitytoreviewandconsiderthebestandmosthelpful
measurestostarttoensuremaximumsafetyforbothmotherandbaby.[2004]
234. Informationshouldbegiventoallparentsaboutsafetyprecautionstobetakenwhen
caringforthebaby(seeAppendixD).[2004]
235. AllchildrenborntomotherstakingenzymeinducingAEDsshouldbegiven1mgof
vitaminKparenterallyatdelivery.[2004]
236. Geneticcounsellingshouldbeconsideredifonepartnerhasepilepsy,particularlyifthe
partnerhasidiopathicepilepsyandapositivefamilyhistoryofepilepsy.[2004]
237. Althoughthereisanincreasedriskofseizuresinchildrenofparentswithepilepsy,
children,youngpeopleandadultswithepilepsyshouldbegiveninformationthattheprobability
thatachildwillbeaffectedisgenerallylow.However,thiswilldependonthefamilyhistory.
[2004]
238. Jointepilepsyandobstetricclinicsmaybeconvenientformothersandhealthcare
professionalsbutthereisinsufficientevidencetorecommendtheirroutineuse.[2004]
239. Itis,however,importantthatthereshouldberegularfollowup,planningofdelivery,
liaisonbetweenthespecialistorepilepsyteamandtheobstetricianormidwife.[2004]
240. Itcanbedifficulttodiagnoseepilepsyinchildren,youngpeopleandadultswithlearning
disabilities,andsocareshouldbetakentoobtainafullclinicalhistory.Confusionmayarise
betweenstereotypicorotherbehavioursandseizureactivity.[2004]
241. Itisimportanttohaveaneyewitnessaccountsupplementedbycorroborativeevidence
(forexample,avideoaccount),wherepossible.[2004]
242. Clear,unbiasedreportingisessential.Witnessesmayneededucationtodescribetheir
observationsaccurately.[2004]
243. Thosewithlearningdisabilitiesmayrequireparticularcareandattentiontotolerate
investigations.[2004]
244. Facilitiesshouldbeavailableforimagingunderanaesthesia,ifnecessary.[2004]
TheEpilepsies
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78
245. Inthechildoryoungpersonpresentingwithepilepsyandlearningdisability,
investigationsdirectedatdetermininganunderlyingcauseshouldbeundertaken.[2004]
246. Inmakingacareplanforachild,youngpersonoradultwithlearningdisabilitiesand
epilepsy,particularattentionshouldbepaidtothepossibilityofadversecognitiveand
behaviouraleffectsofAEDtherapy.[2004]
247. Therecommendationsonchoiceoftreatmentandtheimportanceofregularmonitoring
ofeffectivenessandtolerabilityarethesameforthosewithlearningdisabilitiesasforthegeneral
population.[2004]
248. Enablechildren,youngpeopleandadultswhohavelearningdisabilities,andtheirfamily
and/orcarerswhereappropriate,totakeanactivepartindevelopingapersonalisedcareplanfor
treatingtheirepilepsywhiletakingintoaccountanycomorbidities.[new2012]
249. Ensureadequatetimeforconsultationtoachieveeffectivemanagementofepilepsyin
children,youngpeopleandadultswithlearningdisabilities.[new2012]
250. Donotdiscriminateagainstchildren,youngpeopleandadultswithlearningdisabilities,
andofferthesameservices,investigationsandtherapiesasforthegeneralpopulation.[new
2012]
251. Everytherapeuticoptionshouldbeexploredinchildren,youngpeopleandadultswith
epilepsyinthepresenceorabsenceoflearningdisabilities.[2004]
252. Healthcareprofessionalsshouldbeawareofthehigherrisksofmortalityforchildren,
youngpeopleandadultswithlearningdisabilitiesandepilepsyanddiscussthesewiththem,their
familiesand/orcarers.[2004]
253. Allchildren,youngpeopleandadultswithepilepsyandlearningdisabilitiesshouldhavea
riskassessmentincluding:
bathingandshowering
preparingfood
usingelectricalequipment
managingprolongedorserialseizures
theimpactofepilepsyinsocialsettings
SUDEP
thesuitabilityofindependentliving,wheretherightsofthechild,youngpersonoradultare
balancedwiththeroleofthecarer.[2004]
254. Thephysical,psychologicalandsocialneedsofyoungpeoplewithepilepsyshouldalways
beconsideredbyhealthcareprofessionals.Attentionshouldbepaidtotheirrelationshipswith
familyandfriends,andatschool.[2004]
255. Healthcareprofessionalsshouldadoptaconsultingstylethatallowstheyoungperson
withepilepsytoparticipateasapartnerintheconsultation.[2004]
256. Decisionsaboutmedicationandlifestyleissuesshoulddrawonboththeexpertiseofthe
healthcareprofessionalandtheexperiences,beliefsandwishesoftheyoungpersonwithepilepsy
aswellastheirfamilyand/orcarers.[2004]
257. Duringadolescenceanamedclinicianshouldassumeresponsibilityfortheongoing
managementoftheyoungpersonwithepilepsyandensuresmoothtransitionofcaretoadult
services,andbeawareoftheneedforcontinuingmultiagencysupport.[2004]
TheEpilepsies
Guidance
79
258. Multidisciplinaryservicesprovidedjointlybyadultandpaediatricspecialistshaveakey
roleinthecareoftheyoungpersonwithepilepsy.Thiscanfacilitatethetransitionfrom
paediatrictoadultservicesandaidinthedisseminationofinformation.[2004]
259. Beforethetransitiontoadultservicesismade,diagnosisandmanagementshouldbe
reviewedandaccesstovoluntaryorganisations,suchassupportgroupsandepilepsycharities,
shouldbefacilitated.[2004]
260. Theinformationgiventoyoungpeopleshouldcoverepilepsyingeneralanditsdiagnosis
andtreatment,theimpactofseizuresandadequateseizurecontrol,treatmentoptionsincluding
sideeffectsandrisks,andtherisksofinjury.Otherimportantissuestobecoveredarethe
possibleconsequencesofepilepsyonlifestyleandfuturecareeropportunitiesanddecisions,
drivingandinsuranceissues,socialsecurityandwelfarebenefitissues,suddendeathandthe
importanceofadherencetomedicationregimes.Informationonlifestyleissuesshouldcover
recreationaldrugs,alcohol,sexualactivityandsleepdeprivation(seechapter12).[2004]
261. Thediagnosisandmanagementofepilepsyshouldbereviewedduringadolescence.
[2004]
262. Donotdiscriminateagainstolderpeople,andofferthesameservices,investigationsand
therapiesasforthegeneralpopulation.[new2012]
263. Payparticularattentiontopharmacokineticandpharmacodynamicissueswith
polypharmacyandcomorbidityinolderpeoplewithepilepsy.ConsiderusinglowerdosesofAEDs
and,ifusingcarbamazepine,offercontrolledreleasecarbamazepinepreparations.[new2012]
264. Children,youngpeopleandadultsfromblackandminorityethnicgroupsmayhave
differentculturalandcommunicationneedsandtheseshouldbeconsideredduringdiagnosisand
management.Theneedforinterpretationshouldbeconsideredalongsideothermeansof
ensuringthatapersonsneedsareappropriatelymet.[2004]
265. Aninterpretershouldhavebothculturalandmedicalknowledge.Interpretersfromthe
familyaregenerallynotsuitablebecauseofissuessuchasconfidentiality,privacy,personal
dignity,andaccuracyoftranslation.[2004]
266. Information,includinginformationaboutemploymentrightsanddriving,shouldbe
availableinanappropriateformatorthroughotherappropriatemeansforchildren,youngpeople
andadultswhodonotspeakorreadEnglish.[2004]
267. Children,youngpeopleandadultswithepilepsyshouldhavearegularstructuredreview
andberegisteredwithageneralmedicalpractice.[2004]
268. AdultsshouldhavearegularstructuredreviewwiththeirGP,butdependingonthe
personswishes,circumstancesandepilepsy,thereviewmaybecarriedoutbythespecialist.
[2004]
269. Foradults,themaximumintervalbetweenreviewsshouldbe1yearbutthefrequencyof
reviewwillbedeterminedbythepersonsepilepsyandtheirwishes.[2004]
270. Epilepsyspecialistnurses(ESNs)shouldbeanintegralpartofthenetworkofcareof
children,youngpeopleandadultswithepilepsy.ThekeyrolesoftheESNsaretosupportboth
epilepsyspecialistsandgeneralists,toensureaccesstocommunityandmultiagencyservicesand
toprovideinformation,trainingandsupporttothechild,youngpersonoradult,families,carers
and,inthecaseofchildren,othersinvolvedinthechildseducation,welfareandwellbeing.
[2004]
TheEpilepsies
Guidance
80
271. Children,youngpeopleandadultswithepilepsyshouldhaveanaccessiblepointof
contactwithspecialistservices.[2004]
272. Allchildren,youngpeopleandadultswithepilepsyshouldhaveacomprehensivecare
planthatisagreedbetweentheperson,familyand/orcarerswhereappropriate,andprimary
careandsecondarycareproviders.Thisshouldincludelifestyleissuesaswellasmedicalissues.
[2004]
273. Adultsshouldhaveregularreviews.Inaddition,accesstoeithersecondaryortertiary
careshouldbeavailabletoensureappropriatediagnosis,investigationandtreatmentifthe
personorclinicianviewtheepilepsyasinadequatelycontrolled.[2004]
274. Adultswithwellcontrolledepilepsymayhavespecificmedicalorlifestyleissues(for
example,pregnancyordrugcessation)thatmayneedtheadviceofaspecialist.[2004]
275. Childrenandyoungpeopleshouldhavearegularstructuredreviewwithaspecialist.
[2004]
276. Forchildrenandyoungpeople,themaximumintervalbetweenreviewsshouldbe1year,
butthefrequencyofreviewsshouldbedeterminedbythechildoryoungperson'sepilepsyand
theirwishesandthoseofthefamilyand/orcarers.Theintervalbetweenreviewsshouldbe
agreedbetweenthechildoryoungperson,theirfamilyand/orcarersasappropriate,andthe
specialist,butislikelytobebetween3and12months.[2004]
277. Atthereview,children,youngpeopleandadultsshouldhaveaccessto:writtenand
visualinformation;counsellingservices;informationaboutvoluntaryorganisations;epilepsy
specialistnurses;timelyandappropriateinvestigations;referraltotertiaryservicesincluding
surgery,whereappropriate.[2004]
278. Ifthestructuredreviewistobeconductedbythespecialist,thismaybebestprovidedin
thecontextofaspecialistclinic.[2004]
279. Attheinitialassessmentforarecentonsetseizure,thespecialistshouldhaveaccessto
appropriateinvestigations.[2004]
280. Children,youngpeopleandadultspresentingtoanAccidentandEmergencydepartment
followingasuspectedseizureshouldbescreenedinitially.Thisshouldbedonebyanadultor
paediatricphysicianwithonwardreferraltoaspecialist
whenanepilepticseizureissuspectedor
thereisdiagnosticdoubt.[2004]
281. Protocolsshouldbeinplacethatensureproperassessmentintheemergencysettingfor
children,youngpeopleandadultspresentingwithanepilepticseizure(suspectedorconfirmed).
[2004]
282. Children,youngpeopleandadultswithepilepsyandtheirfamiliesand/orcarersshould
beempoweredtomanagetheirconditionaswellaspossible.[2004]
283. Adultsshouldreceiveappropriateinformationandeducationaboutallaspectsof
epilepsy.Thismaybebestachievedandmaintainedthroughstructuredselfmanagementplans.
[2004]
284. Inchildrenandyoungpeople,selfmanagementofepilepsymaybebestachievedthrough
activechildcentredtrainingmodelsandinterventions.[2004]
andyoungpeople,aspecialistisdefinedthroughoutasapaediatricianwithtrainingandexpertiseinepilepsy.
TheEpilepsies
Guidance
81
285. HealthcareprofessionalsshouldhighlighttheExpertPatientsProgramme
(www.expertpatients.co.uk
)tochildren,youngpeopleandadultswithepilepsywhowishto
managetheirconditionmoreeffectively.[2004,amended2012]
Thiswebaddresshaschangedsincetherecommendationwaspublishedin2004andhasbeenupdated.
TheEpilepsies
Guidance
82
4.1.1 Outlineepilepsycarealgorithms
Outlinecarealgorithmforadults
Outlinecarealgorithmforchildren
TheEpilepsies
Guidance
83
TheEpilepsies
84
BoxACrossReferenceforalgorithms PageNumber
TreatmentwithAEDsonlyinexceptionalcircumstances 136
Diagnosisandinvestigations 87and93
Furtherinvestigations 98,102,103,104,105,114,
116
Investigationsandclassificationbyseizuretypeandepilepsy 119
Referraltotertiarycare 477
Treatment 130
Prolongedorrepeatedseizures;statusepilepticus 443
Womenandgirlswithepilepsy 504
Specialgroups 544,558,563,572
Regularstructuredreview 574,577
Appropriateinformation 493
TheEpilepsies
AuditCriteria
85
5 AuditCriteria
2004
Theauditcriteriaoutlinedbelowmaybeappliedineitherprimaryorsecondarycare,and,where
appropriate,tertiarycare,dependingontheageoftheindividualandthelevelofseizurecontrol.
Thecriteriahavenotbeenidentifiedasbeingrelevanttospecificsettingsasitisimportantthatthese
criteriaareassessedforallindividualsregardlessofwheretheyreceivetheircare.
Therecordsshowthatallindividualspresentingwithsuspectedrecentonsetseizuresshouldbeseen
within2weeksofreferral.
Therecordsshowthenamedspecialistwhoestablishedthediagnosisofepilepsy.
TherecordsshowwhetherornotAEDtherapywasprescribed.IfAEDswereprescribed,detailsofthe
prescription,includingdrug,doseanddateofinitiationshouldbeincluded.
TherecordsshowthatifAEDtherapywasprescribed,thatthedecisiontoinitiatetreatmentwas
madeinconsultationwiththeindividualandfamilyand/orcarers.
TherecordsshowthatifindividualsdecidednottocommencetheAEDtherapyoffered,thisdecision
wasrecorded.
Therecordsshowthatallindividualshavehadtheirseizuresand/orepilepsysyndromeclassified
usingamultiaxialclassificationscheme.
TherecordsshowthatifcombinationAEDtherapyisprescribed,anadequatetrialofmonotherapy
wastried.
Therecordsshowthatallindividualswithadiagnosisofepilepsyhaveanagreedcareplan.
Therecordsshowthatallindividualswithepilepsyhavehadareviewintheprevious12months.
Therecordsshowthatseizurefrequencyhasbeendocumentedinthepast12monthsforall
individualswithadiagnosisofepilepsy.
Therecordsshowadefinedpercentageofindividualswithepilepsyhasbeenseizurefreeforthepast
12months.
Therecordsshowthattheinformationneedsoftheindividualwerediscussedatthereview.
Therecordsshowthattreatmentchoiceshavebeendiscussedwithallwomenandgirlsof
childbearingpotential.
Therecordsshowthatcontraceptivechoiceshavebeendiscussedwithallwomenandgirlsof
childbearingpotentialtakingAEDtherapy.
Therecordsshowthatifindividualswerereferredtotertiaryservices,theywereseenwithin4
weeks.
Therecordsshowthatifindividualswerereferredtotertiaryservices,referralwasappropriate.
Therecordsshowthatallindividualswhohaveindicationsforreferraltotertiaryserviceswere
referred.
TheEpilepsies
Principleofdecisionmaking
86
6 Principleofdecisionmaking
6.1 Whoshouldbeinvolvedinthedecisionmakingprocessforadults
andchildrenwithepilepsy?
1. Healthcareprofessionalsshouldadoptaconsultingstylethatenablesthechild,youngpersonor
adultwithepilepsy,andtheirfamilyand/orcarersasappropriate,toparticipateaspartnersin
alldecisionsabouttheirhealthcare,andtakefullyintoaccounttheirrace,cultureandany
specificneeds.[2004]
Itwasnotpossiblewithinthetimeandresourceconstraintsinpreparingthisguidelinetopreparea
reviewoftheliteraturerelatingtomodelsofdecisionmakingbetweenhealthprofessionalsand
individualswithepilepsyorotherchronicillnesses.Itshouldbenotedthatthereisamuchmore
extensiveliteratureinrelationtootherchronicillnessessuchasdiabetesandasthma.
ThepatientrepresentativesidentifiedarecentpublicationbytheBritishEpilepsyAssociationthat
addressedtheissueofdecisionmakingspecificallyforpeoplewithepilepsy.
BritishEpilepsyAssociation2000
45
TheissueofindividualempowermentwasaddressedinatoolkitdevelopedbytheEpilepsyAdvisory
BoardoftheBEA,andwasendorsedbytheBritishEpilepsyAssociation,JointEpilepsyCouncil,the
EpilepsySpecialistNursesAssociation,andtheRoyalCollegeofNursing.Thetoolkitdidnotoffer
anyreferencesinsupportoftheirrecommendationsondecisionmakingandtheyshouldberegarded
asrepresentingtheopinionsofrespectedauthorities.
Theauthorsstatedthat:
Themodernmanagementofepilepsyincludesregimentedapproachestopatientcarewhichhas
beendevelopedbyclinicians.However,patientsthemselvesshouldbeencouragedtoacknowledge
theirresponsibilityandtheirpartintheteamthatisstrivingtomanageadifficultmedicalcondition.
Theshorthandjargonforthispatientinvolvementistotakeownershipoftheirownepilepsyand
acceptresponsibilityfortheirownhealth.Thisistheprincipleunderpinningtheconceptofindividual
empowerment.
Thedoctorpatientrelationship
Doctorsarenotresponsibleforpeoplewithepilepsy,butrathertheyareresponsibletothem.This
includes:
ensuringanaccuratediagnosis
providingindividualswiththeappropriateinformationregardingtheircondition
agreeingastrategyinpartnershipwiththeindividual,utilisingallcurrentlyavailabletreatment
optionswiththegoalofabolishingseizures.
45
TheEpilepsies
Diagnosis
87
7 Diagnosis
7.1 Introduction
Therearemajorhealth,educationalandpsychosocialimplicationsattachedtomakingadiagnosisof
epilepsyinbothadultsandchildren.Itisvitalthatthespecialistissensitivetotheneedsofthe
individualandtheirfamily/carerswhencommunicatingadiagnosisofepilepsy.Makingadiagnosis
ofepilepsy,however,canbedifficult.Misdiagnosisisafrequentoccurrence,particularlywhenthe
diagnosisismadebyanonspecialist.Individualsmisdiagnosedwithepilepsymayexperiencesocial
andfinancialdeprivationasaresultofhavingthewrongdiagnosticlabelandfromsideeffectsof
antiepilepticmedication.Inaddition,theremaybeariskofunnecessaryteratogenicityasaresultof
AEDtherapyinwomenincorrectlydiagnosedashavingepilepsy.Inasmallnumberofcases,
individualsmaydieprematurelybecausethecorrectdiagnosiswasnotmade,andaseriouscondition
wasneitherdiagnosednortreated.Individualswhohavesymptomsduetoepilepticseizuresbut
whoarewronglydiagnosedashavingpsychiatricorassociateddisordersaredisadvantagedfrom
beinglabelledwithanincorrectdiagnosisandbytheeffectsofcontinuingseizureactivitybecause
AEDsarenotused.Itisthereforecrucialthatspecialistsinvolvedindiagnosingepilepsytakegreat
caretoestablishthecorrectdiagnosis.
7.2 Establishingthediagnosisofepilepsy
2. Thediagnosisofepilepsyinadultsshouldbeestablishedbyaspecialistmedicalpractitioner
withtrainingandexpertiseinepilepsy.[2004]
3. Thediagnosisofepilepsyinchildrenandyoungpeopleshouldbeestablishedbyaspecialist
paediatricianwithtrainingandexpertiseinepilepsy.[2004]
4. Itisrecommendedthatalladultshavingafirstseizureshouldbeseenassoonaspossible
***
by
aspecialistinthemanagementoftheepilepsiestoensurepreciseandearlydiagnosisand
initiationoftherapyasappropriatetotheirneeds.[2004]
5. Itisrecommendedthatallchildrenandyoungpeoplewhohavehadafirstnonfebrileseizure
shouldbeseenassoonaspossible
i
byaspecialistinthemanagementoftheepilepsiesto
ensurepreciseandearlydiagnosisandinitiationoftherapyasappropriatetotheirneeds.
[2004]
Evidencestatement
Diagnosingepilepsyisnoteasy,andmisdiagnosisoccursinaround25%ofcases.(III)
Details
Anadequatediagnosisofepilepsyrequiresdifferentiationbetweenseizuresandothercausesof
transientneurologicaldisturbanceandcollapse;differentiationbetweenacutesymptomaticand
unprovokedepilepticseizures;and,inpeoplewithepilepsy,classificationofthedisorderand
identificationofthecausesoastooptimisetreatment.
46
Secondaryevidence
***
TheGuidelineDevelopmentGroupconsideredthatwitharecentonsetsuspectedseizure,referralsshouldbeurgent,
meaningthatpatientsshouldbeseenwithin2weeks.
TheEpilepsies
Diagnosis
88
Nosystematicreviewscomparingratesofdiagnosisbytraining,title,orpositionwerefound.
Primaryevidence
Smith1999
5
Oneprimarypaperwasidentifiedthatassessedthefrequency,causes,andconsequencesofan
erroneousdiagnosisofepilepsy.Theauthorsfoundanoverallmisdiagnosisrateof26.1%
(n=46/184).Erroneousdiagnosesweremadebyallprofessionalgroups,butthemajorityweremade
bygeneralists.
Scheepers1998
47
Inanotherpopulationstudy,49of214individualswithaprimarydiagnosisofepilepsywere
subsequentlyfoundtobemisdiagnosed.Ofthese,20werefoundtohavehadcardiovascularor
cerebrovascularpathology.Sevenhadonlyeverexperiencedoneseizureandafurther10were
foundtohaveunderlyingpsychopathology.
7.3 Keyfeaturesofthehistoryandexaminationthatallowepilepsy
tobedifferentiatedfromotherdiagnosesinadultsandchildren
6. Adetailedhistoryshouldbetakenfromthechild,youngpersonoradultandaneyewitnessto
theattack,wherepossible,todeterminewhetherornotanepilepticseizureislikelytohave
occurred.[2004]
7. Theclinicaldecisionastowhetheranepilepticseizurehasoccurredshouldthenbebasedon
thecombinationofthedescriptionoftheattackanddifferentsymptoms.Diagnosisshouldnot
bebasedonthepresenceorabsenceofsinglefeatures.[2004]
8. Theinformationthatshouldbeobtainedfromtheadultand/orfamilyorcareraftera
suspectedseizureiscontainedinAppendixA.[2004]
9. Theinformationthatshouldbeobtainedfromthechildoryoungpersonand/orparentorcarer
afterasuspectedseizureiscontainedinAppendixA.[2004]
10. Inachild,youngpersonoradultpresentingwithanattack,aphysicalexaminationshouldbe
carriedout.Thisshouldaddresstheircardiac,neurologicalandmentalstatus,andshould
includeadevelopmentalassessmentwhereappropriate.[2004]
11. Itmaynotbepossibletomakeadefinitediagnosisofepilepsy.Ifthediagnosiscannotbeclearly
established,furtherinvestigations(seesection8)and/orreferraltoatertiaryepilepsy
specialist
(seerecommendation170)shouldbeconsidered.Followupshouldalwaysbe
arranged.[2004]
12. Wherenonepilepticattackdisorderissuspected,suitablereferralshouldbemadeto
psychologicalorpsychiatricservicesforfurtherinvestigationandtreatment.[2004]
Evidencestatements
Adiagnosisofepilepsycanbemadeinthemajorityofcasesonthebasisofinformationobtained
fromindividualandwitnesshistoriesandexaminationoftheindividual.(III)
Inthisrecommendationcentrehasbeenreplacedwithspecialistforconsistencyacrosstherecommendations.
TheEpilepsies
Diagnosis
89
Anumberofclinicalfeaturesmayoccurindifferenttypesofattackdisorder,sodiagnosisshouldbe
basedonacombinationofdifferentsymptomsandnotonthepresenceorabsenceofsingle
features.Nosinglesymptomisdiagnosticofepilepsy.(IIb)
Aclinicalexaminationthatincludesaneurologicalexaminationisessential,sinceanabnormal
examinationafterafirstseizurepredictsrecurrence.(III)
Details
Methodologicalissues
Inanevidencebasedreviewofdiagnosisonewouldbelookingforarticlesthattestaclinical
diagnosisofepilepsy(e.g.setofparticularsymptoms)againstavalidatedtestforepilepsy(gold
standard).Onewouldhopetodeterminethesensitivity(proportionofpeoplewithepilepsywho
haveasetofparticularsymptomsorsigns)andspecificity(proportionofpeoplewhodonothave
epilepsywhodonothaveasetofparticularsymptomsorsigns)ofthetest.Thesetwomeasures
wouldthenbecombinedintoanoverallmeasureoftheefficacyofadiagnostictestcalledthe
likelihoodratiothelikelihoodthatagivencombinationofsymptomswouldbeexpectedinan
individualwithepilepsycomparedwiththelikelihoodthatthesameresultwouldbeexpectedin
someonewithoutepilepsy.
48,49
Unfortunatelyitisdifficulttoprepareanevidencebasedreviewon
theclinicaldiagnosisofepilepsyforreasonsdiscussedbelow.
Secondaryevidence
AHRQ2001
50
Onesystematicreviewthatconsideredhowthediagnosisofepilepsyshouldbemadeinadultsand
childrenwasidentified.Theauthorsnotedthatitwasdifficulttoprepareanevidencebasedreview
ofthepredictivevalueofsymptomsandsignsinindividualswithepilepsyforthefollowingreasons:
Goldstandardfordiagnosiswaslooselyconstruedandincludedbothaclinicalcomponent
andanEEGcomponent.
Theclinicalrequirementsfordiagnosiswerehighlyvariableandincludedsuchsignsand
symptomsastonic/clonicmovements,withorwithoutpostictalconfusion,tonguebiting,
sphincterdisturbance,aura,andlossofconsciousness.Somestudiesrequiredtheeventsto
beunprovoked;othersdidnot.Somestudiesrequiredtheeventsbewitnessed;othersdid
not.
Theseizuretypewasusuallydiagnosedbyclinicalfeaturesandtheepilepsysyndrome,by
seizuretypeandEEGfindings.
Onlyaminorityofstudiesreferredtoestablishedclassificationschemas,forexample,the
InternationalLeagueAgainstEpilepsy(ILAE).
Theauthorsmadethefollowingevidencestatementsfromtheirreviewoftheevidence:
Theliteraturesupportsthediagnosticroleofacompletehistory,especiallyindiagnosingJME
(juvenilemyoclonicepilepsy),toelucidateanadequatedescriptionoftheseizurestopermit
categorizingbyseizuretype,sinceahistorysuggestiveofafocalseizurepredictsrecurrence.A
clinicalexaminationthatincludesacarefulneurologicexaminationisessential,sinceanabnormal
examinationafterafirstseizurealsopredictsrecurrence.
50
Thissystematicreviewprovidedanevidencesummaryofrelevantprimarypapers.Sixpaperswere
identifiedashelpinganswerthequestionastotheroleofhistoryandphysicalexamination.
51,52
Bergandcolleagues
53,54
reportedthat609of613childrenwereassignedasyndromicdiagnosison
thebasisofclinicalfeatures.
TheEpilepsies
Diagnosis
90
Arts,Geerts,Brouwer,andcolleagues
55
reportingon466childrensuggestedthehistoryalone
yieldeda29percentsensitivityand89percentspecificity.
Hoefnagels,Padblerg,Overweg,andcolleagues
52
notedthatitwasimpossibletofindagold
standardforthediagnosisofepilepsyandthereforedevelopedtheirowntodistinguishepilepsy
fromsyncope.Sensitivityandspecificityofseveralcomponentsofahistorywerecomputed,e.g.,
particularsymptomsbefore,during,andaftertheparoxysmalevent.Thosebeforetheeventhad
thehighestsensitivity(88%to98%),andthoseduringtheevent,thehighestspecificity(64%to
94%).
Camfield,Camfield,Dooleyandcolleagues
51
reportedthatinaretrospectiveanalysisof168
childrenseenaftertheirfirstseizure,anabnormalneurologicexamination(in30children)was
predictiveofrecurrence,aswasseizuretype(focalseizureassociatedwithincreasedrisk).
Neitherthesleepwakestatusatthefirstseizurenorahistoryoffebrileseizurespredicted
recurrence.Inthreeadditionalretrospectivestudies,theutilityofvariousinterventionsin
diagnosisand/orpredictionofrecurrencewasreported.
Ambrosetto,Giovanardi,andTassinari
56
reportedonhistory(andEEGfindings)in72individuals
andconcludedthatonlygeneralizedseizuresasthesoleictalphenomenon,andalonginterval
betweenthefirstandsecondseizures,werepredictiveofseizurefrequencysubsequently.
Otherprimarypapers
Sheldon2002
57
SincetheAHRQreview
50
,anadditionalstudyprospectivelysoughtevidencebasedcriteriathat
distinguishedbetweenseizuresandsyncopeinapopulationofadults(n=671)whowerereferredto
threeacademiccentresinCanadaandtheUK(Wales)forassessmentoftransientlossof
consciousness.
57
Inthisstudythecausesoflossofconsciousnesswereknownsatisfactorilyin539adultsandincluded
seizures(19%,102/539,ofthesefocalepilepsy49%andgeneralizedepilepsy51%)andsyncope
(81%,437/539;ofthesetiltpositivevasovagalsyncope67%andcardiaccausesofsyncope33%).
Thepointscorebasedonsymptomsalonecorrectlyclassified94%ofindividuals,diagnosingseizures
with94%sensitivityand94%specificity.
44
Theyproposetheuseofthefollowingquestions:
Questionsusedthat,ifpositive,supportadiagnosisofepilepticseizure:
Attimesdoyouwakeupwithacuttongueafteryourspells?
Attimesdoyouhaveasenseofdjvuorjamaisvubeforeyourspells?
Attimesisemotionalstressassociatedwithlosingconsciousness?
Hasanyonenoticedyourheadturningduringaspell?
Hasanyoneevernotedthatyouareunresponsive,haveunusualposturingorhavejerking
limbsduringyourspellsorhavenomemoryofyourspellsafterwards?
Hasanyonenoticedthatyouareconfusedafteraspell?
Questionsusedthat,ifpositive,supportadiagnosisofsyncope:
Haveyoueverhadlightheadedspells?
Attimesdoyousweatbeforeyourspells?
TheEpilepsies
Diagnosis
91
Isprolongedsittingorstandingassociatedwithyourspells?
7.4 Whatarethekeyfeaturesofthehistoryandexaminationthat
allowanepilepticseizuretobedifferentiatedfromothercauses
ofattackdisorderinadults?
ThisKCQwasnotsubjecttoafullevidencereviewforreasonssetoutinchapter2.
ExpertreviewsonthekeyfeaturesofthehistoryandexaminationcanbefoundinAppendixA.
7.5 Theroleofattack/seizurediariesindiagnosisinadults&children
Nopublishedpaperswereidentifiedthataddressedthequestionoftheuseofseizurediariesto
makethediagnosisofepilepsy.Thisisincontrasttotheexistingliteraturerelatingtotheirusein
monitoringseizurecontrolinindividualswithepilepsy.
7.6 Theroleofhomevideorecordinginmakingthediagnosisof
epilepsyinadultsandchildren?
13. Prospectiverecordingofevents,includingvideorecordingandwrittendescriptions,canbevery
helpfulinreachingadiagnosis.[2004]
Evidencestatements
Thereisanabsenceofevidencetosupporttheclaimthathomevideorecordingcanaidthediagnosis
ofepilepsy.
Noevidenceontheuseofseizurediariesindiagnosiswasfound.
Details
Thedifferentiationbetweenepilepticandnonepilepticseizuresismadeprimarilyonthebasisofthe
clinicalhistory.Onecouldhypothesisethatthedirectrecordingofattackepisodesathome(byuse
ofhandheldhomevideorecorder)couldhelpfacilitatethediagnosisofepilepsybythe
physician/paediatriciantowhomtheadult/childwithadiagnosisofpossibleepilepticseizure?is
referred.
Areviewoftheevidence,however,identifiedpapersoflimitedvalidity(caseseries)and
questionablegeneralisability.Threepaperswereidentifiedthatlookedattheuseofhomevideo
recordingsasanaidtothediagnosisofepilepsyinadults
58
andchildren.
59,60
Onepaperlookedat
theuseofahandheldvideocamcorderinatertiarycentretoassistintheevaluationofseizures,but
itwasexcludedonthegroundsitdidnotrelatetodirectrecordingofattacksathome.
61
Primaryevidence
Newmark1981
58
Newmarkreportedasinglecasehistoryofa66yearoldwomanwitha21monthhistoryof
undiagnosedattacksinwhomhospitalmonitoringhadbeenunsuccessful.Adiagnosisofsecondarily
generalisedtonicclonicseizureswasmadebyanalysisofthehomevideotape.
Sheth1994
59
TheEpilepsies
Diagnosis
92
ShethandBodensteinerreportedasinglecasehistoryofa2yearoldboywhowasevaluatedbya
paediatricianandaneurologistforstereotypicparoxysmaleventswhichhisparentshadrecorded
withavideocamera.Theneurologistmadeaninitialdiagnosisofseizuresandphenobarbitalwas
prescribed.Theseizurescontinuedandarepeatvideo6weekslaterrevealedthediagnosistobe
infantilemasturbationandtherapywasdiscontinued.
Woody1985
60
Woodyreportedtwocasesofchildren(10montholdboy&8yearoldgirl)whohadbeenpreviously
investigatedforundiagnosedattacksusingEEGandinpatientassessment.Thehomevideo
recordingswereofsufficientqualitytoallowacorrectdiagnosistobemadeineachcase(complex
focalseizureandreflexmicturitionepilepsy).
Healtheconomics
Thereisalackofhealtheconomicsevidenceontheareasrelatedtodiagnosisinepilepsy.Inthe
presentguidelinemisdiagnosiswasviewedasahugeproblemnotonlyintermsofhumansuffering
butalsointermsofwasteofresourcesfortheNHSandsocietyasawhole.Withthepurposeof
highlightingthemagnitudeoftheproblem,aneconomicanalysiswascarriedouttoestimatethe
costsofmisdiagnosis(seeAppendixG).
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93
8 Investigations
8.1 Introduction
Arangeofinvestigations,chieflyEEGandbrainimaging,areavailabletoassistclinicianstomakea
multiaxialclassification(Classificationofseizuresandepilepsysyndromes)ofepilepsyinindividuals
suspectedashavingepilepsyonthebasisofinformationobtainedfromtheindividualand/orwitness
historiesandphysicalexamination.
GreatcautionisrequiredinperforminginvestigationssuchasEEGwhentheclinicalhistoryoffers
limitedsupportforadiagnosisofepilepsyastheriskofafalsepositiveresultmayleadto
misdiagnosis.
8.2 TheroleofEEGinmakingadiagnosisofepilepsy
8.2.1 HowgoodisthestandardEEGatdifferentiatingbetweenindividualswhohavehadan
epilepticseizureandthosewhohavehadanonepilepticseizure?
14. AnEEGshouldbeperformedonlytosupportadiagnosisofepilepsyinadultsinwhomthe
clinicalhistorysuggeststhattheseizureislikelytobeepilepticinorigin.[2004]
15. AnEEGshouldbeperformedonlytosupportadiagnosisofepilepsyinchildrenandyoung
people.IfanEEGisconsiderednecessary,itshouldbeperformedafterthesecondepileptic
seizurebutmay,incertaincircumstances,asevaluatedbythespecialist,beconsideredaftera
firstepilepticseizure.[2004]
16. AnEEGshouldnotbeperformedinthecaseofprobablesyncopebecauseofthepossibilityofa
falsepositiveresult.[2004]
17. TheEEGshouldnotbeusedtoexcludeadiagnosisofepilepsyinachild,youngpersonoradult
inwhomtheclinicalpresentationsupportsadiagnosisofanonepilepticevent.[2004]
18. TheEEGshouldnotbeusedinisolationtomakeadiagnosisofepilepsy.[2004]
19. Children,youngpeopleandadultsrequiringanEEGshouldhavethetestperformedsoon
afterithasbeenrequested.[2004]
Evidencestatements
ThestandardEEGhasvariablesensitivityandspecificityindeterminingwhetheranindividualhashad
anepilepticseizure.Intheprimarypapersreviewedthesensitivityrangedfrom26%to56%and
specificityfrom78%to98%.Thelikelihoodratioforapositivetestrangedfrom2.5to13andfora
negativetestfrom0.5to0.76.(III;IIbchildren)
ThefindingofinterictalepileptiformactivityonEEGcanbeusedtohelpconfirmtheclinicaldiagnosis
ofanepilepticseizure.AnegativeEEGcannotbeusedtoruleouttheclinicaldiagnosisofanepileptic
seizure.(III)
Individualswithaclinicaldiagnosisofanonepilepticseizuredisorderareunlikelytohave,butmay
occasionallyhave,epileptiformabnormalitiesonEEG.(III)
TheEpilepsies
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94
Details
Arecentdefinitionofwhatconstitutesastandard/routineinterictalEEGhasbeenprovidedin
guidelinesproducedbytheInternationalLeagueAgainstEpilepsy.
62
Recommendationsforroutine
EEGinvestigationwerethat:
Themodifiedcombinednomenclaturederivedfromthe1020systemshouldbeusedfor
electrodelocation
Theminimumnumberofelectrodesshouldbe21foradultsand9forchildren
Atleastbipolarmontageswithlongitudinalandtransversechainsshouldbeincluded
Artefactsofeyemovementshouldbeexcludedusingeyeopening,eyeclosing,andblink
procedures
Activationprocedures,suchashyperventilationandphoticstimulation,shouldbeused.
62
Secondaryevidence
Linzer1997
63
InthisUSsystematicreview,theauthorsreviewedtheliteratureondiagnostictestinginsyncopein
ordertoproviderecommendationsforacomprehensive,costeffectiveapproachtoestablishingits
cause.
Theauthorsnotedthatintheearly1980sEEGwascommonlyusedintheUStoinvestigate
individualswithsyncope.However,sixstudiesconclusivelyshowedthatEEGmonitoringisoflittle
useinunselectedindividualswithsyncope.Theauthorsqualitativelysummarizedtheresultsof
thesesixstudies.Intheabsenceofahistoryofseizureactivity,EEGdidnotprovideadiagnosisin
morethan500casesreportedintheliterature.Eightof534individualswerediagnosed(diagnosis
notstated)usingEEG;2ofthese8hadclinicaldataprovided,andbothpeoplehadahistoryof
seizures.
Fowle2000
64
OneUKpaperusedsystematicliteraturesearchingtoidentifyrelevantprimarystudies.However,
thispaperdidnotmeetsystematicreviewcriteriaasitdidnotaddressaspecificclinicalquestion:it
presentedageneraloverviewoftheusesoftheEEGinepilepsy.
TheauthorsmadetheimportantpointthatEEGisadiagnostictestwithvariablesensitivityand
specificity.
64
Thus,theEEGmaybeabnormalinnormalpeople(inonestudyofmaleRAFpersonnel
whoareallscreenedusingEEG,0.5%(69/13658),ofthesamplehadepileptiformdischarges
65
).It
mayalsobenormalinpeoplewithepilepsy.
Gilbert2000
66
AsystematicreviewoftheuseofEEGafterafirstunprovokedseizureinchildrenidentifiedfour
relevantprimarystudies.Fromthese,thesensitivityandspecificityoftheEEGwascalculatedtobe
atbest61%and71%respectively.
AHRQ2001
50
AUSsystematicreviewconsideredtheroleoftheEEGinmakingadiagnosisofepilepsy.Theauthors
notedthatitwasdifficulttoprepareanevidencebasedreviewofdiagnosisinepilepsy,includingthe
roleoftheEEG,forthefollowingreasons:
Goldstandardfordiagnosiswaslooselyconstruedandincludedbothaclinicalcomponentand
anEEGcomponent.
Theclinicalrequirementsfordiagnosiswerehighlyvariableandincludedsuchsignsand
symptomsastonic/clonicmovements,withorwithoutpostictalconfusion,tonguebiting,
TheEpilepsies
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95
sphincterdisturbance,aura,andlossofconsciousness.Somestudiesrequiredtheeventstobe
unprovoked;othersdidnot.Somestudiesrequiredtheeventsbewitnessed;othersdidnot.
Theseizuretypewasusuallydiagnosedbyclinicalfeaturesandtheepilepsysyndrome,byseizure
typeandEEGfindings.
Onlyaminorityofstudiesreferredtoestablishedclassificationschemas,forexample,theILAE.
50
Primaryevidence
Theprimarypapersreviewedherehadmethodologicaldeficienciesaccordingtocriteriafor
diagnostictestsproposedbytheEvidenceBasedMedicineWorkingGroup.
49,67
Goodin1984
68
OneUSstudyinvolvedaretrospectivereviewoftheinitialEEG(interictal)reportsofseveral
categoriesofpeoplereferredforstudyintheprevious6yearstodeterminetheproportionwith
epileptiformabnormalities.
Theresultshavebeenextractedfromthepaperandtabulatedbelow.
Table8.1Resultsfromareviewof948individualswithvariousnonepilepticneurologicaland
psychiatricdisordersreferredforEEGand764individualswithepilepsy
A)ResultsofinterictalEEG
Epilepsy(n=764) Notepilepsy(n=948)
Epileptiformactivity 397 38
Normal 367 910
B)Diagnosticvalueofepileptiformactivityforepilepsy
Sensitivity 0.52(397/764)
0.96(910/948)
13.0
0.5
****
Specificity
Likelihoodratioforpositivetest
Likelihoodratiofornegativetest
Inthosewithadiagnosisofnonepilepticneurologicalandpsychiatricdisordersonly4%(38/948)had
epileptiformactivityontheinitialEEG.Inthosewithaclinicaldiagnosisofepilepsy52%(397/764)
hadepileptiformactivityontheinitialEEG.
Theresultscanbeinterpretedasfollows.EpileptiformactivityintheEEGisspecific,butnot
sensitive,forthediagnosisofepilepsy.ApositiveinterictalEEGcanbeusedtohelpconfirmthe
diagnosisofepilepsybutanegativeresultcannotbeusedtoruleoutthediagnosisofepilepsy.
Hoefnagels1991
52
ADutchstudyassessedthediagnosticvalueofasingleinterictalEEGinpeoplepresentingwith
transientlossofconsciousness.
Thestudypopulationconsistedof119consecutivepeople(aged15orover)referredtoa
neurologicaldepartmentwithoneormoreepisodesoftransientlossofconsciousness.Theauthors
wereabletoclassifyallindividualsonclinicalgroundsashavinghadeitheranepilepticseizure(38%)
Result defined as a large increase in pre-test to post-test probability

****
Result defined as a small decrease in pre-test to post-test probability (of uncertain clinical
importance)
TheEpilepsies
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96
orsyncope(62%).TheirfindingsforthetestcharacteristicsofinterictalEEGarepresentedbelow
(presentedinthisforminthepaper).
Table82:ResultsofEEGin118individualsreferredtoaneurologicaldepartmentwithoneormore
episodesoftransientlossofconsciousness
A)ResultsofinterictalEEG
Seizure(n=45) Syncope(n=73)
Normal 15 55
Localisedepileptiformactivity 10 4
Generalisedepileptiformactivity 8 0
Localisedslowactivity 12 14
B)Diagnosticvalueofepileptiformactivityforaseizure
0.95(69/73)
7.3
(2.620.3)
0.6
(0.50.8)
Specificity
Likelihoodratioforpositivetest(CI)
Likelihoodratiofornegativetest(CI)
Theresultscanbeinterpretedasfollows.EpileptiformactivityintheEEGisspecific,butnot
sensitive,forthediagnosisofaseizureasthecauseoftransientlossofconsciousness.Apositive
interictalEEGcanbeusedtoconfirmtheclinicaldiagnosisofaseizurebutanegativeresultcannot
beusedtoruleouttheclinicaldiagnosisofaseizure.
Camfield2000
69
ACanadianstudyexploredthequestionastohowoftenroutineEEGresultscanbecorrectly
predictedfromtheEEGrequisitionforminchildren.
FivehundredconsecutiveinitialEEGrequestswereexamined(childmeanage5years11months).
Basedonlyontherequisition(demographics,referringphysician,andreasonforEEG),theauthors
codedtheirpredictionoftheresultandthentheactualresult.Whenresultswerediscordantfrom
prediction,ajudgmentwasmadeaboutthepotentialimportanceoftheresult.
Overall,EEGresultswerecorrectlypredictedin81%.Predictionforallnonepilepsyreasonswas
accuratein91%(n=320).Thehighestrateofcorrectpredictionwasinthegroupwithnonepileptic
paroxysmaldisorders.Childreninthiscategorywerealmostalways(99%,157/158)predictedto
haveanormalEEG.Incontrast,forchildrenclinicallysuspectedashavingepilepsythecorrectEEG
findingswerecorrectlypredictedin59%ofcases(n=141)(comparisonofpredictionforparoxysmal
vsepilepticdisorders,p<00001chisquared).
Jan2002
70
ASaudiArabianstudyexaminedtherelationshipbetweenclinicalindicationsandEEGresultsin
childrenandassessedthepredictabilityofanormalresult.
FourhundredandthirtyeightconsecutivepaediatricEEGswereincludedprospectively.One
certifiedelectroencephalographer(EEGer)reviewedEEGrequisitionsandrecordedhispredictionofa
normalresult.EEGswerereviewedseparatelyandtherelationshipbetweentheclinicalindications
Result defined as a moderate increase in pre-test to post-test probability
importance)

CI- confidence interval
TheEpilepsies
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97
andEEGabnormalitieswasrecorded.Thechildren'smeanagewas5years(sd4.2).ThefirstEEG
wasstudiedin65%ofcases.Overall,55%oftheEEGswereabnormal.RepeatEEGsweretwiceas
likelytobeabnormal(95%CI1.33,p=0.001).Establishedepilepsy,usingantiepilepticdrugs,and
sleeprecordhighlycorrelatedwithanabnormalresult(p<0.0001).TheEEGerpredicted26%ofthe
EEGstobenormal.
AnormalEEGwascorrectlypredictedin98%ofnonepilepticparoxysmalevents,however,
epileptiformactivityontheEEG(seeTable)wascorrectlypredictedinonly26%ofchildrenwith
seizures.EEGsof15(3.4%)childrenwithestablishedepilepsyrevealedunexpectedfindingsthat
completelychangedtheirmanagement.
70
Theresultshavebeenextractedfromthepaperandtabulatedbelow(onlysubgroupsofseizure
versusnonepilepticparoxysmaleventincluded:44%,194/438ofallEEGrequests).
Table83:ResultsofEEGforseizuresvsnonepilepticparoxysmalevents
A)ResultsofEEG
Seizure(n=154) Nonepilepticparoxysmal
event(n=40)
Focal/multifocalspikesonEEG 18 1
Generalisedepileptiformdischarges 12 0
BackgroundEEGdisturbances(focal&diffuse) 29 0
Normal 95 39
B)Diagnosticvalueofepileptiformactivityforaseizure
0.98(39/40)
13
*****
0.76
Specificity
Likelihoodratioforpositivetest
Likelihoodratiofornegativetest
Stroink2003
71
Aprospective,multicentrehospitalbasedstudyofchildrenwithnewlydiagnosedpossiblesingleor
multipleseizuresassessedtheaccuracyoftheinitialdiagnosisafteroneormoreparoxysmalevents.
760childrenwereincludedwithmeanageof5.4years,ofwhom48.3%wereboys.Inthegroupof
174childrenwithafinaldiagnosisofanepilepticseizuresorepilepsy,97hadepileptiformEEGs,
givingasensitivityof55.7%(95%CI48.0%to63.2%).Inthe50childrenwithotherdiagnosesorin
whomdoubtremained,11hadepileptiformEEGs(specificityof78.0%,95%CI63.7%to88.0%).The
likelihoodratioforapositivetestistherefore2.5andforanegativetest0.5.
*****
Result defined as a large increase in pre-test to post-test probability
importance)
TheEpilepsies
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8.2.2 HowgoodistheEEGatdifferentiatingbetweenindividualswhohavedifferentepilepsy
seizuretypesandepilepsysyndromes?
20. AnEEGmaybeusedtohelpdetermineseizuretypeandepilepsysyndromeinchildren,young
peopleandadultsinwhomepilepsyissuspected.Thisenablesthemtobegiventhecorrect
prognosis.[2004]
ThestandardEEGcanhelpclassifyindividualswithaclinicaldiagnosisofanepilepticseizureinto
differentepilepsyseizuretypesandepilepsysyndromes.(III)
Details
Secondaryevidence
Hirtz2000
72
Anevidencebasedreviewofapproachesforevaluatingafirstnonfebrileseizureinchildrenwas
identified.ThisstatedthatthemajorityofstudiesconfirmedthatanEEGhelpsindeterminationof
seizuretypeandepilepsysyndromeinchildren.
Primaryevidence
King1998
73
AprospectiveAustralianstudyinvestigatedwhetheritwaspossibletodiagnosespecificepilepsy
syndromespromptlybyuseofstandardclinicalmethods,EEGandMRIinindividualspresentingwith
afirstepilepticseizure.
Thestudypopulationwas300consecutiveadultsandchildren(aged5andover)whopresentedwith
afirstunprovokedepilepticseizurewithnoreadilyapparentcause(e.g.,stroke,headinjury).Clinical
datafromindividualsandwitnesseswassystematicallycollectedandapreliminaryclassificationof
theepilepsytypewasmade:generalisedepilepsy;focalepilepsyorseizureunclassified.Theauthors
attemptedtoobtainanEEGwithin24hoursoftheseizure.WheretheEEGwasnegative,asleep
deprivedEEGwasdone.MRIwasdoneelectively.ItisnotcleariftheEEGassessorwasblindedto
theclinicalassessment.
Ageneralisedorfocalepilepsysyndromewasclinicallydiagnosedin141(47%)individualswith159
(53%)casesunclassified.Subsequentanalysisshowedthatonlythreeoftheseclinicaldiagnoses
wereincorrect.AdditionoftheEEGdataenabledtheauthorstodiagnoseanepilepsysyndromein
themajorityofcases(77%,232/300);withonly68(23%)remainingunclassified.
Neuroimagingshowed38epileptogeniclesions,including17tumours.Therewerenolesionsin
thosewithEEGconfirmedidiopathicgeneralisedepilepsyorinchildrenwithbenignrolandic
epilepsy.Theauthorsfinaldiagnoseswere:generalisedepilepsy(23%);focalepilepsy(58%);and
unclassified(19%).
8.2.3 HowcanthediagnosticyieldofthestandardinterictalEEGbeimproved?
21. Forchildren,youngpeopleandadultsinwhomepilepsyissuspected,butwhopresent
diagnosticdifficulties,specialistinvestigationsshouldbeavailable.[2004]
22. RepeatedstandardEEGsmaybehelpfulwhenthediagnosisoftheepilepsyorthesyndromeis
unclear.However,ifthediagnosishasbeenestablished,repeatEEGsarenotlikelytobe
helpful.[2004]
TheEpilepsies
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99
23. RepeatedstandardEEGsshouldnotbeusedinpreferencetosleeporsleepdeprivedEEGs.
[2004]
24. WhenastandardEEGhasnotcontributedtodiagnosisorclassification,asleepEEGshouldbe
performed.[2004]
25. Inchildrenandyoungpeople,asleepEEGisbestachievedthroughsleepdeprivationortheuse
ofmelatonin
.[2004,amended2012]
Evidence
ThereisinsufficienthighqualityevidencetodeterminewhetherperforminganEEGwithinthefirst24
hoursafteraseizureincreasesthelikelihoodofobtainingepileptiformactivity.(III)
RepeatingastandardEEGinaselectedadultpopulationhasbeenshowntoincreasethelikelihoodof
obtainingepileptiformactivity.(III)
RecordingoftheEEGwhilstasleeporaftersleepdeprivationincreasesthelikelihoodofobtaining
epileptiformactivity.(III)
TheuseofmelatoninmaybeusedtoinducesleepinchildrenwhoaretoundergoasleepEEG.(III)
Details
Asreviewedintheprecedingsection,thesensitivityofstandardinterictalEEGislow.Thissection
reviewstheevidenceforincreasingthediagnosticyieldofEEGbythefollowingadditional
techniques:
earlyrecordingofEEGafterseizure;
repeatedlyperformingEEGs
sleep:sleepEEGsandsleepdeprivationEEGs.
Thefollowinggeneralreviewswereconsulted.
50,64,74
Specificreviewarticlesarediscussedbelow.
8.2.3.1 EarlyrecordingofEEGafterseizure
Secondaryevidence
Nosystematicreviewswereidentified.
Primaryevidence
King1998
73
AprospectiveAustralianstudyinvestigatedwhetheritwaspossibletodiagnosespecificepilepsy
Theselectedstudypopulationwas300consecutiveadultsandchildren(aged5andover)who
presentedwithafirstunprovokedepilepticseizurewithnoreadilyapparentcause(e.g.,stroke,head
injury).Clinicaldatafromindividualsandwitnessesweresystematicallycollectedandapreliminary
classificationoftheepilepsytypewasmade:generalisedepilepsy;focalepilepsyorseizure
unclassified.TheauthorsattemptedtoobtainanEEGwithin24hoursoftheseizure.WheretheEEG
wasnegative,asleepdeprivedEEGwasdone.MRIwasdoneelectively.ItwasnotcleariftheEEG
assessorwasblindedtotheclinicalassessment.Theparticipantswerenotsubjecttorandomisation.
ThelicenceforuseofmelatoninintheUKhaschangedsincetherecommendationwaspublishedin2004.The
recommendationhasbeenupdatedaccordinglyandthefootnotethatcontainedtheoldinformationhasbeendeleted.
TheEpilepsies
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100
ThefirstEEGwasperformedwithin12hoursoftheseizurein89(30%)individuals,between1224
hoursin67(22%)individuals,andaftermorethan24hoursin144(48%)individuals.Epileptiform
abnormalitieswereobservedin80(51%)ofthe156whohadanEEGwithinthefirst24hours,
comparedwith49(34%)ofthe144whohadalaterEEG(95%CIfordifferenceinproportions6%
28%).
Sundaram1990
75
SundaramandcolleaguesinvestigatedvariousfactorsaffectinginterictalspikedischargesintheEEGs
of203consecutivecaseswithseizures.
Participantswerealladults(aged16yearsandover)withdefiniteorsuspectedseizureswhowere
referredforanEEG.Adultswithahistorysuggestingnonspecificblackouts,syncope,
pseudoseizuresoralcoholwithdrawalseizures,undergoingassessmentforsurgeryorthosewhohad
anysurgeryforepilepsywereexcluded.
Interictalspikedischargeswerecorrelatedwithage,numberofseizuresintheprevious12months,
timingoftheEEGwithrelationtothelastseizure,AEDtreatment,aetiology,andneurologicalstatus.
Blindingwasnotdocumented.
77%(n=27/35)ofthoseEEGsperformedwithin2daysofthelastseizureshowedISDscomparedwith
33%(n=5/15)forEEGswithin2to7days,and41%(n=62/153)forEEGsmorethan7daysafterthe
lastseizure.
8.2.3.2 RepeatedlyperformingEEGs
Secondaryevidence
Primaryevidence
Salinsky1987
76
OneUSstudyretrospectivelyreviewedtheEEGdataon429adultstodeterminetheprobabilityof
findinginterictalepileptiformactivity(IEA)onEEG.Blindingwasnotdocumented.
Thestudypopulationwashighlyselected,comprisingofadultmaleveterans(armypersonnel)with
epilepsy(95%ofwhomhadcomplexfocalseizures).
In50%ofadultswithIEA,theabnormalitywaspresentonthefirstEEG,in84%bythethirdEEGand
in92%bythefourthEEG.
8.2.3.3 SleepandsleepdeprivationEEGs
Anarrativereviewwhichconsideredtheearlierliterature
77
andarecentcriticalreviewofthe
literature
78
wereconsulted.Therewasconsensusthatnaturalsleepandsleepdeprivationincrease
thediagnosticyieldofEEGinchildrenandadults.Thefollowingissues,however,wereidentified:
PoorqualityofresearchstudiesaddressingimpactofsleepandsleepdeprivationEEGson
diagnosticyield.Manystudiesareretrospective;notblindedandconfoundtheeffectofrepeat
EEGrecordingswiththeeffectsofsleepandsleepdeprivation;
Uncertaintyastowhethersleepitselforsleepdeprivationcausestheobservedincreased
diagnosticyield;
ConflictingadviceontheroleofsleepandsleepdeprivationEEGsinauthoritativereviewslikely
tobeconsultedbypractitioners.
64
TheEpilepsies
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Twoprospectivestudiesoftheroleofsleepandsleepdeprivationwereidentified,bothincludedin
theAgencyforHealthcareResearch&Qualitysystematicreview.
50
Secondaryevidence
Primaryevidence
Carpay1997
79
AprospectiveDutchstudyaimedtoassessthediagnosticyieldofarepeatedEEGafterpartialsleep
deprivationinchildrenandadolescentswithoneormoreseizureswhohadpreviouslyhada
standardEEG.
Thestudypopulationwas552children(age:range1month16years;mean6years)withoneor
morenewlydiagnosedseizures.IntermittentphoticstimulationwasperformedonallEEGs,and
hyperventilationwasinducedwhenthechildwascooperative.AroutineinterictalEEGwas
recorded.WhenthestandardEEGwasclassifiedtobewithoutepileptiformactivity,asleep
deprivedEEGwasrecordedbyusinganagedependentprotocolforsleepdeprivation.Theassessor
oftheEEGswasblindedtotheclinicalassessment.
Fiftysixpercent(309/552)ofthesamplehadapositivestandardEEGand44%(243/552)hadanEEG
withoutepileptiformactivity.In177(73%ofalleligiblechildren)ofthesenegativecases,sleep
deprivedEEGswererecorded.SleepdeprivedEEGsadded11%(61/552)morediagnosestothe56%
ofchildrenwithepileptiformactivityonthestandardEEG(67%intotal).
King1998
73
AnAustralianstudy(prospective)investigatedwhetheritispossibletodiagnosespecificepilepsy
Thestudypopulationwas300consecutiveadultsandchildren(aged5andover)whopresentedwith
afirstunprovokedepilepticseizurewithnoreadilyapparentcause(e.g.,stroke,headinjury).Clinical
datafromindividualsandwitnessesweresystematicallycollectedandapreliminaryclassificationof
theepilepsytypewasmade:generalisedepilepsy;focalepilepsyorseizureunclassified.Theauthors
attemptedtoobtainanEEGwithin24hoursoftheseizure.WheretheEEGwasnegative,asleep
deprivedEEGwasdone.MRIwasdoneelectively.ItisnotcleariftheEEGassessorwasblindedto
theclinicalassessment.
Epileptiformabnormalitieswereshownin43%(129/300)ofthefirstEEGrecords.Amajorityof
thosewithanegativefirstEEG(92%,158/171)underwentasleepdeprivedEEG.Asleepdeprived
EEGadded18%(55/300)morediagnosestothe43%ofthosewithepileptiformactivityonthefirst
EEG(61%intotal).
Schreiner2003
80
SchreinerandPohlmannEdenaimedtoevaluatethepredictivevalueofstandardEEGandEEGwith
sleepdeprivationforseizurerecurrenceinadultsafterafirstunprovokedseizure.157adultswere
includedandwereagedbetween17and84years.61.8%weremale.AstandardEEGwas
performedwithin48hoursofthefirstseizure.AsleepdeprivedEEGwasperformed3to7daysafter
thefirstseizureforthoseinwhomthestandardEEGwasnormalorwasinconclusive.
46adults(29.3%)hadanormalEEG.Ofthe60whoseinitialEEGwasnormalorwasinconclusive,the
sleepdeprivedEEGshowedabnormalitiesin9adults.Conversely,in10adults,sleepdeprivedEEG
didnotdetectabnormalitiesalreadyidentifiedbythestandardEEG.
TheEpilepsies
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8.2.3.4 WhatistheroleofmelatoninforchildrenundergoingasleepEEG?
Inchildren,sleepEEGshavetraditionallybeenundertakenbydeprivingchildrenofsleepthenight
beforetheEEGstudy.Thisprocedure,however,hasbeenshowntobeoflimitedacceptabilityto
parentsofchildrenwithepilepsy.
81
Asanalternative,childrencanbegivenoralmelatonintoinduce
sleep.
82
NoRCTevidenceontheeffectivenessofmelatonininchildrenundergoingEEGassessmentwas
identified.
8.2.4 WhataretherolesoflongtermvideoEEGandambulatoryEEG?
26. LongtermvideoorambulatoryEEGmaybeusedintheassessmentofchildren,youngpeople
andadultswhopresentdiagnosticdifficultiesafterclinicalassessmentandstandardEEG.[2004]
Evidencestatements
LongtermvideoEEGandambulatoryEEGcanhelpdifferentiatebetweenepilepticandnonepileptic
seizuresinindividualswhopresentdiagnosticdifficultiesfollowingclinicalassessmentandstandard
EEG.(III)
LongtermvideoEEGandambulatoryEEGcanhelpclassifyseizuretypeandseizuresyndromein
individualswhopresentdiagnosticdifficultiesfollowingclinicalassessmentandstandardEEG.(III)
Details
InpatientvideoEEGhasanimportantroleinthediagnosisofepilepsywhentheclinicalhistoryand
standardEEGhavebeenunhelpful.TheinpatientvideoEEGcanaidwith:
Differentiatingbetweenepilepticandnonepilepticseizures
Individualswithnonepilepticseizuresareanimportantgroupandaccountfor20%ofreferralsto
tertiarycentresforassessmentoftreatmentrefractoryseizures.Tocomplicatematters,epilepsy
andnonepilepticattackdisordercancoexist.Toestablishthediagnosisitmaybenecessaryto
documentictalevents,bothclinicalandEEG,bymeansoflongtermvideoEEG.Theinpatientvideo
EEGisviewedasthegoldstandardinvestigationforthediagnosisofnonepilepticevents.
Classificationofseizuretypeandepilepsysyndrome
LongtermvideoEEGrecordingcanaidwithbothclassificationofseizuretypeandepilepsy
syndrome.
Threenarrativereviewswereconsulted:oneontheuseoflongtermvideoEEGmonitoringin
adults
83
andtwoonthediagnosisofnonepilepticattackdisorders(NEAD).
84,85
Secondaryevidence
AHRQ2001
50
Eightprimarystudies(4prospectiveand4retrospective)oftheroleoflongtermvideoEEGinthe
diagnosisofepilepsywerereviewedintheAgencyforHealthcareResearch&Qualityreview.These
aresummarisedbelow.TheauthorsofthereviewconcludedthatinpatientvideoEEGand
ambulatoryEEGwerediscretionarytestsandthattheevidencewasinconclusiveonthevalueofany
addedinformation.
Prospectivestudies:
AnAustralianstudyreportedacaseseriesof82children(age2months16years,median6
years)whounderwentinpatientEEGvideotelemetry.
86
Thecommonestreasonforreferralwas
todeterminewhetheraneventwasictal(76%,62/82).Otherreasonsincludedseizurefrequency,
TheEpilepsies
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103
classificationorlocalisationofonset.Eventsoccurredduringtherecordingin80%(66/82)of
subjects.Ofthese,35%(23/66)werejudgedtobeepilepticandtheseizuretypeidentified.
AUSstudyreportedacaseseriesof100infants,childrenandadolescentswhohadoutpatient
videoEEG.
87
Ofthe36whowerereferredtodeterminewhethertheeventswereepileptic,an
overalldiagnosiswasmadein32,ofwhom8hadseizuresand6hadpseudoseizures.
AnItaliancaseseriesevaluatedtheroleoflongtermvideoEEGwithorwithoutsleepdeprivation
inchildrenandadultswithsuspectednocturnalfrontallobeepilepsy(n=23).DaytimevideoEEG
wasnotdiagnostic,however,aftersleepdeprivationadiagnosisofnocturnalfrontallobeepilepsy
wasmadein12cases.
88
AUScaseseriesevaluatedtheabilityofcombinedambulatorycassetteEEGandvideomonitoring
toestablishadiagnosisin125individualswithattacksofunknownnature(previousstandardEEG
negativeand,whereperformed,CT/MRInegative).Attackswererecordedin80%(101/125).Of
these,adiagnosiswasmadein80%(80/101),ofwhich25%(20/80)hadepilepsy,75%(60/80)had
psychogenicseizures,andadualdiagnosiswaspresentin3cases.
89
Retrospectivestudies:
OneUSstudyreviewedthecasenotesof:
138childrenwhounderwentlongtermvideoEEGtodifferentiatebetweenseizureversus
nonseizure.Adiagnosiswasmadein70%(90/138)ofcases.
68childrenwhounderwentlongtermvideoEEGtoclassifytheirseizuretype.A
classificationcouldbemadein88%(60/68).
90
AnotherUSstudyreviewedthecasenotesof444adultsandchildren(agerange1weekto71
years;mean22years)whounderwentdiagnosticlongtermvideoEEG.Casesofknownrefractory
focalepilepsyundergoingsurgicalassessmentwereexcluded.Adiagnosiswasachievedin72%
(321/444)ofcases.Ofthese,56%(180/321)hadepilepticseizuresand44%(141/321)had
psychogenicseizures.
91
InanotherUSstudy,thecasenotesof60childrenagedunder10yearswhowerereferredtoa
tertiarycentrewithsuspectedepilepsybutwhohadanormalinterictalEEGwerereviewed.
92
The
childrenunderwentinpatientvideoEEG.Adiagnosiswasachievedin33cases.Ofthese,24had
nonepilepticattacksand9hadepilepticseizures.
ThediagnosticutilityoflongtermvideoandambulatoryEEGwasassessedin102individuals.The
videoEEGledtoadiagnosisin57cases,ofwhich19caseswereepilepsy.
93
8.2.5 Whatistheroleofprovocationtechniquesandinductionprotocols?
27. Provocationbysuggestionmaybeusedintheevaluationofnonepilepticattackdisorder.
However,ithasalimitedroleandmayleadtofalsepositiveresultsinsomepeople.[2004]
28. PhoticstimulationandhyperventilationshouldremainpartofstandardEEGassessment.The
child,youngpersonoradultandfamilyand/orcarershouldbemadeawarethatsuchactivation
proceduresmayinduceaseizureandtheyhavearighttorefuse.[2004]
Evidencestatements
Thereisconflictingevidenceinadultsastotheroleofinductionprotocols(thereisnoevidencefor
children).(III)
Photicstimulationisnecessarytodetermineiftheindividualisphotosensitivebutcarriesasmallrisk
ofinducingaseizure.(III)
HyperventilationisroutinelyemployedtoincreasethesensitivityofaninterictalEEG.(IV)
TheEpilepsies
Investigations
104
Details
ProlongedinpatientvideoEEGmonitoringmaynotyieldadiagnosisiftheintervalbetweenseizures
islong.Techniqueshavebeendeveloped(provocationtechniques/inductionprotocols)toshorten
monitoringtime.Thesemethodscanbedividedintotwogroups:
thosewhichinfluencephysiologicalprocessestoincreasethelikelihoodofanepilepticseizure
occurring(forexample,standardactivationproceduressuchashyperventilation,photic
stimulation,sleepdeprivationandwithdrawalofmedication);
thoseusingpsychologicalmethodssuchasdirectorindirectsuggestiontoinduceanonepileptic
seizure.
Theuseofprovocationtechniquesiscontroversial.
Anarrativereviewonthediagnosisofpsychogenicnonepilepticseizureswasconsulted.This
reviewedtheliteratureonprovocationtechniquespriorto1996.
85
Thescopeofthisguidelinedoesnotincludethediagnosisofnonepilepticseizures.However,there
areappropriateinvestigationsandeffectivetreatmentthatcanbeusedinthediagnosisand
managementofnonepilepticseizures.
84,94
Secondaryevidence
Primaryevidence
OneRCTandfournonrandomisedstudieswereidentified.
McGonigal2002
95
AUKstudyaimedtoassesstheyieldofrecordedhabitualnonepilepticseizuresduringoutpatient
videoEEG,usingsimplesuggestiontechniquesbasedonhyperventilationandphoticsimulation.The
studydesignwasarandomisedcontrolledtrialofsuggestionversusnosuggestion.Thesetting
wasatertiarycentre.
Theparticipantswere30individuals(22female,8male),agedover16years,withaprobableclinical
diagnosisofnonepilepticseizures;15wererandomisedtoeachgroup.
Themainoutcomemeasureswere:yieldofhabitualnonepilepticseizuresrecorded,and
requirementforadditionalinpatientvideoEEG.
Tenoutof15individualshadhabitualnonepilepticseizureswithsuggestion;5/15hadnonepileptic
seizureswithnosuggestion(p=0.058;notsignificant);8/9individualswithahistoryofprevious
eventsinmedicalsettingshadnonepilepticseizuresrecordedduringstudy.Logisticregression
analysiswithaninteractionclauseshowedasignificanteffectofsuggestioninthosewithahistoryof
previouseventsinmedicalsettings(p=0.003).AnadditionalinpatientvideoEEGwasavoidedin14
ofthe30(47%).
Bhatia1997
96
Anotherstudyconsideredtheusefulnessofshorttermrecordingofvideoelectroencephalography
(VEEG)asanoutpatientprocedurewithplaceboinductionandintravenoussalineincasesof
pseudoseizures.
Fiftycasesofsuspectedpseudoseizureswereenrolled.Theyweredividedinto2groups:Group1
consistedofindividualswithfrankpseudoseizures;Group2thosewherediagnosiswasuncertain.
VEEGrecordingwasdoneand10mlofsalineusedforplaceboinduction.Of50cases,24(48%)were
TheEpilepsies
Investigations
105
inGroup1and26(52%)inGroup2.Fifteen(15/50,30%)hadaspontaneouseventduringVEEG.A
further15(15/45,33%)hadaneventonlyonplaceboinduction.
Parra1998
97
AUSstudyaimedtodeterminethetimingofspontaneouspsychogenicnonepilepticeventsduring
videoEEGtelemetry(VEEG),andtheneedtouseinductionprotocols.
Onehundredconsecutivecases(75females,25males)admittedtotheirinpatientVEEGunitfrom
July1994toJune1996fordifferentialdiagnosisofparoxysmaleventswerestudied.
Thetimetothefirstdiagnosticspontaneousevent,identifiedbytheindividualorafamilymemberas
typical,wasrecorded.Episodeswereclassifiedaspsychogenicnonepilepticevents,physiologicnon
epilepticevents,andepilepticseizures.
ThemeandurationofVEEGwas74+/SD54.1hours.In82individuals,adiagnosticeventoccurred
spontaneously.Thefirsteventwasanepilepticseizurein22,apsychogenicnonepilepticeventin
53,andaphysiologicnonepilepticeventin7.Thetimetofirstdiagnosticeventwassignificantly
shorterforapsychogenicnonepilepticeventthanforanepilepticseizures[15.0+/sd16.3hours
(range5minto58hours)vs.28.6+/sd34.0hours(range1110hours)F=15.621,p<0.0001].Inthe
first24hours,77.4%ofthosewithapsychogenicnonepilepticeventhadanevent.By48hours,all
but2(96.2%)hadhaddiagnosticevents.Afterthefirst58hoursofmonitoring,allindividualswitha
psychogenicnonepilepticeventexperiencedaspontaneousdiagnosticevent.
Dericioglu1998
98
Onestudyaimedtodeterminethebenefitofprovocationmethods(IVsalineorverbalsuggestion)in
individualssuspectedashavingnonepilepticseizures.
Thestudypopulationwas72people(50female;22male;agerange1656)whowerereferredtoa
comprehensiveepilepsycentreinTurkeybetweenJanuary1992toJune1996.
IndividualshadanoutpatientEEGandinductionwitheitherIVsalineorverbalsuggestion.
Nonepilepticseizureswereobservedin52(72.2%)individuals.Thirteenofthesestillhadriskfactors
forepilepsy.Theauthorscouldnotdecidewhetheralloftheirpreviousattackswerenonepileptic
because1030%ofpeoplewithnonepilepticseizuresalsohaveepilepticseizures.Foramore
accuratediagnosistheauthorsdecidedthatthese13,togetherwiththe20individualswhodidnot
haveseizureswithinduction,neededvideoEEGmonitoring.Thirtyninepeoplewhohadnon
epilepticseizuresandnoriskfactorsforepilepsywerethoughttohavepurenonepilepticseizures.
Benbadis2000
99
AUSstudydescribedtheuseofamultimodalityprovocativetechniquethatdidnotuseaplacebo
(didnotuseIVsaline).
Twentyoneindividualswithaclinicalsuspicionforpsychogenicnonepilepticseizureswereeligible
toundergoanactivationprocedureusingsuggestion,hyperventilation,andphoticstimulationduring
thestudyperiod.Of19inductionsperformed,16(16/19,84%)weresuccessfulininducingthe
habitualepisode.
8.2.6 DoesanabnormalEEGpredictseizurerecurrence?
29. Inchildren,youngpeopleandadultspresentingwithafirstunprovokedseizure,unequivocal
epileptiformactivityshownonEEGcanbeusedtoassesstheriskofseizurerecurrence.[2004]
Evidencestatement
TheEpilepsies
Investigations
106
Individualspresentingwithafirstunprovokedseizurewhohaveepileptiformactivityontheirinitial
EEGhaveanincreasedriskofseizurerecurrence.(IIbchildren,IIIadults)
ThespecificityofanepileptiformEEGinpredictingfurtherseizuresrangesfrom0.13to0.99,and
sensitivityfrom0.20to0.91.(II)
Details
Secondaryevidence
Foursystematicreviewswereidentified.
Berg1991
100
Factorspredictiveofseizurerecurrencefollowingafirstunprovokedseizurewereexploredinthis
systematicreviewof16studies.
AllstudiesthatreportedonEEGresultsfoundtherewasahigherriskofrecurrenceassociatedwith
thepresenceofanyabnormalities.Therelativerisk(abnormal/normal)rangedfrom1.2to4.1.The
pooledriskofrecurrenceat2yearswas27%(95%CI21%to33%)withanormalEEG,58%(95%CI
49%to66%)withepileptiformabnormalities,and37%(95%CI27%to48%)withnonepileptiform
abnormalities.TherelativeriskassociatedwithanabnormalEEGwas1.9(95%CI1.5to2.4)inthe
idiopathicgroup,and1.4(95%CI1.0to1.9)intheremotesymptomaticgroup.
BothseizureaetiologyandEEGresultsclearlyandconsistentlyseparatedcasesintohigherandlower
riskgroups.
Gilbert2000
66
Inthisreview,theauthorsaimedtoquantifyandanalysethevalueoftheinformationfromanEEG
afterafirstunprovokedseizureinchildren.
Fourstudiesinvolving831childrenwereincluded.
Thepretestprobabilityofrecurrenceinallstudieswasfoundtobebelowthelowerrangeofthe
rationaltestingregion;thatis,theexpectedvalueoftheinformationgainedfromtheEEGwastoo
lowtoaffecttreatmentrecommendationsinmostchildren.
Hirtz2000
72
AnevidencebasedpracticeparameterstatedthattheEEGhelpsindeterminationofriskof
recurrenceofseizuresinchildrenafterafirstunprovokedseizure.
TheEpilepsies
Investigations
107
Figure8.1Probabilityofseizurerecurrenceafterafirstunprovokedseizureasafunctionofthestandard
EEG
101
ModifiedwithpermissionfromBergatal2000
Gilbert2003
102
TheaimofthemetaanalysiswastocalculatethesensitivityandspecificityofanepileptiformEEGin
predictingfurtherseizures.StudiesusingstandardEEGsandwherefollowupwasforatleastone
yearwereincluded.
NineteenstudieswereincludedinwhichepileptiformEEGswererelatedwithsubsequentseizuresin
4,288individuals.ThespecificityofanepileptiformEEGinpredictingfurtherseizuresrangedfrom
0.13to0.99,andsensitivityfrom0.20to0.91.
TwelvestudieswereincludedinwhichabnormalEEGswererelatedwithsubsequentseizuresin
1,856individuals.ThespecificityofanepileptiformEEGinpredictingfurtherseizuresrangedfrom
0.24to0.90,andsensitivityfrom0.23to0.86.
ThediagnosticaccuracyoftheEEGandthethresholdsforclassifyinganEEGaspositivevariedwidely.
However,theauthorswerenotabletoidentifyanycharacteristicofthestudyparticipantsthat
accountedforthisvariation.Thefactorthatdidaccountfor37%ofthevariationwasreader
thresholdforclassifyingtheEEGasepileptiform.Duetothepresenceofsignificantheterogeneity,it
wasnotpossibletocalculatesummarystatisticsforthesensitivityandspecificityoftheEEGin
predictingfurtherseizures.
102
8.3 Theroleofneuroimaginginthediagnosisofepilepsy
30. Neuroimagingshouldbeusedtoidentifystructuralabnormalitiesthatcausecertainepilepsies.
[2004]
TheEpilepsies
Investigations
108
31. MRIshouldbetheimaginginvestigationofchoiceinchildren,youngpeopleandadultswith
epilepsy.[2004]
32. MRIisparticularlyimportantinthose:
whodevelopepilepsybeforetheageof2yearsorinadulthood
whohaveanysuggestionofafocalonsetonhistory,examinationorEEG(unlessclear
evidenceofbenignfocalepilepsy)
inwhomseizurescontinueinspiteoffirstlinemedication.[2004]
33. Neuroimagingshouldnotberoutinelyrequestedwhenadiagnosisofidiopathicgeneralised
epilepsyhasbeenmade.[2004]
34. CTshouldbeusedtoidentifyunderlyinggrosspathologyifMRIisnotavailableoris
contraindicated,andforchildrenandyoungpeopleinwhomageneralanaestheticorsedation
wouldberequiredforMRIbutnotCT.[2004]
35. Inanacutesituation,CTmaybeusedtodeterminewhetheraseizurehasbeencausedbyan
acuteneurologicallesionorillness.[2004]
36. Children,youngpeopleandadultsrequiringMRIshouldhavethetestperformedsoon
.
[2004]
Evidencestatements
BothMagneticResonanceImaging(MRI)scanningandComputedTomography(CT)scanningcan
identifystructuralabnormalitiesinthebrainthatarethoughttobeaetiologicallyrelevanttoa
diagnosisofepilepsy.(III)
MagneticResonanceImaging(MRI)scanningismoresensitiveandspecificthanComputed
Tomography(CT)scanninginidentifyingstructuralabnormalities.(III)
IndividualsdiagnosedashavingidiopathicgeneralisedepilepsywhoundergoCTand/orMRIscanning
areunlikelytohaveanyaetiologicallyrelevantstructuralabnormalities.(III)
Details
Thisreviewsummarisestheevidencefortheuseofmagneticresonanceimaging(MRI)and
computedtomography(CT)scansinthediagnosisofepilepsy.
BothMRIandCTscansareusedprincipallyintheidentificationofstructuralabnormalitiesinthe
brainthatunderlieseizuredisordersandthusarehelpfulindeterminingtheaetiologyofthedisorder
(axis4classification).
Secondaryevidence
Twosystematicreviewsoftheliteraturewereidentified.
50,72
AHRQ2001
50
Ninestudiesdiscussedtheroleofneuroimaginginthediagnosisofepilepsy,andtheevidence
suggestedthattheroleofMRIinfirstdiagnosisisbestestablishedinindividualsinwhomtheCTis
nondiagnostic.
TheEpilepsies
Investigations
109
Hirtz2000
72
Ninestudiesaddressedtheuseofneuroimaginginchildrenpresentingwithafirstnonfebrile
seizure.TheevidenceconsistentlydemonstratedthatMRIwasmoresensitivethanCTscanning.
However,thestudiesshowedthatonly1.9%ofimagesrevealedclinicallysignificantfindingsthat
contributedtotreatmentormanagement.
Primaryevidence
AsforevidenceonEEG,theprimarypapersreviewedherehavemethodologicaldeficiencies
accordingtocriteriafordiagnostictests.
Diagnosisofepilepsy
Berg2000
101
Bergandcolleaguesdescribedtheuseofimagingin613childrenwithnewlydiagnosedepilepsy.
Datawerecollectedprospectivelyovera4yearperiod.Ofthe613children,488(79.6%)had
imaging:388(63.3%)magneticresonanceimaging,197(32.1%)computedtomographyscans,and97
(15.8%)both.Halfofchildrenwithidiopathicgeneralizedepilepsyhadimagingstudiescompared
with70%to100%ofchildrenwithotherformsofepilepsy,dependingonthespecifictype.
AsummaryofresultsispresentedinTable.
Aetiologicallyrelevantabnormalitieswerefoundin62(12.7%ofthoseimaged).Fourteenofthese
childrenhadotherwisecompletelynormalpresentationsandhistories.Theirabnormalitiesincluded
tuberoussclerosis(n=4),tumours(n=2),anarteriovenousmalformationlaterdiagnosedasatumour,
acavernousangioma,cerebralmalformations(n=3),andotherabnormalities(n=3).Thirteenofthe
14hadfocalseizuresand12hadfocalelectroencephalographic(EEG)findings.Onlyonehadneither.
In18ofthe62childrenwithaetiologicallyrelatedabnormalities,bothaCTandanMRIwere
performed.In15cases,theabnormalitywasidentifiedbytheCTandconfirmedbytheMRI.In3
cases,theCTwasnormalandtheMRIabnormal.
Table83:FrequencyofneuroimagingandyieldbyepilepsysyndromeModifiedwithpermission
fromBergatal2000
101
TheEpilepsies
Investigations
110
EpilepsySyndrome* Total Any
Neuroimaging
N(%)
MRI(CT)
N(%)
Abnormal
N(%)
Etiologically
Relevant
N(%)
Idiopathiclocalisation
related
61 48(78.7) 29(47.5) 0(0) 0(0)
Symptomaticlocalisation
related
195 177(90.8) 151(77.4) 50(28.3) 43(24.3)
Cryptogeniclocalisation
related
103 87(84.5) 103(64.1) 4(4.6) 0(0)
Idiopathicgeneralised(all)
126 62(49.2) 51(40.5) 5(8.1) 0(0)

Childhoodabsence 74 31(41.9) 26(35.1) 1(3.2) 0(0)
Juvenileabsence 15 8(53.3) 7(46.7) 2(25.0) 0(0)
Juvenilemyoclonicepilepsy 12 7(58.3) 6(50.0) 0(0) 0(0)
Allotheridiopathic
generalised
25 16(64.0) 13(52.0) 2(12.5) 0(0)
Cryptogenic/symptomatic
generalised
52 48(92.3) 41(78.8) 15(31.3) 14(29.2)
Infantilespasms 24 22(91.7) 18(75.0) 7(31.8) 7(31.8)
LennoxGastaut 4 4(100) 2(50.0) 1(25.0) 1(25.0)
Doosessyndrome 10 9(90.0) 9(90.0) 0(0) 0(0)
Othercryptogenic/
symptomaticgeneralised
14 13(92.9) 12(85.7) 7(53.8) 6(46.2)
Undetermined(all) 76 66(86.8) 51(67.1) 6(9.1) 5(7.6)
Withbothfocaland
generalisedfeatures
5 5(100) 3(60.0) 0(0) 0(0)
Withneitherclearlyfocal
orgeneralisedfeatures
71 61(85.9) 47(66.2) 6(9.8) 5(8.2)
Total 613 488(79.6) 388(63.3) 80(16.4) 62(12.7)
*Becauseofsmallnumbers,somehierarchicallyrelatedsyndromeswerecollapsedintoasinglecategory.
AbnormalindicatesanyabnormalityandincludespinealcystsandmildChariImalformations.Etiologicallyrelevantindicates
abnormalitiesthatwereassociatedwithincreasedriskofepilepsyandwhichwerepresumedtoberelevanttothechildsepilepsy.
%ofthoseinsyndromecategorywhohadneuroimaging.
Onechildinitiallythoughttohavebenignrolandicepilepsywasclassifiedundersymptomaticlocalisationrelatedepilepsyasaresultof
anabnormalneuroimagingfinding.Rereview2yearslaterrevealedtheabnormalitytobechoroidsfissurecystincidentaltotheepilepsy.
Of5childrenwithIGE,3hadmildChariImalformations,1hadmesialtemporalsclerosis,and1hadachoroidsfissurecyst.
Bunn2002
103
OnestudyaimedtocomparetheclinicalbenefitofCTwithMRIforchildreninvestigatedatadistrict
generalhospital.
TheEpilepsies
Investigations
111
Aretrospectivecasenotereviewoftwooneyearperiods(19921993and19961997)was
undertaken.Allchildrenaged18orunderwhohadaCTscanorMRIofthehead,neck,orspine
requestedbyapaediatricianwereincluded.
AdefinitivediagnosiswasmadewithCTin12%ofchildrenwhopresentedwithseizures,andin27%
withMRI.
Dam1985
104
Theaimofthestudywastocomparethediagnosticvalueofthehistory,clinicalexamination,and
EEGwiththeCTscanintheidentificationofpeoplewithbraintumours.
Thecauseofepilepsyin221individualswithlateonsetofepilepsy(25yearsorolder)was
determinedbyhistory,clinicalexamination,EEGrecording,andCTscan.
Braintumour,asdiagnosedbytheCTscan,wasthecauseofepilepsyin16%(n=36).Thecause
(usinghistory,neurologicalexamination,andCT)couldnotbeidentifiedin38%ofindividuals(n=84).
HoltSeitz1999
105
Theaetiology,earlymortality,predictorsofprognosis,anddiagnosticyieldsofEEGandCTscansin
newonsetseizuresinolderpeoplewereexaminedinadultsaged60orolder.
ParticipantswereidentifiedbyreviewingrecordsofallEEGrecordingsundertakeninatwoyear
period(Jan1994Dec1995)atasinglehospital.88peoplewithdefiniteorprobableseizurewere
identified,but4refusedtoparticipate.TheinitialEEGwasabnormalin61people(73%).CTwas
performedinallindividualsandwereabnormalin57(68%).Only11individualsunderwentMRI
scanningandabnormalitiesweredetectedin7,threeofwhomhadnoabnormalitydetectedinCT.
Jallon1997
106
ASwissstudyaimedtodeterminetheincidenceoffirstseizuresinapopulationof384,657.
Intheyearofstudy,418peoplewerereferredforanEEGwithafirstsuspectedepilepticseizure.
Afterexcluding133individuals(insufficientdata,uncleardiagnosis,livedoutsidestudyarea),273
participantsremained.
AllparticipantsbydefinitionhadanEEGrecording.199individuals(67%)underwentCTscanningof
which61(32%)werenormal.56people(19.7%)underwentMRIscanning,whichwasnormalin
30.4%.MRIwasabnormalin16%ofthosewithnormalCTscans.
Kilpatrick1991
107
ThediagnosticvalueofMRIwasinvestigatedinadultswithlateonsetepilepsy.
50individualswithnewlydiagnosedlateonsetepilepsy(seizuresbeginningafterage25years)were
included.OnlythoseinwhomtheCTscanwasnormal,didnotallowadefinitivediagnosistobe
made,orshowedalesionbelievedtobeirrelevantwereincluded.Anagesexmatchedgroupof20
peoplewithoutseizureswasusedtoassesstheincidenceofMRIinfarctsandlesions.
Ofthe32withnormalCT,MRIwasnormalin20,showedirrelevantlesionsin8,andshowedthe
causeofseizuresin4.Inthe12peoplewithnondiagnosticCT,MRIclarifiedthediagnosisin5and
wasnormalin2.TheincidenceofMRIdetectedlesionswasnogreaterthanintheagesexmatched
groupwithoutseizures.MRIwasdiagnosticin32%(10/31)ofindividualswithfocalseizuresand/or
focalEEGfindingsascomparedwith0%(0/19)ofthosewithoutfocalseizures.
King1998
73
TheEpilepsies
Investigations
112
Aprospectivestudyofpeoplepresentingwithafirstseizurewasundertakentoassessthediagnostic
valueofearlyEEG,sleepdeprivedEEG,andMRI.
300individualswereincludedwhopresentedforthefirsttimewithanunprovokedseizurewithno
readilyapparentcause.Individualswereexcludedmainlyfornonepilepticeventsorprovoked
seizures.
Neuroimagingwasdonefor277participants(92%);263MRIand14CTalone.49ofthe50with
generalizedepilepsyhadnormalMRIscans.Amongthe154withfocalepilepsy,MRIrevealed26
(17%)epileptogeniclesions.Forthe61unclassifiedindividuals,9lesionswererevealedbyMRIand2
lesionsbyCTscan,givingatotalof11/61(18%).CTwasdonein28ofthe38caseswithlesionson
MRI,butthelesionwasonlydetectedin12.AfterMRI,onediagnosiswasrevisedfromgeneralised
tofocalepilepsy.Elevenunclassifiedindividualswithfocallesionswerereclassifiedashavingfocal
epilepsy.Afinaldiagnosisofepilepsywasmadein243(81%)oftheinitialgroup.
73
RamirezLassepas1984
108
TheroleoftheCTscanintheevaluationofadultsaftertheirfirstseizure(s)wasdeterminedinthis
USstudy.
Thehospitalrecordsof148individuals,aged16to90years,hospitalisedforevaluationofafirst
acuteseizurewerereviewed.Includedindividualshadacompleteneurologicalexam,complete
metabolicworkup,EEGrecording,andCTscan.
Aetiologywasdeterminedin71participants(48%),withastructurallesionidentifiedbyCTin55
(37%)and16(11%)hadmetabolicseizures.CTfindingsagreedwiththeresultsoftheneurological
examin82%ofcases.CTrevealedstructurallesionsin14(15%)peoplewithnonfocalfindingsand
in12(22%)withgeneralisedEEGabnormalities.
Roberts1988
109
AprospectivestudyofCTscansinadultswithlateonsetepilepsywassetuptosearchforevidence
ofcerebrovasculardisease.
Thecasenotesof132consecutivenewoutpatientswithahistoryofoneormoreepilepticseizures
withageofonset40yearsorolderwerereviewed.Individualswereexcludediftherewereother
neurologicalsymptomsortherewasdoubtaboutthediagnosis.Controlscanswereobtainedfrom
132controlsubjectsofappropriateageandsex.
15ofthosewithepilepsyhadinfarctsonCTcomparedwith2ofthecontrols(p=0.003).However,
therewasnodifferencebetweenthegroupsinthepresenceofrelevantclinicalfeaturesofsystemic
vascularandcardiacdisease.TheCTevidenceofcerebralatrophywasthesameinbothgroups.
Syndromicdiagnosisandclassification
Atakli1998
110
Onestudyaimedtoidentifyandanalysepitfallsinthediagnosisofjuvenilemyoclonicepilepsy(JME).
Thenotesof76individualswithwelldocumenteddiagnosesofJME(asassessedusingthe
Panayiotopoulosdiagnosticcriteria)wereretrospectivelyanalysed.
AlloftheCT(n=33)andMRI(n=3)investigationswerenormal.
Harvey1997
111
Acommunitybasedcohortofchildrenwithnewonsettemporallobeepilepsy(TLE)wererecruited
tostudythepresentationandnaturalhistoryofthedisorder.
TheEpilepsies
Investigations
113
318childrenwithahistoryof2ormoreunprovokedfocalseizuresofsuspectedTLEoriginwithonset
beforeaged15wererecruited(Jan1991toMar1993).Ofthese,63werediagnosedwithTLE.MRI
wasperformedin58ofthe63(92%)childrenandCTin48ofthe63(76%).Fivechildrendidnot
undergoMRIbecausetheCTwasnormalandtheirparentsdidnotwishthemtoundergoMRI.
MRIrevealedstructuralabnormalitiesofthetemporallobein24ofthe63children(38%).
Jallon2001
112
Onestudydescribedfirstunprovokedseizuresandnewlydiagnosedepilepsiesatinitialpresentation
inalargecohort.
Individualswerereferredtothestudyiftheywereolderthanonemonth,hadatleastone
unprovokedepilepticseizurediagnosedbetweenMay1995andJune1996,andwerelikelytobe
followedupforatleast2years.Afterexclusions(previousdiagnosisofunprovokedseizures,acute
symptomaticseizures,thoselikelytobelosttofollowup)1,942peoplewereincluded.
Oneormoreimagingstudieswereperformedin1,418individuals(73.0%).Inthefirstseizuregroup
(n=926),aneuroimagingstudywasperformedin78.2%oftheparticipants(CTscanonly57.9%;MRI
only6.5%;CTscan+MRI13.8%).Thisratevariedaccordingtotheepilepticsyndrome:55.0%for
idiopathiclocalizationrelated,63.5%foridiopathicgeneralized,82.1%forisolatedseizures,86.0%
forcryptogeniclocalizationrelated,and88.6%forsymptomaticlocalizationrelated.Forthosewith
newlydiagnosedepilepsy(n=1,016),aneuroimagingstudywasperformedin68.3%(CTscanonly
42.9%;MRIonly12.2%;CTscan+MRI13.2%).Thisratevariedaccordingtotheepilepticsyndrome:
40.3%foridiopathicgeneralized,60.4%foridiopathiclocalizationrelated,65.4%forsymptomatic
generalized,74.4%forcryptogenicorsymptomaticgeneralized,78.0%forundeterminedwhether
focalorgeneralized,78.1%forcryptogeniclocalizationrelated,and94.2%forsymptomatic
localizationrelated.
Thesehighratesofimagingpermittedclassificationofseizuresin78.1%ofthefirstseizuregroupand
88.0%ofthenewlydiagnosedepilepsygroup;classificationofsyndromesinallthefirstseizuresand
98.6%ofthosewithnewlydiagnosedepilepsy;andclassificationofaetiologyinallthefirstseizures
and98.8%ofthosewithnewlydiagnosedepilepsy,withareasonablyhighdegreeofcertaintyatthe
timeofinitialdiagnosis.
Lee2002
113
TheroleofMRIintheprocessofclassificationofepilepsieswasinvestigatedinthisstudy.The
registryformsof300consecutiveindividualsregisteredattheYonseiEpilepsyClinicwereexamined
forclinicalinformationandinvestigationsperformed.51peoplewereexcluded(didnothave
epilepsy,singleseizureonly,andnoEEGorMRI).Threediagnosesweremadeforthe249included
participants:firststepdiagnosis(clinicalinformation),secondstepdiagnosis(clinicalandEEG
correlation)andthirdstepdiagnosis(clinical,EEG,andMRIcorrelation).
MRIrevealedstructurallesionsin106(43%)ofthe249.Lesionswerefoundin47(38%)of125
individualswithnegativeEEGsandin59(48%)of124individualswithpositiveinterictalepileptiform
discharges.BothEEGandMRIwerenegativein78(31%)andpositivein59(24%)participants.The
incidenceofMRIlesionsindifferentsyndromesofthesecondstepdiagnosiswas47%inlocalization
relatedepilepsy,6%ingeneralisedepilepsy,and31%inundeterminedepilepsy.Amongthe199with
asecondstepdiagnosis,MRIchangedthediagnosisin30(12%),howevernoneofthesehadasecond
stepdiagnosisofgeneralisedepilepsy.MRIalsodecreasedtheproportionofindividualsinnon
specificcategoriesfrom37%to29%.
TheEpilepsies
Investigations
114
8.4 Theroleofprolactinlevelsandotherbloodtestsasanaidto
diagnosis
37. Measurementofserumprolactinisnotrecommendedforthediagnosisofepilepsy.[2004]
38. Inadults,appropriatebloodtests(forexample,plasmaelectrolytes,glucose,calcium)to
identifypotentialcausesand/ortoidentifyanysignificantcomorbidityshouldbeconsidered.
[2004]
39. Inchildrenandyoungpeople,otherinvestigations,includingbloodandurinebiochemistry,
shouldbeundertakenatthediscretionofthespecialisttoexcludeotherdiagnoses,andto
determineanunderlyingcauseoftheepilepsy.[2004]
40. Allinvestigationsforchildrenshouldbeperformedinachildcentredenvironment.[2004]
Evidencestatement
Thereisconflictingevidenceastothevalueofbloodtests,suchasserumprolactinlevels,in
differentiatingbetweenepilepticandnonepilepticseizures.(III)
Details
Thissectionpresentstheevidencefortheuseofbloodtestsinmakingthediagnosisofepilepsy,and
indifferentiatingbetweenepilepsyandotherconditions,particularlysyncope.Bloodtestsdiscussed
arelevelsofserumprolactin,neuronspecificenolase,serumcreatinekinase,andwhitebloodcount.
Secondaryevidence
AHRQ2001
50
Thissystematicreviewidentifiedtworelevantpapers(Anzola
114
andNeufeld
115
discussedbelow).
Primaryevidence
Theprimarypapersreviewedherehavemethodologicaldeficienciesaccordingtocriteriafor
diagnostictestsproposedbytheEvidenceBasedMedicineWorkingGroup.Themainconcernswere
lackofagoldstandardforreference,andlackofblindingofinvestigatorsorassessors.
49,67
Diagnosisofepilepsy
Fein1997
116
Theutilityofserumandcerebrospinalfluid(CSF)prolactinlevelswasassessedinthediagnosisof
childrenwithseizures.Serumsampleswereanalysedifthesamplesweretakenwithin90minutesof
theseizure,andCSFsampleswithin4hoursoftheseizure.Thecomparisongroupwaschildrenwho
hadnotexperiencedaseizurebutwhootherwiserequiredalumbarpuncture.
Thepositivepredictivevalueofageadjusteddichotomouslevels(elevatedandnormal)ofserum
prolactinwas68%(95%CI4785%)andthenegativepredictivevaluewas76%(95%CI6187%).
Shah2001
117
Onestudyaimedtoanalysetherelationshipbetweendifferenttypesofseizuresandnonepileptic
events,seizureduration,timeofsamplingandserumprolactinlevelsandperipheralwhiteblood
count.Seizureclassificationandbaselineplusbothposteventwhitebloodcountandprolactinlevels
wereavailablefor174events.
TheEpilepsies
Investigations
115
Serumprolactinlevelincreasedabovetwicethelevelatbaselineafteracomplexfocalseizureora
generalizedseizure.PeripheralWBCcountwaselevatedabovetheupperlimitofnormalin36%of
casesafterageneralizedseizure.Ingeneralizedseizures,thelengthofaseizureispositively
associated,whereasthelapsetimebetweentheseizureonsetandblooddrawisnegatively
correlatedwiththeincreaseinWBCcount.
Tumani1999
118
Thetemporalprofileofseriallevelsofneuronspecificenolase(NSE)andserumprolactinwere
comparedin21individualswithsingleseizures.Measurementsweretakenatone,three,sixand24
hoursaftertheevent.
TherewasasignificantdecreaseofNSEandprolactinlevelsovertime(p<0.001).Atonehourafter
theevent,only38%ofindividualshadincreasedNSEcomparedwithabnormalprolactinlevelsin
81%.
Differentialdiagnosisbetweenepilepticandnonepilepticattacks
Alving1998
119
Thisstudyaimedtoevaluatethediscriminativepowerofserumprolactinmeasurementsinthe
differentialdiagnosisbetweenepileptic(ES)andpseudoepilepticseizures(PES).Bloodsamples
weretakenfrom58participantsboth15minutesaftertheseizureand2hoursafterthefirstsample.
Sensitivityforthemaximalriseofserumprolactininpseudoseizures(5.5timesbaselinelevel)was
only20%andthenegativepredictivevalue40%.Forthecutoffinabsolutelevel,(1025U/ml),the
figureswere34%and44%respectively.
Epilepsyvssyncope
Anzola1993
114
Theclinicalusefulnessofplasmaprolactininthedifferentialdiagnosisbetweenepilepsyandsyncope
wasstudiedin59cases.Plasmaprolactinlevelsweremeasuredassoonaspossibleaftertheevent
(P1),onehourafterP1(P2),andinthemorningforthenexttwodays(P3,P4).
LevelsweresignificantlyincreasedinthosewhohadaseizurewhenP1wassampledwithin60
minutesofanattack.Inpeoplewhohadasyncopalattack,plasmalevelsdidnotincrease.Forthose
assessedwithin60minutesoftheattack,thepositivepredictivevalueofthecutoff(P1exceedingby
+3sdofthemeanofP2,P3,P4)was89%andthenegativepredictivevaluewas61%.
Lusic1999
120
Theuseofserumprolactinlevelsinthedifferentialdiagnosisbetweenepilepticandsyncopalattacks
wasexaminedinindividualswithcomplexfocalseizures(CPS)andindividualswithvasovagal
syncopalattacks(VVS)
87
.Theserumlevelsin33peopleweremeasuredassoonaspossibleafterthe
event(within60minutes),onehourafterthefirstsample,and24hourslater.
Meanvaluesofprolactinlevelsinbothgroupswereincreasedimmediatelyaftertheevent(CPS:
1142305mIU/l,VVS:874208mIU/l).Elevatedlevelsimmediatelyaftertheeventwerefoundin
78%ofintheCPSgroup,and60%oftheVVSgroup.
120
Neufeld1997
115
Theobjectiveofthisstudywastodeterminetheroleofsequentialserumcreatinekinase(CK)levels
indifferentiatingbetweengeneralisedtonicclonicseizuresandvasovagalsyncopeinpeople
presentingwithfirsteventsoflossofconsciousness.Serumlevelsweretakenin16individualson
admission(i.e.withinafewhoursoftheevent)and2426hourslater.
TheEpilepsies
Investigations
116
UsingthecriteriaofCKlevels>200mU/ml(3.33kat/l)(oneitheradmissionor2426hourslater)
and/ortheelevationfromthefirsttothesecondmeasurementof>=15mU/ml(0.25kat/l),there
wereonly12%falsenegativesand12%falsepositives.
115
8.5 Cardiovasculartestsasanaidtodiagnosis
41. A12leadECGshouldbeperformedinadultswithsuspectedepilepsy.[2004]
42. Inchildrenandyoungpeople,a12leadECGshouldbeconsideredincasesofdiagnostic
uncertainty.[2004]
43. Incasesofdiagnosticuncertainty,areferraltoacardiologistshouldbeconsidered.[2004]
Evidencestatement
Seizurelikeattackswithacardiovascularcausemaybemisdiagnosedasepilepsy.(III)
Details
ThiswasnotsubjecttoafullevidencereviewforreasonsgiveninChapter2.
Zaidi2000
121
Zaidiandcolleaguesconductedcardiovasculartestsin74peoplewithapreviousdiagnosisof
epilepsy.ParticipantswereincludedifattackscontinueddespiteadequateAEDtherapy,orthere
wasclinicaluncertaintybasedontheseizuredescription.Eachindividualunderwentaheaduptilt
testandcarotidsinusmassageduringcontinuouselectrocardiography,electroencephalographyand
bloodpressuremonitoring.
Analternativediagnosiswasmadein31people(42%).Afterfollowup(10.36.7months),19(61%)
ofthe31withanalternativediagnosisweresymptomfreeandall31hadsubjectivelyimproved.Of
the13peoplewhoweretakingAEDs,11(85%)hadsuccessfullystoppedAEDtherapy.
8.6 Whatistheroleofneuropsychologicalassessmentinthe
diagnosisandmanagementofepilepsy?
44. Neuropsychologicalassessmentshouldbeconsideredinchildren,youngpeopleandadultsin
whomitisimportanttoevaluatelearningdisabilitiesandcognitivedysfunction,particularlyin
regardtolanguageandmemory.[2004]
45. Referralforaneuropsychologicalassessmentisindicated:
whenachild,youngpersonoradultwithepilepsyishavingeducationaloroccupational
difficulties
whenanMRIhasidentifiedabnormalitiesincognitivelyimportantbrainregions
whenachild,youngpersonoradultcomplainsofmemoryorothercognitivedeficitsand/or
cognitivedecline.[2004]
Evidencestatement
Neuropsychologicaldeficitsarecommonlyassociatedwithepilepsyanditstreatment.Awarenessof
theseproblemsmayfacilitateeducation,socialintegrationandemployment.(IV)
Details
TheEpilepsies
Investigations
117
ThissectionwasnotsubjecttoafullevidencereviewforreasonssetoutinChapter2.
Narrativereviews
Twoexpertreviewswereconsulted.
Buelow2002
122
Theargumentsforandagainstneuropsychological(NP)assessmentinallchildrenwithepilepsywere
presentedinthisreview.Argumentsforthetestingofallchildrenwere:
NPtestingshouldnotberestrictedonlytochildrenconsideredforepilepsysurgery.
Childrenwithepilepsymayhaveacademicandlearningdisabilitiesthatmaygounrecognised,
unlessscreenedforearlyidentificationofsuchproblems.
Undetectedlearningdisabilitiescouldleadtolifelonglearningproblemsandpoorsocialadaptive
functioning.
NPtestingcouldidentifychildrenwithaborderlineorlowIQwhomayhavespecificlearning
needs.
Systematicbehaviouralassessmentwouldfacilitatethedevelopmentofmanagementstrategies
forsuchproblemsaspoorselfconceptorstigma.
NPtestingcantrackcognitivechangesinthechildwithepilepsy.
Conversely,theyarguedthatNPtestingshouldbelimitedbecause:
NPtestingmaynotbecosteffectiveforallchildren.
Falsepositiveresultsmayleadtoachildbeinglabelledwithadiagnosisthatisnotaccurate.
Expectationsofchildrenlabelledaslearningdisabledmaybelower,andchildrenmaybe
stigmatised.
Testingofchildrenmaycreatemorefeelingsofbeingdifferentthantheirpeerswithoutepilepsy
andaltertheirselfperceptioninanegativeway.
NPtestingisaspecialistskillthatmaynotbeeasilyavailabletoallchildrenwithepilepsy.
Testingshouldbeperformedforaspecificreason,asthereareresourceimplications.
TheauthorsconcludedthattheneedforNPtestingshouldberaisedandconsideredintheinitial
evaluationofeverychildwithepilepsy.
122
TheGDGconsideredthatneuropsychologicalassessmentprovidesasystematicandstandardised
evaluationofanindividualscognitiveabilitiesand:
maybeusefulinidentifyingcognitivedeficitssuchasmemoryandlanguageimpairmentsthatwill
haveimplicationsforeducational,occupationalandindependentlivinggoalsandmedical
management,suchasadherencetoprescription
mayprovideinformationregardingthelikelycauseofcognitiveimpairment(medication,brain
lesion,seizures,mood)
repeatassessmentsmayprovideinformationregardingthelikelyprognosisofcognitivefunction
inthefuture.
Kwan2001
123
Thisreviewconsideredthecauseandneuropathologyofepilepsy,neuronaldischarges,AED
treatmentandtheassociatedeffectsoncognitionandbehaviour.Psychosocialfactorswerealso
discussed.
Theauthorsconcludedthatabetterunderstandingofthecomplexcognitiveandbehavioural
dimensionsofepilepsywouldallowclinicianstoprovideamoreholistic,personcentredapproachto
TheEpilepsies
Investigations
118
management.Theyrecommendedthateachindividualwithepilepsyshouldbeassessedindividually
withrespecttofactorsuniquetotheirseizuredisorderandtreatment.
TheEpilepsies
Classificationofseizuresandepilepsysyndromes
119
9 Classificationofseizuresandepilepsysyndromes
9.1 Introduction
Itisinadequatetosimplydiagnoseanindividualashavingepilepsy.Epilepsyshouldbeviewedasa
featureorsymptomofanunderlyingneurologicaldisorderandnotasasinglediseaseentity.Itis
importantthatspecialistsandgeneralistswhotreatindividualswithepilepsyunderstandthat
epilepsyshouldbeclassifiedaccordingtoseizuretypeandepilepsysyndrome.Theneedtoconsider
agerelatedepilepsysyndromesisparticularlyimportantinchildrenwithepilepsy.
Itisaxiomaticthatthecorrectclassificationofseizuretypeandepilepsysyndromeshouldleadtothe
individualwithepilepsyreceivingappropriateinvestigations,appropriatetreatment,andinformation
aboutthelikelyprognosisoftheseizuretypeand/orsyndrome.
9.2 Classificationoftheepilepsies
46. Epilepticseizuresandepilepsysyndromesinchildren,youngpeopleandadultsshouldbe
classifiedusingamultiaxialdiagnosticscheme.Theaxesthatshouldbeconsideredare:
descriptionofseizure(ictalphenomenology);seizuretype;syndromeandaetiology.[2004]
47. Theseizuretype(s)andepilepsysyndrome,aetiology,andcomorbidityshouldbedetermined,
becausefailuretoclassifytheepilepsysyndromecorrectlycanleadtoinappropriatetreatment
andpersistenceofseizures.[2004]
48. Children,youngpeopleandadultswithepilepsyshouldbegiveninformationabouttheir
seizuretype(s)andepilepsysyndrome,andthelikelyprognosis.[2004]
Evidencestatements
Theclassificationofepilepsyreliesonevidencefromexpertcommitteereports(InternationalLeague
AgainstEpilepsy).Atpresenttheestablishedclassificationsystemisundergoingreviewandcurrent
proposalshavethestatusofworkinprogress.(IV)
Failuretocorrectlyclassifytheepilepsysyndromecanleadtoinappropriatetreatmentand
persistenceofseizures.(III)
Details
Overviewofclassificationsystems
Theclassificationofepilepsyhaslongbeenasubjectofcontention.Theproblemthefactthat
epilepsyisnotasinglediseaseentity;rather,itisasymptomofarangeofunderlyingneurological
disorders.Theclinicalpresentationdependsonanumberoffactors,chiefly:thepartofthebrain
affected,thepatternofspreadofepilepticdischargesthroughthebrain,thecauseoftheepilepsy
andtheageoftheindividual.Classificationhasthustendedtofocusonboththeclinical
presentation(typeofepilepticseizure),andontheunderlyingneurologicaldisorder(epilepsiesand
epilepsysyndromes).
2
Thefirstepilepsyclassificationsdidnotdistinguishbetweensyndromesandseizures.Termssuchas
grandmalandpetitmalwereused,respectively,toclassifyepilepsypresentingwithtonicclonic
seizuresandthosewithsmallattackssuchasabsences.Thefirstattempttoclassifytheepilepsies
wascarriedoutbyGastaut.
124
HisworkformedthebasisfortheCommissionontheClassification
andTerminologyoftheInternationalLeagueagainstEpilepsy(ILAE)standardisedclassificationsand
TheEpilepsies
120
terminologyforepilepticseizuresandtheepilepsiesandepilepticsyndromesdevelopedinthe1970s
and1980s.
125,126
(Table9.1,Table).
AlthoughtheILAE1981and1989classificationsremainincommonusetheyhavebeenthesubjectof
criticismanddebate.Theyhavebeencriticisedfor:
beingunsatisfactoryforepidemiologicalresearch
3
placingundueemphasisonthetypesofcasereferredtotertiarycentres
127
placingundueemphasisontheroleoftheEEGattheexpenseofnewertechniquessuchasMRI
3
notclassifyingepilepticseizuresaccordingtowhataindividualoreyewitnessreportshappens
duringaseizure(ictalsemiology).
128
InresponsetoconcernsabouttheexistingclassificationsystemstheILAEin1997undertooktomake
arevisionofclassificationapriorityandsetupaTaskForceofexpertsinthefieldtoaddressthis
issue.Thisgroupfirstreportedin2001.
4
TheTaskForcearguedthatitwasnotpossibletoreplace
thecurrentinternationalclassifications
125,126
withsimilarrevisedandupdatedclassificationsthat
wouldbeuniversallyacceptedandmeetalltheclinicalandresearchneedssuchaformal
organizationalsystemwouldbeexpectedtoprovide.Instead,theyproposedthatcliniciansand
researchersshoulduseamultiaxialdiagnosticscheme(Table9.3).Epilepticseizuresandepilepsy
syndromesweretobedescribedandcategorisedinindividualsaccordingtoasystemthatuses
standardisedterminology,andthatwassufficientlyflexibletotakeintoaccountthefollowing
practicalanddynamicaspectsofepilepsydiagnosis:
Someindividualscannotbegivenarecognizedsyndromicdiagnosis;
Seizuretypesandsyndromeschangeasnewinformationisobtained;
Completeanddetaileddescriptionsofictalphenomenologyarenotalwaysnecessary;
Multipleclassificationschemescan,andshould,bedesignedforspecificpurposes(for
example,communicationandteaching;therapeutictrials;epidemiologicinvestigations;
selectionofcandidatesforsurgery;basicresearch;geneticcharacterizations).
Therewasalsoscopetosimplifyorexpandtheclassificationsystemdependingonwhetheritwasto
beusedbyaneurologistwithparticularexpertiseinepilepsyorbyageneralphysicianor
paediatrician.
AfurtherreportoftheTaskForceforClassificationwaspublishedin2006withanupdatedlistof
epilepsysyndromes.Drivenprimarilybyadvancesmadeinbasicandclinicalsciencesoverrecent
years,afurtherrevisionhasnowbeenproposed.Changesmadeessentiallyrepresentsimplification
ofterminology.ForseizuresasimplifiedILAE(2010)classificationhasbeenputforward(table9.4).
Fortheepilepsiesthereisnonewclassificationassuchbutsimplificationofterminology(table9.5).
Thelistofsyndromesremainsasrecognisedin2001,andupdatedinthe2006TaskForcereport.
Descriptorsofaetiologyhavebeenupdated,thetermsidiopathic,symptomaticandcryptogenichave
beenreplacedwithgenetic,structural/metabolicandunknown(table9.6).Table9.7highlightskey
changesinterminologyforeaseofreference.
TheEpilepsies
121
Table9.1Classificationofepilepticseizuresaccordingtoclinicaltype(1981)
1. Focal(local)seizures
1.1. Simplefocalseizures(consciousnessnotimpaired)
1.1.1. Withmotorsigns
1.1.2. Withsomatosensoryorspecialsensorysymptoms(simplehallucinations,forexample,tingling,
lightflashes,buzzing)
1.1.3. Withautonomicsymptomsorsigns(forexample,epigastricsensation,pallor,sweating,flushing,
piloerectionandpapillarydilatation)
1.1.4. Withpsychicsymptoms(disturbanceofhighercerebralfunction)(forexample,djvu,
distortionoftimesense,fear.NBtheserarelyoccurwithoutimpairmentofconsciousnessand
aremuchmorecommonlyexperiencedas1.2complexfocalseizures)
1.2. Complexfocalseizures(withimpairmentofconsciousness)
1.2.1. Withsimplepartialonsetfollowedbyimpairmentofconsciousness
1.2.2. Withimpairmentofconsciousnessatonset
1.3. Focalseizuresevolvingtosecondarilygeneralizedseizures(maybegeneralizedtonicclonic,tonic,or
clonic)
1.3.1. Simplefocalseizuresevolvingtogeneralizedseizures
1.3.2. Complexfocalseizuresevolvingtogeneralizedseizures
1.3.3. Simplefocalseizuresevolvingtocomplexfocalseizuresandthenevolvingtogeneralized
seizures
2. Generalizedseizures(convulsiveornonconvulsive)
2.1. Absenceseizures
(impairmentofconsciousnessaloneorwith:mildclonic,atonicortoniccomponents,automatisms
and/orautonomicsymptomsorsigns)
2.2. Atypicalabsence
2.3. Myoclonicseizures
2.4. Clonicseizures
2.5. Tonicclonicseizures
2.6. Atonicseizures
Unclassifiedseizures
Modifiedfrom:CommissiononClassificationandTerminologyoftheInternationalLeagueAgainst
Epilepsy.Proposalforrevisedclinicalandelectroencephalographicclassificationofepileptic
seizures
126
ReprintedbypermissionofthejournalEpilepsia
TheEpilepsies
122
Table92:Classificationofepilepsiesandepilepticsyndromes(1989)
1. Localizationrelated(focal,local,)epilepsiesandsyndromes
1.1. Idiopathic(listedinorderofageofonset)
1.1.1. Benignchildhoodepilepsywithcentrotemporalspike
1.1.2. Childhoodepilepsywithoccipitalparoxysms
1.2. Symptomatic
1.3. Cryptogenic
2. Generalizedepilepsiesandsyndromes
2.1. Idiopathic(listedinorderofageofonset)
2.1.1. Benignneonatalfamilialconvulsions
2.1.2. Benignneonatalconvulsions
2.1.3. Benignmyoclonicepilepsyininfancy
2.1.4. Childhoodabsenceepilepsy(pyknolepsy)
2.1.5. Juvenileabsenceepilepsy
2.1.6. Juvenilemyoclonicepilepsy(impulsivepetitmal)
2.1.7. Epilepsywithgrandmal(generalizedtonicclonic)seizuresonawakening
2.2. Cryptogenicorsymptomatic(listedinorderofageofonset)
2.2.1. Westsyndrome(infantilespasms)
2.2.2. LennoxGastautsyndrome
2.2.3. Epilepsywithmyoclonicastaticseizures
2.2.4. Epilepsywithmyoclonicabsences
2.3. Symptomatic
2.3.1. Nonspecificetiology
2.3.1.1. Earlymyoclonicencephalopathy
2.3.1.2. Earlyinfantileepilepticencephalopathywithsuppressionburst
2.3.1.3. Othersymptomaticgeneralizedepilepsiesnotdefinedabove
2.3.2. Specificsyndromes
2.3.2.1. Epilepticseizuresmaycomplicatemanydiseasestates.Underthisheadingare
includeddiseasesinwhichseizuresareapresentingorpredominantfeature
3. Epilepsiesandsyndromesundeterminedwhetherfocalorgeneralized
3.1. Withbothgeneralizedandfocalseizures
3.1.1. NeonatalseizuresexcludedfromG/L
3.1.2. Severemyoclonicepilepsyininfancy
3.1.3. Epilepsywithcontinuousspikewavesduringslowwavesleep
3.1.4. Acquiredepilepticaphasia(LandauKleffnersyndrome)
3.2 Withoutunequivocalgeneralizedorfocalfeatures
AllcaseswithgeneralizedtonicclonicseizuresinwhichclinicalandEEGfindingsdonotpermit
classificationasclearlygeneralizedorlocalizationrelated,suchasinmanycasesofsleepgrandmal
areconsiderednottohaveunequivocalgeneralizedorfocalfeatures.
4 Specialsyndromes
4.2 Febrileconvulsions
4.3 Isolatedseizuresorisolatedstatusepilepticus
4.4 Seizuresoccurringonlywhenthereisanacutemetabolicortoxicevent
Modifiedfrom:CommissiononClassificationandTerminologyoftheInternationalLeagueAgainstEpilepsy.Proposalforrevised
classificationofepilepsiesandepilepticsyndromes
125
Idiopathic:Nounderlyingcauseotherthanapossiblehereditarypredisposition.
Symptomatic:Theconsequenceofaknownorsuspecteddisorderofthecentralnervoussystem.
Cryptogenic:Adisorderwhosecauseishiddenoroccult.Cryptogenicepilepsiesarepresumedtobesymptomatic,buttheaetiologyisnot
known.
TheEpilepsies
123
Table93:Aproposeddiagnosticschemeforpeoplewithepilepticseizuresandwithepilepsy
(2001)
Thisdiagnosticschemeisdividedintofiveparts,oraxes,organisedtofacilitatealogicalclinical
approachtothedevelopmentofhypothesesnecessarytodeterminethediagnosticstudiesand
therapeuticstrategiestobeundertakeninindividualpatients:
Axis1:Ictalphenomenology,fromtheGlossaryofDescriptiveIctalTerminology(Blume,
1991)todescribeictaleventswithanydegreeofdetailneeded.
Axis2:Seizuretype,fromtheListofEpilepticSeizures.Localizationwithinthebrainand
precipitatingstimuliforreflexseizuresshouldbespecifiedwhenappropriate.
Axis3:Syndrome,fromtheListofEpilepsySyndromes,withtheunderstandingthata
syndromicdiagnosismaynotalwaysbepossible.
Axis4:Aetiology,fromaClassificationofDiseasesFrequentlyAssociatedwithEpileptic
SeizuresorEpilepsySyndromeswhenpossible,geneticdefects,orspecificpathologic
substratesforsymptomaticfocalepilepsies.
[Axis5:Impairment,thisoptional,butoftenuseful,additionaldiagnosticparametercanbe
derivedfromanimpairmentclassificationadaptedfromanimpairmentclassification
adaptedfromtheWHOICIDH2.]
Modifiedfrom:EngelJ.Aproposeddiagnosticschemeforpeoplewithepilepticseizuresandwithepilepsy:reportoftheILAEtaskforceon
classificationandterminology
4
Table94a:Classificationofseizures(2010)
Classificationofseizures
a
Generalizedseizures
Tonicclonic(inanycombination)
Absence
Typical
Atypical
Absencewithspecialfeatures
Myoclonicabsence
Eyelidmyoclonia
Myoclonic
Myoclonic
Myoclonicatonic
Myoclonictonic
Clonic
Tonic
Atonic
Focalseizures
Unknown
Epilepticspasms
a
Seizurethatcannotbeclearlydiagnosedintooneoftheprecedingcategoriesshouldbeconsidered
unclassifieduntilfurtherinformationallowstheiraccuratediagnosis.Thisisnotconsideredaclassification
category,however.
TheEpilepsies
124
From:BergAT,BerkovicSF,BrodieMJ,BuchhalterJ,CrossJH,vanEmdeBoasW,EngelJ,FrenchJ,GlauserTA,MathernGW,MosheSL,
NordliD,PlouinP,SchefferI.(2010)Revisedterminologyandconceptsfororganisationofseizuresandepilepsies:ReportoftheILAE
CommissiononClassificationandTerminology20052009.Epilepsia;51:676685
Table94b:Descriptorsoffocalseizuresaccordingtodegreeofimpairmentduringseizure(2010)
Descriptorsoffocalseizuresaccordingtodegreeofimpairmentduringseizure
a
Accordingtoseverity
Withoutimpairmentofconsciousnessorawareness
Withobservablemotororautonomiccomponents
Involvingsubjectivesensoryorpsychicphenomenaonly.Withimpairmentofconsciousnessor
awareness.
Evolvingtoabilateral,convulsive
b
seizure(involvingtonic,clonic,ortonicandcloniccomponents).
Accordingtoputativesiteoforigin
Accordingtoelementalsequenceofclinicalfeatures
a
Formoredescriptorsthathavebeenclearlydefinedandrecommendedforuse,pleaseseeBlumeetal.,2001.
Modifiedfrom:BergAT,BerkovicSF,BrodieMJ,BuchhalterJ,CrossJH,vanEmdeBoasW,EngelJ,FrenchJ,GlauserTA,MathernGW,
MosheSL,NordliD,PlouinP,SchefferI.(2010)Revisedterminologyandconceptsfororganisationofseizuresandepilepsies:Reportofthe
ILAECommissiononClassificationandTerminology20052009.Epilepsia;51:676685
Table95:Electroclinicalsyndromesandotherepilepsies(2010)
ElectroclinicalsyndromesandotherEpilepsies
Electroclinicalsyndromesarrangedbyageatonset
a
Neonatalperiod
Benignfamilialneonatalepilepsy(BFNE)
Earlymyoclonicencephalopathy(EME)
Ohtaharasyndrome
Infancy
Epilepsyofinfancywithmigratingfocalseizures
Westsyndrome
Myoclonicepilepsyininfancy(MEI)
Benigninfantileepilepsy
Benignfamilialinfantileepilepsy
Dravetsyndrome
Myoclonicencephalopathyinnonprogressivedisorders
TheEpilepsies
125
Childhood
Febrileseizuresplus(FS+)(canstartininfancy)
Panayiotopoulossyndrome
Epilepsywithmyoclonicatonic(previouslyastatic)seizures
Benignepilepsywithcentrotemporalspikes(BECTS)
Autosomaldominantnocturnalfrontallobeepilepsy(ADNFLE)
Lateonsetchildhoodoccipitalepilepsy(Gastauttype)
Epilepsywithmyoclonicabsences
LennoxGastautsyndrome
Epilepticencephalopathywithcontinuousspikeandwave
duringsleep(CSWS)
b
LandauKleffnersyndrome(LKS)
Childhoodabsenceepilepsy(CAE)
AdolescenceAdult
Juvenileabsenceepilepsy(JAE)
Juvenilemyoclonicepilepsy(JME)
Epilepsywithgeneralizedtonicclonicseizuresalone
Progressivemyoclonusepilepsies(PME)
Autosomaldominantepilepsywithauditoryfeatures(ADEAF)
Otherfamilialtemporallobeepilepsies
Lessspecificagerelationship
Familialfocalepilepsywithvariablefoci(childhoodtoadult)
Reflexepilepsies
Distinctiveconstellations
Mesialtemporallobeepilepsywithhippocampal
sclerosis(MTLEwithHS)
Rasmussensyndrome
Gelasticseizureswithhypothalamichamartoma
Hemiconvulsionhemiplegiaepilepsy
Epilepsiesthatdonotfitintoanyofthesediagnosticcategoriescanbe
distinguishedfirstonthebasisofthepresenceorabsenceofaknown
TheEpilepsies
126
structuralormetaboliccondition(presumedcause)andthenonthe
basisoftheprimarymodeofseizureonset(generalizedvs.focal)
Epilepsiesattributedtoandorganizedbystructuralmetaboliccauses
Malformationsofcorticaldevelopment(hemimegalencephaly,
heterotopias,etc.)
Neurocutaneoussyndromes(tuberoussclerosiscomplex,
SturgeWeber,etc.)
Tumor
Infection
Trauma
Angioma
Perinatalinsults
Stroke
Etc.
Epilepsiesofunknowncause
Conditionswithepilepticseizuresthataretraditionallynotdiagnosed
asaformofepilepsyperse
Benignneonatalseizures(BNS)
Febrileseizures(FS)
aThearrangementofelectroclinicalsyndromesdoesnotreflectaetiology.
bSometimereferredtoasElectricalStatusEpilepticusduringSlowSleep(ESES).
Table96:Underlyingtypeorcause(aetiology)(2010)
Underlyingtypeofcause(aetiology)(takenfromBergetal2010)
1. Genetic:Theconceptofgeneticepilepsyisthattheepilepsyis,asbestunderstood,thedirect
resultofaknownorpresumedgeneticdefect(s)inwhichseizuresarethecoresymptomof
thedisorder.Theknowledgeregardingthegeneticcontributionsmayderivefromspecific
moleculargeneticstudiesthathavebeenwellreplicatedandevenbecomethebasisof
diagnostictests(egSCN1AandDravetsyndrome)ortheevidenceforacentralroleofa
geneticcomponentmaycomefromappropriatelydesignedfamilystudies.Designationofthe
fundamentalnatureofthedisorderasgeneticdoesnotexcludethepossibilitythat
environmentalfactors(outsidetheindividual)maycontributetotheexpressionofdisease.
Atthepresenttimethereisvirtuallynoknowledgetosupportspecificenvironmental
TheEpilepsies
127
influencesascausesoforcontributorstotheseformsofepilepsy
2. Structural/metabolic:Conceptually,thereisadistinctotherstructuralormetaboliccondition
ordiseasethathasbeendemonstratedtobeassociatedwithasubstantiallyincreasedriskof
developingepilepsyinappropriatelydesignedstudies.Structurallesionsofcourseinclude
acquireddisorderssuchasstroke,trauma,andinfection.Theymayalsobeofgeneticorigin
(egtuberoussclerosis,manymalformationsofcorticaldevelopment);however,aswe
currentlyunderstandit,thereisaseparatedisorderinterposedbetweenthegeneticdefect
andtheepilepsy
3. Unknowncause:Unknownismeanttobeviewedneutrallyandtodesignatethatthe
natureoftheunderlyingcauseisasyetunknown;itmayhaveafundamentalgeneticdefect
atitscoreoritmaybetheconsequenceofaseparateasyetunrecogniseddisorder
TheEpilepsies
128
Table97:Majorchangesinterminologyandconceptsforclassificationoftheepilepsiesand
seizures
Oldtermandconcept
Newtermandconcept
Aetiology
Idiopathic:presumedgenetic
Symptomatic:secondarytoaknownor
presumeddisorderofthebrain
Cryptogenic:presumedsymptomatic
Genetic:geneticdefectdirectlycontributestothe
epilepsy,andseizuresarethecoresymptomofthe
disorder
Structuralmetabolic:causedbyastructuralor
metabolicinsultordisorderofthebrain
Ofunknowncause:thecauseisunknownandmight
begenetic,structural,ormetabolic
Seizures
Generalised:firstchangesindicateinitial
involvementofbothhemispheres
Focal:firstchangesindicateactivationofa
systemofneuronslimitedtopartofonecerebral
hemisphere
Spasmswerenotacknowledged
Complex,simplepartial,secondarilygeneralised
Generalised:arisingwithinandrapidlyengaging
bilaterallydistributednetworks
Focal:originatingwithinnetworkslimitedtoone
hemisphere
Additionofepilepticspasms;groupedasunknown
owingtoinsufficientevidencetoclassifyasfocal,
generalised,orboth
Earliertermabandonedinfavourofprecise
descriptionoffocalseizuresaccordingtoictal
semiology
Epilepsies
TheEpilepsies
129
Generalised:epilepsieswithgeneralisedseizures
Focal:epilepsieswithfocalseizures
Earliertermabandoned
Earliertermabandoned
Majorchangesinterminologyandconceptsforclassificationoftheepilepsiesandseizures:BergAT,BerkovicSF,BrodieMJ,etal.Revisedterminologyand
conceptsfororganizationofseizuresandepilepsies:ReportoftheILAECommissiononClassificationandTerminology,20052009.Epilepsia2010;published
onlineFeb26.DOI:10.1111/j.15281167.2010.02522.x.
From:BergAT,CrossJH.Towardsamodernclassificationoftheepilepsies(2010)LancetNeurology.9(5):459461
9.3 Whatistheroleofclassificationinadultsandchildrenwith
epilepsy?
Theexamplepresentedbelowshowstheimportanceofcorrectdiagnosisandclassificationin
juvenilemyoclonicepilepsy(JME).
DelgadoEscueta1984
129
Inonestudy,43individuals,aged15to69years,werereferredforuncontrolledconvulsiveseizures.
AfterthediagnosisofJMEwasestablished,86%wereeitherseizurefreeorsatisfactorilycontrolled
onvalproatealone,orwithotherAEDs.
Grunewald1992
130
InaLondonbasedcaseseries,15definitecasesofJMEwereidentifiedfrom180consecutive
referralstoanepilepsyclinic.Diagnosesonreferralwereusuallyvagueandnonsyndromic.Inmany
cases,thesyndromicfeatureswereaccuratelyrecordedinthenotes,butthereferringphysician
appearedtobeunawareofJMEandacorrectdiagnosisnotmade.FollowingthediagnosisofJME
andoptimisationofdrugtreatments,myoclonicjerksimprovedordisappearedin13ofthe15
individuals.Theauthorssuggestedthatasyndromicclassificationshouldberecordedforallpeople
withepilepsy,andthisshouldberegularlyreviewedparticularlyifseizuresarepoorlycontrolled.
Montalenti2001
131
Montalentiandcolleaguesfoundthatonly31.3%ofindividuals(n=20/63)werecorrectlydiagnosed
onreferraltotheEpilepsyService.Theremainderwereeitherclassifiedashavingidiopathic
generalisedepilepsy(n=10),ordiagnosedashavingfocalepilepsy,orwerenotclassified(n=33).The
mostfrequentreasonformisdiagnosiswasanunderestimationormisinterpretationofmyoclonic
jerksbyboththeindividualorthereferringphysician,suggestingthatthecorrectdiagnosisis
dependentontheknowledgeofthephysician.
Thishasalsobeenidentifiedinotherstudies.
130,132
Anotherfactorassociatedwithmisdiagnosiswas
afailuretoseekahistoryofmyoclonicjerks,againassociatedwiththeknowledgeofthereferring
physicianofthesyndrome.
133,134
TheEpilepsies
Pharmacologicaltreatmentofepilepsy
130
10 Pharmacologicaltreatmentofepilepsy
10.1 Introduction
Themainstayoftreatmentforepilepsyisantiepilepticdrugs(AEDs)takendailytopreventthe
recurrenceofepilepticseizures.ItisimportantthatthetreatmentstrategyandsuitabilityoftheAED
isdeterminedbytheprescriber,incollaborationwiththeindividualwithepilepsyand/orcarer,
beforedrugtherapyiscommenced.Factorsdeterminingsuitabilityinclude:typeofseizureand/or
epilepsysyndrome;childbearingpotential;thepresenceofcomorbidity;individualand/orcarer
preferences;thepresenceofcontraindicationstothedrug;potentialinteractionswithotherdrugs;
potentialadverseeffectsandthelicensedindicationofthedrug.
Thefirstsectionconsiders,inturn,thequestionsofwhenshouldAEDtherapybestartedandwhenit
shoulditbediscontinued.TheissueofmonitoringAEDbloodlevelsandtheuseofotherbloodtests
isalsoconsidered.
Thenextchapterconsidersthemostappropriatetherapyforparticularseizuretypesandepilepsy
syndromesandthetreatmentispresentedbothbydrugandbyepilepsysyndrome.Itisalsonoted
whethertheevidencebasereferstotheuseofasingleAEDinanindividualwithepilepsy
(monotherapy)orwhethermorethanoneAEDisusedincombination(adjunctivetherapy).
The2009PharmaceuticalPriceRegulationScheme(PPRS)statedthatsubjecttodiscussionwith
affectedparties,theDepartmentofHealth(DH)wouldintroducegenericsubstitutioninprimary
care.Genericsubstitutionwouldenablepharmacistsandotherdispenserstofulfilaprescriptionfora
brandedmedicinebydispensinganequivalentgenericmedicine.Apublicconsultationonthe
proposalstoimplementgenericsubstitutiontookplacefrom5Januaryto30March2010.Three
mainresponseswereyielded:
Thereisastronglyheldperceptionbyrespondentsthatgenericsubstitutionposedathreatto
patientsafety.Iftheproposalsweretobeimplemented,theseconcernswouldariseinthe
frontlinedeliveryofNHSservices,impactingontheworkloadofhealthcareprofessionals.
Thepositiononthecosteffectivenessofgenericsubstitutionimplementationisinconclusive.
Thereisastrongsensethattheeffortinvolvedinimplementingaformalgenericsubstitution
schemewassimplytoogreatforthepotentialgain.
Other,lessnationallyprescriptivemechanismsforfurthersupportingtheuseofgeneric
medicinescanbeexplored.
Inthelightofthepublicconsultationfindings,theDHwillnotbeprogressinganyfurtherthe
implementationofgenericsubstitution.InsteadtheDHwillbelookingatfurtherwaystosupportthe
useofgenericmedicinesinawaythatisacceptabletopatients,recognisingthattherearestillsome
savingsthatcanpotentiallybedeliveredinthisarea.
******
Therefore,forthepurposesofthisguidelineupdate,theGDGconsidereditacceptabletoreviewthe
evidencerelatedtoclinicalandcosteffectivenessofspecificdrugtherapyandmake
recommendationsaccordingly
******
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_120433.pdf
TheEpilepsies
131
49. TheAEDtreatmentstrategyshouldbeindividualisedaccordingtotheseizuretype,epilepsy
syndrome,comedicationandcomorbidity,thechild,youngpersonoradultslifestyle,andthe
preferencesofthepersonandtheirfamilyand/orcarersasappropriate(seeAppendixK).
[2004]
50. Thediagnosisofepilepsyneedstobecriticallyevaluatedifeventscontinuedespiteanoptimal
doseofafirstlineAED.[2004]
10.2 Howmanytimesshouldmonotherapybetriedbefore
combinationtherapyisconsidered?
51. Itisrecommendedthatchildren,youngpeopleandadultsshouldbetreatedwithasingleAED
(monotherapy)whereverpossible.Iftheinitialtreatmentisunsuccessful,thenmonotherapy
usinganotherdrugcanbetried.Cautionisneededduringthechangeoverperiod.[2004]
52. Itisrecommendedthatcombinationtherapy(adjunctiveoraddontherapy)shouldonlybe
consideredwhenattemptsatmonotherapywithAEDshavenotresultedinseizurefreedom.If
trialsofcombinationtherapydonotbringaboutworthwhilebenefits,treatmentshouldrevert
totheregimen(monotherapyorcombinationtherapy)thathasprovedmostacceptabletothe
child,youngpersonoradult,intermsofprovidingthebestbalancebetweeneffectivenessin
reducingseizurefrequencyandtolerabilityofsideeffects.[2004]
53. IfanAEDhasfailedbecauseofadverseeffectsorcontinuedseizures,aseconddrugshouldbe
started(whichmaybeanalternativefirstlineorsecondlinedrug)andbuiltuptoanadequate
ormaximumtolerateddoseandthenthefirstdrugshouldbetaperedoffslowly.[2004]
54. Iftheseconddrugisunhelpful,eitherthefirstorseconddrugmaybetapered,dependingon
relativeefficacy,sideeffectsandhowwellthedrugsaretoleratedbeforestartinganotherdrug.
[2004]
Evidencestatements
Thereisnoevidencetoshowwhetheralternativesubstitutionoraddontherapyismoreeffectiveasa
treatmentstrategy.(III)
Evidenceforcombinationtherapywiththenewerantiepilepticdrugsshowedthatasignificant
proportionofadultsandchildrenwhodonotachieveseizurefreedomonmonotherapycouldderive
worthwhilebenefitfromcombinationtherapy.Expertopinionsuggestedthatbeforecombination
therapyisconsidered,adultsandchildrenshouldbegivenatrialofallappropriatemonotherapy
regimens,andthatcautionisneededduringchangeoverperiodsbetweendrugs.(IaNICE)
Details
NosystematicreviewsofRCTswereidentified.OneRCTwasidentifiedthatcomparedalternative
monotherapywithcombinationtherapyinindividualswithrecentlydiagnosedepilepsy.
135
However,
participantsmayhavetriedseveralmonotherapyregimesbeforeinclusion,sothisRCTwasexcluded.
NootherRCTswereidentified.
Otherevidence
Kwan2000
136
TheEpilepsies
132
Aprospectivestudyevaluatedtheeffectivenessofsubstitutiontherapyandaddontherapyafter
treatmentwithafirstAEDfailedinindividualwithnewlydiagnosedepilepsy.Individualswere
assessedasseizurefreeiftheyhadnoseizuresforoneyear.
248individuals,bothadultsandchildren,wereincludedinthestudycohort.Ofallindividualswith
inadequateseizurecontrolonthefirsttoleratedAED,42receivedaddontherapyand35received
substitution.Therewerenosignificantdifferencesinseizurefreedom(addon26%,substitution
17%)andincidenceofadverseeventsleadingtowithdrawal(addon12%,substitution26%)between
thetwogroups(p=0.25).
Deckers2003
137
Atthe5thEuropeanCongressonEpileptology,thetopicofsubstitutionofalternativemonotherapy
ofaddontherapyinadultswasdiscussed.Aliteraturereviewpreparedforthediscussiongroupwas
prepared.
137
Ninepaperswerereviewed;fourevaluatingalternativemonotherapyandfiveaddon
therapy.However,itwasnotalwaysclearwhetherthesubstitutiondrugortheaddondrugwasthe
secondAEDtriedinindividuals.
Theauthorconcludedthatbasedonpublisheddata,thereisnoconclusiveevidenceinfavourof
eitheralternativemonotherapyorsecondlinepolytherapy.Thesuggestedpracticewastotryadd
ontherapybeforeanalternativemonotherapy,andwithdrawthefirstdrugifthecombinationis
successful.
137
10.2.1 WhenshouldAEDtreatmentinadultsandchildrenbestarted?
55. TreatmentwithAEDtherapyisgenerallyrecommendedafterasecondepilepticseizure.[2004]
56. ThedecisiontoinitiateAEDtherapyshouldbetakenbetweenthechild,youngpersonoradult,
theirfamilyand/orcarers(asappropriate)andthespecialistafterafulldiscussionoftherisks
andbenefitsoftreatment.Thisdiscussionshouldtakeintoaccountdetailsofthepersons
epilepsysyndrome,prognosisandlifestyle.[2004]
57. AEDtherapyshouldbeconsideredanddiscussedwithchildren,youngpeopleandadultsand
theirfamilyand/orcarersasappropriateafterafirstunprovokedseizureif:
thechild,youngpersonoradulthasaneurologicaldeficit
theEEGshowsunequivocalepilepticactivity
thechild,youngpersonoradultand/ortheirfamilyand/orcarersconsidertheriskofhaving
afurtherseizureunacceptable
brainimagingshowsastructuralabnormality.[2004]
58. Itshouldberecognisedthatsomechildren,youngpeopleandadults(throughtheirfamilies
and/orcarers,insomeinstances)maychoosenottotakeAEDtherapyfollowingafull
discussionoftherisksandbenefits.[2004]
Evidencestatements
Inadultsandchildrenwhopresentwithafirstunprovokedseizuretheriskofrecurrencevarieswidely.
(IIb)
Factorswhichareassociatedwithanincreasedriskofrecurrenceinclude:
presenceofneurologicalabnormalities
epileptiformabnormalitiesonEEG
TheEpilepsies
133
seizuretypeand/orepilepsysyndrome.(IIb)
Treatmentofafirstunprovokedseizurereducestheriskofrecurrenceintheshortterm.(Iachildren,
Ibadults)
Inchildren,treatmentofafirstunprovokedseizuredoesnotalterthelongtermprognosisforseizure
remission.(Ia)
10.2.1.1 Inadultsandchildrenwhopresentwithasingleseizurewhatarethefeatures(fromhistoryand
investigations)whichpredictriskoffurtherseizures?
Secondaryevidence
Berg1991
100
Asystematicreviewoftheriskofseizurerecurrencefollowingafirstunprovokedseizurewas
undertakenbyBerg&Shinnarin1991.Theirliteraturereviewreviewedallrelevantstudiesupto
1990.Theauthorsconductedametaanalysisof16studiesandfoundthatthreemethodological
factorsexplainedmuchofthereportedvariation:
studyinclusioncriteria(whetherparticipantswereenrolledatthetimeoftheirfirstseizureorif
thosewithpriorseizureswereincluded);
retrospectiveversusprospectiveascertainmentofparticipants;
theintervalbetweenthefirstseizureandtimeatwhichriskwasassessed.
Overallriskofrecurrence
Fromthe16studiesreviewedtheoverallpooledestimateofriskofrecurrencewas51%(95%CI49%
to53%).Toallowforcomparableresultstheriskofrecurrenceattwoyearswascalculated.Therisk
was36%(95%CI32%to39%)intheprospectivefirstseizurestudiesreviewedand43%(95%CI40%
to47%)intheretrospectivefirstseizurestudiesreviewed.
Factorspredictiveofriskofrecurrence
Aetiology(Neurologicalabnormality)Allreviewedstudiesfoundincreasesinriskofrecurrence
associatedwithabnormalneurologicalstatus(congenitalandacquiredneurologicaldeficits)witha
pooledrelativeriskof1.8(95%CI1.5to2.1).
EEGChildren(3studiesreviewed)withepileptiformabnormalitiesonEEGaremorelikelytohavea
recurrencethanchildrenwithnormalEEGs(pooledRR2.0,95%CI1.6to2.6).
AetiologyandEEGThreestudiesprovidedinformationaboutriskofrecurrenceasafunctionof
aetiologyandEEGtogether.TheriskwaslowestinthecryptogenicgroupwhohadnormalEEGs
(24%,95%CI19%to29%)andhighestinthegroupwithabnormalneurologicalstatusandan
abnormalEEG(65%,95%CI55%to76%).
Hirtz2003
138
ThispracticeparameteroftheQualityStandardsSubcommitteeoftheAmericanAcademyof
NeurologyandthePracticeCommitteeoftheChildNeurologySocietysystematicallyreviewedthe
publishedliteraturerelevanttothedecisiontobegintreatmentafterachildoradolescent
experiencesafirstunprovokedseizureandpresentsevidencebasedpracticerecommendations(see
below).Theauthorsreviewedtheevidencebaseupto2001.
Howlikelyisasecondseizure?
Theprobabilityofhavingasecondseizurehadbeenexploredinseverallarge,cohortstudieswith
longtermfollowup.Thecumulativeriskofrecurrenceincreasedovertime;however,instudies
TheEpilepsies
134
wheretheinformationwasavailable,themajorityoftherecurrencesoccurredearly(withinthefirst
1to2years).Atanygiventime,thereportedriskofrecurrencewashighlyvariable.Forexample,at
1year,itrangedfromalowof14%toahighof65%.Inallthesecohortstudiestherewasvariability
inthemixofparticipantsandthedistributionsofimportantprognosticfactors.Treatmentwasalso
notrandomised.Somemethodologicaldifferencesinseizureidentification,agerangesincluded,
recruitment,andfollowupofstudyparticipantsmayhavecontributedtothisvariability.
138
Aretherefactorsthatincreasetheriskofrecurrence?
TheauthorscitedthefindingsoftheBerg&Shinnarreview
100
thattheunderlyingaetiologyand
whethertheEEGisnormalorabnormalwereconsistentlyrelatedtotheriskofrecurrence.
138
Primaryevidence
Hart1990
139
Thislargescaleprospectivecommunitybasedstudy(NationalGeneralPracticeStudyofEpilepsy)
aimedtodeterminetheriskofrecurrenceafterafirstseizure.564individualsclassifiedashaving
definiteseizureswerefollowedupfor2to4years.67%(95%CI63%to71%)hadarecurrence
within12monthsofthefirstseizure,and78%(95%CI74%to81%)hadarecurrencewithin36
months.Seizuresassociatedwithaneurologicaldeficitpresumedpresentatbirthhadahighrateof
recurrence(100%by12months),whereasseizuresthatoccurredwithin3monthsofanacuteinsult
tothebrain,suchasheadinjuryorstroke,orinthecontextofanacuteprecipitantsuchasalcohol,
carriedamuchlowerriskofrecurrence(40%,95%CI29%to51%,by12months).Otherfactors
affectingtheriskofrecurrencewere:
age;
thehighestriskbeingforthoseundertheageof16(83%,95%CI77%to89%,by36months)orover
theageof59(83%,95%CI76%to90%,by36months).
typeoffirstseizure;
theriskofrecurrencebeingmuchhigherforthosewithsimplefocalorcomplexfocalseizures(94%,
95%CI90%to99%,by36months)thanforthosewithgeneralisedtonicclonicseizures(72%,95%CI
67%to77%,by36months).
Macdonald2000
10
Thislargescaleprospectivecommunitybasedstudy(NationalGeneralPracticeStudyofEpilepsy)
aimedtoidentifythefactors,atthetimeofdiagnosis,thatdeterminetheprognosisforremissionof
epilepsy.Aprospectivecommunitybasedcohortstudyof792individualsrecruitedatthetimeof
firstdiagnosisofepilepticseizureswasundertaken;inthoseclassified6monthsafterpresentation,
themedianfollowupperiodwas7.2years(quartilesat6.2and8.2years)afterpresentation.Data
wereanalysedfrom6monthsafterthefirstidentifiedseizure,whichpromptedthediagnosisof
epilepsy,toallowaspectscontingentonadiagnosticassessmenttobefactoredin.Baselineclinical
anddemographicdatawereanalysedusingtheCoxproportionalhazardsregressionmodelwith
remissionofepilepsyfor1,2,3,and5yearsasoutcomemeasures.Thedominantclinicalfeature
predictingremissionwasthenumberofseizuresinthe6monthdiagnosticassessmentperiod.Thus,
thechanceofenteringoneyearofremissionby6yearsforanindividualwhohad2seizuresduring
thisinitial6monthswas95%;for5yearsofremission,itwas47%asopposedto75%for1yearof
remissionand24%for5yearsofremissioniftherehadbeen10ormoreseizuresduringthisperiod.
Theauthorsconcludedthatthenumberofseizuresintheearlyphaseofepilepsy(here,takenasthe
first6monthsafterpresentation)isthesinglemostimportantpredictivefactorforbothearlyand
longtermremissionofseizures.
10
TheEpilepsies
135
10.2.1.2 Inadultsandchildrenwhopresentwithasingleseizure,doestreatmentwithantiepileptic
medicationreducetheriskoffurtherseizures?
Secondaryevidence
Berg1991
100
Asystematicreviewoftheriskofseizurerecurrencefollowingafirstunprovokedseizurewas
undertakenbyBerg&Shinnarin1991.Theirliteraturereviewreviewedallrelevantstudiesupto
1990.TheauthorsidentifiedoneRCT
140
inwhichtreatmentofafirstseizurewasassociatedwitha
significantreductioninriskofrecurrence.
Hirtz2003
138
ThispracticeparameteroftheQualityStandardsSubcommitteeoftheAmericanAcademyof
NeurologyandthePracticeCommitteeoftheChildNeurologySocietysystematicallyreviewedthe
publishedliteraturerelevanttothedecisiontobegintreatmentafterachildoradolescent
experiencesafirstunprovokedseizureandpresentsevidencebasedpracticerecommendations(see
below).Theauthorsreviewedtheevidencebaseupto2001.
Howeffectiveistreatmentafterafirstseizureinpreventionofrecurrences?
Therewerefourrandomisedclinicaltrialsincludingchildrenandadolescentsthatexaminedthe
efficacyoftreatmentafterafirstseizure.Onlyoneofthesestudiesconsistedsolelyofchildren
randomisedtotreatmentversusnotreatmentafterafirstnonfebrileseizure.
140
Inthisstudywitha
totalof31children,2of14children(14%)treatedwithcarbamazepine(CBZ)experienceda
recurrencecomparedwith9of17(53%)whowerenottreated.Followupwasfor1year,and
compliancewasmonitored.Althoughtherecurrencerateupto1yearwassignificantlylowerinthe
treatedgroup,only6of14(43%)childrenrandomisedtoCBZcompletedtheyearwithnosignificant
sideeffectsorseizurerecurrenceand7of17(41%)assignedtonomedicationhadnoseizure
recurrence.
140
Instudiesinvolvingbothchildrenandadults,outcomewasnotprovidedbasedonage.Onestudy
141
inwhich228subjectswererandomisedtovalproicacid(VPA)orplaceboincluded33adolescents
betweentheagesof16and19.Thefollowupperiodforthistrialwasbetween9monthsand5
years.Five(4%)ofthetreatedgroupexperiencedarecurrencecomparedwith63(56%)ofthose
treatedwithplacebo.
141
However,theseresultswerenotfoundinanotherrandomisedstudy
142
(n=419),inwhich114
subjectswerebetween2and16yearsold.Twentyfourpercentofthosetreatedafterafirstseizure
and42%untreatedindividualshadarecurrenceby1year,butnodifferencebyinitialtreatment
assignmentwasseenafter2years;32%ofthosetreatedand40%ofthoseuntreatedhada
recurrenceby2years.
Thefindingsofotherpublishedstudiesinchildrenwerenotreportedasalthoughthecohortswere
prospectivelyfollowed,treatmentwasnotrandomlyassignedandthereforebaselinefactors
affectingriskofrecurrencewerenotcomparable.
DoestreatmentwithAEDafterafirstseizurechangethelongtermprognosisforseizureremission?
Althoughtreatmentafterafirstunprovokedseizuremayreducetheriskofasecondseizure,does
treatmentatthistimemakeanydifferenceinthelongtermprognosisforseizurecontrol?This
questionwasaddressedintworandomised,prospective,butnotplacebocontrolledfirstseizure
studies
142,143
.
Onestudy
142
had419subjects,ofwhom114werebetween2and16yearsofage.Thisstudy
comparedtheprobabilityofexperiencingaremission,thatis,1or2seizurefreeyears,inthose
TheEpilepsies
136
treatedafterafirstseizureversusinpeopletreatedafterasecondseizure.Followupwasforat
least3yearsoraminimumof2yearsseizurefree.Individualstreatedafterthefirstseizureand
thosetreatedafterasecondseizurehadthesameprobabilityofachievinga1or2yearseizure
remission(68%,n=215versus60%,n=204)(relativerisk1.04,95%CI0.82to1.30).
Anothersmallerstudy
143
of31childrenrandomisedtoCBZ(n=14)ornotreatment(n=17)found
similarresults.Aftera15yearfollowup,therateof2yearterminalremissionwasthesameinboth
thetreatedandtheuntreatedgroups(relativerisk0.79,95%CI0.3to2.1).
Primaryevidence(adults&children)
NostudieswereidentifiedsincetheHirtzreview.
138
10.2.2 WhoshouldstartAEDtreatmentinadultsandchildren?
59. AEDtherapyshouldbeinitiatedinadultsontherecommendationofaspecialist.[2004]
60. AEDtherapyinchildrenandyoungpeopleshouldbeinitiatedbyaspecialist.[2004]
61. AEDtherapyshouldonlybestartedoncethediagnosisofepilepsyisconfirmed,exceptin
exceptionalcircumstancesthatrequirediscussionandagreementbetweentheprescriber,the
specialistandthechild,youngpersonoradultandtheirfamilyand/orcarersasappropriate.
[2004]
Evidencestatement
Noevidencewasidentified.
Details
NoevidencethatspecificallyaddressedthequestionastoWhoshouldinitiatetreatment?was
found.Theevidenceonratesandconsequencesofmisdiagnosisreviewedinsection7was
consideredbytheGDGandformedthebasisfortheGPPsabove.
10.2.3 InadultsandchildrenwithepilepsyonAEDsdoesmanagementofcontinuingdrugtherapy
byageneralistasopposedtoaspecialistleadtodifferentclinicaloutcomes?
62. ContinuingAEDtherapyshouldbeplannedbythespecialist.Itshouldbepartofthechild,
youngpersonoradult'sagreedtreatmentplan,whichshouldincludedetailsofhowspecific
drugchoicesweremade,drugdosage,possiblesideeffects,andactiontotakeifseizures
persist.[2004]
63. Ifmanagementisstraightforward,continuingAEDtherapycanbeprescribedinprimarycareif
localcircumstancesand/orlicensingallow.[2004]
64. Theneedsofthechild,youngpersonoradultandtheirfamilyand/orcarersasappropriate
shouldbetakenintoaccountwhenhealthcareprofessionalstakeontheresponsibilityof
continuingprescribing.[2004]
65. Theprescribermustensurethatthechild,youngpersonoradultandtheirfamilyand/orcarers
asappropriatearefullyinformedabouttreatmentincludingactiontobetakenafteramissed
doseorafteragastrointestinalupset.[2004]
TheEpilepsies
137
AkeyissuehereisthegeneralissueofwhoshouldprescribemedicationwhentheAEDmaybe
unlicensedforaparticularclinicalindication.
Evidencestatement
NoevidencewasidentifiedonwhoshouldcontinuetoprescribeAEDtreatment.
Details
NosystematicreviewsorRCTswereidentified.
Consensusstatements
Noconsensusstatementsfromprofessionalbodieswereidentifiedthatdescribedwhichhealthcare
professionalshouldprescribecontinuingAEDtreatment.
10.2.4 Whatistheroleofmonitoringinadultsandchildrenwithepilepsy?
66. Regularbloodtestmonitoringinadultsisnotrecommendedasroutine,andshouldbedone
onlyifclinicallyindicated.[2004]
67. Regularbloodtestmonitoringinchildrenandyoungpeopleisnotrecommendedasroutine,
andshouldbedoneonlyifclinicallyindicatedandrecommendedbythespecialist.[2004]
68. Examplesofbloodtestsinclude:
beforesurgeryclottingstudiesinthoseonsodiumvalproate
fullbloodcount,electrolytes,liverenzymes,vitaminDlevels,andothertestsofbone
metabolism(forexample,serumcalciumandalkalinephosphatase)every25yearsfor
adultstakingenzymeinducingdrugs.[2004]
69. Asymptomaticminorabnormalitiesintestresultsarenotnecessarilyanindicationforchanges
inmedication.[2004]
70. Annualreviewshouldincludeanenquiryaboutsideeffectsandadiscussionofthetreatment
plantoensureconcordanceandadherencetomedication.[2004]
71. Treatmentshouldbereviewedatregularintervalstoensurethatchildren,youngpeopleand
adultswithepilepsyarenotmaintainedforlongperiodsontreatmentthatisineffectiveor
poorlytoleratedandthatconcordancewithprescribedmedicationismaintained.[2004]
Evidencestatements
RoutinemonitoringofAEDbloodlevelsdoesnotleadtoimprovedseizurecontrolforpeoplewith
epilepsy.(Ib)
Thereisnogoodqualityevidencethatshowsroutinemonitoringofsideeffectsleadstobetterhealth
outcomesforindividuals.(IV)
Thereisnoevidencethatshowsroutinemonitoringofdrugusageleadstobetterhealthoutcomesfor
individuals.(IV)
Pleasenotethatvalproatehasbeenchangedtosodiumvalproatetobeconsistentwiththeterminologyusedinthis
update.
TheEpilepsies
138
Details
Inadults/childrenwithepilepsy,doesroutinemonitoringof
AEDbloodlevels
sideeffects
drugusage
leadtobetteroutcomes(e.g.seizurerecurrence,sideeffects)whencomparedwiththosewho
receivenomonitoringormonitoringonlywhenclinicallyindicated?
10.2.4.1 Inadultsandchildrenwithepilepsy,doesroutinemonitoringofAEDbloodlevelsleadtobetter
outcomeswhencomparedwiththosewhoreceivenomonitoringormonitoringonlywhen
clinicallyindicated?
Secondaryevidence
AHRQ2001
50
Thissystematicreviewonthemanagementofpeoplewithnewlydiagnosedepilepsyreviewed24
prospectiveinterventionalstudiesthathadamonitoringcomponent.Noneofthesestudieshadasa
primaryobjectivethetestingofmonitoringinterventionsnecessaryforoptimalcarebutinnearlyall,
thiswasamonitoringinterventiondictatedbyaresearchstudyprotocolandnotoptimalcare.
Therefore,thereviewwasexcluded.
SwedishCouncilonTechnologyAssessmentinHealthcare1998
144
Thisassessmentoftherapeuticdrugmonitoringinthetreatmentofepilepsyidentifiedone
prospectiverandomisedstudy.127peoplewithepilepsywererandomisedeithertotreatmentwith
orwithoutthesupportoftherapeuticdrugmonitoring.Samplesweretakenfrombothgroups,but
resultsforthoseinthetreatmentgrouponlywerepresentedtotheattendingphysician.105
individualswerefollowedupafter12months.Nodifferenceswerefoundinseizurecontrol.
However,alargepercentageofallparticipants(equallylargeinbothgroups)showeddruglevels
outsideofthetargetarea.
Onthebasisofthestudyaboveandoneotherretrospectivestudy,thetechnologyassessmentreport
concludedthattherewaspoorevidencetodemonstratethebenefitsoftherapeuticdrug
monitoring.
144
Primaryevidence
Jannuzzi2000
145
ThisRCTassessedtheclinicalimpactofmonitoringserumconcentrationsofantiepilepticdrugs
(AEDs)inindividualswithnewlydiagnosedepilepsy.180peoplewithfocaloridiopathicgeneralized
nonabsenceepilepsy,aged6to65years,requiringinitiationoftreatmentwithcarbamazepine
(CBZ),valproate(VPA),phenytoin(PHY),phenobarbital(PB),orprimidone(PRM)wererandomly
allocatedtotwogroupsaccordingtoanopen,prospectiveparallelgroupdesign.Inonegroup,
dosagewasadjustedtoachieveserumAEDconcentrationwithinatargetrange,whereasintheother
group,dosagewasadjustedonclinicalgrounds.Individualswerefollowedupfor24monthsoruntil
achangeintherapeuticstrategywasclinicallyindicated.
Baselinecharacteristicsdidnotdifferbetweenthetwogroups.Atotalof116peoplecompleted2
yearfollowup,andtherewerenodifferencesinexitratefromanycausebetweenthemonitored
groupandthecontrolgroup.Theproportionofassessableparticipantswithmeanserumdruglevels
outsidethetargetrange(mostlybelowrange)duringthefirst6monthsofthestudywas8%inthe
monitoredgroupcomparedwith25%inthecontrolgroup(p<0.01).Therewerenosignificant
TheEpilepsies
139
differencesbetweenthemonitoredgroupandthecontrolgroupwithrespecttoindividualsachieving
12monthremission(60%vs.61%),individualsremainingseizurefreesinceinitiationoftreatment
(38%vs.41%),andtimetofirstseizureor12monthremission.Frequencyofadverseeffectswas
almostidenticalinthetwogroups.WiththeAEDsmostcommonlyusedinthisstudy,early
implementationofserumAEDlevelmonitoringdidnotimproveoveralltherapeuticoutcome,and
themajorityofpeoplecouldbesatisfactorilytreatedbyadjustingdoseonclinicalgrounds.
Froscher1981
146
Toevaluatewhetherknowledgeofplasmalevelsofantiepilepticdrugshasaneffectontherapeutic
outcome,127peoplewithepilepsywererandomlyassignedtotwogroups(AandB).Plasmalevels
ofgroupAwerereportedtothetreatingphysicianwhoattemptedtokeeptheplasmalevelswithin
thetherapeuticrange.Thetreatingphysicianwasnotinformedoftheresultsofplasmalevel
determinationsofgroupB.Datafrom105participantswereavailableforassessmentattheendof
thestudyyear.
Seizurecontrolimprovedtoasimilardegreeinbothgroups.TherapeuticresultsofgroupsAandB
werenotsignificantlydifferent.Thereductioninseizurefrequencywasassociatedwithanincrease
inplasmaconcentrationsoftheantiepilepticdrugs.TheproportionofindividualswithserumAED
levelsoutsidetheoptimalrangedidnotchangesubstantially.Theauthorssuggestedthatthe
physiciansdidnotusetheinformationcorrectly.Theythereforeconcludedthat,underthe
conditionsofthestudy,knowledgeofplasmalevelsofantiepilepticdrugsdidnotimprove
therapeuticresults.
10.2.4.2 Inadultsandchildrenwithepilepsy,doesroutinemonitoringofsideeffectsleadtobetterclinical
Secondaryevidence
Deckers1997
147
Asearchforpublishedpapersoncarbamazepineandvalproatemonotherapy(19911995)identified
7relevantpapers.Detailsofthefrequencyofadverseeventsassociatedwithcarbamazepineor
valproatemonotherapywerealsoextractedfromaclinicdatabase.Themethodsofdetectionfor
differentadverseeventswerecomparedacrosstheincludedtrialsandthedatabaseinformation.
Methodsincludedselfreporting,physicalexamination,laboratoryinvestigations,adverseevent
checklists,specifictoxicityscales,andneuropsychologicaltesting.
Forcertainadverseevents(diplopia,dysarthria,affectandmooddisturbances,headache,dizziness,
GIdisturbances,dermatologicaldisturbances,andidiosyncraticreactions)therewasnodifferencein
howtheadverseeventsweredetected.Butsedation,cognitiveimpairments,sexualdysfunction,
hairchanges,nystagmus,gaitdisturbances,tremor,andweightchangewerereportedmore
frequentlywhenroutinelychecked.
Thisreviewdidnotlinkthedetectionofsideeffectswithclinicaloutcomes.However,itisobvious
thatifanindividualisexperiencingadverseeventstheirqualityoflifemaybeaffected,andthat
particularlyforseriousadverseeventssuchastoxicity,monitoringmaybeuseful.
Primaryevidence
NoRCTswereidentified.
Positionstatements
In1993,theILAECommissiononAntiepilepticDrugspublishedguidelinesfortherapeuticmonitoring
ofAEDs.Theyhighlightedthreeareasofconcern:
TheEpilepsies
140
a) Thelackofstrictcorrelationbetweenefficacyand/ortoxicityofAEDsandtheirbloodlevels
forindividuals.
b) Bloodlevelsjudgedonanindividualsamplingmaybemisleadingwherethereexistswide
diurnalvariation.
c) Accuracyofmeasurementsmustbeconsidered.
Inconclusion,theCommissionrecommendedthat
Indiscriminateuseofbloodleveldeterminationsisnotrecommended.
Theuseofbloodlevelstoadjustdosagesothatlevelsfallwithinthedefinedtherapeuticrangeis
awasteoftimeandmoney,andmayevenbedangerous.
Atargetrangeisbetterdevelopedforeachindividualbasedontheseverityoftheepilepsyand
toleranceofsideeffects.
Alistofsituationswherebloodlevelsmaybeusefulwaspresented.Thisincludedroutine
determinationsforallindividualsbasedontheoreticalgroundsonly,tailoreddeterminationswith
specificpurposes(forexample,whenanindividualcomplainsoftoxicsignsthatmaybedoserelated,
orinspecificphysiologicstatessuchaspregnancy),andthosewherebloodlevelsshouldneverbe
used.
148
10.2.4.3 Inadultsandchildrenwithepilepsy,doesroutinemonitoringofdrugusageleadtobetterclinical
NosystematicreviewsorRCTswereidentified.TheILAEStatement(seeabove)onmonitoringwas
consideredwhenmakingrecommendationsinthisarea.
10.2.5 WhatinfluencesAEDtreatmentconcordanceinadultsandchildren?
72. Adherencetotreatmentcanbeoptimisedwiththefollowing:
educatingchildren,youngpeopleandadultsandtheirfamiliesand/orcarersinthe
understandingoftheirconditionandtherationaleoftreatment
reducingthestigmaassociatedwiththecondition(seealsosection18.5)
usingsimplemedicationregimens
positiverelationshipsbetweenhealthcareprofessionals,thechild,youngpersonoradult
withepilepsy,andtheirfamilyand/orcarers.[2004]
73. Healthcareprofessionalshavearesponsibilitytoeducateothersaboutepilepsysoastoreduce
thestigmaassociatedwithit.Theyshouldprovideinformationaboutepilepsytoallpeople
whocomeintocontactwithchildren,youngpeopleandadultswithepilepsy,includingschool
staff,socialcareprofessionalsandothers.[2004]
Evidencestatements
Adherencetotreatmentisassociatedwithmanyfactors.(III)
Noevidenceonfactorsassociatedwithotheraspectsofconcordancewasidentified.(III)
Details
TheEpilepsies
141
Concordancereferstoaconsultationprocessbetweenahealthcareprofessionalandanindividual.
Complianceoradherencereferstoaspecificbehaviour:wasthemedicinetakeninaccordancewith
thewishesofthehealthcareprofessional?
149
Complianceisaproblematicterm.Medicalstudiesof
compliancewithdoctorsinstructionshaveoftenusedanimageofthepatientasapassive,
obedientandunquestioningrecipientofmedicalinstructions.Divergencefromthisimage,
defaulting,has,inthepast,oftenbeenseenasirrationalfromthepurelymedicalperspectiveand
theblamefordefaultisputupontheindividual.
150
ItisimportanttonotethatmuchofthepublishedliteratureonAEDtreatmentadherenceusesthe
termcomplianceandattemptstodetermineindividualvariablesthatmaybeassociatedwithhigh
orlowlevelsofcompliance.Inthisguideline,thetermcomplianceisnotendorsedandtheterm
adherenceispreferred.
ThesystematicreviewconsideredincludeslowerlevelevidencethanRCTorcohortstudies;hence
thegradingoftheevidencestatementsandrecommendations.
Secondaryevidence
Onesystematicreviewofconcordanceinpeoplewithepilepsywasidentified.
151
Theauthorsreviewedtheresearchevidenceandidentifiedthefollowingfactorsassociatedwith
adherencetomedication:
Table1028:Factorsaffectingadherencetomedicationregimensinpeoplewithepilepsy
151
Factorsrelatedtogoodadherence Factorsrelatedtopooradherence
Agedover60years Agedunder60years
Agedover19years Teenager(agedunder19years)
Oncedailydose Fourtimesdailydose
Feelingthatitisimportanttotakemedicationas
prescribed
Feelingstigmatised
FindingtheGPeasytotalkto Experienceofsideeffects
Concernedabouthealthorhealthrisks
Absenceofbarriers,suchascosts,inabilityto
obtainmedication
Interventionstoimproveadherencewerealsoreviewed.Althoughtheliteraturewaslimited,the
authorsconcludedthatmultifacetedcommunicationandsupportprogrammesdesignedtopromote
empowermentweremostlikelytobeeffective.
10.2.6 WhenandhowshouldAEDtreatmentbediscontinuedinadultsandchildren?
74. TherisksandbenefitsofcontinuingorwithdrawingAEDtherapyshouldbediscussedwith
children,youngpeopleandadults,andtheirfamiliesand/orcarersasappropriate,whohave
beenseizurefreeforatleast2years(seeAppendixH
).[2004]
AppendixHprovidestablesfortheprognosisforremissionofseizuresinadults.
TheEpilepsies
142
75. Thedecisiontocontinueorwithdrawmedicationshouldbetakenbythechild,youngpersonor
adult,theirfamilyand/orcarersasappropriate,andthespecialistafterafulldiscussionofthe
risksandbenefitsofwithdrawal.Attheendofthediscussionchildren,youngpeopleand
adults,andtheirfamilyand/orcarersasappropriate,shouldunderstandtheirriskofseizure
recurrenceonandofftreatment.Thisdiscussionshouldtakeintoaccountdetailsofthechild,
youngpersonoradult'sepilepsysyndrome,prognosisandlifestyle.[2004]
76. WhenAEDtreatmentisbeingdiscontinuedinachild,youngpersonoradultwhohasbeen
seizurefree,itshouldbecarriedoutslowly(atleast23months)andonedrugshouldbe
withdrawnatatime.[2004]
77. Particularcareshouldbetakenwhenwithdrawingbenzodiazepinesandbarbiturates(maytake
upto6monthsorlonger)becauseofthepossibilityofdrugrelatedwithdrawalsymptoms
and/orseizurerecurrence.[2004]
78. Thereshouldbeafailsafeplanagreedwithchildren,youngpeopleandadultsandtheirfamilies
and/orcarersasappropriate,wherebyifseizuresrecur,thelastdosereductionisreversedand
medicaladviceissought.[2004]
Evidencestatements
CharacteristicsthatpredictadecreasedriskofrecurrenceofseizuresafterAEDwithdrawalinadults
withepilepsyarethe:
durationofseizurefreedombeforewithdrawal(Ib)
CharacteristicsthatpredictanincreasedriskofrecurrenceofseizuresafterAEDwithdrawalinadults
withepilepsyare:
historyoffocalseizures
historyofmyoclonicseizures
historyoftonicclonicseizures
seizuresaftercommencementofAEDtreatment
onmorethanoneAED(Ib)
CharacteristicsthatpredictadecreasedriskofrecurrenceofseizuresafterAEDwithdrawalin
childrenwithepilepsyare:
periodseizurefree(2yearsormore)(Ia)
CharacteristicsthatpredictanincreasedriskofrecurrenceofseizuresafterAEDwithdrawalin
childrenwithepilepsyare:
historyoffocalseizures
epileptiformabnormalitiesonEEG(Ia)
presenceoflearningdisabilities(Ib)
Thereisnogoodqualityevidence(seeEvidenceTablesinAppendixFformethodologicalissues)that
taperingAEDmedicationatdifferentrateshasadifferenceonoutcomesforpeoplewithepilepsy.
(Ibchildren,noevidenceforadults)
10.2.6.1 InadultsandchildrenwithepilepsyonAEDswhatarethefeatures(fromhistoryand
investigations)whichpredictriskoffurtherseizuresifmedicationisdiscontinued?
Secondaryevidence
TheEpilepsies
143
Berg1994
152
Asystematicreviewwasundertakentodeterminetheriskofrelapseat1and2yearsafter
discontinuationofantiepilepticmedicationandtoexaminethestrengthofassociationbetweenthe
riskofrelapseandthreecommonlyassessedclinicalfactors:
ageofonsetofepilepsy
presenceofanunderlyingneurologiccondition
andanabnormalEEG.
Theauthorsusedexplicitstrategiestoidentifypapers,selectstudiesandextractdata.
Fortytwostudieswereidentified,ofwhich25mettheirinclusioncriteria.Dataon5354individuals
wereincluded.Theproportionofthosewhorelapsedrangedfrom12%to67%.Overall,theriskof
relapseat1yearwas0.25(95%CI,0.21to0.30)andat2yearsitwas0.29(95%CI,0.24to0.34).
Relativetoepilepsyofchildhoodonset,epilepsyofadolescentonsetwasassociatedwitharelative
riskofrelapseof1.79(95%CI,1.46to2.19).Comparedwithchildhoodonsetepilepsy,adultonset
epilepsywasassociatedwitharelativeriskof1.34(95%CI,1.00to1.81).Individualswithremote
symptomaticseizuresweremorelikelytorelapsethanthosewithidiopathicseizures;therelative
riskwas1.55(95%CI,1.21to1.98).AnabnormalEEGwasassociatedwitharelativeriskof1.45
(95%CI,1.18to1.79).
QualityStandardsSubcommitteeoftheAmericanAcademyofNeurology1996
153
TheQualityStandardsSubcommitteeoftheAmericanAcademyofNeurology(AAN)developeda
practiceparameterintendedtohelpphysiciansintheirdecisionstowithdrawAEDs.
ThispracticeparametersystematicallyreviewedtheevidenceondiscontinuationofAEDs.The
authorsreviewedtheevidencebaseupuntil1994.
53studieswereidentifiedthatinvestigatedtheriskofrecurrenceofseizuresfollowing
discontinuationofmedication.TheauthorsidentifiedoneRCT(MRCdiscontinuationstudysee
below).Theninefactorsorclinicalcharacteristicsidentifiedwere:sex,ageofonset,seizuretype,
aetiology,neurologicalexamination/I.Q.,durationofseizurefreedomonAEDs,treatmentregimen,
ageatrelapse,andnormalizationoftheEEG.Only17studiesdiscussedallninefactors.Thenegative
healthoutcomewasrelapse,andthepositivewasbecomingseizurefreewithoutmedication.
Individualsmaintainedonreduceddoseofmedicationwerenotincluded.
Therelapseratesreportedinthe17studiesweresummarizedandweightedaccordingtothe
numberofcasesinthatstudy.Ananalysisofthestudiesyieldedaweightedmean(bynumberof
cases)relapserateof31.2%forchildrenand39.4%foradults.Fromthestudies,certainclinical
characteristicsemergedthatmaypredictsuccessfulremission.Thelongerthedurationofseizure
controlwithAEDs,thebettertheprognosis.Theevidencepresentedinthe17studiessuggestedthat
althoughtheirrecurrenceriskratesdiffer,bothchildrenandadultsmeetingthefollowingprofile
havethegreatestchanceforsuccessfuldrugwithdrawal:
seizurefree2to5yearsonAEDs(mean3.5years);
singletypeoffocalorgeneralizedseizure;
normalneurologicalexaminationandnormalI.Q.;
EEGnormalizedwithtreatment.
153
Sirven2003
154
ThisCochraneReviewsoughtto:
TheEpilepsies
144
a) quantifyseizurerelapseriskafterearly(lessthantwoseizurefreeyears)versuslate(more
thantwoseizurefreeyears)AEDwithdrawalinadultsandchildren;
b) assesswhichvariablesmodifytheriskofseizurerecurrence.
TheauthorssearchedtheCochraneEpilepsyGrouptrialsregister,theCochraneCentralRegisterof
ControlledTrials(TheCochraneLibraryissue1,2003),MEDLINE(January1996toMarch2003),
EMBASE,IndexMedicus,CINAHLandhandsearchedrelevantjournals.
RandomisedcontrolledtrialsthatevaluatedwithdrawalofAEDsaftervaryingperiodsofseizure
remissioninadultandchildrenwithepilepsywereincluded.Thesestudiescomparedanearlyversus
lateAEDdiscontinuation.
**TheMRCdiscontinuationstudywasnotincludedinthisreviewasentryintothisstudyrequired
thatallindividualshadbeenseizurefreeforatleasttwoyears.
Tworeviewersindependentlyextracteddataandassessedtrialquality.Relativerisks(RR)with95%
confidenceintervals(CIs)werecalculatedforeachtrial.SummaryRRsand95%CIsfordichotomous
datawerecalculatedusingarandomeffectsmodel.Atestofstatisticalheterogeneitywas
conductedforeachpooledrelativeriskcalculation.
Seveneligiblecontrolledtrialswereincludedintheanalysisrepresenting924randomisedchildren.
Therewerenoeligibletrialsevaluatingseizurefreeadults.Thepooledrelativeriskforseizure
relapseinearlyversuslateAEDwithdrawalwas1.32(95%CI1.02to1.70).Onthebasisofthis
estimate,thenumberneededtoharm,thatisexposeanindividualtoahigherriskofseizurerelapse
becauseofearlywithdrawalofAED,is10.Earlydiscontinuationwasassociatedwithgreaterrelapse
ratesinpeoplewithfocalseizures(pooledRRis1.52;95%CI0.95to2.41)oranabnormalEEG
(pooledRR1.67;95%CI0.93to3.00)althoughthisdifferencedidnotreachstatisticalsignificance.
Theauthorsconcludedthattherewasevidencetosupportwaitingforatleasttwoormoreseizure
freeyearsbeforediscontinuingAEDsinchildren,particularlyifindividualshaveanabnormalEEGand
focalseizures.TherewasinsufficientevidencetoestablishwhentowithdrawAEDsinchildrenwith
generalizedseizures.TherewasnoevidencetoguidethetimingofwithdrawalofAEDsinseizure
freeadults(beforetwoyears).
Theauthorscalledforfurtherblindedrandomisedcontrolledtrialstoidentifytheoptimaltimingof
AEDwithdrawalandriskfactorspredictiveofrelapse.
154
Primaryevidence(adults)
MRCAEDwithdrawalstudygroup1991
155
ThiswasapragmaticmulticentreRCT(UK/Europe)tocompareseizurecontrolunderpoliciesofslow
withdrawalversusroutinemaintenanceofdrugtherapy.Theaimwastoidentifyimportant
prognosticfactorsinseizurerecurrence.
Individualswereeligibletotakepartinthestudyiftheyhadahistoryoftwoormoreseizures,had
beenfreeofseizuresforatleasttwoyearsandweretakingAEDs.Individualsrandomisedtothe
interventionarm(slowwithdrawal)hadtherapywithdrawnaccordingtoguidelinessuggestedbythe
trialsteeringcommittee.Theaimwastoextendwithdrawaltoaminimumofsixmonths,with
treatmentbeingreducedat4weekintervals(reductionregimenperAEDstatedinpaper).
Participantsinthecontrolarmweremaintainedonexistingdosesunlesstherewereclinical
indicationsthatnecessitatedachange.IndividualswereonthefollowingAEDs:carbamazepine,
valproate,phenytoin,phenobarbital,primidoneandethosuximide.
Followupwasat3,6and12months,andthenyearly.
TheEpilepsies
145
Atotalof1797individualswereeligibleforinclusioninthetrial,ofwhich1021(57%)agreedto
randomisation.Eightrandomisedindividualswerewithdrawn,leavingastudypopulationof1013.
Thestudypopulationwereadults(forcontrolgroup:medianage26,25thcentile16years,75th
centile39years;interventionarmcharacteristicssimilar).Thegroupwhoagreedtoberandomised
wereyoungerandhadaslightlylongerdurationofepilepsyandAEDtreatment.Individualswitha
historyofattemptedAEDwithdrawal(OddsRatioOR0.6,95%CI0.1to0.8)andthosewithadriving
licence(OR0.13,95%CI0.1to0.18)werelesslikelytoagreetoberandomised.
By2yearsafterrandomisation,78%ofthoseinwhomtreatmentwascontinuedand59%inwhomit
waswithdrawnremainedseizurefree,butthereafterthedifferencesbetweenthetwogroups
diminished.Noncompliancewithcontinuedtreatmentaccountedforonlyasmallproportionofthe
risktothegroupcontinuingwithtreatment.
Themostimportantfactorsdeterminingoutcomewerelongerseizurefreeperiods(reducingthe
risk)andmorethanoneantiepilepticdrugandahistoryoftonicclonicseizures(increasingtherisk).
Table1029:Influenceofindividualcharacteristicsonseizurerecurrence
155
Factor Relativerisk(95%CI)
(multivariatemodel)
Historyoffocalseizures,nonegeneralized 2.51(1.00,6.30)
Historyofmyoclonicseizures 1.85(1.09,3.12)
Historyoftonicclonicseizures
(primaryorsecondary)
3.40(1.48,7.84)
Seizuresafterstartoftreatment 1.57(1.10,2.24)
OnmorethanoneAEDatrandomisation 1.79(1.34,2.39)
Periodseizurefreeatrandomisation(years)
3<5 0.67(0.48,0.93)
5<10 0.47(0.32,0.69)
10 0.27(0.15,0.48)
AsfarasEEGstatuswasconcerned,thesamplewasinsufficienttoreachspecificconclusionsabout
theimportanceofanyabnormalityintheentryEEG.
MRCAEDwithdrawalstudygroup1993
156
Theaimofthisstudywastodevelopandtestaprognosticindexfortherecurrenceofseizuresaftera
minimumremissionofseizuresoftwoyearsinpeoplewithahistoryofepilepsy.Thisstudyused
datafromtheRCTreportedabove
155
toidentifyclinicalandtreatmentfactorsofprognostic
importanceindeterminingtherecurrenceofseizures.Asplitsampleapproachwasusedtotestthe
internalvalidityofpredictionsmadeonthebasisofidentifiedprognosticfactors.
TheCoxproportionalhazardsmodelidentifiedseveralfactorsthatincreasedtheriskofseizures
recurring.Theseincludedbeing16yearsorolder;takingmorethanoneantiepilepticdrug;
experiencingseizuresafterstartingantiepilepticdrugtreatment;ahistoryofprimaryorsecondarily
generalisedtonicclonicseizures;ahistoryofmyoclonicseizures;andhavinganabnormal
electroencephalogram.Therisksofseizuresrecurringdecreasedwithincreasingtimewithout
seizures.Themodelallowedestimationoftheriskofseizuresrecurringinthenextoneandtwo
TheEpilepsies
146
yearsunderthepoliciesofcontinuedAEDtreatmentandslowwithdrawalofdrugs.Splitsample
validationsuggestedthatthemodelwaswellcalibrated.
156
Validationwasperformedonasampleofthetrialparticipants.Animportantissuehereisthat
studiesneedtobeconductedtovalidatethesefindingsinabroaderpopulation.
Table10.30presentstheauthorsprognosticindexmodel.ThiswasusedintheSIGNadultguideline
toproduceatableofriskofseizurerecurrencethatcouldeasilybeusedbyclinicians.
157
Table1030:Prognosticindexforrecurrenceofseizureswithinoneandtwoyearsaftercontinuing
AEDtreatmentorstartingslowwithdrawal
AdaptedfromMRCAEDDrugWithdrawalGroup1993
156
andreprintedwithpermissionfromthe
BMJPublishingGroup(BMJ,1993,306,13748)
Startingscore(allindividuals) 175
Age16orolder Add45
TakingmorethanoneAED Add50
SeizuresafterstartofAEDtreatment Add35
Historyofprimaryorsecondarilygeneralizedtonicclonicseizures Add35
Historyofmyoclonicseizures Add50
EEGinlastyear
notavailable Add15
Abnormal Add20
Periodfreefromseizures(t:no.ofyears) Add200/t
TOTALSCORE T
Dividetotalscoreby100andexponentiate z=e
T/100
Probabilityofrecurrenceofseizures:
Continuedtreatment
byoneyear 10.89
z
bytwoyears 10.79
z
Slowwithdrawal
byoneyear 10.69
z
bytwoyears 10.60
z
10.2.6.2 InadultsandchildrenwithepilepsyonAEDs,dodifferentratesofwithdrawalleadtodifferingrisks
ofseizurerecurrenceand/orothersideeffectsofstoppingtreatment?
Secondaryevidence
Primaryevidence
Tennisonetal1994
158
TheaimofthisunblindedRCTwastocompareasixweek(relativelyshort)periodandaninemonth
(relativelylong)periodofdrugtaperinginagroupofchildrenwithepilepsywhohadhadnoseizures
foreithertwoorfouryears.
Allchildrenreceivingcareatthepaediatricepilepsyclinicsatthetwostudyinstitutionswhohadhad
noseizuresforapproximately18monthswereeligibleforthestudy.Childrenwhohadhadasingle
seizureoronlyfebrileseizureswereexcluded,aswerethosewithneonatalseizuresorinfantile
spasms.
Theauthorsrandomlyassigned149childrentoeitherasixweekoraninemonthperiodofdrug
tapering,afterwhichtherapywasdiscontinued.Eachgroupwascomposedofchildrenwhohad
beenseizurefreeforeithertwoorfouryearsbeforedrugtaperingwasbegun.Mostchildrenwere
TheEpilepsies
147
receivingoneantiepilepticdrug;noneweretakingmorethantwo.Thechildrenwereevaluated
periodicallyduringandafterthetaperperiod.Sixteenindividualswerelosttofollowupbeforethe
beginningofthetaperperiod.Proportionalhazardsregressionanalysiswasusedtoassesstheriskof
seizurerecurrenceamongtheremaining133.
Seizuresrecurredin53children(40%).Themeandurationoffollowupwas39months(range,11to
105)forthosewhodidnothavearecurrenceofseizures.Neitherthelengthofthetaperperiod(six
weeksvs.ninemonths,p=0.38)northelengthoftimechildrenwerefreeofseizuresbeforethetaper
periodwasbegun(twoyearsvs.fouryears,p=0.20)significantlyinfluencedtheriskofseizure
recurrence.
Thepresenceofmentalretardation(relativerisk,3.1;95%CI1.5to6.2)orspikesinthe
electroencephalogramatthetimeoftapering(relativerisk,1.9;95%CI1.0to3.4)increasedtherisk
ofseizurerecurrence.
158
10.2.7 Inadults/childrenwithepilepsyonAEDsdoesmanagementofdrugwithdrawalbya
generalistasopposedtoaspecialistleadtodifferentoutcomes?
79. WithdrawalofAEDsmustbemanagedby,orbeundertheguidanceof,thespecialist.[2004]
Evidencestatement
Noevidencewasidentified.
Secondaryevidence
Primaryevidence
NoRCTswereidentified.
Otherevidence
Therewasnospecificevidencereviewedonthediscontinuationoftherapybyeitherspecialistor
generalist.
TheEpilepsies
148
10.2.8 Newrecommendationsandlinktoevidence
Recommendation
80. Whenpossible,choosewhichAEDtoofferonthebasisofthe
presentingepilepsysyndrome.Iftheepilepsysyndromeisnot
clearatpresentation,basethedecisiononthepresenting
seizuretype(s).[new2012]
Relativevaluesofdifferent
outcomes
Goodpracticesuggestsoptimalmanagementinvolvesappropriate
AEDforsyndromediagnosis.
Tradeoffbetweenclinical
benefitsandharms
Severalsyndromesmaypresentwithmultipleseizuretypes,and
thereforeindividualsareatriskofseizureexacerbationwith
certainAEDsifthisisnottakenintoconsideration.Atdiagnosisitis
recognisedthatepilepsysyndromemaybeunclear;choicemay
thenneedtobemadeonthebasisofseizuretype,takinginto
considerationmostlikelyepilepsysyndromeaccordingtoage.
Economicconsiderations Incorrectmanagementofcertainepilepsysyndromesleadsto
suboptimalseizurecontrolandpossiblecognitiveimpact,whichin
turnresultingreatermorbidityinthelongtermandgreater
burdenonNHShealthservices.TheGDGrecognisedthatitis
essentialtoinitiatetreatmentinordertogainseizurecontroland
thatintheabsenceofaclearsyndromicdiagnosis,itisreasonable
toprescribecosteffectiveAEDsonthebasisofpresentingseizure
type(s).
Qualityofevidence ThisrecommendationwasbasedonGDGconsensus.
Otherconsiderations Nootherconsiderations
TheEpilepsies
149
Recommendation
81. Consistentsupplytothechild,youngpersonoradultwith
epilepsyofaparticularmanufacturersAEDpreparationis
recommended,unlesstheprescriber,inconsultationwiththe
child,youngpersonoradult,considersthatthisisnota
concern.Inthecaseofachildoryoungpersonthisdiscussion
mayinvolvetheparentorcareraswell.Differentpreparations
ofsomeAEDsmayvaryinbioavailabilityorpharmacokinetic
profilesandcareneedstobetakentoavoidreducedeffector
excessivesideeffects.Consultthesummaryofproduct
characteristics(SPC)andBritishnationalformulary(BNF;
availableathttp://bnf.org.uk)onthebioavailabilityand
pharmacokineticprofilesofindividualAEDs,butnotethat
thesedonotgiveinformationoncomparingbioavailabilityof
differentgenericpreparations.[new2012]
outcomes
The2004recommendationinthisareastated:
ChangingtheformulationorbrandofAEDisnotrecommended
becausedifferentpreparationsmayvaryinbioavailabilityorhave
differentpharmacokineticprofilesand,thus,increasedpotential
forreducedeffectorexcessivesideeffects
Stakeholderresponsestoconsultationonthisupdateindicated
thatthe2004recommendationinthisareawasthefocusofmuch
debateinpracticeasitwasneverthesubjectofformalevidence
reviewandlabelledasagoodpracticepointin2004.
Althoughstillnotsubjecttoformalevidencereviewinthisupdate,
goodclinicalpracticesuggeststhatbioavailabilityshouldremain
constantwherepossible.Thisisconsistentlyendorsedbypatient
groupsasitisaveryrealissuethatcausesbothpatientsand
epilepsycharitiesconcern.
benefitsandharms
AbruptchangesinAEDlevelswithinthebloodcanleadtolossof
previouslygainedseizurecontrol,orinextremecircumstances
statusepilepticus.Maintenanceofconstantlevelswherepossible
minimisestherisktotheindividual.
TheclinicianandpatientrepresentativesoftheGDGfeltthatan
efficientandcosteffectiveuseofhealthcareresourcesmeant
morethanprescribingthecheapestversionofadrug.Asingle
seizure,inadditiontobeingpotentiallylifethreatening,has
enormouseffectsonanindividualintermsofapotentialimpacton
dailylifethroughlossofdrivinglicenceoremploymentorboth.
Managementoffurtherseizuresresultsinincreasedhealthcare
costs,withmoreappointments,investigationsandadmissions.
Recommendations1,182,184,191and283describetheprinciplesofdecisionmakingandbestpracticeinrelationto
effectiveandappropriateconsultationbetweenhealthcareprofessionalsandchildren,youngpeopleandadultswith
epilepsy.
InNovember2013,theMHRAissuednewadviceaboutoralantiepilepticdrugs(AEDs)andswitchingbetween
differentmanufacturersproductsofaparticulardrug.Followingareviewoftheavailableevidence,theCommissionon
HumanMedicines(CHM)hasclassifiedAEDsinto3categoriesdependingonthelevelofpotentialconcernsrelatedto
switchingbetweendifferentmanufacturersproducts.ConsulttheMHRAadviceformoreinformation.
TheEpilepsies
150
TheGDGmemberswereallawareofexamplesofpeoplechanging
brandswithsubsequentrelapseintheirseizures.Theyalso
recognisedthatstressassociatedwithchange(notjustin
medication)canmakepeoplevulnerabletoseizures.
Economicconsiderations Itisrecognisedthatabruptchangesinbioavailabilitycanleadto
seriousconsequencesaffectingNHSresourceuseforexample
hospitaladmissionforincreasedseizures,increasedaccesstoother
NHSservicesandconsequentimpactonaspectsofqualityoflife.It
wasalsonotedthatgenericsubstitutiondoesnotnecessarily
translatetocostsavingsgiventhatsomegenericallyproduced
drugshavehigherunitcoststhantheirbrandnameequivalent.
TheDepartmentofHealthconsultationexerciseongeneric
prescribingin2009consideredtheseissuesandinconsequence,
didnotproceedwithpharmacyledgenericsubstitutions.
TheGDGalsonotedthatthisremainsacontentiousissueacrossa
numberofclinicalspecialtiesandareawareofcontinued
discussionsbetweenclinicalexpertsandtheMedicinesand
HealthcareRegulatoryAgency(MHRA)inattemptstoresolvethis
issuefromaclinicalandcosteffectivenessperspective.
Qualityofevidence Theoriginal2004recommendationwasdevelopedbyGDG
consensus.AfterrepresentationbyusergroupstoDoHin2009,
therewasacceptancethatepilepsywasdifferenttoother
conditionsandthattherewasmuchlessmarginforerror,inview
ofthepossibleseriousconsequencesthatmayresultfroma
changeinbioavailability.
Withinthefield,itisarguedthatnotallAEDshaveanarrow
therapeuticindexand/orlowsolubility.Thereisawidespectrum
ofAEDswithdifferentpharmacokineticprofiles,therapeutic
indexesandphysiochemicalpropertieswhichmighthavean
impactonbioavailabilitywhichdoesnotnecessarilysupporta
blanketrecommendationagainstchangingformulationorbrandof
AED.Nevertheless,theGDGconsensuswasthatthisdetailed
knowledgeforaparticularAEDshouldalwaysimpacton
prescribingdecisionsbeforeswitchingtheformulationorbrandof
AED.
CommunicationwiththeMHRAindicatesthatthereisnot
currentlyafullreviewofdataonmanyAEDstoenableavalid
evidencebasedpositionacrosstheboardinthisarea.
TheGDGareawarethatsomepublicationsinthisareahave
indicatedthatthereareconcernsthatthebioequivalencestudies
undertakenaspartofthelicensingprocessforgenericantiepileptic
drugsmaynotbelargeenoughorintherightpopulationtoshow
thefullrangeofpossiblebioavailabilities,andthatthe
bioavailabilitylimitsallowedbyregulatoryauthoritiesaretoowide
forapplicationinepilepsy.Regulatoryauthoritiesdonotrequire
thebioavailabilityofnewgenericpreparationstobecompared
TheEpilepsies
151
withexistinggenericpreparations.Intheory,therefore,there
couldbeagreatervariabilitybetweenthebioavailabilityof
differentgenericpreparationsthanbetweenabrandandageneric.
TheGDGareawareoffurtherevidenceinthisareabutrecognise
thattheyhavebeenunabletoreviewitformallywithinthescope
ofthisupdatereviewandarethereforeunabletomakeamore
definitiverecommendation.
Otherconsiderations TheGDGfeltstronglythatintheabsenceofaformalevidence
reviewitshouldremainthecasethatthebestpracticeisto
maintainconsistencyofsupplyofanAED
preparation/manufacturerandtheprescriberneedstoconsider
carefullyinpartnershipwiththeindividual(andfamiliesorcarers
asappropriate)whetheritissafeoracceptableforanindividual
patienttoswitchbetweenbrandsandthereforechangedthefocus
oftheoriginal2004recommendationtothisend.
Inrevisingthisrecommendationinthisway,theGDGfeltthe
followingissueswereimportanttonotehere.
FeedbackfromtheGDGpharmacistrepresentativeendorsedthe
positionthatthereareriskstoswitchingmodifiedrelease
preparationswithnormalreleasepreparationsandinswitching
fromonemodifiedreleasepreparationtoanothermodified
releasepreparationasreleasingprofilesarenotnecessarilythe
same.
Historically,therehasbeenatendencytoavoidswitching
phenytoin,assometimeago,acompanychangedtheexcipient
causinganoutbreakofoverdoseandmanypatientsendedupin
hospitalduetotoxicity.However,theGDGrecognisethemodern
licensingsystemissufficienttopreventthisproblemfrom
occurring
Itwasalsonotedthatmostnormalreleasepreparationscanbe
switchedtoanothernormalreleasepreparationsbecause
bioavailabilitystudieshavebeenconductedpriortothelicensing.
TheGDGfeltitwasimportanttoadviseprescriberstorefertothe
SPCandBNF,butwishedtomakeitclearthatthesesourcesdonot
givecomprehensiveadviceonthesafetyorotherwiseofswitching
betweenbrandsofAEDs.
Itwasalsofeltimportanttoprovidetailoredinformationto
mitigateagainstanyconcernthatlesswellinformedpatientsmay
beencouragedtochangetogenericsinappropriately.Thespecific
needsofchildren,individualswithlearningdisabilities,aswellas
elderlypeoplewhotakemanymedications,shouldbeconsidered
indiscussionsbetweenprescribinghealthcareprofessionalsand
children,youngpeopleandadultswithepilepsy.TheGDGalsofelt
itimportantforprescribinghealthcareprofessionalstoalways
considertheprinciplesofengagingindividualsinmakingdecisions
abouttheircareandthereforefeltitappropriatetohighlight
recommendationsmadeearlierinthisguidelinethatendorsethis
TheEpilepsies
152
positioninafootnotetothisrecommendation.
TheGDGnotedthatchangesinmetabolicfunctionsinolderpeople
arealsoperhapsmoresensitivetosideeffectswhichmayhaveless
noticeableimpactinyoungerpeople,especiallythosewhichaffect
balancewithconsequentproblems.Breakthroughseizuresmay
alsobelessobvioustoanobserverinthisgroup.
TheGDGfeltthatorganisationalstructuresrelatedtomedicines
management,suchasmedicinesmanagementcommittees,should
alsocarefullyconsidertheseissueswhenmakinglocaldecisions.
TheEpilepsies
153
Recommendation
82. Ifusingcarbamazepine,offercontrolledrelease
carbamazepinepreparations.[new2012]
outcomes
TheGDGfeltthatreductionofadverseeffectsandefficacyat
reducingseizureswereimportantoutcomesforthis
recommendation.
benefitsandharms
Carbamazepinecontrolledreleaseformulationhassimilarefficacy
tocarbamazepine,andhasabetteradverseeffectsprofile,with
avoidanceofhighpeakconcentrations.
ACochranereview(Powell2010)lookedatimmediaterelease
versuscontrolledreleasecarbamazepineandfound10randomised
controlledtrials.Therewereconflictingresultsastowhether
controlledreleaseorimmediatereleasecarbamazepinehadan
advantageforreductioninseizurefrequency.However,sixoutof
nineofthetrialsfoundatrendtowardsalessfavourableside
effectsprofileforimmediatereleasecarbamazepinecomparedto
controlledrelease,fourofthesewerestatisticallysignificant.The
GDGsopinionwasthatcontrolledreleaseispreferableto
immediatereleaseasitavoidshighpeakconcentrations.
Economicconsiderations Originaleconomicmodellingundertakenfortheguidelineshowed
thatcontrolledreleasecarbamazepinewasmorecosteffective
thanimmediatereleasecarbamazepine.Inthedecisionmodel,
theywereassumedtobeequallyefficaciousandcontrolledrelease
carbamazepinewasshowntohaveaslightlylowerriskof
withdrawalduetoadverseevents.Basedonthisassumption,
hypotheticalpatientstakingcontrolledreleasecarbamazepine
consistentlyexperiencedmoreQALYsthanthosetaking
immediaterelease.Therankofthedifferentpreparationsinterms
ofcostissensitivetotheunitcostsused.Theweightedaverage
unitcostpermilligramforimmediatereleasecarbamazepineis
higherthantheweightedaverageunitcostpermilligramfor
controlledreleasecarbamazepine.Thisislargelydrivenbythe
priceofnonproprietarynormalreleasecarbamazepinewhichis
morecostlythanbrandnameTegretol.NormalreleaseTegretolis
lesscostlythannonproprietarycontrolledreleasecarbamazepine.
InasensitivityanalysiswherethecostofTegretolwasused,
controlledreleasecarbamazepinewasstillverylikelytorepresent
goodvalueformoney.CostinglistedintheBNFandNHSDrug
Tariffindicatethatcontrolledreleasenonproprietary
carbamazepineandcontrolledreleaseTegretolandcontrolled
releaseCarbagen(anotherbrandnamecarbamazepineproduct)
areverysimilarincost.
Intermsofthedifferentformulationseffectoncomplianceand
sideeffects,thebenefitsofthecontrolledreleasepreparationare
likelytobeworthadifferenceincost.Itappearstobebetter
toleratedandmaythereforeimproveadherence.
Qualityofevidence Therecommendationwasbasedupontheconsensusopinionof
TheEpilepsies
154
theGDG.TheGDGconsultedevidencefromaCochrane
systematicreview.TheCochranereviewincludedrandomised
controlledtrialswithlimitations.Theyweresmalltrialsandonly
oneofthestudiesreportedrandomisation.Noneofthestudies
haddetailsofallocationconcealment.
Otherconsiderations Nootherconsiderations.
Recommendation
83. Whenprescribingsodiumvalproatetowomenandgirlsof
presentandfuturechildbearingpotential,discussthepossible
riskofmalformationandneurodevelopmentalimpairmentsin
anunbornchild,particularlywithhighdosesofthisAEDor
whenusingaspartofpolytherapy.[new2012]
outcomes
TheGDGplacedmostimportanceontheincidenceofmajor
malformations,miscarriagesandneurodevelopmentaloutcomes
forthechildofamotherwithepilepsy.
benefitsandharms
Theriskofharmtothemotherandunbornchildfromseizures
needstobebalancedagainsttheriskofharmfromantiepileptic
medicationtakenbythemotherinpregnancy.
Economicconsiderations NoeconomicevidencewasavailabletoinformtheGDGoncost
effectivenessofAEDsusedtotreatpregnantwomenwithepilepsy.
Noeconomicevaluationhaseverincorporatedteratogenicityof
anydrug,includingsodiumvalproate,intoitsclinicaloutcomes.
TheGDGconsideredthatbothreducedseizurecontroland
potentialharms(malformationsandneurodevelopmentaldelay)
havecostandqualityoflifeimplicationsformotherandunborn
child.Drugsanddosesthatmaybecosteffectiveinthegeneral
epilepsypopulation,suchassodiumvalproate,maynotbeascost
effectiveinthisgroupduetoitspotentialteratogeniceffect.
Qualityofevidence
Evidencecomesfromthreesystematicreviews;onereview
focusedonincidenceofmalformationandtheothertwoonchild
neurodevelopmentaloutcomes.NoindividualRCTswerereviewed.
Oneobservationalcohortstudy
159
thatwaspublishedafterthe
guidelineupdatesearchcutoffwasalsoidentified.Thisstudydid
notmeettheinclusioncriteriafortheevidencereview,butwas
consideredbytheGDGascorroborativeevidencetoinformthis
recommendationparticularlythedosedependentriskwithsodium
valproate.
ThisrecommendationwasalsobasedonGDGconsensusopinion.
Otherconsiderations Thisrecommendationwasupdatedfromthefirsteditionofthis
guideline(2004).
TheEpilepsies
155
Recommendation
84. Maintainahighlevelofvigilancefortreatmentemergent
adverseeffects(forexample,bonehealthissuesand
neuropsychiatricissues)
*******
[new2012]
outcomes
TheGDGfeltthattheappearanceofsevereadverseeffectsshould
becloselymonitored.
benefitsandharms
Theevidenceavailablereportedshorttermoutcomes.We
specificallylookedatadverseeffectswhichwerein10%ormoreof
thetreatmentarmssoitwasunlikelytohighlightseverelongterm
adverseevents.ItwastheGDGconsensusthattherecanbea
higherriskofbonehealthissuessuchasosteopeniaand
osteoporosisinpatientstakingcertaindrugssuchas
carbamazepine,phenobarbitone,phenytoin,primidoneand
sodiumvalproateduetoadecreaseinbonemineraldensity
associatedwiththeseAEDs.
Thereisasmallriskassociatedwithcarbamazepine,divalproex
sodium,felbamate,gabapentin,lamotrigine,levetiracetam,
oxcarbazepine,pregabalin,tiagabine,topiramate,vigabatrinand
zonisamideforsuicidalthoughtsandbehaviour.
Economicconsiderations Therewasnoeconomicevidencespecificallyaddressingtheimpact
ofadverseeventsonthecosteffectivenessofdrugsusedinthe
treatmentofindividualswithepilepsy.However,seriousadverse
events(shortandlongterm)canaffectanindividualsqualityof
lifeandleadtoincreasedcoststotheNHS.Heightenedawareness
ofthesepotentialadverseeventsshouldensurethatapatients
treatmentisalteredoradjustedtoreducedecrementstoutility
andminimisethecostofextrahealthcarevisitswhilstmaintaining
seizurecontrol.
*******
TreatmentwithAEDsisassociatedwithasmallriskofsuicidalthoughtsandbehaviour;availabledatasuggestthat
theincreasedriskappliestoallAEDsandmaybeseenasearlyas1weekafterstartingtreatment.Availablefrom
www.mhra.gov.uk/PrintPreview/DefaultSplashPP/CON019574?DynamicListQuery=&DynamicListSortBy=xCreationDate
&DynamicListSortOrder=Desc&DynamicListTitle=&PageNumber=1&Title=Antiepileptics%20&ResultCount=10
TheEpilepsies
156
10.3 MonotherapyfornewlydiagnosedFocalSeizures
10.3.1 Introduction
Focalseizuresarethemostcommonlyencounteredseizuretypeinadultandpaediatricpractice.
Focalseizuresarebydefinitionthosethatoriginateinoneareaofthebrain.Themostrecent
proposaloftheclassificationoftheepilepsiesbytheILAEhasdefinedfocalseizuresasthosethat
originatewithinnetworkslimitedtoonehemisphere,andwhereforeachseizuretypeictalonsetis
consistentbutpreferentialpropagationpatternsthatcaninvolvethecontralateralhemisphere.
(Bergetal2010)
12
.Theseizuresarethendescribedaccordingtoseverity(e.g.withorwithout
impairmentofconsciousness,orwhethertheyproceedtoabilateralconvulsiveseizure)andpossible
siteoforigin.
Whenindividualsfirstpresent,aimsoftreatmentshouldbeseizurefreedomwithonemedication.
Thetermmonotherapyherereferstotheuseofoneinitialdrugwithnoprevioustrialofsuch.
10.3.2 Methodsoftheevidencereview
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereview.Forthisreviewwe
includedadultsandchildrenwithfocalseizures.Forstudiesinwhichbothfocalandprimary
generalizedseizureswerecombined,a20%thresholdwasusedasathresholdforcontamination
fortheoutcomeofseizurefreedomanda50%thresholdfortheoutcomesofadverseevents.
Onehighqualityindividualpatientdatanetworkmetaanalysis
38
wasidentifiedduringstakeholder
consultation.TheGDGagreedthatthiswasahighqualitystudythatshouldbeincorporatedintothe
evidencereview.Theindividualpatientdatafor6418patientsfrom20randomisedcontrolledtrials
wasincorporatedintotheevidencereviewformonotherapyinnewlydiagnosedfocalseizuresto
complementthefindingsofthepairwisemetaanalysesandassisttheGDGintermsoftheir
decisionmakingandrecommendationdevelopment.
10.3.3 Matrixoftheevidenceforadults
WesearchedforRCTscomparingtheeffectivenessofdifferentmonotherapypharmacological
interventionsforepilepsyinapopulationwithfocalseizures.Theinterventionsweincludedinour
searchwereeslicarbazepineacetate,pregabalin,zonisamide,lacosamide,lamotrigine,gabapentin,
oxcarbazepine,tiagabine,levetiracetam,topiramate,vigabatrin,phenytoin,phenobarbital,
felbamate,clobazam,clonazepam,acetazolamide,primidone,sodiumvalproate,sulthiameand
carbamazepine.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreof
thesetreatments(orplacebo).Belowisamatrixshowingwereevidencewasidentified.Abox
containingafigureindicatesthenumberofstudiesthatwerefoundandthattheevidenceforthis
comparisonhasbeenreviewedinthischapter.Anemptyboxindicatesthatnoevidencewasfound.
Inthiscase,nosectiononthiscomparisonisincludedinthechapter.Itshouldbenotedthatsomeof
thestudiesfromthedirectmetaanalysisarethesameasthoseintheIPDnetworkmetaanalysis.
TheEpilepsies
Placebo
Carbamazepine
CarbamazepineCR
Clonazepam 1
160
;
Gabapentin 2
161,162,
1
IPD
NMA
38

Lamotrigine 6
161,163,164,
165,166,166,
1IPD
NMA
38;
1
161,
1IPD
NMA
38
Levetiracetam 1
167

Oxcarbazepine 1
161,
1
IPDNMA
38
1
161,
1IPD
NMA
38
1
161,
1IPD
NMA
38

Phenytoin 4
168,169,170,
171,
1IPD
NMA
38
1IPDNMA
38
1
172,
1IPD
NMA
38
1
173,
1
IPDNMA
38
Sodiumvalproate 2
171,174
,1
IPDNMA
38

1IPDNMA
38
1
175,
1
IPDNMA
38
3
171,176,177,
1IPD
NMA
38
Topiramate 1
161,
1
IPDNMA
38
1
161,
1IPD
NMA
38
1
161,
1IPD
NMA
38
1
161,
1
IPDNMA
38
1IPD
NMA
38
1IPD
NMA
38
Vigabatrin 3
178,179,180,

TheEpilepsies
1IPD
NMA
38
Tiagabine
Phenobarbital 1
170,
1
IPDNMA
38
1IPDNMA
38
1IPD
NMA
38
1
170,
1
IPDNMA
38
1IPD
NMA
38
1IPD
NMA
38

Primidone 1
170
1
170
1
170

Pla
CBZ
CBZCR CLZ
GBP
LTG
LEV
OXC
PHT
VPA
TPM
VGB
TGB PHB PMD
TheEpilepsies
159
PLAPlaceboCBZCarbamazepineCBZCRControlledreleaseCarbamazepineCLZClonazepam
GBPGabapentinLTGLamotrigineLEVLevetiracetamOXCOxcarbazepine
PHTPhenytoinVPASodiumvalproateTPMTopiramateVGBVigabatrin
IPDNMA:individualpatientnetworkmetaanalysis
10.3.4 Monotherapyforadultswithnewlydiagnosedfocalseizures
10.3.4.1 Carbamazepineversuslamotrigine
Clinicalevidence
FordetailsontheclinicalevidencepleaserefertoAppendixN.
IPDmetaanalysis
CarbamazepineandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
analysisofAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.Theresultsof
thisanalysisarepresentedinsection10.3.5.
Healtheconomicevidence
Twoeconomicevaluations
161,181
ofAEDs,includingcarbamazepineandlamotrigine,usedas
monotherapyinthetreatmentofadultswithnewlydiagnosedfocalseizureswereidentifiedinthe
economicliteraturesearch.Astherewerestillgapsintheeconomicevidencebase,wedevelopedan
originaleconomicmodeltocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocal
seizures.TheresultsofthesestudiesandtheNCGCadultmonotherapymodelarepresentedin
section10.3.6.
Evidencestatements
Efficacystatisticallysignificantresults
Carbamazepinemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingtimetofirstseizure,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.
(LOWQUALITY)
Carbamazepinemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingtimetofirstseizure.(IPDmetaanalysis)
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingcarbamazepine
monotherapycomparedtoparticipantstakinglamotriginemonotherapy.(IPDmetaanalysis)
Efficacystatisticallynonsignificantresults
Nosignificantdifferencebetweencarbamazepinemonotherapyandlamotriginemonotherapyfor
seizurefreedom.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotriginemonotherapyandcarbamazepinemonotherapyfor
theproportionofparticipantswhowithdrewduetolackofefficacy.(VERYLOWQUALITY)
thetimetoexit/withdrawalofallocatedtreatmentduetolackofefficacy.(VERYLOWQUALITY)
TheEpilepsies
160
thetimeto12monthremission.(VERYLOWQUALITY)
thetimeto12monthremission.(IPDmetaanalysis)
Adverseeventsstatisticallysignificantresults
Significantlymoreparticipantstakingcarbamazepinemonotherapywithdrewduetoadverseevents
comparedtoparticipantstakinglamotriginemonotherapy.(MODERATEQUALITY)
Timetoexit/withdrawalofallocatedtreatmentduetoadverseeventsoccurredsignificantlymore
rapidlyinparticipantstakingcarbamazepinemonotherapycomparedtoparticipantstaking
lamotriginemonotherapy.(VERYLOWQUALITY)
Significantlymoreparticipantstakingcarbamazepinemonotherapycomparedtoparticipantstaking
lamotriginemonotherapyhadincidenceof:
fatigue(LOWQUALITY)
tiredness/drowsiness/fatigue/lethargy,althoughthereisuncertaintyoverthemagnitudeofits
clinicaleffect(LOWQUALITY)
allergicrash(MODERATEQUALITY)
QualityofLifeoutcomesstatisticallynonsignificantresults
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandcarbamazepine
monotherapyin:
twoyearanxietyscores(VERYLOWQUALITY)
twoyeardepressionscores(VERYLOWQUALITY)
twoyearAEPscores(VERYLOWQUALITY)
twoyearEQ5Dscores(VERYLOWQUALITY)
twoyearGQoLscores(VERYLOWQUALITY)
Cognitiveoutcomesstatisticallysignificantresults
Therewasasignificantimprovementinphonemicfluency(COWAT)at16and48weeksfor
lamotriginemonotherapyrelativetocarbamazepinemonotherapy.
TherewasasignificantimprovementinStroopColorWordInterferencetestat48weeksfor
lamotriginemonotherapyrelativetocarbamazepinemonotherapy.
Therewasasignificantimprovementintheobsessivecompulsivescoresat48weeksontheSCL90
forcarbamazepinemonotherapyrelativetolamotriginemonotherapy.
Cognitiveoutcomesstatisticallynonsignificantresults
Nosignificantdifferencewasfoundonthemeanscoresofneurotoxicityscalescoresbetween
lamotriginemonotherapyandcarbamazepinemonotherapy.
NosignificantdifferencewasfoundinotherCOWATtestsbetweenlamotriginemonotherapyand
carbamazepinemonotherapy.
NosignificantdifferencewasfoundinotherSCL90testsbetweenlamotriginemonotherapyand
carbamazepinemonotherapy.
Costeffectiveness
TheEpilepsies
161
Availableeconomicevidenceindicatesthatlamotrigineiscosteffectivewhencomparedto
carbamazepine.
Onetrialbasedeconomicanalysisshowedlamotriginetobeassociatedwithincreasedcostsbut
alsobetterhealthoutcomes(higherQALYsandfewerseizures)whencomparedwith
carbamazepine(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisundertakenfortheguidelinefoundcarbamazepineandlamotrigine
tobeverysimilarintermsofeffectiveness,withcarbamazepineassociatedwithhighercosts.This
conclusionwassensitivetoassumptionsabouttheacquisitioncostsoflamotrigineand
carbamazepine(directlyapplicableandminorlimitations).
ApublishedcosteffectivenessanalysisbyHawkinsandcolleaguesfoundthatcarbamazepine
dominatedlamotrigine;however,theiranalysiswasbasedonanowoutofdatesystematic
reviewand200203costs(partiallyapplicableandpotentiallyseriouslimitations).
10.3.4.2 Lamotrigineversusphenytoin
Clinicalevidence
FordetailsontheclinicalevidencepleaserefertoAppendixN.Fordetailsoneachpaperidentifiedin
theliteraturesearchpleaserefertoAppendixL.
IPDmetaanalysis
PhenytoinandlamotriginewereamongAEDsincludedinanindividualpatientdatametaanalysisof
AEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.Theresultsofthisanalysis
arepresentedinsection10.3.5.
HealthEconomicEvidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Lamotriginewasincludedinthe
originaleconomicmodeldevelopedtocompareAEDsusedasmonotherapyinadultswithnewly
diagnosedfocalseizures,butphenytoinwasnot.Phenytoinwasexcludedowingtoitsnarrow
therapeuticwindow.
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyonparticipantstakingphenytoin
monotherapycomparedtoparticipantstakinglamotriginemonotherapy.(IPDmetaanalysisindirect
evidence)
Nosignificantdifferencebetweenlamotriginemonotherapyandphenytoinmonotherapyforthe
proportionofseizurefreeparticipants.(VERYLOWQUALITY)
timetofirstseizure.(VERYLOWQUALITY)
timetofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenlamotriginemonotherapyandphenytoinmonotherapyfortimeto
12monthremission.(IPDmetaanalysis)
TheEpilepsies
162
Significantlylessparticipantstakinglamotriginemonotherapyhadanincidenceofasthenia
comparedtoparticipantsinphenytoinmonotherapy,althoughthereisuncertaintyoverthe
magnitudeofitsclinicaleffect(VERYLOWQUALITY)
Significantlylessparticipantstakinglamotriginemonotherapyhadanincidenceofsomnolence
comparedtoparticipantsinphenytoinmonotherapy(VERYLOWQUALITY)
Significantlymoreparticipantstakingphenytoinmonotherapyhadanincidenceofataxiacompared
toparticipantsinlamotriginemonotherapy(VERYLOWQUALITY)
Adverseeventsstatisticallynonsignificantresults
proportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOWQUALITY)
incidenceofthefollowingadverseevents:
rash(VERYLOWQUALITY)
headache(VERYLOWQUALITY)
dizziness(VERYLOWQUALITY)
Qualityoflifeoutcomesstatisticallysignificantresults
Significantlymoreparticipantsonlamotriginemonotherapyhadimprovementintheoverallscoreof
SEALScomparedtophenytoinmonotherapyin24weekstreatment(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytophenytoinmonotherapywas
identified.
Outcomeswithnoevidence
Therewerenostudiesthatreported:
withdrawalduetolackofefficacy
timetoexit/withdrawalofallocatedtreatment
cognitiveoutcomes
10.3.4.3 Levetiracetamversuscontrolledreleasecarbamazepine
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Asthisleftagapintheeconomic
evidencebase,anoriginaleconomicmodelwasdevelopedtocompareAEDsusedasmonotherapyin
adultswithnewlydiagnosedfocalseizures.Thiswasbasedon(seesection10.3.5)theresultsofthe
systematicreviewofclinicalevidence.ThecompleteresultsoftheNCGCadultmonotherapymodel
Evidencestatements
TheEpilepsies
163
Significantlymoreparticipantsinlevetiracetammonotherapywithdrewduetolackofefficacy
comparedtocontrolledreleasecarbamazepinemonotherapy(LOWQUALITY)
Nosignificantdifferencebetweenlevetiracetammonotherapyandcontrolledreleasecarbamazepine
monotherapyfortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
Adverseeventsstatisticallynonsignificant
monotherapyforthewithdrawalduetoadverseevents.(VERYLOWQUALITY)
monotherapyfortheincidenceof:
fatigue(VERYLOWQUALITY)
somnolence(VERYLOWQUALITY)
nausea(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamtocontrolledreleasecarbamazepinewasidentified.
However,availableeconomicevidenceindicatesthatlevetiracetam,atitscurrent2011cost,isnot
costeffectivewhencomparedtocarbamazepine(directlyapplicableandminorlimitations).
AcosteffectivenessanalysisundertakenfortheguidelinefoundthatatJune2011costs,
levetiracetamisnotcosteffectivewhencomparedtocarbamazepine.Thisconclusionwasrobust
tovarioussensitivityanalysesincludingthosethatwerefavourabletowardslevetiracetam.
o Ifcarbamazepinewasassumedtobemoretolerablethanlevetiracetam,itdominated
levetiracetam;thatis,treatmentwithcarbamazepinewasassociatedwithlowercostsand
betterhealthoutcomes(higherQALYs)thantreatmentwithlevetiracetam.
o Ifcarbamazepinewasassumedtobelesstolerablethanlevetiracetam,thenlevetiracetamwas
moreeffective,buthadanincrementalcosteffectivenessratioof332,152whichexceedsthe
NICEwillingnesstopaythresholdof20,000perQALYgained.
Onlyiflevetiracetamcanbeacquiredfor70percentlessthanitsJune2011unitcostisit
potentiallycosteffectivewhencomparedwithcarbamazepine.Notethatwhenallrelevant
comparatorswereevaluatedtogetherintheNCGCanalysis,lamotriginewaslikelytorepresent
themostcosteffectiveuseofNHSresources.
timetofirstseizure
timeto12monthremission
cognitiveoutcomes
qualityoflifeoutcomes.
TheEpilepsies
164
10.3.4.4 Carbamazepineversusgabapentin
Clinicalevidence
IPDmetaanalysis
CarbamazepineandgabapentinwereamongAEDsincludedinanindividualpatientdatameta
Oneeconomicevaluation
161
ofAEDs,includingcarbamazepineandgabapentin,usedas
monotherapyinthetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedinthe
economicliteraturesearch.Astherewerestillgapsintheeconomicevidencebase,anoriginal
economicmodelwasdevelopedtocompareAEDsusedasmonotherapyinadultswithnewly
diagnosedfocalseizures.ThecompleteresultsoftheNCGCadultmonotherapymodelarepresented
insection10.3.6.
Evidencestatements
Timetoexit/withdrawalofallocatedtreatmentduetolackofefficacyoccurredsignificantlymore
rapidlyinparticipantstakinggabapentinmonotherapycomparedtoparticipantstaking
carbamazepinemonotherapy.(MODERATEQUALITY)
Carbamazepinemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyin
prolongingtimetofirstseizure.(MODERATEQUALITY)
Carbamazepinemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyin
Timeto12monthremissionoccurredsignificantlymorerapidlyoncarbamazepinemonotherapy
comparedtogabapentinmonotherapy.(MODERATEQUALITY)
comparedtogabapentinmonotherapy.(IPDmetaanalysis)
Nosignificantdifferencebetweengabapentinmonotherapyandcarbamazepinemonotherapyfor
timetotreatmentfailure.(IPDmetaanalysis)
Significantlyfewerpatientswithdrewduetoadverseeventswithgabapentinmonotherapy
comparedtocarbamazepinemonotherapy.(MODERATEQUALITY)
Timetoexit/withdrawalofallocatedtreatmentduetoadverseeventsoccurredsignificantlyless
rapidlyonparticipantstakinggabapentinmonotherapycomparedtoparticipantstaking
carbamazepinemonotherapy.(MODERATEQUALITY)
Significantlymorepatientsoncarbamazepinemonotherapyhadincidenceofallergicrashcompared
togabapentinmonotherapy.(MODERATEQUALITY)
TheEpilepsies
165
Nosignificantdifferencebetweencarbamazepinemonotherapyandgabapentinmonotherapyfor
incidenceoftiredness/drowsiness/fatigue/lethargy(VERYLOWQUALITY)
Thereisnosignificantdifferencebetweengabapentinmonotherapyandcarbamazepine
monotherapyin:
gabapentinmonotherapyandcarbamazepinemonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatgabapentinisnotcosteffectivewhencomparedto
carbamazepine.
Onetrialbasedeconomicevaluationfoundthatcarbamazepinedominatedgabapentin;thatis,
treatmentwithcarbamazepinewasassociatedwithlowercostsandbetterhealthoutcomes
(higherQALYsandfewerseizures)thantreatmentwithgabapentin(partiallyapplicableandhad
potentiallyseriouslimitations).
Acosteffectivenessanalysisundertakenfortheguidelinealsoshowedthatcarbamazepine
dominatedgabapentin.Thisconclusionwasrobusttovarioussensitivityanalyses.Notethat
whenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,lamotriginewas
likelytorepresentthemostcosteffectiveuseofNHSresources(directlyapplicableandhadminor
limitations).
10.3.4.5 Vigabatrinversuscarbamazepine
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Carbamazepinewasincludedinthe
diagnosedfocalseizures,butvigabatrinwasnot.Vigabatrinwasexcludedowingtoitspotentialfor
longtermadverseeffects.
Evidencestatements
TheEpilepsies
166
Significantlymorepatientswereseizurefreewithcarbamazepinemonotherapythanvigabatrin
monotherapy,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOW
QUALITY)
Significantlyfewerpatientswithdrewduetolackofefficacywithcarbamazepinemonotherapythan
vigabatrinmonotherapy.(VERYLOWQUALITY)
Carbamazepinemonotherapyissignificantlymoreeffectivethanvigabatrinmonotherapyin
prolongingtimetofirstseizure.(MODERATEQUALITY)
Nosignificantdifferencebetweenvigabatrinmonotherapyandcarbamazepinemonotherapyfor
timetoexit/withdrawalofallocatedtreatment.(VERYLOWQUALITY)
Significantlymoreparticipantsoncarbamazepinemonotherapycomparedtovigabatrin
monotherapywithdrewduetoadverseevents.(VERYLOWQUALITY)
Significantlymoreparticipantsoncarbamazepinemonotherapycomparedtovigabatrin
monotherapyexperienceddrowsiness,althoughthereisuncertaintyoverthemagnitudeofits
clinicaleffect.(VERYLOWQUALITY)
Therewasnosignificantdifferencebetweenvigabatrinmonotherapyandcarbamazepine
monotherapyfortheincidenceofthefollowingadverseevents:
appendages(VERYLOWQUALITY)
generalisedrash(VERYLOWQUALITY)
visualdisturbances(VERYLOWQUALITY)
myoclonicjerks(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingvigabatrinandcarbamazepinewasidentified.
cognitiveoutcomes
10.3.4.6 Clonazepamversuscarbamazepine
Clinicalevidence
TheEpilepsies
167
diagnosedfocalseizures,butclonazepamwasnotincludedduetothelackofefficacydatareported
inthetrial.
Evidencestatements
Nosignificantdifferencebetweenclonazepammonotherapyandcarbamazepinemonotherapyfor
theproportionofparticipantswhowithdrewduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingclonazepamandcarbamazepinewasidentified.
seizurefreedom
timetofirstseizure
incidenceofadverseevents
cognitiveoutcomes
10.3.4.7 Oxcarbazepineversusphenytoin
Clinicalevidence
IPDmetaanalysis
PhenytoinandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatametaanalysis
ofAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.Theresultsofthis
analysisarepresentedinsection10.3.5.
Nostudieswereidentifiedintheeconomicliteraturesearch.Oxcarbazepinewasincludedinthe
therapeuticwindow.
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingphenytoin
monotherapycomparedtoparticipantstakingoxcarbamazepinemonotherapy.(IPDmetaanalysis)
TheEpilepsies
168
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyforthe
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyfortime
tofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyfortime
to12monthremission.(IPDmetaanalysis)
Adverseeffectsstatisticallysignificantresults
Significantlyfewerparticipantsinoxcarbazepinemonotherapywithdrewduetoadverseevents
comparedtoparticipantsinphenytoinmonotherapy.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepineandphenytoinwasidentified.
cognitiveoutcomes
10.3.4.8 Oxcarbazepineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
181
ofAEDs,includingoxcarbazepineandsodiumvalproate,usedas
diagnosedfocalseizures.ThecompleteresultsofthisstudyandtheNCGCadultmonotherapymodel
Evidencestatements
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandsodiumvalproatemonotherapy
fortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
fortimetotreatmentfailure.(IPDmetaanalysis)
TheEpilepsies
169
fortimetofirstseizure.(IPDmetaanalysis)
fortimeto12monthremission.(IPDmetaanalysis)
fortheproportionofparticipantswithdrawnduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatoxcarbazepineisnotcosteffectivewhencomparedto
sodiumvalproate.
ApublishedcosteffectivenessanalysisbyHawkinsandcolleaguesfoundthatoxcarbazepinewas
moreeffectivethansodiumvalproate,butwithanunacceptablyhighincrementalcost
effectivenessratioof156,545perQALY;however,theiranalysiswasbasedonanowoutofdate
systematicreviewand200203costs(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisundertakenfortheguidelinealsoshowedthatoxcarbazpeinewas
moreeffectiveandmorecostlythansodiumvalproate,butwithamuchlowerincrementalcost
effectivenessratioof37,551perQALY.ThisvaluestillexceedstheNICEwillingnesstopay
thresholdof20,000perQALYgained.Whenallrelevantcomparatorswereevaluatedtogether
intheNCGCanalysis,lamotriginewaslikelytorepresentthemostcosteffectiveuseofNHS
resources.Thisconclusionwasconsistentacrossvarioussensitivityanalyses.
cognitiveoutcomes
10.3.4.9 Phenobarbitalversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
CarbamazepineandphenobarbitalwereamongAEDsincludedinanindividualpatientdatameta
diagnosedfocalseizures,butphenobarbitalwasnotduetothelackofefficacydatareportedinthe
trial.
Evidencestatements
TheEpilepsies
170
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingphenobarbital
monotherapycomparedtoparticipantstakingcarbamazepinemonotherapy.(IPDmetaanalysis)
Phenobarbitalmonotherapyissignificantlymoreeffectivethancarbamazepinemonotherapyin
Nosignificantdifferencebetweenphenobarbitalmonotherapyandcarbamazepinemonotherapyfor
Adverseeffectsstatisticallynonsignificantresults
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalandcarbamazepinewasidentified.
seizurefreedom
qualityoflifeoutcomes
cognitiveoutcomes.
10.3.4.10 Primidoneversuscarbamazepine
Clinicalevidence
diagnosedfocalseizures,butprimidonewasnotduetothelackofefficacydatareportedinthetrial.
Evidencestatements
Significantlymoreparticipantsintheprimidonemonotherapygroupwithdrewduetoadverseevents
comparedtoparticipantsinthecarbamazepinemonotherapygroup.(MODERATEQUALITY)
Costeffectiveness
Noeconomicevidencecomparingprimidoneandcarbamazepinewasidentified.
TheEpilepsies
171
seizurefreedom
timetofirstseizure
cognitiveoutcomes.
10.3.4.11 Phenytoinversusphenobarbital
Clinicalevidence
IPDmetaanalysis
PhenytoinandphenobarbitalwereamongAEDsincludedinanindividualpatientdatametaanalysis
Nostudieswereidentifiedintheeconomicliteraturesearch.Neitherphenytoinnorphenobarbital
wasincludedintheoriginaleconomicmodeldevelopedtocompareAEDsusedasmonotherapyin
adultswithnewlydiagnosedfocalseizures.Phenytoinwasexcludedowingtoitsnarrowtherapeutic
windowandphenobarbitalwasexcludedduetothelackofefficacydatareportedintheevidence.
Evidencestatements
Phenobarbitalmonotherapyissignificantlymoreeffectivethanphenytoinmonotherapyin
Nosignificantdifferencebetweenphenytoinmonotherapyandphenobarbitalmonotherapyfortime
totreatmentfailure.(IPDmetaanalysis)
Nosignificantdifferencebetweenphenytoinmonotherapyandphenobarbitalmonotherapyfortime
Nosignificantdifferencebetweenphenytoinmonotherapyandphenobarbitalmonotherapyforthe
proportionofparticipantswhowithdrewduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenytoinandphenobarbitalwasidentified.
TheEpilepsies
172
seizurefreedom
cognitiveoutcomes.
10.3.4.12 Phenytoinversusprimidone
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Neitherphenytoinnorprimidonewas
includedintheoriginaleconomicmodeldevelopedtocompareAEDsusedasmonotherapyinadults
withnewlydiagnosedfocalseizures.Phenytoinwasexcludedowingtoitsnarrowtherapeutic
windowandprimidonewasexcludedduetothelackofefficacydatareportedintheevidence.
Evidencestatements
comparedtoparticipantsinthephenytoinmonotherapygroup.(MODERATEQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenytoinandprimidonewasidentified.
seizurefreedom
timetofirstseizure
cognitiveoutcomes.
10.3.4.13 Phenobarbitalversusprimidone
Clinicalevidence
TheEpilepsies
173
Nostudieswereidentifiedintheeconomicliteraturesearch.Neitherphenobarbitalnorprimidone
wereincludedintheoriginaleconomicmodeldevelopedtocompareAEDsusedasmonotherapyin
adultswithnewlydiagnosedfocalseizuresduetothelackofefficacydatareportedintheevidence.
Evidencestatements
comparedtoparticipantsinthephenobarbitalmonotherapygroup.(MODERATEQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalandprimidonewasidentified.
seizurefreedom
timetofirstseizure
cognitiveoutcomes
10.3.4.14 Carbamazepineversusphenytoin
Clinicalevidence
IPDmetaanalysis
CarbamazepineandphenytoinwereamongAEDsincludedinanindividualpatientdatametaanalysis
therapeuticwindow.
Evidencestatements
Nosignificantdifferencebetweencarbamazepinemonotherapyandphenytoinmonotherapyforthe
proportionofseizurefreeparticipants(VERYLOWQUALITY).
Nosignificantdifferencebetweencarbamazepinemonotherapyandphenytoinmonotherapyfor
TheEpilepsies
174
timeto12monthremission.(IPDmetaanalysis)
Nosignificantdifferencebetweencarbamazepinemonotherapyandphenytoinmonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparingcarbamazepineandphenytoinwasidentified.
Nosignificantdifferencebetweencarbamazepinemonotherapyandphenytoinmonotherapyforany
ofthecognitivetestoutcomes:
digitsymbol(VERYLOWQUALITY)
digitspanforward(VERYLOWQUALITY)
digitspanbackward(VERYLOWQUALITY)
ConsistentLongTermRetrievalScore(VERYLOWQUALITY)
FingerTap(VERYLOWQUALITY)
GroovedPegboard(VERYLOWQUALITY)
ChoiceReactionTime(VERYLOWQUALITY)
P3latency(VERYLOWQUALITY)
P3amplitude(VERYLOWQUALITY)
timetofirstseizure
10.3.4.15 Carbamazepineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
CarbamazepineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
TheEpilepsies
175
181
ofAEDs,includingcarbamazepineandsodiumvalproate,usedas
Evidencestatements
comparedtosodiumvalproatemonotherapy.(IPDmetaanalysis)
Carbamazepinemonotherapyissignificantlymoreeffectivethansodiumvalproatemonotherapyin
Nosignificantdifferencebetweencarbamazepinemonotherapyandsodiumvalproatemonotherapy
Nosignificantdifferencebetweencarbamazepinemonotherapyandsodiumvalproatemonotherapy
Nosignificantdifferencesbetweencarbamazepineandsodiumvalproateforanyofthefollowing
cognitiveoutcomes:motor,speedandintegration,memory,concentrationandmentalflexibility
after6monthsoftreatment.
Costeffectiveness
Availableeconomicevidenceindicatesthatcarbamazepineiscosteffectivewhencomparedto
sodiumvalproate.
Thecosteffectivenessanalysisundertakenfortheguidelineshowedthattreatmentwith
carbamazepinewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
thantreatmentwithsodiumvalproate,withanexpectedincrementalcosteffectivenessratioof
7,512.Thisconclusionwasconsistentacrossvarioussensitivityanalyses.However,whenall
relevantcomparatorswereevaluatedtogether,lamotriginewaslikelytorepresentthemostcost
effectiveuseofNHSresources(directlyapplicableandminorlimitations).
ThestudybyHawkinsandcolleaguesfoundsodiumvalproatetobemorecosteffectivethan
carbamazepine;however,theiranalysiswasbasedonanowoutofdatesystematicreviewand
200203costs(partiallyapplicableandpotentiallyseriouslimitations).
withdrawalduetoadverseevents
10.3.4.16 Sodiumvalproateversusphenytoin
Clinicalevidence
TheEpilepsies
176
IPDmetaanalysis
PhenytoinandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Nostudieswereidentifiedintheeconomicliteraturesearch.Sodiumvalproatewasincludedinthe
therapeuticwindow.
Evidencestatements
Nosignificantdifferencebetweensodiumvalproatemonotherapyandphenytoinmonotherapyfor
theproportionofseizurefreeparticipants.(VERYLOWQUALITY)
thetimetotreatmentfailure.(IPDmetaanalysis)
theproportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproateandphenytoinwasidentified.
cognitiveoutcomes
10.3.4.17 Carbamazepineversustopiramate
Clinicalevidence
TheEpilepsies
177
IPDmetaanalysis
CarbamazepineandtopiramatewereamongAEDsincludedinanindividualpatientdatameta
161,181
ofAEDs,includingcarbamazepineandtopiramate,usedas
diagnosedfocalseizures.ThecompleteresultsofthesestudiesandtheNCGCadultmonotherapy
modelarepresentedinsection10.3.6.
Evidencestatements
Timetoexit/withdrawalofallocatedtreatmentduetolackofefficacyoccurredsignificantlymore
rapidlyontopiramatemonotherapycomparedtocarbamazepinemonotherapy,althoughthereis
uncertaintyoverthemagnitudeofitsclinicaleffect.(LOWQUALITY)
Nosignificantdifferencebetweencarbamazepinemonotherapyandtopiramatemonotherapyfor
timetotreatmentfailure(IPDmetaanalysis).
timetofirstseizure.(VERYLOWQUALTY)
timeto12monthremission.(LOWQUALITY)
Significantlymoreparticipantstakingcarbamazepinemonotherapycomparedtotopiramate
monotherapyhadincidenceofallergicrash.(MODERATEQUALITY)
thetimetoexit/withdrawalofallocatedtreatmentduetoadverseevents.(VERYLOWQUALITY)
incidenceoftiredness/drowsiness/fatigue/lethargy.(VERYLOWQUALITY)
QualityofLifeoutcomesstatisticallysignificantresults
Topiramatemonotherapyhadasignificantlyreducedscorecomparedtocarbamazepine
monotherapyinthetwoyearanxietyscores,althoughthereisuncertaintyoverthemagnitudeofits
clinicaleffect.(MODERATEQUALITY)
TheEpilepsies
178
Thereisnosignificantdifferencebetweencarbamazepinemonotherapyandtopiramate
monotherapyin:
twoyearEQ5Dscores.(VERYLOWQUALITY)
twoyearGQoLscores.(VERYLOWQUALITY)
topiramatemonotherapyandcarbamazepinemonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthattopiramateisunlikelytobeconsideredcosteffective
whencomparedwithcarbamazepine,howeverthereisuncertaintyinthisconclusion.
Oneeconomicevaluationconductedalongsidearandomisedcontrolledtrialshowedthat
treatmentwithtopiramatewasassociatedwithincreasedcostsandbetterhealthoutcomes
(higherQALYs)comparedtocarbamazepine.Howeverthesameanalysisshowedthatpatients
receivingtopiramateexperiencedmoreseizuresthanpatientsreceivingcarbamazepine.When
allcomparatorsfromthetrialwereevaluatedtogether,topiramatewasdominatedby
oxcarbazepine;thatis,oxcarbazepineproducedgreaterQALYgains(andfewerseizures)ata
lowercost(partiallyapplicableandpotentiallyseriouslimitations).
Onepublishedcosteffectivenessanalysisshowedtopiramatetobemorecostlyandmore
effectivethancarbamazepine,butwithanunacceptablyhighincrementalcosteffectivenessratio
(89,736perQALY)(partiallyapplicableandpotentiallyseriouslimitations);however,thisanalysis
wasbasedonanowoutofdatesystematicreviewand200203costs(partiallyapplicableand
Resultsofthecosteffectivenessanalysisundertakenfortheguidelinefoundthattopiramatewas
notcosteffectivecomparedtocarbamazepine.Carbamazepinedominatedtopiramate;thatis,
treatmentwithcarbamazepinewasassociatedwithlowercostsandbetterhealthoutcomes
(higherQALYs)thantreatmentwithtopiramate.Thisconclusionwasrobusttovarioussensitivity
analyses.NotethatwhenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,
lamotriginewaslikelytorepresentthemostcosteffectiveuseofNHSresources(directly
applicableandminorlimitations).
10.3.4.18 Topiramateversussodiumvalproate
Clinicalevidence
Noclinicalevidencewasidentified.
IPDmetaanalysis
TopiramateandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
TheEpilepsies
179
181
ofAEDs,includingtopiramateandsodiumvalproate,usedas
Nosignificantdifferencebetweentopiramatemonotherapyandsodiumvalproatemonotherapyfor
Costeffectiveness
Availableeconomicevidenceindicatesthattopiramateisnotcosteffectivewhencomparedto
sodiumvalproate.
Acosteffectivenessanalysisundertakenfortheguidelinefoundthatsodiumvalproate
dominatedtopiramate;thatis,treatmentwithsodiumvalproatewasassociatedwithlowercosts
andbetterhealthoutcomes(higherQALYs)thantreatmentwithtopiramate.However,whenall
effectiveuseofNHSresources.Thisconclusionwasconsistentacrossvarioussensitivityanalyses
(directlyapplicableandminorlimitations).
ThecosteffectivenessanalysisbyHawkinsandcolleaguesfoundtopiramatetobemoreeffective,
althoughnotcosteffective,comparedtosodiumvalproate,buttheiranalysiswasbasedonanow
outofdatesystematicreviewand200203costs(partiallyapplicableandpotentiallyserious
limitations).
cognitiveoutcomes.
10.3.4.19 Carbamazepineversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
CarbamazepineandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
TheEpilepsies
180
161,181
ofAEDs,includingcarbamazepineandoxcarbazepine,usedas
Evidencestatements
Nosignificantdifferencebetweencarbamazepinemonotherapyandoxcarbazepinemonotherapyfor
thetimetotreatmentfailure.(IPDmetaanalysis)
theproportionofparticipantswhowithdrewduetolackofefficacy.(VERYLOWQUALITY)
thetimetofirstseizure.(VERYLOWQUALITY).
thetimetofirstseizure.(IPDmetaanalysis)
withdrawalduetoadverseevents.(VERYLOWQUALITY)
incidenceof:
tiredness/drowsiness/fatigue/lethargy(VERYLOWQUALITY)
allergicrash(VERYLOWQUALITY)
Thereisnosignificantdifferencebetweenoxcarbazepinemonotherapyandtopiramate
monotherapyin:
oxcarbazepinemonotherapyandcarbamazepinemonotherapy.
Costeffectiveness
TheEpilepsies
181
Availableeconomicevidenceindicatesthatoxcarbazepinemaybecosteffectivewhencomparedto
carbamazepine,buttheconclusionisdependentonthethresholdwillingnesstopay.
Onetrialbasedeconomicevaluationshowedoxcarbazepinetobecosteffectivecomparedto
carbamazepine,withanincrementalcosteffectivenessratioof6,200perQALY(partially
applicableandpotentiallyseriouslimitations).
Onepublishedcosteffectivenessanalysisfoundoxcarbazepinetobemorecostlyandmore
effectivethancarbamazepinebutwithanunacceptablyhighincrementalcosteffectivenessratio
of81,130perQALY;however,thisanalysiswasbasedonanowoutofdatesystematicreview
and200203costs(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisdevelopedfortheguidelinealsofoundoxcarbazepinetobemore
costlyandmoreeffectivethancarbamazepine,withanunacceptablyhighincrementalcost
effectivenessratioof127,224perQALY.Thisconclusionwasconsistentacrossvarioussensitivity
analyses.NotethatwhenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,
lamotriginewaslikelytorepresentthemostcosteffectiveuseofNHSresources.
10.3.4.20 Gabapentinversuslamotrigine
Clinicalevidence
IPDmetaanalysis
GabapentinandlamotriginewereamongAEDsincludedinanindividualpatientdatametaanalysisof
161
ofAEDs,includinggabapentinandlamotrigine,usedasmonotherapyin
thetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedintheeconomicliterature
search.Astherewerestillgapsintheeconomicevidencebase,anoriginaleconomicmodelwas
developedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.
ThecompleteresultsofthisstudyandtheNCGCadultmonotherapymodelarepresentedinsection
10.3.6.
Evidencestatements
Timetoexit/withdrawalofallocatedtreatmentduetolackofefficacyoccurredsignificantlyless
rapidlyinparticipantstakinglamotriginemonotherapycomparedtoparticipantstakinggabapentin
monotherapy.(MODERATEQUALITY)
Timetotreatmentfailureoccurredsignificantlylessrapidlyinparticipantstakinglamotrigine
monotherapycomparedtoparticipantstakinggabapentinmonotherapy.(IPDmetaanalysis)
Timeto12monthremissionoccurredsignificantlymorerapidlyonlamotriginemonotherapy
comparedtogabapentinmonotherapyalthoughthereisuncertaintyoverthemagnitudeofits
clinicaleffect.(LOWQUALITY)
Nosignificantdifferencebetweengabapentinmonotherapyandlamotriginemonotherapyforthe
proportionofparticipantswhowithdrewduetolackofefficacy.(LOWQUALITY)
TheEpilepsies
182
proportionofseizurefreeparticipants.(LOWQUALITY)
Nosignificantdifferencebetweengabapentinmonotherapyandlamotriginemonotherapyfortime
tofirstseizure.(VERYLOWQUALITY)
Significantlylessparticipantstakinglamotriginemonotherapycomparedtoparticipantstaking
gabapentinmonotherapyhadanincreaseinbodyweight,althoughthereisuncertaintyoverthe
magnitudeofitsclinicaleffect.(MODERATEQUALITY)
Significantlylessparticipantstakinggabapentinmonotherapycomparedtoparticipantstaking
lamotriginemonotherapyhadskinrash,althoughthereisuncertaintyoverthemagnitudeofits
clinicaleffect.(MODERATEQUALITY)
proportionofparticipantswhowithdrewduetoadverseevents.(LOWQUALITY)
toexit/withdrawalofallocatedtreatmentduetoadverseevents.(VERYLOWQUALITY)
Lamotriginemonotherapyhadasignificantlyreducedscorecomparedtogabapentinmonotherapyin
thetwoyeardepressionordinalscores.(MODERATEQUALITY)
Thereisnosignificantdifferencebetweengabapentinmonotherapyandlamotriginemonotherapy
in:
gabapentinmonotherapyandlamotriginemonotherapy.
Costeffectiveness
Availableeconomicevidenceindicatesthatgabapentinisnotcosteffectivewhencomparedwith
lamotrigine.
TheEpilepsies
183
Oneeconomicevaluationconductedalongsidearandomisedcontrolledtrialshowedlamotrigine
dominatedgabapentin;thatis,treatmentwithlamotriginewasassociatedwithlowercostsand
betterhealthoutcomes(higherQALYsandfewerseizures)thantreatmentwithgabapentin
(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisdevelopedfortheguidelinealsoshowedthatlamotriginedominated
gabapentin.Thisconclusionwasconsistentacrossvarioussensitivityanalyses(directlyapplicable
andminorlimitations).
10.3.4.21 Gabapentinversustopiramate
Clinicalevidence
IPDmetaanalysis
GabapentinandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysisof
161
ofAEDs,includinggabapentinandtopiramate,usedasmonotherapyin
thetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedintheeconomicliterature
developedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.The
completeresultsofthisstudyandtheNCGCadultmonotherapymodelarepresentedinsection
10.3.6.
Evidencestatements
rapidlyinparticipantstakingtopiramatemonotherapycomparedtoparticipantstakinggabapentin
Topiramatemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyinprolonging
thetimetofirstseizure.(MODERATEQUALITY).
Topiramatemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyinprolonging
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyforthe
timeto12monthremission.(VERYLOWQUALITY)
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyfortimeto
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyfortimeto
treatmentfailure.(IPDmetaanalysis)
TheEpilepsies
184
rapidlyonparticipantstakingtopiramatemonotherapycomparedtoparticipantstakinggabapentin
Topiramatemonotherapyhadsignificantlyreducedscorescomparedtogabapentinmonotherapyin
theanxietyscores,althoughthereisuncertaintyinthemagnitudeofclinicaleffect.(MODERATE
QUALITY)
Thereisnosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyin:
gabapentinmonotherapyandtopiramatemonotherapy.
Costeffectiveness
Availableeconomicevidenceindicatesthattopramatemaynotbecosteffectivewhencomparedto
gabapentin,butthereisuncertaintyinthisconclusion.
Oneeconomicevaluationconductedalongsidearandomisedcontrolledtrialshowedthat
topiramatedominatedgabapentin;thatis,treatmentwithgabapentinwastobemorecostlyand
lesseffective(fewerQALYsandmoreseizures)thantreatmentwithtopiramate(partially
Acosteffectivenessanalysisundertakenfortheguidelineshowedthattopiramatewasnotcost
effectivecomparedtogabapentin.Althoughtopiramatewasfoundtobemoreeffective,ithad
anincrementalcosteffectivenessratioof41,868perQALY,whichexceedstheNICEwillingness
topaythresholdof20,000perQALYgained.However,intheNCGCanalysis,bothtopiramate
andgabapentinweremorecostlyandlesseffectivethancarbamazepine,lamotrigineandsodium
valproate(directlyapplicableandminorlimitations).
10.3.4.22 Lamotrigineversustopiramate
Clinicalevidence
TheEpilepsies
185
IPDmetaanalysis
TopiramateandlamotriginewereamongAEDsincludedinanindividualpatientdatametaanalysisof
161,181
ofAEDs,includinglamotrigineandtopiramate,usedas
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingtopiramate
Topiramatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyinprolonging
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyforthe
timetoexit/withdrawalofallocatedtreatmentduetolackofefficacy.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyfortime
tofirstseizure.(VERYLOWQUALITY)
to12monthremission.(VERYLOWQUALITY)
rapidlyonparticipantstakingtopiramatemonotherapycomparedtoparticipantstakinglamotrigine
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyforthe
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapy
in:
TheEpilepsies
186
lamotriginemonotherapyandtopiramatemonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatlamotrigineiscosteffectivewhencomparedwith
topiramate.
Onetrialbasedeconomicevaluationshowedlamotriginetobemorecostlyandmoreeffective
(higherQALYsandfewerseizures)thantopiramatewithanincrementalcosteffectivenessratioof
6,727perQALY(partiallyapplicableandpotentiallyseriouslimitations).However,both
topiramateandlamotrigineweremorecostlyandlesseffectivethanoxcarbazepineinthis
analysis.Sincetheanalysiswasundertaken,lamotrigineandtopiramatehavecomeoffpatent
andtheirunitcostshavecomedownconsiderably(partiallyapplicableandpotentiallyserious
limitations).
Onepublishedcosteffectivenessanalysisfoundthatlamotriginedominatedtopiramate;thatis,
treatmentwithlamotriginewasassociatedwithlowercostsandbetteroutcomes(higherQALYs)
thantreatmentwithtopiramate;however,thisanalysiswasbasedonanowoutofdate
systematicreviewand200203costs(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisundertakenfortheguidelinealsofoundthatlamotriginedominated
topiramate.Thisconclusionwasconsistentacrossvarioussensitivityanalyses(directlyapplicable
10.3.4.23 Gabapentinversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
GabapentinandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
161
ofAEDs,includingoxcarbazepineandgabapentin,usedasmonotherapy
inthetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedintheeconomic
literaturesearch.Astherewerestillgapsintheeconomicevidencebase,anoriginaleconomic
modelwasdevelopedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocal
seizures.ThecompleteresultsofthisstudyandtheNCGCadultmonotherapymodelarepresented
insection10.3.6.
Evidencestatements
rapidlyinparticipantstakingoxcarbazepinemonotherapycomparedtoparticipantstaking
gabapentinmonotherapy.(MODERATEQUALITY)
TheEpilepsies
187
Timetotreatmentfailureoccurredsignificantlylessrapidlyinparticipantstakingoxcarbazepine
monotherapycomparedtoparticipantstakinggabapentinmonotherapy.(IPDmetaanalysis)
Oxcarbazepinemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyin
prolongingtimetofirstseizure,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.
(LOWQUALITY)
Oxcarbazepinemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyin
Timeto12monthremissionoccurredsignificantlymorerapidlyonoxcarbazepinemonotherapythan
gabapentinmonotherapy.(MODERATEQUALITY)
Timeto12monthremissionoccurredsignificantlymorerapidlyonoxcarbazepinemonotherapythan
gabapentinmonotherapy.(IPDmetaanalysis)
Nosignificantdifferencebetweengabapentinmonotherapyandoxcarbazepinemonotherapyforthe
timetoexit/withdrawalofallocatedtreatmentduetoadverseevents.(VERYLOWQUALITY)
Nosignificantdifferencebetweengabapentinmonotherapyandoxcarbazepinemonotherapyforthe
Thereisnosignificantdifferencebetweengabapentinmonotherapyandoxcarbazepine
monotherapyin:
gabapentinmonotherapyandoxcarbazepinetopiramatemonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatoxcarbazepineiscosteffectivewhencomparedto
gabapentin.
Onetrialbasedeconomicevaluationfoundthatoxcarbazepinedominatedgabapentin;thatis,
treatmentwithoxcarbazepinewasassociatedwithlowercostsandbetterhealthoutcomes
(higherQALYsandfewerseizures)thantreatmentwithgabapentin(partiallyapplicableand
Acosteffectivenessanalysisundertakenfortheguidelineshowedoxcarbazepinetobemore
costlyandmoreeffectivethangabapentin,withanincrementalcosteffectivenessratioof
13,887perQALYgained.Thisconclusionwasconsistentacrossvarioussensitivityanalyses.
However,whenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,
lamotriginewaslikelytorepresentthemostcosteffectiveuseofNHSresources(directly
TheEpilepsies
188
10.3.4.24 Lamotrigineversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
161,181
ofAEDs,includinglamotrigineandoxcarbazepine,usedas
Evidencestatements
Oxcarbazepinemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingthetimetofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepinemonotherapyforthe
Nosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepinemonotherapyfor
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepine
monotherapyin:
TheEpilepsies
189
lamotriginemonotherapyandoxcarbazepinemonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatoxcarbazepinemaybecosteffectivewhencomparedto
lamotrigine,butevidenceisconflicting;hence,thereisconsiderableuncertaintyinthisconclusion.
Onetrialbasedeconomicevaluationfoundthatoxcarbazepinedominatedlamotrigine;thatis,
(higherQALYsandfewerseizures)thantreatmentwithlamotrigine(partiallyapplicableand
OnepublishedcosteffectivenessanalysisundertakenbyHawkinsandcolleaguesfound
oxcarbazepinebemorecostlyandmoreeffectivethanlamotrigine,withanincrementalcost
effectivenessratioof4,879perQALYgained.However,thisanalysiswasbasedonanowoutof
datesystematicreviewand200203costs(partiallyapplicableandpotentiallyseriouslimitations).
Thecosteffectivenessanalysisdevelopedfortheguidelinefoundthatoxcarbazepinewasnot
costeffectivecomparedtolamotrigine.Althoughoxcarbazepinewasfoundtobemoreeffective,
ithadanincrementalcosteffectivenessratioof180,137perQALY,whichfarexceedstheNICE
willingnesstopaythresholdof20,000perQALYgained.Thisconclusionwasconsistentacrossa
rangeofsensitivityanalyses(directlyapplicableandminorlimitations).
10.3.4.25 Topiramateversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
TopiramateandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
161,181
ofAEDs,includingtopiramateandoxcarbazepine,usedas
Evidencestatements
TheEpilepsies
190
Nosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepinemonotherapyforthe
Nosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepinemonotherapyfor
Thereisnosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepine
monotherapyin:
topiramatemonotherapyandoxcarbazepinemonotherapy.
Costeffectiveness
Availableeconomicevidenceindicatesthattopiramateisnotcosteffectivecomparedto
oxcarbazepine.
Resultsofatrialbasedeconomicevaluationfoundoxcarbazepinedominatedtopiramate;thatis,
(higherQALYsandfewerseizures)thantreatmentwithtopiramate(partiallyapplicableand
OnepublishedcosteffectivenessanalysisundertakenbyHawkinsandcolleaguesshowed
topiramatewastobemorecostlyandmoreeffectivethanoxcarbazepine,butwithan
unacceptablyhighincrementalcosteffectivenessratioof102,933perQALYgained.However,
thisanalysiswasbasedonanowoutofdatesystematicreviewand200203costs(partially
TheEpilepsies
191
Thecosteffectivenessanalysisdevelopedfortheguidelinefoundthatoxcarbazepinewascost
effectivecomparedtotopiramate.Underbasecasecostingassumptions,oxcarbazepine
dominatedtopiramate.Andunderalternativecostingassumptions,whichwerefavourableto
topiramate,oxcarbazepinewasmorecostlyandmoreeffective,butwithanincrementalcost
effectivenessratioundertheNICEwillingnesstopaythresholdof20,000perQALYgained.
However,whenallrelevantcomparatorswereevaluatedtogether,lamotriginewaslikelyto
representthemostcosteffectiveuseofNHSresources(directlyapplicableandminorlimitations).
10.3.4.26 Lamotrigineversusphenobarbital
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandlamotriginewereamongAEDsincludedinanindividualpatientdatametaanalysis
Nostudieswereidentifiedintheeconomicliteraturesearch.Lamotriginewasincludedinthe
trial.
Evidencestatements
Lamotriginemonotherapyissignificantlymoreeffectivethanphenobarbitalmonotherapyin
prolongingthetimetoexit/withdrawal.(IPDmetaanalysis)
Phenobarbitalmonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
Nosignificantdifferencebetweenlamotriginemonotherapyandphenobarbitalmonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalandlamotriginewasidentified.
seizurefreedom
cognitiveoutcomes
TheEpilepsies
192
10.3.4.27 Lamotrigineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
SodiumvalproateandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
181
ofAEDs,includinglamotrigineandsodiumvalproate,usedas
Evidencestatements
Lamotriginemonotherapyissignificantlymoreeffectivethansodiumvalproatemonotherapyin
Nosignificantdifferencebetweenlamotriginemonotherapyandsodiumvalproatemonotherapyfor
Costeffectiveness
Availableeconomicevidenceindicatedthatlamotriginewascosteffectivewhencomparedtosodium
valproate
Acosteffectivenessanalysisundertakenfortheguidelinefoundthatlamotriginedominated
sodiumvalproate;thatis,treatmentwithlamotriginewasassociatedwithlowercostsandbetter
healthoutcomes(higherQALYs)thantreatmentwithsodiumvalproate.Thisconclusionwas
consistentacrossvarioussensitivityanalyses.
ApublishedcosteffectivenessanalysisbyHawkinsandcolleaguesfoundthatsodiumvalproate
dominatedlamotrigine,buttheiranalysiswasbasedonanowoutofdatesystematicreviewand
200203costs.
seizurefreedom
cognitiveoutcomes
TheEpilepsies
193
10.3.4.28 Oxcarbazepineversusphenobarbital
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandphenobarbitalwereamongAEDsincludedinanindividualpatientdatameta
Nostudieswereidentifiedintheeconomicliteraturesearch.Oxcarbazepinewasincludedinthe
trial.
Evidencestatements
Oxcarbazepinemonotherapyissignificantlymoreeffectivethanphenobarbitalmonotherapyin
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenobarbitalmonotherapyfor
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenobarbitalmonotherapyfor
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepineandphenobarbitalwasidentified.
seizurefreedom
cognitiveoutcomes
10.3.4.29 Phenobarbitalversussodiumvalproate
Clinicalevidence
TheEpilepsies
194
IPDmetaanalysis
PhenobarbitalandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Nostudieswereidentifiedintheeconomicliteraturesearch.Sodiumvalproatewasincludedinthe
trial.
Evidencestatements
Sodiumvalproatemonotherapyissignificantlymoreeffectivethanphenobarbitalmonotherapyin
Sodiumvalproatemonotherapyissignificantlymoreeffectivethanphenobarbitalmonotherapyfor
reducingthetimetofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweensodiumvalproatemonotherapyandphenobarbitalmonotherapy
forthetimeto12monthremission.(IPDmetaanalysis)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproateandphenobarbitalwasidentified.
seizurefreedom
cognitiveoutcomes
10.3.4.30 Gabapentinversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
GabapentinandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
TheEpilepsies
195
181
ofAEDs,includinggabapentinandsodiumvalproate,usedas
economicmodelwasdevelopedtocompareAEDsusedasmonotherapyinnewlydiagnosedfocal
seizures.ThecompleteresultsofthesestudiesandtheNCGCadultmonotherapymodelare
presentedinsection10.3.6.
Evidencestatements
Nosignificantdidfferencebetweengabapentinmonotherapyandsodiumvalproatemonotherapyfor
timetoexit/withdrawaloftreatment.(IPDmetaanalysis)
Nosignificantdifferencebetweengabapentinmonotherapyandsodiumvalproatemonotherapyfor
Costeffectiveness
Availableeconomicevidenceindicatesthatgabapentinisnotcosteffectivewhencomparedto
sodiumvalproate.
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatsodiumvalproate
dominatedgabapentin;thatis,treatmentwithsodiumvalproatewasassociatedwithlowercosts
andbetterhealthoutcomes(higherQALYs)thantreatmentwithgabapentin.However,whenall
effectiveuseofNHSresources.Thisconclusionwasconsistentacrossvarioussensitivityanalyses
seizurefreedom
cognitiveoutcomes
10.3.4.31 Phenobarbitalversustopiramate
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysis
TheEpilepsies
196
Nostudieswereidentifiedintheeconomicliteraturesearch.Topiramatewasincludedintheoriginal
economicmodeldevelopedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosed
focalseizures,butphenobarbitalwasnotduetoalackofefficacydata.
Evidencestatements
Topiramatemonotherapyissignificantlymoreeffectivethanphenobarbitalmonotherapyin
Nosignificantdifferencebetweenphenobarbitalmonotherapyandtopiramatemonotherapyforthe
Nosignificantdifferencebetweenphenobarbitalmonotherapyandtopiramatemonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparingtopiramateandphenobarbitalwasidentified.
seizurefreedom
cognitiveoutcomes
10.3.4.32 Phenytoinversustopiramate
Clinicalevidence
IPDmetaanalysis
PhenytoinandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysisof
Nostudieswereidentifiedintheeconomicliteraturesearch.Topiramatewasincludedintheoriginal
focalseizures,butphenytoinwasnotduetoitsnarrowtherapeuticwindow.
Evidencestatements
Nosignificantdidfferencebetweenphenytoinmonotherapyandtopiramatemonotherapyfortime
toexit/withdrawaloftreatment.(IPDmetaanalysis)
TheEpilepsies
197
Nosignificantdifferencebetweenphenytoinmonotherapyandtopiramatemonotherapyforthe
Nosignificantdifferencebetweenphenytoinmonotherapyandtopiramatemonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparingtopiramateandphenytoinwasidentified.
seizurefreedom
cognitiveoutcomes
10.3.4.33 Phenobarbitalversusgabapentin
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysis
Nostudieswereidentifiedintheeconomicliteraturesearch.Gabapentinwasincludedintheoriginal
focalseizures,butphenobarbitalwasnotduetoalackofefficacydata.
Evidencestatements
Phenobarbitalmonotherapyissignificantlymoreeffectivethangabapentinmonotherapyin
prolongingthetimetofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenphenobarbitalmonotherapyandgabapentinmonotherapyfor
Nosignificantdifferencebetweenphenobarbitalmonotherapyandgabapentinmonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparinggabapentinandphenobarbitalwasidentified.
TheEpilepsies
198
seizurefreedom
cognitiveoutcomes
10.3.4.34 Phenytoinversusgabapentin
Clinicalevidence
IPDmetaanalysis
PhenytoinandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysisof
Nostudieswereidentifiedintheeconomicliteraturesearch.Gabapentinwasincludedintheoriginal
focalseizures,butphenytoinwasnotduetoitsnarrowtherapeuticwindow.
Evidencestatements
Phenytoinmonotherapyissignificantlymoreeffectivethangabapentinmonotherapyinprolonging
Nosignificantdifferencebetweenphenytoinmonotherapyandgabapentinmonotherapyfortimeto
exit/withdrawaloftreatment.(IPDmetaanalysis)
Nosignificantdifferencebetweenphenytoinmonotherapyandgabapentinmonotherapyforthe
Costeffectiveness
Noeconomicevidencecomparinggabapentinandphenytoinwasidentified.
seizurefreedom
cognitiveoutcomes
TheEpilepsies
199
10.3.5 Individualpatientdatanetworkmetaanalysisasmonotherapyforfocalepilepsy
DuringtheliteraturereviewweidentifiedanetworkmetaanalysisofIndividualPatientData(IPD).It
includedIPDevidencefromrandomizedcontrolledtrialsofeightdifferentAEDs(carbamazepine,
sodiumvalproate,phenytoin,phenobarbital,oxcarbazepine,lamotrigine,gabapentinand
topiramate)inmonotherapyoffocalseizures(TudurSmithetal,2007)
38
.Itshouldberecognisedthat
thiswasanetworkmetaanalyseswhichcombinesdirectandindirectanalyses.
ThedataondirectcomparisonscamefromeightCochranestudiesincludingdirectanalysesof
carbamazepineversussodiumvalproate,phenytoinversussodiumvalproate,carbamazepineversus
phenytoin,phenytoinversusphenobarbitone,carbamazepineversusphenobarbitone,sodium
valproateversusphenobarbitone,oxcarbazepineversusphenytoinandlamotrigineversus
carbamazepine.Directevidencewasnotavailableforsomepairwisecomparisonssuchas
oxcarbazepineversuslamotrigineorphenobarbital,astherewasnorandomisedcontrolledtrials
availableatthetimeofwritingtheCochranereviews.Alsotrialscomparingdrugssuchas
oxcarbamazepineversusphenobarbitoneareunlikelytobeconductedinthefuturebecauseof
changingfashionsfortreatment(TudurSmithetal,2007)
38
.
Theoutcomesincludedweretimetotreatmentfailureduetoinadequateseizurecontrol,intolerable
adverseeffectsoracombinationofboth;timeto12monthremissionfromseizures(daysfrom
randomisationandendofaperiodof12monthswithoutseizures);andtimetofirstseizureafter
randomisation.Itincludeddatafrom4265focalparticipantsfortimetotreatmentfailure,3526
focalparticipantsfortimeto12monthremissionand2959focalparticipantsfortimetofirstseizure.
Thefollowingtablesshowtheresultsforthevariousoutcomes,comparingeachAEDwiththecurrent
standardAED,carbamazepine.Thesignificantresultsarehighlightedinbold.
Timetotreatmentfailure
Intervention Comparator Hazardratio(95%CI)
Lamotrigine Carbamazepine 0.70(0.58to0.83)
Oxcarbazepine Carbamazepine 0.88(0.69to1.12)
Sodiumvalproate Carbamazepine 1.00(0.82to1.24)
Topiramate Carbamazepine 1.13(0.93to1.37)
Gabapentin Carbamazepine 1.16(0.96to1.41)
Phenytoin Carbamazepine 1.24(0.98to1.57)
Phenobarbital Carbamazepine 1.60(1.22to2.10)
(a) HR<1CBZworse;HR>1CBZbetter
WhencomparedwithalltheAEDsintheIPDanalysislamotriginewasfoundtobesignificantlybetter
comparedtootherAEDsexceptfromoxcarbazepinefortimetotreatmentfailure.
Timeto12monthremission
Intervention Comparator Hazardratio
Carbamazepine Oxcarbazepine 1.00(0.82to1.22)
Carbamazepine Phenobarbital 1.01(0.77to1.31)
Carbamazepine Phenytoin 1.15(0.94to1.41)
Carbamazepine Lamotrigine 1.15(0.96to1.37)
Carbamazepine Topiramate 1.19(0.99to1.43)
Carbamazepine Sodiumvalproate 1.20(1.01to1.42)
Carbamazepine Gabapentin 1.38(1.15to1.67)
TheEpilepsies
200
Carbamazepinewasfoundtobesignificantlybetterthansodiumvalproateandgabapentinfortime
to12monthremission.
Timetofirstseizure
Phenobarbital Carbamazepine 0.77(0.61to0.96)
Oxcarbazepine Carbamazepine 0.99(0.83to1.19)
Topiramate Carbamazepine 1.00(0.85to1.18)
Phenytoin Carbamazepine 1.04(0.88to1.24)
Sodiumvalproate Carbamazepine 1.23(1.06to1.41)
Lamotrigine Carbamazepine 1.29(1.13to1.48)
Gabapentin Carbamazepine 1.35(1.15to1.59)
Carbamazepinewasfoundtobesignificantlybetterthansodiumvalproate,lamotrigineand
gabapentinfortimetofirstseizure.Phenobarbitalwassignificantlybetterthancarbamazepine.
FurtherdatashowingeachAEDcomparisonforthethreeoutcomesoftheIPDarepresentedin
appendixN.
10.3.6 HealtheconomicevidenceofAEDsusedasmonotherapyforadultswithnewlydiagnosed
focalepilepsy
Twostudies
161,181
assessingthecosteffectivenessofAEDsusedasmonotherapywereincludedin
theeconomicevidencereview.SeeeconomicevidencetablesinappendixMforstudydetails,
includingqualityassessmentsoftheirmethodologyandapplicability.Followingthereviewofthe
clinicalandcosteffectivenessliterature,itwasconsideredthatmostAEDswerebroadlysimilarin
theirefficacy,butevidenceoftheircosteffectivenesswaslimitedand,attimes,conflicting.Given
theselimitationsintheevidencebase,anoriginaleconomicmodelwasdevelopedtocompareAEDs
usedasfirstlinemonotherapyinadultswithnewlydiagnosedfocalepilepsy.Thiswasbasedon
evidencefromtheTudurSmithnetworkmetaanalysis(seesection10.3.5)andclinicalreview
detailedabove.SeeappendixPforfulldetailsandresultsofmodelling.
Economicstudycharacteristics
Table1: MonotherapyforadultswithnewlydiagnosedfocalepilepsyEconomicstudy
characteristics
Study Limitations Applicability OtherComments
NCGCModeladult
monotherapy(see
AppendixPfor
details)
Minorlimitations Directlyapplicable Decisionanalyticmodel;

comparatorsincluded
carbamazepine,carbamazepine
controlledrelease,
oxcarbazepine,sodium
valproate,lamotrigine,
topiramateandlevetiracetam;
timehorizon15years;clinical
databasedonTudurSmith
networkmetaanalysisand
Brodie2007(seeappendixPfor
details)
Marson(2007)after Potentiallyserious Partiallyapplicable(c) Economicevaluationalongside
TheEpilepsies
201
June2001
161
limitations(a,b) randomisedcontrolledtrial;cost
perQALYanalysis;comparators
includedcarbamazepine,
lamotrigine,gabapentin,
topiramateandoxcarbazepine;
2yeartimehorizon;includes
datacollectedafterJune2001
whenoxcarbazepinewas
introduced
Marson(2007)after
June2001
161
Potentiallyserious
limitations(a,b)
Partiallyapplicable(d) Economicevaluationalongside
randomisedcontrolledtrial;cost
perseizureavoidedanalysis;
comparatorsincluded
carbamazepine,lamotrigine,
gabapentin,topiramateand
oxcarbazepine;2yeartime
horizon;includesdatacollected
afterJune2001when
oxcarbazepinewasintroduced
Hawkins(2005)
181
Potentiallyserious
limitations(a,c,e)
Partiallyapplicable(f) Decisionanalyticmodel;
comparatorsincluded
carbamazepine,oxcarbazepine,
sodiumvalproate,lamotrigine
andtopiramate;timehorizon15
years;clinicaldatabasedon
networkmetaanalysisthat
includedseveralstudieswith
mixedfocalandgeneralised
epilepsypopulations
(a) Unitcostsofinterventionsarefrom2002/03(inHawkins)and2005(inMarson)andsincepublication,lamotrigineandtopiramate
havecomeoffpatentandthenonproprietarypriceisdramaticallylower
(b) ResponderstoEQ5Dquestionnairesat2yearfollowupwerehealthierthannonresponders
(c) ThestudydidnotincludeallcomparatorsofinteresttotheGDG,namelylevetiracetam.
(d) Analysisbasedonseizuresavoided,notQALYs
(e) EffectivenessdatawasderivedfromanetworkmetaanalysisthatincludedonestudythatwasnotincludedintheNCGCclinicalreview
(Beunanen1996).
(f) Costsandeffectsdiscountedat6%and1.5%perannum,respectively.
Economicstudyresults
NCGCModeladultmonotherapy(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixP.
Table2: MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofNCGCmodel
AED
Totalcost
()per
patient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
LTG
8,841 8.8795 At20KperQALYthreshold,probabilitymost

costeffective
Basecase:82%
Allcheapest:61%
CostofmodifiedreleaseCBZ:52%
CostsofgenericLTGandTegretol:51%
TheEpilepsies
202
AED
Totalcost
()per
patient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
ImprovedtolerabilityofLEV:82%
LEVcost50%and70%reduced:80%and74%
At30KperQALYthreshold:74%
VPA 9,291 8.8391 Dominated At20KperQALYthreshold,probabilitymost
costeffective
Basecase:5%
Allcheapest:1%
LTGandCBZunsuitable:76%
IfLTGandCBZunsuitableandLEVcost50%and
70%reduced:59%and38%
CBZ 9,596 8.8797 3,778,200
(extdom)
At20KperQALYthreshold,probabilitymost
costeffective
Basecase:10%
Allcheapest:37%
GBP 9,973 8.7958 Dominated At20KperQALYthreshold,probabilitymost
costeffective
Basecase:0%
Allcheapest:0%
70%reduced:1%and1%
OXC
11,327 8.8933 180,137 At20KperQALYthreshold,probabilitymost

costeffective
Basecase:2%
Allcheapest:1%
TheEpilepsies
203
AED
Totalcost
()per
patient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
TPM 11,354 8.8288 Dominated At20KperQALYthreshold,probabilitymost
costeffective
Basecase:0%
Allcheapest:0%
70%reduced:0%and0%
LEV 12,187 8.8622 Dominated At20KperQALYthreshold,probabilitymost
costeffective
Basecase:0%
Allcheapest:0%
Evidencestatements
ResultsofthebasecasefoundthatlamotriginewasthemostcosteffectiveAEDforthefirstline
treatmentofadultswithnewlydiagnosedfocalseizures.Lamotriginedominatedgabapentin,
levetiracetam,sodiumvalproate,andtopiramatewithlowercostsandimprovedhealthoutcomes
(higherQALYs).Thisconclusionwasrobusttovarioussensitivityanalyses.
Inthebasecase,carbamazepinewasruledoutthroughextendeddominance,butinkeysensitivity
analysesaroundthecostsofcarbamazepineandlamotrigine,resultsindicatedthatcarbamazepine
maybethemostcosteffectiveAEDforthefirstlinetreatmentofadultswithnewlydiagnosedfocal
seizures.Thereissomeuncertaintyinadecisionbetweencarbamazepineandlamotrigine.
ResultsofallanalysesshowedthatoxcarbazepinewasthemosteffectivefirstlineAED,butthatits
additionalcostcomparedtocarbamazepineandlamotriginewasnotjustifiedbytheadditional
benefit.
Incircumstanceswherecarbamazepineandlamotriginearenotsuitable,sodiumvalproateor
oxcarbazepinerepresentthenextmostcosteffectivefirstlineAEDsforthetreatmentofnewly
diagnosedfocalseizures.Inthesamescenario,levetiracetammaybeconsideredcosteffectiveifits
unitcostisreducedby50%.
TheEpilepsies
204
Marson2007
161
(partiallyapplicable,potentiallyseriouslimitations)
SeeeconomicevidencetableinappendixMforstudydetai
Table3: MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofMarson
2007
161
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
CBZ 1,095 1.491 At20KperQALYthreshold,probability
mostcosteffectivecomparedto:
OXC:17%
TPM:42%
LTG:41%
GBP:86%
OXC 1,839 1.611 6,200 At20KperQALYthreshold,83%
probabilitymostcosteffectivecompared
toCBZ
TPM 1,930 1.541 Dominate

d
At20KperQALYthreshold,58%
toCBZ
LTG 2,078(a) 1.563 Dominate

d(b)
toCBZ
GBP 2,573 1.480 Dominate

d
toCBZ
(a) AcquisitioncostsofLTGandTPMhavedecreasedsignificantlysincethisevaluationwasundertaken.
(b) Inanalysisofentiretrialperiodandthusexcludingoxcarbazepinefromanalysis,LTGiscosteffectivecomparedtoCBZ(11,851per
QALY)
Evidencestatements
OxcarbazepineisthemostcosteffectiveAEDevaluatedasmonotherapy,lesscostlyandmore
effectiveintermsofQALYgainthangabapentin,lamotrigineandtopiramate.Oxcarbazepineismore
costlyandmoreeffectiveintermsofQALYsgainedthancarbamazepine,witheachadditionalQALY
costing6,200(partiallyapplicableandpotentiallyseriouslimitations).
CarbamazepineistheleastcostlyandsecondleasteffectiveAEDintermsofQALYgainevaluatedas
monotherapy(partiallyapplicableandpotentiallyseriouslimitations).
GabapentinisthemostcostlyandleasteffectiveAEDintermsofQALYgainevaluatedas
LamotrigineandtopiramatearemorecostlyandlesseffectiveintermsofQALYgainthan
oxcarbazepine(partiallyapplicableandpotentiallyseriouslimitations).
Whenoxcarbazepinewasexcludedfromtheanalysisinordertousedatafromtheentiretrialperiod,
lamotriginewasthemostcosteffectiveAEDevaluatedasmonotherapy.Also,itislikelythatif
TheEpilepsies
205
currentcostsoflamotriginewereused,itwouldbecosteffectivecomparedtoalternativeAEDs
evaluatedasmonotherapy.
Marson2007
161
SeeeconomicevidencetableinappendixMforstudydetails.
Table4: MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofMarson
2007
161
AED
Totalcost()
perpatient
Totaleffects
(seizures)
ICER
(/
seizure
avoided)
(a) Uncertainty
CBZ 1,151 50.9 At160,400,800and1600per
seizureavoided,probabilitymostcost
effectivecomparedto:
OXC:15%,10%,10%,9%
TPM:73%,67%,65%,63%
LTG:59%,52%,50%,48%
GBP:95%,92%,90%,90%
OXC 1,815 32.0 35 At160,400,800and1600per
effectivecomparedtoCBZ:
85%,90%,90%,91%
d
At160,400,800and1600per
27%,33%,35%,37%
LTG 1,946(b) 50.9 Dominate
d(c)
At160,400,800and1600per
41%,48%,50%,52%
GBP 2,594 85.3 Dominate
d
At160,400,800and1600per
5%,8%,10%,10%
(a) Nowillingnesstopaythresholdforseizuresavoidedexists.
(b) AcquisitioncostsofLTGandTPMhavedecreasedsignificantlysincethisevaluationwasundertaken.
(c) Inanalysisofentiretrialperiodandthusexcludingoxcarbazepinefromanalysis,LTGmaybecosteffectivecomparedtoCBZ(80per
seizureavoided)
Evidencestatements
OxcarbazepinewouldappeartobethemostcosteffectiveAEDevaluatedasmonotherapy,less
costlyandmoreeffectiveintermsoftotalseizuresexperiencedthangabapentin,lamotrigineand
topiramate.Oxcarbazepineismorecostlyandmoreeffectiveintermsoftotalseizuresexperienced
thancarbamazepine,witheachadditionalseizureavoidedcosting35(partiallyapplicableand
potentiallyseriouslimitations).Withoutanexplicitwillingnesstopayperseizureavoidedthreshold,
itisindeterminableastowhetheroxcarbazepinewouldbeconsideredcosteffectivecomparedto
carbamazepine.
TheEpilepsies
206
Patientstakinggabapentin,lamotrigineandtopiramateexperiencedmoretotalseizuresandincurred
highercoststhanpatientstakingcarbamazepineoroxcarbazepine,indicatingthattheseAEDsmay
notbecosteffective(partiallyapplicableandpotentiallyseriouslimitations).
Hawkins2005
181
Table5: MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofHawkins
2005
181
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
CBZ 4,428 9.392 At20KperQALYthreshold,probability
mostcosteffective
Basecase:42%
VPA 4,572 9.404 11,731 At20KperQALYthreshold,probability
mostcosteffective
Basecase:46%
d
At20KperQALYthreshold,probability
mostcosteffective
Basecase:0%
OXC 6,294 9.415 Extended
Dominanc
e
At20KperQALYthreshold,probability
mostcosteffective
Basecase:12%
TPM 7,838 9.430 126,519 At20KperQALYthreshold,probability
mostcosteffective
Basecase:0%
(a) AcquisitioncostsofLTGandTPMhavedecreasedsignificantlysincethisevaluationwasundertaken
Evidencestatements
SodiumvalproateisthemostcosteffectiveAEDevaluatedasmonotherapygivenathreshold
willingnesstopayof20,000perQALY(partiallyapplicableandpotentiallyseriouslimitations).
LamotriginewastheleasteffectiveamongAEDsevaluatedasmonotherapyandwasmorecostly
thancarbamazepineandsodiumvalproate(partiallyapplicableandpotentiallyseriouslimitations).
OxcarbazepineandtopiramatearenotcosteffectivecomparedtoalternativeAEDsevaluatedas
10.3.7 Monotherapyforchildrenwithnewlydiagnosedfocalepilepsy
10.3.7.1 Matrixoftheevidenceforchildren

Placebo
Carbamazepine
Phenobarbital
Lamotrigine 1
164

Phenytoin
TheEpilepsies
207
Valproate
Oxcarbazepine 1
182

Vigabatrin 1
183

Pla CBZ PHB LTG PHT VPA OXC VGB
Placebo(Pla)Carbamazepine(CBZ)Phenobarbital(PHB)Lamotrigine(LTG)
Phenytoin(PHT)Sodiumvalproate(VPA)Oxcarbazepine(OXC)Vigabatrin(VGB)
Clobazam(CLB)
10.3.7.2 LamotrigineversusCarbamazepine
Clinicalevidence
FordetailsonthedirectclinicalevidencepleaserefertoAppendixN.Fordetailsoneachpaper
identifiedintheliteraturesearchpleaserefertoAppendixL.
184
ofAEDs,includingcarbamazepineandlamotrigine,usedas
monotherapyinthetreatmentofchildrenwithnewlydiagnosedfocalepilepsywasidentifiedinthe
economicmodelwasdevelopedtocompareAEDsusedasmonotherapyinnewlydiagnosedchildren.
ThiswasbasedonclinicalevidencefromNietoBarerra2001
164
andGuerreiro1997
182
.Thecomplete
resultsofthisstudyandtheNCGCchildrenmonotherapymodelarepresentedinsection10.3.8.
Evidencestatements
theproportionofseizurefreechildren.(VERYLOWQUALITY)
Significantlymorechildrentakinglamotriginemonotherapyhadaninfectioncomparedtochildren
takingcarbamazepinemonotherapy,althoughthereisuncertaintyoverthemagnitudeofitsclinical
effect.(VERYLOWQUALITY).
Significantlymorechildrentakingcarbamazepinemonotherapyexperienceddizzinesscomparedto
childrentakinglamotriginemonotherapy.(LOWQUALITY).
theproportionofchildrenwithdrawnduetoadverseevents.(VERYLOWQUALITY)
theincidenceofthefollowingadverseevents:
pharyngitis(VERYLOWQUALITY)
Costeffectiveness
TheEpilepsies
208
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedfirstlinetreatmentwith
lamotriginemightbecosteffectivecomparedtofirstlinetreatmentwithcarbamazepine,butthere
wasconsiderableuncertaintyinthisresult(partiallyapplicableandpotentiallyseriouslimitations).
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedlamotriginemonotherapytobe
morecostlyandlesseffectivethancarbamazepinemonotherapy(directlyapplicableandpotentially
seriouslimitations).
timetofirstseizure
cognitiveoutcomes
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.
Evidencestatements
Significantlyfewerparticipantsonoxcarbazepinemonotherapywithdrewduetoadverseevents
comparedtophenytoinmonotherapy.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepineandphenytoininchildrenwithnewlydiagnosed
focalepilepsywasidentified.
timetofirstseizure
cognitiveoutcomes
TheEpilepsies
209
10.3.7.4 Vigabatrinversuscarbamazepine
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenvigabatrinmonotherapyandcarbamazapinemonotherapyforthe
proportionofseizurefreechildren.(VERYLOWQUALITY)
proportionofchildrenwithdrawnduetoadverseevents.(VERYLOWQUALITY)
incidenceof:
irritability/excitability(VERYLOWQUALITY).
weightincrease(VERYLOWQUALITY).
excessivesedation(VERYLOWQUALITY).
urticarialrash(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingvigabatrinandcarbamazepineinchildrenwithnewlydiagnosed
focalepilepsywasidentified.
timetofirstseizure
cognitiveoutcomes
10.3.8 HealtheconomicevidenceofAEDsusedasmonotherapyforchildrenwithnewly
diagnosedfocalepilepsy
Onestudy
184
assessingthecosteffectivenessofAEDsusedasmonotherapywasincludedinthe
economicevidencereview.SeeeconomicevidencetablesinappendixMforstudydetails,including
qualityassessmentofthemethodologyandapplicability.Astherewerestillgapsintheevidence
base,anoriginaleconomicmodelwasdevelopedtocompareAEDsusedasfirstlinemonotherapyin
TheEpilepsies
210
childrenwithnewlydiagnosedfocalepilepsy.ThiswasbasedonclinicalevidencefromNietoBarrera
2001
164
andGuerreiro1997
182
.SeeappendixRforfulldetailsandresultsofmodelling.
Table6: MonotherapyforchildrenwithnewlydiagnosedfocalepilepsyEconomicstudy
characteristics
NCGCModel
children
monotherapy(see
AppendixRfor
details)
comparatorsincluded
carbamazepine,
lamotrigineand
oxcarbazepine;time
horizon15yearsstarting
age2years;clinicaldata
basedonclinicalreview
Frew2007
184
Potentiallyseriouslimitations Partiallyapplicable Patientsimulation
decisionmodel;
comparatorsforfirstline
monotherapyincluded
standarddrugs(CBZ,VPA
andPHT)andLTG;time
horizonvariedbetween3
monthsand15years.
NCGCModelchildrenmonotherapy(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixR.
Table7: MonotherapyforchildrenwithnewlydiagnosedfocalepilepsyResultsofNCGCmodel
AED
Totalcost
()per
patient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
CBZ 15,170 10.343 At20KperQALYthreshold,probabilitymost
costeffective
Basecase:86.74%
Cohortstartingage=10yrs:73.38%
At30KperQALYthreshold:86.72%
LTG 15,612 10.251 Dominate
d
costeffective
Basecase:12.16%
OXC 16,467 10.183 Dominate
d
costeffective
Basecase:1.1%
Evidencestatements
TheEpilepsies
211
CarbamazepineisthemosteffectiveandleastcostlyamongtheAEDsevaluatedasmonotherapyin
childrenwithnewlydiagnosedfocalepilepsy(directlyapplicableandminorlimitations).
Lamotrigineandoxcarbazepinearemorecostlyandlesseffectivethancarbamazepine(directly
Frew(2007)
184
Table8: MonotherapyforchildrenwithnewlydiagnosedfocalepilepsyResultsofFrew2007
184
AED
Totalcost
()per
patient
Total
effects
(QALYs)
ICER
(/QALY) Uncertainty
Baseline(no
newAEDs)
Pointestimatescannot
bedeterminedfrom
thedataprovided
At20KperQALYthreshold,
probabilitymostcosteffective
Basecase:60%
LTG(firstline
monotherapy)
bedeterminedfrom
thedataprovided
Morecostlyandpossibly
moreeffective,butICER
cannotbedetermined
fromthedataprovided.
Basecase:40%
Evidencestatements
In40%ofsimulations,firstlinemonotherapywithlamotriginewasoptimalcomparedtoastrategy
involvingonlyolderdrugs(carbamazepine,sodiumvalproateand/orphenytoin).Therefore,
lamotriginemonotherapymaybecosteffective,butthereisconsiderableuncertaintyinthisdecision
(partiallyapplicableandpotentiallyseriouslimitations).Ifcurrentcostsforlamotriginewereused,
firstlinemonotherapywithlamotriginemaybeoptimalinagreaterproportionofsimulations.
Firstlinetreatmentinchildren,youngpeopleandadultswithnewlydiagnosedfocalseizures
Recommendation
85. Offercarbamazepineorlamotrigineasfirstlinetreatmentto
children,youngpeopleandadultswithnewlydiagnosedfocal
seizures.[new2012]
outcomes
Inchildren,youngpeopleandadults,seizurefreedom,withdrawal
duetoadverseeventsandtimetotreatmentfailure,timetofirst
seizureandtimeto12monthremissionwerethemostclinically
importantoutcomesforthisrecommendation.
benefitsandharms
Theefficacyatreducingseizureshastobebalancedagainstthe
potentialsideeffectsforeachofthesedrugs.
Lamotrigineandcarbamazepinewerebothfoundtohaveefficacy.
Carbamazepinehadalongertimetofirstseizure(inthemeta
analysisofdirectevidenceandtheIPDresults)andtherewasno
significantdifferenceforseizurefreedom.Lamotriginehasa
betteradverseeventsprofilethancarbamazepine.Lamotrigine
requiresslowtitrationtoreduceriskofrash,whichmaymakeit
unsuitableforindividualsrequiringrapidcontrol.Themeta
analysisofdirectevidencefoundsignificantlymoreparticipantson
carbamazepinecomparedtolamotriginewithdrewduetoadverse
TheEpilepsies
212
eventsandthedirectevidenceandIPDresultsshowed
carbamazepineprolongedthetimetofirstseizureandhada
shortertimetowithdrawalthanlamotrigine.Oxcarbazepinehasa
similaradverseeventsprofileandefficacytocarbamazepineand
lamotrigine,excepttheIPDanalysisfoundthatoxcarbazepinehad
longertimetofirstseizurethanlamotrigine.Whereasthedirect
evidencefoundnodifference.
Carbamazepinehadmoreefficacythansodiumvalproatebut
sodiumvalproateshowednosignificantdifferencesto
oxcarbazepine.Sodiumvalproatewouldnotbefirstchoicein
femalesofpresentorfuturechildbearingpotential,becauseof
increasedrisksofteratogenicity.
Inchildren,lamotrigineandcarbamazepinehavesimilarefficacy
andadverseeventsprofiles,withtheexceptionofincidenceof
dizzinesswhichismoreprominentwithcarbamazepine.
Lamotrigineandoxcarbazepinehadmoreefficacy(IPDresultsfor
timetowithdrawal,butnodifferenceinthedirectevidence)and
lessadverseeventsthanphenytoin.Itshouldbenotedthatthe
IPDmetaanalysisforlamotrigineversusphenytoinwasbasedon
indirectevidence.Phenytoinhadnosignificantdifferencewhen
comparedtocarbamazepine.Topiramatehadsimilarefficacyto
sodiumvalproateandoxcarbazepine.Howeverphenytoinand
topiramatehavedisadvantagesduetodruginteractionsandtheir
adverseeventsprofiles.Gabapentinwaslesseffectivethanother
AEDs.Vigabatrinisnotrecommendedbecauseofitsadverse
effectsinlongtermuse.Phenobarbitalisnotrecommended
becauseofadverseeffects.Clobazamisnotrecommended
becauseofconcernswithtolerability.Thereforethesedrugswere
notthoughttobeappropriatetorecommendasfirstline
treatment.
Economicconsiderations
TheGDGconsideredallrelevantsourcesofeconomicevidenceand
variousbasecaseandsensitivityanalysesfromtheoriginalNCGC
decisionmodelwhendevelopingtheirrecommendationsforfirst
linetreatmentofindividualswithnewlydiagnosedfocalseizures.
TheresultsoftheNCGCanalysisshowedthathealthbenefitsin
termsofQALYsgainedaresimilaracrossthevariousAEDsandit
showedthattherearesomedifferencesincost,particularly
betweendrugsthatarebeingproducedandprescribedgenerically
andthosethatarenot.Becauseofitslowacquisitioncostand
goodtolerability,theanalysisfoundthatlamotrigineislikelytobe
themostcosteffectiveAED.ResultsfromtheSANADtrialalso
foundlamotriginelikelytobeacosteffectivefirstlineAED,and
givenreductionsinitsunitcost,itmaybeevenmorecosteffective
nowthanwhenthetrialwasundertaken.Basedontheseresults,
theGDGfeltthatlamotriginewaslikelytorepresentgoodvaluefor
NHSresourcesandshouldbeofferedtopatientswithnewly
TheEpilepsies
213
diagnosedfocalseizureswhorequiretreatment.Inmakingtheir
recommendations,theGDGalsoconsideredtheresultsofaseries
ofkeysensitivityanalyseswhichindicatedthatcarbamazepinemay
beascosteffectiveaslamotriginedependingonthecosting
assumptionsmade.Becauseofthissubstantialuncertaintyand
givencarbamazepinescurrentplaceinthecareofpeoplewith
focalseizures,theGDGbelievedittooshouldbeanoptionforthe
firstlinetreatmentofindividualswithnewlydiagnosedfocal
seizures.
Amongchildren,theNCGCanalysisshowedthatastrategyof
offeringcarbamazepineasfirstlinetreatmentislikelytobemost
costeffective,butthatlamotrigineoroxcarbazepinemightbe
costeffectiveifcarbamazepinewereunsuitable.
TheGDGwishedtoguidehealthcareprofessionals,patientsand
commissionersoncosteffectivealternativestolamotrigineand
carbamazepineinthesituationwherethesewereconsidered
unsuitable.Todothis,theyreliedontheresultsofasensitivity
analysisinwhichlamotrigineand/orcarbamazepinewereremoved
fromconsideration.Insuchascenario,sodiumvalproatewas
consideredthemostcosteffectivealternativeandforpatientsfor
whomsodiumvalproatetooisinappropriate,oxcarbazepineis
mostlikelytorepresentthebestvalueforNHSresources.
Theestimationofoxcarbazepinesrelativecosteffectivenessasa
firstlineAEDwasdifferentintheNCGCanalysiscomparedtothe
findingsoftheSANADtrial.Bothanalysesfoundoxcarbazepineto
bethemosteffectiveAEDintermsofQALYgain,butwherethe
SANADtrialfoundittobecosteffective,theNCGCanalysisdidnot.
TheQALYdifferencebetweenoxcarbazepineandcarbamazepine
measuredintheSANADtrialwasnearly9timeslargerthanthe
samedifferencemodelledbytheNCGCanalysis.Giventhenon
significantdifferencesintermsofefficacyandtolerabilitybetween
oxcarbazepineandcarbamazepinefoundintheSANADtrialand
usedintheNCGCanalysisitseemsthattherearebenefitsto
treatmentwithoxcarbazepinenotcapturedbytheNCGCdecision
model.Thatsaid,itisunclearwhatbenefitsaredrivingthe
substantialQALYgainenjoyedbypatientsreceivingoxcarbazepine
intheSANADtrialoverandabovepatientsreceivingotherdrugs,
evenlamotrigine.TheQALYdifferencebetweenoxcarbazepine
andcarbamazepineismorethantwicethedifferencebetween
lamotrigineandcarbamazepine.
TheGDGconsideredthestrengthsandlimitationsofthetwo
sourcesofeconomicevidence,particularlyastheyappliedto
conclusionsaboutoxcarbazepine.Astrengthofawithintrial
analysislikeSANADisthatitisbasedonactualpatientdata;
however,alimitationisthatthesamewithintrialanalysisisonly
basedonthatdataandnotthesynthesisofalltrialdataacrossall
comparatorsofinterest.Anotherlimitationisthatthewithintrial
analysisfromSANADisbasedonlyoncostsandQALYsmeasured
overa2yeartimehorizon,whichispotentiallytooshortwhen
consideringthemanagementofalongtermconditionlike
TheEpilepsies
214
epilepsy.TheNCGCmodelisnotwithoutlimitations,butitwas
basedonalltheavailableevidence(includingSANAD),thankstoa
networkmetaanalysisundertakenbyTudurSmithand
colleagues
38
,includedallthecomparatorsrelevanttothedecision
problemanduseddataandinformedassumptionsaboutthe
extrapolationoftreatmenteffectsupto15years.
Withoutaclearunderstandingofexactlywhatisdrivingthe
differencebetweentheSANADtrialresultsandtheNCGCanalysis
results,theGDGwasfacedwithagenuineuncertaintyaboutthe
costeffectivenessofoxcarbazepine.Giventhisuncertaintyand
theknowledgethatthemeandailycostofoxcarbazepineisabout
2timesthatofcarbamazepineand5timesthatoflamotrigine,the
GDGdecidedtorecommendoxcarbazepineasareasonable
alternativewhenneitherofthesetwoaresuitableorwheneither
ispoorlytolerated.
InformedbytheevidencefromKwanandBrodie,theGDG
assumedthatthecosteffectivenessofdifferentAEDsusedasfirst
linemonotherapywouldholdtruefortheiruseassecondline
monotherapy.Forexample,iflamotriginewastrialledandpoorly
toleratedandcarbamazepinewasunsuitableforanygivenreason,
sodiumvalproatewouldrepresentthenextmostcosteffective
choice(oroxcarbazepineifsodiumvalproatewasinappropriate).
OtherAEDslicensedforuseasmonotherapy,includinggabapentin,
levetiracetamandtopiramate,werenotshowntobecosteffective
atcurrent2011prices.Howevernonproprietarylevetiracetamis
expectedtocometomarketwithinthenearfutureanditsrelative
costeffectivenesscomparedwiththeAEDslistedinthis
recommendationissensitivetochangesinunitcost.Becauseitis
difficulttoknownotonlyhowmuchthepriceoflevetiracetamwill
dropwiththeintroductionofgenericcompetition,butalsohow
muchthecostofotherAEDsmaychangeaswell,theGDGmade
recommendationsforthetreatmentofnewlydiagnosedfocal
seizuresbasedoncurrentinformation.Asubsequent
recommendationprovidesadditionalinformationtousersofthe
guidelineregardingthecircumstancesunderwhichlevetiracetam
islikelytobeacosteffectivefirstlineAED.
Phenytoinwasnotconsideredintheeconomicanalysisbecauseit
hasanarrowtherapeuticwindow.
Qualityofevidence Inadults,thestudiesincludedintheevidencewereoflowquality
duetoseriouslimitationsinthestudydesign.Manyofthestudies
wereunblindedorhadinadequatedetailingofrandomisationand
allocationconcealmentwithsomeofthestudieshavinghigh
dropout.Oneimportantstudy(theSANADtrialMarson,2007
41
wasalargepragmatictrialwhichinformedmanyofthe
comparisons.Thiswasanunblindedmulticentrestudy.Inchildren,
threestudieswereincluded(NietoBarrera,2001
164
,Guerreiro,
1997andZamponi1999)themajorityofwhichwereunblinded
withlimitations.
Otherconsiderations TheGDGfoundnoevidencetorefutetheplaceofdrugslistedas
TheEpilepsies
215
firstlineintheoriginalguideline.Theonlyexceptionwasfor
topiramatewhichhasbeenadvisedasadjunctivetherapybecause
itwasnotfoundtobecosteffectiveinthisanalysis.
Sodiumvalproateinhibitsthemetabolismoflamotrigine.This
needstobetakenintoconsiderationwhenintroducingor
withdrawingeithermedication.Onwithdrawalofsodium
valproate,lamotriginelevelsmaydropandthismaybethereason
forbreakthroughseizures.TheGDGconsideredthatinpractice
therewouldbeaconcomitantincreaseinthelamotriginedose.
Oxcarbazepineandcarbamazepinearehepaticenzymeinducing
drugsandmayinteractwithothermedications;thismayinfluence
thechoiceofAEDinsomeindividuals.Themetabolismof
lamotriginemaybeincreasedbyoestrogensincontraceptives.
Intheeventofusinganalternativedrug,rash,hyponatraemia,
enzymeinduction,CNSrelatedandotheradverseeventsfromthe
previousdrugsshouldallbetakenintoconsideration.
Thereisincreasedriskofsideeffectswithcarbamazepineinolder
people.Carbamazepinehasbeenassociatedwithahigher
incidenceofprematuredeathinoldpeoplecomparedto
lamotrigine.TheGDGsuggestedtheuseofthecontrolledrelease
preparationofcarbamazepineandtouselowdosesandescalate
verycautiously.Pleaserefertorecommendations80and253.
Otherwiseuseanalternativefirstlinetherapyinthispopulation.It
isbettertousenonenzymeinducingAEDsasthispopulationare
likelytobetakingothermedications.
DuringtheliteraturereviewweidentifiedananalysisofIndividual
PatientData(IPD)whichincludeddatafromeightIPDCochrane
reviewsanddatafromtheSANADtrialofeightdifferentAEDs
(carbamazepine,sodiumvalproate,phenytoin,phenobarbital,
oxcarbazepine,lamotrigine)inmonotherapyoffocalseizures
38
.
WeusedtheIPDanalysisassupplementaryevidencetothedirect
evidence.TheGDGconsideredtheIPDanalysisinthedecision
makingprocessalongsidethedirectevidence.
Inrelationtothefindings,commonresultswerefoundinour
directevidenceandtheIPDanalysis
38
.Inallanalyses,nosingle
drugwassignificantlymoreeffectivethancarbamazepinefortime
to12monthsremission.TheIPDanalysis
38
foundthatsodium
valproatewassignificantlylesseffectivethancarbamazepinein
achievingtimeto12monthsremissionandhadashortertimeto
firstseizure.Therewasnodirectevidenceforthisdrug
comparison.Othercomparisonswhichhadnodirectevidencebut
hadIPDresultsincludedphenytoinhadashortertimetotreatment
failurethanoxcarbazepineorphenobarbitalandashortertimeto
firstseizurethanphenobarbital.Resultswhichwerenon
significantforthedirectevidencebutsignificantfortheIPD
analysisincludedlamotriginewhichhadashortertimetofirst
seizurethantopiramateoroxcarbazepine.TheGDGconsidered
thatthedifferenceinresultsforsomecomparisonsoriginatedfrom
TheEpilepsies
216
thedifferentstudiescontributingtothedirectevidenceandthe
IPDanalyses.StudiesincludedintheIPDanalyseswereexcluded
fromthedirectevidencemainlyonthebasisthattheydidnot
meetthecutoffpointforexclusionofseizuretypesandtheage
distribution.
TheGDGconsideredthatdifferentpatientsreactdifferentlytothe
differentdrugsandtheremaybeaneedtotrydifferentoptionsto
getthebalancerightbetweenseizurefreedomandadverse
effects.IfthefirstAEDisineffective,asecondAEDshouldbe
addedalongsidetheinitialAEDand,ifseizuresarecontrolled,the
firstAEDmaybewithdrawn,recognisingthatsomepatientswill
prefertoremainontwoAEDsifseizurefree.TheGDGconsidered
thatitisgenerallypreferabletoavoidpolytherapy.
Recommendation
z
.
Offerlevetiracetam,oxcarbazepineorsodiumvalproate
(providedtheacquisitioncostoflevetiracetamfallstoatleast
50%ofJune2011valuedocumentedintheNationalHealth
ServiceDrugTariffforEnglandandWales)ifcarbamazepine
andlamotrigineareunsuitableornottolerated.Ifthefirst
AEDtriedisineffective,offeranalternativefromthesefive
AEDs.Beawareoftheteratogenicrisksofsodiumvalproate
outcomes
Seizurefreedom,withdrawalduetoadverseeventsand
withdrawalduetolackofefficacywereconsideredtobethemost
importantoutcomes.
benefitsandharms
Althoughbothlevetiracetamandcarbamazepinecontrolled
releasehadverysimilarfindingsintermsofefficacy,levetiracetam
hadahigherwithdrawalrateduetolackofefficacycomparedto
carbamazepinecontrolledreleasewhichiswhyitwasnot
recommendedasthedrugoffirstchoice.Howeveritmaybeuseful
forpeopleinwhomotherfirstlineAEDsarenotsuitable.
Oxcarbazepinehasasimilaradverseeventsprofileandefficacyto
carbamazepineandlamotrigine,excepttheIPDanalysisfoundthat
oxcarbazepinehadlongertimetofirstseizurethanlamotrigine.
Whereasthedirectevidencefoundnodifference.Carbamazepine
hadmoreefficacythansodiumvalproateandsodiumvalproate
showednosignificantdifferencestooxcarbazepine.Sodium
valproatewouldnotbeafirstchoiceinfemalesofpresentor
futurechildbearingpotential,becauseofincreasedrisksof
z
TheEpilepsies
217
teratogenicity.
TheGDGconsideredthatlevetiracetamlacksinteractionwith
otherdrugs.
TheGDGconsideredtheresultsoftheNCGCcosteffectiveness
analysis,inwhichsomeAEDslicensedforuseasmonotherapy,
includinggabapentin,levetiracetamandtopiramate,werenot
showntobecosteffectiveatcurrent2011prices.Giventhe
currentuseoflevetiracetaminclinicalpracticeandtheimminent
arrivalofgenericproductstothemarkettheGDGconsideredit
importanttoprovideadditionalinformationtousersofthe
guidelineregardingthecircumstancesunderwhichlevetiracetam
islikelytobeacosteffectivefirstlineAED.
Theanalysesshowedthatthereisquiteabitofuncertaintyaround
thecosteffectivenessoflevetiracetam,drivenbyalimitedclinical
evidencebaseandquestionsaboutitsfuturecost.Lamotrigine
wasfoundtobemorecosteffectivethanlevetiracetam,andthis
resultwasconsistentacrossarangeofsensitivityanalyses
(dominatinglevetiracetaminsomeandrepresentingbettervalue
formoneygiventheNICEthresholdinothers).Carbamazepine
wasalsomorecosteffectivethanlevetiracetam,exceptwhen
levetiracetamwasassumedtobemoretolerablethan
carbamazepineand70percentlesscostlythanitiscurrently.
TheGDGnextconsideredthesituationwhereincarbamazepine
andlamotrigineareconsideredunsuitableorhavebeenpoorly
tolerated.Basedontheinterpretationoftheevidence,theGDG
recommendedthatsodiumvalproateandoxcarbazepineare
consideredinthisgroup.Thesensitivityanalysisaroundcostwas
undertakenforthisclinicalscenarioaswell,andfoundthe
probabilityoflevetiracetambeingconsideredcosteffective
relativetosodiumvalproateandoxcarbazepineimprovesasprice
decreases.A50percentpricedecreasemakeslevetiracetammore
costeffectivethanoxcarbazepinebutnotcosteffectivecompared
tosodiumvalproate.However,iflevetiracetamismoretolerable
thancarbamazepine,thena50percentpricedecreasemakes
levetiracetamcosteffectivecomparedtobothdrugs,although
substantialuncertaintysurroundsthisconclusion.
WhenallrecommendedfirstlineAEDs(carbamazepine,
lamotrigine,oxcarbazepineandsodiumvalproate)areremoved
fromtheanalysisduetocontraindications,gabapentinistheAED
mostlikelytobeconsideredcosteffective.However,ifthefuture
acquisitioncostoflevetiracetamis20to30percentlessthanwhat
itiscurrently,thenlevetiracetambecomesthemostcosteffective
AEDgiventheNICEwillingnesstopaythreshold.TheGDG
consideredthisscenarioandconcludedthatinthesituationwhere
allrecommendedfirstlinedrugsarecontraindicatedorunsuitable,
thereisalikelihoodthatgabapentinandtopiramatemightnotbe
appropriateeither,thuslendingfurtherweighttothechoiceof
levetiracetamevenatcurrentcosts.Withtheexpectationthata
modestdropinitspricewillmoveitfrommarginallynotcost
TheEpilepsies
218
effectivetomostcosteffective,theGDGdecideditshouldbe
offeredinpreferencetogabapentininthisclinicalsituation.
TheGDGconsideredtheuncertaintiesaroundlevetiracetam
drivingtheresultsofthebasecaseandvarioussensitivityanalyses.
Theyalsoacceptedthattheydidnotknownotonlyhowmuchthe
priceoflevetiracetamwilldropwiththeintroductionofgeneric
competition,norhowmuchthecostofotherAEDsmightchange
aswell.Aftercarefulconsideration,theGDGdeterminedthat
levetiracetamshouldbeofferedasafirstlinetreatmentundertwo
circumstances.Firstly,inthecircumstancewhenallthe
recommendedfirstlinetreatments(carbamazepine,lamotrigine,
oxcarbazepineandsodiumvalproate)areunsuitable.Secondly,as
analternativetooxcarbazapineandsodiumvalproate(when
carbamazepineandlamotrigineareunsuitable,poorlytoleratedor
ineffective),iflevetiracetamcanbeacquiredforacostatleast50
percentlessthanJune2011unitcosts.TheGDGfeltthatthis
recommendationandthedetailincludetherein,wouldclearly
outlinetheconditionsunderwhichtreatmentwithlevetiracetam
wouldrepresentacosteffectiveuseoflimitedNHSresources.
Qualityofevidence Inadults,thestudiesincludedintheevidencewereoflowquality
duetoseriouslimitationsinthestudydesign.Manyofthestudies
wereunblindedorhadinadequatedetailingofrandomisationand
allocationconcealmentwithsomeofthestudieshavinghigh
dropout.Oneimportantstudy(theSANADtrialMarson,2007
41
wasalargepragmatictrialwhichinformedmanyofthe
comparisons.Thiswasanunblindedmulticentrestudy.Inchildren,
onestudyincludedoxcarbazepine(Guerreiro,1997)whichhad
seriouslimitations.
Onetrialwithhighdropoutratesinbotharmsshowedtherewas
nosignificantdifferencebetweenlevetiracetamand
carbamazepineintheproportionofseizurefreeparticipantsand
withdrawalduetoadverseevents.However,significantlyhigher
proportionofparticipantsonlevetiracetamwithdrewduetolack
ofefficacycomparedtocarbamazepine.ThisispartlyaGDG
consensusopinionbasedrecommendation.
Otherconsiderations Levetiracetamisonlylicensedforpeopleover16yearolds.Itis
usefulbecauseitdoesnotinteractwithhormonal
contraception.TheGDGopinionwasthatthelimitedevidence
currentlyavailablesuggeststhatlevetiracetamdoesnotcarryan
increasedriskofteratogenicity.
Sodiumvalproateinhibitsthemetabolismoflamotrigine.This
forbreakthroughseizures.TheGDGconsideredthatinpractice
therewouldbeaconcomitantincreaseinthelamotriginedose.
Oxcarbazepineisahepaticenzymeinducingdrugandmayinteract
withothermedications;thismayinfluencethechoiceofAEDin
someindividuals.
TheEpilepsies
219
(carbamazepine,sodiumvalproate,phenytoin,phenobarbital,
oxcarbazepine,lamotrigine)inmonotherapyoffocalseizures
38
.
Inrelationtothefindings,commonresultswerefoundinour
directevidenceandtheIPDanalysis
38
.Inallanalyses,nosingle
drugwassignificantlymoreeffectivethancarbamazepinefortime
to12monthsremission.TheIPDanalysis
38
foundthatsodium
valproatewassignificantlylesseffectivethancarbamazepinein
achievingtimeto12monthsremissionandhadashortertimeto
firstseizure.Therewasnodirectevidenceforthisdrug
comparison.Othercomparisonswhichhadnodirectevidencebut
hadIPDresultsincludedphenytoinhadashortertimetotreatment
failurethanoxcarbazepineorphenobarbitalandashortertimeto
firstseizurethanphenobarbital.Resultswhichwerenon
significantforthedirectevidencebutsignificantfortheIPD
analysisincludedlamotriginewhichhadashortertimetofirst
seizurethantopiramateoroxcarbazepine.TheGDGconsidered
thatthedifferenceinresultsforsomecomparisonsoriginatedfrom
thedifferentstudiescontributingtothedirectevidenceandthe
IPDanalyses.StudiesincludedintheIPDanalyseswereexcluded
fromthedirectevidencemainlyonthebasisthattheydidnot
meetthecutoffpointforexclusionofseizuretypesandtheage
distribution.
differentdrugsandtheremaybeaneedtotrydifferentoptions
mayneedtobetriedtogetthebalancerightbetweenseizure
freedomandadverseeffects.IfthefirstAEDisineffective,a
secondAEDshouldbeaddedalongsidetheinitialAEDand,if
seizuresarecontrolled,thefirstAEDmaybewithdrawn,
recognisingthatsomepatientswillprefertoremainontwoAEDsif
seizurefree.TheGDGconsideredthatitisgenerallypreferableto
avoidpolytherapy.
Recommendation
87. ConsideradjunctivetreatmentifasecondwelltoleratedAED
isineffective(seerecommendations85and86).[new2012]
outcomes
TheEpilepsies
220
benefitsandharms
Phenytoinhadlessefficacyandmoreadverseeventsthan
lamotrigine,oxcarbazepineandnosignificantdifferencecompared
tocarbamazepine.Topiramatehadsimilarefficacytosodium
valproateandoxcarbazepine.Howeverphenytoinandtopiramate
havedisadvantagesduetodruginteractionsandtheiradverse
eventsprofiles.GabapentinwaslesseffectivethanotherAEDs.
Vigabatrinisnotrecommendedbecauseofitsadverseeffectsin
longtermuse.Phenobarbitalisnotrecommendedbecauseof
adverseeffects.Clobazamisnotrecommendedbecauseof
concernswithtolerability.Thereforethesedrugswerenotthought
tobeappropriatetorecommendasfirstlinetreatment.
Levetiracetamandcarbamazepinecontrolledreleasehadvery
similarfindingsintermsofefficacy,butlevetiracetamhadahigher
withdrawalrateduetolackofefficacycomparedto
recommendedasthedrugoffirstchoice.HowevertheGDG
consideredittobeusefulforpeopleinwhomotherfirstlineAEDs
arenotsuitableandthatlevetiracetamlacksinteractionwithother
drugs.
TheGDGconsideredthatthefiveAEDs(lamotrigine,
carbamazepine,oxcarbazepine,sodiumvalproateand
levetiracetam)offeredasfirstlinetreatmentinnewlydiagnosed
focalseizuresmayhaveinstanceswheretheyaretoleratedbutare
noteffective.ThereforeduetotheconcernswiththeotherAEDs,
theGDGagreedthatinthesecasesadjunctivetreatmentshouldbe
considered.
Economicconsiderations Theoriginalcosteffectivenessanalysisundertakenforthe
guidelineindicatesthattheAEDsusedasadjunctivetherapyfor
refractoryfocalseizuresweremoreeffectiveandmorecostlythan
continuingpatientsonmonotherapy.However,adjunctivetherapy
withasubsetofAEDsmaybecosteffectiveattheNICEthreshold
of20,000perQALY.Thereisconsiderableuncertaintyastowhich
AEDrepresentstheoptimaluseofNHSresourcesasmuchdepends
onwhatisappropriatefortheindividualpatientandonhis/her
previoustreatmenthistory.
Qualityofevidence Thisrecommendationwasbasedontheclinicalexpertiseofthe
GDGandviaconsensusandtheevidencebasefromadjunctive
treatmentofrefractoryfocalseizureswhichincludedplacebo
controlledtrialswhichshoweditwasbettertohaveanytreatment
thannotreatment.
Otherconsiderations
Sodiumvalproatewouldnotbefirstchoiceinfemalesofpresentor
teratogenicity.
Sodiumvalproateinhibitsmetabolismoflamotrigine.Thisneedsto
TheEpilepsies
221
betakenintoconsiderationwhenintroducingorwithdrawing
eithermedication.Onwithdrawalofsodiumvalproate,
lamotriginelevelsmaydropandthismaybethereasonfor
breakthroughseizures.Thereshouldbeconcomitantincreasein
thelamotriginedose.
Thereisincreasedriskofsideeffectswithcarbamazepineinolder
people.Carbamazepinehasbeenassociatedwithahigher
incidenceofprematuredeathinoldpeoplecomparedto
lamotrigine.TheGDGsuggestedtheuseofthecontrolledrelease
preparationofcarbamazepineandtouselowdosesandescalate
verycautiously.Otherwiseuseanalternativefirstlinetherapyin
thispopulation.ItisbettertousenonenzymeinducingAEDsas
thispopulationarelikelytobetakingothermedications.
10.3.10 Newresearchrecommendations(forfulllistseesection2.11)
10.3.10.1 Newlydiagnosedseizures(focal&generalised)monotherapy
diagnosedepilepsy?
Focalseizures:carbamazepine,eslicarbazepineacetate,lacosamide,lamotrigine,
Generalisedseizures:lamotrigine,levetiracetam,sodiumvalproateandzonisamide.
Whythisisimportant
LevetiracetamandotherAEDslicensedforthetreatmentoffocalandgeneralisedseizuressince
publicationoftheoriginalguidelineTheepilepsies(NICEclinicalguideline20)in2004havenotbeen
evaluatedasfirstlinemonotherapy.
aprospectiverandomisedcontrolledtrial
allagegroups
TheEpilepsies
222
10.4 Therapyforrefractoryfocalseizures
10.4.1 Introduction
Focalseizures,asstatedintheprevioussection,originatefromoneareaofthebrain.Theyarethe
mostcommonseizuretypeinadultsandchildren.Althoughseizurefreedomremainsthegoalof
therapy,inthispopulationoptimalseizurecontrolmaybemoreachievable.Treatmentsuccesshas
beenmostrecentlydefinedbytheILAEasaseizurefreedurationthatisatleastthreetimesthe
longestseizurefreeintervalpriortostartingthenewtreatmentwithasustainedresponseover12m
(Kwanetal2009)
185
.
RecentEMA
aa
decisionsregardinglicensingofAEDSforuseinchildrenindicatethatforfocal
epilepsiesespeciallycryptogenicandsymptomatic,andidiopathicgeneralisedepilepsies,with
absences,myoclonicand/orgeneralisedconvulsiveseizures,()theefficacyofAEDsseemstobe
comparableinchildhoodandadulthood.Focalepilepsiesinchildrenolderthan4yearsoldhavea
similarclinicalexpressiontofocalepilepsiesinadolescentsandadults.Inrefractoryfocalepilepsies,
theresultsofefficacytrialsperformedinadultscouldtosomeextentbeextrapolatedtochildren
providedthedoseisestablished.Asaresultofthis,andwiththeagreementoftheGDGwehave
combineddataforadultsandchildrenintherefractoryfocalseizuresreview.
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereviews.
Forthisreviewweincludedadultsandchildrenwithrefractoryfocalseizures.Forstudiesinwhich
bothfocalandprimarygeneralisedseizureswerecombined,a20%thresholdwasusedasathreshold
forcontaminationfortheoutcomeofseizurefreedomanda50%thresholdfortheoutcomesof
adverseevents.
10.4.3 Matrixoftheevidence
WesearchedforRCTscomparingtheeffectivenessofdifferentpharmacologcialinterventionsfor
epilepsyinadultswithrefractoryfocalepilepsy.Theinterventionsweincludedinoursearchwere;
eslicarbazepineacetate,pregabalin,zonisamide,lacosamide,lamotrigine,gabapentin,
oxcarbazepine,tiagabine,levetiracetam,topiramate,vigabatrin,phenytoin,phenobarbital,
felbamate,clobazam,clonazepam,acetazolamide,primidone,sodiumvalproate,sulthiameand
carbamazepine.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreof
thesetreatments(orplacebo).Belowisamatrixshowingwhereevidencewasidentified.Abox
Inthiscase,nosectiononthiscomparisonisincludedinthechapter.
SingleAEDtherapyforrefractoryfocalseizures
Placebo
Lamotrigine
Tiagabine 1
186

Oxcarbazepine 1
187

aa http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070043.pdf
TheEpilepsies
223
Sodium
valproate
1
188

PLA LTG TGB OXC VPA
TheEpilepsies
PartialPharmacologicalUpdateofClinicalGuideline20 224
AdjunctiveAEDtherapyforrefractoryfocalseizures
Placebo
Carbamazepine
Clobazam 1
189

Eslicarbazepine
acetate
4
190193

Felbamate 1
194

Gabapentin 6
195199
,
200

Lacosamide 3
201,202
,
203

Lamotrigine 12
204213
,
214
,
215
1
216

LamotrigineXR 1
217

Levetiracetam 12
218225
,
226
,
227
,
228
,
229
1
230

Levetiracetam
XR
1
231

Oxcarbazepine 2
232
,
233

Phenytoin
Pregabalin 6
234238
,
215
1
215

Sodium
valproate
1
239
1
240

Topiramate 11
239,241248
,
249
,
250
1
251
2
239,252

TheEpilepsies
PartialPharmacologicalUpdateofClinicalGuideline20 225
Tiagabine 4
253256
1
257,258
1
259
2
257,258

Vigabatrin 9
206,260263,264266
,
267
1
268

Zonisamide 5
269272
,
273

Primidone 1
274

PLC CBZ CLB ECBZ FBM GBP LAC LTG LTG
XR
LEV LEV
XR
OXC PHT PGB VPA TPM TGB
Placebo(PLA) Clobazam(ClB)Eslicarbazepineacetate(ECBZ) Felbamate(FBMl) Gabapentin(GBP) Lacosamide(LAC)Lamotrigine(LTG)LamotrigineXR(LTGXR)
Levetiracetam(LEV) LevetiracetamXR(LEVXR) Oxcarbazepine(OXC) Topiramate(TPM)Tiagabine(TGB) Vigabatrin(VGB)Zonisamide(Zon)
TheEpilepsies
226
10.4.4 SingleAEDtherapyforrefractoryfocalseizures
Directclinicalevidence
181
oflamotrigine,sodiumvalproateandcarbamazepineasmonotherapyin
thetreatmentofadultswithrefractoryfocalepilepsywasidentifiedintheeconomicliterature
search.Theresultsofthisstudyarepresentedinfullinsection10.4.5.
Evidencestatements
theincidenceofheadache.(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedlamotriginemonotherapytobe
morecostlyandequallyeffectiveassodiumvalproatemonotherapyinapopulationwithrefractory
focalepilepsy(partiallyapplicableandveryseriouslimitations).Inthisanalysis,carbamazepine
monotherapywaslesscostlyandmoreeffectivethanbothsodiumvalproateandlamotrigine.
seizurefreedom
atleast50%reductioninseizurefrequency
timetofirstseizure
cognitiveoutcomes
10.4.4.2 Tiagabineversusplacebo
TheEpilepsies
227
Evidencestatements
Nosignificantdifferencebetweentiagabinemonotherapyandplacebofortheproportionof
participantswithdrawnduetolackofefficacy.(VERYLOWQUALITY)
Nosignificantdifferencebetweentiagabinemonotherapyandplacebofortheproportionof
participantswithdrawnduetoadverseevents.(VERYLOWQUALITY)
Nosignificantdifferencebetweentiagabinemonotherapyandplacebofortheincidenceofthe
followingadverseevents:
abnormalthinking(difficultyinconcentration)(VERYLOWQUALITY)
insomnia(VERYLOWQUALITY)
paresthesia(VERYLOWQUALITY)
amnesia(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingtiagabinemonotherapytoplacebowasidentified.
seizurefreedom
timetofirstseizure
cognitiveoutcomes
10.4.4.3 Oxcarbazepineversusplacebo
Evidencestatements
TheEpilepsies
228
Significantlymoreparticipantsonoxcarbazepinemonotherapyexperiencedseizurefreedom
comparedtoplacebo,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERY
LOWQUALITY)
Timetomeetingexit/withdrawalofallocatedtreatment(timetomeetoneoftheexitcriteria)
occurredsignificantlylessrapidlyinparticipantstakingplacebomonotherapycomparedto
participantstakingoxcarbazepinemonotherapy.(LOWQUALITY)
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandplacebofortheproportionof
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandplacebofortheincidenceofthe
vomiting(VERYLOWQUALITY)
pruritis(VERYLOWQUALITY)
diplopia(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytoplacebowasidentified.
timetofirstseizure
cognitiveoutcomes
10.4.5 HealthEconomicEvidenceforsingleAEDtherapyforrefractoryfocalseizures
Onestudy
181
assessingthecosteffectivenessofAEDsusedasmonotherapyinadultswithrefractory
focalepilepsywasincludedintheeconomicevidencereview.Seeeconomicevidencetablesin
appendixMforstudydetails,includingqualityassessmentsoftheirmethodologyandapplicability.
Table9: TherapyinadultswithrefractoryfocalepilepsyEconomicstudycharacteristics
Hawkins(2005)
181
Potentiallyseriouslimitations
(a)
Partiallyapplicable
(b,c)
Decisionanalyticmodel;
comparatorsincluded
carbamazepinesodium
valproateand
lamotrigine;timehorizon
TheEpilepsies
229
15years;clinicaldata
basedonnetworkmeta
analysisofdatafrom
Gilliam1998
188
andKerr
2001
275
(a) Unitcostsofinterventionsarefrom2002/03andsincethenlamotriginehascomeoffpatentandthenonproprietarypriceis
dramaticallylower.
(b) Effectivenessdatawasderivedfromanetworkmetaanalysisthatincludedatleastoneunpublishedstudythatwasnotreviewedas
partofoursystematicreview.
(c) Costsdiscountedat6%perannum;QALYsdiscountedat1.5%perannum.
Hawkins2005
181
SeeeconomicevidencetableinappendixMfordetails.
Table10: SingleAEDtherapyinrefractoryfocalseizuresEconomicsummaryoffindings
Hawkins2005
181
AED
Totalcost
()per
patient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
CBZ 5,599 8.865 At20KperQALYthreshold,probabilitymost
costeffective
Basecase:79%
VPA 5,728 8.856 Dominate
d
costeffective
Basecase:21%
LTG 6,749 8.856 Dominate
d
costeffective
Basecase:0%
Evidencestatements
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedcarbamazepinetobethemost
effectiveandleastcostly,andthereforemostcosteffectiveAEDusedinthetreatmentofrefractory
focalseizures.Thesameanalysisshowslamotrigineandsodiumvalproatetherapynottobecost
effective.Thisevidenceispartiallyapplicableandhasveryseriouslimitations.
10.4.6 Adjunctivetherapyinchildren,youngpeopleandadultswithrefractoryfocalseizures
10.4.6.1 Lamotrigineversusplacebo
Clinicalevidence
181
ofAEDsusedasadjunctivetherapyinthetreatmentofadultsandone
economicevaluation
184
ofAEDsusedinthetreatmentofchildrenandyoungpeoplewithrefractory
focalseizureswereidentifiedintheeconomicliteraturesearch.Astherewerestillgapsinthe
TheEpilepsies
230
economicevidencebase,twooriginaleconomicmodelsweredevelopedtocompareAEDsusedas
adjunctivetherapyinthetreatmentofrefractoryfocalseizures:onemodelfortheevaluationof
treatmentforadultsandanotherspecificallyforchildrenandyoungpeople.Thecompleteresultsof
thesepublishedstudiesandtheNCGCadjunctivetherapymodelsarepresentedinsections10.4.7
and10.4.8.
Evidencestatements
Significantlymoreparticipantsonlamotrigineadjunctivetherapycomparedtoplacebohadatleasta
50%reductioninseizurefrequency.(LOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandplaceboforseizurefreedom
(VERYLOWQUALITY).
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandplaceboforwithdrawaldueto
lackofefficacy(LOWQUALITY).
Significantlymoreparticipantsonlamotrigineadjunctivetherapycomparedtoplacebowithdrewdue
toadverseevents.(MODERATEQUALITY)
Significantlymoreparticipantsonlamotrigineadjunctivetherapycomparedtoplacebohadan
incidenceof:
dizziness(LOWQUALITY)
diplopia(LOWQUALITY)
ataxia(MODERATEQUALITY)
blurredvision(MODERATEQUALITY)
nausea(MODERATEQUALITY)
somnolence(MODERATEQUALITY)
vomiting,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
pain(LOWQUALITY)
vertigo(MODERATEQUALITY)
tremor,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(MODERATE
QUALITY)
Significantlymoreparticipantsonplacebocomparedtolamotrigineadjunctivetherapyhadan
incidenceofrespiratorydisorder(LOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandplacebofortheincidenceof
thefollowingadverseevents:
headache(LOWQUALITY)
rash(VERYLOW)
drowsiness(VERYLOW)
faintness(VERYLOW)
dyspepsia(VERYLOW)
TheEpilepsies
231
nasalcongestion(VERYLOW)
fatigue(VERYLOW)
flushing(VERYLOW)
coordinationabnormality(VERYLOW)
asthenia(VERYLOW)
visionabnormality(VERYLOW)
rhinitis(VERYLOW)
tiredness(VERYLOW)
accidentalinjury(VERYLOW)
infection(LOWQUALITY)
diarrhoea(LOWQUALITY)
fever(LOWQUALITY)
abdominalpain(LOWQUALITY)
otitismedia(LOWQUALITY)
pharyngitis(LOWQUALITY)
death(VERYLOW)
aggravationofseizures(VERYLOW)
QualityofLifeoutcomesstatisticallysignificant
Significantlymoreparticipantsinthelamotrigineadjunctivetherapygroupcomparedtotheplacebo
grouphadhigherscoresinthefollowingpsychologicaldomaintests:
happiness
mastery
Thereisnosignificantdifferencebetweenlamotrigineadjunctivetherapyandplacebothefollowing
aspectsofhealthrelatedqualityoflife:
physical
social
psychological
Thereisnosignificantdifferencebetweenlamotrigineadjunctivetherapyandplaceboforthe
followingcognitivetests:
Strooptest
LeedsPsychomotortest
Numbercancellationtest
Costeffectiveness
Availableeconomicevidenceindicatesthatinthetreatmentofchildren,youngpeopleandadults,
adjunctivelamotrigineiscosteffectivecomparedtoplacebo.
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongadults,theaddition
oflamotriginewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
thancontinuationofexistingtherapyalone(placebo),withanexpectedincrementalcost
TheEpilepsies
232
effectivenessratioof7,507.Thisconclusionwasconsistentacrossarangeofsensitivityanalyses
ApublishedcosteffectivenessanalysisbyHawkinsandcolleaguesalsofoundthatamongadults,
lamotriginewascosteffectivecomparedtoplacebo,butfoundthatitwasextendedlydominated
byadjunctiveoxcarbazepine.However,theiranalysiswasbasedonanowoutofdatesystematic
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongchildren,the
additionoflamotriginewasassociatedwithincreasedcostsandbetterhealthoutcomes(higher
QALYs)thancontinuationofexistingtherapyalone(placebo),withanincrementalcost
effectivenessratioof5,717perQALY.Thisconclusionwasconsistentacrossarangeof
sensitivityanalyses.Notethatwhenallrelevantcomparatorswereevaluatedtogether,
oxcarbazepineextendedlydominateslamotrigineandisthemostcosteffectiveadjunctiveAED
forchildrengivenawillingnesstopaythresholdof20,000perQALYgained(directlyapplicable
ApublishedcosteffectivenessbyFrewandcolleaguesfoundthattherewastoomuchuncertainty
toreachadefinitiveconclusionabouttherelativecosteffectivenessofanyparticularadjunctive
AEDstrategy(partiallyapplicableandpotentiallyseriouslimitations).
timetofirstseizure
10.4.6.2 Lamotrigineextendedreleaseversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Lamotrigineextendedreleasewasnot
includedintheoriginaleconomicmodelasitisnotcurrentlyavailableintheUK.
Evidencestatements
Significantlymoreparticipantsonlamotrigineextendedreleaseadjunctivetherapywereseizurefree
thantheplacebo.(MODERATEQUALITY)
Significantlymoreparticipantsonlamotrigineextendedreleaseadjunctivetherapythantheplacebo
experiencedatleasta50%reductioninseizurefrequency.(MODERATEQUALITY)
Significantlymoreparticipantsonlamotrigineextendedreleaseadjunctivetherapywithdrewdueto
adverseeventscomparedtothosetakingplacebo,althoughthereisuncertaintyoverthemagnitude
ofitsclinicaleffect.(LOWQUALITY)
Significantlymoreparticipantsinthelamotrigineextendedreleaseadjunctivetherapythanthe
placeboexperienceddizziness.(MODERATEQUALITY)
TheEpilepsies
233
Significantlyfewerparticipantsinthelamotrigineextendedreleaseadjunctivetherapyexperienced
nasopharyngitisthantheplacebo.(MODERATEQUALITY)
Nosignificantdifferencebetweenlamotrigineextendedreleaseadjunctivetherapyandplacebofor
theincidenceofheadache.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglamotrigineextendedreleaseadjunctivetherapytoplacebowas
identified.However,theeconomicevidencefornormalreleaseformulationlamotrigineindicates
thatitiscosteffectivewhencomparedwithplacebo.Thecosteffectivenessofextendedrelease
formulationlamotrigineisdependentonhowmuchmoreitmightcostthannormalrelease
formulationlamotrigineandwhetheritisequallyeffectiveandmoreorlesstolerable.
timetofirstseizure
cognitiveoutcomes
10.4.6.3 Lamotrigineversuslevetiracetam
Clinicalevidence
FordetailsoftheclinicalevidencepleaserefertoAppendixN.Fordetailsoneachpaperidentifiedin
181
ofAEDs,includinglamotrigineandlevetiracetam,usedasadjunctive
therapyinthetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomic
literaturesearch.NostudiescomparingtheseAEDsinthetreatmentofchildrenandyoungpeople
wereidentified.Astherewerestillgapsintheeconomicevidencebase,twooriginaleconomic
modelsweredevelopedtocompareAEDsusedasadjunctivetherapyinthetreatmentofrefractory
focalseizures:onemodelfortheevaluationoftreatmentforadultsandanotherspecificallyfor
childrenandyoungpeople.ThecompleteresultsofthisstudyandtheNCGCadjunctivetherapy
modelsarepresentedinsections10.4.7and10.4.8.
Evidencestatements
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandlevetiracetamadjunctive
therapyfortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
therapyforwithdrawalduetoadverseevents.(VERYLOWQUALITY)
TheEpilepsies
234
therapyfortheincidenceof:
therapyforincidenceofdeath.(VERYLOWQUALITY)
Cognitiveeventsandqualityoflifestatisticallysignificantresults
TherewasasignificantimprovementinProfileofMoodStates(POMS)angerhostilitysubscaleand
family/friendcompletedmeasureofdepressivesymptomsforlamotrigineadjunctiverelativeto
levetiracetamadjunctivetherapy.
TherewasasignificantimprovementinIDASscalesofirritabilityandanxietyforlamotrigine
adjunctivetherapycomparedtolevetiracetamadjunctivetherapy.
TherewasasignificantimprovementinIDASscaleofdepressionforlevetiracetamadjunctivetherapy
comparedtolamotrigineadjunctivetherapy.
Cognitiveeventsandqualityoflifestatisticallynonsignificantresults
Nosignificantimprovementsforlamotrigineadjunctiverelativetolevetiracetamadjunctiveatendof
maintenanceperiodformostofthesubscalesincluding:
POMStotalmooddisturbance,depressiondejection,vigoractivity,fatigueinertia,confusion
bewildermentandtensionanxietysubscales.
NDDIEpatientcompletedmeasureofdepressivesymptoms
ESSdaytimesleepinessmeasure
STAXImeasureoftheexperience,expression,andcontrolofanger
BDIIImeasureofseverityofdepressivesymptoms.
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivelevetiracetamisnotcosteffectivecompared
toadjunctivelamotrigine.
OnepublishedcosteffectivenessanalysisbyHawkinsandcolleaguesshowedadjunctive
levetiracetamtobemorecostlyandmoreeffectivethanadjunctivelamotrigine,buthad
incrementalcosteffectivenessratiosthatexceededtheNICEwillingnesstopaythresholdof
20,000perQALYgained.However,theiranalysiswasbasedonanowoutofdatesystematic
Resultsofthecosteffectivenessanalysesundertakenfortheguidelinealsoshowedthatinthe
treatmentofchildren,youngpeopleandadults,giventhecurrent2011costoflevetiracetam,
adjunctivelevetiracetamwasmorecostlyandmoreeffectivethanadjunctivelamotrigine.
o Amongadults,theincrementalcosteffectivenessratioforlevetiracetamwas33,192.This
conclusionwasconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminor
limitations).
o Amongchildren,theincrementalcosteffectivenessratioforlevetiracetamwas24,503.This
conclusionisconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminor
limitations).
TheEpilepsies
235
Resultsoftheguidelineanlysesindicatedthatonlyiflevetiracetamcanbeacquiredforatleast30
percentlessthanitscurrent2011unitcostisitpotentiallycosteffectivewhencomparedwith
lamotrigine.
timetofirstseizure
10.4.6.4 Lamotrigineversustiagabine
Clinicalevidence
181
ofAEDs,includinglamotrigineandtiagabine,usedasadjunctivetherapy
inthetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomicliterature
developedtocompareAEDsusedasadjunctivetherapyinadultswithrefractoryfocalseizures.The
completeresultsofthisstudyandtheNCGCadultsadjunctivetherapymodelarepresentedin
section10.4.8.
Evidencestatements
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandtiagabineadjunctivetherapy
forseizurefreedom(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandtiagabineadjunctivetherapy
for50%reductioninseizurefrequency.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandtiagabinetherapyforincidence
of:
disturbedsleep(VERYLOWQUALITY)
nervousness(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivetiagabineisnotcosteffectivewhencompared
tolamotrigine.
TheEpilepsies
236
Onepublishedevaluationfoundthatlamotriginedominatedtiagabine;thatis,treatmentwith
adjunctivelamotriginewasassociatedwithlowercostsandbetterhealthoutcomes(higher
QALYs)thantreatmentwithadjunctivetiagabine(partiallyapplicableandpotentiallyserious
limitations).
Thecosteffectivenessanalysisdevelopedfortheguidelinefoundthatadjunctivetiagabinewas
morecostlyandmoreeffectivethanadjunctivelamotrigine,butwithanunacceptablyhigh
incrementalcosteffectivenessratioof131,882perQALY.Thisconclusionwasconsistentacross
arangeofsensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
Clinicalevidence
HealthEconomicevidence
181
economicevaluation
184
and10.4.8.
Evidencestatements
Significantlymoreparticipantsontopiramateadjunctivetherapythanlamotrigineadjunctivetherapy
experiencedseizurefreedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.
(VERYLOWQUALITY)
Significantlymoreparticipantsontopiramateadjunctivetherapycomparedtolamotrigineadjunctive
therapyhadanincidenceofheadache,althoughthereisuncertaintyinthemagnitudeofitsclinical
effect.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandtopiramateadjunctivetherapy
forwithdrawalduetoadverseevents.(VERYLOWQUALITY)
TheEpilepsies
237
fortheincidenceof
Lamotrigineadjunctivetherapyhadsignificantlybetterscorescomparedtotopiramateadjunctive
therapyfor:
COWA
POLtesttotaloverallscore
combinedcognitivescores
Topiramateadjunctivetherapyhadsignificantlybetterscorescomparedtolamotrigineadjunctive
therapyfor:
Stroopcolourwordinterference
Symboldigitmodalities(correctnumber)
for:
RAVLTdelayedrecall
Lafayettegroovedpegboard
Digitcancellationtest
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivetopiramatemaybecosteffectivecomparedto
lamotrigine,butthereisuncertaintyinthisconclusion.
Resultsfromonepublishedevaluationfoundthattopiramatewasmorecostlyandmoreeffective
thatlamotrigine,withanincrementalcosteffectivenessratioof35,484perQALY.However,
theiranalysiswasbasedonanowoutofdatesystematicreviewand200203costs(partially
Thecosteffectivenessanalysisdevelopedfortheguidelinealsofoundthatadjunctivetopiramate
wasmorecostlyandmoreeffectivethanadjunctivelamotrigine,butthattheincrementalcost
effectivenessratiovarieddependingonassumptionsmade.ThebasecaseshowedtheICERto
exceedtheNICEwillingnesstopaythresholdof20,000,butinsensitivityanalyseswherealarger
proportionofpatientswereassumedtoachieveseizurefreedomfromtreatment,theICERcame
downto16,569.Similarly,whenthelowestacquisitioncostofalldrugswasused,theICER
droppedfurtherto12,026(directlyapplicableandminorlimitations).
timetofirstseizure
TheEpilepsies
238
10.4.6.6 Levetiracetamversusplacebo
Clinicalevidence
181
ofAEDs,includinglevetiracetamandplacebo,usedasadjunctive
therapyinthetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomic
literaturesearch.NostudiescomparingtheseAEDsinthetreatmentofchildrenandyoungpeople
wereidentified.Astherewerestillgapsintheeconomicevidencebase,twooriginaleconomic
modelsweredevelopedtocompareAEDsusedasadjunctivetherapyinthetreatmentofrefractory
focalseizures:onemodelfortheevaluationoftreatmentforadultsandanotherspecificallyfor
childrenandyoungpeople.ThecompleteresultsofthisstudyandtheNCGCadjunctivetherapy
modelsarepresentedinsections10.4.7and10.4.8.
Evidencestatements
Significantlymoreparticipantsonlevetiracetamadjunctivetherapythanplaceboexperiencedat
leasta50%reductioninseizurefrequency.(LOWQUALITY)
Significantlymoreparticipantsonlevetiracetamadjunctivetherapythanplaceboexperiencedseizure
freedom.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboforwithdrawaldue
tolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantsonlevetiracetamadjunctivetherapythantheplacebohadhigher
incidenceof:
infection(MODERATEQUALITY)
asthenia(MODERATEQUALITY)
Significantlymoreparticipantsonplacebothanlevetiracetamadjunctivetherapyhadhigher
incidenceofaggravationofseizures(MODERATEQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboforwithdrawaldue
toadverseevents(VERYLOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboforincidenceof:
abdominalpain(VERYLOWQUALITY)
alanineaminotransferase(VERYLOWQUALITY)
TheEpilepsies
239
aspartateaminotransferase(VERYLOWQUALITY)
decreasesinplatelets(VERYLOWQUALITY)
decreasesinwhitebloodcells(VERYLOWQUALITY)
agitation(VERYLOWQUALITY)
nasopharyngitis(VERYLOWQUALITY)
accidentalinjury(VERYLOWQUALITY)
diarrhoea(VERYLOWQUALITY)
flu(VERYLOWQUALITY)
pain(VERYLOWQUALITY)
rhinitis(LOWQUALITY)
anorexia(LOWQUALITY)
hostility(LOWQUALITY)
increasedcough(LOWQUALITY)
upperrespiratoryinfection(VERYLOWQUALITY)
aggression(VERYLOWQUALITY)
psychomotorhyperactivity(VERYLOWQUALITY)
irritability(VERYLOWQUALITY)
incidenceofsomnolence(VERYLOWQUALITY)
death(VERYLOWQUALITY)
Qualityoflifeoutcomesstatisticallysignificantresults
Participantsinlevetiracetam(1000mgand3000mg)adjunctivegrouphadsignificantimprovementin
meanscorescomparedtoplaceboonthefollowingQOLIE31measures:
seizureworry
overallQoL
cognitivefunctioning
totalscore
socialfunction
Participantsinthelevetiracetamgroupworsenedwhereasplacebopatientsimprovedonthe
aggressivebehaviourscore.
Participantsinlevetiracetam(1000mgand3000mg)adjunctivegrouphadnosignificant
improvementinmeanscorescomparedtoplaceboonthefollowingQOLIE31measures:
Emotionalwellbeing
Energyfatigue
Medicationeffects
TheEpilepsies
240
Healthstatus
Participantsinlevetiracetamadjunctivegrouphadnodifferenceinmeanscoreschangescompared
toplaceboonthefollowingcognitivemeasures:
WFAML2changeofgeneralmemory,visualmemory,verbalmemory,attention/concentration.
LeiterRERSchangeinthecognitive/socialandemotions/regulationsdomains
CHQPF50Socialemotional/behavioural/behaviour/mentalhealthandpsychosocialscores.
Costeffectiveness
Availableeconomicevidenceindicatesthatinthetreatmentofchildrenandadults,adjunctive
levetiracetammaybecosteffectivecomparedtoplacebo.
oflevetiracetamwasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
sensitivityanalyses.However,whenallrelevantcomparators,atJune2011costs,wereevaluated
together,adjunctiveoxcarbazepineandlamotriginewerelikelytorepresentmorecosteffective
usesofNHSresources(directlyapplicableandminorlimitations).
o Onlyiflevetiracetamcanbeacquiredforatleast30percentlessthanitscurrent2011unitcost
diditdominateoxcarbazepineandwasitfoundtobepotentiallycosteffectivecomparedwith
lamotrigine.
OnepublishedanalysisbyHawkinsandcolleaguesfoundthatlevetiracetamwasmorecostlyand
moreeffectiveatanincrementalcosteffectivenessratioexceendingtheNICEwillingnesstopay
threshold;however,theiranalysiswasbasedonanowoutofdatesystematicreviewand2002
additionoflevetiracetamwasassociatedwithincreasedcostsandbetterhealthoutcomes(higher
effectivenessratioof14,286perQALY.Thisconclusionisconsistentacrossarangeofsensitivity
analyses.However,whenallrelevantcomparators,atJune2011costs,wereevaluatedtogether,
adjunctiveoxcarbazepineandlamotriginewerelikelytorepresentmorecosteffectiveusesof
NHSresources(directlyapplicableandminorlimitations).
o Onlyiflevetiracetamcanbeacquiredforatleast40percentlessthanitscurrent2011unitcost
diditdominateoxcarbazepineandwasitfoundtobecosteffectivecomparedwith
lamotrigine.
timetofirstseizure
10.4.6.7 Levetiracetamextendedreleaseversusplacebo
Clinicalevidence
TheEpilepsies
241
Nostudieswereidentifiedintheeconomicliteraturesearch.Levetiracetamextendedreleasewas
notincludedintheoriginaleconomicmodelasitisnotcurrentlyavailableintheUK.
Evidencestatements
Significantlymoreparticipantsonlevetiracetamadjunctivetherapy(extendedrelease)thanplacebo
experiencedseizurefreedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.
(MODERATEQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapy(extendedrelease)andplacebo
fortheproportionofparticipantsexperiencingatleasta50%reductioninseizurefrequency.
(MODERATEQUALITY)
fortheproportionofparticipantshavingtreatmentwithdrawnduetolackofefficacy.(LOW
QUALITY)
fortheproportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(LOW
QUALITY)
fortheincidenceofheadache.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingextendedreleaselevetiracetamadjunctivetherapytoplacebowas
identified.However,theeconomicevidencefornormalreleaseformulationlevetiracetamindicates
thatitiscosteffectivewhencomparedwithplacebo.Thecosteffectivenessofextendedrelease
formulationlevetiracetamisdependentonhowmuchmoreitmightcostthannormalrelease
formulationlevetiracetamandwhetheritisequallyeffectiveandmoreorlesstolerable.Notethat
whenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,adjunctive
oxcarbazepineandlamotriginewerelikelytorepresentmorecosteffectiveuseofNHSresources.
timetofirstseizure
cognitiveoutcomes
10.4.6.8 Topiramateversusplacebo
Clinicalevidence
TheEpilepsies
242
181
economicevaluation
184
and10.4.8.
Evidencestatements
Significantlymoreparticipantsontopiramateadjunctivetherapythanplaceboexperiencedatleasta
50%reductioninseizurefrequency.(MODERATEQUALITY)
Significantlymoreparticipantsontopiramateadjunctivetherapythanplaceboexperiencedseizure
freedom.(MODERATEQUALITY)
Nosignificantdifferencewasfoundbetweentopiramateadjunctivetherapyandplaceboforthe
proportionofparticipantswithdrawnduetolackofefficacy(VERYLOWQUALITY).
Significantlymoreparticipantsontopiramateadjunctivetherapythanplacebowithdrewdueto
adverseevents.(MODERATEQUALITY)
Significantlymoreparticipantsontopiramateadjunctivetherapythanplaceboexperiencedan
incidenceof:
anorexia(MODERATEQUALITY)
abdominaldiscomfort/pain,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect
(LOWQUALITY)
somnolence(LOWQUALITY)
confusion,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
weightdecrease(VERYLOWQUALITY)
fatigue(LOWQUALITY)
impairedconcentration,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect
(VERYLOWQUALITY)
abnormalthinking,althoughthereisuncertaintyinthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
ataxia(LOWQUALITY)
paraesthesia,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
emotionallability(VERYLOWQUALITY)
TheEpilepsies
243
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplacebofortheincidenceof:
nausea/vomiting(VERYLOW)
headache(VERYLOW)
amblyopia(VERYLOW)
dizziness/somnolence(VERYLOW)
speechdisorder(VERYLOW)
aphasia(VERYLOW)
abnormalvision(VERYLOW)
anxiety(VERYLOW)
depression(VERYLOW)
nervousness(VERYLOW)
amnesia(VERYLOW)
upperrespiratorytractinfection(VERYLOW)
pharyngitis(VERYLOW)
asthenia(VERYLOW)
injury(VERYLOW)
nystagmus(VERYLOW)
diplopia(VERYLOW)
diarrhoea(VERYLOW)
nausea(VERYLOW)
incidenceofmemorydifficulty(VERYLOW)
speechdifficulty(VERYLOW)
aggravationofseizures(VERYLOWQUALITY)
sinusitis(VERYLOWQUALITY)
coughing(VERYLOWQUALITY)
moodproblems(VERYLOWQUALITY)
viralinfenction(VERYLOWQUALITY)
otitismedia(VERYLOWQUALITY)
purpura(VERYLOWQUALITY)
fever(VERYLOWQUALITY)
Participantsintopiramateadjunctivegrouphadsignificantlyworsescoresforthefollowingtests
comparedtoplacebogroup:
SDMT
COWA
Stroopword
Stroopcolour
Costeffectiveness
Availableeconomicevidenceindicatesthatinthetreatmentofchildrenandadults,topiramateis
costeffectivecomparedtoplacebo.
TheEpilepsies
244
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongadultstheaddition
oftopiramatewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
sensitivityanalyses.Notethatwhenallrelevantcomparatorswereevaluatedtogetherinthe
NCGCbasecaseanalysis,adjunctiveoxcarbazepineandlamotriginewerelikelytorepresentmore
costeffectiveuseofNHSresources.However,intwosensitivityanalyses,onewherealarger
proportionofpatientswereassumedtoachieveseizurefreedomfromtreatmentandanother
whenthelowestacquisitioncostofalldrugswasused,topiramatewaslikelytobemorecost
effectivethanbothoxcarbazepineandlamotrigine(directlyapplicableandminorlimitations).
OnepublishedanalysisbyHawkinsandcolleaguesfoundthattopiramatewasmorecostlyand
moreeffectiveatanincrementalcosteffectivenessratioexceedingtheNICEwillingnesstopay
threshold;however,theiranalysiswasbasedonanowoutofdatesystematicreviewand2002
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongchildrenthe
additionoftopiramatewasassociatedwithincreasedcostsandbetterhealthoutcomes(higher
analyses.Notethatwhenallrelevantcomparatorswereevaluatedtogether,oxcarbazepine
dominatesadjunctivetopiramateandisthemostcosteffectiveadjunctiveAEDgivenawillingness
topaythresholdof20,000perQALYgained(directlyapplicableandminorlimitations).
timetofirstseizure
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Adjunctivesodiumvalproatewasnot
includedintheoriginaleconomicmodelasitisnotcommonlyusedasadjunctivetreatment.
Evidencestatements
Nosignificantdifferencebetweentopiramateadjunctivetherapyandsodiumvalproateadjunctive
therapyforwithdrawalduetolackofefficacy.(VERYLOWQUALITY)
TheEpilepsies
245
therapyforwithdrawalduetoadverseevents.(LOWQUALITY)
therapyfortheincidenceof:
memorydifficulty(VERYLOWQUALITY)
speechdifficulty(VERYLOWQUALITY)
depression(VERYLOWQUALITY)
Significantlyworsescorescomparedtobaselineforimmediaterecallfortopiramateadjunctive
therapyandsignificantimprovementcomparedtobaselineforsodiumvalproateadjunctivetherapy.
Nosignificantchangebetweentopiramateadjunctivetherapyandsodiumvalproateadjunctive
therapyforscoresofcognitiveorqualityoflifeonthefollowingmeasures:
motorspeed/motorfluency
alertness/reactionspeed
informationprocessingspeed
memory
profileofMoodStates(POMS)scale
Costeffectiveness
Noeconomicevidencecomparingadjunctivetopiramatetoadjunctivesodiumvalproatewas
identified.
seizurefreedom
timetofirstseizure
10.4.6.10 GabapentinversusPlacebo
Clinicalevidence
181
economicevaluation
184
TheEpilepsies
246
and10.4.8.
Evidencestatements
Significantlymoreparticipantsongabapentinadjunctivetherapythanplaceboexperiencedatleasta
Nosignificantdifferencebetweengabapentinadjunctivetherapyandplacebofortheproportionof
seizurefreeparticipants.(VERYLOWQUALITY)
Nosignificantdifferencebetweengabapentinadjunctivetherapyandplaceboforwithdrawaldueto
lackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantsongabapentinadjunctivetherapythanplacebowithdrewdueto
Significantlymoreparticipantsongabapentinadjunctivetherapythanplaceboexperiencedthe
incidenceof:
dizziness(MODERATEQUALITY)
ataxia(MODERATEQUALITY)
viralinfection,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(MODERATE
QUALITY)
fever(MODERATEQUALITY)
Significantlymoreparticipantsonplacebothangabapentinadjunctivetherapyexperienced
aggravationofseizures.(MODERATEQUALITY)
Nosignificantdifferencebetweengabapentinadjunctivetherapyandplacebofortheincidenceof:
nystagmus(VERYLOWQUALITY)
tremor(VERYLOWQUALITY)
rhinitis(VERYLOWQUALITY)
drowsiness(VERYLOWQUALITY)
blurredvision(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatinthetreatmentofchildrenandadults,gabapentinis
costeffectivecomparedtoplacebo.
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongadultstheaddition
ofgabapentinwasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
TheEpilepsies
247
sensitivityanalyses.Notethatwhenallrelevantcomparatorswereevaluatedtogetherinthe
NCGCbasecaseanalysis,adjunctiveoxcarbazepineandlamotriginewerelikelytorepresentmore
costeffectiveuseofNHSresources.However,whenneitheroxcarbazepinenorlamotrigineare
suitablegabapentinislikelytobethemostcosteffectiveadjunctiveAED(directlyapplicableand
minorlimitations).
OnepublishedanalysisbyHawkinsandcolleaguesfoundthatforadultsgabapeninwasmore
costlyandmoreeffectiveatanincrementalcosteffectivenessratioexceedingtheNICE
willingnesstopaythreshold;however,theiranalysiswasbasedonanowoutofdatesystematic
Acosteffectivenessanalysisundertakenfortheguidelineshowedthatamongchildrenthe
additionofgabapentinwasassociatedwithincreasedcostsandbetterhealthoutcomes(higher
analyses.Notethatwhenallrelevantcomparatorswereevaluatedtogether,oxcarbazepineisthe
mostcosteffectiveadjunctiveAEDgivenawillingnesstopaythresholdof20,000perQALY
gained(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Adjunctivesodiumvalproatewasnot
includedintheoriginaleconomicmodelasitisnotcommonlyusedasadjunctivetreatment.
Evidencestatements
Nosignificantdifferencebetweengabapentinadjunctivetherapyandsodiumvalproateadjunctive
therapyfortheproportionofparticipantsachievingatleasta50%reductioninseizurefrequency
(VERYLOWQUALITY)
therapyfortheproportionofparticipantsachievingseizurefreedom(VERYLOWQUALITY)
TheEpilepsies
248
therapyforwithdrawalduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivegabapentintoadjunctivesodiumvalproatewas
identified.
timetofirstseizure
cognitiveoutcomes
10.4.6.12 Gabapentinversusvigabatrin
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Asthereweregapsintheeconomic
evidencebase,anoriginaleconomicmodelwasdevelopedtocompareAEDsusedasadjunctive
therapyinadultswithrefractoryfocalseizures.ThecompleteresultsofthesestudiesandtheNCGC
adultsadjunctivetherapymodelarepresentedinsection10.4.8.
Evidencestatements
Nosignificantdifferencebetweengabapentinadjunctivetherapyandvigabatrinadjunctivetherapy
fortheproportionofparticipantsachievingatleasta50%reductioninseizurefrequency(VERYLOW
QUALITY)
fortheproportionofparticipantsachievingseizurefreedom(VERYLOWQUALITY)
Costeffectiveness
Resultsofthecosteffectivenessanalysisundertakenfortheguidelineshowedadjunctivevigabatrin
tobemorecostlyandmoreeffectivethanadjunctivegabapentinwithanincrementalcost
effectivenessratioof10,712perQALY(directlyapplicableandveryseriouslimitations).However,
theeconomicanalysisdidnottakeaccountofthepotentiallongtermadverseeffectsassociatedwith
vigabatrin.
TheEpilepsies
249
timetofirstseizure
cognitiveoutcomes
10.4.6.13 Gabapentinversuslamotrigine
Clinicalevidence
181
economicevaluation
184
and10.4.8.
Evidencestatements
Nosignificantdifferencebetweengabapentinadjunctivetherapyandlamotrigineadjunctivetherapy
foratleast50%reductioninseizurefrequency.(VERYLOWQUALITY)
Nosignificantdifferencebetweengabapentinadjunctivetherapyandlamotrigineadjunctivetherapy
forseizurefreedom.(VERYLOWQUALITY)
Nosignificantdifferencegabapentinadjunctivetherapyandlamotrigineadjunctivetherapyforthe
incidenceof:
weakness(VERYLOWQUALITY)
tinglingsensationinlimbs(VERYLOWQUALITY)
epigastricdiscomfort(VERYLOWQUALITY)
palpilations(VERYLOWQUALITY)
anxiety(VERYLOWQUALITY)
phobia(VERYLOWQUALITY)
TheEpilepsies
250
tiredness(VERYLOWQUALITY)
anorexia(VERYLOWQUALITY)
rashes(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatlamotrigineiscosteffectivecomparedtogabapentin.
OnepublishedanalysisbyHawkinsandcolleaguesfoundthatadjunctivegabapentindominated
lamotrigine,buttheiranalysiswasbasedonanowoutofdatesystematicreviewand200203
costs(partiallyapplicableandpotentiallyseriouslimitations).
Resultsofthecosteffectivenessanalysesundertakenfortheguidelinealsoshowedthatinthe
treatmentofchildren,youngpeopleandadults,adjunctivelamotriginewasmorecostlyandmore
effectivethanadjunctivegabapentin.
o Amongadults,theincrementalcosteffectivenessratioforlamotriginewas4,111.This
conclusionwasconsistentacrossarangeofsensitivityanalyses.Notethatwhenallrelevant
comparatorswereevaluatedtogether,gabapentinisruledoutthroughextendeddominance
bylamotrigineandplacebo(directlyapplicableandminorlimitations).
o Amongchildren,theincrementalcosteffectivenessratioforlamotriginewas17,291.This
conclusionisconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminor
limitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.14 Tiagabineversusplacebo
Clinicalevidence
181
ofAEDs,includingtiagabineandplacebo,usedasadjunctivetherapyin
thetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomicliterature
developedtocompareAEDsusedasadjunctivetherapyinadultswithrefractoryfocalseizures.The
completeresultsofthisstudyandtheNCGCadultsadjunctivetherapymodelarepresentedin
section10.4.8.
Evidencestatements
TheEpilepsies
251
Significantlymoreparticipantsontiagabineadjunctivetherapythanplaceboexperiencedatleast
50%reductioninseizurefrequency.(LOWQUALITY)
Nosignificantdifferencebetweentiagabineadjunctivetherapyandplaceboforseizurefreedom
(VERYLOWQUALITY)
Nosignificantdifferencebetweentiagabineadjunctivetherapyandplaceboforwithdrawaldueto
Significantlymoreparticipantsontiagabineadjunctivetherapythanplacebowithdrewdueto
adverseevents.(LOWQUALITY)
Significantlymoreparticipantsontiagabineadjunctivetherapythantheplaceboexperiencedthe
incidenceof:
tremor,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOWQUALITY)
nervousness,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOW
QUALITY).
Nosignificantdifferencebetweentiagabineadjunctivetherapyandplaceboforincidenceof:
abnormalthinking(VERYLOWQUALITY)
asthenia(VERYLOWQUALITY)
infection(VERYLOWQUALITY)
injury(VERYLOWQUALITY)
flusyndrome(VERYLOWQUALITY)
Qualityoflifeoutcomesstatisticallynonsignificantresults
Nosignificantassociationonthequalityoflifetestsfortiagabineadjunctivetherapyandplacebo.
Nosignificantassociationonthecognitivetestsfortiagabineadjunctivetherapyandplacebo.
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivetiagabineisnotcosteffectivewhencompared
withplacebo.
Onepublishedcosteffectivenessanalysisshowedadjunctivetiagabinetobemorecostlyand
moreeffectivethanplacebo,butwithincrementalcosteffectivenessratiosof25,452perQALY
(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisundertakenfortheguidelinealsoshowedtiagabinetobemore
costlyandmoreeffectivethanplacebo,butwithanICERof32,679perQALY.Whenallrelevant
comparatorswereevaluatedtogetherintheNCGCanalysis,tiagabinewasdominatedby
adjunctivetherapywithlevetiracetam,oxcarbazepine,pregabalinandtopiramate.Furthermore,
TheEpilepsies
252
oxcarbazepineandlamotriginewerelikelytorepresentmorecosteffectiveuseofNHSresources
giventheNICEwillingnesstopaythresholdof20,000perQALY(directlyapplicableandminor
limitations).
timetofirstseizure
timeto12monthremission.
10.4.6.15 Tiagabineversusphenytoin
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Astherewerestillgapsinthe
economicevidencebase,anoriginaleconomicmodelwasdevelopedtocompareAEDsusedas
adjunctivetherapyinadultswithrefractoryfocalseizures.Tiagabinewasincludedinthemodel,but
phenytoinwasnotowingtoitsnarrowtherapeuticwindow.
Evidencestatements
Nosignificantdifferencebetweentiagabineadjunctivetherapyandphenytoinadjunctiveforthe
proportionofparticipantsexperiencingatleasta50%reductioninseizurefrequency.(VERYLOW
QUALITY)
Qualityoflifeoutcomesstatisticallynonsignificantresults
Nosignificantassociationonthequalityoflifetestsfortiagabineadjunctivetherapyandphenytoin
adjunctivetreatment.
Nosignificantassociationonthecognitivetestsfortiagabineadjunctivetherapyandphenytoin
adjunctivetreatment.
Costeffectiveness
Noeconomicevidencecomparingadjunctivetiagabinetoadjunctivephenytoinwasidentified.
seizurefreedom
timetofirstseizure
TheEpilepsies
253
10.4.6.16 Tiagabineversuscarbamazepine
Clinicalevidence
adjunctivetherapyinadultswithrefractoryfocalseizures.Tiagabinewasincludedinthemodel,but
carbamazepinewasnotasitismostoftenusedasmonotherapy.
Evidencestatements
Significantlymoreparticipantsoncarbamazepineadjunctivetherapythantiagabineadjunctive
therapyexperiencedatleast50%reductioninseizurefrequency.(MODERATEQUALITY)
Qualityoflifeandcognitiveoutcomesstatisticallysignificantresults
Significantimprovementfortiagabinemeanscorescomparedtocarbamazepineonthefollowing
tests:
Financialstatus
Moodratingscale
Digitcancellationcorrecttest
Qualityoflifeandcognitiveoutcomesstatisticallynonsignificantresults
Nosignificantdifferencedifferencebetweentiagabineandcarbamazepineonmeanscoresof:
theQOLIEscale
WPSIsubtests
Abilitytests
Costeffectiveness
Noeconomicevidencecomparingadjunctivetiagabinetoadjunctivecarbamazepinewasidentified.
seizurefreedom
timetofirstseizure
TheEpilepsies
254
10.4.6.17 Vigabatrinversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Vigabatrinwasexcludedfromone
study
181
owingtoitspotentialtoxicity.Astherewerestillgapsintheeconomicevidencebase,an
originaleconomicmodelwasdevelopedtocompareAEDsusedasadjunctivetherapyinadultswith
refractoryfocalseizures.ThecompleteresultsofthisstudyandtheNCGCadultsadjunctivetherapy
Evidencestatements
Significantlymoreparticipantsonvigabatrinadjunctivetherapythanplaceboexperiencedatleasta
50%reductioninseizurefrequency(MODERATEQUALITY)
Significantlymoreparticipantsonvigabatrinadjunctivetherapythanplaceboexperiencedseizure
freedomalthoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOWQUALITY)
Nosignificantdifferencebetweenvigabatrinadjunctivetherapyandplaceboforwithdrawaldueto
Significantlymoreparticipantsonvigabatrinadjunctivetherapythanplaceboexperienced
withdrawalduetoadverseevents(MODERATEQUALITY)
Significantlymoreparticipantsonvigabatrinadjunctivetherapythantheplaceboexperienced:
drowsiness(MODERATEQUALITY)
Significantlymoreparticipantsonplacebothanvigabatrinadjunctivetherapyexperienced
Nosignificantdifferencebetweenvigabatrinadjunctivetherapyandplacebofortheincidenceof:
agitation(VERYLOWQUALITY)
abnormalvision(VERYLOWQUALITY)
weightgain(VERYLOWQUALITY)
constipation(VERYLOWQUALITY)
milddepression(VERYLOWQUALITY)
TheEpilepsies
255
doublevision(VERYLOWQUALITY)
confusion(VERYLOWQUALITY)
suicide(VERYLOWQUALITY)
attemptedsuicide(VERYLOWQUALITY)
Cognitiveeventsstatisticallysignificantresults
Significantimprovementforvigabatrinadjunctivetherapymeanscoresforthefollowingmeasures
comparedtoplacebo:
motorspeed
flexibility
designlearningtask
Significantlyworsescoresforvigabatrinadjunctivetherapymeanscoresforthefollowingmeasures
comparedtoplacebo:
digitcancellationscale
strooptests
Costeffectiveness
Resultsofthecosteffectivenessanalysisundertakenfortheguidelineshowedthatadjunctive
vigabatrinwasmorecostlyandmoreeffectivethanplacebo,withanincrementalcosteffectiveness
ratioof9,460perQALY(directlyapplicableandveryseriouslimitations).However,theeconomic
analysisdidnottakeaccountofthepotentiallongtermadverseeffectsassociatedwithvigabatrin
whichwouldlikelyreduceitscosteffectivenessrelativetootherpharmacologicaloptions.
timetofirstseizure
10.4.6.18 Pregabalinversusplacebo
Clinicalevidence
adjunctivetherapyinadultswithrefractoryfocalseizures.Thecompleteresultsofthisstudyandthe
NCGCadultsadjunctivetherapymodelarepresentedinsection10.4.8.
Evidencestatements
TheEpilepsies
256
Significantlymoreparticipantsonpregabalinadjunctivetherapythanplaceboexperiencedatleast
50%reductioninseizurefrequency(LOWQUALITY)
Significantlymoreparticipantsonpregabalinadjunctivetherapythanplaceboexperiencedseizure
freedom(LOWQUALITY)
Significantlymoreparticipantsonplacebothanpregabalinadjunctivetherapyexperienced
withdrawalduetolackofefficacy(MODERATEQUALITY)
Significantlymoreparticipantsonpregabalinadjunctivetherapythanplacebowithdrewdueto
Significantlymoreparticipantsonpregabalinadjunctivetherapythantheplaceboexperienced
incidenceof:
ataxia(LOWQUALITY)
weightgain(MODERATEQUALITY)
vertigo,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
tremor,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOWQUALITY)
amblyopia(LOWQUALITY)
diplopia,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
Significantlymoreparticipantsonplacebothanpregabalinadjunctivetherapyexperiencedincidence
ofheadache(LOWQUALITY).
Nosignificantdifferencebetweenpregabalinadjunctivetherapyandplacebofortheincidenceof:
asthenia(LOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivepregabalinisnotcosteffectivewhen
comparedwithplacebo.
Resultsofthecosteffectivenessanalysisundertakenfortheguidelineshowedthattheaddition
ofpregabalinwasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
thancontinuationofexistingtherapyalone(placebo),butwithanexpectedincrementalcost
effectivenessratioof22,721perQALYwhichexceedstheNICEwillingnesstopaythreshold.
NotewhenallrelevantcomparatorswereevaluatedtogetherintheNCGCanalysis,adjunctive
pregabalinwasdominatedbyadjunctivelevetiracetam,oxcarbazepineandtopiramate.This
conclusionwasconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminor
limitations).
timetofirstseizure
TheEpilepsies
257
cognitiveoutcomes
10.4.6.19 Pregabalinversuslamotrigine
Clinicalevidence
HealtheconomicEvidence
adjunctivetherapyinadultswithrefractoryfocalseizures.Thecompleteresultsofthisstudyandthe
NCGCadultsadjunctivetherapymodelarepresentedinsection10.4.8.
Evidencestatments
Significantlymoreparticipantsonpregabalinadjunctivetherapythanlamotrigineadjunctivetherapy
experiencedatleast50%reductioninseizurefrequencyalthoughthereisuncertaintyoverthe
magnitudeofitsclinicaleffect.(VERYLOWQUALITY)
Nosignificantdifferencebetweenpregabalinadjunctivetherapyandlamotrigineadjunctivetherapy
forseizurefreedom.(VERYLOWQUALITY)
forwithdrawalduetolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantsonpregabalinadjunctivetherapythanlamotrigineadjunctivetherapy
experiencedincidenceof:
somnolence,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
Significantlymoreparticipantsonlamotrigineadjunctivetherapythanpregabalinadjunctivetherapy
experiencedincidenceofheadache(LOWQUALITY).
forincidenceof:
TheEpilepsies
258
vertigo(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivepregabalinisnotcosteffectivewhen
comparedwithadjunctivelamotrigine.
ofpregablinwasassociatedwithbothincreasedcostsandbetterhealthoutcomes(higherQALYs)
thantheadditionoflamotrigine,butwithanunacceptablyhighincrementalcosteffectiveness
ratioof50,270perQALYwhichexceedstheNICEwillingnesstopaythreshold.Thisconclusion
wasconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.20 Clobazamversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Clobazamwasnotincludedinthe
originaleconomicmodelowingtoitssedativesideeffectsandthefactthattheireffectivenessmay
wanewithlongtermandcontinuoususe.
Evidencestatements
Significantlymoreparticipantsonclobazamadjunctivetherapythanplaceboexperiencedseizure
freedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOWQUALITY)
Nosignificantdifferencebetweenclobazamadjunctivetherapyandplaceboforwithdrawaldueto
Nosignificantdifferencebetweenclobazamadjunctivetherapyandplacebofortheproportionof
Costeffectiveness
Noeconomicevidencecomparingadjunctiveclobazamtoplacebowasidentified.
TheEpilepsies
259
timetofirstseizure
cognitiveoutcomes
10.4.6.21 Lacosamideversusplacebo
Clinicalevidence
adjunctivetherapyinadultswithrefractoryfocalseizures.ThecompleteresultsoftheNCGCadults
adjunctivetherapymodelarepresentedinsection10.4.8.
Evidencestatements
Significantlymoreparticipantsonlacosamideadjunctivetherapythanplaceboexperiencedatleast
50%reductioninseizurefrequency(LOWQUALITY)
Nosignificantdifferencebetweenlacosamideadjunctivetherapyandplaceboforseizurefreedom.
(VERYLOWQUALITY)
Nosignificantdifferencebetweenlacosamideadjunctivetherapyandplaceboforwithdrawaldueto
lackofefficacy(VERYLOWQUALITY)
Significantlymoreparticipantsonlacosamideadjunctivetherapythanplacebowithdrewdueto
adverseevents(LOWQUALITY)
Significantlymoreparticipantsonlacosamideadjunctivetherapythantheplaceboexperienced:
vomiting,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
diplopia,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOWQUALITY)
visionblurred,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOW
QUALITY)
Nosignificantdifferencebetweenlacosamideadjunctivetherapyandplacebofortheincidenceof:
TheEpilepsies
260
URI(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivelacosamideisnotcosteffectivewhen
oflacosamidewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
lacosamidewastheleasteffectiveandthirdmostcostlyadjunctiveAED.Thisconclusionwas
consistentacrossarangeofsensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.22 Zonisamideversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsonzonisamideadjunctivetherapythanplaceboexperiencedatleast
Nosignificantdifferencebetweenzonisamideadjunctivetherapyandplaceboforseizurefreedom.
(VERYLOWQUALITY)
TheEpilepsies
261
Nosignificantdifferencebetweenzonisamideadjunctivetherapyandplaceboforwithdrawaldueto
Significantlymoreparticipantsonzonisamideadjunctivetherapythanplacebowithdrewdueto
adverseevents(MODERATEQUALITY)
Significantlymoreparticipantsonzonisamideadjunctivetherapythantheplaceboexperiencedinthe
titrationperiod:
dizziness,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
somnolence(titrationphase)althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect
(VERYLOWQUALITY)
Significantlymoreparticipantsonplacebothanzonisamideadjunctivetherapyexperienced
Nosignificantdifferencebetweenzonisamideadjunctivetherapyandplaceboforincidenceof:
somnolence(fixeddosephase)(VERYLOWQUALITY)
abnormalthinking(VERYLOWQUALITY)
ataxia(VERYLOWQUALITY)
nauseaorvomiting(VERYLOWQUALITY)
increaseinliverenzymes
decreasedleukocytecount
decreasedplateletcount
increaseinserumcreatinine
weightgain
weightloss
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivezonisamideisnotcosteffectivewhen
ofzonisamidewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
lacosamidewasthethirdleasteffectiveandsecondmostcostlyadjunctiveAED.Thisconclusion
wasconsistentacrossarangeofsensitivityanalyses(directlyapplicableandminorlimitations).
TheEpilepsies
262
timetofirstseizure
cognitiveoutcomes
10.4.6.23 Eslicarbazepineacetateversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsoneslicarbazepineacetateadjunctivetherapythanplacebo
experiencedatleast50%reductioninseizurefrequency.(LOWQUALITY)
Significantlymoreparticipantsoneslicarbazepineacetateadjunctivetherapythanplacebo
experiencedseizurefreedom.(LOWQUALITY)
Nosignificantdifferencebetweeneslicarbazepineacetateadjunctivetherapyandplacebofor
withdrawalduetolackofefficacy(VERYLOWQUALITY)
Significantlymoreparticipantsoneslicarbazepineacetateadjunctivetherapythanplacebowithdrew
duetoadverseevents.(LOWQUALITY)
Significantlymoreparticipantsoneslicarbazepineacetateadjunctivetherapythanplacebohadan
incidenceof:
nausea(LOWQUALITY)
QUALITY)
Nosignificantdifferencebetweeneslicarbazepineacetateadjunctivetherapyandplaceboforthe
incidenceof:
aggravationofseizures(VERYLOWQUALITY)
TheEpilepsies
263
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctiveeslicarbazepineacetateisnotcosteffective
whencomparedwithplacebo.
ofeslicarbazepineacetatewasassociatedwithincreasedcostsandbetterhealthoutcomes
(higherQALYs)thancontinuationofexistingtherapyalone(placebo),butwithanexpected
incrementalcosteffectivenessratioof53,585perQALYwhichexceedstheNICEwillingnessto
paythreshold.NotewhenallrelevantcomparatorswereevaluatedtogetherintheNCGC
analysis,adjunctiveeslicarbazepineacetatewasdominatedbyadjunctivelevetiracetam,
oxcarbazepine,pregabalinandtopiramate.Thisconclusionwasconsistentacrossarangeof
sensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.24 Felbamateversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Felbamatewasnotincludedamong
comparatorsintheNCGCeconomicmodelforadjunctiveAEDtreatmentforrefractoryfocalseizures
duetoitspotentialforseriousadverseeffectsanditslimiteduseonanamedpatientbasis.
Evidencestatements
Significantlymoreparticipantsonfelbamateadjunctivetherapythantheplaceboexperienced:
headache(MODERATEQUALITY)
insomnia,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOWQUALITY)
nausea,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOW
QUALITY)
Nosignificantdifferencebetweenfelbamateadjunctivetherapyandplaceboforwithdrawaldueto
adverseevents.(VERYLOWQUALITY)
Nosignificantdifferencebetweenfelbamateadjunctivetherapyandplacebofortheincidenceof:
dyspepsia(VERYLOWQUALITY)
TheEpilepsies
264
anxiety(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivefelbabamatetoplacebowasidentified.
seizurefreedom
timetofirstseizure
cognitiveoutcomes
10.4.6.25 Oxcarbazepineversusplacebo
Clinicalevidence
181
economicevaluation
184
and10.4.8.
Evidencestatements
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythanplaceboexperiencedat
least50%reductioninseizurefrequency.(VERYLOWQUALITY)
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythanplaceboexperienced
seizurefreedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOW
QUALITY)
TheEpilepsies
265
Nosignificantdifferencebetweenoxcarbazepineadjunctivetherapyandplaceboforthewithdrawal
duetolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythantheplacebowithdrewdue
toadverseevents.(LOWQUALITY)
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythanplaceboexperiencedan
incidenceof:
somnolence(LOWQUALITY)
ataxia(LOWQUALITY)
nystagmus(LOWQUALITY)
abnormalgait,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
vertigo,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOWQUALITY)
nausea(LOWQUALITY)
QUALITY)
abnormalvision(LOWQUALITY)
fatigue(LOWQUALITY)
Nosignificantdifferencebetweenoxcarbazepineadjunctivetherapyandplacebofortheincidence
of:
upperrespiratoryinfection(VERYLOWQUALITY)
viralinfection(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatinthetreatmentofchildren,youngpeopleandadults,
adjunctiveoxcarbazepineiscosteffectivewhencomparedwithplacebo.
ofoxcarbazepinewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
thancontinuationofexistingtherapyalone(placebo),withanincrementalcosteffectivenessratio
of13,983perQALY.Thisconclusionisconsistentacrossarangeofsensitivityanalyses.Note
thatwhenallrelevantcomparatorswereevaluatedtogether,oxcarbazepineisthemostcost
effectiveadjunctiveAEDifthewillingnesstopaythresholdisatleast23,000perQALYorwhen
lamotrigineisnotarelevanttreatmentoption(directlyapplicableandminorlimitations).
TheEpilepsies
266
OnepublishedanalysisbyHawkinsandcolleaguesfoundthatforadultsoxcarbazepinewasmore
costlyandmoreeffectiveatanincrementalcosteffectivenessratioof17,095;however,their
analysiswasbasedonanowoutofdatesystematicreviewand200203costs(partiallyapplicable
andpotentiallyseriouslimitations).
additionofoxcarbazepinewasassociatedwithincreasedcostsandbetterhealthoutcomes
(higherQALYs)thancontinuationofexistingtherapyalone(placebo),withanincrementalcost
analyses.Notethatwhenallrelevantcomparatorswereevaluatedtogether,oxcarbazepineisthe
mostcosteffectiveadjunctiveAEDgivenawillingnesstopaythresholdof20,000perQALY
gained(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.26 Sodiumvalproateversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Sodiumvalproatewasnotincluded
amongcomparatorsintheNCGCeconomicmodelforadjunctivetreatmentforrefractoryfocal
seizuresbecauseitismostcommonlyusedasafirstlinemonotherapy.
Evidencestatements
Nosignificantdifferencebetweensodiumvalproateadjunctivetherapyandplaceboforthe
Costeffectiveness
Noeconomicevidencecomparingadjunctivesodiumvalproatetoplacebowasidentified.
seizurefreedom
50%reductioninseizurefrequency
TheEpilepsies
267
timetofirstseizure
cognitiveoutcomes
10.4.6.27 Primidoneversussodiumvalproate
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Neithersodiumvalproatenor
primidonewereincludedintheNCGCeconomicmodelofadjunctiveAEDsusedinthetreatmentof
refractoryfocalseizuresassodiumvalproateismostcommonlyusedasfirstline.
Evidencestatements
Significantlymoreparticipantsonsodiumvalproatethanprimidonehadatleast50%reductionin
seizurefrequency,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOW
QUALITY)
Nosignificantdifferencebetweenprimidoneandsodiumvalproateforseizurefreedom.(VERYLOW
QUALITY)
Nosignificantdifferencebetweenprimidoneandsodiumvalproateforwithdrawalduetoadverse
events.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivesodiumvalproatetoadjunctiveprimidonewas
identified.
timetofirstseizure
cognitiveoutcomes
TheEpilepsies
268
10.4.7 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforadultswithrefractory
focalepilepsy
11studiespublishedsincethesystematicreview
40,276
ofeconomicstudiesundertakentoinform
TA76andTA79wereidentifiedintheeconomicliteraturesearch.Nineofthesestudies
277285
were
excludedfromtheeconomicevidencereviewduetopoorapplicabilityorveryseriouslimitations.
FulldetailsofexclusionareincludedinappendixM.
Twostudies
181,286
assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinadultswith
refractoryfocalepilepsywereincludedintheeconomicevidencereview.Seeeconomicevidence
tablesinappendixMforstudydetails,includingqualityassessmentsoftheirmethodologyand
applicability.Astherewerestillgapsintheeconomicevidencebase,anoriginaleconomicmodel
wasdevelopedtocompareAEDsusedasadjunctivetherapyinadultpatientswithrefractoryfocal
epilepsy.Thiswasbasedonclinicalevidencefrompairwisemetaanalysesofplacebocontrolled
trials(seesection10.4.6).SeeappendixQforfulldetailsandresultsofmodelling.
Table11: AdjunctivetherapyforadultswithrefractoryfocalepilepsyEconomicstudy
characteristics
NCGCModeladults
adjunctivetherapy
(seeAppendixQfor
details)
comparatorsincludedplacebo,
lamotrigine,oxcarbazepine,
gabapentin,topiramate,
levetiracetam,tiagabine,
pregabalin,lacosamide,
eslicarbazepineacetate,
zonisamideandvigabatrin;
databasedonpairwisemeta
analysesofplacebocontrolled
trials
Hawkins(2005)
181
Potentiallyserious
limitations(a)
Partiallyapplicable(b,c) Decisionanalyticmodel;
comparatorsincludedplacebo,
lamotrigine,gabapentin,
tiagabine,oxcarbazepine,
topiramate,levetiracetam;
databasedonnetworkmeta
analysisthatincludedsome
studieswithmixedfocaland
generalisedepilepsy
populations
Spackman(2007)
286
Potentiallyserious
limitations
Partiallyapplicable(b) Decisionanalyticmodel;
comparatorsincluded
zonisamideandlevetiracetam;
timehorizon15years
(a) Unitcostsofinterventionsarefrom2002/03andsincepublication,lamotriginehascomeoffpatentandthenon
proprietarypriceisdramaticallylower
(b) StudydidnotincludeallcomparatorsconsideredrelevanttotheGDG,namelythenewerAEDs.
(c) Costsandeffectsdiscountedat6%and1.5%perannum,respectively.
TheEpilepsies
269
NCGCadultsadjunctivetherapymodel(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixQ.
Table12: AdjunctivetherapyforadultswithrefractoryfocalseizuresSummaryofNCGCmodel
findings
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
Placebo 8,928 8.197 At20KperQALYthreshold,
Basecase:4%
Alternativeseizurefreevalues:1%
Allcheapest:0%
ExcludingLTGandOXC:13%
LEVcost30%and50%reduced:3%
and2%
GBP 9,394 8.255 8,035
(extdom)
Basecase:23%
Allcheapest:18%
and16%
LTG 9,431 8.264 7,507 At20KperQALYthreshold,
Basecase:31%
Allcheapest:29%
and22%
OXC 10,564 8.314 22,660 At20KperQALYthreshold,
Basecase:22%
Allcheapest:17%
and15%
TPM
10,606 8.302 Dominate

d
Basecase:11%
Allcheapest:32%
TheEpilepsies
270
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
and7%
LEV 11,157 8.316 296,500 At20KperQALYthreshold,
Basecase:6%
Allcheapest:2%
and36%
PGB 11,291 8.301 Dominate
d
Basecase:2%
Allcheapest:1%
and1%
TGB 11,673 8.281 Dominate
d
Basecase:1%
Allcheapest:0%
and1%
LAC 11,777 8.24 Dominate
d
Basecase:0%
Allcheapest:0%
and0%
ZON 13,237 8.26 Dominate
d
Basecase:0%
Allcheapest:0%
and0%
ESL 13,322 8.279 Dominate At20KperQALYthreshold,
TheEpilepsies
271
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
d probabilitymostcosteffective
Basecase:0%
Allcheapest:0%
and0%
Note: VGBwasincludedinananalysis,andwasfoundtobeverycosteffective(11,754comparedtolamotrigine).This
findingisnotpresentedhereasthemodeldoesnotadequatelycapturethepotentialharmsofvisiondefectthat
havebeenassociatedwithlongtermuseofVGB.
Evidencestatements
ResultsofthebasecasefoundthatlamotriginewaslikelytobethemostcosteffectiveAEDforthe
adjunctivetreatmentofadultswithrefractoryfocalseizures.Oxcarbazepinemayalsobecost
effectiveasadjunctivetherapyinthispopulation.Thereisconsiderableuncertaintyintheseresults.
Incircumstanceswherelamotrigineandoxcarbazepinehavebeenpreviouslytriedandfoundtobe
ineffectiveornottolerated,gabapentinortopiramatearelikelytobecosteffectiveadjunctiveAEDs.
Resultsoftheanalysisshowedthatlevetiracetamisthemosteffectiveadjunctivetherapy,butthatat
June2011costs,itsadditionalcostcomparedtolamotrigineandoxcarbazepineisnotjustifiedbythe
additionalbenefit.However,withonlya30percentreductioninitsunitcost,levetiracetamislikely
todominateoxcarbazepineandbeconsideredcosteffectivecomparedtolamotrigine.
Adjunctivetreatmentwithoxcarbazepineorlevetiracetamdominatesadjunctivetreatmentwith
newerAEDsincludingeslicarbazepineacetate,lacosamide,pregabalin,tiagabineandzonisamide.
Hawkins2005
181
Table13: AdjunctivetherapyforadultswithrefractoryfocalepilepsySummaryofHawkins
2005
181
findings
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
Basecase:40%
GBP 5,861 8.747 Extended
Dominanc
e
Basecase:2%
LTG 5,926 8.746 Extended
Dominanc
e
Basecase:2%
TGB 6,133 8.758 Extended
Dominanc
e
Basecase:2%
TheEpilepsies
272
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
Basecase:52%
LEV 6,984 8.775 Dominated At20KperQALYthreshold,
Basecase:2%
TPM 7,026 8.777 Dominated At20KperQALYthreshold,
Basecase:0%
Evidencestatements
AdjunctiveoxcarbazepineisthemosteffectiveandmostcosteffectiveAEDamongevaluated
adjunctiveAEDs(partiallyapplicableandpotentiallyseriouslimitations).
Adjunctivegabapentin,adjunctivelamotrigineandadjunctivetiagabineareruledoutthrough
extendeddominancebyadjunctiveoxcarbazepineandplacebo(monotherapy)(partiallyapplicable
andpotentiallyseriouslimitations).
Adjunctivelevetiracetamandadjunctivetopiramatearemorecostlyandlesseffectivethan
adjunctiveoxcarbazepine(partiallyapplicableandpotentiallyseriouslimitations).
Spackman2007
286
(directlyapplicable,potentiallyseriouslimitations)
Table14: AdjunctivetherapyforadultswithrefractoryfocalepilepsySummaryofSpackman
2007
286
findings
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
LEV 15,610 7.897
ZON 15,630 7.923 761 Noprobabilisticsensitivityanalysis
wasperformed.Theresultsdidnot
changedramaticallyinoneway
sensitivityanalysesofdiscounting
rates,shortertimehorizon,variation
toproportionofresponders,variation
inutilityweights.Annualcostofeach
AEDdidimpactresults:costofLEV
halvedorcostofZONdoubledmakes
ICERofZON45K+.
Evidencestatements
Adjunctivezonisamideiscosteffectivecomparedtoadjunctivelevetiracetam(partiallyapplicable
andpotentiallyseriouslimitations).However,othereconomicevaluationsshowedboth
levetiracetamandzonisamidetobemorecostlyandlesseffectivethanotheradjunctiveAEDs.
TheEpilepsies
273
10.4.8 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildrenwithrefractory
focalepilepsy
Onestudy
184
assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinchildrenwith
refractoryfocalepilepsywasidentifiedintheeconomicliteraturesearchandincludedinthe
economicevidencereview.Astherewerestillgapsintheevidencebase,anoriginaleconomicmodel
wasdevelopedtocompareAEDsusedasadjunctivetherapyinchildrenwithrefractoryfocal
epilepsy.Thiswasbasedonclinicalevidencefrompairwisemetaanalysesofplacebocontrolled
trials(seesection10.4.6).SeeappendixRforfulldetailsandresultsofmodelling.
Table15: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyEconomicstudy
characteristics
NCGCModel
childrenadjunctive
therapy(see
AppendixRfor
details)
comparatorsincluded
placebo,gabapentin,
lamotrigine,
levetiracetam,
oxcarbazepineand
topiramate;timehorizon
15years;clinicaldata
basedonpairwisemeta
analysesofplacebo
controlledtrials.
Frew(2007)
184
(a)
Partiallyapplicable(b,
c)
comparatorswere
treatmentsequences
includinggabapentin,
lamotrigine,
oxcarbazepineand
topiramateaspossible
adjunctivetherapyall
comparedtoabaseline
ofonlyolderAEDs
(carbamazepine,sodium
valproateand
phenytoin);timehorizon
upto15years;clinical
databasedonNieto
Barrera2001
164
,
Zamponi1999
183
;
(a) 2002/03UKpounds
(b) Costsdiscountedat6%perannum;Effectsdiscountedat1.5%perannum
(c) AnalysisdidnotincludeallcomparatorsofinteresttotheGDG,namelylevetiracetam.
NCGCModelchildrenadjunctivetherapy(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixR.
TheEpilepsies
274
Table16: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyResultsfromNCGC2010
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
Basecase:35%
Allcheapest:1%
and34%
Cohortstartingage=10yrs:42%
GBP 19,018 9.462 3,752 At20KperQALYthreshold,
Basecase:18%
Allcheapest:20%
and15%
LTG 19,174 9.471 17,291
(extdom)
Basecase:15%
Allcheapest:41%
and12%
Basecase:19%
Allcheapest:17%
and14%
TPM
19,922 9.509 Dominate

d
Basecase:7%
Allcheapest:17%
and5%
TheEpilepsies
275
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
LEV 20,448 9.523 341,875 At20KperQALYthreshold,

Basecase:6%
Allcheapest:4%
and20%
Evidencestatements
TherewasconsiderableuncertaintyintheresultsoftheeconomicevaluationofdifferentAEDsused
inthetreatmentofchildrenwhohavefailedfirstlineAEDs.NosingleAEDcouldbeidentifiedas
clearlycosteffective,althoughbasedontheexpectedcostsandQALYs,oxcarbazepineislikelytobe
costeffective.Sensitivityanalysesaroundunitcostsalsoindicatedthatlamotriginemaybecost
effectiveifcostsarereducedcomparedtothebasecase.
Incircumstanceswherelamotrigineandoxcarbazepinehavebeenpreviouslytriedandfoundtobe
ineffectiveornottolerated,gabapentinortopiramatearelikelytobecosteffectiveadjunctiveAEDs.
Resultsoftheanalysisshowedthatlevetiracetamisthemosteffectiveadjunctivetherapy,butthatat
currentcosts,itsadditionalcostcomparedtoalternativeAEDsisnotjustifiedbytheadditional
benefit;howeverthisconclusionisverysensitivetochangesinitsunitcost.Givena50percent
reductionitislikelytodominateoxcarbazepineandbeconsideredcosteffectivecomparedto
lamotrigine.Givena30percentreductioninitsunitcost,levetiracetamislikelytobeoptimalwhen
oxcarbazepineandlamotrigineareinappropriate.
Frew2007
184
Table17: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyResultsfromFrew
2007
184
AED
Totalcost
()per
patient
Total
effects
(QALYs)
ICER
(/QALY) Uncertainty
Baseline(no
newAEDs)
bedeterminedfrom
thedataprovided
Basecase:0%
TPM(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Morecostlyandpossibly
moreeffective,butICER
cannotbedetermined
fromthedataprovided.
Basecase:30%
OXC(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Likelydominated At20KperQALYthreshold,
Basecase:30%
LTG(secondline
monotherapy)
bedeterminedfrom
TheEpilepsies
276
AED
Totalcost
()per
patient
Total
effects
(QALYs)
ICER
(/QALY) Uncertainty
thedataprovided Basecase:23%
LTG(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Basecase:23%
GBP(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Basecase:18%
Evidencestatements
CosteffectivenessofadjunctiveAEDsincludinggabapentin,lamotrigine,oxcarbazepineand
topiramatecomparedtoabaselinestrategyofonlyolderAEDsishighlyuncertain.Nodefinitive
conclusionaboutrelativecosteffectivenesscanbedetermined.
Adjunctivetreatmentinchildren,youngpeopleandadultswithrefractoryfocalseizures
NICEhasalsoissuedguidanceontheuseofretigabineasanoptionfortheadjunctivetreatmentof
partial(focalhasbeenusedinthisguideline)onsetseizureswithorwithoutsecondarygeneralisation
inadultsaged18yearsandolderwithepilepsyinRetigabinefortheadjunctivetreatmentofpartial
onsetseizuresinepilepsy(NICEtechnologyappraisalguidance232).
TheEpilepsies
277
Recommendation
88. Offercarbamazepine,clobazam
,gabapentin
,lamotrigine,
levetiracetam,oxcarbazepine,sodiumvalproateortopiramate
asadjunctivetreatmenttochildren,youngpeopleandadults
withfocalseizuresiffirstlinetreatments(see
recommendations85and86)areineffectiveornottolerated.
Beawareofteratogenicrisksofsodiumvalproate(see
outcomes
Inchildren,youngpeopleandadults,theachievementofseizure
freedomoratleasta50%reductioninseizurefrequencywere
consideredtobethemostclinicallyrelevantoutcomes.
Tolerability,asmeasuredbywithdrawalsduetoadverseevents,
wasalsoconsideredimportant.
benefitsandharms
Theevidenceforadultsshowedthatsignificantlymoreparticipants
receivingclobazam,levetiracetam,levetiracetamextended
release,oxcarbazepineandtopiramateachievedseizurefreedom
thanplacebo.Significantlymoreongabapentin,oxcarbazepine,
lamotrigine,levetiracetamandtopiramateexperiencedatleasta
50%reductioninseizurefrequencywhencomparedtoplacebo.
Fromtheevidenceforchildren,significantlymoreparticipantson
lamotrigineandoxcarbazepinecomparedtoplaceboexperienced
atleasta50%reductioninseizurefrequency.Morepeopleon
oxcarbazepine(adultsandchildren)achievedseizurefreedomthan
thoseonplaceboinarefractorypopulationonmonotherapy.In
children,significantlymoreparticipantsonlevetiracetam
comparedtoplaceboexperiencedatleasta50%reductionin
seizurefrequency.
Thedrugsrecommendedabovehadunfavourableadverseevents
profiles,buttheGDGfoundthisunsurprisinggiventhattheywere
beingevaluatedascombinationtreatmentinarefractory
population.Manyoftheadverseeventsobservedinthetrials
weredoserelatedandinclinicalpracticethesecanbemitigated
throughcarefuldosetitration.Significantlymoreparticipants
receivinggabapentin,lamotrigine,topiramateandoxcarbazepine
withdrewduetoadverseeventscomparedtoplacebo.
Gabapentinhadhigherincidenceofsomnolence,dizzinessand
ataxiaandaggravationofseizureswhencomparedtoplacebo.
Therewasnosignificantdifferencebetweenlevetiracetamand
placeboforwithdrawalduetoadverseeventsalthoughincidence
ofadverseeventswassignificantlyhigherinthelevetiracetamarm.
Nospecificadverseeventswerereportedinthetrialforclobazam,
buttheGDGconsidereditstendencytohavesedativesideeffects
anditsefficacycanwaneoverextendeduse.Oxcarbazepineand
lamotriginehadalessfavourableadverseeventsprofilecompared
toplacebo.Topiramatehadhigherincidenceofheadachewhen
comparedwithlamotrigine.Inchildrentakinglamotriginethe
incidenceofdizziness,tremor,nauseaandataxiawerehigher
Atthetimeofpublication(Janaury2012),thisdrugdidnothaveUKmarketingauthorisationforthisindicationand/or
TheEpilepsies
278
comparedtotoplacebo.
Adecisionmodelwasbuilttoweighuptheclinicalbenefitsofeach
adjunctiveAED,measuredbyseizurecontrolandseizure
reduction,comparedtotheharmsfromadverseeventsas
measuredbywithdrawalsfromtreatmentduetoadverseevents.
Forthedrugsrecommendedhere,thetreatmentbenefits
outweighedtheharmsfortheaveragepatientandtheQALYs
gainedjustifiedtheadditionalcostsoverplacebo(noadjunctive
AED).
Threeeconomicevaluationswereincludedinthesystematic
reviewofpublishedliterature(twoforadultsandoneforchildren),
andoriginaleconomicmodellingwasundertakentoovercome
limitationsofandfillingapsnotcoveredbythepublished
evidence.
Theoriginalcosteffectivenessanalysisundertakenforthe
guidelineindicatesthatthereisconsiderableuncertaintyasto
whichAEDrepresentstheoptimaluseofNHSresourcesasagreat
dealdependsonwhatisappropriatefortheindividualpatientand
onhis/herprevioustreatmenthistory.TheGDGchoseto
recommendlamotrigineandoxcarbazepineonthebasisthatthey
werethetwoAEDswiththegreatestprobabilityofbeingcost
effectiveinthebasecaseandotherscenarios.Therefore,ifeither
lamotrigineoroxcarbazepinehavenotbeentriedasmonotherapy,
eitherfirstorsecondline,thentheyarelikelytorepresentcost
effectivechoicestoaddinasadjunctivetherapy.TheGDGfelt
thatsomecombinationsmightbemoreeffectiveormore
tolerable,andthusmightbemorecosteffective,butneitherthe
clinicalevidencereviewnoreconomicmodelwasdesignedto
identifyparticularAEDcombinations.
GiventhatlamotrigineandoxcarbazepineareamongAEDs
recommendedasfirstlinetreatmentofnewlydiagnosedfocal
seizures,apatientwithrefractoryfocalseizuresrequiringfurther
treatmentmayhavealreadytriedoneorboth.TheGDG
recommendedgabapentinonthebasisthatinthebasecase,itwas
likelytobethemostcosteffectiveAEDwhenlamotrigineand
oxcarbazepinewerenotrelevanttreatmentoptions.However,
giventheuncertaintyhighlightedbytheresultsoftheother
sensitivityanalyses,particularlyaroundtheestimatesofseizure
freedomandassumptionsofcost,theGDGdecidedtorecommend
topiramateasanadditionalchoiceforadjunctivetherapy.
TheGDGconsideredtheresultsofthebasecaseanalysis,inwhich
levetiracetam,althoughthemosteffectiveadjunctiveAED,wasnot
showntobecosteffectivegiventheNICEwillingnesstopay
threshold.Itwasalsounlikelytobeconsideredcosteffective
comparedtogabapentinandtopiramatewhenlamotrigineand
oxcarbazepinewereremovedfromtheanalysis(assumingthey
havebeenalreadytriedasmonotherapy).TheGDGlookedtoa
seriesofsensitivityanalysesaroundprojectedreductionsinthe
priceoflevetiracetaminordertodeterminethepricepointat
TheEpilepsies
279
whichthedrugmightbecomecosteffective.Thesensitivity
analysesshowedthattheunitcostoflevetiracetamneedonly
comedownby30percentinordertodominateoxcarbazepineand
beconsideredcosteffectivecomparedtolamotrigine
(ICER=19,264perQALY).Italsobecomesthemostcosteffective
drugunderthe20,000perQALYthresholdwhenlamotrigineand
oxcarbazepineareexcluded;thatis,levetiracetamdominates
topiramate(evenwhenonlynonproprietarycostsareused)and
hasanICERof17,213comparedtogabapentin.
TheGDGconsideredtheuncertaintiesaroundlevetiracetamand
howitsfuturecostmightimpactitsrelativecosteffectiveness
comparedtootheravailableAEDsusedinthetreatmentof
refractoryfocalseizures.Theyalsoacceptedthattheyknew
neitherhowmuchthepriceoflevetiracetamwilldropwiththe
introductionofgenericcompetition,norhowmuchthecostof
otherAEDsmightchangeaswell.TheGDGconsideredthe
dramaticreductioninthecostofotherAEDs,suchaslamotrigine
andtopiramate,followinglossofpatentprotectionand
introductionofgenericcompetition.Lookingtotheseother
examples,theyconsidereditverylikelythatasimilarreduction
wouldoccurforlevetiracetamsoonafterpublicationofthe
guidelineandthatarecommendationwithoutlevetiracetamwould
quicklybecomeinaccurate.Theyalsoconsideredthewidespread
useoflevetiracetamincurrentclinicalpractice,basednotonlyon
theirownexperiencebutalsoonthefeedbackofstakeholders
duringconsultationoftheguideline.Consideringtheevidence,the
uncertaintiesandtheirclinicalexperience,theGDGtherefore
determinedthatlevetiracetamshouldbeofferedamonginitial
adjunctivetherapyoptions.
Qualityofevidence
Foradults,themajorityoftheevidencewasplacebocontrolled
andtherewerefewheadtoheadcomparisons.Allofthestudies
wererandomisedcontrolledtrials,themajorityofwhichwere
doubleblind.Mostofthestudiesgaveuncleardetailsoftheir
methodsofrandomisation,allocationconcealmentandblinding.
Thestatisticallysignificantresultsfor50%reductioninseizure
frequencywerefromtheplacebocontrolledstudies.Fewofthe
drugswhichwerecomparedtodrugswerestatisticallysignificant
andwherethisdidoccurtherewasuncertaintyinthemagnitudeof
clinicaleffect.Thequalityoverallwasgenerallyloworverylow.
Thepublishedeconomicevidencevariedhadproblemsof
methodologicalqualityandapplicabilitytothedecisionmaking
contextoftheguideline.Somehadoutofdatecoststhatcould
changethestudysconclusionsordidnotincludealloftherelevant
comparators.Theoriginaldecisionmodelsundertakenforthe
guidelineaimedtoovercometheselimitations,butstillhadsome
oftheirown.Limitationsoftheoriginalanalyses,particularly
whereassumptionshadtobemade,relatetothelackofdata
availabilityonlongertermeffectivenessanddiscontinuation,
limitedhealthstateutilitydataandlimitedtonodatatoinform
estimatesofNHSresourceuse.
TheEpilepsies
280
Otherconsiderations Thedrugsrecommendedaboveareolderandthereforethereis
longtermexperiencewiththem.Eslicarbazepineacetate,
lacosamide,pregabalin,andzonisamideshowedefficacybutwere
notincludedforfirstlineadjunctivetreatmentastheyarenewer
drugsandtheGDGfeltthatthereneededtobemorelongterm
evidenceoftheirefficacyandcosteffectivenessforadjunctive
treatment.Thereislimitedevidencefortiagabinebeingeffective.
Gabapentinwasincludedasfirstlineadjunctivedrugoption,but
basedontheclinicalexperienceoftheGDGwasregardedasless
effectivethantheotherAEDs.
TheGDGconsideredtheadditionofoxcarbazepinewithouttrying
carbamazepineasunusualbutmaybeconsidered,asitisless
enzymeinducing.
TheGDGwereawarethatinclinicalpracticeasecondAEDisadded
tothefirst.Theyalsoagreedwithpublishedliteraturewhich
statesthatifthelatterhelpsthefirstmaybetakenawayifthe
patientagrees.
287
GDGdiscussioncentredaroundsomekeyissues.Namely,care
shouldbetakenwithclobazamwhenwithdrawingandaslow
withdrawalofclobazamover/upto46mginviewoftheriskof
withdrawalseizures.Theynotedthatsodiumvalproateinhibits
themetabolismoflamotrigineandthisneedstobetakeninto
considerationwhenintroducingorwithdrawingeithermedication.
ClinicalexperienceledtheGDGtobelievethatonwithdrawalof
sodiumvalproate,lamotriginelevelsmaydropandthismaybe
therreasonforbreakthroughseizures.Theyalsonotedthatthere
shouldbeaconcomitantincreaseinthelamotriginedosebutdid
notwishtomakeaspecificrecommendation.Topiramatemay
affectphenytoinlevels.
NICEhasalsoissuedguidanceontheuseofretigabineasanoption
fortheadjunctivetreatmentofpartial(focalhasbeenusedinthis
guideline)onsetseizureswithorwithoutsecondarygeneralisation
inadultsaged18yearsandolderwithepilepsyinRetigabinefor
theadjunctivetreatmentofpartialonsetseizuresinepilepsy(NICE
technologyappraisalguidance232).
TheEpilepsies
281
Recommendation
89. Ifadjunctivetreatment(seerecommendation88)isineffective
ornottolerated,discusswith,orreferto,atertiaryepilepsy
specialist.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistareeslicarbazepineacetate
,lacosamide,
phenobarbital,phenytoin,pregabalin
,tiagabine,vigabatrin
andzonisamide
.Carefullyconsidertheriskbenefitratio
whenusingvigabatrinbecauseoftheriskofanirreversible
effectonvisualfields.[new2012]
outcomes
Inadultsandchildren,achievementofatleasta50%reductionin
seizurefrequencywasanimportantoutcome.TheseAEDshave
evidenceofefficacyinsomepatients,andmaybenefitpatients
whohavenotrespondedtoand/orwhohaveexperiencedadverse
effectswithotherAEDs.
benefitsandharms
Thebalanceofbenefitandadverseeffectsneedstobecarefully
monitoredinallpatients,anditmustberecognisedthatdifferent
individualsmayhavedifferentresponsestovariousAEDs.From
thedirectevidenceforadults,lacosamide,zonisamide,
eslicarbazepineacetate,tiagabine,vigabatrinandpregabalinhad
moreparticipantswithatleast50%reductioninseizurefrequency
whencomparedtoplacebo.Eslicarbazepineacetate,and
pregabalinalsohadmoreseizurefreedomthanplacebo.
PhenobarbitalwasaddedbytheGDGbasedontheirprofessional
opinion.Tiagabinewasfoundtohavenodifferencewhen
comparedtolamotrigine,levetiracetamorphenytoin.Intermsof
efficacy,therewasnosignificantdifferencebetweenvigabatrin
andgabapentin.
Alsopregabalinwasshowntohavealessfavourableadverse
eventsprofile,causinggreaterwithdrawalduetoadverseevents
thanplacebo.Eslicarbazepineacetate,lacosamide,vigabatrin,
zonisamideandtiagabinehadmorewithdrawalduetoadverse
eventsandmoreadverseeventsthanthanplaceboarm.There
wasnodifferencebetweenphenytoinandtiagabineorlamotrigine
andtiagabineforwithdrawalduetoadverseevents.
Vigabatrinhasaharmfulandirreversiblesideeffectsprofilewith
retinaltoxicitycausingvisualimpairment,accordingtotheGDG
expertiseandepilepsyliterature.Thesesideeffectsoccuroverthe
longertermandwouldnotbeobservedinanyoftheshortterm
trialscombinedintheevidence.
TheGDGwereawarethatprimidonehadpreviouslybeen
recommendedforadjunctivetherapyforfocalseizuresinthe2004
guideline.However,becauseoftheresultsoftheevidencereview
thatclearlydemonstratedtheimprovedclinicalandcost
effectivenessofotherAEDs,theGDGdidnotwishtomakea
recommendationfortheuseofprimidone.TheGDGsclinical
TheEpilepsies
282
opinionwasthatprimidoneisnowrarelyusedininitiating
antiepileptictherapyandisonlyofferedtoindividualsasa
continuingprescription.Itisnotusedinchildrenasafirstline
therapy.
Thedrugsrecommendedforconsiderationherewereeffectiveto
varyingdegress,butthetreatmentbenefits,intermsofQALYs
gained,orinsomecaseslost,didnotjustifiedtheadditionalcosts
overdrugsrecommendedinthepreviousrecommendation
(gabapentin,lamotrigine,oxcarbazepine,topiramate).
Economicconsiderations Threeeconomicevaluationswereincludedinthesystematic
evidence.Onepublishedstudyshowedadjunctivezonisamideto
becosteffectivecomparedtoadjunctivelevetiracetam,butinall
otherstudiesand/orintheoriginalmodellingworkundertakenfor
theguideline,neitherlevetiracetamnorzonisamidewereshownto
becosteffectivecomparedtoalternativeAEDs.
Intheeconomicanalysisundertakenfortheguideline,
eslicarbazepineacetate,lacosamide,pregabalin,tiagabineand
zonisamidewereallmorecostlyandlesseffectivethanothercost
effectivetreatmentalternatives.Therefore,theGDGfeltthatthey
shouldnotberecommendedamonginitialadjunctivetherapy
options.Ratherthesedrugsshouldbeconsideredonlyforcases
wherepreviouslyrecommendeddrugsarecontraindicatedorhave
beentriedandwereeitherineffectiveornottolerated.
Vigabatrinwasspecificallyexcludedfromvariouspublished
economicevaluationsduetoitspotentialforlongtermtoxicityand
adverseeffects.Itwasincludedintheoriginaleconomicanalysis
undertakenforthisguidelineandwasshowntobeveryeffective
andcosteffective.However,averyseriouslimitationofthemodel
wasthatitdidnotaccountforvigabatrinspotentialforlongterm
toxicityanddevelopmentofvisualfielddefects.Vigabatrinscost
effectivenessinthemodelwasdrivenbyitsefficacyandrelatively
lowratesofwithdrawalduetoadverseeventsfromshortterm
trialdata.Hadthemodelaccountedforlongterm,irreversible
effectstovision,itisunlikelytohaveperformedquiteaswell.The
GDGrecogniseditsrelativeeffectivenessoverotherAEDs,and
consideredtheriskoflongtermvisualfielddefecttooutweighits
clinicalbenefit.TheGDGrecommendedthatthesepatientsshould
bediscussedwithorreferredtoatertiaryepilepsyspecialist.
Whilstthismaybemorecostly,theGDGconsideredthatthiswas
worthwhileasthesepatientsmayrequiremorecomplexcarein
ordertoachieveasuccessfuloutcome.
Qualityofevidence
Overallthequalityofevidencewaslowandmostofthestudies
TheEpilepsies
283
hadunclearornodetailsofrandomisation,allocationconcealment
orblindingandhigherdropoutinthetreatmentarms.Therewas
noevidencefoundforphenobarbitalbutthisrecommendationis
basedonGDGexpertise.
Thepublishedeconomicevidencehadproblemsofmethodological
qualityandapplicabilitytothedecisionmakingcontextofthe
guideline.Somehadoutofdatecoststhatcouldchangethe
studysconclusionsordidnotincludealloftherelevant
oftheirown.Duetothislimitation,resultsconcerningvigabatrins
costeffectivenesswereoflimitedvaluetoGDGdecisionmaking.
Limitationsoftheoriginalanalyses,particularlywhereassumptions
hadtobemade,relatetothelackofdataavailabilityonlonger
termeffectivenessanddiscontinuation,limitedhealthstateutility
dataandlimitedtonodatatoinformestimatesofNHSresource
use.
Otherconsiderations TheGDGconsensusopinionwasthatmanagementshouldbe
discussedwithpatientsortheyshouldbeofferedreferralto,a
tertiaryepilepsyspecialistifadjunctivetreatmentwithAEDslisted
inrecommendation1.13.2.1isineffectiveornottoleratedbecause
achievingsuccessfultreatmentmaybecomplex.
Theynotedthatlongtermexperiencewithsomeofthesedrugs
(pregabalin,lacosamide,zonisamideandeslicarbazepineacetate)
islimited.
TheGDGdiscussedthefactthatcareshouldbetakenwhen
withdrawingphenobarbitalandshouldbeslowlywithdrawnin
viewoftheriskofwithdrawalseizuresbutdidnotwishtomakea
specificrecommendationinthisarea.
Thegroupdiscussedtheneedforcarefulevaluationofrisk/benefit
foreachindividualtobeundertakenforeachindividualandthe
finalGDGconsensusopinionwasthatvigabatrinshouldonlybe
prescribedintertiaryepilepsyspecialistcare.
10.4.10 ResearchRecommendations(forfulllistseesection2.11)
diagnosedepilepsy?
a. Focalseizures:carbamazepine,eslicarbazepineacetate,lamotrigine,lacosamide,
b. Generalisedseizures:lamotrigine,levetiracetam,sodiumvalproateandzonisamide.
Whyisthisimportant?
LevetiracetamandotherAEDSlicensedforthetreatmentoffocalandgeneralisedseizuressince
publicationoftheoriginalguidelinein2004havenotbeenevaluatedasfirstlinemonotherapy.
TheEpilepsies
284
Researchshouldinclude:
Aprospectiverandomisedcontrolledtrial.
Allages
Primaryoutcomeofseizurefreedom
Secondaryoutcomesshouldincludeseizurereduction,qualityoflifeandcognitiveoutcome.
Anattempttoobtainsomedataonpharmacoresistance.
10.5 GeneralisedTonicClonicSeizures(GTCS)
10.5.1 Introduction
Tonicclonicseizuresaredefinedasthosewhereindividualshavesuddenonset,tonicstiffening,
followedbyrhythmic,clonicjerkingofthelimbs.Itisthemostcommonpresentingseizuretype,
andanindividualmaymanifestwithsuchaseizuretypepriortoanyunderlyingsyndromeor
causebeingdetermined.Itisclassifiedasageneralisedseizuretype,althoughtheseseizuresmay
beseenasareofseveraltypesincertainsyndromes.Furthermore,suchanapparentclinical
manifestationmaybeseeniftherehasbeenrapidspreadoftheseizurefromafocalsource.
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereviews.Forthisreviewwe
includedpeopleexperiencinggeneralisedtonicclonicseizures.
WesearchedforRCTscomparingtheeffectivenessofdifferentpharmacologicalinterventionsfor
epilepsyinapopulationexperiencinggeneralisedtonicclonicseizures.Theinterventionswe
includedinoursearchwerelamotrigine,levetiracetam,topiramate,oxcarbazepine,phenytoin,
clobazam,clonazepam,phenobarbitonal,primidone,acetazolamide,sodiumvalproate,
zonisamideandcarbamazepine.WelookedforanyRCTstudiesthatcomparedtheeffectiveness
oftwoormoreofthesetreatments(orplacebo).Belowisamatrixshowingwereevidencewas
identified.Aboxcontainingafigureindicatesthenumberofstudiesthatwerefoundandthatthe
evidenceforthiscomparisonhasbeenreviewedinthischapter.Anemptyboxindicatesthatno
evidencewasfound.Inthiscase,nosectiononthiscomparisonisincludedinthechapter.It
shouldbenotedthatsomeofthestudiesfromthedirectmetaanalysisarethesameasthosein
theIPDnetworkmetaanalysis.
Matrixoftheevidenceformonotherapyadults
Lamotrigine
Carbamazepine 1
163,
1IPD
NMA
38
Phenytoin 1
172,
1IPD
NMA
38
1
171,
1IPD
NMA
38
Sodium
valproate
1(Marson,
unpublished),
1IPDNMA
38
2
171,288,
1
IPDNMA
38
4
171,176,177,289,
1IPDNMA
38
TheEpilepsies
285
Matrixoftheevidenceformonotherapychildren

Oxcarbazepine 1IPDNMA
38
1IPDNMA
38
1
173,
1IPD
NMA
38
1
175,
38

Topiramate 1IPDNMA
38
1IPDNMA
38
1IPDNMA
38
1(Marson,
unpublished),
1IPDNMA
38

Phenobarbital 1IPDNMA
38
1
290
,1IPD
NMA
38
1IPDNMA
38
1IPDNMA
38
1IPD
NMA
38
1IPD
NMA
38
Gabapentin 1IPDNMA
38
1IPDNMA
38
1IPDNMA
38
1IPDNMA
38
1IPD
NMA
38
1IPD
NMA
38
1IPD
NMA
38
LTG CBZ PHT VPA OXC TPM PHB GBP

Placebo
Oxcarbazepine
Phenytoin 1
182

Sodium
valproate

Carbamazepine
PCB OXC PHT VPA CBZ
TheEpilepsies
286
MatrixoftheevidenceforAdjunctivetherapy

Placebo
Clobazam 1
291

Lamotrigine 1
292

Lamotrigine
XR
1
293

Levetiracetam 1
294

Topiramate 2
295,
Barrett
(unpublished
inHTA)
40

PCB CLB LTG LTG
XR
LEV TPM
TheEpilepsies
287
10.5.4 Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresinadults
10.5.4.1 Lamotrigineversuscarbamazepine
Clinicalevidence
Evidencestatements
Timeto12monthremissionoccurredsignificantlymorerapidlyinparticipantstakingcarbamazepine
monotherapycomparedtoparticipantstakinglamotriginemonotherapyalthoughthereis
uncertaintyinthemagnitudeofclinicaleffect.(IPDmetaanalysis)
Nosignificantdifferencebetweenlamotriginemonotherapyandcarbamazepinemonotherapyinthe
thetimetowithdrawaloftreatment.(IPDmetaanalysis).
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytocarbamazepinemonotherapyin
patientswithgeneralisedtonicclonicseizureswasidentified.
cognitiveoutcomes
10.5.4.2 Lamotrigineversusphenytoin
Clinicalevidence
Evidencestatements
TheEpilepsies
288
Timeto12monthremissionoccurredsignificantlymorerapidlyinparticipantstakingphenytoin
Timetofirstseizureoccurredsignificantlymorerapidlyinparticipantstakinglamotrigine
monotherapycomparedtoparticipantstakingphenytoinmonotherapy.(IPDmetaanalysis)
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandphenytoinmonotherapy
intheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
forthetimetofirstseizure.(VERYLOWQUALITY)
forthetimetoexit/withdrawalfromtreatment.(IPDmetaanalysis)
Significantlymoreparticipantstakingphenytoinmonotherapycomparedtolamotrigine
monotherapyhadincidenceofthefollowingadverseevents:
asthenia,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect(VERYLOW
QUALITY)
Nosignificantdifferencebetweenlamotriginemonotherapyandphenytoinmonotherapyinthe
incidenceof:
Nosignificantdifferencebetweenlamotriginemonotherapyandphenytoinmonotherapyinthe
proportionofpatientswhowithdrewduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytophenytoinmonotherapyinpatients
withgeneralisedtonicclonicseizureswasidentified.
cognitiveoutcomes
Clinicalevidence
TheEpilepsies
289
Evidencestatements
timeto12monthremission.(IPDmetaanalysis).
timetoexit/withdrawaloftreatment.(IPDmetaanalysis).
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytophenytoinmonotherapyin
cognitiveoutcomes
10.5.4.4 Oxcarbazepineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
analysisofAEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonic
seizures.Theresultsofthisanalysisarepresentedinsection10.5.5.
Evidencestatements
TheEpilepsies
290
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytosodiumvalproatemonotherapyin
cognitiveoutcomes
10.5.4.5 Phenytoinversuscarbamazepine
Clinicalevidence
Evidencestatements
Phenytoinmonotherapyismoreeffectivethancarbamazepinemonotherapyinachievingagreater
Nosignificantdifferencebetweenphenytoinmonotherapyandcarbamazepinemonotherapyforthe
timeto12monthremission.(IPDmetaanalysis).
Costeffectiveness
TheEpilepsies
291
Noeconomicevidencecomparingphenytoinmonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
Clinicalevidence
Evidencestatements
thetimetoexit/withdrawaloftreatment.(IPDmetaanalysis)
theincidenceofdeath(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalmonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
TheEpilepsies
292
10.5.4.7 Phenytoinversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
PhenytoinandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenytoinmonotherapyandsodiumvalproatemonotherapyfor
theproportionofparticipantswithdrawnduetolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantstakingphenytoinmonotherapycomparedtosodiumvalproate
monotherapywithdrewtodueadverseevents,althoughthereisuncertaintyinthemagnitudeof
gastrointestinaldisturbances(VERYLOWQUALITY)
Costeffectiveness
TheEpilepsies
293
Noeconomicevidencecomparingphenytoinmonotherapytosodiumvalproatemonotherapyin
cognitiveoutcomes
10.5.4.8 Sodiumvalproateversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
SodiumvalproateandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingcarbamazepine
monotherapycomparedtoparticipantstakingsodiumvalproatemonotherapy.(IPDMETAANALYSIS)
Nosignificantdifferencebetweensodiumvalproatemonotherapyandcarbamazepinemonotherapy
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
TheEpilepsies
294
Clinicalevidence
IPDmetaanalysis
LamotrigineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Economicevidencecouldnotbeextractedfromtheunpublisheddataforthissubgroupofpatients.
Evidencestatements
Timeto12monthremissionoccurredsignificantlymorerapidlyonsodiumvalproatemonotherapy
comparedtolamotriginemonotherapy.(IPDmetaanalysis)
Sodiumvalproatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
Nosignificantdifferencebetweenlamotriginemonotherapyandsodiumvalproatemonotherapyin
thetimetofirstseizureat12monthsfollowup(LOWQUALITY).
thetimetoexit/withdrawalofallocatedtreatmentat12monthsfollowup(VERYLOWQUALITY).
thetimetotreatmentfailure.(IPDmetaanalysis).
Nosignificantdifferencebetweenlamotriginemonotherapyandvalproatemonotherapyinthe
incidenceofotheradverseevents(forfulllistpleaseseeextractions)at12monthsfollowup(VERY
LOWQUALITY).
Costeffectiveness
Evidenceofcosteffectivenesscouldnotbeextractedfromtheunpublisheddataforthissubgroupof
patients.
seizurefreedom
incidenceofothersideeffects(pleaseseeevidencereviewAppendixL)
TheEpilepsies
295
Clinicalevidence
IPDmetaanalysis
TopiramateandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Economicevidencecouldnotbeextractedfromtheunpublisheddataforthissubgroupofpatients.
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingtopiramate
monotherapycomparedtoparticipantstakingsodiumvalproatemonotherapy.(IPDMETAANALYSIS)
Nosignificantdifferencebetweentopiramatemonotherapyandsodiumvalproatemonotherapyin
thetimetofirstseizureat12monthsfollowup(VERYLOWQUALITY).
thetimetofirstseizure(IPDmetaanalysis).
Nosignificantdifferencebetweensodiumvalproatemonotherapyandtopiramatemonotherapyfor
timetoexit/withdrawalofallocatedtreatmentat12monthsfollowup(VERYLOWQUALITY).
Nosignificantdifferencebetweensodiumvalproatemonotherapyandtopiramatemonotherapyfor
Nosignificantdifferencebetweentopiramatemonotherapyandvalproatemonotherapyat12
monthsfollowupintheincidenceof:
tiredness,drowsiness,fatigueandlethargy(VERYLOWQUALITY)
otheradverseevents(forfulllistpleaseseeevidenceextractionsAppendixL)(VERYLOW
QUALITY).
Costeffectiveness
patients.
seizurefreedom
TheEpilepsies
296
cognitiveoutcomes
10.5.4.11 LamotrigineversusPhenobarbital
Clinicalevidence
IPDmetaanalysis
LamotrigineandphenobarbitalwereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenlamotriginemonotherapyandphenobarbitalmonotherapyfor
timetoexit/withdrawal.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
outcomesrelatingtoqualityoflife.
Clinicalevidence
IPDmetaanalysis
LamotrigineandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysisof
AEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonicseizures.The
resultsofthisanalysisarepresentedinsection10.5.5.
TheEpilepsies
297
Timeto12monthremissionoccurredsignificantlymorerapidlyontopiramatemonotherapy
comparedtolamotriginemonotherapy.(IPDmetaanalysis)
Evidencestatements
toexit/withdrawal.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
10.5.4.13 Lamotrigineversusgabapentin
Clinicalevidence
IPDmetaanalysis
LamotrigineandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysisof
Evidencestatements
Nosignificantdifferencebetweenlamotriginemonotherapyandgabapentinmonotherapyfortime
TheEpilepsies
298
seizurefreedom
cognitiveoutcomes
10.5.4.14 LamotrigineversusOxcarbazepine
Clinicalevidence
IPDmetaanalysis
LamotrigineandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
seizurefreedom
cognitiveoutcomes
10.5.4.15 Topiramateversuscarbamazepine
Clinicalevidence
TheEpilepsies
299
IPDmetaanalysis
TopiramateandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandcarbamazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
10.5.4.16 Gabapentinversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
GabapentinandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
TheEpilepsies
300
seizurefreedom
cognitiveoutcomes
10.5.4.17 Oxcarbazepineversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandcarbamazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
TheEpilepsies
301
10.5.4.18 Phenobarbitalversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenobarbitalmonotherapyandoxcarbazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
10.5.4.19 Topiramateversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
TopiramateandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
TheEpilepsies
302
seizurefreedom
cognitiveoutcomes
10.5.4.20 Gabapentinversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
GabapentinandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweengabapentinmonotherapyandoxcarbazepinemonotherapyfor
seizurefreedom
TheEpilepsies
303
cognitiveoutcomes
10.5.4.21 Phenobarbitalversusgabapentin
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysis
ofAEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonicseizures.The
Evidencestatements
seizurefreedom
cognitiveoutcomes
10.5.4.22 Topiramateversusgabapentin
Clinicalevidence
IPDmetaanalysis
TopiramateandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysisof
TheEpilepsies
304
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandgabapentinmonotherapyfortimeto
exit/withdrawal.(IPDmetaanalysis)
firstseizure.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
10.5.4.23 TopiramateversusPhenobarbital
Clinicalevidence
IPDmetaanalysis
TopiramateandPhenobarbitalwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandphenobarbitalmonotherapyfor
TheEpilepsies
305
seizurefreedom
cognitiveoutcomes
10.5.4.24 Phenobarbitalversusphenytoin
Clinicalevidence
IPDmetaanalysis
PhenobarbitalversusphenytoinwereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenobarbitalmonotherapyandphenytoinmonotherapyfortime
seizurefreedom
cognitiveoutcomes
10.5.4.25 Topiramateversusphenytoin
Clinicalevidence
TheEpilepsies
306
IPDmetaanalysis
TopiramateversusphenytoinwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandphenytoinmonotherapyfortimeto
seizurefreedom
cognitiveoutcomes
10.5.4.26 Gabapentinversusphenytoin
Clinicalevidence
IPDmetaanalysis
GabapentinversusphenytoinwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweengabapentinmonotherapyandphenytoinmonotherapyfortimeto
TheEpilepsies
307
seizurefreedom
cognitiveoutcomes
Clinicalevidence
IPDmetaanalysis
GabapentinversussodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
seizurefreedom
cognitiveoutcomes
TheEpilepsies
308
10.5.4.28 Phenobarbitalversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
PhenobarbitalversussodiumvalproatewereamongAEDsincludedinanindividualpatientdata
metaanalysisofAEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonic
Evidencestatements
Timetoexit/withdrawaloccurredsignificantlymorerapidlyinparticipantstakingsodiumvalproate
monotherapycomparedtoparticipantstakingphenobarbitalmonotherapy.(IPDMETAANALYSIS)
Nosignificantdifferencebetweenphenobarbitalmonotherapyandsodiumvalproatemonotherapy
Nosignificantdifferencebetweenphenobarbitalmonotherapyandsodiumvalproatemonotherapy
seizurefreedom
cognitiveoutcomes
10.5.5 Individualpatientdatanetworkmetaanalysisasmonotherapyforgeneralisedtonicclonic
epilepsy
DuringtheliteraturereviewweidentifiedanetworkmetaanalysisofIndividualPatientData(IPD).
TheIPDwasasummaryofIPDevidencefromrandomizedcontrolledtrialsofeightdifferentAEDs
(sodiumvalproate,phenytoin,lamotrigine,oxcarbazepine,gabapentin,carbamazepine,topiramate
andphenobarbital)inmonotherapyofgeneralisedtonicclonicseizures(TudurSmithetal,2007)
38
.It
shouldberecognisedthatthisisanetworkmetaanalyseswhichcombinesdirectandindirect
analyses.
TheoutcomesincludedintheIPDanalysisweretimetotreatmentfailureduetoinadequateseizure
control,intolerableadverseeffectsoracombinationofboth;timeto12monthremissionfrom
seizures(daysfromrandomisationandendofaperiodof12monthswithoutseizures);andtimeto
firstseizureafterrandomisation.Itincludeddatafrom1552generalisedtonicclonicparticipantsfor
timetotreatmentwithdrawal,1360generalisedtonicclonicparticipantsfortimeto12month
TheEpilepsies
309
remissionand1765generalisedtonicclonicparticipantsfortimetofirstseizure.Thefollowing
tablesshowtheresultsforthevariousoutcomes,comparingeachAEDwiththecurrentstandard
AED,sodiumvalproate.Thesignificantresultsarehighlightedinbold.
Timetotreatmentfailure
Phenytoin Sodiumvalproate 1.03(0.71to1.51)
Lamotrigine Sodiumvalproate 1.30(0.97to1.75)
Oxcarbazeine Sodiumvalproate 1.50(0.84to2.68)
Gabapentin Sodiumvalproate 1.59(0.22to11.50)
Topiramate Sodiumvalproate 1.74(1.28to2.36)
Phenobarbital Sodiumvalproate 1.83(1.07to3.13)
(a) HR<1VPAworse;HR>1VPAbetter
Sodiumvalproatewasfoundtobesignificantlybetterthancarbamazepine,topiramateand
phenobarbitalfortimetotreatmentfailure.
Timeto12monthremission
Oxcarbazepine Sodiumvalproate 1.10(0.73to1.67)
Sodiumvalproatewasfoundtobesignificantlybetterthanlamotriginefortimeto12month
remission.
Timetofirstseizure
Oxcarbazepine Sodiumvalproate 1.32(0.90to1.94)
Sodiumvalproatewasfoundtobesignificantlybetterthanlamotriginefortimetofirstseizure.
TheEpilepsies
310
10.5.6 Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresinchildren
Clinicalevidence
Evidencestatements
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytophenytoinmonotherapyin
childrenwithgeneralisedtonicclonicseizureswasidentified.
timetofirstseizure
cognitiveoutcomes
10.5.7 Adjunctivetherapyforthetreatmentofgeneralisedtonicclonicseizures
10.5.7.1 Clobazamversusplacebo
Clinicalevidence
Evidencestatements
TheEpilepsies
311
Significantlymoreparticipantstakingclobazamadjunctivetherapywereseizurefreecomparedto
placebo.However,thereisuncertaintyaboutthemagnitudeoftheclinicaleffect.(VERYLOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingclobazamadjunctivetherapytoplacebowasidentified.
timetofirstseizure
cognitiveoutcomes
Clinicalevidence
evidencebase,originaleconomicmodellingwasundertakentoevaluateAEDs,includinglamotrigine,
usedinthetreatmentofpatientswithrefractorygeneralisedtonicclonicseizures.Fullresultsofthe
NCGCGTCSmodelarepresentedinsection10.5.8.
Evidencestatements
Significantlymoreparticipantsinlamotrigineadjunctivetherapyachievedatleasta50%reductionin
seizurefrequencycomparedtoplacebo.(LOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandplacebofortheproportionof
seizurefreeparticipants.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandplacebofortheproportionof
participantshavingtheirtreatmentwithdrawnduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatlamotrigineadjunctive
therapyiscosteffectivecomparedtoplacebointhetreatmentofrefractorygeneralisedtonicclonic
seizures.Thisevidenceisdirectlyapplicableandhasminorlimitations.
TheEpilepsies
312
timetofirstseizure
cognitiveoutcomes
10.5.7.3 Lamotrigineextendedreleaseversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantstakinglamotrigineextendedreleaseadjunctivetherapywereseizure
freecomparedtoparticipantstakingplacebo.(MODERATEQUALITY)
Significantlymoreparticipantstakinglamotrigineextendedreleaseadjunctivetherapyachievedat
leasta50%reductioninseizurefrequencycomparedtoparticipantstakingplacebo.(MODERATE
QUALITY)
theproportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOW
QUALITY)
headache
vomiting
Clinicalevidence
evidencebase,originaleconomicmodellingwasundertakentoevaluateAEDs,including
levetiracetam,usedinthetreatmentofpatientswithrefractorygeneralisedtonicclonicseizures.
FullresultsoftheNCGCGTCSmodelarepresentedinsection10.5.8.
Evidencestatements
TheEpilepsies
313
Significantlymoreparticipantstakinglevetiracetamadjunctivetherapywereseizurefreecompared
toparticipantstakingplacebo.(HIGHQUALITY)
Significantlymoreparticipantstakinglevetiracetamadjunctivetherapyachievedatleasta50%
reductioninseizurefrequencycomparedtoparticipantstakingplacebo.(HIGHQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplacebofortheproportion
ofparticipantshavingtreatmentwithdrawnduetolackofefficacy.(LOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplacebofortheproportion
ofparticipantshavingtreatmentwithdrawnduetoadverseevents.(LOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplacebofortheincidenceof
nasopharyngitis.(MODERATEQUALITY)
fatigue(LOWQUALITY)
aggravationofseizures(LOWQUALITY)
Qualityoflifestatisticallynonsignificantresults
Nostatisticallysignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboin
achievingagreaterimprovementinthequalityoflife.(LOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatlevetiracetamadjunctive
therapyiscosteffectivecomparedtoplacebointhetreatmentofrefractorygeneralisedtonicclonic
seizures.However,lamotrigineadjunctivetherapyislesscostlyandmoreeffectivethan
levetiracetamadjunctivetherapy.Thisevidenceisdirectlyapplicableandhasminorlimitations.
timetofirstseizure
cognitiveoutcomes
Clinicalevidence
181
wasidentifiedintheeconomicliteraturesearchandincludedinthe
evidencereview.Astherewerestillgapsintheeconomicevidencebase,originaleconomic
TheEpilepsies
314
modellingwasundertakentoevaluateAEDs,includingtopiramate,usedinthetreatmentofpatients
withrefractorygeneralisedtonicclonicseizures.FullresultsofthisstudyandtheNCGCGTCSmodel
Evidencestatements
Significantlymoreparticipantstakingtopiramateadjunctivetherapycomparedtoplaceboachieved
atleast50%reductioninseizurefrequency.(VERYLOWQUALITY)
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplaceboinachievingagreater
Nosignificantdifferencebetweentopiramateadjunctivetherapyandcarbamazepinemonotherapy
fortheproportionofparticipantswhowithdrewduetoadverseevents(VERYLOWQUALITY)
Nostatisticallysignificantdifferencebetweentopiramateadjunctivetherapyandplaceboforthe
incidenceofthefollowingadverseevents:
difficultywithmemory(VERYLOWQUALITY)
psychomotorslowing(VERYLOWQUALITY)
upperrespiratorytractinfection(VERYLOWQUALITY)
weightloss(VERYLOWQUALITY)
speechdisordersandrelatedspeechproblems(VERYLOWQUALITY)
aggressivereaction(VERYLOWQUALITY)
confusion(VERYLOWQUALITY)
Costeffectiveness
Twoeconomicevaluationsbasedoncostutilityanalysesshowthattopiramateadjunctivetherapyis
moreeffectiveandmorecostlythanplacebo,withincrementalcosteffectivenessratiosof34,417
and75,723perQALYgained,respectively.Thefirstestimateisfromapartiallyapplicablestudy
withpotentiallyseriouslimitations.Inthesecondanalysis,topiramateadjunctivetherapywas
dominatedbylamotrigineadjunctivetherapyandextendedlydominatedbylevetiracetamadjunctive
therapy.Thisanalysisisdirectlyapplicableandhasminorlimitations.
TheEpilepsies
315
10.5.8 HealtheconomicevidenceforAEDsusedasadjunctivetherapyinadultswithrefractory
generalisedtonicclonicseizures
Onestudy
181
assessingthecosteffectivenessoftopiramateusedasadjunctivetherapyinpatients
withrefractorygeneralisedtonicclonicseizureswasidentifiedintheeconomicliteraturesearchand
includedintheeconomicevidencereview.Astherewerestillgapsintheevidencebase,anoriginal
economicmodelwasdevelopedtocompareAEDsusedasadjunctivetherapyinpatientswith
refractorygeneralisedtonicclonicseizures.Thiswasbasedonevidenceincludedintheclinical
review
292,294,295
.SeeappendixSforfulldetailsandresultsofmodelling.
Table18: Adjunctivetherapyforpatientswithrefractorygeneralisedtonicclonicseizures
NCGCGTCSmodel
(seeappendixSfor
details)
Minorlimitations Directlyapplicable
15yeartimehorizon;
comparatorsincluded
monotherapy(placebo),
lamotrigine,topiramate
andlevetiracetam;
effectivenessdatafrom
studiesincludedin
clinicalreview
292,294,295
Hawkins2005
181
Potentiallyserious
limitations(a)
Partiallyapplicable(b,
c)
15yeartimehorizon;
effectivenessdatafrom
Barret1998
296
andBiton
1999
295
.
(a) Unitcostestimatesarefrom2002/03,andsincethen,unitcostoftopiramatehasreducedandmaychangeconclusionsofthecost
effectivenessanalysis.
(b) Analysisincludesonlytwocomparatorsofinterest
(c) Costsdiscounted6%perannum;effectsdiscounted1.5%perannum
EconomicstudyresultsNCGCGTCSmodel
ResultsofNCGCGTCmodel
AED
Totalcost
()per
patient
Totaleffect
(QALYs)per
patient
ICER
(/QALY) Uncertainty
Placebo 6,248 7.515 Atthresholdsof20Kand30K/QALY,
monotherapy(placebo)hasa0%probabilityof
beingoptimal.
IfLTGisexcludedfromtheanalysis:
monotherapyhas24.95%and5%probabilityof
beingoptimalat20Kand30K/QALY
respectively.
LTG 6,614 7.761 1,488 Atathresholdof20Kand30K/QALY,LTGhas
a98.74%and96.16%probabilityofbeing
optimal,respectively.
LEV
9,556 7.738 Dominate

d
Atthresholdsof20Kand30K/QALY,LEVhasa
1.26%and3.84%probabilityofbeingoptimal,
respectively.
TheEpilepsies
316
AED
Totalcost
()per
patient
Totaleffect
(QALYs)per
patient
ICER
(/QALY) Uncertainty
IfLTGisexcludedfromtheanalysis:
ICER=14,834andhas74.86%and94.83%
probabilityofbeingoptimalat20Kand30K
/QALY,respectively.
d
Atthresholdsof20Kand30K/QALY,TPMhas
a0%probabilityofbeingoptimal.
IfLTGisexcludedfromtheanalysis:TPMis
extendedlydominatedbyLEVandhas0.19%
and0.18%probabilityofbeingoptimalat20K
and30K/QALY,respectively.
IfLTGisexcludedandonlynonproprietarycosts
forTPMareused,TPMisextendedlydominated
byLEVandhasa<2%chanceofbeingoptimalat
20Kand30K/QALY.
Evidencestatements
Evidencefromonecosteffectivenessanalysisindicatesthatlamotrigineisthemostcosteffective
adjunctiveAEDforthetreatmentofrefractorygeneralisedtonicclonicseizures.Thisevidenceis
directlyapplicableandhasminorlimitations.
Evidencefromonecosteffectivenessanalysisindicatesthatlevetiracetamismorecostlyandless
effectivethanlamotrigineinthetreatmentofrefractorygeneralisedtonicclonicseizures.However,
iflamotrigineisnotaclinicallyappropriateoption,levetiracetamisverylikelytobeconsideredcost
effectivegivenathresholdof20,000perQALY.Thisevidenceisdirectlyapplicableandhasminor
limitations.
Evidencefromonecosteffectivenessanalysisindicatesthattopiramateismorecostlyandless
effectivethanlamotrigineandisextendedlydominatedbylevetiracetamwhenlamotrigineisnota
clinicallyappropriatedrugoption.Thisevidenceisdirectlyapplicableandhasminorlimitations.
EconomicstudyresultsHawkins2005
181
ResultsofHawkins2005
181
AED
Totalcost
()per
patient
Totaleffect
(QALYs)per
patient
ICER
(/QALY) Uncertainty
Placebo 5,064 8.737 Atthresholdof30K/QALY,monotherapy
(placebo)has59%probabilityofbeingoptimal
TPM 7,471 8.807 34,417 Atthresholdof30K/QALY,topiramatehasa
41%probabilityofbeingoptimal
Evidencestatements
Evidencefromonecosteffectivenessanalysisindicatesthattopiramateismorecostlyandmore
effectivethancontinuedmonotherapy,butwithanincrementalcosteffectivenessratiogreaterthan
20,000and30,000perQALYgained,itisunlikelytobeconsideredcosteffectiveinthispatient
group.Thisevidenceispartiallyapplicableandhaspotentiallyseriouslimitations.
TheEpilepsies
317
Firstlinetreatmentinchildren,youngpeopleandadultswithnewlydiagnosedgeneralisedtonic
clonic(GTC)seizures
Recommendation
90. Offersodiumvalproateasfirstlinetreatmenttochildren,
youngpeopleandadultswithnewlydiagnosedGTCseizures.
Beawareofteratogenicrisksofsodiumvalproate(see
91. Offerlamotrigineifsodiumvalproateisunsuitable.Ifthe
personhasmyoclonicseizuresorissuspectedofhaving
juvenilemyoclonicepilepsy(JME),beawarethatlamotrigine
mayexacerbatemyoclonicseizures.[new2012]
outcomes
Inchildren,youngpeopleandadults,seizurefreedomandadverse
effectswereconsideredtobethemostimportantoutcomes.Time
towithdrawal,timeto12monthremissionandtimetofirstseizure
werealsoconsideredimportant.
benefitsandharms
Inadults,therewasnosignificantdifferenceintheproportionof
participantsachievingseizurefreedombetweensodiumvalproate,
lamotrigine,carbamazepineandoxcarbazepine.Therewerefew
significantdifferencesinthedirectevidenceforefficacyandfor
mostcomparisonsintheIPDanalyses.Howeversodiumvalproate
wassignificantlybetterthanphenobarbital,topiramateand
carbamazepinefortimetowithdrawal.Phenytoinandsodium
valproateweresignificantlybetterthanlamotriginefortimetofirst
seizure.Phenytoin,carbamazeine,sodiumvalproateand
topiramateweresignificantlybetterthanlamotriginefortimeto
12monthremission.
Basedontheevidenceforapopulationwithgeneralisedtonic
clonicseizuresonlytherewasnosignificantdifferencebetween
lamotrigine,sodiumvalproateandtopiramateintermsoftimeto
treatmentfailureortimetofirstseizure.
TheGDGconsensusopinionwasthatthereisatendencyfordrugs
suchascarbamazepineandoxcarbazepinetoexacerbatecertain
seizurestypessuchasmyoclonicandabsenceseizures.Therefore,
theyconcludedthatalthoughthereisevidencetosupporttherole
ofcarbamazepineandoxcarbazepineinthetreatmentof
generalisedtonicclonicseizures,theyshouldonlybeconsidered
onceotherseizuretypeshavehadtimetopresentfollowing
initiationoffirstlinedrugs.TheGDGconsideredthatduetothe
seriousnessofsideeffectsreportedfortopiramatesuchas
psychiatricandbehaviouralchangesreportedintheSANADtrial,it
isnotadrugoffirstchoicewhereotherdrugsareaseffective.
PhenytoinwasshowntohaveefficacybuttheGDGconsidereditto
haveaveryhighadverseeventsprofile.Thelongtermeffectssuch
asgumhypertrophy,coursingoffacies,hirsuitism,cerebellar
atrophywouldmakeitunfavourabletouselongterm.TheGDG
alsoconsideredthepharmacokineticstobeunpredictablewhich
TheEpilepsies
318
makesdosingdifficult.
Sodiumvalproateandhighdoselamotrigineareassociatedwith
increasedriskofneuraltubeandotherdefectsandsothewomen
ofchildbearingageshouldbeinformedofsuchrisks.
TheGDGconsideredthatthebenefitsofreductionofseizures
outweighedtheadverseeffects.
Economicconsiderations Noeconomicevidencewasidentifiedintheliteratureandno
economicevaluationwasundertakentoinformthecost
effectivenessoffirstlineAEDsusedtotreatnewlydiagnosed
patientsexperiencinggeneralisedtonicclonicseizures.TheGDG
feltthatanextrapolationfromtheSANADstudypopulationwith
generalisedepilepsiestoapopulationwithgeneralisedtonicclonic
seizureswasappropriateandthattherelativecosteffectivenessof
sodiumvalproatewasunlikelytobedifferentbetweenthese
groups.
Sodiumvalproateemergedasthedrugmostlikelytobecost
effectiveinthecostperseizureavoidedanalysisconductedaspart
oftheSANADtrial
161
.Greaterweightwasgiventothisanalysisas
thereductioninseizurefrequency,particularlyofgeneralised
tonicclonicseizures,isconsideredtobethemostimportant
clinicaloutcome.Thepublishedeconomicevidenceforthecost
effectivenessoflamotrigineinpatientswithIGEwasoutofdate
andaroughreestimationbasedoncurrentcostswasundertaken.
Thenewresultsindicatethatlamotriginehasthelowesttotalcost
andisalsolikelytobeconsideredcosteffective.
Qualityofevidence
Diagnostic,demographicanddosingconsiderationsmustbetaken
intoconsideration.Therewasalackofpowerofthedirectstudies
particularlywithregardtoadverseevents.Theoverallqualityof
directevidencewasverylowwithpoorreportingofrandomisation
methods,allocationconcealmentandmanystudieswere
unblinded.Therewasahighdropoutrateinthemajorityof
studies.Thetimetoeventdatacamefromanetworkmeta
analysisofindividualpatientdata.
Otherconsiderations
(carbamazepine,gabapentin,lamotrigine,oxcarbazepine,
phenobarbital,phenytoin,sodiumvalproateandtopiramate)
TheGDGconsideredtheIPDanalysisinthedecisionmaking
processalongsidethedirectevidence.Mostoftheevidenceforthe
GTCSreviewcamefromtheIPDanalysis,thisdifferenceoccurred
becausetheIPDanalysissubgroupedtheindividualpatientdata
intospecificseizuretypeswhereasthedirectevidencewasbased
onhowtheauthorshadchosentocategoriseandpresentthedata.
Sodiumvalproateinhibitsthemetabolismoflamotrigineandthis
musttobetakenintoconsiderationwhenintroducingor
TheEpilepsies
319
forbreakthroughseizures.Thereshouldbeaconcomitant
increaseinthelamotriginedose.
TheGDGisawarethatlevetiracetamiswidelyusedincurrent
practiceasafirstlinemonotherapyinthetreatmentofnewly
diagnosedgeneralisedtonicclonicseizures,particularlywhen
sodiumvalproateisunsuitable.Therewasmuchdebateasto
whetherlevetiracetamshouldberecommendedalongsideorin
preferencetolamotrigine,especiallyconsideringlamotrigines
potentialtoexacerbatemyoclonicseizuresthatmayormaynot
havepreviouslypresented.However,theGDGsfinaldecisionnot
torecommendlevetiracetamasfirstlinemonotherapyinthis
groupofpatientsisinaccordancewithNICEmethodologywhich
statesthatuseforanindicationforwhichtheproductdoesnot
haveamarketingauthorizationmayberecommendedifthereis
clearevidencetosupportthis.Levetiracetamisnotcurrently
licensedasmonotherapyinthetreatmentofgeneralisedepilepsies
andnorandomisedcontrolledtrialevidencewasidentifiedto
demonstrateitseffectivenesscomparedtoalternativedrugs.
Furthermore,intheabsenceofsuchevidenceitisimpossibleto
measurelevetiracetamsrelativecosteffectivenesscomparedto
otherdemonstrablycosteffectiveAEDsusedtotreattonicclonic
seizures.Consequently,levetiracetamisrecommendedas
adjunctivetherapy,whereevidenceisavailabletodemonstrateits
clinicalandcosteffectiveness.
TheGDGconsidereditimportanttodirectusersoftheguidelineto
therecommendationsforthetreatmentofmyoclonicseizuresand
juvenilemyoclonicepilepsywhereotherdrugs,including
topiramateandlevetiracetam,maybeconsideredifsodium
valproateorlamotrigineareunsuitable.
TheEpilepsies
320
Recommendation
92. Considercarbamazepineandoxcarbazepinebutbeawareof
theriskofexacerbatingmyoclonicorabsenceseizures.[new
2012]
outcomes
effectswereconsideredtobethemostimportantoutcomes.
benefitsandharms
Inadults,therewasnosignificantdifferenceinseizurefreedom
betweensodiumvalproate,lamotrigine,carbamazepineand
oxcarbazepine.Inchildrentherewasnodifferencebetween
sodiumvalproateandcarbamazepine.
Therewerefewsignificantdifferencesinthedirectevidencefor
efficacyandformostcomparisonsintheIPDanalyses.Sodium
valproatewassignificantlybetterthancarbamazepinefortimeto
withdrawal.Carbamazepinewassignificantlybetterthan
lamotriginefortimeto12monthremission.
Qualityofevidence Diagnostic,demographicanddosingconsiderationsmustbetaken
intoconsideration.Therewasalackofpowerofstudies
evidencewasverylowwithpoorreportingofrandomisation
studies.
Otherconsiderations DuringtheliteraturereviewweidentifiedananalysisofIndividual
(carbamazepine,gabapentin,lamotrigine,oxcarbazepine,
phenobarbital,phenytoin,sodiumvalproateandtopiramate)
TheGDGconsensusopinionreflectswidespreadclinicalexperience
thatdrugssuchascarbamazepineandoxcarbazepinemay
exacerbatecertainseizurestypes,andspecificallymyoclonicand
absenceseizures.Therefore,theyconcludedthatalthoughthereis
evidencetosupporttheroleofcarbamazepineandoxcarbazepine
inthetreatmentofgeneralisedtonicclonicseizures,theyshould
onlybeconsideredonceotherseizuretypeshavehadtimeto
presentfollowinginitiationoffirstlinedrugs.
TheEpilepsies
321
Adjunctivetreatmentinchildren,youngpeopleandadultswithnewlydiagnosedGTCseizures
Recommendation
93. Offerclobazam
,lamotrigine,levetiracetam,sodiumvalproate
ortopiramateasadjunctivetreatmenttochildren,young
peopleandadultswithGTCseizuresiffirstlinetreatments
(seerecommendations90,91and92)areineffectiveornot
tolerated.Beawareofteratogenicrisksofsodiumvalproate
outcomes
Themostimportantoutcomeswereadverseeffectsand50%
reductioninseizurefrequency.
benefitsandharms
Lamotrigine,levetiracetamandtopiramateasadjunctivetherapies
allsignificantlyreducedseizurefrequencybyatleast50%when
comparedtoplacebo.Therewassignificantlymoreseizure
freedomwithclobazamandlevetiracetamcomparedtoplacebo
butlamotrigineandtopiramateshowednodifferencecomparedto
placebo.
Therewasnosignificantdifferenceforanyadverseevent,
withdrawalduetoadverseeventsorlackofefficacyfor
lamotrigine,levetiracetamandtopiramateadjunctivetherapies
whencomparedtoplacebo.
TheGDGconsideredtheevidencefromtheeconomicevaluation
undertakenfortheguidelineinwhichlamotrigineemergedasa
verycosteffectiveadjunctivetherapyinpatientsexperiencing
refractorygeneralisedtonicclonicseizures.Iflamotriginehad
beentriedpreviously,levetiracetamwasalsolikelytobeacost
effectiveadjunctiveAED.Topiramatewasnotshowntobecost
effective,butintheeventthatotheralternativesfailtoproduce
thedesiredreductioninseizurefrequency,theGDGfeltthatit
shouldbeconsidered.Clobazamwasnotevaluatedaspartofthe
costeffectivenessanalysisbecausetheclinicalstudiesdidnot
reportalloutcomesnecessaryforinclusion.However,theGDG
consideredthatitseffectivenesscomparedtoplaceboanditssmall
unitcostislikelytomakeitcosteffective.
Qualityofevidence
intoconsideration.Therewasalackofpowerinthestudies
particularlywithregardtosideeffects.Theoverallqualityof
evidencewaslow:somehadnodetailsofrandomisationor
allocationconcealment,highdropoutrateoraverysmallsample
size.
TheEpilepsies
322
Otherconsiderations Thereisapharmacodynamicinteractionbetweenlevetiracetam
andcarbamazepineandbetweenlamotrigineandcarbamazepine
sosideeffectsmaybeenhanced.
mustbetakenintoconsiderationwhenintroducingorwithdrawing
breakthroughseizures.Thereshouldbeaconcomitantincreasein
lamotriginedose.Careshouldbetakenwhenwithdrawing
clobazamwithaslowwithdrawalupto46monthsinviewofthe
riskofwithdrawalseizures.Topiramatemayaffectphenytoin
levels.
Recommendation
94. Ifthereareabsenceormyoclonicseizures,orifJMEis
suspected,donotoffercarbamazepine,gabapentin,
oxcarbazepine,phenytoin,pregabalin,tiagabineorvigabatrin.
[new2012]
outcomes
Reductioninseizuresandadverseeffectswereconsideredtobe
themostimportantoutcomes.
benefitsandharms
Clinicalpracticesuggeststhatabsenceandmyoclonicseizurescan
beaggravatedbythesemedications.Giventhatthesetwoseizure
typesmayaccompanygeneralisedtonicclonicseizures,theGDG
feltthatuseofthesemedicationswouldleadtonoclinicalbenefit
andcouldcauseharm.
Economicconsiderations Noeconomicevidencewasavailabletoinformthecost
effectivenessoftheseAEDsinthispopulation;howevertheir
potentialtoaggravateabsenceseizuresmakesthemveryunlikely
tobecosteffective.Aggravationofseizuresislikelytonegatively
impacthealthrelatedqualityoflifeandincreaseNHSresourceuse.
Qualityofevidence
Wefoundnoevidenceforthesedrugsinrelationtogeneralised
tonicclonicseizures.ThisrecommendationwasbasedonGDG
consensus.
Otherconsiderations None.
10.6 AbsenceSeizures
10.6.1 Introduction
Absenceseizuresarecharacterisedbyparoxysmalepisodesbehaviouralarrestwithlossof
consciousness,associatedwithgeneralisedspikeandwaveactivityonEEG.Typicalabsencesseizures
TheEpilepsies
323
areabruptinonsetandoffset,shortinduration(usually<10seconds),andoccurfrequently.
SynchronousspikewaveactivityisseenontheEEGatafrequencyof3Hzorabove.Suchareseenas
partofchildhoodonsetepilepsysyndromessuchaschildhoodabsenceepilepsyandjuvenileabsence
epilepsy.Atypicalabsencesmaynotbeasabruptinonsetoroffset,aretypicallylongerinduration
(>20seconds),andconsciousnessmaynotbetotallylost.FurthertheEEGduringtheattackismore
heterogeneouswithirregularslowerspikewaveactivity(12Hz).Suchmaybeseeninisolation,or
associatedwithotherseizuretypesaspartofanepilepsysyndromeegLennoxGastautsyndrome.
includedpeoplewithmyoclonicseizures.
FordetailsonthematrixoftheevidencepleaserefertotheevidencereviewforIGEinsection10.13.
10.6.4 AEDsforthetreatmentofabsenceseizures
Clinicalevidence
FordetailsontheclinicalevidencepleaserefertotheevidencereviewforIGEinsection10.13.For
detailsoneachpaperidentifiedintheliteraturesearchpleaserefertoAppendixL.
TheEpilepsies
324
Firstlinetreatmentinchildren,youngpeopleandadultswithabsenceseizures
Recommendation
95. Offerethosuximideorsodiumvalproateasfirstlinetreatment
tochildren,youngpeopleandadultswithabsenceseizures.If
thereisahighriskofGTCseizures,offersodiumvalproate
first,unlessitisunsuitable.Beawareofteratogenicrisksof
outcomes
TheGDGconsideredseizurefreedomandadverseeventstobethe
mostimportantoutcomesforthisrecommendation.
benefitsandharms
TheGDGconsideredthatthedifferentsideeffectprofilesof
sodiumvalproateandethosuximidecouldnotdeterminewhich
oneofthesedrugsbeusedfirst,althoughtheremaybeindividual
factorsthatmaydeterminethechoiceofonedrugovertheother.
Significantlymorepatientsonvalproateshoweddifficultiesin
attention.Cautionshouldbeusedwithsodiumvalproateingirlsof
childbearingpotential.
Economicconsiderations NoeconomicevaluationswereavailabletoinformtheGDGonthe
costeffectivenessofanyAEDsusedtotreatCAE,JAEor
generalisedabsenceseizures.AtthetimetheGDGconsideredthe
evidence,thereweresignificantcostdifferencesbetween
ethosuximidecapsules(0.68per250mg)andethosuximidesyrup
(0.108to0.165per250mg).AccordingtothePrescriptionCost
Analysisof2008,99.7%ofethosuximideprescriptionswerefor
syrup.Whenethosuximidesyrupisprescribed,thedailyunitcosts
ofethosuximideandsodiumvalproateareverycomparable.On
thisbasistheGDGconsideredthatclinicaljudgementandpatient
choiceshouldguidethedecisionforwhichofthelikelycost
effectivedrugstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasretrievedfroma
doubleblindedstudyofaverygoodquality,adoubleblindedof
unclear/lowqualityandfromtwounblindedstudies.
Otherconsiderations
TheGDGconsideredthatthedataavailableforchildhoodabsence
epilepsycanbeextrapolatedtothoseindividualswithjuvenile
absenceepilepsy,andalsotothosewhohavegeneralisedabsence
seizuresbutwhodonotmeetthecriteriaforchildhoodabsence
epilepsyorjuvenileabsenceepilepsy.
TheEpilepsies
325
Recommendation
ifethosuximideandsodiumvalproateare
unsuitable,ineffectiveornottolerated.[new2012]
outcomes
benefitsandharms
TheGDGconsideredthatthesideeffectprofileoflamotriginewas
morefavourable,butitsefficacywaslessfavourable,when
comparedwithethosuximideandsodiumvalproate.
generalisedabsenceseizures.TheGDGconsideredthatat
recommendeddailydoseslamotrigine,sodiumvalproateand
ethosuximidesyruphavebroadlysimilarunitcosts,butthat
lamotriginewaslesseffectivethansodiumvalproateand
ethosuximideinthispopulation.Butifsodiumvalproateand/or
ethosuximidedonotproducetheclinicalbenefitdesired,theGDG
feltthatlamotriginewasapotentiallycosteffectivealternative.
Qualityofevidence
Theevidencebasewasretrievedfromadoubleblindedstudyof
verygoodqualityandfromtwounblindedstudies.
Otherconsiderations
TheGDGconsideredthatthedataavailableforCAEcanbe
extrapolatedtothoseindividualswithJAE,andthosewhohave
generalisedabsenceseizuresbutwhodonotmeetthecriteriafor
childhoodabsenceepilepsyorjuvenileabsenceepilepsy.
TheEpilepsies
326
Adjunctivetreatmentinchildren,youngpeopleandadultswithabsenceseizures
Recommendation
97. IftwofirstlineAEDs(seerecommendations95and96)are
ineffectiveinchildren,youngpeopleandadultswithabsence
seizures,consideracombinationoftwoofthesethreeAEDsas
adjunctivetreatment:ethosuximide,lamotrigine
orsodium
valproate.Beawareofteratogenicrisksofsodiumvalproate
outcomes
TheGDGconsideredseizurefreedom,reductioninseizure
frequencyandadverseeventstobethemostimportantoutcomes
forthisrecommendation.
benefitsandharms
TheGDGconsideredthatifatleasttwoofthefirstlineAEDshave
failedtoproducethedesiredeffect(seizurefreedom),thenitis
appropriatetotryawelltoleratedcombinationoftwoofthem.
Althoughthereisnoevidenceinthispopulationspecifically,GDG
experienceisthatanyofthethreecanbesafelycombinedand
giventheireffectivenessasindividualdrugs,theexpectationisthat
theyareeffectiveincombination.
Cautionshouldbeusedwithsodiumvalproateingirlsofchild
bearingpotential.
NoeconomicevaluationswereavailabletoinformtheGDGonthe
costeffectivenessofanyAEDsusedasmonotherapyoradjunctive
therapytotreatCAE,JAEorgeneralisedabsenceseizures.There
wasnoevidencetosuggestthatanyspecificcombinationof
ethosuximide,lamotrigineandsodiumvalproateisbetterthan
another.Anycombinationisexpectedtobebroadlysimilarin
termsofcostaswell.Therefore,theGDGconsideredthatclinical
judgementandpatientchoiceshouldguidethedecisionforwhich
ofthelikelycosteffectiveAEDcombinationstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasextrapolatedfrom
theevidenceforeachofthesedrugsasmonotherapyinnewly
diagnosedabsenceseizuresandwassupportedbyGDGconsensus.
Otherconsiderations
TheEpilepsies
327
Recommendation
98. Ifadjunctivetreatment(seerecommendation97)isineffective
ornottolerated,discusswith,orreferto,atertiaryepilepsy
specialistandconsiderclobazam
,clonazepam,
levetiracetam
,topiramate
orzonisamide
.[new2012]
outcomes
Reductioninseizureswasconsideredtobethemostimportant
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepam,topiramateor
zonisamidewerepossiblealternativesinaccordancewithtertiary
epilepsycare.TheGDGconsidereditimportanttomentionthese
drugsaspotentialoptionstooffertopatientsbetweenthetimeof
referraltoandconsultationwithatertiaryspecialist.Itwas
thoughtthatthesearesomeofthedrugsthatatertiaryspecialist
mightuse,basingthedecisiononclinicalexperiencetreating
patientswithrefractoryabsenceseizures.Therewasnodifference
foundfortopiramateandsodiumvalproatefortimetofirstseizure
fromsodiumvalproatebuttopiramatehadashortertimeto
withdrawal.Duetotheseriousnessofsideeffectsreportedfor
topiramatesuchaspsychiatricandbehaviouralchangesreported
intheSANADtrial,theGDGfeltitisnotadrugoffirstchoice
whereotherdrugsaresuitable.
TheGDGrecommendedthatthesepatientsshouldbediscussed
withorreferredtoatertiaryepilepsyspecialist.Whilstthismaybe
morecostly,theGDGconsideredthatthiswasworthwhileasthese
patientsmayrequiremorecomplexcareinordertoachievea
successfuloutcome.Withregardtothespecificdrugslistedhere,
therewerenoeconomicevaluationsavailabletoinformtheGDG
onthecosteffectivenessofclobazam,clonazepam,topiramateor
zonisamide.
Qualityofevidence
Therewasnoevidenceavailableforabsenceseizuresforclobazam,
clonazepamandzonisamidesothesedrugswereaddedtothis
recommendationbasedonGDGclinicalexpertise.Therewas
limitedevidenceavailablefortopiramateinabsenceseizuresfrom
alargeunblindedpragmatictrial.
Otherconsiderations Careshouldbetakenwithclobazamandclonazepamduetoaslow
withdrawalupto46monthsinviewoftheriskofwithdrawal
seizures.
ForfurtherguidanceonmedicationadherencetorefertotheNICE
MedicinesAdherenceguideline.
TheEpilepsies
328
Recommendation
99. Donotoffercarbamazepine,gabapentin,oxcarbazepine,
phenytoin,pregabalin,tiagabineorvigabatrin.[new2012]
outcomes
Seizurefreedomandadverseeffectswereconsideredtobethe
mostimportantoutcomes.
benefitsandharms
Clinicalpracticesuggeststhatabsenceseizurescanbeaggravated
bythesemedications.TheGDGfeltthatuseofthesemedications
wouldleadtonoclinicalbenefitandcouldcauseharm.
effectivenessoftheseAEDsinthispopulation;however,their
impacthealthrelatedqualityoflifeandincreaseNHSresource
use.
Otherconsiderations Thereisnoevidenceofbenefitonuseofthesemedications
TheEpilepsies
329
10.7 MyoclonicSeizures
10.7.1 Introduction
Myoclonicseizuresaredefinedassudden,briefinvoluntarysingleormultiplecontraction(s)of
muscle(s)ormusclegroupsofvariablelimblocation.Myoclonicseizuresareseenaspartofseveral
epilepsysyndromesegjuvenilemyoclonicepilepsy,Dravetsyndrome.Inthesecircumstances
treatmentshouldbeconsideredinthecontextofthediagnosedsyndromeratherthanindividual
seizuretypes.Howeverthereareavarietyofstaticencephalopathiesnotfulfillingcriteriaforspecific
epilepsysyndromes,wheremyoclonicseizuresarethemajorifnotonlyseizuretype.Furtherthere
areanumberofprogressivemyoclonicepilepsiesforwhichspecifictreatmentofmyoclonusmay
requireconsideration.
includedpeoplewithmyoclonicseizures.
myoclonicseizures.Thefollowinginterventionswereincludedinoursearch:clobazam,clonazepam,
lamotrigine,levetiracetam,piracetam,sodiumvalproate,topiramateandzonisamide.Welookedfor
anyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
Belowisamatrixshowingwhereevidencewasidentified.Aboxcontainingafigureindicatesthe
numberofstudiesthatwerefoundandthattheevidenceforthiscomparisonhasbeenreviewedin
thischapter.Anemptyboxindicatesthatnoevidencewasfound.Inthiscase,nosectiononthis
comparisonisincludedinthechapter.
Placebo
Lamotrigine
Levetiracetam 1
297

Clobazam
Clonazepam
Piracetam
Topiramate
Sodium
Valproate
1
165
1
298

Zonisamide
Pla LTG LEV CLB CLN PRC TPM VPA ZNS
TheEpilepsies
330
10.7.4 Monotherapyforthetreatmentofmyoclonicseizures
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandsodiumvalproate
monotherapyfortheproportionofseizurefreeparticipants(VERYLOWQUALITY).
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandsodiumvalproate
monotherapyfortheproportionofparticipantswithdrawnduetolackofefficacy(VERYLOW
QUALITY).
theproportionofparticipantswithdrawnduetoadverseevents(VERYLOWQUALITY).
Nostatisticallysignificantdifferencebetweenlamotrigineandsodiumvalproateforincidenceofthe
erythematousrash(VERYLOWQUALITY)
weightincrease(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytosodiumvalproatemonotherapyina
populationofpatientswithmyoclonicseizureswasidentified.
timetofirstseizure
cognitiveoutcomes
10.7.4.2 Topiramatemonotherapy/adjunctivetherapyversussodiumvalproatemonotherapy/adjunctive
therapy
Clinicalevidence
TheEpilepsies
331
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapy/adjunctivetherapyandsodium
valproatemonotherapy/adjunctivetherapyfortheproportionofseizurefreeparticipants.(VERY
LOWQUALITY)
valproatemonotherapy/adjunctivetherapyfor50%reductioninseizurefrequency.(VERYLOW
QUALITY)
Costeffectiveness
populationofpatientswithmyoclonicseizureswasidentified.
timetofirstseizure
cognitiveoutcomes
10.7.5 Adjunctivetherapyforthetreatmentofmyoclonicseizures
10.7.5.1 Levetiracetamadjunctivetherapyversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctiveweremyoclonicseizurefree
comparedtoplacebo.However,thereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
TheEpilepsies
332
Significantlymoreparticipantsreceivinglevetiracetamadjunctiveachieved50%orabovereduction
inseizurefrequencycomparedtoplacebo(MODERATEQUALITY).
Thereisnosignificantdifferencebetweenthelevetiracetamadjunctivegroupandtheplacebogroup
ontheincidenceof:
Qualityoflifestatisticallysignificantresults
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadexperienced
improvementinhealthrelatedqualityoflifecomparedtoplacebo(MODERATEQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamadjunctivetherapytoplaceboinapopulationof
patientswithmyoclonicseizureswasidentified.
timetofirstseizure
cognitiveeffects.
TheEpilepsies
333
Firstlinetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
youngpeopleandadultswithnewlydiagnosedmyoclonic
seizures,unlessitisunsuitable.Beawareofteratogenicrisksof
outcomes
TheGDGplacedmostimportanceonefficacyasmeasuredby
seizurefreedom,timetofirstseizureandtimetowithdrawaland
adverseevents.
benefitsandharms
Theevidenceformonotherapyinthetreatmentofpatientswith
myoclonicseizuresisverylimited,basedonunblindedstudieswith
verysmallsamplesorsubgroupscomparingonlylamotrigineor
topiramatetosodiumvalproate.ThereforetheGDGusedevidence
extrapolatedfromjuvenilemyoclonicepilepsytomakethis
recommendation.
Theevidencecomparingsodiumvalproateandlamotrigineor
topiramateinapopulationexperiencingmyoclonicseizureswasnot
poweredtoshowadifferenceintermsofeffectivenessor
tolerability.Resultsfromanunpublishedsubgroupanalysis(SANAD
datasests)forjuvenilemyoclonicepilepsyshowedthatsodium
valproatewasmoreeffectivethanlamotriginealthoughtherewas
nosignificantdifferenceobservedintermsoftreatmentfailure.
SodiumvalproateisthemosteffectivedrugfortreatingIGE,butit
hascertaindisadvantages.Theriskofteratogenicityassociatedwith
theuseofsodiumvalproateuseissignificant,particularlyathigher
doses,socautionisadvisedintheuseofvalproateinwomenof
childbearingpotential.Ingirlswhoseseizurescontinueandwhoare
approachingchildbearingpotential,thecontinueduseofsodium
valproateshouldbereviewedandoptionsdiscussed.
Althoughtherewasevidenceforlamotrigineinthisgroup,theGDG
considereditaninappropriatetreatmentoptionduetoitsinefficacy
andpossibleriskofexacerbationofmyoclonicseizures.
Exacerbationofseizureswasnotfoundinthestudyformyoclonic
seizuresbutthismaybebecausetheadverseeventdatawas
derivedfromtheoverallgeneralisedepilepsygroup,andwasnot
specifictothemyoclonicseizuressubgroup,whoaccountedfor
22.2%ofthegeneralisedepilepsygroup.
costeffectivenessofanyAEDsusedtotreatpatientsexperiencing
myoclonicseizures.However,asintheformulationof
recommendationsforthetreatmentofjuvenilemyoclonicepilepsy
(JME),theGDGdrewfromthecosteffectivenessevidencefor
sodiumvalproateinidiopathicgeneralisedepilepsyasawhole.On
thisbasis,theyputgreateremphasisonthecostperseizureavoided
analysisfromSANADbecausereductionofseizurefrequencyis
TheEpilepsies
334
consideredtobethemostimportantclinicaloutcome.
Qualityofevidence
Theevidenceformyoclonicseizureswaslimited.Twounblinded
studiesofverylowqualityevidencewereincludedwithnodetails
onrandomisationandnoallocationconcealment.Onewasasmall
subgroupfromaverysmallpilotstudyofjuvenilemyoclonic
epilepsyandtheotherwasasmallsubgroupwhichtheauthorsdid
notstatisticallycompareduetothesizeandimbalanceof
distribution.Thisrecommendationwasbasedonevidencefor
monotherapyextrapolatedfromJMEpopulations.TheJMEdata
mainlycamefromalargepragmaticunblindedtrial(SANAD).
Otherconsiderations ForfurtherguidanceonmedicationadherencetorefertotheNICE
TheEpilepsies
335
Firstlinetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
101. Considerlevetiracetam
ortopiramate
ifsodiumvalproateis
unsuitableornottolerated.Beawarethattopiramatehasaless
favourablesideeffectprofilethanlevetiracetamandsodium
valproate.[new2012]
outcomes
TheGDGplacedgreaterimportanceonefficacyasmeasuredby
seizurefreedom,timetofirstseizureandtimetowithdrawaland
adverseevents.
benefitsandharms
Topiramatecanbeconsidered,butbeawareofthelessfavourable
sideeffectprofile.Theevidencewaslimitedfortopiramateinthis
groupandsoevidencewasextrapolatedfromtheJMEreviewwhich
foundnodifferencebetweentopiramateandsodiumvalproatefor
efficacyoradverseevents.
ItistheGDGconsensusopinionthattopiramatehasnotbeenshown
tobeeffectiveinIGEwithphotosensitivity.Therearelimiteddata
onthesafetyoftopiramateinpregnancy.Atpresenttheriskin
pregnancyappearsoveralltobesimilartolamotrigine.Topiramate,
particularlyathigherdoses,mayreducetheefficacyofthe
combinedoralcontraceptive.Finally,duetotheseriousnessofside
effectsreportedfortopiramatesuchaspsychiatricandbehavioural
changesreportedintheSANADtrial,theGDGfeltitisnotadrugof
firstchoicewhereotherdrugsaresuitable.
Atthetimeofwritingthisguidelinelevetiracetamisnotcurrently
licensedformonotherapyintheUKbutitiseffectiveasadjunctive
therapyinmyoclonicseizuresandhastheadvantageofhavingno
significantreportedinteractionswithothermedications.Further,
theGDGexperienceisthatithasaveryfavourablesideeffect
profile.ItisalsotheonlyotherAEDthathasbeendemonstratedto
beeffectiveinthesuppressionofphotoparoxysmalresponse(ina
phaseIItrialof12photosensitivepatientsbyKasteleijnNolstin
1996).TheGDGdecidedtorecommendofflabeluseof
levetiracetamformyolonicseizuresastheevidenceforefficacyand
tolerabilityinadjunctivetherapyconcurredwiththeirclinical
experienceofitsuseinmonotherapy.Additionally,theGDGfeltthat
therewasaneedformoreoptionstobeavailabletotreatpatients
withmyoclonicseizuresgiventheadverseeffectprofilefor
alternativedrugsforwhichthereisevidence.Atthetimeofwriting
theguideline,thereareinsufficientdatatojudgethesafetyof
levetiracetaminpregnancy.
TheEpilepsies
336
TheGDGconsideredthattherearepatientsforwhomsodium
valproateiscontraindicatedornottoleratedandforthesepatients,
topiramatemaybeacosteffectivealternative.Thepublished
economicevidenceforthecosteffectivenessoftopiramatein
patientswithIGEwasoutofdateandaroughreestimationbased
oncurrentcostswasundertaken.Thenewresultsindicatethat
topiramatehasthehighesttotalcostbutthatitislikelytobe
consideredcosteffective.
Thereiscurrentlynoevidenceonwhichtoassessthecost
effectivenessoflevetiracetamasamonotherapyinpatients
experiencingmyoclonicseizures.Intheabsenceofanyapplicable
economicevidence,theGDGconsideredthecosteffectiveness
resultsoflevetiracetamasamonotherapyinapopulationwithfocal
epilepsywhereitwasmoreeffectivethantopiramateandalsohada
slightlylowertotalcostovertheentire15yeartimehorizon.In
addition,theGDGlookedtotheresultsofthedecisionmodel
undertakentoevaluateadjunctivetherapiesinapopulationwith
refractorygeneralisedtonicclonicseizures,wherelevetiracetam
wasalsolesscostlyandmoreeffectivethantopiramate.Onthe
assumptionthatlevetiracetamisatleastaseffectiveastopiramate
inthetreatmentofmyoclonicseizures,theGDGconcludedthat,as
observedinotherpopulations,itwaslikelytorepresentreasonable
valuetotheNHSwhensodiumvalproateisanunsuitabletreatment
option.Researchintoboththeeffectivenessandcosteffectiveness
oflevetiracetamasamonotherapyinthispopulationisessentialto
reducethesubstantialuncertaintyinthisdecision.
Qualityofevidence
Thedataformyoclonicseizureswaslimitedthereforetheevidence
wasextrapolatedfromJMEandadjunctivetherapyformyoclonic
seizuresandGDGclinicalexpertise.TheJMEdatamainlycamefrom
alargepragmaticunblindedtrial(SANAD).Thelevetiracetam
adjunctivedatacamefromagoodqualitydoubleblindedstudywith
allparticipantshavingmyoclonicseizures.
TheEpilepsies
337
Adjunctivetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
102. Offerlevetiracetam,sodiumvalproateortopiramate
as
adjunctivetreatmenttochildren,youngpeopleandadults
withmyoclonicseizuresiffirstlinetreatments(see
recommendations100and101)areineffectiveornot
outcomes
Atleastof50%seizurereductionandadverseeffectswere
consideredthemostimportantoutcomes.
benefitsandharms
Levetiracetamiseffectiveasadjunctivetherapyinmyoclonic
seizuresandhastheadvantageofnosignificantinteractionswith
othermedications.Thereareinsufficientdatatojudgethesafety
oflevetiracetaminpregnancyatthetimeofwritingtheguideline.
Therewasnoevidencefortopiramateasadjunctivetherapybut
therewassomeevidenceextrapolatedformonotherapyfromJME
whichfoundittobeeffectiveandtheGDGthoughtitwouldalso
beeffectiveasadjunctivetherapy.
costeffectivenessoflevetiracetamortopiramateastreatments
specificallyinpatientsexperiencingrefractorymyoclonicseizures.
TheGDGconsideredtheclinicalevidenceforadjunctive
levetiracetaminapopulationwithJMEwhichshowsittobeeven
moreeffectivecomparedtoplacebothaninapopulationwith
primarygeneralisedtonicclonicseizures.Onthatbasis,theGDG
feltthatthecosteffectivenessofadjunctivelevetiracetamwas
likelytobethesameorbetterthanintheanalysisconductedfor
patientswithprimarygeneralisedtonicclonicseizures,
summarisedinsection10.5.8anddetailedinappendixS.Inthe
sameanalysis,topiramatewasnotshowntobecosteffective,but
intheeventthatadjunctivelevetiracetamfailstoproducethe
desiredreductioninseizurefrequency,theGDGfeltthatitcould
beconsidered.
Qualityofevidence Theoverallqualitygradingforlevetiracetamwaslowtomoderate
quality.TherewasonlyonedoubleblindstudyofIGEwith
myoclonicseizuresforlevetiracetamversusplacebo.Therewasno
evidenceavailablefortopiramateadjunctivetherapybutJMEdata
fortopiramatemainlycamefromalargepragmaticunblindedtrial
(SANAD).
TheEpilepsies
338
Recommendation
103. Ifadjunctivetreatment(seerecommendation102)is
ineffectiveornottolerated,discusswith,orreferto,atertiary
epilepsyspecialistandconsiderclobazam
,clonazepam,
piracetamorzonisamide
.[new2012]
outcomes
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepam,piracetamor
zonisamidewerepossiblealternativesinaccordancewithtertary
patientswithrefractorygeneralisedseizuretypes.
Economicconsiderations TheGDGrecommendedthatthesepatientsshouldbediscussed
onthecosteffectivenessofclobazam,clonazepam,piracetamor
zonisamide.
Qualityofevidence
TherewasnoevidenceavailableformyoclonicseizuresorJMEfor
thesedrugssothisrecommendationwasbasedonGDGclinical
expertise.
Otherconsiderations Careshouldbetakenwithclobazamandclonazepamduetoaslow
seizures.
TheEpilepsies
339
Recommendation
outcomes
benefitsandharms
Clinicalpracticesuggeststhatmyoclonicseizurescanbe
aggravatedbythesemedications.TheGDGfeltthatuseofthese
medicationswouldleadtonoclinicalbenefitandcouldcause
harm.
effectivenessoftheseAEDsinthispopulation;however,their
impacthealthrelatedqualityoflifeandincreaseNHSresourceuse.
TheEpilepsies
340
10.8 Tonicoratonicseizures
10.8.1 Introduction
Tonicandatonicseizuresaregeneralisedseizuresthatonoccurrencemaycausean
individualtofall,socalleddropattacks.Tonicseizuresinvolveabruptgeneralised
musclestiffening.Theyusuallylastlessthanaminuteandrecoveryisrapid.EEGatthe
timeoftheseizuredemonstrateslowvoltagefastactivity.Seizuresofthistypemaybe
seeninisolation,ormorecharacteristicallyareseenwithotherseizuretypesaspartof
anepilepsysyndrome.Atonicseizuresarecharacterisedbysuddenonsetoflossof
muscletoneinassociationwithanEEGchange,polyspikesandwave,orfalttening,or
lowvoltagefastactivity.Itisunsualtoseethisseizuretypeinisolation;moretypically
itisseeninassociationwithotherseizuretypesaspartofanepilepsysyndrome.Both
seizuretypesarepartoftheelectroclinicalpictureseeninLennoxGastautsyndrome.
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereviews.Forthisreview
weincludedadultsandchildrenwithtonicoratonicseizures.
Noclinicalorcosteffectivenessevidencewasfoundforadultsandchildrenwithtonicoratonic
seizures.
TheEpilepsies
341
Firstlinetreatmentinchildren,youngpeopleandadultswithtonicoratonicseizures
Recommendation
youngpeopleandadultswithtonicoratonicseizures.Be
awareofteratogenicrisksofsodiumvalproate(see
outcomes
Seizurefreedom,atleast50%reductioninseizurefrequency(all
seizuresanddropattackseizures)andtolerability,asmeasured
bywithdrawalduetoadverseevents,wereconsideredtobethe
benefitsandharms
Thepotentialbenefitsofreducingseizuresneedtobebalanced
againstthepotentialforadverseeffects.Noevidencewasfound
foradultsandchildrenexperiencingtonicoratonicseizures.
EvidencewasextrapolatedfromtheLennoxGastautevidence
reviewwheredrugswereassessedontheoutcomeofreduction
indropattacks(dropseizures).NoRCTevidencewasretrieved
onsodiumvalproateinthisarea.However,thereisevidencethat
sodiumvalproateiseffectiveinreducingothergeneralised
seizures(tonicclonic,clonicandmyocolonic)andtheGDG
opinionwasthatthisevidencecouldbeextrapolatedtothis
group.
Economicconsiderations NoeconomicevaluationswereavailabletoinformtheGDGon
thecosteffectivenessofanyAEDsusedtotreatpatientswith
tonicoratonicseizures.
However,theGDGconsideredthatatinitialpresentation,
treatmentchoiceisinfluencedbythepredominantseizuretype.
Inthissituationmosttonicandatonicseizuresarelikelyto
representageneralised,ratherthanfocalseizuretype.
Therefore,theGDGextrapolatedtheevidenceofcost
effectivenessforsodiumvalproatefromtheresultsofSANAD,
presentedinsection10.5.4.
Qualityofevidence WefoundnoRCTsinnewlydiagnosedpatientsorthatcompared
sodiumvalproatewithanotherantiepilepticdrug.Wealsofound
noRCTsthatcomparedtwodrugsasaddontreatment.The
recommendationisbasedonextrapolatedevidencefromLennox
GastautsyndromeandGDGconsensusopinion.
Otherconsiderations Thereisnospecificdataforfirstlinetreatmentinchildrenand
youngpeoplewithtonicoratonicseizures.Thus,datahasbeen
extrapolatedfromtheLennoxGastautpopulation.
Itisrecognisedthatatthetimeepilepsyisdiagnosed,itmaynot
bepossibletoidentifythespecificepilepsysyndrome.Thechoice
ofAEDwillthenbemadeonthepredominantseizuretype(or
types).
TheEpilepsies
342
Adjunctivetreatmentinchildren,youngpeopleandadultswithtonicoratonicseizures
Recommendation
asadjunctivetreatmenttochildren,young
peopleandadultswithtonicoratonicseizuresiffirstline
treatmentwithsodiumvalproateisineffectiveornot
tolerated.[new2012]
outcomes
Seizurefreedom,atleast50%reductioninseizurefrequency(all
seizuresanddropattackseizures)andtolerability,asmeasuredby
withdrawalduetoadverseevents,wereconsideredtobethemost
importantoutcomes.
benefitsandharms
review,wherestudiesevaluatedresponseindropattacks.
Lamotrigineadjunctivetreatmentismoreeffectiveinreducing
dropattacksbyatleast50%andhasasimilarsideeffectsprofile
Economicconsiderations Thetreatmentoftonicoratonicseizures,similarlytoLennox
Gastautsyndromegenerallyrequiresanumberofconcomitant
AEDsbecausenosingleAEDislikelytobringaboutasatisfactory
response.TheGDGconsideredtheresultsoftwocost
effectivenessanalysesfromtheLennoxGastautreview,wherein
lamotriginewaslesscostlyandmoreeffectivethanstandard
monotherapyintermsofreducingthefrequencyofallseizuresand
dropattackseizuresandlesscostlyandmoreeffectivethan
topiramateinreducingofallseizuretypesandproducedmore
QALYs.Theanalyseshadsomepotentiallyseriouslimitations,but
theGDGconsideredthatlamotrigineisarelativelyinexpensive
AEDandwasshowntobeeffectiveintermsofreducingthe
numberofdropattacksandtonicclonicseizuresintheclinical
review.Itwasalsoassociatedwithfewersideeffectsthan
topiramateandrufinamide.Onthisbasis,theGDGjudgeditthe
AEDmostlikelytobeconsideredcosteffective.
Qualityofevidence
review.Thetwostudiesincludedforthecomparisonoflamotrigine
adjunctiveversusplacebowereoflowqualityduetoserious
limitationsinthestudydesignasbothofthemhadnoinformation
onrandomisationandnoallocationconcealment.
TheEpilepsies
343
Recommendation
107. Discusswithatertiaryepilepsyspecialistifadjunctive
treatment(seerecommendation106)isineffectiveornot
tolerated.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistarerufinamide
andtopiramate
.[new
2012]
outcomes
Shouldthespecificepilepsysyndromediagnosisnotbecertain
followingatrialoftwomedications,assessmentbytertiary
epilepsyspecialistisrecommendedtodiscusssyndrome,causeand
furtherdrugmanagement.Seizurefreedom,atleast50%reduction
inseizuresanddropattackseizurefrequency,aswellas
withdrawalduetoadverseeventswereconsideredtobethemost
importantoutcomes.
benefitsandharms
review.Ifadjunctivetreatmentisnottoleratedorineffective
furthertreatmentmaybesuccessfulbuttheGDGfeltthatthis
shouldbediscussedwithatertiaryepilepsyspecialist.Thebalance
betweenreducingseizures(whichmaybeinjuriousand
debilitating)andadverseeffectsneedstobeconsideredwhen
choosingdrugtreatment.
Rufinamideandtopiramateadjunctivetreatmentsweremore
effectiveinreducingfrequencyofallseizuresbyatleast50%.
Rufinamidewasalsomoreeffectiveinreducingthefrequencyof
dropattackseizuresbyatleast50%.However,bothrufinamide
andtopiramatehadworsesideeffectprofilescomparedto
placebo.
Economicconsiderations Thetreatmentoftonicandatonicseizures,similarlytoLennox
GastautsyndromemayrequiresanumberofconcomitantAEDs
becausenosingleAEDislikelytobringaboutasatisfactory
response.Dropattackscanbedangerousanddebilitatingand
thereforeachievingadequateseizurecontrolwithadjunctiveAEDs
canpotentiallyimprovequalityoflifeandreduceaccidents
requiringemergencyand/orroutinecare.TheGDGconsideredthe
resultsofonecosteffectivenessanalysis,whereintopiramateand
rufinamidewerelesscostlyandmoreeffectivethanstandard
treatmentinthereductionofallseizuretypes,includingdrop
attacks.However,anothercostutilityanalysisindicatedthat
topiramatewasmorecostlyandlesseffectivethanlamotrigineand
thatrufinamide,whilemoreeffectivethanlamotrigine,washighly
unlikelytobecosteffective.Theseanalyseshadsomeserious
limitations,buttheGDGconsideredthatwiththeestimateddaily
costofrufinamidenearly10timesthatoflamotrigine,itishighly
unlikelythattheextrabenefitobservedwithrufinamidecompared
tolamotriginejustifiesthesubstantialadditionalcost.Therefore,
theGDGdecidedthattopiramateandrufinamideshouldbe
reservedforthosepatientsforwhomstandardmonotherapyand
TheEpilepsies
344
adjunctivelamotriginehavebeenineffectiveornottolerated.
Qualityofevidence
EvidencewasextrapolatedfromtheLennoxGastautsyndrome
evidencereview.Theevidenceforbothtopiramateandrufinamide
wasoflowquality.Therewerenoheadtoheadcomparisonsof
rufinamideandtopiramatewithanyotherantiepilepticdrugin
LennoxGastautsyndrome.
Otherconsiderations Clinicalexperiencewithrufinamideisconsiderablylessthanwith
lamotriginewhichwasshowntobeeffective.
Recommendation
outcomes
benefitandharms
Clinicalpracticesuggeststhatseizurescanbeaggravatedbythese
medications.TheGDGfeltthatuseofthesemedicationswould
leadtonoclinicalbenefitandcouldcauseharm.
Noeconomicevidencewasavailabletoinformthecost
potentialtoaggravateseizuresmakesthemveryunlikelytobe
costeffective.Aggravationofseizuresislikelytonegativelyimpact
healthrelatedqualityoflifeandincreaseNHSresourceuse.
Qualityofevidence ThisrecommendationwasbasedonGDGexpertise.
Otherconsiderations
Thereisnoevidenceofbenefitonuseofthesemedications
TheEpilepsies
345
10.9 InfantileSpasms(Westsyndrome)
10.9.1 Introduction
Infantilespasmsareaspecificseizuretypepresentinginthefirstyearoflife,mostcommonly
between3and9monthsofage.Spasmsarebriefaxialmovementslasting0.22seconds,most
commonlyflexorinnature,involvingflexionofthetrunkwithextensionoftheupperandlower
limbs.Theytypicallyoccurinclusters,andmostcommonlyonawakening.TheEEGcharacteristically
showsrandomhighvoltageslowwavesandspikes,socalledhypsarrhythmia,andtogetherwiththe
developmentalplateautypicallyseenattheonsetofspasms,formthetriadofWestsyndrome.
HoweverfullEEGcriteriaofhypsarrhythmiaarenotalwaysseenwithspasms,especiallyattheonset,
andinthesecircumstancesmanagementshouldbethesame.Spasmsmaybeseenwithmany
underlyingcauses,whethergenetic(e.g.mutationonCDKL5gene),structural/metabolic(e.g.
tuberoussclerosis)orunknown.
Longtermprognosisispoorforneurodevelopmentalprogress,impairedin85%ofpatients.Many
respondtofirstlinetherapy;longtermneurodevelopmentalprogressisthoughttobebetterifthere
isashortlagtotreatment,aswellasapromptresponsetotreatment,althoughtheunderlyingcause
isequallyrelevant.However,60%willsubsequentlydeveloplaterepilepsyevenifspasmsinitially
respondtotreatment.
Forthisreviewweincludedadultsandchildrenwithinfantilespasmswithorwithouttuberous
sclerosisasacause.Theoutcomeswerethesameasotherreviewsexceptinsteadoftheproportion
ofparticipantsachievingseizurefreedomwelookedattheproportionofparticipantsexperiencinga
cessationofspasmsandtheproportionofparticipantsexperiencingaresolutionofhypsarrhythmia.
10.9.3 Matrixoftheevidenceforadjunctivetherapy
infantilespasms.Theinterventionsweincludedinoursearchwerenitrazepam,pyridoxine,
adrenocorticotropichormone,hydrocortisone,prednisolone,prednisone,vigabatrin,topiramate,
clobazam,clonazepam,zonisamideandsodiumvalproate.WelookedforanyRCTstudiesthat
comparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).Belowisamatrix
showingwereevidencewasidentified.Aboxcontainingafigureindicatesthenumberofstudiesthat
werefoundandthattheevidenceforthiscomparisonhasbeenreviewedinthischapter.Anempty
boxindicatesthatnoevidencewasfound.Inthiscase,nosectiononthiscomparisonisincludedin
thechapter.

Placebo
Nitrazepam
Prednisolone 1
299

Prednisone 2
300,301

Hydrocortisone
1
302

Vigabatrin 1
303
4
299,304

TheEpilepsies
346
PCBplaceboVGBvigabatrinACTHadrenocortiocotrophichormone
PNLprednisolonePNEprednisoneHYDhydrocortisone
NPMnitrazepam
10.9.3.1 Vigabatrinversusplacebo(inapopulationwithouttuberoussclerosis)
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenvigabatrinandplaceboforcessationofspasmsinapopulation
withouttuberoussclerosis.(LOWQUALITY)
Nosignificantdifferencebetweenvigabatrinandplaceboforresolutionofhypsarrhythmiaina
populationwithouttuberoussclerosis.(MODERATEQUALITY)
Nosignificantdifferencebetweenvigabatrinandplaceboforatleast70%reductioninseizure
frequencyinapopulationwithouttuberoussclerosis.(MODERATEQUALITY)
Nosignificantdifferencebetweenvigabatrinandplaceboinapopulationwithouttuberoussclerosis
fortheincidenceofthefollowingadverseevents:
drowsiness(LOWQUALITY)
irritability(LOWQUALTY)
death(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingvigabatrintoplacebowasidentifiedinapopulationwithout
tuberoussclerosisexperiencinginfantilespasms.
10.9.3.2 VigabatrinversusACTH(inapopulationwithtuberoussclerosis)
Clinicalevidence
306
ACTH 1
299
1
307

PCB VGB ACTH PNL PNE HYD NPM
TheEpilepsies
347
Evidencestatements
NosignificantdifferencebetweenvigabatrinandACTHforcessationofspasmsinapopulationwith
tuberoussclerosis.(LOWQUALITY)
NosignificantdifferencebetweenvigabatrinandACTHforresolutionofhypsarrhythmiaina
populationwithtuberoussclerosis.(LOWQUALITY)
SignificantlymoreparticipantsonACTHthanvigabatrininapopulationwithtuberoussclerosishad
anincidenceof:
irritability(MODERATEQUALITY)
hypertension(MODERATEQUALITY)
NosignificantdifferencebetweenvigabatrinandACTHforwithdrawalduetoadverseeventsina
populationwithtuberoussclerosis(VERYLOWQUALITY)
NosignificantdifferencebetweenvigabatrinandACTHinapopulationwithtuberoussclerosisfor
incidenceofdeath.(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingvigabatrintoACTHwasidentifiedinapopulationwithtuberous
sclerosisexperiencinginfantilespasms.
10.9.3.3 VigabatrinversusACTH(inapopulationwithouttuberoussclerosis)
Clinicalevidence
Evidencestatements
SignificantlymoreparticipantsonACTHcomparedtovigabatrinhadcessationofspasmsina
populationwithouttuberoussclerosisalthoughthereisuncertaintyinthemagnitudeofclinical
effect.(LOWQUALITY)
SignificantlymoreparticipantsonACTHcomparedtovigabatrinhadresolutionofhypsarrhythmiain
apopulationwithouttuberoussclerosis.(MODERATEQUALITY)
SignificantlymoreparticipantsonACTHthanvigabatrininapopulationwithouttuberoussclerosis
hadanincidenceofirritability(MODERATEQUALITY)
TheEpilepsies
348
NosignificantdifferencebetweenvigabatrinandACTHforwithdrawalduetoadverseeventsina
populationwithouttuberoussclerosis.(LOWQUALITY)
NosignificantdifferencebetweenvigabatrinandACTHinapopulationwithouttuberoussclerosisfor
gastrointestinaldisturbances(LOWQUALITY)
increasedappetite(LOWQUALITY)
dermatologicalproblems(LOWQUALITY).
Costeffectiveness
NoeconomicevidencecomparingvigabatrintoACTHwasidentifiedinapopulationwithouttuberous
10.9.3.4 Vigabatrinversushydrocortisone(inapopulationwithonlytuberoussclerosis)
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsonvigabatrincomparedtohydrocortisonehadcessationofspasmsin
apopulationwithonlytuberoussclerosis.(MODERATEQUALITY)
Nosignificantdifferencebetweenvigabatrinandhydrocortisoneinapopulationwithonlytuberous
sclerosisfortheincidenceofthefollowingadverseevents:
hyperexcitability/hyperkinesia(VERYLOWQUALITY)
sleepdisorders(VERYLOWQUALITY)
abdominaldistension(VERYLOWQUALITY)
hypertension(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingvigabatrintohydrocortisonewasidentifiedinapopulationwith
onlytuberoussclerosisexperiencinginfantilespasms.
10.9.3.5 Vigabatrinversusprednisolone(inapopulationwithouttuberoussclerosis)
Clinicalevidence
TheEpilepsies
349
Evidencestatements
Nosignificantdifferencebetweenvigabatrinandprednisoloneforcessationofspasmsina
populationwithouttuberoussclerosis.(VERYLOWQUALITY)
Nosignificantdifferencebetweenvigabatrinandprednisoloneforresolutionofhypsarrhythmiaina
Significantlymoreparticipantsonprednisolonethanvigabatrininapopulationwithouttuberous
sclerosishadanincidenceofirritability(MODERATEQUALITY)
Nosignificantdifferencebetweenvigabatrinandprednisoloneforwithdrawalduetoadverseevents
inapopulationwithouttuberoussclerosis.(VERYLOWQUALITY)
Nosignificantdifferencebetweenvigabatrinandprednisoloneinapopulationwithouttuberous
sclerosisfortheincidenceoffollowingadverseevents:
increasedappetite(VERYLOWQUALITY)
fluidandelectrolyte(includinghighb.p)(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingvigabatrintoprednisolonewasidentifiedinapopulationwithout
10.9.3.6 ACTHversusprednisone(inapopulationwithtuberoussclerosis)
Clinicalevidence
Evidencestatements
SignificantlymoreparticipantsonACTHcomparedtoprednisoneinapopulationwithtuberous
sclerosishadcessationofspasms.(MODERATEQUALITY)
SignificantlymoreparticipantsonACTHcomparedtoprednisoneinapopulationwithtuberous
sclerosishadresolutionofhypsarrhythmia.(MODERATEQUALITY)
TheEpilepsies
350
Costeffectiveness
NoeconomicevidencecomparingACTHtoprednisonewasidentifiedinapopulationwithtuberous
10.9.3.7 ACTHversusprednisone(inapopulationwithtuberoussclerosis)
Clinicalevidence
Evidencestatements
Efficacynonstatisticallysignificantresults
NosignificantdifferencebetweenACTHandprednisoneforresponsetotreatment(definedastotal
cessationofspasmsanddisappearanceofhypsarrhythmia)inapopulationwithouttuberous
sclerosis.(VERYLOWQUALITY)
NosignificantdifferencebetweenACTHandprednisoneforincidenceofhypertensionina
populationwithouttuberoussclerosis(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingACTHtoprednisonewasidentifiedinapopulationwithout
10.9.3.8 PrednisoloneversusACTH(inapopulationwithouttuberoussclerosis)
Clinicalevidence
Evidencestatements
NosignificantdifferencebetweenprednisoloneandACTHforcessationofspasmsinapopulation
withouttuberoussclerosis.(VERYLOWQUALITY)
NosignificantdifferencebetweenprednisoloneandACTHforresolutionofhypsarrhythmiaina
NosignificantdifferencebetweenprednisoloneandACTHforwithdrawalduetoadverseeventsina
populationwithouttuberoussclerosis(VERYLOWQUALITY)
TheEpilepsies
351
NosignificantdifferencebetweenprednisoloneandACTHinapopulationwithouttuberoussclerosis
fortheincidenceofthefollowingadverseevents:
increasedappetite(VERYLOWQUALITY)
fluidandelectrolyte(includinghighb.p)(VERYLOWQUALITY)
bloodpressureabove110/80mmHg(VERYLOWQUALITY)
bloodpressureabove120/90mmHg(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingprednisolonetoACTHwasidentifiedinapopulationwithout
10.9.3.9 NitrazepamversusACTH
Clinicalevidence
Evidencestatements
NosignificantdifferencebetweennitrazepamandACTHforatleast50%reductioninseizure
frequency.(VERYLOWQUALITY)
NosignificantdifferencebetweennitrazepamandACTHforwithdrawalduetoadverseevents(VERY
LOWQUALITY)
NosignificantdifferencebetweennitrazepamandACTHforincidenceofdeath.(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingnitrazepamtoACTHwasidentifiedinapopulationexperiencing
infantilespasms.
TheEpilepsies
352
Firstlinetreatmentininfantswithinfantilespasms
Recommendation
109. Discusswith,orreferto,atertiarypaediatricepilepsy
specialistwhenaninfantpresentswithinfantilespasms.[new
2012]
outcomes
benefitsandharms
Infantilespasmsisarareseizuretypewhichrequiresinputfrom
specialistswithexpertiseinthearea.Theadverseeventsprofileof
individualdrugsneedstobeevaluatedandfullydiscussedwith
parents.ThiswasarecommendationbasedontheGDGexpertise
asitisthoughtimportantthatchildrenwithinfantilespasms
shouldsee,orreceiveadvicefrom,aspecialist.Limitedevidence
suggestsearlyresolutionofhypsarrhythmialeadstobetter
prognosis.
Economicconsiderations Noeconomicevidencewasavailabletoinformrecommendations
aboutthetreatmentofinfantilespasms.However,theGDG
consideredthatdiscussionwith,orreferraltoatertiarypaediatric
specialistandearlyinterventioninthisgroupofpatientsmaylead
toabetterprognosis,preventinglongtermcognitivedeterioration
andassociateddecrementstohealthrelatedqualityoflife.
Qualityofevidence
Therewasnoevidencesoughtforthisrecommendation.The
recommendationwasbasedonGDGexpertise.
Otherconsiderations
Theadverseeventsprofileofindividualmedicinesneedstobe
evaluatedandfullydiscussedwithparents.Theriskofvisualfield
constrictioncausedbyvigabatrinisunknownwithshorttermuse;
theshorttermsideeffectsofhighdosesteroidsincludinghigh
bloodpressure,glucoseintoleranceandimmunosuppression
requiremonitoring.
TheEpilepsies
353
Recommendation
110. Offerasteroid(prednisoloneortetracosactide
)or
vigabatrinasfirstlinetreatmenttoinfantswithinfantile
spasmsthatarenotduetotuberoussclerosis.Carefully
considertheriskbenefitratiowhenusingvigabatrinor
steroids.[new2012]
outcomes
Cessationofspasms,resolutionofhypsarrhythmiaandsideeffects
areconsideredimportantprimaryoutcomemeasures.
benefitsandharms
Significantlymoreparticipants(withouttuberoussclerosisas
cause)onACTH(tetracosactide)thanvigabatrinhadcessationof
spasmsandresolutionofhypsarrhythmia.Nodifferencewas
foundinefficacyinastudyofvigabatrinversusprednisoloneor
prednisoloneversusACTHorprednisoneversusACTHforthose
withouttuberoussclerosisascause.
TheGDGconsideredthedrugstohaveclinicallyrelevant
differencesintheirsideeffectsprofile.Itisunknownwhether
shorttermuseofvigabatrinisassociatedwiththedevelopmentof
visualfileddefects.Althoughvisualfieldsshouldbemonitored,
thiswillbeverydifficultifnotimpossibleinchildrenwitha
cognitiveageoflessthan9years.Shorttermsideeffectsofhigh
dosesteroidssuchashighbloodpressureandglucoseintolerance
shouldbemonitored.Theevidenceindicatedthathypertension
andirritabilityareworsewithsteroids.ACTHhadahigher
incidenceofirritabilitythanvigabatrinwhethertuberoussclerosis
wasthecauseornot.Prednisolonehadahigherincidenceof
irritabilitythanvigabatrininapopulationwheretuberoussclerosis
wasexcluded.
NoeconomicevidencewasavailabletoinformtheGDGofthe
relativecosteffectivenessofanydrugsusedinthetreatmentof
infantilespasms.Thepopulationofchildrenexperiencinginfantile
spasmsisquitesmall,treatmentdurationisshortanditisdifficult
toweighupthebenefitsandharmsoftreatmentintermsof
qualityoflifeinchildrensoyoung.Earlydiagnosisandtreatment
areessentialasthismayimpactonlongertermcognitiveandsocial
outcomes.Thepotentialsideeffectsofsteroids(hypertension,
irritabilityandimmunosuppressionleadingtopotentiallysevere
infections),poseadditionalcostsintermsofmanagementand
monitoring.
Qualityofevidence
Overallnumberandqualityofstudieswaslimited.Therewas
heterogeneityofcauseofinfantilespasms,dosageof
interventions,anddurationofthetreatmentandfollowup.Allof
thestudieswereoflimitedpoweranddonotexcludethe
possibilityofsignificantdifferencesbetweenthetreatments.
TheEpilepsies
354
Otherconsiderations Comparedwiththeoriginalguideline(2004),oneadditionalRCT
wasappropriateforconsideration.
TheEpilepsies
355
Recommendation
111. Offervigabatrinasfirstlinetreatmenttoinfantswith
infantilespasmsduetotuberoussclerosis.Ifvigabatrinis
ineffective,offerasteroid(prednisoloneortetracosactide
).
Carefullyconsidertheriskbenefitratiowhenusingvigabatrin
orsteroids.[new2012]
outcomes
Cessationofspasms,resolutionofhypsarrhythmiaandadverse
eventsareconsideredimportantprimaryoutcomemeasures.
benefitsandharms
Vigabatrinissignificantlymoreeffectiveatstoppingspasmsthan
steroidsinpatientswithinfantilespasmscausedbytuberous
sclerosis.
Significantlymorepatients(includingthosewithtuberoussclerosis
ascause)onACTHthanprednisolonehadcessationofspasmsand
resolutionofhypsarrhythmia.Therewasnosignificantdifference
betweenvigabatrinandACTHinstudieswheretuberoussclerosis
wasthecause.
TheGDGconsideredthedrugstohaveclinicallyrelevant
differencesintheiradverseeventsprofile.Itisunknownwhether
shorttermuseofvigabatrinisassociatedwiththedevelopmentof
visualfileddefects.Althoughvisualfieldsshouldbemonitored,
thiswillbeverydifficultifnotimpossibleinchildrenwitha
cognitiveageoflessthan9years.TheGDGsuggestmonitoringof
visualfields,wherepossible.Shorttermsideeffectsofhighdose
steroidssuchashighbloodpressureandglucoseintolerance
shouldbemonitored.TheevidencefoundACTHhadhigher
incidenceofirritabilityandhypertensionthanvigabatrinforthose
withtuberoussclerosisasthecause.
TheGDGfeltthatoveralltheadvantagesofvigabatrinoutweighed
thepotentialadverseeffects.Steroidswerefoundtobeless
effectiveatstoppingseizuresbuttheGDGconsideredthattheyare
avaluableoptionifvigabatrinisineffective.
Economicconsiderations NoeconomicevidencewasavailabletoinformtheGDGofthe
relativecosteffectivenessofanydrugsusedinthetreatmentof
infantilespasmsassociatedwithtuberoussclerosis.The
populationofchildrenexperiencinginfantilespasmsisquitesmall,
treatmentdurationisshortanditisdifficulttoweighupthe
benefitsandharmsoftreatmentintermsofqualityoflifein
childrensoyoung.Earlydiagnosisandtreatmentareessentialas
thismayimpactonlongertermcognitiveandsocialoutcomes.The
potentialsideeffectsofsteroids(hypertension,irritabilityand
immunosuppressionleadingtopotentiallysevereinfections),pose
additionalcostsintermsofmanagementandmonitoring.
TheEpilepsies
356
Qualityofevidence
Overallnumberandqualityofstudieswaslimited.Heterogeneity
ofcause,dosageofinterventions,anddurationofthetreatment
andfollowup.Allofthestudieswereoflimitedpoweranddonot
excludethepossibilityofsignificantdifferencesbetweenthe
treatments.
10.9.5.1 Infantilespasms
Doestreatmentresponserelatetocauseininfantilespasms?Doesearlytreatmentsuccessinseizure
controlandresolutionofthehypsarrhythmicEEGinfluencethelongtermdevelopmentaland
cognitiveoutcomesmorethantheunderlyingcauseofthespasms?
Whythisisimportant
TheUKInfantileSpasmsStudy(UKISS)
bb
demonstrated14dayoutcomeefficacyofsteroidsover
vigabatrin,althoughthisexcludedchildrenwithtuberoussclerosis.Thisstudyprovidednospecific
subgroupanalysisbasedonthecauseofthespasms.Therewasnoanalysisontheeffectof
treatmentlagonthestudyfindings.Furtherdataareavailableonbehaviouraloutcomesat14
monthsand4yearswithregardtodifferenttreatmentsbutwithnoanalysisbasedoncauseor
treatmentlag.Furtherdevelopmentalandcognitiveoutcomeswouldbeuseful,includingresponse
byspecificcauseandbytreatmentlag.
prospectiverandomiseddesign,includingsubgroupanalysesbasedonbothcauseand
treatmentlag;thiswouldrequirelargenumbersofpatientsandwouldneedtobe
multicentre,possiblyinvolvingWesternEurope
EEGoutcomes
developmentalstatusatpresentation,andatfollowup

bb
LuxAL,EdwardsSW,HancockEetal.(2004)TheUnitedKingdomInfantileSpasmsStudycomparingvigabatrinwith
prednisoloneortetracosactideat14days:amulticentre,randomisedcontrolledtrial.Lancet364:17738.
TheEpilepsies
357
10.10 Dravetsyndrome(SMEI)
10.10.1 Introduction
Severemyoclonicepilepsyofinfancy,nowspecificallyreferredtoasDravetsyndrome(asfirst
describedbytheepileptologistCharlotteDravet)isanepilepsysyndromethatlieswithintheGEFS+
(geneticepilepsywithfebrileseizuresplus)spectrum.Typicallychildrenwillpresentwithinthefirst
yearoflifewithprolonged,andoftenfocalfebrileseizures,withthesubsequentappearanceinthe
secondyear(oruptofouryearsoflife)ofotherseizuretypesincludingfocal,generalizedtonicclonic
andmyocloniceizures.Developmentisoftennormaloverthefirstyear,butsubsequentlyoverthe
secondyearstartstoslow.Atleast80%ofchildrenwiththiselectroclinicalsyndromehavea
mutationinthesodiumchannelgene,SCN1A.Althoughreferredtoasanepilepticencephalopathy,
thedegreetowhichtheepilepsycontributestotheneurodevelopmentalimpairmentisunclear,and
theremaybeacontributionfromthegeneticbackground.Therearealsootherindividualswhodo
notdevelopmyoclonusbutotherwisefulfilltheclinicalpicture,andthereforeareknownassevere
myoclonicepilepsyborderline(SMEB).Theaimoftreatmentremainstocontrolseizuresand
minimizetheoccurrenceofstatusepilepticuswherepossible.Itisimportanttoappreciatethatsome
antiepilepticmedications,particularlylamotriginemayaggravatetheseizures,andspecifically
myoclonicseizures.Thelongtermprognosisispoorforbothseizurecontrolandneuro
developmentaloutcomeandthereisanincreasedmortality,includingsuddenunexpecteddeathin
epilepsy(SUDEP).
includedadultsandchildrenwithDravetsyndrome.
epilepsyinapopulationwithseveremyoclonicepilepsyofinfancy.Theinterventionsweincludedin
oursearchwerestiripentol,levetiracetam,topiramate,clobazam,clonazepam,phenobarbitaland
sodiumvalproate.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreof
thesetreatments(orplacebo).Belowisamatrixshowingwereevidencewasidentified.Abox
Placebo
Stiripentol 1
308

Levetiracetam
Topiramate
Clobazam
Clonazepam
TheEpilepsies
358
Phenobarbital
Sodium
valproate

Pla STP TPM GLB CLN PHB VPA LEV
Placebo(Pla)Topiramate(TPM)Stiripentol(STP)Clobazam(CLB)
Levetiracetam(LEV)Sodiumvalproate(VPA)Phenobarbital(PHB)Clonazepam(CLN)
10.10.4 AdjunctivetreatmentofDravetSyndrome(SMEI)
10.10.4.1 StiripentoladjunctivetherapyversusPlacebo
Clinicalevidence
Evidencestatements
ForpeoplewithDravetsyndrome,significantlymorepatientsonstiripentoladjunctivetherapywere
seizurefreecomparedtoplacebo;howeverthereisuncertaintyoverthemagnitudeoftheclinical
effect.(LOWQUALITY)
ForpeoplewithDravetsyndrome,significantlymorepatientsonstiripentoladjunctivetherapy
experiencedatleasta50%reductioninseizurefrequencycomparedtoplacebo;howeverthereis
uncertaintyoverthemagnitudeoftheclinicaleffect.(LOWQUALITY)
ForpeoplewithDravetsyndrome,significantlymorepatientsonstiripentoladjunctivetherapy
experienceddrowsinesscomparedtopatientstakingplacebo;howeverthereisuncertaintyoverthe
magnitudeoftheclinicaleffect.(LOWQUALITY)
ForpeoplewithDravetsyndrome,therewasnosignificantdifferencebetweenstiripentoladjunctive
therapyandplaceboontheincidenceofthefollowingadverseevents:
hyperexcitability(VERYLOWQUALITY)
aggressiveness(VERYLOWQUALITY)
lossofappetite(VERYLOWQUALITY)
lossofweight(VERYLOWQUALITY)
neutropenia(10001500/Ml)(VERYLOWQUALITY)
TheEpilepsies
359
withdrawalduetoadverseevents,
withdrawalduetolackofefficacy,
timetofirstseizure,
cognitiveoutcomes
Costeffectiveness
Noeconomicevidencecomparingadjunctivestiripentoltoplaceboinapopulationofpatientswith
Dravetsyndromewasidentified.
FirstlinetreatmentinchildrenwithDravetsyndrome(SMEI)
Recommendation
specialistwhenachildpresentswithsuspectedDravet
syndrome.[new2012]
outcomes
Reductioninseizuresandminimisingadverseeffectswere
consideredtobethemostimportantoutcomes.
benefitsandharms
Dravetsyndromeisarareepilepsysyndromewhichrequiresinput
fromspecialistswithexpertiseinthearea.Theadverseevents
profileofindividualdrugsneedstobeevaluatedandfully
discussedwithparents.Thiswasarecommendationbasedonthe
GDGexpertiseasitisthoughtimportantthatchildrenwithDravet
syndromeshouldsee,orreceiveadvicefrom,aspecialistwhohas
theappropriateexperience.
aboutthetreatmentofDravetsyndrome.However,theGDG
consideredthatdiscussionwith,orreferraltoatertiarypaediatric
specialistandappropriateinterventioninthisgroupofpatients
mayleadtoabetterprognosisforseizurecontrol,minimiselong
termcognitivedeteriorationandassociateddecrementstohealth
relatedqualityoflife.
Qualityofevidence Therewasnoevidencesoughtforthisrecommendation.The
Otherconsiderations Theadverseeventsprofileofindividualmedicinesneedstobe
evaluatedandfullydiscussedwithparents.
Recommendation
asfirstline
treatmentinchildrenwithDravetsyndrome.[new2012]
TheEpilepsies
360
Recommendation
asfirstline
treatmentinchildrenwithDravetsyndrome.[new2012]
outcomes
Seizurefreedomandwithdrawalduetoadverseeventswere
benefitsandharms
NoevidencewasfoundformonotherapytreatmentofDravet
syndrome(SMEI).Onfirstpresentation,thediagnosisofDravet
syndromemaybeunclearoruncertain,andthereforetreatment
choicewillbeinfluencedbythepredominantseizuretype,
typicallygeneralisedtonicclonicormyoclonicseizures.Sodium
valproateandtopiramatehavebeenshowntobeeffectiveinthe
treatmentofothergeneralisedseizuresandepilepsysyndromes.
Thedrugsrecommendedabovearealsolikelytoreducetheriskof
convulsivestatusepilepticus,incontrasttootherdrugsincluding
lamotrigine,whichmayexacerbatemyoclonicseizuresinthisand
otherepilepsysyndromes(BNF).
Economicconsiderations NoeconomicevidencewasavailabletoinformtheGDGonthe
costeffectivenessofanyAEDsusedinthetreatmentofchildren
withDravetsyndrome(SMEI).Sodiumvalproatewasshowntobe
acosteffectivemonotherapyinotherepilepsypopulationsand
theGDGconsidereditlikelytobecosteffectiveinthispopulation
aswell.Basedonclinicalexperience,theGDGconsidered
topiramatetobeanothereffectiveandpossiblycosteffectiveAED
forpatientswithDravetsyndrome(SMEI).
Qualityofevidence
NoRCTwasfoundinnewlydiagnosedpatientswhichcompared
sodiumvalproateortopiramatewithanotherantiepilepticdrug.
TherecommendationwasbasedonGDGconsensusopinionand
extrapolatedevidencefromotherseizuretypeandepilepsy
syndromes.
Otherconsiderations Nootherconsideration.
Adjunctivetreatmentinchildren,youngpeopleandadultswithDravetsyndrome(SMEI)
Recommendation
114. Discusswithatertiaryepilepsyspecialistiffirstline
treatments(seerecommendation113)inchildren,young
peopleandadultswithDravetsyndromeareineffectiveor
nottolerated,andconsiderclobazam
orstiripentolas
adjunctivetreatment.[new2012]
outcomes
TheGDGconsideredthatthemostimportantoutcomeswerea
greaterthan50%reductioninseizuresandseizurefreedomfor
thisrecommendation,aswellasareductioninepisodesof
convulsivestatusepilepticus(SE).
benefitsandharms
Onlyonestudywasfoundwhichcomparedstiripentoltoplacebo
asadjunctivetreatmenttoclobazamandsodiumvalproateand
TheEpilepsies
361
Recommendation
114. Discusswithatertiaryepilepsyspecialistiffirstline
treatments(seerecommendation113)inchildren,young
peopleandadultswithDravetsyndromeareineffectiveor
nottolerated,andconsiderclobazam
orstiripentolas
adjunctivetreatment.[new2012]
thisshowedasignificantdifferenceinfavourofstiripentolfor
seizurefreedomandatleasta50%reductioninseizure
frequency.TheGDGconsideredthebenefitstooutweightherisks
ofusingstiripentol.Patientsonstiripentolexperiencedrowsiness
andappropriatemanipulationofthedrugmayalleviatethisside
effect.Cautionshouldbegivenwithanydrugsthatare
metabolisedbytheliver.Stiripentolimpairsthebreakdownof
VPAandCLBandotherAEDsmetabolisedbytheliver.
costeffectivenessofanyAEDsinthetreatmentofchildrenwith
Dravetsyndrome(SMEI).Stiripentolisaveryexpensivedrug
relativetootherfirstlineAEDscurrentlyavailableintheNHSthat
areusedtotreatDravetsyndrome(SMEI).TheGDGconsidered
thatatanaveragecostof0.016permg,theannualcostof30mg
perkilogramperdayfora3yearoldchildofaverageweight(16.5
kg)isalmost3000.Adoseof30mgperkilogramisonlythe
averagedoseofstiripentolandtheannualcostwouldrisewithan
increaseddoseandalsoincreasedageandweightofthe
child.TheGDGconsideredthatpatientswithDravetsyndrome
(SMEI)whereseizuresarepoorlycontrolledareatriskof
developingconvulsivestatusepilepticuswhichisassociatedwith
anincreasedriskofmortalityandmorbidityand
hospitalisation.Althoughtheclinicalevidenceshowsadjunctive
stiripentoltobemoreeffectivethanplacebo,thereis
considerableuncertaintyastowhetherassociatedhealthgains,
measuredintermsofseizurereduction,areworththissubstantial
extracost.
Qualityofevidence Lowqualityevidence.TherewasonlyonetrialinDravetsyndrome
(SMEI),anditincludedasmallnumberofpatientsandprovided
nodetailsofconcealmentofallocation.
Otherconsiderations ThisAEDhasorphanstatus.Dravetsyndrome(SMEI)isalifelong
conditionwhichusuallyhasanonsetinthefirstyearoflifeandis
associatedwithpoorseizurecontrol,severelearningdifficulties
andanincreasedmortalityrate.
TheEpilepsies
362
Recommendation
115. Donotoffercarbamazepine,gabapentin,lamotrigine,
oxcarbazepine,phenytoin,pregabalin,tiagabineorvigabatrin.
[new2012]
outcomes
Withdrawalduetoadverseeventsandincidenceofadverseevents
wereconsideredtobethemostimportantoutcomesforthis
recommendation.
benefitsandharms
NootherRCTsofAEDsusedinDravetsyndrome(SMEI)were
identified.Thereforethisrecommendationisbasedonthe
consensusopinionoftheGDG.Thesedrugshavethepotentialto
exacerbateseizuresinDravetsyndrome(SMEI).
effectivenessofanyAEDsinthetreatmentofchildrenwithDravet
syndrome(SMEI);howeverthepotentialforthesedrugsto
aggravateseizuresmakesthemveryunlikelytobecosteffective.
Aggravationofseizuresislikelytonegativelyimpacthealthrelated
qualityoflifeandincreaseNHSresourceuse,particularlyasthese
patientsareatahigherriskfordevelopingconvulsivestatus
epilepticuswhichisassociatedwithincreasedrisksof
hospitalisation,morbidity,andmortality.
Qualityofevidence
NoRCTevidencewasfoundforanyoftheseAEDsandtherefore
therecommendationisbasedonGDGconsensusopinion.
Otherconsiderations TheGDGconsideredthatthereisnonewevidencetochallenge
drugstobeavoided(fromoriginalguideline)butdecidedtoadd
phenytoin.
10.10.6.1 EpilepsySyndromes
WhatistheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswithonset
inchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome(SMEI)?
Whyisthisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidencebaseforthemost
Researchshouldinclude:
Multicentrerandomisedcontrolledcomparativetrialswithcentralizednationaldatacollection.
Theketogenicdietasoneoftherandomisedtreatments.
Primaryoutcomeseizurefreedom.
Secondaryoutcomemeasuresincludingseizurereduction,qualityoflifeandcognitiveoutcome.
Anattempttoobtainsomedataonpharmacoresistance.
TheEpilepsies
363
Thepossibilitytoincludeallchildrenwithspecificepilepsysyndromestobeconsideredfortrial.
10.11 LennoxGastautSyndrome
LennoxGastautsyndromeisanepilepsysyndromecharacterisedbymultipleseizuretypes(including
atonic,tonic[oftenreferredtoasdropattacks],tonicclonicandatypicalabsenceseizures),
cognitiveimpairmentandspecificEEGfeatures.Ageofonsetistypicallybetween3and10years,
usuallybefore8years,with1030%havinganearlierhistoryofinfantilespasms.Thecharacteristic
EEGpatternofdiffuseslowspikeandwave(<2.5Hz)maynotbepresentatonsetbutmayevolve
withtime;someauthorsalsorequirethepresenceoffast(10Hz)rhythmsinsleep,withorwithout
tonicseizures,tomakethediagnosis.Episodesofnonconvulsivestatusepilepticusarecommon,but
maybeunderrecognised.Longtermprognosisforbothneurocognitiveoutcomeandseizurecontrol
ispoor,withahighrateofbehaviourdisorder.Aimsofmanagementshouldbediscussedcarefully
witheachfamilyandmedicationkepttoaminimumwherepossibletoavoidtoxicity.
includedadultsandchildrenwithLennoxGastautSyndrome.
LennoxGastautsyndrome.Thefollowinginterventionswereincludedinoursearch;rufinamide,
clobazam,clonazepam,felbamate,ethosuximide,lamotrigine,levetiracetam,sodiumvalproateand
topiramate.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthese
treatments(orplacebo).
Placebo
Rufinamide 1
309

Lamotrigine
2
310,311

Topiramate 1
312

Levetiracetam
Felbamate 1
313

Ethosuximide
Clobazam
Clonazepam
TheEpilepsies
364
Placebo(Pla)Rufinamide(RFM)Lamotrigine(LTG)Clonazepam(CLZ)
Topiramate(TPM)Levetiracetam(LEV)Felbamate(FBM)Ethosuximide(ETX)
Sodiumvalproate(VPA)Clobazam(CLB)
10.11.4 AdjunctivetreatmentforLennoxGastautsyndrome
Clinicalevidence
314
ofAEDs,includinglamotrigineandplacebo,usedasadjunctivetherapy
inthetreatmentofchildrenwithLennoxGastautsyndromewasidentifiedintheeconomicliterature
search.Thecompleteresultsofthisstudyarepresentedinsection10.11.5.
Evidencestatements
Significantlymoreparticipantstakinglamotrigineadjunctiveexperiencedatleast50%reductionin
dropattackseizurefrequencycomparedtoplacebo.(MODERATEQUALITY)
Significantlymoreparticipantstakinglamotrigineadjunctiveexperiencedatleast50%reductionin
tonicclonicseizurefrequencycomparedtoplacebo.(MODERATEQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctiveandplacebofortheproportionofseizure
freeparticipants.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctiveandplacebofortheproportionof
participantsexperiencedatleast50%reductioninseizurefrequency(VERYLOWQUALITY)
Significantlymoreparticipantstakingplaceboexperiencedfatiguecomparedtolamotrigine
adjunctive.(LOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctiveandplacebofortheproportionof
Nosignificantdifferencewasfoundbetweenlamotrigineadjunctiveandplacebofortheincidenceof
Sodium
valproate

Pla
RF
M
LTG
TP
M
LEV
FB
M
ETX
CLB
CLZ
VPA
TheEpilepsies
365
moreintenseseizures(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatadjunctivelamotrigineis
lesscostlyandmoreeffectivethanplacebointhetreatmentoftotalseizuresanddropattack
seizuresinpeoplewithLennoxGastautsyndrome.Thisevidenceispartiallyapplicableandhas
potentiallyseriouslimitations.
timetofirstseizure,
cognitiveoutcomes
Clinicalevidence
314
Evidencestatements
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedatleast50%
reductioninfrequencyofallmajorseizurescomparedtoplacebo,howeverthereisuncertaintyover
themagnitudeofthisclinicaleffect.(LOWQUALITY)
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplacebofortheproportionof
participantsfreefromdropattackseizures.(VERYLOWQUALITY)
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplacebofortheproportionof
participantsexperiencedatleast50%reductionindropattackseizurefrequency(VERYLOW
QUALITY)
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedsomnolence
comparedtoplacebo,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOW
QUALITY)
TheEpilepsies
366
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedanorexiacompared
toplacebo,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOWQUALITY)
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedfatiguecompared
toplacebo,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOWQUALITY)
Nosignificantdifferencewasfoundbetweentopiramateadjunctiveandplacebofortheincidenceof
behaviouralproblems(VERYLOWQUALITY)
moreintenseseizures(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatadjunctivetopiramateis
lesscostlyandmoreeffectivethanplacebointhetreatmentofdropattackseizuresinpeoplewith
LennoxGastautsyndrome.Adjunctivetopiramateismorecostlyandmoreeffectivethanplaceboin
termsoftotalseizurereduction,withanincrementalcosteffectivenessratioof58peradditional
1%ofsuccessfullytreatedpatients.Thisevidenceispartiallyapplicableandhaspotentiallyserious
limitations.
timetofirstseizure
cognitiveoutcomes
10.11.4.3 Felbamateversusplacebo
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenfelbamateadjunctivetherapyandplacebofortheproportionof
participantsfreefromseizures(atonicandtonicclonicseizure).(VERYLOWQUALITY)
TheEpilepsies
367
Significantlymoreparticipantstakingfelbamateadjunctivetherapyexperiencedanorexiacompared
toplacebo.(MODERATEQUALITY)
Significantlymoreparticipantstakingfelbamateadjunctivetherapyexperiencedvomitingcompared
toplacebo.(MODERATEQUALITY)
Significantlymoreparticipantstakingfelbamateadjunctivetherapyexperiencedsomnolence
comparedtoplacebo,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOW
QUALITY)
Significantlyfewerparticipantstakingfelbamateadjunctivetherapyexperienceddiarrhoea
comparedtoplacebo.(MODERATEQUALITY)
Nosignificantdifferencebetweenfelbamateadjunctivetherapyandplacebofortheproportionof
Nosignificantdifferencewasfoundbetweenfelbamateadjunctiveandplacebofortheincidenceof
upperrespiratorytractinfection(VERYLOWQUALITY)
injury(VERYLOWQUALITY)
purpura(VERYLOWQUALITY)
abnormalgait(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingfelbamateadjunctivetherapytoplacebowasidentifiedina
populationwithLennoxGastautsyndrome.
timetofirstseizure
cognitiveoutcomes
10.11.4.4 Rufinamideversusplacebo
Clinicalevidence
TheEpilepsies
368
314
Evidencestatements
Significantlymoreparticipantsinrufinamideadjunctiveexperiencedatleast50%reductioninseizure
frequencycomparedtoplacebo.(LOWQUALITY)
Significantlymoreparticipantsinrufinamideadjunctiveexperiencedatleast50%reductionin
frequencyoftonicatonicseizurescomparedtoplacebo.(LOWQUALITY)
Nosignificantdifferencebetweenrufinamideadjunctiveandplacebofortheproportionof
participantswithdrawnduetolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantstakingrufinamideadjunctiveexperiencedvomitingcomparedto
placebo.(LOWQUALITY)
Nosignificantdifferencebetweenrufinamideadjunctiveandplacebofortheproportionof
Nosignificantdifferencewasfoundbetweenrufinamideadjunctiveandplacebofortheincidenceof
pyrexia(VERYLOWQUALITY)
diarrhoea(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatadjunctiverufinamideis
lesscostlyandmoreeffectivethanplacebointhetreatmentofdropattackseizuresinpeoplewith
LennoxGastautsyndrome.Adjunctiverufinamideismorecostlyandmoreeffectivethanplaceboin
termsoftotalseizurereduction,withanincrementalcosteffectivenessratioof85peradditional
1%ofsuccessfullytreatedpatients.Thisevidenceispartiallyapplicableandhaspotentiallyserious
limitations.
timetofirstseizure,
cognitiveoutcomes
TheEpilepsies
369
10.11.5 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildrenwithLennox
Gastautsyndrome
Twostudies
314,315
assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinchildrenwith
LennoxGastautsyndromewereidentifiedintheeconomicliteraturesearchandincludedinthe
economicevidencereview.SeeappendixMforfullstudydetails.
Onestudy
314
wasexcludedbecauseitmeasuredoutcomesintermsofadditionalcostper1%
increaseinsuccessfullytreatedpatientandwasthereforeonlypartiallyapplicable.Theotherstudy
315
wasincludedintheeconomicevidencereview.
Table21: AdjunctivetherapyforchildrenwithLennoxGastautsyndromeEconomicstudy
characteristics
Verdian(2010)
315
(a,b,c)
Partiallyapplicable(d) Decisionanalyticmodel;
comparatorsincluded
lamotrigine,rufinamide
andtopiramate;time
horizon3years;clinical
databasedonindirect
treatmentcomparisonof
datapresentedinclinical
review
309,311,312
Benedict(2010)
314
(a,b)
Partiallyapplicable
(e,f)
comparatorsincluded
lamotrigine,rufinamide
andtopiramate;time
horizon3years;clinical
databasedonindirect
treatmentcomparisonof
datapresentedinclinical
review
309
,
311
,
312
;2
analysesconducted:one
onreductionindrop
attackseizurefrequency
andotheronpercent
reductionintotalseizure
frequency
(a) Authorsdonotdetailhownonreportedoutcomesforlamotrigineandtopiramatewerehandled.Detailsof
howadverseeventswerecostedwerenotreported.
(b) Potentialconflictofinterestintermsoffundingsource
(c) Estimatesofresourceusebasedonexpertopinionoffivephysicians
(d) HRQoLdatawasnoteliciteddirectlyfrompatientsand/orcarers
(e) Analysisbasedpercentofsuccessfullytreatedpatients,notQALYs
(f) Costsdiscountedat3.5%perannum;nodiscountingappliedtoestimateofeffect
TheEpilepsies
370
Table22: AdjunctivetherapyforchildrenwithLennoxGastautsyndromeResultsofVerdian
2010
315
AED
Totalcost
()per
patient
Totaleffects
(QALY)
ICER
(/QALY) Uncertainty
LTG 21,783 1.42 Atthresholdof20Kand30KperQALY,
probabilityofLTGbeingmorecosteffective
thanRUFis92%and85%respectively
TPM 23,360 1.36 Dominated
byLTG
Atthresholdof20Kand30KperQALY,
probabilityofTPMbeingmorecosteffective
thanRUFis48%and35%respectively(a)
RUF 24,992 1.44 154,831
comparedto
LTG
probabilityofRUFbeingmorecosteffective
thanLTGis8%and15%respectively.
probabilityofRUFbeingmorecosteffective
thanTPMis52%and65%respectively.
ICERofRUFmostsensitivetochangesin
initialprobabilitiesofresponseat3months.
(a) PresentationofprobabilisticsensitivityanalysisincompleteinthatitonlypresentscomparisonsofRUFvsLTGandRUF
vsTPMbutfailstopresentcomparisonofTPMvsLTG.
Table23: AdjunctivetherapyforchildrenwithLennoxGastautsyndromeResultsofBenedict
2010
AED
Totalcost
()per
patient
Totaleffects
(%
successfully
treated
patients)
ICER
(/1%
increasein
successfully
treated
patients) Uncertainty
Measuredonoutcomeofreductionindropattackseizures
TPM 50,728 7.2% Atthresholdof100per1%increasein
successfullytreatedpatients(drop
attacks),probabilityofTPMbeingoptimal
is36%
LTG 50,975 5.2% Dominated Atthresholdof100per1%increasein
successfullytreatedpatients(drop
attacks),probabilityofLTGbeingoptimalis
10%
RUF 50,985 11.3% 62 Atthresholdof100for1%increasein
successfullytreatedpatients,probabilityof
RUFbeingoptimalis54%;Oneway
sensitivityanalysisindicatesICERforRUFis
sensitivetodecreaseinrateof
hospitalisationfordropattackseizures
Monotherapy
(placebo)
51,437 3.3% Dominated Atthresholdof100for1%increasein
successfullytreatedpatients,probabilityof
RUFbeingoptimalis0%
Measuredonoutcomeofreductionintotalseizures
LTG 37,064 6.9% Couldnotbedeterminedfromgraph(a)
Monotherapy
(placebo)
38,366 2.3% Dominated Couldnotbedeterminedfromgraph
TPM 38,557 5.6% Dominated Couldnotbedeterminedfromgraph
TheEpilepsies
371
AED
Totalcost
()per
patient
Totaleffects
(%
successfully
treated
patients)
ICER
(/1%
increasein
successfully
treated
patients) Uncertainty
RUF 38,828 7.7% 2,151 Couldnotbedeterminedfromgraph(a);
OnewaysensitivityanalysisindicatesICER
forRUFissensitivetodecreaseinrateof
hospitalisationfordropattackseizures
(a) Textstatesthatatthresholdof900per1%increaseinsuccessfullytreatedpatientsRUFhasa>80%probabilityof
beingoptimal;however,theCEACpresentedcannotbeinterpretedtoconfirmthis.
Evidencestatements
Twoeconomicevaluationsbasedondecisionanalyticmodelsshowthatlamotrigineislikelytobethe
mostcosteffectiveAEDfortheadjunctivetreatmentofchildrenwithLennoxGastautsyndrome.
Lamotriginewaslesscostlyandmoreeffectivethantopiramateasmeasuredintermsofproportion
successfullytreatedforallseizuretypesandQALYsgained.
Twostudiesshowedthatadjunctiverufinamideismorecostlyandmoreeffectivethanlamotrigine
andtopiramate,butneitherstudydemonstratesittobethemostcosteffective.Costeffectiveness
wasindeterminableinoneanalysisasthemeasurementofeffectwasnotQALYsandtheICERwas
verysensitivetoassumptionsabouttherateofhospitalisationcausedbydropattackseizures.In
theotheranalysis,rufinamidehadanunacceptablyhighICERcomparedtolamotrigine(154,831).
Bothstudiesarepartiallyapplicableandhavepotentiallyseriouslimitations.
Recommendation
specialistwhenachildpresentswithsuspectedLennox
Gastautsyndrome.[new2012]
outcomes
Reductioninseizuresandminimisingadverseeffectswere
benefitsandharms
LennoxGastautsyndromeisarareepilepsysyndromewhich
requiresinputfromspecialistswithexpertiseinthearea.The
adverseeventsprofileofindividualdrugsneedstobeevaluated
andfullydiscussedwithparents.Thiswasarecommendation
basedontheGDGexpertiseasitisthoughtimportantthat
childrenwithLennoxGastautshouldsee,orreceiveadvicefrom,
aspecialistwhohastheappropriateexperience.
Economicconsiderations EeconomicevidencerelatingtothetreatmentofLennoxGastaut
syndromewasisolatedtodrugoptionsforuseasadjunctive
therapy.TheGDGconsideredthatdiscussionwith,orreferralto
atertiarypaediatricspecialistandappropriateinterventionin
thisgroupofpatientsmayleadtoabetterprognosisforseizure
control,minimiselongtermcognitivedeteriorationand
associateddecrementstohealthrelatedqualityoflife.
Qualityofevidence Therewasnoevidencesoughtforthisrecommendation.The
Otherconsiderations Theadverseeventsprofileofindividualmedicinesneedstobe
evaluatedandfullydiscussedwithparents.
TheEpilepsies
372
FirstlinetreatmentinchildrenwithLennoxGastautsyndrome
Recommendation
117. Offersodiumvalproateasfirstlinetreatmenttochildren
withLennoxGastautsyndrome.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new
2012]
outcomes
Seizurefreedom,atleast50%reductioninseizurefrequencyand
withdrawalduetoadverseeventswereconsideredtobethe
benefitsandharms
Thepotentialbenefitsofreducingseizuresneedtobebalanced
againstthepotentialforadverseeffects.NoRCTevidencewas
retrievedonsodiumvalproateinthisarea.Thereishowever
evidencethatsodiumvalproateiseffectiveinreducingseizures
inidiopathicgeneralisedepilepsyandtheGDGopinionwasthat
thisevidencecouldbeextrapolatedtochildrenandyoung
peoplewithLennoxGastautsyndrome.
Economicconsiderations Noeconomicevidencewasavailabletodeterminethecost
effectivenessofanyAEDsusedasfirstlinetreatmentina
populationofpatientswithnewlydiagnosedLennoxGastaut
syndrome.However,theGDGconsideredthatatinitial
presentation,treatmentchoiceisinfluencedbythepredominant
seizuretype,andinthiscasethatistypicallyageneralised
seizuretype.Therefore,theGDGextrapolatedtheevidenceof
costeffectivenessforsodiumvalproatefromtheresultsof
SANAD,presentedinsection10.3.8.
Qualityofevidence WefoundnoRCTsinnewlydiagnosedpatientsorthatcompared
sodiumvalproatewithanotherantiepilepticdrug.Wealsofound
noRCTsthatcomparedtwodrugsasaddontreatment.The
recommendationisbasedonextrapolatedevidencefrom
idiopathicgeneralisedepilepsyandGDGconsensusopinion.
Otherconsiderations TheGDGconsideredthatthereisnonewevidencetochallenge
firstlinetreatment(fromoriginalguideline).
Atinitialpresentation,thediagnosisofthesyndromemaybe
unclearoruncertain,andthereforetreatmentchoicewillbe
influencedbythepredominantseizuretype.
Lowratesofseizurefreedomcanbeexpectedinthissyndrome
asverifiedbyresultsofclinicaltrials.
Sodiumvalproateinhibitsmetabolismoflamotrigineandthis
valproate,lamotriginelevelsmaydropandthismaybethe
reasonforbreakthroughseizures.Thereshouldbea
concomitantincreaseinlamotriginedose.
TheEpilepsies
373
Adjunctivetreatmentinchildren,youngpeopleandadultswithLennoxGastautsyndrome
Recommendation
118. Offerlamotrigineasadjunctivetreatmenttochildren,young
peopleandadultswithLennoxGastautsyndromeiffirstline
treatmentwithsodiumvalproateisineffectiveornot
tolerated.[new2012]
outcomes
importantoutcomes.
benefitsandharms
Lamotrigineadjunctivetreatmentismoreeffectiveinreducingat
least50%theseizurefrequencyandhasasimilarsideeffects
profilewhencomparedtoplacebo.
Economicconsiderations ThetreatmentofLennoxGastautsyndromegenerallyrequiresa
numberofconcomitantAEDsbecausenosingleAEDislikelyto
bringaboutasatisfactoryresponse.TheGDGconsideredthe
resultsoftwocosteffectivenessanalyses,whereinlamotriginewas
lesscostlyandmoreeffectivethanstandardmonotherapyinterms
ofreducingthefrequencyofallseizuresanddropattacksandless
costlyandmoreeffectivethantopiramateinreducingthe
frequencyofallseizuretypesandproducedmoreQALYs.The
analyseshadsomepotentiallyseriouslimitations,buttheGDG
consideredthatlamotrigineisarelativelyinexpensiveAEDandwas
showntobeeffectiveintermsofreducingthenumberofdrop
attacksandtonicclonicseizuresintheclinicalreview.Itwasalso
associatedwithfewersideeffectsthantopiramateandrufinamide.
Onthisbasis,theGDGjudgedittheAEDmostlikelytobe
consideredcosteffective.
Qualityofevidence
Thetwostudiesincludedforthecomparisonoflamotrigine
adjunctiveversusplacebowereoflowqualityduetoserious
limitationsinthestudydesignasbothofthemhadnoinformation
onrandomisationandnoallocationconcealment.
Otherconsiderations
Sodiumvalproateinhibitsmetabolismoflamotrigineandthis
increaseinlamotriginedose.
TheEpilepsies
374
Recommendation
119. Discusswithatertiaryepilepsyspecialistifadjunctive
treatment(seerecommendation118)isineffectiveornot
tolerated.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistarerufinamideandtopiramate.[new2012]
outcomes
importantoutcomes.
benefitsandharms
Ifadjunctivetreatmentisnottoleratedorineffectivefurther
treatmentmaybesuccessfulbuttheGDGfeltthatthisshouldbe
discussedwithatertiaryepilepsyspecialist.Thebalancebetween
reducingseizures(whichmaybedebilitating)andadverseeffects
needstobeconsideredwhenchoosingdrugtreatment.
Rufinamideadjunctivetreatmentwasmoreeffectiveinreducingat
least50%theseizurefrequency.Bothrufinamideandtopiramate
treatmentshadworstsideeffectprofilecomparedtoplacebo.
Economicconsiderations ThetreatmentofLennoxGastautsyndromegenerallyrequiresa
numberofconcomitantAEDsbecausenosingleAEDislikelyto
bringaboutasatisfactoryresponse.Dropattacks,commonin
peoplewithLennoxGastautcanbedebilitatinganddangerous,
thereforeachievingadequateseizurecontrolwithadjunctiveAEDs
canpotentiallyimprovequalityoflifeandreduceaccidents
requiringemergencyand/orroutinecare.TheGDGconsideredthe
resultsofonecosteffectivenessanalysis,whereintopiramateand
rufinamidewerelesscostlyandmoreeffectivethanstandard
treatmentinthereductionofallseizuretypes,includingdrop
attacks.Butanothercostutilityanalysisindicatedthattopiramate
wasmorecostlyandlesseffectivethanlamotrigineandthat
rufinamide,whilemoreeffectivethanlamotriginewashighly
unlikelytobecosteffective.Theanalyseshadsomeserious
limitations,buttheGDGconsideredthatwiththeestimateddaily
costofrufinamidenearly10timesthatoflamotrigine,itishighly
unlikelythattheextrabenefitobservedwithrufinamidecompared
tolamotriginejustifiesthesubstantialadditionalcost.Therefore,
theGDGdecidedthattopiramateandrufinamideshouldbe
reservedforthosepatientsforwhomstandardmonotherapyand
adjunctivelamotriginehavebeenineffectiveornottolerated.
Qualityofevidence
Theevidenceforbothtopiramateandrufinamidewasoflow
quality.Therewerenoheadtoheadcomparisonsofrufinamide
andtopiramatewithanyotherantiepilepticdruginLennoxGastaut
Syndrome.
Otherconsiderations Clinicalexperiencewithrufinamideisconsiderablylessthanwith
lamotriginewhichwasshowntobeeffective.
TheEpilepsies
375
Recommendation
outcomes
benefitandharms
Clinicalpracticesuggeststhatseizurescanbeaggravatedbythese
medications,andcancompromisecognitionwithriskofnon
convulsivestatusepilepticus.TheGDGfeltthatuseofthese
harm.
Noeconomicevidencewasavailabletoinformthecost
potentialtoaggravateseizuresmakesthemveryunlikelytobe
costeffective.Aggravationofseizuresislikelytonegatively
use.
Qualityofevidence ThisrecommendationwasbasedonGDGexpertise.
Otherconsiderations
Thereisnoevidenceofbenefitonuseofthesemedications
Recommendation
121. Onlyofferfelbamate
incentresprovidingtertiaryepilepsy
specialistcareandwhentreatmentwithalloftheAEDslisted
inrecommendations119and120hasprovedineffectiveor
nottolerated.[new2012]
outcomes
benefitandharms
Felbamateadjunctivewasnotfoundtobemoreeffective
comparedtoplaceboanddemonstratedaserioussideeffect
burden.
Noeconomicevidenceisavailabletoevaluatetherelativecost
effectivenessoffelbamateinthetreatmentofpeoplewith
LennoxGastautsyndrome.However,thepotentialforserious
adverseevents,suchasaplasticanaemia,andtheneedfor
ongoingmonitoringmakeitunlikelytobeacosteffectiveAEDfor
theaveragepatient.
Qualityofevidence OneRCTwasidentifiedwhichhadseriouslimitations.
Otherconsiderations
TheGDGconsideredfelbamatetobealastlinetherapy,reserved
forpatientswhohavenotrespondedtoalternative,costeffective
treatmentoptions.Itisonlyavailableonanamedpatientbasis.
Useoffelbamatemustbeaccompaniedbymonitoringofliverand
bonemarrowfunction.
TheEpilepsies
376
10.12 Benignepilepsywithcentrotemporalspikes,Panayiotopoulos
syndromeandlateonsetchildhoodoccipitalepilepsy(Gastaut
type)
Benignepilepsywithcentrotemporalspikes(formerlybenignrolandicepilepsy)isoneofthemost
commonepilepsiesinchildhood.Itischaracterisedbyfocalmotorseizures,inthemajorityfrom
sleep,inanotherwisenormalindividual.TheEEGcharacteristicallyshowsfocalspikesinthe
centrotemporoalregions,unilateralorbilateral,enhancedbysleep.Themajorityofchildrenpresent
between5and8years,withallseizuresresolvingbytheageof14years.Seizurefrequencyishighly
variable;insomeseizureswillbeinfrequent.Atonsettherefore,theremaybesomediscussionasto
whethertreatmentisnecessary,rememberingthetermbenignreferstotheprognosisratherthan
theseizuresthemselves.Somefamiliesprefertoavoidtreatmentifpossible.Someauthorshave
reportedassociatedverbaldeficitsondetailedtestingatthetimeoftheactiveepilepsy;whether
treatmentimpactsontheoccurrenceofthisisunknown.
Panayiotopoulossyndromeisanepilepsyofearlyonset,mean5yearsofage(range114)
characterisedbyinfrequentseizures,commonlyprolonged.Seizuresbeginwithautonomicfeatures
suchasvomiting,pallorandsweatingfollowedbyeyedeviationandimpairmentofconsciousness.
Statusepilepticusmayoccur.Prognosisisexcellent,manyindividualsmayhaveoneortwoseizures
only,andsotreatmentisoftenunnecessary.Initiallydescribedasanoccipitalepilepsy,thereis
evidencethatregionsoutwiththeoccipitallobegeneratetheseizuresandthereforeitisnowmore
accuratelyreferredtoasanautonomicepilepsy.EEGmaydemonstrateoccipitalspikes,although
multifocalspikesarealsooftenseen.
Lateonsetchildhoodoccipitalepilepsy(Gastauttype)isanepilepsythatpresentslater,atamean
ageof8years(range316).Seizuresarecharacterisedbyinitialvisualhallucinations(thanoftencan
bedrawnindetail)and/orictalblindnessandillusions.Seizuresarefrequent,briefanddiurnal;
impairmentofconsciousnessisrareunlessassociatedwithhemiclonicorgeneralisedconvulsions.
Postictalheadacheiscommon.TheEEGischaracterisedbyoccipitalspikeswhichattenuateoneye
opening(fixationoffsensitivity).Seizuresoftenremitwithin25years.
includedadultsandchildrenwithBECTS,Panayiotopoulossyndromeandlateonsetchildhood
occipitalepilepsy(Gastauttype).
epilepsyinapopulationwithbenignfocalepilepsiesofchildhood.Theinterventionsweincludedin
oursearchwerelamotrigine,levetiracetam,topiramate,gabapentin,oxcarbazepine,sulthiame,
sodiumvalproateandcarbamazepine.WelookedforanyRCTstudiesthatcomparedthe
effectivenessoftwoormoreofthesetreatments(orplacebo).Belowisamatrixshowingwere
evidencewasidentified.Aboxcontainingafigureindicatesthenumberofstudiesthatwerefound
andthattheevidenceforthiscomparisonhasbeenreviewedinthischapter.Anemptyboxindicates
thatnoevidencewasfound,inthiscase,nosectiononthiscomparisonisincludedinthechapter.
TheEpilepsies
377
Placebo
Lamotrigine
Levetiracetam
Topiramate
Gabapentin
Oxcarbazepine 1
316

Sulthiame 1
317

Sodiumvalproate
Carbamazepine 1
318

PLA CBZ VPA GBP LEV TPM OXC SLM LTG
PLAPlaceboLTGLamotrigineLEVLevetiracetam
TPMTopiramateGBPGabapentinOXCOxcarbazepine
SLMSulthiameVPASodiumvalproateCBZCarbamazepine
10.12.4 MonotherapyforthetreatmentofadultsandchildrenwithBECTS,Panayiotopoulos
syndromeandlateonsetchildhoodoccipitalepilepsy(Gastauttype)
10.12.4.1 Sulthiameversusplacebo
Clinicalevidence
Evidencestatements
Significantlymorepatientstakingsulthiamemonotherapywereseizurefreecomparedtoplacebo.
(HIGHQUALITY)
Nosignificantdifferencebetweensulthiamemonotherapyandplaceboforwithdrawaldueto
adverseevents.(HIGHQUALITY)
Nosignificantdifferencebetweensulthiamemonotherapyandplaceboforwithdrawalduetolackof
efficacy.(LOWQUALITY)
Costeffectiveness
TheEpilepsies
378
Noeconomicevidencecomparingsulthiamemonotherapytoplacebowasidentified.
timetofirstseizure
cognitiveoutcomes
10.12.4.2 Levetiracetamversusoxcarbazepine
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Levetiracetammonotherapyand
oxcarbazepinemonotherapywerecomparedaspartoftheNCGCeconomicmodelevaluating
differentmonotherapyAEDsusedinthetreatmentofadultswithnewlydiagnosedfocalepilepsy.
Foradescriptionandresultsoftheanalysis,seesection10.3.6.Nosimilarcomparisonwasavailable
fortheeconomicmodelbuilttoevaluateAEDsforchildrenwithnewlydiagnosedfocalepilepsy.
Evidencestatements
Therewasnosignificantdifferencebetweenlevetiracetammonotherapyandoxcarbazepine
monotherapyforseizurefreedom.(VERYLOWQUALITY)
monotherapyforwithdrawalduetolackofefficacy.(VERYLOWQUALITY)
monotherapyforwithdrawalduetoadverseevents.(VERYLOWQUALITY)
monotherapyfortheincidenceofdecreasedappetite.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglevetiracetammonotherapytooxcarbazepinemonotherapywas
identifiedinapopulationofpatientswithBECTS.Inanadultpopulationwithnewlydiagnosedfocal
epilepsyoxcarbazepinemonotherapywaslesscostlyandmoreeffectivethanlevetiracetam
monotherapy.Thisanalysishasminorlimitationsandispartiallyapplicabletothisreview.
TheEpilepsies
379
timetofirstseizure
cognitiveoutcomes
10.12.4.3 Topiramateversuscarbamazepine
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Topiramatemonotherapyand
carbamazepinemonotherapywerecomparedaspartoftheNCGCeconomicmodelevaluating
differentmonotherapyAEDsusedinthetreatmentofadultswithnewlydiagnosedfocalepilepsy.
Foradescriptionandresultsoftheanalysis,seesection10.3.6.Nosimilarcomparisonwasavailable
fortheeconomicmodelbuilttoevaluateAEDsforchildrenwithnewlydiagnosedfocalepilepsy.
Evidencestatements
Therewasnosignificantdifferencebetweentopiramatemonotherapyandcarbamazepine
monotherapyforseizurefreedom(VERYLOWQUALITY)
Significantlymoreparticipantsinthecarbamazepinemonotherapygrouphadanincidenceofrash
comparedtoparticipantsinthetopiramatemonotherapygroup.(LOWQUALITY)
monotherapyforwithdrawalduetoadverseevents(VERYLOWQUALITY).
monotherapyfortheincidenceofsomnolence(VERYLOWQUALITY).
Costeffectiveness
Nostudiescomparingtopiramatemonotherapytocarbamazepinemonotherapywereidentified.In
anadultpopulationwithnewlydiagnosedfocalepilepsycarbamazepinemonotherapywaslesscostly
andmoreeffectivethantopiramatemonotherapy.Thisanalysishasminorlimitationsandispartially
applicabletothisreview.
timetofirstseizure
TheEpilepsies
380
cognitiveoutcomes
FirstlinetreatmentinchildrenandyoungpeoplewithBECTs,Panayiotopoulossyndromeandlate
onsetchildhoodoccipitalepilepsy(Gastauttype)
Recommendation
122. Discusswiththechildoryoungperson,andtheirfamily
and/orcarers,whetherAEDtreatmentforbenignepilepsy
withcentrotemporalspikes,Panayiotopoulossyndromeor
lateonsetchildhoodoccipitalepilepsy(Gastauttype)is
indicated.[new2012]
outcomes
Seizurefreedomandreductioninseizurefrequencyare
importantoutcomes,butsotooistheavoidanceofadverse
effectsofdrugtreatment.
benefitsandharms
NoRCTevidencewasfoundforPanayiotopoulossyndromeor
lateonsetchildhoodoccipitalepilepsy.ForBECTSwefound
evidencethatsulthiamewasmoreeffectivethanplacebo,
howeverthisdrugisunlicensedintheUK.Inoneunblindedand
onesingleblindedstudytherewerenodifferencesfoundin
efficacyortolerabilitybetweenlevetiracetamand
oxcarbazepineorcarbamazepinecomparedtotopiramate(apart
fromasignificantlyhigherrateofrashwithcarbamazepine).
DuetothelimitedevidencetheGDGdecidedtoextrapolatethe
resultsforBECTS,Panayiotopoulossyndromeorlateonset
childhoodoccipitalepilepsyfromthefocalseizuresreview
becausetheyareepilepsiescharacterisedbyfocalseizures.This
recommendationwasbasedonGDGconsensus.
ThebalancebetweentreatingBECTsandtheadverseeffectsof
drugtreatmentshouldbeevaluatedinconjunctionwithfamily
and/orcarertodeterminewhetherthechildrequirestreatment.
Insomecases,seizuresaresoinfrequentthatthechildandtheir
familyand/orcarersmaydecidetoforgotreatmentinorderto
avoidthepossiblesideeffects.
Economicconsiderations Noeconomicevidenceinthispopulationwasavailable;
however,thedecisionastowhethertreatmentisindicatedor
notshouldbemadeverycarefullyasthepossiblecostand
qualityoflifeconsequencescouldbesubstantialifapatients
seizuresarepoorlycontrolled.Ifseizureswerepoorly
controlled,thecostsavingsgeneratedbyoptingagainstdrug
treatmentcouldbequicklyoffsetbyhospitaladmissions,
outpatientappointmentsand/orGPconsultations.
TheEpilepsies
381
Recommendation
122. Discusswiththechildoryoungperson,andtheirfamily
and/orcarers,whetherAEDtreatmentforbenignepilepsy
withcentrotemporalspikes,Panayiotopoulossyndromeor
lateonsetchildhoodoccipitalepilepsy(Gastauttype)is
indicated.[new2012]
Qualityofevidence Thequalityofevidencerangedfromhightoverylowdepending
onoutcomeandtherewasnoevidencecomparingdrug
treatmenttonotreatmentapartfromsulthiameagainstplacebo
butthisisunlicensedintheUK.Thisrecommendationwasbased
onGDGconsensusopinion.
Recommendation
orlamotrigine
asfirstlinetreatment
tochildrenandyoungpeoplewithbenignepilepsywith
centrotemporalspikes,Panayiotopoulossyndromeorlate
onsetchildhoodoccipitalepilepsy(Gastauttype).[new2012]
outcomes
benefitsandharms
Wefoundevidencethatsulthiamewasmoreeffectivethan
placebo,howeverthisdrugisunlicensedintheUK.Therewereno
differencesinseizurefreedom,withdrawalduetolackofefficacy,
withdrawalduetoadverseeventsorincidenceofadverseevents
betweenlevetiracetamandoxcarbazepineandcarbamazepine
comparedtotopiramate,apartfromcarbamazepinehad
significantlyhigherratesofrashthantopiramate.Duetothe
limitedevidence(twostudiesunblindedandsingleblinded)the
GDGdecidedtoextrapolatetheresultsforBECTS,Panyaiotopoulos
type)fromthefocalseizuresreviewbecauseepilepsies
characterisedbyfocalseizures.
Theextrapolatedresultsfromfocalseizuresfoundlamotrigineand
carbamazepinebothhadefficacy.Carbamazepinehadalonger
timetofirstseizure(inthemetaanalysisofdirectevidenceand
theIPDresults)andtherewasnosignificantdifferenceforseizure
freedom.Lamotriginehasabetteradverseeventsprofilethan
carbamazepine.Lamotriginerequiresslowtitrationtoreducerisk
ofrash,whichmaymakeitunsuitableforindividualsrequiring
rapidcontrol.Themetaanalysisofdirectevidencefound
significantlymoreparticipantsoncarbamazepinecomparedto
lamotriginewithdrewduetoadverseeventsandthedirect
evidenceandIPDresultsshowedcarbamazepineprolongedthe
timetofirstseizureandhadashortertimetowithdrawalthan
TheEpilepsies
382
lamotrigine.Oxcarbazepinehasasimilaradverseeventsprofile
andefficacytocarbamazepineandlamotrigine,excepttheIPD
analysisfoundthatoxcarbazepinehadlongertimetofirstseizure
thanoxcarbazepine.Whereasthedirectevidencefoundno
difference.
Carbamazepinehadmoreefficacythansodiumvalproatebut
sodiumvalproateshowednosignificantdifferencesto
oxcarbazepine.Sodiumvalproatewouldnotbefirstchoicein
femalesofpresentorfuturechildbearingpotential,becauseof
increasedrisksofteratogenicity.
Inchildren,lamotrigineandcarbamazepinehavesimilarefficacy
andadverseeventsprofiles,withtheexceptionofincidenceof
dizzinesswhichismoreprominentwithcarbamazepine.
Lamotrigineandoxcarbazepinehadmoreefficacy(IPDresultsfor
timetowithdrawal,butnodifferenceinthedirectevidence)and
lessadverseeventsthanphenytoin.Itshouldbenotedthatthe
IPDmetaanalysisforlamotrigineversusphenytoinwasbasedon
indirectevidence.Phenytoinhadnosignificantdifferencewhen
comparedtocarbamazepine.Topiramatehadsimilarefficacyto
sodiumvalproateandoxcarbazepine.Howeverphenytoinand
topiramatehavedisadvantagesduetodruginteractionsandtheir
adverseeventsprofiles.Gabapentinwaslesseffectivethanother
AEDs.Vigabatrinisnotrecommendedbecauseofitsadverse
effectsinlongtermuse.Phenobarbitalisnotrecommended
becauseofadverseeffects.Clobazamisnotrecommended
becauseofconcernswithtolerability.Thereforethesedrugswere
notthoughttobeappropriatetorecommendasfirstline
treatment.
Economicconsiderations Althoughnoeconomicevidenceontherelativecosteffectiveness
ofAEDswasavailableforthispopulationspecifically,theGDG
consideredtheresultsoftheeconomicmodellingundertakenfor
thetreatmentoffocalepilepsytobeapplicabletothisgroupof
patientsaswell.AschildrenwithBECTS,Panyaiotopoulos
type)arelikelytorespondtothefirstAEDofferedandarelikelyto
experiencespontaneousremissionduringadolescence,these
drugsmaybeevenmorecosteffectiveinthisgroupthaninthe
generalpopulationofpatientswithfocalepilepsy.
OtherAEDslicensedforuseasmonotherapyinfocalepilepsy,
includinggabapentin,levetiracetamandtopiramate,werenot
showntobecosteffectiveatcurrent2011prices.However,as
nonproprietarylevetiracetamisexpectedtocometomarket
withinthenearfutureanditsrelativecosteffectivenesscompared
withtheAEDslistedinthisrecommendationissensitivetochanges
TheEpilepsies
383
inunitcost.Becauseitisdifficulttoknownotonlyhowmuchthe
competition,butalsohowmuchthecostofotherAEDsmay
changeaswell,theGDGmaderecommendationsforthetreatment
ofchildrenwithBECTS,Panayiotopoulossyndromeandlateonset
childhoodoccipitalepilepsy(Gastauttype)basedoncurrent
information.Asubsequentrecommendationprovidesadditional
informationtousersoftheguidelineregardinghowmuchthecost
oflevetiracetammustdropinordertobeconsideredcosteffective
andhowthismightaffectitsrelativeplacementamongfirstline
AEDs.
Qualityofevidence
TherewasnoevidenceforPanayiotopoulossyndromeandlate
onsetchildhoodoccipitalepilepsy(Gastauttype)andlittle
evidenceavailableforBECTS.ThestudiesthatdidexistforBECTs
showednosignificantdifferencesexceptforsulthiame,whichis
notlicensedintheUK.Thequalityofthisevidencewasmainly
verylowandtherewasalackofblindingandallocation
concealment.Thesulthiamestudywashighquality.
Asweextrapolatedtheresultsfromfocalseizures,thequalityis
relevantforthesestudies.Inadults,thestudiesincludedinthe
evidencewereoflowqualityduetoseriouslimitationsinthestudy
design.Manyofthestudieswereunblindedorhadinadequate
detailingofrandomisationandallocationconcealment.Withsome
ofthestudieshavinghighdropout.Oneimportantstudy(the
SANADtrialMarson,2007
41
)wasalargepragmatictrialwhich
informedmanyofthecomparisons.Thiswasanunblinded
multicentrestudy.Inchildren,threestudieswereincluded(Nieto
Barrera,2001)
164
,Guerreiro,1997andZamponi1999whichthe
majoritywereunblindedwithlimitations.
Otherconsiderations TheGDGconsideredthatBECTswillremitbytheageof14years
andprognosissforremissionisexcellentthereforetreatmentisof
shortduration.
TheGDGfoundnoevidencetorefutetheplaceofdrugslistedas
firstlineintheoriginalguidelineexceptfortopiramatewhichhas
beenadvisedasadjunctivetherapy.
thelamotriginedose.
thechoiceofAEDinsomeindividuals.Furthermore,theGDG
consideredthepotentialforcarbamazepineandoxcarbazepineto
exacerbateorunmaskcontinuousspikesandwavesduringslow
sleep(CSWS),whichoccurinsomechildrenwithBECTS.
Themetabolismoflamotriginemaybeincreasedbyoestrogensin
TheEpilepsies
384
incontraceptives.
differentdrugsanddifferentoptionsmayneedtobetriedwiththe
hopeofgettingthebalancerightbetweenseizurefreedomand
sideeffects.IfthefirstAEDisineffective,asecondAEDshouldbe
addedalongsidetheinitialAEDand,ifseizuresarecontrolled,the
firstAEDmaybewithdrawn,recognisingthatsomepatientswill
prefertoremainontwoAEDsifseizurefree.TheGDGconsidered
thatitisgenerallypreferabletoavoidpolytherapy.
TheEpilepsies
385
Recommendation
cc
.
Offerlevetiracetam
,oxcarbazepine
,orsodiumvalproate
(providedtheacquisitioncostoflevetiracetamfallstoatleast
50%ofJune2011valuedocumentedintheNationalHealth
ServiceDrugTariffforEnglandandWales)ifcarbamazepine
andlamotrigineareunsuitableornottolerated.Ifthefirst
AEDtriedisineffective,offeranalternativefromthesefive
AEDs.Beawarethatcarbamazepineandoxcarbazepinemay
exacerbateorunmaskcontinuousspikeandwaveduringslow
sleep,whichmayoccurinsomechildrenwithbenignepilepsy
withcentrotemporalspikes.Beawareofteratogenicrisksof
outcomes
Seizurefreedom,withdrawalduetoadverseeventsand
withdrawalduetolackofefficacywereconsideredtobethemost
importantoutcomes.
benefitsandharms
Althoughbothlevetiracetamandcarbamazepinecontrolled
releasehadverysimilarfindingsintermsofefficacy,levetiracetam
hadahigherwithdrawalrateduetolackofefficacycomparedto
carbamazepineextendedreleasewhichiswhyitwasnot
recommendedasthedrugoffirstchoice.Howeveritmaybeuseful
forpeoplewhenthefirstlineAEDsarecontraindicated.
TheGDGconsideredthatlevetiracetamlacksinteractionwith
otherdrugs.
Economicconsiderations OtherAEDslicensedforuseasmonotherapy,includinggabapentin,
levetiracetamandtopiramate,werenotshowntobecosteffective
atcurrent2010prices.Giventhecurrentuseoflevetiracetamin
clinicalpracticeandtheimminentarrivalofagenericproductto
themarkettheGDGconsidereditimportanttoprovideadditional
informationtousersoftheguidelineregardingthecircumstances
underwhichlevetiracetamislikelytobeacosteffectivefirstline
AED.
Theanalysesshowedthatthereisquiteabitofuncertaintyaround
thecosteffectivenessoflevetiracetam,drivenbyalimitedclinical
evidencebaseandquestionsaboutitsfuturecost.Lamotrigine
wasfoundtobemorecosteffectivethanlevetiracetam,andthis
resultwasconsistentacrossarangeofsensitivityanalyses
(dominatinglevetiracetaminsomeandrepresentingbettervalue
formoneygiventheNICEthresholdinothers).Carbamazepine
wasalsomorecosteffectivethanlevetiracetam,exceptwhen
levetiracetamwasassumedtobemoretolerablethan
carbamazepineand70percentlesscostlythanitiscurrently.
cc
TheEpilepsies
386
TheGDGnextconsideredthesituationwhereincarbamazepine
andlamotrigineareconsideredunsuitableorhavebeenpoorly
tolerated.Basedontheinterpretationoftheevidence,theGDG
recommendedthatsodiumvalproateandoxcarbazepineare
consideredinthisgroup.Thesensitivityanalysisaroundcostwas
undertakenforthisclinicalscenarioaswell,andfoundthe
probabilityoflevetiracetambeingconsideredcosteffective
relativetosodiumvalproateandoxcarbazepineimprovesasprice
decreases.A50percentpricedecreasemakeslevetiracetammore
costeffectivethanoxcarbazepinebutnotcosteffectivecompared
tosodiumvalproate.However,iflevetiracetamismoretolerable
thancarbamazepine,thena50percentpricedecreasemakes
levetiracetamcosteffectivecomparedtobothdrugs,although
substantialuncertaintysurroundsthisconclusion.
WhenallrecommendedfirstlineAEDs(carbamazepine,
lamotrigine,oxcarbazepineandsodiumvalproate)areremoved
fromtheanalysisduetocontraindications,gabapentinistheAED
mostlikelytobeconsideredcosteffective.However,ifthefuture
acquisitioncostoflevetiracetamis20to30percentlessthanwhat
itiscurrently,thenlevetiracetambecomesthemostcosteffective
AEDgiventheNICEwillingnesstopaythreshold.TheGDG
consideredthisscenarioandconcludedthatinthesituationwhere
allrecommendedfirstlinedrugsarecontraindicatedorunsuitable,
thereisalikelihoodthatgabapentinandtopiramatemightnotbe
appropriateeither,thuslendingfurtherweighttothechoiceof
levetiracetamevenatcurrentcosts.Withtheexpectationthata
modestdropinitspricewillmoveitfrommarginallynotcost
effectivetomostcosteffective,theGDGdecideditshouldbe
offeredinpreferencetogabapentininthisclinicalsituation.
TheGDGconsideredtheuncertaintiesaroundlevetiracetam
drivingtheresultsofthebasecaseandvarioussensitivityanalyses.
Theyalsoacceptedthattheydidnotknownotonlyhowmuchthe
competition,norhowmuchthecostofotherAEDsmightchange
aswell.Aftercarefulconsideration,theGDGdeterminedthat
levetiracetamshouldbeofferedasafirstlinetreatmentof
childrenwithBECTS,Panayiotopoulossyndromeandlateonset
childhoodoccipitalepilepsy(Gastauttype)underthetwo
circumstances.Firstly,inthecircumstancewhenallthe
recommendedfirstlinetreatments(carbamazepine,lamotrigine,
oxcarbazepineandsodiumvalproate)areunsuitable.Secondly,as
analternativetooxcarbazapineandsodiumvalproate(when
carbamazepineandlamotrigineareunsuitable,poorlytoleratedor
ineffective),iflevetiracetamcanbeacquiredforacostatleast50
percentlessthanJune2011unitcosts.TheGDGfeltthatthis
recommendationandthedetailincludetherein,wouldclearly
outlinetheconditionsunderwhichtreatmentwithlevetiracetam
wouldrepresentacosteffectiveuseoflimitedNHSresources.
Qualityofevidence
Therewasnoevidencefoundforbenignepilepsywith
centrotemporalspikes,Panayiotopoulossyndromeandlateonset
TheEpilepsies
387
childhoodoccipitalepilepsy(Gastauttype)soweextrapolated
fromfocalseizuresfornewlydiagnosedepilepsy.Onetrialwith
highdropoutratesinbotharmsshowedtherewasnosignificant
differencebetweenlevetiracetamandcarbamazepineinthe
proportionofseizurefreeparticipantsandwithdrawaldueto
adverseevents.However,significantlyhigherproportionof
participantsonlevetiracetamwithdrewduetolackofefficacy
comparedtocarbamazepine.
Otherconsiderations ThisisapartlyGDGconsensusopinionbasedrecommendation.
Levetiracetamisonlylicensedforpeopleover16yearsold.Itis
usefulbecauseitdoesnotinteractwithhormonal
contraception.TheGDGopinionwasthatthelimitedevidence
currentlyavailablesuggeststhatlevetiracetamdoesnotcarryan
TheEpilepsies
388
Recommendation
125. Consideradjunctivetreatmentifasecondwelltolerated
AEDisineffective(seerecommendations123and124).[new
2012]
outcomes
Inchildren,youngpeopleandadultswiththesesyndromesthere
shouldbecarefulevaluationabouttheneedfortreatment.
Howeveriftreatmentrequired,seizurefreedom,withdrawaldue
toadverseeventsandtimetotreatmentfailure,timetofirst
benefitsandharms
Weextrapolatedtheresultsfromfocalseizuresforthis
recommendation.
Phenytoinhadlessefficacyandmoreadverseeventsthan
lamotrigine,oxcarbazepineandnosignificantdifferencecompared
tocarbamazepine.Topiramatehadsimilarefficacysodium
valproateandoxcarbazepine.Howeverphenytoinandtopiramate
havedisadvantagesduetodruginteractionsandtheiradverse
eventsprofiles.GabapentinwaslesseffectivethanotherAEDs.
Vigabatrinisnotrecommendedbecauseofitsadverseeffectsin
longtermuse.Phenobarbitalisnotrecommendedbecauseof
adverseeffects.Clobazamisnotrecommendedbecauseof
concernswithtolerability.Thereforethesedrugswerenotthought
tobeappropriatetorecommendasfirstlinetreatment.
Levetiracetamandcarbamazepinecontrolledreleasehadvery
similarfindingsintermsofefficacy,butlevetiracetamhadahigher
withdrawalrateduetolackofefficacycomparedto
recommendedasthedrugoffirstchoice.HowevertheGDG
consideredittobeusefulforpeopleinwhomotherfirstlineAEDs
arenotsuitableandthatlevetiracetamlacksinteractionwithother
drugs.
TheGDGconsideredthatthefiveAEDs(lamotrigine,
carbamazepine,oxcarbazepine,sodiumvalproateand
levetiracetam)offeredasfirstlinetreatmentinnewlydiagnosed
focalseizuresmayhaveinstanceswheretheyaretoleratedbutare
noteffective.ThereforeduetotheconcernswiththeotherAEDs,
theGDGagreedthatinthesecasesadjunctivetreatmentshouldbe
considered.
Economicconsiderations Theoriginalcosteffectivenessanalysisundertakenforthe
guidelineindicatesthattheAEDsusedasadjunctivetherapyfor
refractoryfocalseizuresweremoreeffectiveandmorecostlythan
continuingpatientsonmonotherapy.However,adjunctivetherapy
withasubsetofAEDsmaybecosteffectiveattheNICEthreshold
of20,000perQALY.Thereisconsiderableuncertaintyastowhich
AEDrepresentstheoptimaluseofNHSresourcesasmuchdepends
onwhatisappropriatefortheindividualpatientandonhis/her
previoustreatmenthistory.
TheEpilepsies
389
Qualityofevidence
Thisrecommendationwasbasedontheclinicalexpertiseofthe
GDGandviaconsensus.
Otherconsiderations Sodiumvalproatewouldnotbefirstchoiceinfemalesofpresentor
teratogenicity.
thelamotriginedose.
TheEpilepsies
390
AdjunctivetreatmentinchildrenandyoungpeoplewithBECTs,Panayiotopoulossyndromeand
lateonsetchildhoodoccipitalepilepsy(Gastauttype)
Recommendation
,clobazam
,gabapentin
,
lamotrigine
,levetiracetam
,oxcarbazepine
,sodium
valproateortopiramate
asadjunctivetreatmenttochildren
andyoungpeoplewithbenignepilepsywithcentrotemporal
spikes,Panayiotopoulossyndromeorlateonsetchildhood
occipitalepilepsy(Gastauttype)iffirstlinetreatments(see
outcomes
Inchildren,youngpeopleandadults,theachievementofseizure
freedomoratleasta50%reductioninseizurefrequencywere
consideredtobethemostclinicallyrelevantoutcomes.
Tolerability,asmeasuredbywithdrawalsduetoadverseevents,
wasalsoconsideredimportant.
benefitsandharms
recommendation.
Theevidenceforadultsshowedthatsignificantlymore
participantsreceivingclobazam,levetiracetam,levetiracetam
extendedrelease,oxcarbazepineandtopiramateachievedseizure
freedomthanplacebo.Significantlymoreongabapentin,
oxcarbazepine,lamotrigine,levetiracetamandtopiramate
experiencedatleasta50%reductioninseizurefrequencywhen
comparedtoplacebo.Fromtheevidenceforchildren,significantly
moreparticipantsonlamotrigineandoxcarbazepinecomparedto
placeboexperiencedatleasta50%reductioninseizurefrequency.
Morepeopleonoxcarbazepine(adultsandchildren)achieved
seizurefreedomthanthoseonplaceboinarefractorypopulation
onmonotherapy.Inchildren,significantlymoreparticipantson
levetiracetamcomparedtoplaceboexperiencedatleasta50%
Thedrugsrecommendedabovehadunfavourableadverseevents
profiles,buttheGDGfoundthisunsurprisinggiventhattheywere
beingevaluatedascombinationtreatmentinarefractory
population.Manyoftheadverseeventsobservedinthetrials
weredoserelatedandinclinicalpracticethesecanbemitigated
TheEpilepsies
391
throughcarefuldosetitration.Significantlymoreparticipants
receivinggabapentin,lamotrigine,topiramateandoxcarbazepine
withdrewduetoadverseeventscomparedtoplacebo.
Gabapentinhadhigherincidenceofsomnolence,dizzinessand
ataxiaandaggravationofseizureswhencomparedtoplacebo.
Therewasnosignificantdifferencebetweenlevetiracetamand
placeboforwithdrawalduetoadverseeventsalthoughincidence
ofadverseeventswassignificantlyhigherinthelevetiracetamarm.
Nospecificadverseeventswerereportedinthetrialforclobazam,
butGDGconsidereditstendencytohavesedativesideeffectsand
itsefficacycanwaneoverextendeduse.Oxcarbazepineand
lamotriginehadalessfavourableadverseeventsprofilecompared
toplacebo.Topiramatehadhigherincidenceofheadachewhen
comparedwithlamotrigine.Inchildrentakinglamotriginethe
incidenceofdizziness,tremor,nauseaandataxiawerehigher
comparedtotoplacebo.
Forthedrugsrecommendedhere,thetreatmentbenefits
outweighedtheharmsfortheaveragepatientandtheQALYs
gainedjustifiedtheadditionalcostsoverplacebo(noadjunctive
AED).
Economicconsiderations Weextrapolatedfromtheeconomicconsiderationsforfocal
seizures.
evidence.
Theoriginalcosteffectivenessanalysisundertakenforthe
guidelineindicatesthatthereisconsiderableuncertaintyasto
whichAEDrepresentstheoptimaluseofNHSresourcesasagreat
dealdependsonwhatisappropriatefortheindividualpatientand
onhis/herprevioustreatmenthistory.TheGDGchoseto
recommendlamotrigineandoxcarbazepineonthebasisthatthey
werethetwoAEDswiththegreatestprobabilityofbeingcost
effectiveinthebasecaseandotherscenarios.Therefore,ifeither
lamotrigineoroxcarbazepinehavenotbeentriedasmonotherapy,
eitherfirstorsecondline,thentheyarelikelytorepresentcost
effectivechoicestoaddinasadjunctivetherapy.TheGDGfelt
thatsomecombinationsmightbemoreeffectiveormore
tolerable,andthusmightbemorecosteffective,butneitherthe
clinicalevidencereviewnoreconomicmodelwasdesignedto
identifyparticularAEDcombinations.
GiventhatlamotrigineandoxcarbazepineareamongAEDs
recommendedasfirstlinetreatmentofnewlydiagnosedfocal
seizures,apatientwithrefractoryfocalseizuresrequiringfurther
TheEpilepsies
392
treatmentmayhavealreadytriedoneorboth.TheGDG
recommendedgabapentinonthebasisthatinthebasecase,itwas
likelytobethemostcosteffectiveAEDwhenlamotrigineand
oxcarbazepinewerenotrelevanttreatmentoptions.However,
giventheuncertaintyhighlightedbytheresultsoftheother
sensitivityanalyses,particularlyaroundtheestimatesofseizure
freedomandassumptionsofcost,theGDGdecidedtorecommend
topiramateasanadditionalchoiceforadjunctivetherapy.
TheGDGconsideredtheresultsofthebasecaseanalysis,inwhich
levetiracetam,althoughthemosteffectiveadjunctiveAED,wasnot
showntobecosteffectivegiventheNICEwillingnesstopay
threshold.Itwasalsounlikelytobeconsideredcosteffective
comparedtogabapentinandtopiramatewhenlamotrigineand
oxcarbazepinewereremovedfromtheanalysis(assumingthey
havebeenalreadytriedasmonotherapy).TheGDGlookedtoa
seriesofsensitivityanalysesaroundprojectedreductionsinthe
priceoflevetiracetaminordertodeterminethepricepointat
whichthedrugmightbecomecosteffective.Thesensitivity
analysesshowedthattheunitcostoflevetiracetamneedonly
comedownby30percentinordertodominateoxcarbazepineand
beconsideredcosteffectivecomparedtolamotrigine
(ICER=19,264perQALY).Italsobecomesthemostcosteffective
drugunderthe20,000perQALYthresholdwhenlamotrigineand
oxcarbazepineareexcluded;thatis,levetiracetamdominates
topiramate(evenwhenonlynonproprietarycostsareused)and
hasanICERof17,213comparedtogabapentin.
TheGDGconsideredtheuncertaintiesaroundlevetiracetamand
howitsfuturecostmightimpactitsrelativecosteffectiveness
comparedtootheravailableAEDsusedinthetreatmentof
refractoryfocalseizures.Theyalsoacceptedthattheyknew
neitherhowmuchthepriceoflevetiracetamwilldropwiththe
introductionofgenericcompetition,norhowmuchthecostof
otherAEDsmightchangeaswell.TheGDGconsideredthe
dramaticreductioninthecostofotherAEDs,suchaslamotrigine
andtopiramate,followinglossofpatentprotectionand
introductionofgenericcompetition.Lookingtotheseother
examples,theyconsidereditverylikelythatasimilarreduction
wouldoccurforlevetiracetamsoonafterpublicationofthe
guidelineandthatarecommendationwithoutlevetiracetamwould
quicklybecomeinaccurate.Theyalsoconsideredthewidespread
useoflevetiracetamincurrentclinicalpractice,basednotonlyon
theirownexperiencebutalsoonthefeedbackofstakeholders
duringconsultationoftheguideline.Consideringtheevidence,the
uncertaintiesandtheirclinicalexperience,theGDGtherefore
determinedthatlevetiracetamshouldbeofferedamonginitial
adjunctivetherapyoptions.
Qualityofevidence
Weextrapolatedtheevidencefromfocalseizuresforthis
recommendation.
Foradults,themajorityoftheevidencewasplacebocontrolled
andtherewerefewheadtoheadcomparisons.Allofthestudies
TheEpilepsies
393
wererandomisedcontrolledtrials,themajorityofwhichwere
doubleblind.Mostofthestudiesgaveuncleardetailsoftheir
methodsofrandomisation,allocationconcealmentandblinding.
Thestatisticallysignificantresultsfor50%reductioninseizure
frequencywerefromtheplacebocontrolledstudies.Fewofthe
drugswhichwerecomparedtodrugswerestatisticallysignificant
andwherethisdidoccurtherewasuncertaintyinthemagnitudeof
clinicaleffect.Thequalityoverallwasgenerallyloworverylow.
oftheirown.Limitationsoftheoriginalanalyses,particularly
whereassumptionshadtobemade,relatetothelackofdata
availabilityonlongertermeffectivenessanddiscontinuation,
limitedhealthstateutilitydataandlimitedtonodatatoinform
estimatesofNHSresourceuse.
Otherconsiderations Thedrugsrecommendedaboveareolderandthereforethereis
longtermexperiencewiththem.Eslicarbazepineacetate,
lacosamide,pregabalin,andzonisamideshowedefficacybutwere
notincludedforfirstlineadjunctivetreatmentastheyarenewer
drugsandtheGDGfeltthatthereneededtobemorelongterm
evidenceoftheirefficacyandcosteffectivenessforadjunctive
treatment.Thereislimitedevidencefortiagabinebeingeffective.
Gabapentinwasincludedasfirstlineadjunctivedrugoption,but
basedontheclinicalexperienceoftheGDGwasregardedasless
effectivethantheotherAEDs.
TheGDGconsideredtheadditionofoxcarbazepinewithouttrying
carbamazepineasunusualbutmaybeconsidered,asitisless
enzymeinducing.
TheGDGwereawarethatinclinicalpracticeasecondAEDisadded
tothefirst.Theyalsoagreedwithpublishedliteraturewhich
statesthatifthelatterhelpsthefirstmaybetakenawayifthe
patientagrees.
287
GDGdiscussioncentredaroundsomekeyissues.Namely,care
shouldbetakenwithclobazamwhenwithdrawingandaslow
withdrawalofclobazamover/upto46minviewoftheriskof
withdrawalseizures.Theynotedthatsodiumvalproateinhibits
themetabolismoflamotrigineandthisneedstobetakeninto
considerationwhenintroducingorwithdrawingeithermedication.
ClinicalexperienceledtheGDGtobelievethatonwithdrawalof
sodiumvalproate,lamotriginelevelsmaydropandthismaybe
therreasonforbreakthroughseizures.Theyalsonotedthatthere
shouldbeaconcomitantincreaseinthelamotriginedosebutdid
notwishtomakeaspecificrecommendation.Topiramatemay
affectphenytoinlevels.
TheEpilepsies
394
Recommendation
epilepsyspecialist.OtherAEDsthatmaybeconsideredbythe
tertiaryepilepsyspecialistareeslicarbazepineacetate
,
lacosamide
,phenobarbital,phenytoin,pregabalin
,
tiagabine
,vigabatrin
andzonisamide
.Carefullyconsider
theriskbenefitratiowhenusingvigabatrinbecauseofthe
riskofanirreversibleeffectonvisualfields.[new2012]
outcomes
Inadultsandchildren,achievementofatleasta50%reductionin
seizurefrequencywasanimportantoutcome.TheseAEDshave
evidenceofefficacyinsomepatients,andmaybenefitpatients
whohavenotrespondedtoand/orwhohaveexperiencedadverse
effectswithotherAEDs.
benefitsandharms
recommendation.
Thebalanceofbenefitandadverseeffectsneedstobecarefully
monitoredinallpatients,anditmustberecognisedthatdifferent
individualsmayhavedifferentresponsestovariousAEDs.From
thedirectevidenceforadults,lacosamide,zonisamide,
eslicarbazepineacetate,tiagabine,vigabatrinandpregabalinhad
moreparticipantswithatleast50%reductioninseizurefrequency
whencomparedtoplacebo.Eslicarbazepineacetate,and
pregabalinalsohadmoreseizurefreedomthanplacebo.
PhenobarbitalwasaddedbytheGDGbasedontheirprofessional
opinion.Tiagabinewasfoundtohavenodifferencewhen
comparedtolamotrigine,levetiracetamorphenytoin.Intermsof
efficacy,therewasnosignificantdifferencebetweenvigabatrin
andgabapentin.
Alsopregabalinwasshowntohavealessfavourableadverse
eventsprofile,causinggreaterwithdrawalduetoadverseevents
thanplacebo.Eslicarbazepineacetate,lacosamide,vigabatrin,
zonisamideandtiagabinehadmorewithdrawalduetoadverse
eventsandmoreadverseeventsthanthanplaceboarm.There
wasnodifferencebetweenphenytoinandtiagabineorlamotrigine
andtiagabineforwithdrawalduetoadverseevents.
Vigabatrinhasaharmfulandirreversiblesideeffectsprofilewith
retinaltoxicitycausingvisualimpairment,accordingtotheGDG
expertiseandepilepsyliterature.Thesesideeffectsoccuroverthe
longertermandwouldnotbeobservedinanyoftheshortterm
trialscombinedintheevidence.
TheEpilepsies
395
Thedrugsrecommendedforconsiderationherewereeffectiveto
varyingdegress,butthetreatmentbenefits,intermsofQALYs
gained,orinsomecaseslost,didnotjustifiedtheadditionalcosts
overdrugsrecommendedinthepreviousrecommendation
(gabapentin,lamotrigine,oxcarbazepine,topiramate).
Economicconsiderations Weextrapolatedtheeconomicconsiderationsfromfocalseizures
evidence.Onepublishedstudyshowedadjunctivezonisamideto
becosteffectivecomparedtoadjunctivelevetiracetam,butinall
otherstudiesand/orintheoriginalmodellingworkundertakenfor
theguideline,neitherlevetiracetamnorzonisamidewereshownto
becosteffectivecomparedtoalternativeAEDs.
Intheeconomicanalysisundertakenfortheguideline,
eslicarbazepineacetate,lacosamide,pregabalin,tiagabineand
zonisamidewereallmorecostlyandlesseffectivethanothercost
effectivetreatmentalternatives.Therefore,theGDGfeltthatthey
shouldnotberecommendedamonginitialadjunctivetherapy
options.Ratherthesedrugsshouldbeconsideredonlyforcases
wherepreviouslyrecommendeddrugsarecontraindicatedorhave
beentriedandwereeitherineffectiveornottolerated.
Vigabatrinwasspecificallyexcludedfromvariouspublished
economicevaluationsduetoitspotentialforlongtermtoxicityand
adverseeffects.Itwasincludedintheoriginaleconomicanalysis
undertakenforthisguidelineandwasshowntobeveryeffective
andcosteffective.However,averyseriouslimitationofthemodel
wasthatitdidnotaccountforvigabatrinspotentialforlongterm
toxicityanddevelopmentofvisualfielddefects.Vigabatrinscost
effectivenessinthemodelwasdrivenbyitsefficacyandrelatively
lowratesofwithdrawalduetoadverseeventsfromshortterm
trialdata.Hadthemodelaccountedforlongterm,irreversible
effectstovision,itisunlikelytohaveperformedquiteaswell.The
GDGrecogniseditsrelativeeffectivenessoverotherAEDs,and
consideredtheriskoflongtermvisualfielddefecttooutweighits
clinicalbenefit.TheGDGrecommendedthatthesepatientsshould
bediscussedwithorreferredtoatertiaryepilepsyspecialist.
Whilstthismaybemorecostly,theGDGconsideredthatthiswas
worthwhileasthesepatientsmayrequiremorecomplexcarein
ordertoachieveasuccessfuloutcome.
Qualityofevidence
Weextrapolatedtheevidencefromfocalseizuresforthis
recommendation.
TheEpilepsies
396
Overallthequalityofevidencewaslowandmostofthestudies
hadunclearornodetailsofrandomisation,allocationconcealment
orblindingandhigherdropoutinthetreatmentarms.Therewas
noevidencefoundforphenobarbitalbutthisrecommendationis
basedonGDGexpertise.
oftheirown.Duetothislimitation,resultsconcerningvigabatrins
costeffectivenesswereoflimitedvaluetoGDGdecisionmaking.
Limitationsoftheoriginalanalyses,particularlywhereassumptions
hadtobemade,relatetothelackofdataavailabilityonlonger
termeffectivenessanddiscontinuation,limitedhealthstateutility
dataandlimitedtonodatatoinformestimatesofNHSresource
use.
Otherconsiderations TheGDGconsensusopinionwasthatmanagementshouldbe
discussedwithpatientsortheyshouldbeofferedreferralto,a
tertiaryepilepsyspecialistifadjunctivetreatmentwithAEDslisted
inrecommendation127isineffectiveornottoleratedbecause
achievingsuccessfultreatmentmaybecomplex.
Theynotedthatlongtermexperiencewithsomeofthesedrugs
(pregabalin,lacosamide,zonisamideandeslicarbazepineacetate)
islimited.
TheGDGdiscussedthefactthatcareshouldbetakenwhen
withdrawingphenobarbitalandshouldbeslowlywithdrawnin
viewoftheriskofwithdrawalseizuresbutdidnotwishtomakea
specificrecommendationinthisarea.
Thegroupdiscussedtheneedforcarefulevaluationofrisk/benefit
foreachindividualtobeundertakenforeachindividualandthe
finalGDGconsensusopinionwasthatvigabatrinshouldonlybe
prescribedintertiaryepilepsyspecialistcare.
TheEpilepsies
397
10.13 IdiopathicGeneralisedEpilepsy(IGE)
Theidiopathicgeneralisedepilepsiesareagroupofepilepsiescharacterisedbytypicalabsences,
myoclonicjerksandgeneralisedtonicclonicseizures,aloneorinvaryingcombinationsinotherwise
normalindividuals.Theyprobablyconstituteuptoonethirdofalltheepilepsiesandaregenetically
determined.TheEEGischaracteristic,demonstratingadistinctpatternofgeneralisedpolyspikewave
dischargesand/orgeneralisedspikewavewhichmaybeprovokedbyhyperventilationorsleep
deprivation.SomeIGEsareassociatedwithphotosensitivity.
Dependingontherelativeprevalenceofindividualseizuretypes,theageofonsetandfrequencyof
spikewaveactivity,IGEmaybefurthercategorisedintoindividualsyndromes.Thepredominant
characteristicsofthosetobeconsideredinthisreviewareoutlinedinthetable.
Thissectioncontainsstudiesthatlookatidiopathicgeneralisedepilepsies(IGE)(includingall)and
lookingseparatelyonthefollowingsubgroups:
EpilepsywithTonicClonicSeizuresonly
Childhoodabsenceepilepsy,juvenileabsenceepilepsyandotherabsenceepilepsysyndromes
JuvenileMyoclonicEpilepsy.
Table24: Characteristicsoftheindividualsyndromes
Epilepsysyndrome Ageofonset
Predominant
seizure
types/frequency EEG Prognosis
ChildhoodAbsence
Epilepsy
410years Absence,
many/day
GTCSinfrequent
3Hzgeneralised
spikeandwave
80%remitby
adulthood
JuvenileAbsence
Epilepsy
913years Absence
GTCSin80%
Myoclonicjerks
infrequent
34Hzgeneralised
spikeandwave
Photosensitivity8%
Lifelong;seizure
controlin7080%
Juvenile
myoclonic
epilepsy
516years Myoclonicjerkson
awakeninginall
GTCSinmost
Absencein>30%
(maybeintial
seizuretype)
36Hzgeneralised
polyspikeandwave
Photosensitivityin
>30%
Lifelong;seizure
controlinupto
90%patients
EpilepsywithGTCS
only
630years GTCS12hours
afterwaking
Generalised
polyspikewavein
upto50%patients
Lifelong;seizure
controlin90%
10.13.2 MethodsoftheevidencereviewofIGE
Forthisreviewweincludedadultsandchildrenwiththefollowingsyndromes:Absenceseizures
(childhoodabsenceepilepsy,juvenileabsenceepilepsyandotherabsenceepilepsysyndromes),
JuvenileMyoclonicEpilepsyandEpilepsywithTonicClonicSeizuresonly.
TheEpilepsies
398
IGE.Thefollowinginterventionswereincludedinoursearch;clobazam,clonazepam,ethosuximide,
lamotrigine,levetiracetam,sodiumvalproatetopiramateandzonisamide.WelookedforanyRCT
studiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
Belowarethematrixshowingwhereevidencewasidentified.Aboxcontainingafigureindicatesthe
TheEpilepsies
399

Placebo
Lamotrigine
Levetiracetam 1
294

Topiramate 1
41

Oxcarbazepine
Phenytoin
Clobazam
Clonazepam
Phenobarbital
Primidone

Acetazolamide
Sodium
valproate
2
41
,(Glaxo
SmithKline
unpublishe
dinHTA)
40
1
41

Zonisamide
Carbamazepine
Pla LTG LEV TPM OXC PHT CLB CZP PBT PRM ACT VPA ZN
TheEpilepsies
400
MatrixoftheevidenceforIGE
Matrixoftheevidenceforchildhoodabsenceepilepsy,juvenileabsenceepilepsyandother
absenceepilepsysyndromes

Placebo
Lamotrigine 1
319

Levetiracetam 1
320

Topiramate
Ethosuximide 1
321

Zonisamide
Clobazam
Clonazepam
Sodium
valproate
3
41,321,
(Marson
unpub.)
1(Marson
unpub.)
4
321,322,
323,324

Pla LTG LEV TPM ETX ZNS CLB CZP VPA
TheEpilepsies
401
MatrixoftheevidenceforJuvenileMyoclonicEpilepsy
Placebo
Lamotrigine
Levetiracetam
1
298

Topiramate
Clobazam
Clonazepam
Zonisamide
Sodium
valproate
2,
165,
(Marson,
unpub.)
1
297
;
1(Marson,
unpub.)

Pla LTG LEV TPM CLB CZP ZNS VPA
Placebo(Pla)Lamotrigine(LTG)Levetiracetam(LEV)Topiramate(TPM)
Clobazam(CLB)Clonazepam(CZP)Zonisamide(ZNS)Sodiumvalproate(VPA)
Ethosuximide(ETX)Oxcarbazepine(OXC)Phenytoin(PHT)Phenobarbital(PBT)
Primidone(PRM)Acetazolamide(ACT)
IPDNMA:individualpatientdatanetworkmetaanalyses
10.13.4 MonotherapyforthetreatmentofIGEinnewlydiagnosedpatients
Clinicalevidence
161,181
ofAEDs,includinglamotrigineandsodiumvalproate,usedas
monotherapyinthetreatmentofpeoplewithnewlydiagnosedIGEwereidentifiedandincludedin
theeconomicliteraturesearch.Thecompleteresultsofthesestudiesarepresentedinsection
10.13.6.
Evidencestatements
Sodiumvalproatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingtimetoexit/withdrawal(MODERATEQUALITY).
Timetofirstseizureoccurredsignificantlymorerapidlyonsodiumvalproatemonotherapycompared
tolamotriginemonotherapy.(MODERATEQUALITY)
TheEpilepsies
402
Timeto12monthremissionoccurredsignificantlylessrapidlyonlamotriginemonotherapy
comparedtosodiumvalproate.(MODERATEQUALITY)
theproportionofparticipantswithseizurefreedom(VERYLOWQUALITY).
Nosignificantdifferencebetweenlamotriginemonotherapyversussodiumvalproatemonotherapy
intheproportionofparticipantswithdrawnduetoadverseevents(VERYLOWQUALITY).
Thereisnosignificantdifferencebetweenlamotriginemonotherapyversussodiumvalproate
monotherapyintheincidenceof:
tiredness,drowsiness,fatigueandlethargy(VERYLOWQUALITY).
othersideeffects(pleaseseeextractionforfulllist)(VERYLOWQUALITY).
QualityofLifestatisticallysignificantresults
Significantlymoreparticipantstakinglamotriginemonotherapycomparedtosodiumvalproate
monotherapyhadhigherscoresat2yearsontheGQoLquestionnaire.
QualityofLifestatisticallynonsignificantresults
Thereisnosignificantdifferencebetweenlamotrigineandsodiumvalproatemonotherapyin:
twoyearanxietyscores
twoyeardepressionscores
twoyearAEPscores
twoyearneurotoxicityscalescores
twoyearEQ5Dscores
Costeffectiveness
Evidencefromonecosteffectivenessanalysisconductedalongsidearandomisedcontrolledtrial
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,lamotriginemonotherapyismore
effectivethansodiumvalproateintermsoftotalQALYsgainedandalsolesscostlywhenusing2010
drugcosts.Thisevidenceisdirectlyapplicablebuthaspotentiallyseriouslimitations.
Evidencefromanothercosteffectivenessanalysisindicatesthatlamotriginemonotherapyismore
costlyandlesseffectivethansodiumvalproateintermsoftotalQALYsgained.Theevidenceis
directlyapplicablebutasitusescostsfrom200102,ithaspotentiallyseriouslimitations.
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,sodiumvalproatemonotherapyis
morecostlyandmoreeffectiveatpreventingseizuresthanlamotriginemonotherapy(ICER=5per
seizureavoided).Thisevidenceispartiallyapplicableandhaspotentiallyseriouslimitations.
atleasta50%reductioninseizurefrequency
anyoutcomesrelatingtocognitiveeffects.
TheEpilepsies
403
Clinicalevidence
161
ofAEDs,includingtopiramateandsodiumvalproate,usedas
monotherapyinthetreatmentofpeoplewithnewlydiagnosedIGEwasidentifiedandincludedinthe
economicliteraturesearch.Thecompleteresultsofthisstudyarepresentedinsection10.13.6.
Evidencestatements
Valproatemonotherapyissignificantlymoreeffectivethantopiramatemonotherapyinprolonging
timetoexit/withdrawalofallocatedtreatment(MODERATEQUALITY).
thetimetofirstseizure(LOWQUALITY).
Nosignificantdifferencebetweentopiramatemonotherapyversussodiumvalproatemonotherapyin
theincidenceof:
tiredness,drowsiness,fatigueandlethargy(VERYLOWQUALITY)
othersideeffects(pleaseseeextractionforfulllist)(VERYLOWQUALITY).
Significantlymoreparticipantstakingtopiramatemonotherapycomparedtosodiumvalproate
monotherapyhadhigherscoresat2yearsontheGQoLquestionnaire.
Thereisnosignificantdifferencebetweensodiumvalproatemonotherapyandtopiramate
monotherapyin:
twoyearAEPscores
twoyearEQ5Dscores
Costeffectiveness
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,topiramatemonotherapyisverylikely
TheEpilepsies
404
tobecosteffectivecomparedwithsodiumvalproatewhenusing2010drugcosts(ICER=944per
QALYgained).Thisevidenceisdirectlyapplicablebuthaspotentiallyseriouslimitations.
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,topiramatemonotherapyismore
costly,butlesseffectiveatpreventingseizuresthansodiumvalproatemonotherapy.Thisevidenceis
partiallyapplicablebuthaspotentiallyseriouslimitations.
cognitiveoutcomes.
Clinicalevidence
161
ofAEDs,includinglamotrigineandtopiramate,usedasmonotherapyin
thetreatmentofpeoplewithnewlydiagnosedIGEwasidentifiedandincludedintheeconomic
literaturesearch.Thecompleteresultsofthisstudyarepresentedinsection10.13.6.
Evidencestatements
Topiramatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyinprolonging
thetimetofirstseizure,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect(LOW
QUALITY).
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyinthe
timetoexit/withdrawalofallocatedtreatment(VERYLOWQUALITY).
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyinthe
Thereisnosignificantdifferencebetweenlamotriginemonotherapyversustopiramatemonotherapy
intheincidenceof:
tiredness,drowsiness,fatigueandlethargy(VERYLOWQUALITY).
othersideeffects(pleaseseeevidenceextractionAppendixL)(VERYLOWQUALITY).
QualityofLifestatisticallysignificantresults
Significantlymoreparticipantstakinglamotriginemonotherapycomparedtotopiramate
monotherapyhadhigherscoresontheGQoLquestionnaire.
TheEpilepsies
405
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapy
in:
twoyearAEPscores
twoyearEQ5Dscores.
Costeffectiveness
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,topiramatemonotherapyisverylikely
tobecosteffectivewhencomparedwithlamotriginemonotherapywhenusing2010drugcosts
(ICER=4,982).Thisevidenceisdirectlyapplicablebuthaspotentiallyseriouslimitations.
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,topiramatemonotherapyismore
costlyandmoreeffectiveatpreventingseizuresthanlamotriginemonotherapy(ICER=11per
seizureavoided).However,sodiumvalproatemonotherapyismostcosteffectiveinthisanalysis.
Thisevidenceispartiallyapplicablebuthaspotentiallyseriouslimitations.
atleast50%reductioninseizurefrequency.
cognitiveoutcomes.
10.13.5 Adjunctivetherapyinchildren,youngpeopleandadultswithIGE
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch,howevertheNCGCmodelevaluating
adjunctiveAEDsinthetreatmentofadultswithrefractorygeneralisedtonicclonicseizuresused
clinicalevidencefromthiscomparison.Forresultsofthisanalysis,seesection10.5.8.
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapywereseizurefree
comparedtoplacebo.(MODERATEQUALITY)
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadatleasta50%
reductioninseizurefrequencycomparedtoplacebo.(MODERATEQUALITY)
TheEpilepsies
406
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyversusplaceboforthe
proportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOWQUALITY)
Thereisnosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboforthe
incidenceof:
nasopharyngitis(VERYLOWQUALITY)
fatigue(VERYLOWQUALITY).
Nosignificantdifferencebetweenlevetiracetamadjunctivetherapyandplaceboinachievinga
greaterimprovementinthequalityoflife(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamadjunctivetherapytoplacebowasidentified.
However,adjunctivelevetiracetamwasfoundtobecosteffectiveinthetreatmentofadultswith
refractorygeneralizedtonicclonicseizuresifadjunctivelamotriginewasnotanappropriateclinical
option.Fordetailsonthisevidence,seesection10.5.7.
timetofirstseizure
cognitiveoutcomes.
10.13.6 HealtheconomicevidenceforAEDsusedasmonotherapyinthetreatmentofpatients
withnewlydiagnosedIGE
161,181
assessingthecosteffectivenessofAEDsusedasmonotherapyin
patientswithnewlydiagnosedIGEwereidentifiedintheeconomicliteraturesearchandincludedin
theeconomicevidencereview.SeeappendixMforfullstudydetailsandassessmentsoflimitations
andapplicability.Thesestudieswereconsideredsufficienttoinformrecommendationsinthis
population,thereforenooriginaleconomicmodellingwasundertaken.
Table25: MonotherapyforpatientswithIGEEconomicstudycharacteristics
Marson(2007)
161
(a,b)
Directlyapplicable
(c)
Economicevaluation
conductedalongsideRCT;
comparatorsincluded
sodiumvalproate,
lamotrigineand
topiramate;2yeartime
TheEpilepsies
407
horizon;effectmeasured
asQALYsgained
Marson(2007)
161
(a,b)
Partiallyapplicable
(c,d)
Economicevaluation
conductedalongsideRCT;
comparatorsincluded
sodiumvalproate,
lamotrigineand
topiramate;2yeartime
horizon;effectmeasured
asseizuresavoided
Hawkins(2005)
181
(e,f,g)
Partiallyapplicable(h) Decisionanalyticmodel;
15yeartimehorizon;
effectivenessdatabased
onanunpublished
study
275
(a) SensitivityanalysisincompleteinthatitonlypresentscomparisonsofVPAvLTGandVPAvTPMbutfailstopresent
comparisonofLTGvTPM.
(b) Unitcostsestimatesarefrom2005.
(c) StudypopulationincludedpatientswithIGE(63%)andsomepatientswithanunclassifiedepilepsy(27%).
(d) Analysisofcostperseizuresavoided,notQALYs.
(e) Costsdiscountedat3.5%perannum;QALYsdiscounted1.5%perannum.
(f) Unitcostestimatesarefrom20012002.
(g) Treatmenteffectsbasedonresultsofanunpublishedstudy
275
thatwasnotincludedinNCGCsystematicreview.
(h) Didnotincludeallcomparatorsrelevanttotheguidelinereview,namelytopiramate.
Table26: MonotherapyforpatientswithIGEEconomicstudycharacteristics
AED
Totalcost
()per
patient
Totaleffects
perpatient
ICER
Uncertainty
CostperQALYanalysis (QALYs) (/QALY)
VPA 1,390 1.648 Bootstrappedestimatesindicatethatata
willingnesstopaythresholdof20,000/QALY,
VPAhasa5%and37%probabilityofbeing
costeffectivecomparedtoTPMandLTG
respectively.Atawillingnesstopay
thresholdof30,000/QALY,thisfigureis97%.
TPM 1,568 1.809 1,606 Bootstrappedestimatesindicatethatata
TPMhasa95%probabilityofbeingcost
effectivecomparedtoVPA.Atawillingness
topaythresholdof30,000/QALY,thisfigure
is97%.
LTG 1,906(a) 1.701 Dominated Bootstrappedestimatesindicatethatata
LTGhasa63%probabilityofbeingcost
effectivecomparedtoVPA.Atawillingness
topaythresholdof30,000/QALY,thisfigure
is68%.
Costperseizureavoided
analysis
(total
seizures)
(/seizure
avoided)
TheEpilepsies
408
AED
Totalcost
()per
patient
Totaleffects
perpatient
ICER
Uncertainty
VPA 1,136 44.1 Bootstrappedestimatesindicatethatata
willingnesstopaythresholdof1,600/seizure
avoided,VPAhasan84%and99%probability
ofbeingcosteffectivecomparedtoTPMand
LTG,respectively.
TPM 1,568 75.1 Dominated Bootstrappedestimatesindicatethatata
avoided,TPMhasa16%probabilityofbeing
costeffectivecomparedtoVPA.
LTG 1,761(a) 120.9 Dominated Bootstrappedestimatesindicatethatata
avoided,LTGhasa1%probabilityofbeing
costeffectivecomparedtoVPA.
(a) Unitcostsestimatesarefrom2005,andsincethen,unitcostsoflamotrigineandtopiramatehavereducedandmay
changeconclusionsofthecosteffectivenessanalysis.
AstheunitcostsofantiepilepticdrugsusedintheSANADtrialwerefrom2005andtheunitcostsof
lamotrigineandtopiramatehavechangeddramaticallysincethen,itwasconsideredappropriateto
updatetheseandperformanincrementalanalysisbasedoncurrentAEDcosts.Currentunitcostsfor
lamotrigine,sodiumvalproate,andtopiramateweretakenfromtheBNF59
325
andaweighted
averagecostpermilligramwascalculatedbasedonrelativequantitiesprescribedfromthe
PrescriptionCostAnalysis2008
326
.Totaldrugcostswerethencombinedwiththehospitalisationand
othercostspublishedinSANADtocalculateamorecurrentaveragecostperpatient.Theupdated
resultsarepresentedintable10.21.
Table27: MonotherapyforpatientswithIGEResultsofMarson2007
161
AED
Totalcost
()per
patient(a)
Totaleffects
perpatient
ICER
Uncertainty(b)
CostperQALYanalysis (QALYs) (/QALY)
LTG 1,090 1.701 Dominated Noanalysisofuncertaintycouldberecreated
intheupdateofdrugunitcosts.
VPA 1,476 1.648 Dominated Noanalysisofuncertaintycouldberecreated
TPM 1,565 1.809 4,402 Noanalysisofuncertaintycouldberecreated
Costperseizureavoided
analysis
(total
seizures)
(/seizure
avoided)
LTG 1,090 120.9 Noanalysisofuncertaintycouldberecreated

VPA 1,476 44.1 5 Noanalysisofuncertaintycouldberecreated
TPM 1,565 75.1 Dominated Noanalysisofuncertaintycouldberecreated
(a) Inthepublishedanalyses,estimatesoftotalcostwereslightlydifferentduetodifferentnumbersofpatientsbeing
includedinthecostperQALYandcostperseizureavoidedanalyses.Inthisrecalculation,theyreassumedtohavebeen
thesame.
(b) Uncertaintyisnotreflectedinthesenewestimates,asbootstrappedestimatescouldnotberecalculatedorcost
effectivenessacceptabilitycurvesreplotted.
(c) Sodiumvalproateismorecostlyandmoreeffectiveinpreventingseizures.Noexplicitwillingnesstopayperseizure
avoidedthresholdexiststoassessthecosteffectivenessofinterventionsonthismeasure.
TheEpilepsies
409
Evidencestatements
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,lamotriginemonotherapyismore
effectivethansodiumvalproateintermsoftotalQALYsgained.Usingstudycostsfrom2005,
lamotrigineismorecostlythansodiumvalproate,butusingcostsfrom2010,lamotrigineislesscostly
thansodiumvalproate.Thisevidenceisdirectlyapplicablebuthaspotentiallyseriouslimitations.
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,sodiumvalproatemonotherapyis
moreeffectiveatpreventingseizuresthanlamotriginemonotherapy.Usingstudycostsfrom2005,
lamotrigineismorecostlythansodiumvalproateandwasthusdominated;usingcostsfrom2010,
lamotrigineislesscostlythansodiumvalproateandtheICERforsodiumvalproateis5perseizure
avoided.Withoutanexplicitwillingnesstopaythresholdforseizuresavoided,thecosteffectiveness
ofsodiumvalproatefromthisanalysisisindeterminable.Thisevidenceispartiallyapplicableandhas
potentiallyseriouslimitations.
Table28: MonotherapyforpatientswithIGEResultsofHawkins2005{Hawkins,20057/id
AED
Totalcost
()per
patient
Totaleffects
(QALYs)per
patient
ICER
(/QALY) Uncertainty
VPA 4,288 9.814 Atathresholdof30,000perQALY,VPAhasa
95%probabilityofbeingoptimal.
d
Atathresholdof30,000perQALY,LTGhasa
5%probabilityofbeingoptimal.
(a) Theanalysisusedunitcostsfrom200102.Sincethen,thecostofLTGhasreduceddramaticallyandmayaffect
conclusions.
Evidencestatements
Evidencefromacosteffectivenessanalysisindicatesthatlamotriginemonotherapyismorecostly
andlesseffectivethansodiumvalproateintermsoftotalQALYsgained.Theevidenceispartially
applicablebutasitusescostsfrom200102,ithaspotentiallyseriouslimitations.
10.13.7 Monotherapyforthetreatmentofchildhoodabsenceepilepsy,juvenileabsenceepilepsy
andotherabsenceepilepsysyndromes
Clinicalevidence
Nostudieswereidentified.
Evidencestatements
Significantlymoreparticipantsinsodiumvalproatemonotherapywereseizurefreeatonemonth
comparedtolamotriginemonotherapy(LOWQUALITY).
TheEpilepsies
410
Significantlymoreparticipantsinsodiumvalproatemonotherapywereseizurefreeat35month
comparedtolamotriginemonotherapy(VERYLOWQUALITY).
seizurefreedomat12months(VERYLOWQUALITY).
theproportionofparticipantswhowithdrewduetolackofefficacy(VERYLOWQUALITY).
Nosignificantdifferencebetweenlamotriginemonotherapyandvalproatemonotherapyinthetime
toexit/withdrawalofallocatedtreatmentat12monthsfollowup(VERYLOWQUALITY).
Significantlymoreparticipantsinsodiumvalproatemonotherapyhadanincidenceofsleepproblem
comparedtolamotriginemonotherapy,howeverthereisanuncertaintyovertheclinicalimportance
ofitseffect(LOWQUALITY).
incidenceofotheradverseevents(forfulllistpleaseseeevidenceextractionsAppendixL)at12
monthsfollowup(VERYLOWQUALITY).
incidenceofthefollowingadverseeventsat1620weeksfollowup:
hyperactivity(VERYLOWQUALITY)
hostility(VERYLOWQUALITY)
personalitychange(VERYLOWQUALITY)
Cognitiveeffectstatisticallysignificantresults
Significantlymorepatientsinsodiumvalproatemonotherapyhadattentionaldysfunctioncompared
tolamotriginemonotherapyat1620weeksfollowup(MODERATEQUALITY).
Costeffectiveness
patientsandnoothereconomicstudiescomparinglamotriginemonotherapytosodiumvalproate
monotherapyinapopulationofpatientswithCAEorJAEwereidentified.
TheEpilepsies
411
Clinicalevidence
Evidencestatements
Sodiumvalproatemonotherapyissignificantlymoreeffectivethantopiramatemonotherapyin
prolongingtimetoexit/withdrawalofallocatedtreatmentat12monthsfollowup(MODERATE).
theincidenceoftiredness,drowsiness,fatigueandlethargyat12monthsfollowup(VERYLOW
QUALITY).
theincidenceofotheradverseevents(forfulllistpleaseseeextractionsinAppendixL)at12months
followup(VERYLOWQUALITY).
Costeffectiveness
patientsandnoothereconomicstudiescomparingtopiramatemonotherapytosodiumvalproate
monotherapyinapopulationofpatientswithCAEorJAEwereidentified.
seizurefreedom
cognitiveoutcomes
TheEpilepsies
412
10.13.7.3 Sodiumvalproateversusethosuximide
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenethosuximidemonotherapyandsodiumvalpraote
monotherapyontheproportionofseizurefreeparticipants(VERYLOWQUALITY).
Nostatisticallysignificantdifferencebetweenethosuximidemonotherapyandvalproate
monotherapyontheproportionofparticipantsachievingatleast50%reductioninseizurefrequency
(VERYLOWQUALITY).
Nostatisticallysignificantdifferencebetweenethosuximidemonotherapyandvalproate
monotherapyfortimetoexit/withdrawalofallocatedtreatment.(VERYLOWQUALITY)
Significantlymorepatientsonethosuximidemonotherapyhadanincidenceofnausea,vomitingor
bothcomparedtovalproicacidmonotherapyat1620weeksfollowup(HIGHQUALITY).
Significantlymorepatientsonvalproicacidmonotherapyhadanincidenceofhostilitycomparedto
ethosuximidemonotherapyat1620weeksfollowup;howeverthereisuncertaintyoverthe
magnitudeoftheclinicaleffect(MODERATEQUALITY).
Significantlymorepatientsonvalproicacidmonotherapyhadanincidenceofpersonalitychange
comparedtoethosuximidemonotherapyat1620weeksfollowup;howeverthereisuncertainty
overthemagnitudeoftheclinicaleffect(MODERATEQUALITY).
Nostatisticallysignificantdifferencebetweenethosuximidemonotherapyandvalproicacid
monotherapyintheincidenceofthefollowingadverseeventsat1620weeksfollowup:
fatigue(LOWQUALITY)
sleepproblem(LOWQUALITY)
stomachupset(LOWQUALITY)
hyperactivity(LOWQUALITY)
initialtiredness(VERYLOWQUALITY)
decreasednumberofplatelets(withouttruethrombocytopaenia)(VERYLOWQUALITY)
Cognitiveeffectstatisticallysignificantresults
TheEpilepsies
413
Significantlymorepatientsonvalproicacidmonotherapyhadattentionaldysfunctioncomparedto
ethosuximidemonotherapyat1620weeksfollowup(HIGHQUALITY).
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytoethosuximidemonotherapyina
populationofpatientswithCAEorJAEwasidentified.
timetofirstseizure
10.13.7.4 Ethosuximideversuslamotrigine
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsinethosuximidemonotherapywereseizurefreecomparedto
lamotriginemonotherapy(MODERATEQUALITY).
Timetoexit/withdrawalofallocatedtreatmentwassignificantlymorerapidinlamotrigine
monotherapycomparedtoethosuximidemonotherapy).(MODERATEQUALITY)
Significantlymorepatientsinethosuximidemonotherapyhadanincidenceofnausea,vomitingor
bothcomparedtolamotriginemonotherapyat1620weeksfollowup.Howeverthereisuncertainty
overthemagnitudeoftheclinicaleffect(LOWQUALITY).
Significantlymorepatientsinethosuximidemonotherapyhadanincidenceofstomachupset
comparedtolamotriginemonotherapyat1620weeksfollowup.Howeverthereisuncertaintyover
themagnitudeoftheclinicaleffect(LOWQUALITY).
Nosignificantdifferencebetweenethosuximidemonotherapyandlamotriginemonotherapyinthe
incidenceofthefollowingadverseeventsat1620weeksfollowup:
TheEpilepsies
414
headache(VERYLOWQUALITY).
Cognitiveeffectstatisticallynonsignificantresults
Nosignificantdifferencebetweenethosuximidemonotherapyandlamotriginemonotherapyin
attentionaldysfunctionat1620weeksfollowup(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingethosuximidemonotherapytolamotriginemonotherapyina
populationofpatientswithCAEorJAEwasidentified.
timetofirstseizure
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenlevetiracetamandplaceboforseizurefreedom.(VERYLOW
QUALITY)
Nosignificantdifferencebetweenlevetiracetamandplacebofor50%reductioninseizurefrequency.
(VERYLOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamandplaceboforwithdrawalduetoadverseevents.
(VERYLOWQUALITY)
timetofirstseizure
TheEpilepsies
415
outcomesrelatingtoadverseevents
10.13.8 Adjunctivetherapyforthetreatmentofchildhoodabsenceepilepsy,juvenileabsence
epilepsyandotherabsenceepilepsysyndromes
10.13.8.1 Sodiumvalproateversusethosuximide
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenvalproicacidadjunctiveandethosuximideadjunctiveforthe
proportionofparticipantswithatleast80%reductioninseizurefrequency(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingadjunctivevalproicacidtoadjunctiveethosuximideinapopulation
ofpatientswithCAEorJAEwasidentified.
seizurefrequency
timetofirstseizure
outcomesrelatingtocognitiveeffects
10.13.9 MonotherapyforthetreatmentofJuvenileMyoclonicEpilepsy(JME)
Clinicalevidence
TheEpilepsies
416
Evidencestatements
Timetofirstseizurewassignificantlylessinchildrenreceivinglamotriginecomparedtochildren
receivingsodiumvalproate.(MODERATEQUALITY)
seizurefreedom.(VERYLOWQUALITY)
withdrawalduetolackofefficacy.(VERYLOWQUALITY)
timetoexit/withdrawalofallocatedtreatment.(VERYLOWQUALITY)
erythematousrash.(VERYLOWQUALITY)
fatigue.(VERYLOWQUALITY)
weightincrease.(VERYLOWQUALITY)
tiredness,drowsiness,fatigueorlethargy(VERYLOWQUALITY)
otheradverseevents(seeevidenceextractionAppendixL)(VERYLOWQUALITY)
Costeffectiveness
populationofpatientswithJMEwasidentified.
seizurefreedom
50%reductioninseizurefrequency
cognitiveoutcomes.
TheEpilepsies
417
10.13.10 Monotherapy/adjunctivetherapyforthetreatmentofjuvenilemyoclonicepilepsy(JME)
Clinicalevidence
Evidencestatements
valproatemonotherapy/adjunctivetherapyfortheproportionofseizurefreeparticipants.(VERY
LOWQUALITY).
valproatemonotherapy/adjunctivetherapyontheproportionofparticipantsexperiencingatleasta
50%reductioninseizurefrequency(50to<100%)(VERYLOWQUALITY).
timetofirstseizure.(VERYLOWQUALITY).
timetoexit/withdrawalofallocatedtreatment(VERYLOWQUALITY).
valproatemonotherapy/adjunctivetherapyforwithdrawalduetolackofefficacy(VERYLOW
QUALITY).
valproatemonotherapy/adjunctivetherapyforwithdrawalduetoadverseevents(VERYLOW
QUALITY).
valproatemonotherapy/adjunctivetherapyfortheincidenceofthefollowingadverseevents:
concentration/attentiondifficulty(VERYLOWQUALITY)
alopecia(VERYLOWQUALITY)
psychomotorslowing(VERYLOWQUALITY)
TheEpilepsies
418
appetiteincrease(VERYLOWQUALITY)
abnormalvision(VERYLOWQUALITY)
tiredness,drowsiness,fatigueorlethargy(VERYLOWQUALITY)
otheradverseevents(seeevidenceextractionAppendixL)(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingtopiramatemonotherapy/adjunctivetherapytosodiumvalproate
monotherapy/adjunctivetherapyinapopulationofpatientswithJMEwasidentified.
cognitiveoutcomes
outcomesrelatingtoqualityoflife
10.13.11 AdjunctivetreatmentforforthetreatmentofofJuvenileMyoclonicEpilepsy(JME)
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyweremyoclonicseizure
freecomparedtoplacebo;however,thereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapywereseizurefree(any
seizuresubtype);howeverthereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyachieved50%orabove
reductioninmyoclonicseizurefrequencycomparedtoplacebo(MODERATEQUALITY).
Thereisnosignificantdifferencebetweenthelevetiracetamadjunctivegroupandtheplacebogroup
ontheincidenceof:
TheEpilepsies
419
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadexperienced
improvementinhealthrelatedqualityoflifecomparedtoplacebo(MODERATEQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamadjunctivetherapytoplaceboinapopulationof
patientswithJMEwasidentified.
timetofirstseizure
cognitiveeffects
10.13.12 AEDsforthetreatmentofepilepsywithgeneralisedtonicclonicseizuresonly
Epilepsywithgeneralisedtonicclonicseizuresaloneisasdescribed;allindividualshavegeneralised
tonicclonicseizures,1753%12hoursafterawakening.Howeverseizuresmayalsooccurduring
relaxationorleisure,orindeedatothertimes.Ithasanageofonset630years,peak1617years.
InterictalEEGshowsanormalbackgroundwithgeneralisedspikewaveandmultiplespikewave
dischargesof24Hz.Seizuresmaybeprecipitatedbysleepdeprivationandexcessivealcohol
consumption.
includedadultsandchildrenwithepilepsywithgeneralisedtonicclonicseizuresonly.
Pleaseseesection10.5inthegeneralizedtonicclonicseizuresevidencereviewforclinicalevidence
relatingtoepilepsywithgeneralisedtonicclonicseizuresonly.
IdiopathicGeneralisedEpilepsy(useforunclassifiedIGEforspecificsyndromessee
below)
FirstLinetreatmentinchildren,youngpeopleandadultswithIGE
TheEpilepsies
420
Recommendation
youngpeopleandadultswithnewlydiagnosedIGE,
particularlyifthereisaphotoparoxysmalresponseonEEG.Be
awareofteratogenicrisksofsodiumvalproate(see
dd
ifsodiumvalproateisunsuitableornot
tolerated.Beawarethatlamotriginecanexacerbate
myoclonicseizures.IfJMEissuspectedseerecommendations
134and135.[new2012]
outcomes
TheGDGplacedgreaterimportanceonefficacyasmeasuredby
seizurefreedom,withdrawalduetolackofefficacy,timeto
withdrawalandcosteffectivenessinthetrialsthanthequalityof
life(measuredbyEQ5D).EQ5Dwasundertakenonasmall
subgroupofindividualsandexcludedchildren.
benefitsandharms
SodiumvalproateisthemosteffectivedrugforIGEbuthas
disadvantages.Theriskofteratogenicityassociatedwith
valproatesuseissignificant,particularlyathigherdoses,so
cautionisadvisedintheuseofsodiumvalproateinwomenof
childbearingpotential.Ingirlswhoseseizurescontinueandwho
areapproachingchildbearingpotential,thecontinueduseof
sodiumvalproateshouldbereviewedandoptionsdiscussed.
Therewasnodifferencebetweentheproportionofpatients
achievingseizurefreedomorwithdrawalduetoadverseevents.
Patientstakingtopiramateandlamotrigineexperiencedtreatment
failure(duetolackofefficacyandadverseevents)fasterthan
patientstakingsodiumvalproate.Patientstakingsodium
valproatehadashortertimeto12monthremissionthan
topiramateorlamotrigine.Sodiumvalproatewasalsobetterat
delayingthetimetofirstseizurethanlamotrigine.Therewereno
differencesbetweenlamotrigineandsodiumvalproatefor
incidenceofparticularadverseevents.ItisalsoGDGconsensus
thatlamotrigineisnoteffectivewithIGEwithphotosensitivity.
TheGDGfeltthatlamotriginecanbegoodattreatingotherIGE
seizuretypessuchasGTCseizuresbutmayexacerbatemyoclonic
seizures.Lamotrigineinhighdose(>400mg/day)isassociatedwith
Lamotriginemayreducetheconcentrationofprogesterone
componentoforalcontraceptives,sotheefficacyofsystemic
progesteroneonlymethodsisreduced.Oestrogensmay
significantlyreducetheconcentrationoflamotrigine.
Economicconsiderations Sodiumvalproateemergedasthedrugmostlikelytobecost
dd
TheEpilepsies
421
ofSANAD.Greaterweightwasgiventothisanalysisasthe
reductioninseizurefrequencyisconsideredtobethemost
importantclinicaloutcome.TheGDGconsideredtheseemingly
inconsistentresultsbetweenthecostperseizureavoidedanalysis
andthecostperQALYgainedanalysisandconcludedthatsomeof
thedifferencemaybeattributabletotheQALYcapturingelements
ofhealthrelatedqualityoflifeotherthanthoseassociatedwith
seizures.Lamotriginedidhavealowerrateofwithdrawaldueto
adverseeventscomparedtosodiumvalproatebutthiswasnot
statisticallysignificant.Anotherpossiblereasonforthe
contradictoryresultmaystemfromthefactthatQALYswereonly
measuredinadultsandtotalnumberofseizureswascountedfor
bothadultsandchildren.Themajorityofthepatientpopulationin
thesestudyarmswasundertheageof20,thusthecostperQALY
analysismaynotbebaseduponatrulyrepresentativesample.
GivenGDGemphasisonoutcomesofeffectsuchasthe
achievementofseizurefreedom/reductionandtreatment
retention(i.e.avoidanceofwithdrawalforanyreason),sodium
valproateisconsideredtobeadrugthatproducesfavourable
outcomestopatientsandrepresentsgoodvaluetotheNHS.
TheGDGconsideredthattherearepatientsforwhomsodium
valproateiscontraindicatedornottoleratedandforthese
patients,lamotrigineortopiramatemaybecosteffective
alternatives.Thepublishedeconomicevidenceforthecost
effectivenessoflamotrigineandtopiramatewasoutofdateanda
roughreestimationbasedoncurrentcostswasundertaken.The
newresultsindicatethatlamotriginehasthelowesttotalcostand
topiramatehasthehighest.Patientstakingtopiramatewere
reportedtoenjoymoreQALYsandexperiencefewerseizuresthan
patientstakinglamotrigine.Althoughresultswouldpointto
topiramateasthemostcosteffectivedrugbetweenthetwo,other
clinicaloutcomeswerealsotakenintoaccount.Inthesubgroupof
patientswithIGE,nostatisticallysignificantdifferenceswere
demonstratedbetweentopiramateandlamotrigineforwithdrawal
duetoadverseeventsorremissionofseizuresat12months.
Althoughbothdrugsarelikelytobeconsideredcosteffective,the
GDGbasedtheirrecommendationforlamotrigineinpreferenceto
topiramateontheirclinicalexperiencewiththesideeffectprofile
oftopiramate.Ifandwhentopiramatedoesrepresenttheoptimal
choice,theclinicianandthepatientshouldbeawareof
topiramatespsychiatricandbehaviouralsideeffects.
Qualityofevidence
TheoverallGRADEratingofevidencewasmoderateorverylow
quality.Themajorityoftheevidencecamefromalarge,pragmatic,
unblindedtrial.
CliniciansshouldconsiderthatVPAmayinhibitthehepatic
TheEpilepsies
422
metabolismofotherdrugsandenzymeinducingdrugsmay
enhancethemetabolismofVPA.
TheEpilepsies
423
commendation
130. Considertopiramate
butbeawarethatithasaless
favourablesideeffectprofilethansodiumvalproateand
lamotrigine
.[new2012]
outcomes
TheGDGplacedimportanceonefficacyasmeasuredbytimeto
withdrawal,timetofirstseizureandtimeto12monthremission,
adverseeventsandcosteffectivenessinthetrials.
benefitsandharms
Inacomparativetrialofsodiumvalproateveruslamotrigineverus
topiramate,sodiumvalproatewassignificantlybetteratprolonging
thetimetoexitcomparedtotopiramatewhereastopiramatewas
significantlybetteratprolongingtimetofirstseizurethan
lamotrigine,althoughtherewasuncertaintyinthemagnitudeof
clinicaleffect.
Howevertopiramatehasdisadvantagesduetodruginteractions
anditsadverseeventsprofile.
Economicconsiderations TheGDGconsideredthattherearepatientsforwhomsodium
alternatives.Thepublishedeconomicforthecosteffectivenessof
lamotrigineandtopiramateevidencefromtheSANADtrialwasout
ofdateandaroughreestimationbasedoncurrentcostswas
undertaken.Thenewresultsindicatethatlamotriginehasthe
lowesttotalcostandtopiramatehasthehighest.Patientstaking
topiramatewerereportedtoenjoymoreQALYsandexperience
fewerseizuresthanpatientstakinglamotrigine.Althoughresults
wouldpointtotopiramateasthemostcosteffectivedrugbetween
thetwo,otherclinicaloutcomeswerealsotakenintoaccount.In
thesubgroupofpatientswithIGE,nostatisticallysignificant
differencesweredemonstratedbetweentopiramateand
lamotrigineforwithdrawalduetoadverseeventsorremissionof
seizuresat12months.
Althoughbothdrugsarelikelytobeconsideredcosteffective,the
GDGbasedtheirrecommendationforlamotrigineinpreferenceto
topiramateontheirclinicalexperiencewiththesideeffectprofile
oftopiramate.Ifandwhentopiramatedoesrepresenttheoptimal
choice,theclinicianandthepatientshouldbeawareof
topiramatespsychiatricandbehaviouralsideeffects.
Qualityofevidence
TheoverallGRADEratingofevidencewasmoderateorverylow
quality.Theevidencecamefromalarge,pragmatic,unblended
trial.
Otherconsiderations
Nootherconsiderations.
Adjunctivetreatmentinchildren,youngpeopleandadultswithIGE
TheEpilepsies
424
Recommendation
,levetiracetam
,sodiumvalproateor
topiramate
peopleandadultswithIGEiffirstlinetreatments(see
recommendations128,129and130)areineffectiveornot
outcomes
TheGDGbasedgreaterimportanceforthisrecommendationon
seizurefreedomand50%reductioninseizurefrequencywhen
levetiracetamusedasadjunctivetherapyinIGE.
benefitsandharms
Sodiumvalproatewasshowntobethemosteffectiveas
monotherapy,butlamotrigineandtopiramatewereconsidered
reasonablealternativesifsodiumvalproatewasunsuitable.The
GDGconcludedthatgiventheireffectivenessasmonotherapy,
anyofthesedrugscouldbereasonablyusedincombinationwith
anotherandshouldthereforeberepeatedinthe
recommendationforadjunctivetherapy.
Levetiracetamasaddontreatmentisalsoaneffectiveadjunctive
therapyinIGEandhastheadvantageofnosignificantinteractions
withothermedications.Thereisinsufficientdatatojudgethe
safetyoflevetiracetaminpregnancyatthetimeofwritingthe
guideline.
costeffectivenessofanyofthesedrugs,asadjunctivetreatment
inpatientswithIGE.Lamotrigine,sodiumvalproateand
topiramatewereallconsideredcosteffectiveasmonotherapyin
thetreatmentofIGEandthisprovidessomeguidanceastotheir
likelycosteffectivenessasadjunctivetherapy.TheGDGalso
consideredtheevidenceofcosteffectivenessforlamotrigine,
levetiracetamandtopiramateasadjunctivetreatmentfor
generalisedtonicclonicseizuresfromtheNCGCcosteffectiveness
analysissummarisedinsection10.5.8anddetailedinappendixS.
ManyofthestudiesusedintheNCGCeconomicmodelincluded
patientswithIGEthereforetheGDGconsidereditsconclusions
applicabletothispopulationaswell.
Qualityofevidence Evidenceforlevetiracetamcomesfromthedataonadjunctive
treatmentofjuvenilemyoclonicepilepsybecauseno
adjunctivestudiesinIGEwereidentifiedandatthetimeofwriting
isnotcurrentlylicensedinmonotherapy.TheoverallGRADE
ratingofevidencewasmoderatetoverylow
Otherconsiderations
Forfurtherguidanceonmedicationadherencetorefertothe
NICEMedicinesAdherenceguideline.
Cliniciansshouldbeawarethattheremaybepotentialproblems
fromwithdrawalfromthesedrugs.
TheEpilepsies
425
Recommendation
epilepsyspecialistandconsiderclobazam
,clonazepamor
zonisamide
.[new2012]
outcomes
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepamorzonisamide
werepossiblealternativesinaccordancewithtertaryepilepsycare.
TheGDGconsidereditimportanttomentionthesedrugsas
potentialoptionstooffertopatientsbetweenthetimeofreferral
toandconsultationwithatertiaryspecialist.Itwasthoughtthat
thesearesomeofthedrugsthatatertiaryspecialistmightuse,
basingthedecisiononclinicalexperiencetreatingpatientswith
refractorygeneralisedseizuretypes.
onthecosteffectivenessofclobazam,clonazepamorzonisamide.
Qualityofevidence TherewasnoevidenceavailableforIGEforthesedrugssothis
recommendationwasbasedonGDGclinicalexpertise.
Otherconsiderations
Careshouldbetakenwithclobazamandclonazepamduetoaslow
seizures.
Recommendation
outcomes
benefitsandharms
Clinicalpracticesuggeststhatmyoclonicseizurescanbe
aggravatedbythesemedications.TheGDGfeltthatuseofthese
harm.
TheEpilepsies
426
Recommendation
potentialtoaggravateIGEmakesthemveryunlikelytobecost
effective.Aggravationofseizuresislikelytonegativelyimpact
JuvenileMyoclonicEpilepsy(JME)
Firstlinetreatmentinchildren,youngpeopleandadultswithJME
Recommendation
youngpeopleandadultswithnewlydiagnosedJME,unlessit
isunsuitable.Beawareofteratogenicrisksofsodium
outcomes
TheGDGplacedmostimportanceonefficacyasmeasuredby
seizurefreedom,timetofirstseizure,timetowithdrawaland
adverseeventsinJME.
benefitsandharms
Theevidenceformonotherapytreatmentofjuvenilemyoclonic
epilepsyisverylimited,predominantlybasedonasingle
unpublishedsubgroupanalysis.Resultsindicatethatsodium
valproatewasmoreeffectivethanlamotriginealthoughtherewas
nosignificantdifferenceobservedintermsoftreatmentfailure.
Nodifferencewasobservedbetweentopiramateandsodium
valproate,althoughresultsforalloutcomestrendedtowards
sodiumvalproatebeingmoreeffective.Althoughsodium
valproateismoreeffectivethanlamotrigineandmaybemore
effectivethantopiramateinthetreatmentofJME,ithascertain
disadvantages.Theriskofteratogenicityassociatedwiththeuse
ofvalproateissignificant,particularlyathigherdoses,socaution
isadvisedintheuseofsodiumvalproateinwomenof
childbearingpotential.Ingirlswhoseseizurescontinueandwho
areapproachingchildbearingpotential,thecontinueduseof
sodiumvalproateshouldbereviewedandoptionsdiscussed.
costeffectivenessofanyAEDsusedtotreatpatientswithJME.
However,theGDGdrewfromthecosteffectivenessevidencefor
sodiumvalproateinidiopathicgeneralisedepilepsyasawhole.
Onthisbasis,theyputgreateremphasisonthecostperseizure
avoidedanalysisfromSANADbecausereductionofseizure
frequencyisconsideredtobethemostimportantclinical
outcome.
Qualityofevidence TherewaslimitedevidenceforJMEmonotherapy.Onlythree
unblindedstudieswerefoundwithoverallGRADEratingof
evidencemoderatetoverylowquality.Twoofthesestudieshad
verysmallsamples(onewasapilotstudywhereastheotherwasa
TheEpilepsies
427
Recommendation
youngpeopleandadultswithnewlydiagnosedJME,unlessit
isunsuitable.Beawareofteratogenicrisksofsodium
subgroupwhichtheauthorsdidnotanalysestatisticallyduetothe
smallnumberandimbalanceofdistribution.Theotherlarger
unblindedstudy(SANAD)foundonlysodiumvalproatetohave
longertimetofirstseizurethanlamotrigine.
Otherconsiderations Forfurtherguidanceonmedicationadherencetorefertothe
CliniciansshouldconsiderthatVPAmayinhibitthehepatic
metabolismofotherdrugsandenzymeinducingdrugsmay
enhancethemetabolismofVPA.
TheEpilepsies
428
Recommendation
135. Considerlamotrigine
,levetiracetam
,ortopiramate*if
sodiumvalproateisunsuitableornottolerated.Beawarethat
topiramatehasalessfavourablesideeffectprofilethan
lamotrigine,levetiracetamandsodiumvalproate,andthat
lamotriginemayexacerbatemyoclonicseizures.[new2012]
outcomes
TheGDGplacedgreatestimportanceonefficacyasmeasuredby
seizurefreedom,timetofirstseizureandtimetowithdrawalin
JME.
benefitsandharms
TheGDGfeltthatlamotriginemaybegoodattreatingotherJME
seizuretypessuchasGTCseizuresbutmayexacerbatemyoclonic
seizures.Lamotrigineinhighdose(>400mg/day)isassociatedwith
increasedriskofteratogenicity.Lamotriginemayreducethe
concentrationofprogesteronecomponentoforalcontraceptives,
sotheefficacyofsystemicprogesteroneonlymethodsisreduced.
Oestrogensmaysignificantlyreducetheconcentrationof
lamotrigine.
ItistheGDGconsensusthattopiramatehasnotbeenshowntobe
effectiveinIGEwithphotosensitivity.Therearelimiteddataon
thesafetyoftopiramateinpregnancyandatpresenttherisk
appearsoverallsimilartolamotrigine.Topiramateparticularlyat
higherdosesmayreducetheefficacyofthecombinedoral
contraceptive.
Duetotheseriousnessofsideeffectsreportedfortopiramatesuch
aspsychiatricandbehaviouralchangesreportedintheSANADtrial,
theGDGfeltitisnotadrugoffirstchoicewhereotherdrugsare
suitable.
Atthetimeofwritingthisguideline,levetiracetamisnotlicensed
formonotherapyintheUK.Ithasbeenshowntobeeffectiveas
adjunctivetherapyinjuvenilemyoclonicepilepsyandhasthe
advantageofhavingnosignificantreportedinteractionswithother
medications.Further,theGDGexperienceisthatithasavery
favourablesideeffectprofile.Ithasbeendemonstratedtobe
effectiveforphotosensitivity(inaphaseIItrialof12photosensitive
patientsbyKasteleijnNolstin1996).
TheGDGdecidedtorecommendofflabeluseoflevetiracetamfor
juvenilemyolonicepilepsyastheevidenceforefficacyand
tolerabilityinadjunctivetherapyconcurredwiththeirclinical
experienceofitsuseinmonotherapy.Additionally,giventhe
particularadverseeventsassociatedwithalternativefirstline
drugsforjuvenilemyoclonicepilepsy,theGDGfelttheretobea
needformoreoptions.Atthetimeofwritingtheguideline,there
isinsufficientdatatojudgethesafetyoflevetiracetamin
TheEpilepsies
429
pregnancy.
Economicconsiderations TheGDGconsideredthattherearepatientsforwhomsodium
alternatives.Thepublishedeconomicevidenceforthecost
effectivenessoflamotrigineandtopiramateinpatientswithIGE
wasoutofdateandaroughreestimationbasedoncurrentcosts
wasundertaken.Thenewresultsindicatethatlamotriginehasthe
lowesttotalcostandtopiramatehasthehighest,withbothlikely
tobeconsideredcosteffective.
GDGexperiencewasthatlamotriginespotentialtoexacerbate
myoclonicseizuresinsomepatientsmaymakeitlessornotcost
effectiveasaggravationofseizuresislikelytonegativelyimpact
healthrelatedqualityoflifeandincreaseuseofNHSresources.
However,lamotrigineshouldnotbeignoredasapossible
treatmentoptionasitcanbehelpfulincontrollingotherseizure
typescommonlyexperiencedbypatientswithJME.
Thereiscurrentlynoevidenceonwhichtoassessthecost
effectivenessoflevetiracetamasamonotherapyinpatientswith
JME.Intheabsenceofanyapplicableeconomicevidence,theGDG
consideredthecosteffectivenessresultsoflevetiracetamasa
monotherapyinapopulationwithfocalepilepsywhereitwas
moreeffectivethantopiramateandalsohadaslightlylowertotal
costovertheentire15yeartimehorizon.Inaddition,theGDG
lookedtotheresultsofthedecisionmodelundertakentoevaluate
adjunctivetherapiesinapopulationwithrefractorygeneralised
tonicclonicseizures,wherelevetiracetamwasalsolesscostlyand
moreeffectivethantopiramate.However,inbothofthese
models,lamotrigineismorecosteffectivethanlevetiracetamand
topiramate.Butgiventhepotentialproblemsoflamotriginein
patientswithJME,theGDGconsidereditlesslikelytobeascost
effectivehere.
Ontheassumptionthatlevetiracetamisatleastaseffectiveas
topiramateinthetreatmentofJME,theGDGconcludedthat,as
observedinotherpopulations,itwaslikelytorepresent
reasonablevaluetotheNHSwhensodiumvalproateand
lamotrigineareunsuitabletreatmentoptions.Researchintoboth
theeffectivenessandcosteffectivenessoflevetiracetamasa
monotherapyinthispopulationisessentialtoreducethe
substantialuncertaintyinthisdecision.
Qualityofevidence TherewaslimitedevidenceforJMEmonotherapy.Onlythree
unblindedstudieswerefoundwithoverallGRADEratingof
evidencemoderatetoverylowquality.Twoofthesestudieshad
verysmallsamples(onewasapilotstudywhereastheotherwasa
subgroupwhichtheauthorsdidnotanalysestatisticallyduetothe
TheEpilepsies
430
smallnumberandimbalanceofdistribution.Theotherlarger
unblindedstudy(SANAD)foundonlysodiumvalproatetohave
longertimetofirstseizurethanlamotrigine.Datafor
levetiracetamasadjunctivetherapycamefromastudywhereall
participantshadmyoclonicseizuresandahighpercentagehad
juvenilemyoclonicseizures.GDGopinionwasalsousedtoinform
recommendations.
Adjunctivetreatmentinchildren,youngpeopleandadultswithJME
Recommendation
,levetiracetam,sodiumvalproateor
topiramate
peopleandadultswithJMEiffirstlinetreatments(see
outcomes
50%seizurereductionandadverseeffectswereconsideredthe
benefitsandharms
Levetiracetamiseffectiveasadjunctivetherapyinmyoclonic
seizuresandhastheadvantageofnosignificantinteractionswith
othermedications.Thereareinsufficientdatatojudgethesafety
oflevetiracetaminpregnancyatthetimeofwritingtheguideline.
Lamotrigine,sodiumvalproateandtopiramateareeffectivefor
JMEmonotherapyandtheGDGconsensuswasthattheywere
appropriateforuseasadjunctivetherapy.
costeffectivenessoflevetiracetamortopiramateasatreatment
specificallyinpatientswithJME.Theclinicalevidencefor
adjunctivelevetiracetaminapopulationwithJMEshowsittobe
evenmoreeffectivecomparedtoplacebothaninapopulation
withprimarygeneralisedtonicclonicseizures.Onthatbasis,the
GDGfeltthatthecosteffectivenessofadjunctivelevetiracetam
waslikelytobethesameorbetterthanintheanalysisconducted
forpatientswithgeneralisedtonicclonicseizures,summarisedin
section10.5.8anddetailedinappendixS.Inthesameanalysis,
topiramatewasnotshowntobecosteffective,butintheevent
thatadjunctivelevetiracetamfailstoproducethedesired
reductioninseizurefrequency,theGDGfeltthatitcouldbe
considered.
Qualityofevidence TheoverallGRADEqualityratingfortheevidenceoflevetiracetam
asadjunctivetherapywaswasmoderatetoverylowquality.
TheEpilepsies
431
Recommendation
,levetiracetam,sodiumvalproateor
topiramate
peopleandadultswithJMEiffirstlinetreatments(see
HowevertherewasonlyonedoubleblindstudyofIGEwith
myoclonicseizureswhere93.4%hadjuvenilemyoclonicepilepsy
and6.6%hadjuvenileabsenceepilepsy.
Otherconsiderations Forfurtherguidanceonmedicationadherencetorefertothe
Recommendation
ineffectiveornottolerated,discusswith,orreferto,a
tertiaryepilepsyspecialistandconsiderclobazam
,
clonazepamorzonisamide
.[new2012]
outcomes
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepamor
zonisamidewerepossiblealternativesinaccordancewithtertary
patientswithrefractorygeneralisedseizuretypes.
withorreferredtoatertiaryepilepsyspecialist.Whilstthismay
bemorecostly,theGDGconsideredthatthiswasworthwhileas
thesepatientsmayrequiremorecomplexcareinordertoachieve
asuccessfuloutcome.Withregardtothespecificdrugslisted
here,therewerenoeconomicevaluationsavailabletoinformthe
GDGonthecosteffectivenessofclobazam,clonazepamor
zonisamide.
Qualityofevidence TherewasnoevidenceavailableforJMEforthesedrugssothis
recommendationwasbasedonGDGclinicalexpertise.
Otherconsiderations Careshouldbetakenwithclobazamandclonazepamduetoa
slowwithdrawalupto46monthsinviewoftheriskof
withdrawalseizures.
TheEpilepsies
432
Recommendation
,
clonazepamorzonisamide
.[new2012]
Recommendation
outcomes
benefitsandharms
ClinicalpracticesuggeststhatJMEcanbeaggravatedbythese
medications.TheGDGfeltthatuseofthesemedicationswould
leadtonoclinicalbenefitandcouldcauseharm.
effectivenessoftheseAEDsinthispopulation,howevertheir
potentialtoaggravateJMEmakesthemveryunlikelytobecost
effective.Aggravationofseizuresislikelytonegativelyimpact
TheEpilepsies
433
Epilepsywithgeneralisedtonicclonic(GTC)seizuresonly
Firstlinetreatmentinchildren,youngpeopleandadultswithnewlydiagnosedepilepsy
withGTCseizuresonly
Recommendation
139. Offerlamotrigineorsodiumvalproateasfirstlinetreatment
tochildren,youngpeopleandadultswithepilepsywithGTC
seizuresonly.Iftheyhavesuspectedmyoclonicseizures,or
aresuspectedofhavingJME,offersodiumvalproatefirst,
unlessitisunsuitable.Beawareofteratogenicrisksofsodium
outcomes
effectswereconsideredtobethemostimportantoutcomes.
benefitsandharms
Intheevidenceforepilepsywithgeneralisedtonicclonicseizures
onlytherewasnosignificantdifferencebetweenlamotrigine,
sodiumvalproateandtopiramateintermsoftimetotreatment
failureortimetofirstseizure.Inextrapolatedevidencefrom
generalisedtonicclonicseizurestherewasnosignificantdifference
intheproportionofparticipantsachievingseizurefreedom
oxcarbazepine.Therewerefewsignificantdifferencesinthedirect
evidenceforefficacyandformostcomparisonsintheIPDanalyses.
Howeversodiumvalproatewassignificantlybetterthan
Phenobarbital,topiramateandcarbamazepinefortimeto
withdrawal.Phenytoinandsodiumvalproateweresignificantly
betterthanlamotriginefortimetofirstseizure.Phenytoin,
carbamazepine,sodiumvalproateandtopiramatewere
significantlybetterthanlamotriginefortimeto12month
remission.
TheGDGconsensusopinionwasthatthereisatendencyfordrugs
suchascarbamazepineandoxcarbazepinetoexacerbatecertain
seizurestypessuchasmyoclonicandabsenceseizures.Therefore,
theyconcludedthatalthoughthereisevidencetosupporttherole
ofcarbamazepineandoxcarbazepineinthetreatmentof
generalisedtonicclonicseizures,theyshouldonlybeconsidered
onceotherseizuretypeshavehadtimetopresentfollowing
initiationoffirstlinedrugs.TheGDGconsideredthatduetothe
psychiatricandbehaviouralchangesreportedintheSANADtrial,it
isnotadrugoffirstchoicewhereotherdrugsareaseffective.
Sodiumvalproateandhighdoselamotrigineareassociatedwithan
increasedriskofneuraltubeandotherdefectsandsothewomen
ofchildbearingageshouldbeinformedofsuchrisks.
TheGDGconsideredthatthebenefitsofreductionofseizures
outweighedtheadverseeffects.
Economicconsiderations Noeconomicevidencewasidentifiedintheliteratureandno
economicevaluationwasundertakentoinformthecost
effectivenessoffirstlineAEDsusedtotreatnewlydiagnosed
patientsexperiencinggeneralisedtonicclonicseizures.TheGDG
TheEpilepsies
434
feltthatanextrapolationfromtheSANADstudypopulationwith
generalisedepilepsiestoapopulationwithgeneralisedtonicclonic
seizureswasappropriateandthattherelativecosteffectivenessof
sodiumvalproatewasunlikelytobedifferentbetweenthese
groups.
Sodiumvalproateemergedasthedrugmostlikelytobecost
oftheSANADtrial
161
.Greaterweightwasgiventothisanalysisas
thereductioninseizurefrequency,particularlyofgeneralised
tonicclonicseizures,isconsideredtobethemostimportant
clinicaloutcome.Thepublishedeconomicevidenceforthecost
effectivenessoflamotrigineinpatientswithIGEwasoutofdate
andaroughreestimationbasedoncurrentcostswasundertaken.
Thenewresultsindicatethatlamotriginehasthelowesttotalcost
andisalsolikelytobeconsideredcosteffective.
Qualityofevidence
Theevidenceforepilepsywithgeneralisedtonicclonicseizures
onlyhadanoverallGRADEqualityratingoflowtoverylow.The
evidencecamefromalarge,pragmatic,unblindedtrialandno
significantdifferenceswerefound.Furtherevidencewas
extrapolatedfromtheGTCseizuresdata.Therewasalackof
powerofstudiesparticularlywithregardtoadverseevents.The
overallqualityofevidencewasverylowwithpoorreportingof
randomisationmethods,allocationconcealmentandmanystudies
wereunblinded.Therewasahighdropoutrateinthemajorityof
studies.Timetoeventdatawasavailablefromanetworkmeta
analysisofindividualpatientdata.
Otherconsiderations Diagnostic,demographicanddosingconsiderationsmustbetaken
intoconsideration.Phenytoinwasshowntohaveefficacybutthe
GDGconsideredittohaveaveryhighadverseeventsprofile.
musttobetakenintoconsiderationwhenintroducingor
increaseinthelamotriginedose.TheGDGisawarethat
levetiracetamiswidelyusedincurrentpracticeasafirstline
monotherapyinthetreatmentofnewlydiagnosedgeneralised
tonicclonicseizures,particularlywhensodiumvalproateis
unsuitable.Therewasmuchdebateastowhetherlevetiracetam
shouldberecommendedalongsideorinpreferencetolamotrigine,
especiallyconsideringlamotriginespotentialtoexacerbate
myoclonicseizuresthatmayormaynothavepreviouslypresented.
However,theGDGsfinaldecisionnottorecommend
levetiracetamasfirstlinemonotherapyinthisgroupofpatientsis
inaccordancewithNICEmethodologywhichstatesthatuseforan
indicationforwhichtheproductdoesnothaveamarketing
authorizationmayberecommendedifthereisclearevidenceto
supportthis.Levetiracetamisnotcurrentlylicensedas
monotherapyinthetreatmentofgeneralisedepilepsiesandno
randomisedcontrolledtrialevidencewasidentifiedto
demonstrateitseffectivenesscomparedtoalternativedrugs.
TheEpilepsies
435
Furthermore,intheabsenceofsuchevidenceitisimpossibleto
measurelevetiracetamsrelativecosteffectivenesscomparedto
otherdemonstrablycosteffectiveAEDsusedtotreattonicclonic
seizures.Consequently,levetiracetamisrecommendedas
adjunctivetherapy,whereevidenceisavailabletodemonstrateits
clinicalandcosteffectiveness.
TheGDGconsidereditimportanttodirectusersoftheguidelineto
therecommendationsforthetreatmentofmyoclonicseizuresand
juvenilemyoclonicepilepsywhereotherdrugs,including
topiramateandlevetiracetam,maybeconsideredifsodium
valproateorlamotrigineareunsuitable.
Recommendation
butbeaware
oftheriskofexacerbatingmyoclonicorabsenceseizures.
[new2012]
outcomes
Inchildren,youngpeopleandadults,seizurefreedomand
adverseeffectswereconsideredtobethemostimportant
outcomes.
benefitsandharms
Therewaslimitedevidenceavailableforfirstlinetreatmentof
newlydiagnosedepilepsywithGTCseizuresonlysotheevidence
wasextrapolatedfromtheGTCseizuresreview.
Inadults,therewasnosignificantdifferenceinseizurefreedom
oxcarbazepine.Inchildrentherewasnodifferencebetween
sodiumvalproateandcarbamazepine.
TheGDGconsensusopinionreflectswidespreadclinical
experiencethatdrugssuchascarbamazepineandoxcarbazepine
mayexacerbatecertainseizurestypes,andspecificallymyoclonic
andabsenceseizures.Therefore,theyconcludedthatalthough
thereisevidencetosupporttheroleofcarbamazepineand
oxcarbazepineinthetreatmentofgeneralisedtonicclonic
seizures,theyshouldonlybeconsideredonceotherseizuretypes
havehadtimetopresentfollowinginitiationoffirstlinedrugs.
Carbamazepineandoxcarbazepineareassociatedwithan
increasedriskofcongenitaldefectsandsothewomenofchild
bearingageshouldbeinformedofsuchrisks.
Economicconsiderations Noeconomicevidenceforcarbamazepineoroxcarbazepineina
populationwithepilepsywithgeneralisedtonicclonicseizures
onlyorgeneralisedepilepsywasavailable.TheGDGconsidered
theirrelativecosteffectivenesscomparedtosodiumvalproate
andlamotrigineinpopulationswithfocalepilepsyandconcluded
thatitmightbebroadlysimilar.However,theGDGconsidered
thatcarbamazepineandoxcarbazepinemayaggravateother
seizuretypes,thusnegativelyimpactingpatientqualityoflifeand
potentiallyincreasingNHSresourceuse.Onthisbasis,theyfeltit
wouldbeamoreefficientuseofNHSresourcestoconsiderthese
TheEpilepsies
436
Recommendation
butbeaware
oftheriskofexacerbatingmyoclonicorabsenceseizures.
[new2012]
AEDsonlyafterlamotrigineorsodiumvalproatehavebeentried
andotherseizuretypeshavehadtimetopresent.
Qualityofevidence Diagnostic,demographicanddosingconsiderationsmustbetaken
intoconsideration.Therewasalackofpowerofstudies
evidencewasverylowwithpoorreportingofrandomisation
studies.
Adjunctivetreatmentinchildren,youngpeopleandadultswithnewlydiagnosedepilepsywith
generalisedtonicclonic(GTC)seizuresonly
Recommendation
141. Offerclobazam
,lamotrigine,levetiracetam,sodium
valproateortopiramateasadjunctivetreatmenttochildren,
youngpeopleandadultswithepilepsywithGTCseizuresonly,
iffirstlinetreatments(seerecommendation139and140)are
ineffectiveornottolerated.Beawareofteratogenicrisksof
outcomes
Themostimportantoutcomeswereadverseeffectsand50%
benefitsandharms
Therewasnoevidenceavailableforadjunctivetreatmentofnewly
diagnosedepilepsywithgeneralisedtonicclonicseizuresonlyso
theevidencewasextrapolatedfromtheGTCseizuresreview.
Lamotrigine,levetiracetamandtopiramateasadjunctivetherapies
allsignificantlyreducedseizurefrequencybyatleast50%when
comparedtoplacebo.Therewassignificantlymoreseizure
freedomwithclobazamandlevetiracetamcomparedtoplacebo
butlamotrigineandtopiramateshowednodifferencecomparedto
placebo.
Therewasnosignificantdifferenceforanyadverseevent,
withdrawalduetoadverseeventsorlackofefficacyfor
lamotrigine,levetiracetamandtopiramateadjunctivetherapies
Economicconsiderations TheGDGconsideredtheevidencefromtheeconomicevaluation
undertakenfortheguidelineinwhichlamotrigineemergedasa
verycosteffectiveadjunctivetherapyinpatientsexperiencing
refractorygeneralisedtonicclonicseizures.Iflamotriginehad
beentriedpreviously,levetiracetamwasalsolikelytobeacost
effectiveadjunctiveAED.Topiramatewasnotshowntobecost
effective,butintheeventthatotheralternativesfailtoproduce
TheEpilepsies
437
thedesiredreductioninseizurefrequency,theGDGfeltthatit
shouldbeconsidered.Clobazamwasnotevaluatedaspartofthe
costeffectivenessanalysisbecausetheclinicalstudiesdidnot
reportalloutcomesnecessaryforinclusion.However,theGDG
consideredthatitseffectivenesscomparedtoplaceboanditssmall
unitcostislikelytomakeitcosteffective.
Qualityofevidence
intoconsideration.Therewasalackofpowerinthestudies
particularlywithregardtosideeffects.Theoverallqualityof
evidencewaslow:somehadnodetailsofrandomisationor
allocationconcealment,highdropoutrateoraverysmallsample
size.
Otherconsiderations Thereisapharmacodynamicinteractionbetweenlevetiracetam
andcarbamazepineandbetweenlamotrigineandcarbamazepine
sosideeffectsmaybeenhanced.
mustbetakenintoconsiderationwhenintroducingorwithdrawing
breakthroughseizures.Thereshouldbeaconcomitantincreasein
lamotriginedose.Careshouldbetakenwhenwithdrawing
clobazamwithaslowwithdrawalupto46minviewoftheriskof
withdrawalseizures.Topiramatemayaffectphenytoinlevels.
Childhoodabsenceepilepsy,juvenileabsenceepilepsyandotherabsenceepilepsy
syndromes
Firstlinetreatmentinchildren,youngpeopleandadultswithchildhoodabsenceepilepsy,
juvenileabsenceepilepsyandotherabsenceepilepsysyndromes
Recommendation
142. Offerethosuximideorsodiumvalproateasfirstline
treatmenttochildren,youngpeopleandadultswithabsence
syndromes.IfthereisahighriskofGTCseizures,offersodium
valproatefirst,unlessitisunsuitable.Beawareofteratogenic
2012]
outcomes
benefitsandharms
TheGDGconsideredthatthedifferentsideeffectprofilesof
sodiumvalproateandethosuximidecouldnotdeterminewhich
oneofthesedrugsbeusedfirst,althoughtheremaybeindividual
factorsthatmaydeterminethechoiceofonedrugovertheother.
Significantlymorepatientsonsodiumvalproateshoweddifficulties
inattention.Cautionshouldbeusedwithsodiumvalproateingirls
ofchildbearingpotential.
TheEpilepsies
438
generalisedabsenceseizures.AtthetimetheGDGconsideredthe
evidence,thereweresignificantcostdifferencesbetween
ethosuximidecapsules(0.68per250mg)andethosuximidesyrup
(0.108to0.165per250mg).AccordingtothePrescriptionCost
Analysisof2008,99.7%ofethosuximideprescriptionswerefor
syrup.Whenethosuximidesyrupisprescribed,thedailyunitcosts
ofethosuximideandsodiumvalproateareverycomparable.On
thisbasistheGDGconsideredthatclinicaljudgementandpatient
choiceshouldguidethedecisionforwhichofthelikelycost
effectivedrugstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasretrievedfroma
doubleblindedstudyofaverygoodquality,adoubleblindedof
unclear/lowqualityandfromtwounblindedstudies.Ablinded
studywasfoundforjuvenileabsenceepilepsyforlevetiracetam
versusplacebowhichfoundnosignificantdifferences,however
thisstudylasted14days.
Otherconsiderations
TheEpilepsies
439
Recommendation
ifethosuximideandsodiumvalproateare
unsuitable,ineffectiveornottolerated.[new2012]
outcomes
benefitsandharms
TheGDGconsideredthatthesideeffectprofileoflamotriginewas
morefavourable,butitsefficacywaslessfavourable,when
comparedwithethosuximideandsodiumvalproate.
generalisedabsenceseizures.TheGDGconsideredthatat
recommendeddailydoseslamotrigine,sodiumvalproateand
ethosuximidesyruphavebroadlysimilarunitcosts,butthat
lamotriginewaslesseffectivethansodiumvalproateand
ethosuximideinthispopulation.Butifsodiumvalproateand/or
ethosuximidedonotproducetheclinicalbenefitdesired,theGDG
feltthatlamotriginewasapotentiallycosteffectivealternative.
Qualityofevidence
Theevidencebasewasretrievedfromadoubleblindedstudyof
verygoodqualityandfromtwounblindedstudies.
Otherconsiderations
TheGDGconsideredthatthedataavailableforCAEcanbe
extrapolatedtothoseindividualswithJAE,andthosewhohave
generalisedabsenceseizuresbutwhodonotmeetthecriteriafor
childhoodabsenceepilepsyorjuvenileabsenceepilepsy.
TheEpilepsies
440
Adjunctivetreatmentinchildren,youngpeopleandadultswithchildhoodabsence
epilepsy,juvenileabsenceepilepsyandotherabsenceepilepsysyndromes
Recommendation
144. IftwofirstlineAEDs(seerecommendations142and143)are
ineffectiveinchildren,youngpeopleandadultswithabsence
epilepsysyndromes,consideracombinationoftwoofthese
threeAEDsasadjunctivetreatment:ethosuximide,
lamotrigine
orsodiumvalproate.Beawareoftheteratogenic
2012]
outcomes
TheGDGconsideredseizurefreedom,reductioninseizure
frequencyandadverseeventstobethemostimportantoutcomes
benefitsandharms
TheGDGconsideredthatifatleasttwoofthefirstlineAEDshave
failedtoproducethedesiredeffect(seizurefreedom),thenitis
appropriatetotryawelltoleratedcombinationoftwoofthem.
Althoughthereisnoevidenceinthispopulationspecifically,GDG
experienceisthatanyofthethreecanbesafelycombinedand
giventheireffectivenessasindividualdrugs,theexpectationisthat
theyareeffectiveincombination.
Cautionshouldbeusedwithsodiumvalproateingirlsofchild
bearingpotential.
NoeconomicevaluationswereavailabletoinformtheGDGonthe
costeffectivenessofanyAEDsusedasmonotherapyoradjunctive
therapytotreatCAE,JAEorgeneralisedabsenceseizures.There
wasnoevidencetosuggestthatanyspecificcombinationof
ethosuximide,lamotrigineandsodiumvalproateisbetterthan
another.Anycombinationisexpectedtobebroadlysimilarin
termsofcostaswell.Therefore,theGDGconsideredthatclinical
judgementandpatientchoiceshouldguidethedecisionforwhich
ofthelikelycosteffectiveAEDcombinationstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasextrapolatedfrom
theevidenceforeachofthesedrugsasmonotherapyinnewly
diagnosedabsenceseizuresandwassupportedbyGDGconsensus.
TheEpilepsies
441
Recommendation
,
clonazepam,levetiracetam
,topiramate
orzonisamide
.
[new2012]
outcomes
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepam,topiramate
orzonisamidewerepossiblealternativesinaccordancewith
tertiaryepilepsycare.TheGDGconsidereditimportantto
mentionthesedrugsaspotentialoptionstooffertopatients
betweenthetimeofreferraltoandconsultationwithatertiary
specialist.Itwasthoughtthatthesearesomeofthedrugsthata
tertiaryspecialistmightuse,basingthedecisiononclinical
experiencetreatingpatientswithchildhoodabsenceepilepsy,
juvenileabsenceepilepsyandotherabsenceepilepsysyndromes.
Therewasnodifferencefoundfortopiramateandsodium
valproatefortimetofirstseizurefromsodiumvalproatebut
topiramatehadashortertimetowithdrawal.Duetothe
psychiatricandbehaviouralchangesreportedintheSANADtrial,
theGDGfeltitisnotadrugoffirstchoicewhereotherdrugsare
suitable.
withorreferredtoatertiaryepilepsyspecialist.Whilstthismay
bemorecostly,theGDGconsideredthatthiswasworthwhileas
thesepatientsmayrequiremorecomplexcareinordertoachieve
asuccessfuloutcome.Withregardtothespecificdrugslisted
here,therewerenoeconomicevaluationsavailabletoinformthe
GDGonthecosteffectivenessofclobazam,clonazepam,
topiramateorzonisamide.
Qualityofevidence Therewasnoevidenceavailableforchildhoodabsenceepilepsy,
juvenileabsenceepilepsyandotherabsenceepilepsysyndromes
forclobazam,clonazepamandzonisamidesothesedrugswere
addedtothisrecommendationbasedonGDGclinicalexpertise.
Therewaslimitedevidenceavailablefortopiramatefromalarge
unblindedpragmatictrial.
Otherconsiderations Careshouldbetakenwithclobazamandclonazepamduetoa
slowwithdrawalupto46minviewoftheriskofwithdrawal
seizures.
TheEpilepsies
442
Recommendation
outcomes
benefitsandharms
Clinicalpracticesuggeststhatabsenceseizurescanbeaggravated
bythesemedications,andcancompromisecognitionwithriskof
nonconvulsivestatusepilepticus.TheGDGfeltthatuseofthese
harm.
use.
TheEpilepsies
443
10.14 Otherepilepsysyndromes
Thereremainfurtherepilepsysyndromeswithrecognizablecharacteristicelectroclinicalfeaturesin
whichnaturalhistoryandprognosisareknown.Manyofthesesyndromesarerareandevidence
basewithregardtotheirmanagementlacking.Inviewofthis,inmanyindividualsmanagementmay
becontinuedundertertiarypaediatricneurologycare.
Clinicalevidence
Noevidencewasretrievedforotherepilepsysyndromes.
Recommendation
147. Refertoatertiarypaediatricepilepsyspecialistallchildren
andyoungpeoplewithcontinuousspikeandwaveduring
slowsleep,LandauKleffnersyndromeormyoclonicastatic
epilepsy.[new2012]
outcomes
Manychildrenwiththesesyndromesareveryunlikelytoachieve
seizurefreedom.Thechildrenusuallyhaveadditionallearning
disabilities.Optimalseizurecontrolwithoutunacceptableside
effectswasthereforethemostimportantoutcomeforthis
recommendation.
benefitsandharms
NoRCTstudieswerefoundandthereforethisrecommendationis
basedontheconsensusopinionoftheGDG.Thesesyndromes,if
untreated,canleadtosignificantcognitiveimpairmentand
reducededucationalpotential,withahighriskofcomorbidities.
TheGDGfeltthatitwasimportantthatthesechildrenbereferred
toatertiaryepilepsyspecialisttomanagetheircare.
ingroupswithCSWS,LKSorMAE.
Qualityofevidence NoRCTdatawasavailableforanyofthesesyndromes.This
recommendationisbasedonGDGconsensusopinion.
TheEpilepsies
444
10.14.3.1 EpilepsySyndromes
WhataretheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswith
onsetinchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome?
Whythisisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidenceforthemost
multicentrerandomisedcontrolledcomparativetrialswithcentralisednationaldata
collection
theketogenicdietasoneoftherandomisedtreatments
anattempttoobtaindataonpharmacoresistance
thepossibilityofincludingallchildrenwithspecificepilepsysyndromesforconsiderationin
thetrial.
10.15 Prolongedseizuresandconvulsivestatusepilepticus
Generalisedseizures(TC,tonic,clonic)
Inthepast,statusepilepticus(SE)wasdefinedasaseizurelastinglongerthan30minutesortwoor
moreseizureswithin30minuteswithoutareturntothebaselinelevelofconsciousnessbetween
seizures.Morerecently,thedefinitionevolvedtobeaseizurelongerthan5minutesortwoormore
seizureswithoutareturnofconsciousnessbetweenseizures
327
.Serialseizuresaredefinedas3or
moretonicclonicseizuresinanhour.
SEcanbedividedintoanumberofsubtypes,eitherbyseizuretypeorbyresponsetotreatment.
ClinicalSEcanbeeitherfocalorgeneralised,andeachofthesetypescanbedividedbyduration:
earlySE(530minutes)
establishedSE(>30minutes)
refractorySE(seizurespersistdespitetreatmentwithadequatedosesoftwoorthreeinitial
anticonvulsantmedications)
327
.
TheBNFstatesthat:immediatemeasurestomanagestatusepilepticusincludepositioningthe
patienttoavoidinjury,supportingrespirationincludingtheprovisionofhighflowoxygen,
maintainingbloodpressure,andthecorrectionofanyhypoglycaemia.Parenteralthiamineshouldbe
consideredifalcoholabuseissuspected;pyridoxineshouldbegivenifthestatusepilepticusiscaused
bypyridoxinedeficiency.
TheEpilepsies
445
ConvulsiveSEshouldbetreatedurgentlywithintravenouslorazepam,repeatedonceafter10
minutesifseizuresrecur.Intravenousdiazepamiseffectivebutitisassociatedwithahighriskof
thrombophlebitis(reducedbyusinganemulsionformulation).Absorptionofdiazepamfrom
intramuscularinjectionorfromsuppositoriesistooslowfortreatmentofstatusepilepticus.
Intravenousclonazepamcanalsobeusedasanalternative.
Wherefacilitiesforresuscitationarenotimmediatelyavailable,diazepamcanbeadministered
rectallyormidazolamcanbegivenintothebuccalcavity.
Itisimportantthatifseizuresrecurorfailtorespondwithin30minutes,phenytoinsodium,
fosphenytoin,orphenobarbitalsodiumshouldbeused.Ifthesemeasuresfailtocontrolseizure
within60minutes,anaesthesiawiththiopental,midazolam,orinadults,anonbarbiturate
anaestheticsuchaspropofol[unlicensedindication],shouldbeinstitutedwithfullintensivecare
support.
Phenytoinsodiummaybegivenbyslowintravenousinjection,withECGmonitoring,followedbythe
maintenancedosage.Intramuscularuseofphenytoinisnotrecommended(absorptionisslowand
erratic).
Intheory,fosphenytoin,aprodrugofphenytoin,whengivenintravenouslycausesfewerinjection
sitereactionsthanphenytoin.IntravenousadministrationrequiresECGmonitoring.Althoughitcan
alsobegivenintramuscularly,absorptionistooslowbythisroutefortreatmentofstatusepilepticus.
Dosesoffosphenytoinshouldbeexpressedintermsofphenytoinsodium.
Paraldehydestillhasalimitedplace.Itremainsavaluableanticonvulsantbutinlimitedsituationsas
itmayproveeffectivewhenotheranticonvulsantshavefailedtoterminatetheseizure.Given
rectallyitcauseslittlerespiratorydepressionandisthereforeusefulwherefacilitiesforresuscitation
arepoor.
Forthisreviewweincludedpeoplewithprolongedseizuresandconvulsivestatusepilepticus.
peoplewithprolongedseizuresandconvulsivestatusepilepticus.Thefollowinginterventionswere
includedinoursearch;lorazepam,diazepam,midazolam,clonazepam,paraldehyde,phenytoin,
fosphenytoin,phenobarbital,propofol,thiopental,isoflurane,sodiumvalproate,levetiracetam,
phentobarbitalandlidocaine.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwo
ormoreofthesetreatments(orplacebo).
Belowisamatrixshowingwhereevidencewasidentifiedseparatelyforadultsandchildren.Abox
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinadults(community)
Placebo
Intravenous
lorazepam
1
328
TheEpilepsies
446
Intravenous
diazepam
1
328

Rectal/Intravenou
sdiazepam
1
328

Pla RIV
LZP
IVDZP RIV
DZP
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinchildren(community)
Placebo
Buccal/intranasal
midazolam

Rectal/Intravenous
diazepam
4
329331
,
332

Pla B/INMDM Rectal/IV
diazepam
Matrixoftheevidenceforthetreatmentofacuterepetitiveseizures(childrenandadults)
Placebo
Diazepamgel
2*
333,334

Pla Diazepamgel
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinadults(initial
treatmentinAccidentandEmergency(A+E))
Placebo
Intravenous
lorazepam

Intravenous
diazepam

1
335
Intravenous
diazepamand
phenytoin

1
336

Intravenous
phenytoin

1
336
1
336

TheEpilepsies
447

Intravenous
phenobarbital

1
336
1
336
1
336

Intravenous
phenobarbital
andphenytoin

1
337

Intravenous
sodiumvalproate
2*
338,
339

Pla IVLZP IVDZP IVDZP,
PHT
IV
PHT
IV
PBT
IVPBT,
PHT
IV
VPA
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinchildren(initial
treatmentinER)
Placebo
Buccal/intranasal
midazolam

Rectal/Intravenous
diazepam
3
329331

Intramuscular
midazolam

Intravenous
diazepam
1
340

Intranasal
lorazepam

Intramuscular
paraldehyde
1
341

Pla BINMDM RIV
DZP
IMMDM IV
DZP
INLZP IM
PLH
Matrixoftheevidenceforthetreatmentofrefractorystatusepilepticusinchildren
Placebo
Intravenous
diazepam

Intranasal
lorazepam

Sodium
valproate
infusion
1
342

TheEpilepsies
448
Placebo(Pla)Diazepamgel(DZPgel)Intravenouslorazepam(IVLZP)Rectal/Intravenouslorazepam(IVLZP)
Intravenousdiazepam(IVDZP)Rectal/Intravenousdiazepam(RIVDZP)Intravenousphenytoin(IVPHT)
Intravenousdiazepamandphenytoin(IVDZP,PHT)Intravenousphenobarbital(IVPBT)
Intravenousphenobarbitalandphenytoin(IVPBT,PHT)Intravenoussodiumvalproate(IVVPA)
Buccal/Intranasalmidazolam(BINMDM)Rectal/Intravenousdiazepam(RIVDZP)Intramuscularmidazolam(IMMDM)
Intranasallorazepam(INLZP)Rectalsodiumvalproate(RVPA)Intramuscularparaldehyde(IMPLH)Intravenousdiazepam(IVDZP)
Intravenouspropofol(IVPRF)Intravenousmidazolam(IVMDM)Sodiumvalproateinfusion(VPAIF)Diazepaminfusion(DZPIF)
Midazolaminfusion(MDMIF)
10.15.4 AEDsforthetreatmentofprolongedseizuresandconvulsivestatusepilepticusinthe
community
148. Caremustbetakentosecurethechild,youngpersonoradultsairwayandassesshisorher
respiratoryandcardiacfunction.[2004]
149. Treatmentshouldbeadministeredbytrainedclinicalpersonnelor,ifspecifiedbyan
individuallyagreedprotocoldrawnupwiththespecialist,byfamilymembersorcarerswith
appropriatetraining.[2004]
10.15.4.1 Intravenousdiazepamversusplacebo
Clinicalevidence
Evidencestatements
Midazolam
infusion

Diazepam
infusion
1
343

Rectalsodium
evaporate
1
344

Intravenous
Midazolam

Intravenous
lidocaine
1
345

Intravenous
propofol
1
346

Pla IVDZP IN
LZP
VPA
IF
MDMIF DZP
IF
RVPA IV
MDM
IVLID IVPRF
TheEpilepsies
449
Significantlymorepatientsreceivingintravenousdiazepamwereseizurefreecomparedtoplacebo.
(HIGHQUALITY)
Intravenousdiazepamwasassociatedwithasignificantlylowerincidenceofdeaththanplacebo,
howeverthereisuncertaintyofthemagnitudeoftheeffect.(MODERATEQUALITY)
Nostatisticallysignificantdifferencebetweenintravenousdiazepamandplacebofortheincidence
of:
hypotension,cardiacdysrhythmiaorrespiratoryintervention(MODERATEQUALITY)
theproportionofparticipantsmovedtotheICU(MODERATEQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIVdiazepamtoplaceboinpatientswithconvulsivestatus
epilepticuswasidentified.
timetocessationofseizure.
10.15.4.2 Intravenouslorazepamversusplacebo
Clinicalevidence
Evidencestatements
Significantlymorepatientsreceivingintravenouslorazepamwereseizurefreecomparedtoplacebo.
(HIGHQUALITY)
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandplacebofor:
incidenceofhypotension,cardiacdysrhythmiaorrespiratoryintervention(LOWQUALITY)
proportionofparticipantsmovedtotheICU(LOWQUALITY)
death(LOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoplaceboinpatientswithconvulsivestatus
TheEpilepsies
450
timetocessationofseizure.
10.15.4.3 Intravenouslorazepamversus/intravenousdiazepam
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenouslorazepamandintravenousdiazepaminachieving
seizurefreedom.(MODERATEQUALITY)
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamfor
theincidenceofthefollowingevents:
proportionofparticipantsmovedtotheICU(LOWQUALITY)
hypotension,cardiacdysrhythmiaorrespiratoryintervention(LOWQUALITY)
death(LOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglorazepamtodiazepaminpatientswithconvulsivestatus
Therewerenostudiesthatreportedtimetocessationofseizures.
10.15.5 Treatmentofprolongedseizuresandconvulsivestatusepilepticusinchildren(community)
10.15.5.1 Buccalmidazolamversusrectaldiazepam
Clinicalevidence
Evidencestatements
TheEpilepsies
451
Asignificantlylowerproportionofparticipantsinbuccalmidazolamhadseizurerecurrencewithinan
hourcomparedtoparticipantsinrectaldiazepam(MODERATEQUALITY)
Nosignificantdifferencebetweenbuccalmidazolamandrectaldiazepamfor:
theproportionofseizurefreeparticipants(VERYLOWQUALITY)
theproportionofparticipantswithseizurerecurrencewithin24hours(LOWQUALITY)
thetimetocessationofseizures
thetimetocessationofseizureswithinonehour
thetimetocessationofseizureswithin24hours
Nosignificantdifferencebetweenbuccalmidazolamandrectaldiazepamfortheproportionof
childrenrequiredintubation(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingbuccalmidazolamtorectaldiazepaminpatientswithstatus
10.15.5.2 Intranasalmidazolamversusrectaldiazepam
Clinicalevidence
Evidencestatements
Asignificantlylowerproportionofparticipantsinrectaldiazepamwereseizurefreewithin10
minutescomparedtoparticipantsinintranasalmidazolam,howeverthereisuncertaintyoverthe
magnitudeofclinicaleffect(VERYLOWQUALITY)
Nosignificantdifferencebetweenintranasalmidazolamandrectaldiazepamfortimetocessationof
seizures.(MODERATEQUALITY)
Costeffectiveness
Noeconomicevidencecomparingintranasalmidazolamtorectaldiazepaminpatientswithstatus
TheEpilepsies
452
incidenceofadverseevents.
10.15.6 Treatmentofacuterepetitiveseizures(childrenandadults)
10.15.6.1 Diazepamgelversusplacebo
Clinicalevidence
Evidencestatements
Nosignificantdifferencewasfoundbetweendiazepamgelandplacebofortheproportionofseizure
freeparticipants.(LOWQUALITY)
Significantlymoreparticipantsreceivingdiazepamgelexperiencedsomnolencethanplacebo.(LOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingdiazepamgeltoplaceboinpatientswithacuterepetitiveseizures
wasidentified.
10.15.7 Treatmentofconvulsivestatusepilepticusinadultsinhospitals
10.15.7.1 Intravenousdiazepamandphenytoinversusintravenousphenobarbital
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenintravenousdiazepamwithphenytoinand
phenobarbitalinachievingseizurefreedom.(VERYLOWQUALITY)
TheEpilepsies
453
Nosignificantdifferencebetweenintravenousdiazepamwithphenytoinandphenobarbitalforthe
incidenceof:
hypoventilation(VERYLOWQUALITY)
hypotension(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIVdiazepamandphenytointoIVphenobarbitalinpatientswith
convulsivestatusepilepticuswasidentified.
10.15.7.2 IVDiazepamandphenytoinversusIVphenobarbitalandoptionalphenytoin
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsinintravenousphenobarbitalandoptionalphenytoinwereseizure
freecomparedtointravenousdiazepamandphenytoin;howeverthereisuncertaintyinthe
magnitudeoftheclinicaleffect.(LOWQUALITY)
Nosignificantdifferencebetweenintravenousdiazepamwithphenytoinandphenobarbitaland
optionalphenytoinfortimetocessationofseizures.
Nosignificantdifferencebetweenintravenousdiazepamwithphenytoinandintravenous
phenobarbitalwithoptionalphenytoinfortheincidenceof:
intubation(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIVdiazepamandphenytointoIVphenobarbitalandoptional
phenytoininpatientswithconvulsivestatusepilepticuswasidentified.
TheEpilepsies
454
10.15.7.3 IVDiazepamandphenytoinversusIVphenytoin
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenintravenousdiazepamwithphenytoinandphenytoin
inachievingseizurefreedom.(VERYLOWQUALITY)
Nostatisticallysignificantdifferencebetweenintravenousdiazepamwithphenytoinandphenytoin
fortheincidenceof:
hypotension.(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIVdiazepamandphenytointoIVphenytoininpatientswith
10.15.7.4 IVlorazepamversusIVdiazepam
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamforthe
proportionofseizurefreeparticipants(afteronedoseofthedrug).(LOWQUALITY)
Nosignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamforthe
proportionofseizurefreeparticipants(afterseconddoseofthedrug).(VERYLOWQUALITY)
Nosignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamfortimeto
cessationofseizures.(VERYLOWQUALITY)
TheEpilepsies
455
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoIVdiazepaminpatientswithconvulsivestatus
Therewerenostudiesthatreportedincidenceofadverseevents.
10.15.7.5 IVlorazepamversusIVdiazepamplusphenytoin
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamand
phenytoininachievingseizurefreedom.(VERYLOWQUALITY)
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamand
phenytoinfortheincidenceof:
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoIVdiazepamandphenytoininpatientswith
10.15.7.6 IVlorazepamversusIVphenytoin
Clinicalevidence
Evidencestatements
TheEpilepsies
456
Significantlymoreparticipantsinintravenouslorazepamexperiencedseizurefreedomcomparedto
intravenousphenytoin,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOW
QUALITY)
Nosignificantdifferencebetweenintravenouslorazepamandintravenousphenytoinforthe
incidenceof:
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoIVphenytoininpatientswithconvulsivestatus
therewerenostudiesthatreported:
timetocessationofseizures.
10.15.7.7 IVphenytoinversusIVPhenobarbital
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenousphenytoinandintravenousphenobarbitalforthe
proportionofparticipantsachievingseizurefreedom.(VERYLOWQUALITY)
Nosignificantdifferencebetweenintravenousphenytoinandintravenousphenobarbitalforthe
incidenceof:
Costeffectiveness
NoeconomicevidencecomparingIVphenytointoIVphenobarbitalinpatientswithconvulsivestatus
TheEpilepsies
457
10.15.7.8 IVphenytoinversusIVsodiumvalproate
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenousphenytoinandintravenoussodiumvalproateforthe
seizurerecurrence(within12hours).(VERYLOWQUALITY)
incidenceof:
cardiacsideeffects(VERYLOWQUALITY)
respiratorysideeffects(VERYLOWQUALITY)
liverdysfunction(VERYLOWQUALITY)
death(VERYLOWQUALITY).
Costeffectiveness
NoeconomicevidencecomparingIVphenytointoIVsodiumvalproateinpatientswithconvulsive
statusepilepticuswasidentified.
10.15.7.9 IVphenytoinversusIVfosphenytoin
Clinicalevidence
Nostudieswereidentified.
Fourcostminimisationstudies
347350
comparingintravenousphenytointointravenousfosphenytoin
wereindentifiedintheeconomicliteraturesearch.Allfourwereexcludedfromthehealtheconomic
evidencereviewduetothefactthattheyhadpoorapplicabilityandpotentiallyserious
methodologicallimitations.SeeeconomicevidencetableinappendixMfordetails.
Despitethepoorapplicabilityandpotentiallyseriouslimitationsofthesestudies,theyhighlight
importanteconomicconsiderations.Thestudiesassumethatphenytoinandfosphenytoinare
bioequivalentandhaveequivalentefficacy,thereforethereshouldbenobetweendrugdifferences
intermsoftheproportionofpatientsachievingseizurecontrol.Thus,differencesintreatment
relatedcostsbetweenthedrugsarelikelytobedrivenbythetimespentintheemergency
departmentandthemanagementofdrugrelatedadverseevents.Thestudiesassertthat
fosphenytoincanbeadministeredmorerapidlyandthatithasalowerincidenceofadverseevents
TheEpilepsies
458
thanphenytoin.Consequently,costdifferencesbasedontheseoutcomesmayfavourfosphenytoin.
However,withoutpublishedevidencespecificallycomparingfosphenytoinwithphenytoininpatients
withconvulsivestatusepilepticus,anyextrapolationoftheresultsconductedinotherpatientgroups
mustbetreatedwithcaution.
10.15.8 Treatmentofconvulsivestatusepilepticusinchildren
10.15.8.1 Intranasalmidazolamversusrectal/IVdiazepam
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintranasalmidazolamandintravenous/rectaldiazepamfor:
theproportionofseizurefreeparticipantswithin10minutes(VERYLOWQUALITY)
theproportionofseizurefreeparticipantswithin5minutes(MODERATEQUALITY)
thetimetocessationofseizures.
Costeffectiveness
NoeconomicevidencecomparingbuccalorintranasalmidazolamtorectalorIVdiazepaminchildren
withconvulsivestatusepilepticuswasidentified.
Therewerenostudiesthatreportedanincidenceofadverseevents.
10.15.8.2 IntramuscularmidazolamversusIVdiazepam
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintramuscularmidazolamandintravenousdiazepamforthe
proportionofseizurefreeparticipants(VERYLOWQUALITY)
TheEpilepsies
459
Nosignificantdifferencebetweenintramuscularmidazolamandintravenousdiazepamforthe
recurrenceofseizures.(VERYLOWQUALITY)
Nosignificantdifferencebetweenintramuscularmidazolamandintravenousdiazepamforthetime
tocessationofseizures(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingintramuscularmidazolamtoIVdiazepaminpatientswith
10.15.8.3 Intranasallorazepamversusintramuscularparaldehyde
Clinicalevidence
Evidencestatements
SignificantlyfewerparticipantswhoreceivedintranasallorazepamrequiredtwoormoreAEDs
comparedtoparticipantsinintramuscularparaldehydegroup.(MODERATEQUALITY)
Nosignificantdifferencebetweenintranasallorazepamandintramuscularparaldehydeforthe
Nosignificantdifferencebetweenintranasallorazepamandintramuscularparaldehydeforthe
seizurerecurrencewithin24hours.(VERYLOWQUALITY)
Nosignificantdifferencebetweenintranasallorazepamandintramuscularparaldehydeforthetime
tocessationofseizures.
Ahigherproportionofparticipantstakingintranasallorazepamhadadropindiastolicbloodpressure
byatleast5mmHg,howeverthereisuncertaintyinthemagnitudeofthisclinicaleffect.(LOW
QUALITY)
Adverseeventsnonstatisticallysignificantresults
Nostatisticallysignificantdifferencebetweenintranasallorazepamandintramuscularparaldehyde
forthe:
incidenceofdeath(VERYLOWQUALITY)
dropinsystolicbloodpressurebyatleast5mmHg(VERYLOWQUALITY).
Costeffectiveness
TheEpilepsies
460
Noeconomicevidencecomparingintranasallorazepamtointramuscularparaldehydeinchildren
withconvulsivestatusepilepticuswasidentified.
10.15.8.4 IV/rectallorazepamversusIV/rectaldiazepam
Clinicalevidence
Evidencestatements
NosignificantdifferencebetweenIV/rectallorazepamandIV/rectaldiazepamforthetimeto
cessationofseizures.
NostatisticallysignificantdifferencebetweenIV/rectallorazepamandIv/rectaldiazepamforthe:
incidenceofrespiratorydepression(VERYLOWQUALITY)
theproportionofchildrenrequiringintensivecare(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIV/rectallorazepamandIV/rectaldiazepaminchildrenwith
10.15.8.5 IV/rectallorazepamversusIV/rectaldiazepamandphenytoin
Clinicalevidence
Evidencestatements
NosignificantdifferencebetweenIV/rectallorazepamandIV/rectaldiazepamandphenytoinforthe
proportionofseizurefreeparticipants.(MODERATEQUALITY)
NodifferencebetweenintranasalIV/rectallorazepamandIV/rectaldiazepamandphenytoinforthe
seizurerecurrencewithin18hours.(VERYLOWQUALITY)
TheEpilepsies
461
NostatisticallysignificantdifferencebetweenIV/rectallorazepamandIv/rectaldiazepamand
phenytoinfortheincidenceofrespiratorydepression(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingIV/rectallorazepamandIV/rectaldiazepamandphenytoinin
childrenwithconvulsivestatusepilepticuswasidentified.
10.15.8.6 BuccalmidazolamversusIVdiazepam
Clinicalevidence
Evidencestatements
TimetocessationofseizureswassignificantlylessinchildrenreceivingIVdiazepamcomparedto
childrenreceivingbuccalmidazolam.(LOWQUALITY)
NosignificantdifferencebetweenbuccalmidazolamandIVdiazepamfortheproportionofseizure
freeparticipants.(MODERATEQUALITY)
NodifferencebetweenintranasalbuccalmidazolamandIVdiazepamfortheincidenceofthe
CNSdepression
respiratorydepression
apnea
cardiacarrhythmia.
Costeffectiveness
NoeconomicevidencecomparingbuccalmidazolamandIVdiazepaminchildrenwithconvulsive
10.15.8.7 Buccalmidazolamversusrectaldiazepam
Clinicalevidence
TheEpilepsies
462
Evidencestatements
Nosignificantdifferencebetweenbuccalmidazolamandrectaldiazepamforthetimetocessationof
seizures.
Nosignificantdifferencebetweenbuccalmidazolamandrectaldiazepamfortheproportionof
childrenrequiredintubation(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingbuccalmidazolamandrectaldiazepaminchildrenwithconvulsive
10.15.9 Treatmentofrefractorystatusepilepticus
150. RegularAEDsshouldbecontinuedatoptimaldosesandthereasonsforstatusepilepticus
shouldbeinvestigated.[2004]
151. Asthetreatmentpathwayprogresses,theexpertiseofananaesthetist/intensivistshouldbe
sought.[2004]
152. Ifeitherthewholeprotocolorintensivecareisrequiredthetertiaryserviceshouldbe
consulted.[2004]
153. Anindividualtreatmentpathwayshouldbeformulatedforchildren,youngpeopleandadults
whohaverecurrentconvulsivestatusepilepticus.[2004]
10.15.9.1 Treatmentofrefractorystatusepilepticusinchildren
10.15.9.2 IVDiazepamversussodiumvalproateinfusion
Clinicalevidence
Evidencestatements
Sodiumvalproateinfusionhadasignificantlylowertimetocessationofseizuresthanintravenous
diazepam;howeverthereisuncertaintyoverthemagnitudeofthisclinicaleffect.(MODERATE
QUALITY)
TheEpilepsies
463
Nostatisticallysignificantdifferencebetweenintravenousdiazepamandsodiumvalproateinfusion
Significantlymoreparticipantsintheintravenousdiazepamgroupexperiencedrespiratory
depressioncomparedtothesodiumvalproategroup;howeverthereisuncertaintyoverthe
magnitudeofthisclinicaleffect.(VERYLOWQUALITY)
Significantlymoreparticipantsintheintravenousdiazepamgroupexperiencedhypotension
comparedtothesodiumvalproategroup;howeverthereisuncertaintyoverthemagnitudeofthis
Costeffectiveness
NoeconomicevidencecomparingIVdiazepamtosodiumvalproateinfusioninchildrenwith
refractorystatusepilepticuswasidentified.
10.15.9.3 Midazolaminfusionversusdiazepaminfusion
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenmidazolaminfusionanddiazepaminfusionfor:
theproportionofseizurefreedom(VERYLOWQUALITY)
timetocessationofseizures(VERYLOWQUALITY)
Nosignificantdifferencebetweenmidazolaminfusionanddiazepaminfusionfortheincidenceof:
thenumberofpatientsrequiringintubation(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingmidazolaminfusiontodiazepaminfusioninchildrenwith
Therewerenostudiesthatreportedthetimetocessationofseizures.
TheEpilepsies
464
10.15.9.4 MidazolaminfusionversusIVlidocaine
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenmidazolaminfusionandintravenouslidocaineforthe
Nostatisticallysignificantdifferencebetweenmidazolaminfusionandintravenouslidocaineforthe
incidenceof:
hypothermia(VERYLOWQUALITY)
acidosis(VERYLOWQUALITY)
ventilationrequirement(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingmidazolaminfusiontoIVlidocaineinchildrenwithrefractory
10.15.9.5 IVMidazolamversusrectalsodiumvalproate
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenmidazolaminfusionandrectalsodiumvalproatefortheproportion
ofseizurefreeparticipants.(VERYLOWQUALITY)
Nosignificantdifferencebetweenmidazolaminfusionandrectalsodiumvalproateforthetimeto
cessationofseizures.(VERYLOWQUALITY)
TheEpilepsies
465
Costeffectiveness
NoeconomicevidencecomparingIVmidazolamtorectalsodiumvalproateinchildrenwith
10.15.9.6 IVMidazolamversusIVpropofol
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenousmidazolaminfusionandintravenouspropofolforthe
Nosignificantdifferencebetweenintravenousmidazolaminfusionandintravenouspropofolforthe
incidenceof:
elevatedserumcreatinephosphokinase(VERYLOWQUALITY)
serumtriglyceridecholesterol(VERYLOWQUALITY)
apnoea(VERYLOWQUALITY).
Costeffectiveness
NoeconomicevidencecomparingIVmidazolamtoIVpropofolinchildrenwithrefractorystatus

TheEpilepsies
466
Firstlinetreatmentforchildren,youngpeopleandadultswithprolongedorrepeated
generalised,convulsive(tonicclonic,tonicorclonic)seizuresinthecommunity
Recommendation
154. Giveimmediateemergencycareandtreatmenttochildren,
youngpeopleandadultswhohaveprolonged(lasting5
minutesormore)orrepeated(threeormoreinanhour)
convulsiveseizuresinthecommunity.[2012]
outcomes
Cessationofseizuresisthemostimportantoutcome.Allevidence
hasusedthecriterionthataprolongedseizureisonethat
continuesforlongerthan5minutes.
benefitsandharms
Thereisariskofseriousimmediateandlongtermmorbidityand
mortalityifconvulsiveseizurenotterminatedby30minutesand
thereforetreatmentisrequiredurgently.
Economicconsiderations Urgentandappropriatecarewithconsequentsuccessful
treatmentdeliveredinthecommunityislikelytoreducevisitsto
A+Eandsubsequenthospitalisation.Earlycontrolofseizuresmay
alsoreducethemortalityandmorbidityrisksassociatedwith
prolongedtonicclonicseizures.
Qualityofevidence Thisrecommendationwasbasedontheconsensusopinionofthe
GDG.
Otherconsiderations Nofurtherevidencehasbeenpublishedtooverturnthe
recommendationfromthepreviouseditionofthisguideline
(2004).TheGDGrecognisesthatinsomesituationsapersonalised
careplanmaydifferfromtheabove.
TheEpilepsies
467
Recommendation
155. Onlyprescribe
buccalmidazolamorrectaldiazepam
for
useinthecommunityforchildren,youngpeopleandadults
whohavehadapreviousepisodeofprolongedorserial
convulsiveseizures.[new2012]
outcomes
Cessationofseizures,adverseeffectsanddrugtolerancearethe
mostimportantoutcomes.Itisimportantthatpatientsrequiring
emergencymedicationshaveaccesstothem,butitisalso
importantthattheynotbeoverprescribed,particularlyingroups
unlikelytorequirethem.
benefitsandharms
Overuseofbuccalmidazolamorotherrescue(emergency)
benzodiazepinescanleadtodrugtoleranceandincidenceof
adverseevents,suchassedationandrespiratorysuppression.The
GDGconsideredthatoverandpotentiallyinappropriate
prescriptionofemergencybenzodiazepinesshouldnotbeusedas
ameanstoalleviateindividual,parentalorcarersanxiety.
relativecosteffectivenessofselectiveorgeneralprescribingof
emergencybenzodiazepines.However,theGDGconsideredit
importanttodirectclinicianstomoreappropriateandmore
selectiveprescribingoftheseemergencymedicationsastheycan
beverycostlyandcarryseriousrisksifadministeredincorrectly.
Targetingtheirusageinthecommunitytothosepatientswitha
knownriskofprolongedorrepeatedconvulsiveseizureshasthe
potentialtosaveNHSresourcesbothintermsofthemedications
themselvesandintermsofavoidinghospitalisationdueto
inappropriateadministration.
Qualityofevidence Therewasnoclinicalevidence.Thisrecommendationwasbased
onconsensusopinionoftheGDG.
Otherconsiderations Theremaybeaccessandequalityissuesarisingfromtheexclusion
ofchildreninneedofemergencybenzodiazepinesfromnormal
activitiesduetoalackoftrainedpersonnel.
Inlinewithnormalstandardsinemergencycare.
TheEpilepsies
468
Recommendation
156. Administerbuccalmidazolamas
firstlinetreatmentin
children,youngpeopleandadultswithprolongedorrepeated
seizuresinthecommunity.Administerrectaldiazepam
if
preferredorifbuccalmidazolam
isnotavailable.If
intravenousaccessisalreadyestablishedandresuscitation
facilitiesareavailable,administerintravenouslorazepam.
[new2012]
outcomes
Cessationofseizureswasconsideredthemostimportantoutcome.
Easeandacceptabilityofadministrationofbuccalmidazolamis
alsoimportant.
benefitsandharms
Buccalmidazolamismoreeffectiveandmoredignifiedandsocially
acceptablethanrectaldiazepam.Theadvantageoflorazepamover
diazepamliesonthepharmacokineticsanditslongerhalflife;
howeverIVlorazapamisonlyappropriateinsituationswhereIV
accessisestablishedandresuscitationfacilitiesareavailable.
Therisksofpotentialsideeffectsofthesedrugsareoutweighedby
theneedtostopseizuresrapidly
relativecosteffectivenessofbuccalmidazolam,rectaldiazepam
andIVlorazepam.Acquisitioncostsofbuccalmidazolamare
greaterthanrectaldiazepam,buttheclinicalevidenceshowsitto
bemoreeffectiveintermsofcontrollingseizures,preventing
recurrenceofseizuresandrequiringfeweradditionalrescueor
emergencydrugstotreattheinitialepisode.Inadditiontobeing
moreeffective,buccalmidazolamalsohaspracticaladvantages
comparedtorectaldiazepambecausethebuccalrouteprovidesa
simplerandmoredignifiedmethodofadministration.Delaysto
effectiveadministrationoftreatmentatthisacutestagecanhavea
veryimportantimpactonsubsequentcostsandoutcomesforthis
groupofpatients.
Qualityofevidence Inadults,thequalityofevidenceusewasmoderateasitwasa
doubleblindedstudywithgoodrandomizationandallocation
concealment.Thisstudyincludedintravenousrouteof
administrationbutwasdeliveredbyparamedicsoutofhospital.In
children,threeRCTswereincluded;twodoubleblindedandone
unblinded.Thereweredifferentroutesofdrugadministration
betweenstudies.
Otherconsiderations None

Inlinewithnormalstandardsinemergencycare
TheEpilepsies
469
Recommendation
157. Dependingonresponsetotreatment,thepersonssituation
andanypersonalisedcareplan,callanambulance,particularly
if:
theseizureiscontinuing5minutesaftertheemergency
medicationhasbeenadministered
thepersonhasahistoryoffrequentepisodesofserial
seizuresorhasconvulsivestatusepilepticus,orthisisthe
firstepisoderequiringemergencytreatmentor
thereareconcernsordifficultiesmonitoringthepersons
airway,breathing,circulationorothervitalsigns.[new
2012]
outcomes
Rapidcessationofseizuresisthemostimportantoutcome.All
evidencehasusedthecriterionthataprolongedseizureisthat
continuingbeyond5minutes.
benefitsandharms
Thereisariskofseriousimmediateandlongtermmorbidityand
mortalityifaconvulsiveseizurenotterminatedby30minutes.
Thereforetheaimshouldbeforindividualtoreachhospitalbefore
thisdurationhaspassed.Thereisanunknownriskofsideeffects
onfirsttimeadministrationofemergencymedicationanda
possibilitythatfurtherseizureswillrequiretreatmentwith
intravenousmedication
Economicconsiderations Promptandeffectivetreatmentofprolongedandrepeated
seizuresislikelytoleadtolessandshorterdurationof
hospitalisation.
Qualityofevidence Thereisnoclinicalevidence.Thisrecommendationwasbasedon
theconsensusopinionoftheGDG.
Otherconsiderations Thisrecommendationisamodificationofoneinthefirsteditionof
thisguideline(2004),astheviewoftheGDGwasthatfurther
clarificationwasrequiredaspartofthemanagementofconvulsive
statusepilepticus.
TheEpilepsies
470
Treatmentforchildren,youngpeopleandadultswithconvulsivestatusepilepticusinhospital
Recommendation
158. Forchildren,youngpeopleandadultswithongoing
generalisedtonicclonicseizures(convulsivestatus
epilepticus)whoareinhospital,immediately:
secureairway
givehighconcentrationoxygen
assesscardiacandrespiratoryfunction
checkbloodglucoselevelsand
secureintravenousaccessinalargevein.
SeealsothesuggestedprotocolsinappendixK.[new2012]
outcomes
Statusepilepticusshouldberegardedasamedicalemergencyand
consequentlybasicresuscitationguidelinesforinitialtreatment
shouldbefollowed.Further,hypoglycaemiashouldbeexcludedas
acauseofageneralisedtonicclonicseizure.
benefitsandharms
Basicresuscitativeproceduresshouldnotdelaythetreatment
targetedatcessationoftheseizures.
Economicconsiderations Noeconomicdatawasavailabletoinformontherelativecost
effectivenessofemergencymeasures.Howeverbasicresuscitative
proceduresarerecommendedtoreduceintensivecareadmission
andlongertermmorbidity.
Qualityofevidence Thisrecommendationwasbasedontheconsensusopinionofthe
GDG.
Otherconsiderations Modifiedrecommendationfromoriginalguideline(GPP),asthe
viewoftheGDGwasthatfurtherclarificationwasrequiredaspart
ofthemanagementofconvulsivestatusepilepticus.
TheEpilepsies
471
Recommendation
159. Administerintravenouslorazepamasfirstlinetreatmentin
hospitalinchildren,youngpeopleandadultswithongoing
generalisedtonicclonicseizures(convulsivestatus
epilepticus).Administerintravenousdiazepamifintravenous
lorazepamisunavailable,orusebuccalmidazolamifunableto
secureimmediateintravenousaccess.Administeramaximum
oftwodosesofthefirstlinetreatment(includingprehospital
treatment).SeealsothesuggestedprotocolsinappendixK.
[new2012]
outcomes
Cessationofseizureswasconsideredthemostimportantoutcome.
benefitsandharms
ThebenefitsoutweighharmsfortheuseofIVlorazepam.The
advantageoflorazepamoverotherAEDsliesinits
pharmacokineticsasittendstoworkquicklyandforalongertime
(longerhalflife)andconsequentlypatientsneedfeweradditional
rescuedrugs.Howevertherehavebeenissueswiththeavailability
oflorazepamandinthisinstancetheGDGopinionwasthat
intravenousdiazepamwouldbeasuitablealternative.Therewas
nosignificantdifferencefoundbetweenintravenouslorazepam
andintravenousdiazepamintheevidence.
relativecosteffectivenessofdifferentemergencyAEDsusedto
treatpatientswithstatusepilepticusoncetheyhavereached
hospital.Atcurrentprice,lorazepamisaninexpensivedrug(0.35
per4mgdose)andtheevidenceshowedittobeeffective
comparedtoarangeofotherdrugs(diazepam,paraldehyde,
phenytoin).Midazolamwasshowntobeeffectiveinthe
communitysetting,anditsgreatereffectivenessoverdiazepam
almostreachedstatisticalsignificanceinthehospitalsetting.Its
greatercostcomparedtolorazepammaybejustifiedifmore
immediateaccessisrequired.
Qualityofevidence Theevidenceforthisrecommendationwasretrievedfromtwo
doubleblindedRCTsofpoorquality,withoutinformationon
randomizationandallocationconcealment.
Otherconsiderations Duetothepotentialriskofrespiratorycompromiseassociated
withtheuseofbenzodiazepines,facilitiesforsupporting
respiratorydepressionorfailureshouldbeimmediatelyavailable.
Nofurtherpublishedevidenceoverturnstheoriginal
recommendation.
TheEpilepsies
472
Recommendation
160. Ifseizurescontinue,administerintravenousphenobarbitalor
phenytoinassecondlinetreatmentinhospitalinchildren,
youngpeopleandadultswithongoinggeneralisedtonic
clonicseizures(convulsivestatusepilepticus).Seealsothe
suggestedprotocolsinappendixK.[new2012]
outcomes
Cessationofseizureswasconsideredtobethemostimportant
outcome.
benefitsandharms
Phenytoinwithbenzodiazepineswasequallyeffectiveas
phenobarbital.BothemergencyAEDSareequalintermsofadverse
events.
relativecosteffectivenessofdifferentemergencyAEDsusedto
treatpatientswithconvulsivestatusepilepticusoncetheyhave
reachedhospital.TheGDGconsideredthattheunitcostofiv
phenobarbital,phenytoinorsodiumvalproatewasbroadlysimilar
andthateachhavesimilarefficacyprofiles.Electrocardiographic
(ECG)andbloodpressuremonitoringmustaccompanythe
intravenousadministrationofphenytoin.
Qualityofevidence Thequalityofevidenceforthisrecommendationwasmoderateto
poor;onestudywasdoubleblindedstudywithnoallocation
concealmentandthreestudieswereunblindedwithpartialorno
allocationconcealment.
TheEpilepsies
473
Refractoryconvulsivestatusepilepticus
Recommendation
161. FollowthesuggestedprotocolsinappendixKfortreating
refractoryconvulsivestatusepilepticusinsecondarycare.
[2012]
outcomes
Notapplicable.
benefitsandharms
Statusepilepticusisamedicalemergencyandmustbetreatedas
soonaspossibletostoptheseizuresinordertoavoidbrain
damageandinsomecasesdeath.Refractoryconvulsivestatus
epilepticusiswhereseizureshavenotbeencontrolledwithinitial
treatment,thereforetheneedtostoptheseizuresisveryurgent.
Economicconsiderations Notapplicable.
Qualityofevidence ThisrecommendationwasbasedonGDGconsensus.The
childrensprotocolwasproducedbytheBritishPaediatric
NeurologyAssociationandtheadultsprotocolwascompiledbythe
firstepilepsyguidelinedevelopmentgroupin2004.Theadults
protocolhasfurtherbeenupdatedbythecurrentepilepsy
guidelinedevelopmentgroup.
Otherconsiderations TheGDGconsideredtheneedforemergencyprotocolstobein
placetoensurepatientsreceivethecorrectmedicationtostopthe
seizuresasquicklyaspossible.
TheEpilepsies
474
Recommendation
,propofol
orthiopental
sodium
totreat
adultswithrefractoryconvulsivestatus
epilepticus.Adequatemonitoring,includingbloodlevelsof
AEDs,andcriticallifesystemssupportarerequired.Seealso
thesuggestedprotocolsinappendixK.[new2012]
outcomes
TheGDGconsideredcessationofseizuresandtimetocessationof
seizuresasthemostimportantoutcomes.
benefitsandharms
Useofthiopentalsodiumrequiresadequatecriticalcaresupport
withcontinuous(oratleastdaily)EEGmonitoringtoensureseizure
cessation.Continualreviewrequiredofdurationoftreatmentvers
usseizurecessationwithpropofolorthiopental.
Economicconsiderations Noeconomicdatawasavailabletoinformcosteffectivenessof
treatment.Shorterdurationofstatusepilepticuslikelytoreduce
longtermintensivecareadmissionandlongtermsequelae.
Qualityofevidence NoRCTevidencewasfoundforadultrefractorypopulation.The
recommendationonpropofolandthiopentalwasbasedonGDG
expertiseandtherecommendationonmidazolamwasbasedon
evidencederivedfromchildrenpopulation.
Otherconsiderations TheGDGstatedthatnofurtherpublishedevidenceoverturnsthe
originalrecommendation.
Inlinewithnormalstandardsinemergencycare.
TheEpilepsies
475

Recommendation
orthiopentalsodium
to
treatchildrenandyoungpeoplewithrefractoryconvulsive
statusepilepticus.Adequatemonitoring,includingblood
levelsofAEDs,andcriticallifesystemssupportarerequired.
SeealsothesuggestedprotocolsinappendixK.[2012]
outcomes
TheGDGconsideredcessationofseizuresandtimetocessationof
seizuresasthemostimportantoutcome.
benefitsandharms
Useofthiopentalsodiumrequiresadequatecriticalcaresupport
withcontinuous(oratleastdaily)EEGmonitoringtoensureseizure
cessation.Continualreviewrequiredofdurationoftreatmentvs
seizurecessation.Propofolnotrecommendedfortreatmentof
statusepilepticusinchildren.
Economicconsiderations Noeconomicdatawasavailabletoinformcosteffectivenessof
treatment.Shorterdurationofstatusepilepticuslikelytoreduce
longtermintensivecareadmissionandlongtermsequelae.
Qualityofevidence Therecommendationofmidazolamwasretrievedfrom5un
blindedRCTsofpoorquality.Therecommendationofthiopental
wasbasedonGDGexpertiseandconsensus,includingBritish
PaediatricNeurologyAssociationpreparedguidelines(appendixC)
Otherconsiderations TheGDGstatedthatnofurtherpublishedevidenceoverturnsthe
originalrecommendation.
10.15.11.1 Treatmentofconvulsivestatusepilepticus(i.e.notjustrefractory)
Whatisthemosteffectiveandsafestanticonvulsanttotreat:
a. established(usuallylastinglongerthan30minutes)convulsivestatusepilepticus
b. refractoryconvulsivestatusepilepticus
Whyisthisimportant?
Convulsivestatusepilepticus(CSE)shouldbetreatedasanemergency.Themostimportantaspectof
treatmentistotrytostoptheseizure.Prompt,successfultreatmentofCSEavoidstheneedfor
admissiontoanintensivecareunit(ICU).Themostcommonlyusedmedicationisphenytoin.This
shouldbeusedwithcareandclosemonitoringbecauseoftheriskofhypotensionandcardiac
arrhythmia.Sodiumvalproateandlevetiracetamarepotentiallyaseffectiveandsaferalternatives
butthereareverylimitedcomparativedata.
CSEthatisrefractorytofirstlinetreatment(RCSE)israreandoftencomplicatedbyirreversible
neurologicalandintellectualsequelae,includingdeath.Reasonsforthesecomplicationsincludethe
underlyingcauseofRCSE,itsdurationandmanagement.Themajority,ifnotallpatientswithRCSE
TheEpilepsies
476
aremanagedinanICU.TherearenoagreeddrugsortreatmentprotocolsfortreatingRCSE.The
threemostcommonlyusedanticonvulsantsarethiopentalsodium,midazolamandpropofol
(propofolisrarelyusedinchildren).Dataontreatmentinchildren,youngpeopleandadultsare
limitedandanecdotal.Arecentlycompleted2yearauditofeveryoneyoungerthan16yearswith
RCSEtreatedinanICUinEngland,WalesandScotlandwillprovideuniqueepidemiologicaldataon
paediatricRCSE,itscausesandcurrentmanagement.Thesedatacouldbeusedtodesigna
randomisedcontrolledtrial(RCT)ofspecificdrugtreatmentsandprotocols.
Theresearchshouldinclude
amulticentrerandomisedcomparativetrialofintravenouslevetiracetam,sodiumvalproateand
phenytoinininitialtreatmentofstatusepilepticus
amulticentreRCToftreatmentofrefractorystatusepilepticusinICUs,includingmidazolamand
thiopentalsodium(andpropofolinadults)
primaryoutcomeofcessationofCSE
secondaryoutcomesincludingrecurrencewithinadesignatedperiod(probably12hours),
mortalityandmorbidity
costdataincludingtreatmentcostsanddaysinintensivecare.
10.16 Nonconvulsivestatusepilepticus
164. Nonconvulsivestatusepilepticusisuncommonandmanagementislessurgent.Asuggested
guidelinecanbefoundinappendixK.[2004]
Nonconvulsivestatusepilepticusisanunderdiagnosedsyndromewherebyclinicallysubtleseizures
resultinadepressedlevelofconsciousness.Nonconvulsivestatusepilepticusisdividedintotwo
mainsubgroups:generalisednonconvulsivestatusandfocalstatus.Nonconvulsivestatusepilepticus
isatermusedtodenotearangeofconditionsinwhichelectrographicseizureactivityisprolonged
andresultsinnonconvulsiveclinicalsymptomsincludingchangeinbehaviorandor
awarenesss.SubtlegeneralisedconvulsivestatuswasdefinedinthestudyconductedbyTreimanetal
336
asthestageofgeneralisedconvulsivestatuswhenthepatientisincontinuouscomabutonly
subtlemotorconvulsionsareseen.Tomsonetal
351
definednonconvulsivestatusepilepticusasa
stateofimpairedconsciousnessorresponsivenesswithoutconvulsionslastingatleast60minutes.
Forthisclinicalquestion,weadditionallysearchedforanyobservationalstudiesasitwasinitially
thoughtthatnorandomisedevidenceonnonconvulsivestatusepilepticuswasavailable.
TheBNFstatesthat:theurgencytotreatnonconvulsivestatusepilepticusdependsuponthe
severityofthepatientscondition.Ifthereisincompletelossofawareness,usualoralantiepileptic
therapyshouldbecontinuedorrestarted.Patientswhofailtorespondtooralantiepileptictherapy
orhavecompletelackofawarenesscanbetreatedinthesamewayasforconvulsivestatus
epilepticus,althoughanaesthesiaisrarelyneeded.
NoRCTs(blindedorunblinded)werefoundforthisevidencereviewsoobservationalstudieswere
includedasastudydesignprovidinglowerqualityofevidence.
TheEpilepsies
477
Forthisreviewweincludedadultsandchildrenwithnonconvulsivestatusepilepticus.Theonly
outcomemeasuresincludedinthisreviewwere:theproportionofparticipantswhoseseizurewas
stopped(seizurefree),durationoftimetocessationofseizure,andincidenceofadverseevents.
10.16.3 AEDsforthetreatmentofnonconvulsiveStatusEpilepticus(observationalstudy)
10.16.3.1 IVdiazepamversusIVclonazepam
Clinicalevidence
Thirtytwopatientswithnonconvulsivestatusepilepticuswerediagnosedatthedepartmentof
NeurologyattheSoderHospitalinSweden,aspartofaprospectivestudycarriedoutbyTomsonet
al1.Nonconvulsivestatusepilepticuswasdefinedasastateofimpairedconsciousnessor
responsivenesswithoutconvulsionslastingatleast60minutes.AnictalEEGshowingcontinuousor
almostcontinuousseizureactivitywasrequiredforinclusion.Themedianageatonsetwas51years.
Tenpatientshadstatusastheirfirstepilepticmanifestation,butmostpatientshadaprevioushistory
ofepilepsy.Themediandurationofepilepsyatonsetofstatuswas4years.
ThreepatientsrecoveredspontaneouslyfromstatusduringEEGrecording.Twentyfivepatientswere
treatedwithIVdiazepam(510mg),3patientsweretreatedwithclonazepam(1mg),and1withboth.
TheeffectonEEGandclinicalstatewasimmediateandlastingin10patientsandimmediatebut
followedbyrecurrenceofthestatuswithinhoursin18patients.In1,noimmediateeffectwas
evidence.In8patients,aslastingeffectwasnotachieveduntilIVphenytoin(250500mg)wasadded.
Nonewrecommendationsweredeveloped.
10.16.5 Genericprescribing
Thiswasnotakeyclinicalquestion,andthereforenoevidencereviewwasundertaken.Thisisan
importantissueintheprescribingofAEDs,andprescriberisadvisedtoconsulttheBNFforspecific
advicefordifferentAEDS.Forexample,forcarbamazepine,theBNFstatesthatdifferent
preparationsmayvaryinbioavailability;toavoidreducedeffectorexcessivesideeffects,itmaybe
prudenttoavoidchangingtheformulation;forphenytoin,thatonthebasisofsingledosetests
therearenoclinicallyrelevantdifferencesinbioavailabilitybetweenavailablephenytoinsodium
tabletsandcapsulesbuttheremaybeapharmacokineticbasisformaintainingthesamebrandof
phenytoininsomepatients.
352
10.17 Whenshouldanindividualwithepilepsybereferredfor
assessmentinatertiarycentre?
Individualswithpoorlycontrolledepilepsymaybenefitfromreferraltoatertiarycentreandfurther
assessment,whichmayincludeassessmentforepilepsysurgery.Theexactnumberofindividuals
whomaybenefitfromsuchareferralisunclear.Thereis,however,evidencethatepilepsysurgery
TheEpilepsies
478
maybeunderusedasatreatmentmodalityforpoorlycontrolledepilepsyintheUKowingtosuitable
individualsnotbeingreferredtoatertiarycentre.
353
165. Allchildren,youngpeopleandadultswithepilepsyshouldhaveaccessviatheirspecialisttoa
tertiaryservicewhencircumstancesrequire.[2004]
166. Thetertiaryserviceshouldincludeamultidisciplinaryteam,experiencedintheassessmentof
children,youngpeopleandadultswithcomplexepilepsy,andhaveadequateaccessto
investigationsandtreatmentbybothmedicalandsurgicalmeans.[2004]
167. Theexpertiseofmultidisciplinaryteamsinvolvedinmanagingcomplexepilepsyshould
includepsychology,psychiatry,socialwork,occupationaltherapy,counselling,neuroradiology,
clinicalnursespecialists,neurophysiology,neurology,neurosurgeryandneuroanaesthesia.
TeamsshouldhaveMRIandvideotelemetryfacilitiesavailabletothem.[2004]
168. Theneurosurgeoninthemultidisciplinaryteamshouldhavespecialistexperienceofand/or
traininginepilepsysurgeryandhaveaccesstoinvasiveEEGrecordingfacilities.[2004]
169. Ifseizuresarenotcontrolledand/orthereisdiagnosticuncertaintyortreatmentfailure,
ee
forfurther
assessment.Referralshouldbeconsideredwhenoneormoreofthefollowingcriteriaare
present:
theepilepsyisnotcontrolledwithmedicationwithin2years
managementisunsuccessfulaftertwodrugs
thechildisagedunder2years
achild,youngpersonoradultexperiences,orisatriskof,unacceptablesideeffectsfrom
medication
thereisaunilateralstructurallesion
thereispsychologicaland/orpsychiatriccomorbidity
thereisdiagnosticdoubtastothenatureoftheseizuresand/orseizuresyndrome.[2004]
170. Inchildren,thediagnosisandmanagementofepilepsywithinthefirstfewyearsoflifemaybe
extremelychallenging.Forthisreason,childrenwithsuspectedepilepsyshouldbereferredto
tertiaryservicesearly,becauseoftheprofounddevelopmental,behaviouralandpsychological
effectsthatmaybeassociatedwithcontinuingseizures.[2004]
171. Behaviouralordevelopmentalregressionorinabilitytoidentifytheepilepsysyndromeina
child,youngpersonoradultshouldresultinimmediatereferraltotertiaryservices.[2004]
172. Children,youngpeopleandadultswithspecificsyndromessuchasSturgeWebersyndrome,
thehemisphericsyndromes,Rasmussensencephalitisandhypothalamichamartomashouldbe
referredtoatertiaryepilepsyservice.[2004]
173. Psychiatriccomorbidityand/ornegativebaselineinvestigationsshouldnotbea
contraindicationforreferraltoatertiaryservice
ff
.[2004]
Evidencestatement
ee
ff
Inthisrecommendation,centrehasbeenreplacedwithserviceforconsistencyacrosstherecommendations.
TheEpilepsies
479
Intemporallobeepilepsy,surgeryissuperiortoprolongedmedicaltherapy.(Ib)
Details
ThissectionwasnotsubjecttoafullevidencereviewforreasonsgiveninChapterTwo.
Chilcott1999
354
Onesystematicreviewwasidentified.OneRCT(comparingdifferentformsofsurgery)and6case
serieswereincludedinthisreview.Noquantitativeanalysiswaspossible,butanarrativesummary
waspresented.
Theauthorsconcludedthattherearestrongargumentsforensuringthatallyoungpeoplewith
medicallyrefractoryseizuresareevaluatedbyaneurologist/paediatricianorotherspecialistwithan
interestinepilepsy,sothatallsuitablepatientsareidentifiedandmaybeofferedsurgery.Surgery
hasahighchanceofcontrollingepilepsyforthesepeople,allowingthemtocompletetheir
education,integratesocially,achieveemploymentandavoidalifetimeofantiepilepticdrugsand
hospitalattendance.
354
Wiebe2001
355
ThisRCTassessedtheefficacyandsafetyofsurgeryinadultswithpoorlycontrolledtemporallobe
epilepsy.
Eightyparticipantswererandomlyassignedtoeithersurgery(n=40)ortreatmentwithAEDsfor12
months(n=40).Theprimaryoutcomewasfreedomfromseizuresthatimpairedawarenessofself
andsurroundings.Theanalysiswasdoneonanintentiontotreatbasis.
Ofthe36whounderwentsurgery,58%werefreefromseizuresthatimpairedawarenessat12
months,comparedwith8%inthemedicalgroup(p<0.001).38%ofthoseinthesurgicalgroup
comparedwith3%inthemedicalgroupwereseizurefree,includingauras,at12months(p<0.001).
OneindividualdiedofSUDEPinthemedicalgroup.Nodeathsoccurredinthesurgicalgroup.
Theauthorssuggestedthatthistrialsupportedthebeliefthatprolongedtrialsofmedicationwere
futileandthatpeoplewithtemporallobeepilepsyshouldbeevaluatedforsurgery.However,they
stressthatthequestionofwhetherearlysurgerywassuperiortomedicaltherapywasnot
addressed.
Healtheconomics
Clinicalresearchhasshownthatsurgeryisadesirableoptionfortreatmentofcertainformsof
refractoryepilepsy.Thereisalackofhealtheconomicsevidenceintheassessmentofsurgeryinthe
managementofepilepsy.Onereviewwitheconomicanalysisandoneeconomicevaluationon
epilepsysurgerywerefound.However,norandomisedcontrolledtrialalongsideaneconomic
evaluationwasfound.
Chilcottandcolleagues1999
354
Theobjectiveofthissystematicreviewistoassesstheeffectivenessofsurgeryforepilepsyin
childrenandadultswithrefractoryepilepsy.
Theauthorsidentifiedfourstudiesinvestigatingtheeconomicsofsurgeryforrefractoryepilepsy,but
theydidnotidentifyanypublishedstudyconcerningthecostandeffectivenessofsurgeryfor
epilepsyintheUK.
Thestudyreported:
thecostsofevaluationandassessmentofcandidatesforsurgery,andthecostsofsurgery
TheEpilepsies
480
thecostsoflongtermmedicalmanagementwithandwithoutsurgery
thecosteffectivenessintermsofcostperseizurefreeyearofsurgeryforepilepsycomparedto
usualcare
comparisonsofresultswithother,internationalstudies.
Threestagestotheevaluationweredistinguished:
Stage1
toidentifyindividualssuitableforfurtherinvestigation.Thiscoveredoutpatientvisits,MRIscan,
EEG,neuropsychologytests.
Stage2
toidentifyindividualswithasingletemporalorextratemporallobefocussuitableforfurther
investigation.ItcoveredEEGtelemetry(withorwithoutictalspecificarea/PET)
Stage3
todeterminethesafetyandappropriatenessofsurgery.ItcoveredWadatest,intracranial
monitoring,andfurtherEEGtelemetry.
TheanalysiswasfromtheperspectiveoftheNHS,althoughitalsoincludedaqualitativediscussionof
theindirectcostsassociatedwithepilepsy.CostsareinUK1998poundssterling.Thecost
effectivenessanalysistookafifteenyeartimehorizonanddiscountedbothcostsandbenefitsat6%
perannum.
Onewayandmultiwaysensitivityanalyseswereincluded.
Theauthorsconcludedthat:
Inatypicalheathauthority,between3and14surgicalcandidateswouldbeidentifiedperyear.The
costperpersongoingforwardtosurgeryforassessmentwasestimatedbetween10kand16k.
Thetotalcostperyearforassessmentandsurgeryforahealthyauthoritywasestimatedbetween
60kand220k.
Theaveragecostperpersonperyearofactiveepilepsy(atleastoneseizureinthelastyear)is
530comparedto75forinactiveepilepsy.
Surgeryresultsinapproximately65%ofindividualsundergoingtemporalloberesection(TLR)and
45%ofindividualsundergoingextratemporalresection(ETR)becomingseizurefree.10%of
thoseonmedicalmanagementbecomeseizurefree.
Thebasecasemodelmarginalcostperseizurefreeyearcomparedtomedicalmanagementis
2291forTLRindividuals,4,096forETRindividualsand2,329forallsurgicalcases.
Theresultswereparticularlysensitivetothetimehorizonusedintheanalysis.
Keyparametersweretheeffectivenessofsurgeryandtheproportionofthosewhoproceedto
surgeryfromneuropsychologicaltesting.
Theauthorsrecognisedthattherewasalackoftrialdata,alikelyreferralbiasincaseseriesfromthe
majorcentres,differencesinpracticebetweentrialcentres.ThereviewalsostatesthataNHI
consensusstatementrecognisedthattherewasalackofevidencelinkingseizurecontroltoqualityof
lifeandidentifiedthisasanareaforresearch.Forthesereasons,thereviewshouldbeviewedwith
caution.
TheEpilepsies
Theroleofnondrugtreatmentsinthemanagementoftheepilepsies
481
11 Theroleofnondrugtreatmentsinthe
managementoftheepilepsies
11.1 Introduction
Althoughthemainstayoftreatmentforindividualswithepilepsyispharmacological,nondrug
treatmentssuchaspsychologicalinterventions,theketogenicdietandvagusnervestimulationare
alsoused.
Psychologicalinterventionssuchasrelaxationtherapy,cognitivebehaviourtherapyandbiofeedback
havebeenusedaloneorincombinationinthetreatmentofepilepsy,withtheaimofreducing
seizurefrequencyandimprovethequalityoflife.
Theketogenicdiet(KD)isahighfat,lowcarbohydrateandproteindietdesignedtomimicthe
biochemicalresponseofthebodytostarvationwhenketonebodiesbecomethemainfuelforthe
brainsenergydemands(Hartman2008)
356
.Ithaslongbeenusedfortreatmentofrefractory
epilepsyinchildren,althoughtheexactmechanismofactionisunclear.
Itcanbedifficulttotreatindividualswithdrugresistantepilepsywhohavebeenassessedasbeing
unsuitableforsurgery.Vagusnervestimulation(VNS)isafurtheradjunctivetreatmentthatmaybe
consideredinsuchcases.
11.2 Doesthetreatmentofepilepsyinadultsorchildrenwith
psychologicalmethodsleadtoareductioninseizurefrequency
and/orabetterqualityoflife?
174. Psychologicalinterventionsmaybeusedasadjunctivetherapy.Theyhavenotbeenprovento
affectseizurefrequencyandarenotanalternativetopharmacologicaltreatment.[2004]
175. Psychologicalinterventions(relaxation,cognitivebehaviourtherapy,biofeedback)maybe
usedinconjunctionwithAEDtherapyinadultswhereeitherthepersonorthespecialist
considersseizurecontroltobeinadequatewithoptimalAEDtherapy.Thisapproachmaybe
associatedwithanimprovedqualityoflifeinsomepeople.[2004]
176. Psychologicalinterventions(relaxation,cognitivebehaviourtherapy)maybeusedinchildren
andyoungpeoplewithdrugresistantfocalepilepsy.[2004]
TheEpilepsies
482
11.3 KetogenicDiet
11.3.1 Introduction
Theketogenicdiet(KD)isahighfat,lowcarbohydrateandproteindietdesignedtomimicthe
biochemicalresponseofthebodytostarvationwhenketonebodiesbecomethemainfuelforthe
brainsenergydemands(Hartman2008)
356
.Ithaslongbeenusedinthetreatmentofrefractory
epilepsyinchildren,althoughtheexactmechanismofactionisunclear.
TheKDdietwasinitiallyreportedforuseinepilepsyin1921(Wilder1921)
357
.Theinitialdietused
wastheclassicalketogenicdiet,basedontheratiooffattocarbohydrate(withprotein),of3or4:1.
Lateranalternativewassuggestedusingtriglycerideoilasasupplement,theMediumChain
Triglyceride(MCT)Diet(Huttenlocheretal1971)
358
.Thesedietshavetobecarefullyadministered
withtheaidofadietician.
Inthischapterweexaminetheeffectiveness,adverseeffectsandcosteffectivenessofketogenic
dietscomparedtonochangeindiet(placebo)andtonodiet(normaldiet)inthetreatmentof
childhoodepilepsy.Therehavebeentworandomisedcontrolledtrialsexaminingefficacy.Onevery
smalltrialcomparedtheketogenicdietagainstplacebo.Theothertrialcomparedtheketogenicdiet
(classicalorMCTvariant)withacontrolgroup(normaldiet).Additionaldatafromthissecond
comparisonincludedananalysisontherelativeefficacyandtolerabilitybetweentheclassicaland
theMCTketogenticdiets.
includedadultsandchildrenwithepilepsy.Norandomiseddatawasfoundforadults.
WesearchedforRCTscomparingtheeffectivenessofdifferentvariantsoftheketogenicdietandno
changeindiet.Thefollowinginterventionswereincludedinoursearch;ketogenicdiet,ketogenic
dietplusglucose,MediumChainTriglyceridesDiet(MCT)andmodifiedAtkinsdiet.Welookedfor
anyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
thischapter.Anemptyboxindicatesthatnoevidencewasfound,andinthiscase,nosectiononthis
Normal
diet
(without
dietetic
input)
Ketogenic
diet
1
359

Ketogenic
dietplus
glucose
1
360

TheEpilepsies
483
MCT
ketogenic
diet
1
361

Normal
diet
(without
dietetic
input)
Ketogenic
diet
Ketogenic
dietplus
glucose
MCT
ketogenic
diet
11.3.3.1 KetogenicDietversusnochangeintreatment(withoutdieteticinput)
Clinicalevidence
Evidencestatements
Theketogenicdietismoreeffectivethannochangeintreatmentintheproportionofparticipants
experiencingatleast50%reductioninseizures.However,thereisuncertaintyaboutthemagnitude
oftheeffect.(LOWQUALITY)
Nosignificantdifferencebetweentheketogenicdietandthenochangeintreatmentinthe
proportionofparticipantsachievingseizurefreedom(VERYLOWQUALITY)
Theketogenicdiethassignificantlygreaterincidenceofthefollowingadverseeventscomparedtono
changeintreatment,howeverthereisuncertaintyofthemagnitudeoftheclinicaleffect:
vomiting(LOWQUALITY)
constipation(LOWQUALITY)
medicationneededforconstipation(LOWQUALITY)
lackofenergy(LOWQUALITY)
hunger.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingtheketogenicdiettonochangeintreatmentwasidentified.
TheEpilepsies
484
timetofirstseizure,
cognitiveoutcomes
11.3.3.2 KetogenicDietversusketogenicdietplusglucose
Theauthorsofthetrialsbelievethatusinga60gsolutionofglucoseoverthecourseofadayin
conjunctionwithaketogenicdietnegatesurinaryandserumketosiscreatingaplaceboarm.Theuse
ofanartificialsweetener(saccharin,whichtastessimilartoglucose)doesnotaddcarbohydrateand
thereforewasusedinthetreatmentarm.Ketosiswasneverlostbypatientsintheglucosearm.
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweentheketogenicdietandplacebointheproportionof
participantsexperiencingatleast50%reductioninseizurefrequency.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingtheketogenicdiettoplacebowasidentified.
seizurefreedom
timetofirstseizure
incidenceofadverseevents,
cognitiveoutcomes
TheEpilepsies
485
11.3.3.3 ClassicalketogenicdietversusMediumChainTriglyceridesketogenicdiet(MCT)
Theclassicalketogenicdietisbasedonaratioof4:1or3:1fattocarbohydrateandprotein.Thefat
componentisprovidedbylongchainfat.FortheMCTketogenicdiet,mediumchaintriglyceridesare
usedasanalternativefatsource.MCTyieldsmoreketonesperkilocaloriethantheclassical
ketogenicdiet.Itisabsorbedmoreefficientlyandiscarrieddirectlytotheliverintheportalblood,
thuslessfatisneededandsointheorymorecarbohydrateandproteincanbeincludedinthediet.
Clinicalevidence
Evidencestatements
TherewasnosignificantdifferencebetweentheclassicalketogenicdietandMCTketogenicdietfor
theproportionofparticipantsexperiencingatleasta50%reductioninseizurefrequencyat12
months.(VERYLOWQUALITY)
TherewasnosignificantdifferencebetweentheclassicalketogenicdietandtheMCTketogenicdiet
fortheincidenceof:
Costeffectiveness
NoeconomicevidencecomparingtheclassicalketogenicdiettotheMCTketogenicdietwas
identified.
seizurefreedom
timetofirstseizure,
cognitiveoutcomes
TheEpilepsies
486
Recommendation
177. Referchildrenandyoungpeoplewithepilepsywhose
seizureshavenotrespondedtoappropriateAEDstoatertiary
paediatricepilepsyspecialistforconsiderationoftheuseofa
ketogenicdiet.[new2012]
outcomes
GDGconsideredefficacybasedon50%seizurereductionand
adverseeffectstobethemostimportantoutcomes.
benefitsandharms
Onestudyshowedthatmorechildrenachievedatleasta50%
reductioninseizurefrequencyontheketogenicdietthanno
changeintreatment.However,anothersmallerstudyshowedthat
therewasnosignificantdifferenceineffectbetweentheketogenic
dietandplacebo.TheGDGplacedlessweightonthissmaller
study,asitwasnotpoweredsufficientlytodemonstrateany
difference.Althoughtheketogenicdietwasconsideredmore
effective,theevidencedidnotsupportarecommendationforany
specificvariantoftheketogenicdiet.Anybenefitmaybemitigated
bythefrequencyofsideeffectsanddifficultyincomplyingwith
thediet.
Thedietmaybeassociatedwithsignificantgastrointestinalside
effects,includingdiarrhoea,constipation,vomitingandhunger.
Sideeffectscanbeimprovedbydietarymanipulationandmay
improvespontaneouslyafterafewweeks.Compliancewith,and
adherenceto,thedietisgenerallymoredifficultthancompliance
withantiepilepticmedication.Thisislargelybecausethedietis
unnatural,involvesacompletechangeofeatinghabits,and
frequentlylifestyle,andthisinvolvesthewholefamilyaswellas
thechild.Compliancewiththedietmustbecompleteand
consistenttooptimiseitsefficacy.
AccordingtoGDGexperience,asuccessfulandsustainedresponse
totheketogenicdietcanallowforthesuccessfulwithdrawalof
someorallconcomitantAEDsinsomepatients,whichmayleadto
areductioninsideeffectsexperienced.Successfulwithdrawalof
thesedrugsmaynottranslatetooverallcostsavingsduetothe
highcostsofdietinitiationandfollowup.
Economicconsiderations TheGDGrecognisedthatimplementationoftheketogenicdiet
wouldrepresentanadditionalcostcomparedwithnodietary
change,butbasedontheclinicalevidencewouldalsoreduce
seizurefrequencyforsomepatients.Intheabsenceofafull
economicevaluationtoassessthepotentialcosteffectivenessof
theketogenicdiet,theGDGconsideredsomeofthesubstantial
costsofimplementingthediet,particularlythoserelatedto
initiationandfollowup.Initiationofthedietrequiressubstantial
dieteticinputintermsofteachingfamiliesaboutthediet,
followingupandmakingadjustmentsduringthefirstseveral
weeksandmonthsandliaisingwithotherhealthprofessionals
involvedinthechildscare.GDGmemberswithexperienceof
administeringtheketogenicdietestimatedthatintermsofa
dieticianstime,initiatingthedietwouldrequireroughlyeight
TheEpilepsies
487
hourstosetupandtwohoursperweekoffollowupforthefirst
severalmonths.AccordingtothePSSRU
362
,thehourlyratefor
dieticiantimeisbetween23and30,whichmeansthatthefirst
threemonthsoftreatment,includinginitiation,wouldcost
between780and1,020perpatient.
Becauseofthishighinitialcost,itisessentialthatathorough
assessmentbemadepriortodietinitiationtoidentifythose
patientsforwhomthedietisasuitabletreatmentoption.Thediet
willmostoftenbeinitiatedasanoutpatient,buttherearesome
patientswhowillrequireinitiationasaninpatient.Themajorityof
costsassociatedwiththeketogenicdietcomefrominitiationand
followupwithinthefirstyear,althoughongoingcostswillinclude
regularcontactwiththeketogenicdietclinicstafftomonitorand
manipulatethediet,ensuredietarysupplementation(vitamins,
mineralsandKetoCal)andregularbloodtests.Followingtheinitial
threemonthsthiswouldamounttoapproximatelyonehourper
monthofdieticiantimeforaslongasthechildisonthediet.The
clinicalandbloodtestmonitoringwillbegreaterthanthat
requiredforchildrentakingantiepilepticmedication.Itispossible
thatthelongerthedietissuccessfullymaintained,achievingthe
desiredresponse,themorecosteffectiveitmaybe.
TheGDGconsideredthatbecauseofthehighinitialcostsandthe
potentialdifficultyinimplementationofandadherencetothediet,
itshouldbereservedforthosechildrenwhohavepreviouslytried
otherAEDsbutfailedtoachievethedesiredlevelofseizure
control.
Basedontheclinicalevidence,theMCTketogenicdietwasnot
clearlymoreeffectivethantheclassicalketogenicdiet,yetthecost
ofadministeringitisgreaterduetotheadditionalcostofLiquigen
(2.90per100mL).Intheabsenceofevidencetoindicategreater
effect,theGDGfeltthattheclassicalketogenicdietshouldbetried
firstandtheMCTketogenicdietshouldbereservedforthose
patientswithspecialconsiderations,suchasolderchildrenor
thosewhoareunabletocopewithortoleratetheclassicalvariant.
Qualityofevidence Verylimitedtrialdata.Theevidenceismostlyoflowquality.There
arealimitednumberofeventsandverywideconfidenceintervals.
Otherconsiderations Thereiscurrentlyvariationinaccesstoketogenicdietacross
EnglandandWaleswhichwillbeimportantwhenimplementing
thisrecommendation.
TheEpilepsies
488
11.3.6 Ketogenicdietinadults
Whatistheeffectivenessandtolerabilityoftheketogenicdietinadultswithepilepsy?
Whyisthisimportant?
Therearenodataontheuseoftheketogenicdietinadults.Thismayreflectthefactthatthediet
hasbeenshowntobeineffectiveandtheresultsunpublished,or,asismorelikely,thatthediethas
neverbeenusedinthisagegroup.Inviewofthenumerousanecdotalandrandomisedcontrolled
datademonstratingitseffectivenessandthatthenumberofantiepilepticdrugsprescribedmaybe
reducedasaresultofthisdietaryapproachinthepaediatricepilepsies,itisappropriatetoundertake
arandomisedcontrolledtrialofketogenicdietinadultpatientswithdrugresistantepilepsy.
aninitialpilotstudyofthefeasibilityandacceptabilityoftheketogenicdietinadultswhoare
independentinactivitiesofdailylivingandwhohavenolearningdifficulties
ifthepilotstudyindicatesthattheketogenicdietisfeasibleandacceptable,amulticentre
randomisedcontrolledstudyshouldbedesigned;thiscouldevaluateoneormorevariantsof
thedietversusanormaldiet
primaryoutcomewouldbereductioninseizurefrequency
secondaryoutcomeswouldincludequalityoflifeandreductionofantiepilepticdrugburden
costdatashouldincludethetotalcostofthediet(includingdieteticsupport),reduceddrug
costsandreducedadmissions
11.4 Inpeoplewithdrugresistantepilepsy,isvagusnervestimulation
(VNS)effectiveasanadjunctivetreatment?
frequencyofseizuresinadultswhoarerefractorytoantiepilepticmedicationbutwhoarenot
suitableforresectivesurgery.Thisincludesadultswhoseepilepticdisorderisdominatedby
focalseizures
(withorwithoutsecondarygeneralisation)orgeneralisedseizures.[2004,
amended2012]
frequencyofseizuresinchildrenandyoungpeoplewhoarerefractorytoantiepileptic
medicationbutwhoarenotsuitableforresectivesurgery.Thisincludeschildrenandyoung
peoplewhoseepilepticdisorderisdominatedbyfocalseizures
(withorwithoutsecondary
generalisation)orgeneralisedseizures
.[2004,amended2012]
Evidencestatement
EvidencefromVagusnervestimulationforrefractoryepilepsyinchildren,NICEinterventionalprocedureguidance50
(2004).
TheEpilepsies
489
TheevidenceshowsthatVNSappearstobeaneffectiveandwelltoleratedtreatmentfordrug
resistantfocalseizures.Stimulationusingthehighstimulationparadigmissignificantlybetterthan
lowstimulation.(Ia)
Details
SecondaryEvidence
OneCochranereview
363
andonetechnologyappraisal
364
wereidentifiedthataddressedtheuseof
VNSinthemanagementoffocalseizuresanddrugresistantepilepsyrespectively.
Inaddition,guidanceontheuseofVNSasaninterventionalprocedureinchildren
365
waspublished
byNICEin2004.Theguidanceisincludedintheguidelinerecommendationsabove.
Privitera2003
363
PriviteraandcolleaguesreviewedtheevidenceontheeffectsofVNShighlevelstimulation
comparedtolowlevel(presumedsubtherapeuticdose)stimulationinpeoplewithdrugresistant
focalseizures.Randomised,doubleblindcontrolledtrialsofVNScomparinghighandlow
stimulationparadigmsinadultsorchildrenwereincluded.
Thefollowingoutcomeswereassessed:
a. 50%orgreaterreductionintotalseizurefrequency;
b. treatmentwithdrawal(anyreason);
c. adverseeffects.
Primaryanalyseswereintentiontotreat.Sensitivitybestandworstcaseanalyseswerealso
undertaken.Summaryoddsratios(ORs)wereestimatedforeachoutcome.
Thetwoincludedstudies
366,367
wereparalleltrials,sponsoredbyCyberonicsaspartoftheirpre
approvalprogramforVNS.EachtrialtestedtwostimulationparadigmsforVNS.Allparticipants
wereimplantedwithastimulator,butthecontrolgroupreceivedlessfrequentandlowerintensity
stimulation.Inaddition,participantsinthecontrolgroupdidnotreceiveanyelectricalcurrentwhen
thedevicewasactivatedbythehandheldmagnet.Atotalof312individualswererandomisedto
treatment.
StimulationparametersintheE03trial
366
were:current0.5to3.0mA(activeandcontrol);frequency
20to50Hz(control1to2);pulsewidth500(control130);ontime30to90seconds(control30
seconds);offtime5minutes(control90minutes).
StimulationparametersintheE05trial
367
were:current3.5mA(activeandcontrol);frequency30Hz
(control1);pulsewidth500(control130);ontime30seconds(activeandcontrol30);offtime5
minutes(control180minutes).Inclusioncriteriawereasfollows:age12to60years;zeroto3
concomitantAEDs;minimum6seizurespermonth.
PeoplewithpepticulcerswereexcludedfromtheE05trial.IntheE03trial,onepersondroppedout
priortorandomization.IntheE05trial,oneparticipantdroppedoutandanotherwasexcludedfrom
theefficacyanalysisbecausehedidnotkeepaseizurediary;bothparticipantsprovidedadverse
eventdata.Thesetwoparticipantscontributedtothebestandworstcasescenarios.
ResultsoftheoverallefficacyanalysisshowedthatVNSstimulationusingthehighstimulation
paradigmwassignificantlybetterthanlowstimulation.TheoverallOR(95%confidenceinterval(CI))
for50%respondersacrossallstudieswas1.93(95%CI1.1to3.3).Thiseffectdidnotvary
substantiallyandremainedstatisticallysignificantforboththebestandworstcasescenarios(Overall
TheEpilepsies
490
oddsratiofor50%respondersacrossallstudies1.99(95%CI1.1to3.4)(bestcase)and1.84(95%CI
1.06to3.18)(worstcase)).
ResultsfortheoutcomewithdrawalofallocatedtreatmentsuggestedthatVNSiswelltoleratedas
nosignificantdifferencewasfoundbetweenthehighandlowstimulationgroups(overalloddsratio
1.08(95%CI0.07to17.51),andwithdrawalswererare.Statisticallysignificantadverseeffects
associatedwithimplantation(lowversusbaseline)werehoarseness,cough,pain,andparesthesia
(hoarseness4.74(99%CI2.12to10.60);cough2.97(99%CI1.48to5.94);andparesthesia6.36(99%
CI2.69to15.08)).Statisticallysignificantadverseeffectsassociatedwithstimulation(highversus
low)werehoarsenessanddyspnea(hoarseness4.50(99%CI2.45to8.27)anddyspnea2.65(99%CI
1.15to6.08)),suggestingtheimplantationisassociatedwithhoarseness,butthestimulation
producesadditionalhoarseness.
Thereviewersconcludedthatforfocalseizures,VNSappearedtobeaneffectiveandwelltolerated
treatment.
363
Bryant1998
368
ThistechnologyassessmentwaspublishedpriortothepublicationoftheE05trialsoconclusions
abouteffectivenessarenotpresented.(SeeCochranereviewabove)
Corabian2001
364
TheAlbertaHeritageFoundationforMedicalResearchpublishedahealthtechnologyreportonthe
useofvagusnervestimulationforpeoplewithrefractoryepilepsy.ThisupatedapreviousTechNote
publishedin1998.CorabianandLeggetfound:
Nopublishedprospectivecontrolledtrialsorothercomparativestudiesusingcontrolsconducted
toevaluatethesafetyandefficacyofVNStherapyfortreatmentofgeneralizedepilepsy;
Nopublishedprospectivecontrolledtrialsorothercomparativestudiesusingcontrolsconducted
toevaluatethesafetyandefficacyofVNStherapyfortreatmentofspecifictypesofepilepsyin
children;
Noresultsobtainedfromprospectivecontrolledstudiesorothercomparativestudiesusing
controlsthathavebeenpublishedonthedirectcomparisonbetweentheuseofVNSandtheuse
ofnewAEDsasadjunctivetherapiesforseizurefrequencyreductioninrefractoryepilepsy;and
Noprospectivecontrolledstudiesorothercomparativestudieswithcontrolsdesignedand
conductedtodeterminetheeffectofVNSonseizurecontrolinrefractoryepilepsyintermsof
reducedseizureintensity/durationandAEDintakeinindividualswithrefractoryepilepsyor
improvedQOL.
However,theauthorsdidreviewseveraluncontrolledtrials.TheyconcludedthatVNSwassafeand
effectivewhenaddedtotheexistingtreatmentregimenforsomeindividuals(agedover12years)in
termsofareductioninseizurefrequency.
Raeburn2003
369
ThecostutilityofVNSinmedicallyrefractoryepilepsywasestimatedbasedonametaanalysisof
twoRCTs.However,oneofthepublicationsusedreportedpreliminaryresultsfromatrialpublished
infulllater.Thismetaanalysiswasthereforeexcluded.
Fisher1999
370
AreportoftheTherapeuticsandTechnologyAssessmentSubcommitteeoftheAmericanAcademyof
NeurologyassessedtheeffectivenessofVNSforepilepsy.ThesametwoRCTswereevaluatedasin
theCochranereviewbyPriviteraandcolleagues.
363
TheEpilepsies
491
Thereportconcludedthatthedegreeofimprovementinseizurecontrolremainscomparabletothat
ofnewAEDs,butislowerthanthatofmesialtemporallobectomyinsuitableresectioncandidates.
ThecommitteerecommendedthatVNSwasindicatedforadultsandadolescentsovertheageof12
yearswithmedicallyrefractoryfocalseizureswhoarenotcandidatesforpotentiallycurativesurgical
resections.
Primaryevidence
NoRCTswereidentifiedasbeingpublishedsincetheHTA(2000onwards).
Healtheconomics
Bryant1998
368
ThistechnologyappraisalassessedthehealtheconomicevidencerelatedtoVNS.
Aslongtermeffectivenessisunknown,thecosteffectivenessanalysiswaslimitedtothefirstyear.
Thecostperseizuresavedwasintherange246to410.OnestudyofthecostbenefitratioofVNS
concludedthatthecostofVNScouldbeexpectedtobepaidbackbysavingsindirectmedicalcosts
after2years.
TheauthorsconcludedthattherestillremainedquestionsonthecostbenefitofVNS.
Boon1999
371
Thiswasacosteffectivenessstudyinwhich25individualsweretreatedbyVNSimplantation,20of
whomhadsufficientfollowupdata..Themeanagewas30(range:1245;sd=9.0)yearsandthe
meandurationofepilepsywas17years(range:535years;sd=8.0).
Thestudysamplewerepartofapopulationof150whounderwentanextensivepresurgical
evaluationthatincludedscalpvideoEEGmonitoring,optimummagneticresonanceimaging(MRI),
interictalfluorodeoxyglucosepositronemissiontomography(FDGPET)andneuropsychological
assessment.Afterthoroughpresurgicalevaluation,105of150(70%)wereconsideredasthenon
surgicalcandidatesbecauseaconfinedandresectableepileptogeniczonecouldnotbeidentified.
TheywereeitherofferedcontinuingdrugtherapywitharematchingoftheirstandardAEDs(n=50),
participationinphase3drugtrialswithnovelAEDssuchastopiramate,gabapentinorlevetiracetam
(n=30),orVNS(n=25).25individualsgaveinformedconsenttohaveavagusnervestimulator
implanted.Thiswasabeforeandafterstudy,carriedoutinasinglecentre.Themeanpost
transplantationfollowuptimewas26months(range:650months;SD:14.4).Individualswere
followedonanoutpatientbasisatregularintervals,usuallyevery24weeksduringrampingupand
every1to3monthsthereafter.Losstofollowupcomprised5wholackedsufficientfollowupdata.
Mean(SD)seizurefrequencydecreasedfrom14seizures/month(range:240)intheperiodbefore
implantationto9seizures/month(range:030)(p=0.0003)afterimplantation.
ThemeannumberanddosageofAEDsremainedunchangedin14individualsafterimplantation.For
oneindividual,twoAEDsweretapered,foranother,onlyoneAEDwastapered.In4individuals,an
additionalAEDwasadministered.
Regardingthesideeffects,10individualsreportedhoarseness,voicechange,paresthaesiasinthe
throatorintheareaaroundthestimulator.Dysphagiaandpersistentcoughingduringstimulation
werereportedin10individualsduringstimulation.Inthreecases,thesesideeffectsrequireda
temporaryreductionofoutputcurrentbutstimulationdidnothavetobeinterrupted.
Atthetimeofmaximumfollowupsixindividualsreportedsideeffects.Thesesideeffectsdidnot
requireanychangeofstimulationoutputandsubsidedovertime.
TheEpilepsies
492
Inconclusion,thestudyexperienceconfirmedtheefficacyrate(50%reductioninseizurefrequency
inabout25%ofindividuals)observedintheliteraturethatcomparesfavourablywithnewAEDssuch
aslamotrigine,topiramate,andgabapentin.ResultsinthestudysuggestedthatVNSremains
effectiveinthelongterm,offeringafavourablesafetyprofile,acutesideeffectsbeingrelatedto
initialstimulationandresolvingspontaneouslywithouttheneedtostopthestimulation.
Thecostanalysisconsideredepilepsyrelateddirectmedicalcosts.ItincludedthecostsofAEDs,
clinicvisits,hospitaladmissions,laboratorytests,andtheVNSstimulatorandimplantation
procedure.Foreachindividual,theyearlycostofAEDswascalculatedonthebasisofthemean
numberandtypeofAEDsintheyearsbeforeandfollowuptimeaftertheimplantation.Theyearly
costofclinicvisitswascalculatedintheyearspriortoimplantationandduringthefollowuptime
afterimplantation.Thecostanalysisdidnotcoverthecostsassociatedwithhospitaladmissionsdue
toconditionsunrelatedtoepilepsyorepilepticseizuresandadmissionsscheduledsolelyinthe
contextofthepresurgicalevaluation.Foreachindividual,acomparisonwasmadebetweenthe
meanyearlysumofthesecostsintheyearsbeforeandtheavailablefollowuptimeafterthe
implantation.Thepairedstudent'sttestwasusedforstatisticalanalysis.
Themainresultswerethatthemeanyearlyepilepsyrelateddirectmedicalcostsperindividual
droppedfrom$6,682(range:$829$21,888)intheperiodbeforeimplantationto$3,635(range:
$684$12,486)(p=0.0046),aftertheVNSimplantation.
TheauthorsconcludedthatVNSisanefficaciousandsafetreatmentformedicallyrefractory
epilepticseizuresduringthefirstyearsafterimplantation.Itappearedtobeequallyeffectiveand
safeinthelongtermandlackedthecommonsideeffectsofAEDs.VNShasafavourablecost
benefit.
371
TheEpilepsies
Informationneedsofindividuals,families,andcarers
493
12 Informationneedsofindividuals,families,and
carers
12.1 Introduction
Havingafirstseizureisaverytraumaticandworryingeventfortheindividualandtheirfamilyand/or
carers.Ifepilepsyisdiagnosed,thenthediagnosiscanhavewiderangingphysicalandpsychological
andsocialconsequenceswhichmaybeasdifficulttodealwithastheseizuresthemselves.The
managementofepilepsyinindividualsmayrequirelongtermdrugtreatmentandregularreviewof
theirconditionisessential.
Itisthereforecrucialthatappropriateinformationandsupportfortheindividualwithepilepsyand
theirfamilyand/orcarersisprovidedateachstageofthecarepathway.Individualswithepilepsy,
theirfamilies,andprofessionalsinvolvedintheircareneedinformationappropriatetothe
individualsdevelopmentalage,gender,culture,andstageoflife.Potentialpositiveoutcomesof
informationgivingandsupportincludereducedmortalityandmorbidity,individualempowerment
andthemeanstomakeinformeddecisionstoachievethebestpossiblequalityoflife.
12.2 Informationneedsoftheindividualwithepilepsy,thefamily,the
carer,andspecialgroups
180. Children,youngpeopleandadultswithepilepsyandtheirfamiliesand/orcarersshouldbe
given,andhaveaccesstosourcesof,informationabout(whereappropriate):
epilepsyingeneral
seizuretype(s),triggersandseizurecontrol
managementandselfcare
riskmanagement
firstaid,safetyandinjurypreventionathomeandatschoolorwork
psychologicalissues
socialsecuritybenefitsandsocialservices
insuranceissues
educationandhealthcareatschool
employmentandindependentlivingforadults
importanceofdisclosingepilepsyatwork,ifrelevant(iffurtherinformationorclarificationis
needed,voluntaryorganisationsshouldbecontacted).
roadsafetyanddriving
prognosis
suddendeathinepilepsy(SUDEP)
statusepilepticus
lifestyle,leisureandsocialissues(includingrecreationaldrugs,alcohol,sexualactivityand
sleepdeprivation)
familyplanningandpregnancy
TheEpilepsies
494
voluntaryorganisations,suchassupportgroupsandcharitableorganisations,andhowto
contactthem.[2004]
181. Thetimeatwhichthisinformationshouldbegivenwilldependonthecertaintyofthe
diagnosis,andtheneedforconfirmatoryinvestigations.[2004]
182. Informationshouldbeprovidedinformats,languagesandwaysthataresuitedtothechild,
youngpersonoradultsrequirements.Considerationshouldbegiventodevelopmentalage,
gender,cultureandstageoflifeoftheperson.[2004]
183. Ifchildren,youngpeopleandadults,andfamiliesand/orcarershavenotalreadyfoundhigh
qualityinformationfromvoluntaryorganisationsandothersources,healthcareprofessionals
shouldinformthemofdifferentsources(usingtheInternet,ifappropriate:see,forexample,
thewebsiteoftheJointEpilepsyCounciloftheUKandIreland,
www.jointepilepsycouncil.org.uk).[2004]
184. Adequatetimeshouldbesetasideintheconsultationtoprovideinformation,whichshould
berevisitedonsubsequentconsultations.[2004]
185. Checklistsshouldbeusedtoremindchildren,youngpeopleandadults,andhealthcare
professionals,aboutinformationthatshouldbediscussedduringconsultations.[2004]
186. Everyoneprovidingcareortreatmentforchildren,youngpeopleandadultswithepilepsy
shouldbeabletoprovideessentialinformation.[2004]
187. Thechild,youngpersonoradultwithepilepsyandtheirfamilyand/orcarersasappropriate
shouldknowhowtocontactanamedindividualwheninformationisneeded.Thisnamed
individualshouldbeamemberofthehealthcareteamandberesponsibleforensuringthatthe
informationneedsofthechild,youngpersonoradultand/ortheirfamilyand/orcarersare
met.[2004]
Evidencestatements
Individualswithepilepsyrequireinformationon:
epilepsyingeneral
seizuretype(s),triggersandobtainingoptimalseizurecontrol
prognosis
safety,riskandinjuryprevention
psychologicalissues(especiallystress)
socialsecuritybenefits,drivingregulationsandinsurance
employment;lifestyleandsocialissues.(III)
Counsellingissuesareanxiety,depression,emotionalsupportandinformation.(III)
Peoplewithepilepsypreferverbalandwritteninformationthatispersonallyrelevant.(III)
Details
Thereisextensiveliteratureonthegeneralinformationneedsoftheindividualwithepilepsyand
theirfamiliesorcarers.
TheEpilepsies
495
ItwasagreedwiththeindividualpatientrepresentativesontheGDGthattherecommendationson
informationneedsshouldbemappedtokeypointsonthecarepathwayratherthansummarisedina
separatesectionoftheguideline.
Asfarastheevidencebaseisconcernedthefocuswasonpublishedstudiesthatreportedthe
informationneedsofpeoplewithepilepsyandtheirfamiliesorcarers.Publishedstudiesthathave
surveyedorinterviewedpeoplewithepilepsyand/ortheircarers/familyandreportedspecificallyon
informationneedswereincluded.Evidencethatreportedhealthcareprofessionalsviewsastowhat
individualsinformationneedsareandstudieslookingmoregenerallyattheexperienceofadultsand
childrenlivingwithepilepsywereexcluded.
In2001,LynetteCouldridgeandcolleaguespublishedasystematicreview
372
ontheinformationand
counsellingneedsofpeoplewithepilepsy.AllthepapersreferencedintheCouldridgereviewwere
reviewed,andasimilarstrategywasusedtoidentifyanyrelevantpaperspublishedsince.The
knowledgeandexperienceoftheGDGwereusedtohelpintheidentificationofgreyliteratureand
surveysthatcontributedtotheevidencebase.
InthisreviewthefindingsoftheCouldridgereview
372
werepresentedwithresearchidentifying
specificinformationneedsatspecificpointsonthecarepathwaywassummarised.
Secondaryevidence
Couldridge2001
372
Thispaperreviewedkeyprimaryresearchontheinformationneedsofpeoplewithepilepsy
publishedbetween1990and2000.Fortyprimaryresearchpaperswerereviewed.Thefollowing
questionsrelevanttothiskeyclinicalquestionwereaddressedbythereview:
Whataretheinformationandcounsellingneedsofpeoplewithepilepsy?
Individualsrequireinformationon:
Epilepsyingeneral;diagnosisandtreatmentoptions;medicationandsideeffects;seizuresand
seizurecontrol;prognosis;injuryprevention;psychologicalissues(especiallystress);social
security,drivingandinsurance;employment;lifestyleandsocialissues.
Counsellingissuesidentifiedwere:
Anxiety,depression,emotionalsupportandinformation.
Whatisthepreferredformat,timinganddeliveryofepilepsyinformation?
Littleevidencewasfoundtoidentifythebesttimingofeducationprogrammesorwhetherneeds
changedovertime,althoughsomeresearchershighlightedaneedforcounsellingatthetimeof
diagnosis.
373
Thereisevidencetosuggestthatinformationtailoredtoindividualneedsandcircumstancesis
thepreferredmethod.Individualspreferverbalandwritteninformationthatispersonally
relevant.
TheEpilepsies
496
12.3 Whatinformationisrequiredatdifferentstagesofthecare
pathway
FirstSeizure
ThisshouldrelatetoinformationgiveninprimarycareorAccidentandEmergencydepartmentsto
individualsbeforetheyarereferredforaspecialistopinion.
188. Thepossibilityofhavingseizuresshouldbediscussed,andinformationonepilepsyshouldbe
providedbeforeseizuresoccur,forchildren,youngpeopleandadultsathighriskofdeveloping
seizures(suchasafterseverebraininjury),withalearningdisability,orwhohaveastrong
familyhistoryofepilepsy.[2004]
189. Essentialinformationonhowtorecogniseaseizure,firstaid,andtheimportanceofreporting
furtherattacksshouldbeprovidedtoachild,youngpersonoradultwhohasexperienceda
possiblefirstseizure,andtheirfamily/carer/parentasappropriate.Thisinformationshouldbe
providedwhilethechild,youngpersonoradultisawaitingadiagnosisandshouldalsobe
providedtotheirfamilyand/orcarers.[2004]
Evidencestatement
Informationisneededonmanagingtheconditioninchildrenwithnewonsetseizures.(III)
Details
McNelis1998
374
TheChildReportofPsychosocialCareScalewasusedtomeasurechildren'ssatisfactionwith
healthcarereceived,needforinformationandsupportandseizurerelatedconcernsandfearsin
childrenwithnewonsetseizures.Thesampleof63children(33girlsand30boys),814years,
completedthescaletwotimes,3monthsand6monthsaftertheirfirstseizure.Resultsindicated
thatchildrenwantedinformationrelatedtotheseizurecondition,especiallymanagingtheir
condition,andsupport,intheformoftalkingtootherchildrenwithseizures.
Investigations
Thisshouldrelatetoinitialoutpatientappointmentwiththeappropriatespecialist/epilepsyspecialist
nurseandanysubsequentfollowupappointments.
carersasappropriateonthereasonsfortests,theirresultsandmeaning,therequirementsof
specificinvestigations,andthelogisticsofobtainingthem.[2004]
Evidencestatement
Adultswantinformationaboutthereasonsfortests,theresultsandmeaningoftheseresults.(III)
Details
Dilorio1993
375
AUSstudyof59adultswithepilepsy(mean39.3years,range19to60years)foundthatindividuals,
nurses,anddoctorssimilarlyrankedmajorareasoflearningneed.Howeverthereweredifferences
intherankingofindividuallearningneeds.
375
TheEpilepsies
497
Althoughthisstudydidnotrelatethelearningneedtotiming,boththeresultsoftestsandthe
reasonsforsuchtestswererankedhigherbyindividualsthanbyhealthcareproviders,anditcouldbe
arguedthatthisinformationwouldbebestprovidedwhentestsareordered/performedandresults
arediscussed.
Ridsdale2002
376
AUKRCTofanurseinterventionrecruited90adultswithnewlydiagnosedepilepsy(meanage40
years,range17to83years).Asubgroupof31individualswereidentifiedforinterviewinthe
qualitativearmofthetrial,24agreedtoparticipate.Somefoundadiagnosisofepilepsywhentest
resultswerenormalconfusing.
Diagnosis
Thisshouldrelatetoinitialoutpatientappointmentwithspecialist/epilepsyspecialistnurseandany
subsequentappointmentsasappropriate.
191. Children,youngpeopleandadultswithepilepsyshouldbegivenappropriateinformation
beforetheymakeimportantdecisions(forexample,regardingpregnancyoremployment).
[2004]
192. Children,youngpeopleandadultsandtheirfamiliesand/orcarersshouldbegivenan
opportunitytodiscussthediagnosiswithanappropriatehealthcareprofessional.[2004]
Evidencestatements
Adultswantthediagnosistobeconfirmedandcounsellingtobeavailable.(III)
Adultswantbasicinformationonepilepsy(whatitis,causes,howcommonitisetc.)andsomewant
moreextensiveinformation(education,employment,leisure,benefits,socialimplicationsetc).(III)
Youngerandmiddleagedpeoplewantinformationonepilepsyanddriving.(III)
Olderpeoplewithepilepsywanttolearnabouttheirnewconditioninadditiontomanagingcurrent
ones,includingthecomplicationsofaddingnewdrugstothecurrentregime.(III)
Thereisaneedforinformationtobegiventocarerstoenablethemtohelptheindividualwith
epilepsymanagetheircondition,aswellastointerveneeffectivelywhentheyareunabletohelp
themselves.(III)
Bereavedrelativeswouldlikeinformationonepilepsytobeprovidedautomaticallytotheindividual
withepilepsyeitheronorsoonafterdiagnosis.(III)
Individualswithepilepsyandtheirfamiliesshouldbeinformedabouttherisksofsuddendeath,but
thereisuncertaintyaboutmakingthisinformationmoregenerallyavailable.(III)
Childrenwantanexplanationofthediagnosis.(III)
Familieswantprovisionofinformation,addressingconcernsandconcernsandfears,andproviding
emotionalsupportassoonaspossibleafterdiagnosis.(III)
Details
Averis1996
377
InanAustralianquestionnairesurveyof200adultswithepilepsywhoattendedaspecialistclinic,
confirmationofthediagnosiswasratedasthesecondmostimportantfactorinthemanagementof
TheEpilepsies
498
epilepsy(afteravailabilityofthedoctorattimeofneed).Thestaffoftheclinicbelievedthat
educationshouldbeginatdiagnosisandcovertopicsastheybecomerelevanttotheindividual.
CSAG2000
11
TheCSAGreportstatedthatmanyolderpeoplewouldhavelikedcounsellingandmoretimewiththe
doctorornurseatthetimeofdiagnosis.
Goldstein1997
378
InaUKsurveyof94adultswithepilepsyattendingatertiaryclinic,73%ofthe70respondentsat
diagnosisweretoldwhatepilepsywas,butonly42%properlyunderstoodtheexplanation.31.4%of
respondentswouldhavelikedbasicinformationonepilepsy(whatitis,causesetc)40%wouldhave
likedextensiveinformation(education,employment,leisure,benefitsetc)and17.1%wouldhave
likedboth.4.3%didnotwanttoknowmoreaboutepilepsy.
May2002
379
InanRCTtoevaluatetheuseofaneducationalpackagetoimproveadults'knowledgeand
understandingoftheirepilepsy,therewasnodifferenceinthelevelsofimprovementbetweenthose
withalongandshortdurationofepilepsy(<=5yearsvs>5years).However,theauthorssuggested
thatitwasreasonabletoofferaneducationalprogramassoonaspossibleafterdiagnosis.
Buck1996
380
InaUKcommunitybasedsurveyof677adultswithepilepsy,thedurationofepilepsyinfluencedthe
likelihoodthatindividualswoulddiscusssocialimplications;79%ofthosewithareporteddurationof
lessthanoneyearcomparedwithonly59%ofthosewithadurationofmorethan10years
(differenceinproportions11,95%CI2to20).Theauthorssuggestedthatthismaybebecause
individualscometoacceptthesocialimplicationsofepilepsyintime,orthatdoctorsassumethisto
bethecase.Anotherreasonofferedwasthatindividualsbelievethatitislessappropriatetodiscuss
socialissues(asopposedtoclinicalissues)whentherearetimeconstraintsintheconsultation.
Ridsdale2002
376
AUKRCTtoevaluatetheeffectofanurseinterventiononknowledgeofepilepsy,satisfaction,and
wellbeingrecruited90adultswithnewlydiagnosedepilepsy(meanage40years,range17to83
years).Asubgroupof31individualswereidentifiedforinterviewinthequalitativearmofthetrial,
24agreedtoparticipate.Youngerandmiddleagedpeoplereportedmoredifficultyindealingwith
thediagnosis,particularlywithrespecttodriving.Olderindividualsfrequentlyhadothermedical
problemsandinthiscontext,anewdiagnosisofepilepsyseemedtodisturbthemless.Themain
challengeforthisgroupwastolearnabouttheirnewconditioninadditiontomanagingcurrentones,
includingthecomplicationsofaddingnewdrugstothecurrentregime.Manyindividualsreported
beingabletoacceptthediagnosismoreafteranurseexplainedhowcommonepilepsyis.Safety
informationwasappreciated,andmanyreportedreceivingwritteninformationonrequest.Other
issuesraisedweretreatment(takingthepills,whattodowhenforgotten,interactions,sideeffects,
freeprescriptionsetc).Theauthorsconcludedthatchallengesofcomingtotermswiththediagnosis
andselfmanagementweredifferentforindividualsofdifferentages.Inthiscontext,nurses
providedtimeandanapproachwhichallowedindividualstoremembertheirownquestionsand
rememberthespecificinformationtheyrequired.Thehypothesisofthenurseintervention(alliedto
informationprovision)beingvaluedbyindividualsmostwhentheyarefirstdiagnosedwas
supported.
Ridsdale1999
381
Inaninterviewstudyofadultswithepilepsy(meanage47years,range18to75years)individuals
feltthatinformationaboutthediagnosiswasextremelyimportant.Specifically3individualswhohad
TheEpilepsies
499
beenchildrenwhentheywerediagnosedreportedthatexplanationsweregiventotheirparents,but
nottothem.
Austin2002
382
Inabeforeandafterstudyofanpsychoeducationalinterventionstudy,commentsfromthe10
participantfamiliesofchildrenwithepilepsyindicatedthattheinterventionwouldbemost
effectivelyadministeredearlyinthecourseofthedisorder.Thetailoredinterventionincluded
provisionofinformation,addressingconcernsandconcernsandfears,andprovidingemotional
support.
Kennelly2002
383
Inaninterviewstudyof78semistructuredinterviewswiththebereavedrelativesofindividualswith
epilepsywhohaddiedofSUDEP,severalissuesaroundtheprovisionofinformationwereidentified.
Therelativeswantedinformationonepilepsytobeprovidedautomaticallytotheindividualeither
onorsoonafterdiagnosis.Theyalsostressedtheneedforinformationtobegiventocarersaswell
astheindividualwithepilepsytoenablethemtohelpthemmanagetheircondition,aswellasto
interveneeffectivelywhentheyareunabletohelpthemselves.
Elwyn2003
384
Focusgroupinterviewswith19individualswithepilepsyidentifiedbothalackofsupportatdiagnosis
andalackoftimeandencouragementtoexpresstheirconcerns,whichwasparticularlyimportantat
diagnosis.
InformationneedsandSUDEP
193. InformationonSUDEPshouldbeincludedinliteratureonepilepsytoshowwhypreventing
seizuresisimportant.TailoredinformationonthepersonsrelativeriskofSUDEPshouldbe
partofthecounsellingchecklistforchildren,youngpeopleandadultswithepilepsyandtheir
194. TheriskofSUDEPcanbeminimisedby:
optimisingseizurecontrol
beingawareofthepotentialconsequencesofnocturnalseizures.[2004]
195. Tailoredinformationanddiscussionbetweenthechild,youngpersonoradultwithepilepsy,
theirfamilyand/orcarers(asappropriate)andhealthcareprofessionalsshouldtakeaccountof
thesmallbutdefiniteriskofSUDEP.[2004]
196. Wherefamiliesand/orcarershavebeenaffectedbySUDEP,healthcareprofessionalsshould
contactfamiliesand/orcarerstooffertheircondolences,invitethemtodiscussthedeath,and
offerreferraltobereavementcounsellingandaSUDEPsupportgroup.[2004]
Evidencestatements
Bereavedrelativeswouldlikeindividualswithepilepsytobepresentedwithinformationontheriskof
SUDEPduringafacetofaceconsultationbytheresponsiblemedicalprofessional,eitheratorsoon
afterdiagnosis.(III)
Bereavedrelativesneedinformationfrommedicalprofessionalstohelpthemcometotermswiththe
deathofapersonfromSUDEP.(III)
Details
TheEpilepsies
500
Kennelly2002
383
Inaninterviewstudyof78semistructuredinterviewswiththebereavedrelativesofindividualswith
epilepsywhohaddiedofSUDEP,severalissuesaroundtheprovisionofinformationwereidentified.
Therewasanexpresseddissatisfactionwiththelevelofinformationprovidedeithertothemorto
theircarers.
TherewassomeuncertaintyaboutwhetherinformationaboutSUDEPshouldbemoregenerally
available.Theyfeltthatpeoplewithepilepsyandtheirfamiliesshouldbeinformedabouttherisksof
suddendeath.Theyalsofeltthatinformationontheriskswerevitalastheythemselvessometimes
trivialisedtheseriousnessofthecondition.InformationonSUDEPinepilepsyliteraturewouldhave
allowedthemtotakepreventativemeasures,oratleastbebetterpreparedwhenthesuddendeath
occurred.However,otherrelativesfeltthatSUDEPshouldnotbeoveremphasisedastherisksare
relativelylowandpeoplewithepilepsymightliveingreaterfearthannecessary.
Mostrelativesthoughtthatthemosteffectivewaytopresentindividualswithinformationonthe
relativelyrareriskofsuddendeathwasduringafacetofaceconsultationbytheresponsiblemedical
professional,eitheratorsoonafterdiagnosis.
Bereavedrelativesneededinformationfrommedicalprofessionalstohelpthemcometotermswith
thedeath.Howevertheyreporteddifficultiesinaccessingmedicalprofessionals,particularlythe
specialistresponsibleformanagingthecareofthepersonwithepilepsy.Theauthorsrecommended
that
itshouldbestandardpracticeafterasuddendeathfromepilepsyforthemedical
professionalinchargetoofferanappointmenttothebereavedrelativestodiscussthe
case.Thiswouldofferfamiliestheopportunitytoaskquestionstowhichtheywant
answersandtogaingreaterunderstandingofwhythedeathoccurred.Thiscouldgreatly
helpinthegrievingprocess.
383
Manyrelativessaidthattheyneededadditionalsupportduringthemonthsafterasuddendeath.
Suggestionsincludedtheestablishmentofalocalsupportnetworkinwhichlocalhealthservices
offerbereavedfamiliesaneedsassessmentandprovideanamedcontactforregularchecksand
reviewsoftheirsituation.Relativesfeltthatthemostappropriatepeopletotakeresponsibilityfor
providingthisservicewerelocalprimarycarestafforsupportgroupstaff.
Drugtreatment
197. Informationthatisprovidedaboutantiepilepticdrugs(AEDs)needstobeinthecontextof
thatprovidedbythemanufacturer,forexample,indications,sideeffectsandlicencestatus.
[2004]
Details
Ascouldbeexpected,therewasconsiderableevidenceontheinformationneedsofindividualswith
epilepsyandotherswithregardtodrugtreatment,sideeffects,etc.However,nomentionof
preferredtimingwasgiven.
Othertreatment
Noevidenceontheinformationneedsofindividualsonnondrugtreatmentscouldbefound.
Remission
Mills1997
385
AUKquestionnairesurveyfoundthatin394adultswithepilepsy,peoplewhohadhadanattackin
thepast12monthsweremorelikelytowantdiscussionoftopics(causes,sideeffects,lawsetc),
TheEpilepsies
501
significantlysoforhospitalattendersbutnotforGPattenders.However,theperceivedadequacyof
informationwassimilarforbothsettings.
RefractoryEpilepsyandSurgery
carersasappropriateaboutthereasonsforconsideringsurgery.Thebenefitsandrisksofthe
surgicalprocedureunderconsiderationshouldbefullyexplainedbeforeinformedconsentis
obtained.[2004]
Evidencestatement
Individualswantaccurateandbalancedinformationonsurgery.(III)
Swarztrauber2003
386
Focusgroupinterviewswereconductedwithadults,includingasubgroupofAfricanAmericans,and
adolescentswithrefractoryepilepsy,andtheirparents.Theaimoftheinterviewswastodetermine
howindividualsfeltaboutcurrenttreatmentsforrefractoryepilepsyandtodescribetheir
experiences.
Adultswantedmoreinformationonthesurgicaltreatmentofepilepsy.Theyalsohadperceptionsof
exaggeratedrisksofsurgery,andmanyparticipantsfeltthatsurgerywasalastditcheffortand
experimental.Manyadultsfeltthatphysiciansportrayedsurgeryinanegativeway.
Parentswantedtheirchildrentobeabletotakepartinthedecisionaboutsurgerywhenthechild
wasoldenough.
Specialgroupsseerelevantsection.
12.4 WhatistheriskofSUDEPinindividualswithepilepsy
EvidenceStatement
Forthosewithsevereepilepsy,adeathrateof1:200peryearcanbeestimated,whereasona
populationbasistherateisbetween1:500and1:1000peryearimplyingthatformildidiopathic
epilepsytherateislessthan1:1000.Forthoseinremissiontheriskappearstobenegligible.(III)
Details
AsummaryoftheriskofdeathfromSUDEPinkeygroupsofpeoplewithepilepsywasrequestedby
theGDG.Thisinformationcouldbeusedinrecommendationsonindividualinformationandadvice.
AsystematicreviewoftheliteraturerelatingtotheincidenceandprevalenceofSUDEPandits
possibleriskfactorswasnotdoneforreasonspresentedinChapter2.
TheliteraturereviewonSUDEPfromtheSUDEPReport
18
ispresentedandafurtherreviewarticle
wasidentifiedthatsummarizedtheavailableevidenceonthemortalityassociatedwithepilepsyup
to1996.
387
Secondaryevidence
TheNationalSentinelClinicalAuditofEpilepsyRelatedDeath
18
Inchronicepilepsy,SUDEPisthemaincauseofexcessmortality,andinthisgroupofpeoplethe
mortalityratehasbeenfoundtobe4.5timeshigherthanexpected,withmorethanhalfattributed
toSUDEP.
17
IntheUKitisestimatedthat500deathsperannumareSUDEP.Youngpeoplewith
TheEpilepsies
502
severeepilepsyandlearningdisabilitymaybeatevenhigherriskofSUDEP,withonerecentstudy
showingadeathrate15.9timesgreaterthanexpected.
388
SUDEPisdefined
389
as:sudden,unexpected,witnessedorunwitnessed,nontraumaticand
nondrowningdeathinindividualswithepilepsy,withorwithoutevidenceforaseizure,andexcluding
documentedstatusepilepticus,inwhichpostmortemexaminationdoesnotrevealatoxicologicalor
anatomiccausefordeath.
CasecontrolstudieshavebeenusedtodeterminepossibleriskfactorsforSUDEP.Reportedrisk
factors
390
forSUDEPinclude:
youngage
generalisedtonicclonicseizures
uncontrolledepilepsy
learningdisability
seizuresoccurringduringsleep
unwitnessedseizuresandpooradherencetoantiepilepticdrugregimen.
Themostsignificantriskfactorshownbycasecontrolledstudies,however,istheoccurrenceof
seizures,andtheriskofSUDEPappearstobedirectlyrelatedtothefrequencyofseizures.
391
Indeed,
mostoftheexcessmortalityofepilepsyisrelatedtoseizurefrequency.Inarecentcasecontrol
study,Nilssonandcolleaguesreportedthatpeoplewhohadnotbeenseizurefreeduringtheyear
hada23foldincreasedofSUDEPcomparedtopeoplewithfullycontrolledseizures.
391
Tomson,
392
in
areviewofpublishedstudies,concludedthattheriskofSUDEPis40timeshigherinpeoplewho
continuetohaveseizures.Sperlingandcolleaguesfoundthateliminationofseizuresaftersurgery
reducedthemortalityrateinpeoplewithepilepsytoalevelindistinguishablefromthatofthe
generalpopulation.
393
Theysuggestedthatuncontrolledseizuresareamajorriskfactorforexcess
mortalityinepilepsy.ThereasonforthisrelationshipseemstobethatmostSUDEPsareseizure
related.
390,391,394,395
Inlinewithotherstudiesofriskitisimportantthattherelativeriskisnotusedaloneasthisdoesnot
indicatehowcommonoruncommontheconditionisinthepopulationunderstudy.Itisimportant
thatanindicationoftheabsoluteriskofSUDEPisgivenindifferentpopulationgroupswithepilepsy.
ODonoghue1997
387
Thisnarrativereviewclearlysetsoutthemethodologicalproblemsassociatedwiththeepidemiology
ofepilepsymortality.ThreestrategieshavebeenusedtostudytheincidenceofSUDEP:
1) ratesofdeathinlargepopulationusingdeathcertificatesandcoronersreports;
2) antiepilepticdrugprescriptionasasurrogateforthediagnosisofepilepsyand
3) followupofacohortofpeoplewithepilepsyforadefinedperiodoftime.
Approaches1&2haveparticularproblemsrelatingtotheaccuracyandcompletenessof
ascertainmentofthenumberofdeathsandthesizeofthepopulationstudied.Approach3isprone
toselectionbiasasthecohortstudiedmaybeattendeesatspecialisttertiarycentersratherthanthe
wholepopulationofpeoplewithepilepsy.
Theauthorsdiscussedtheevidenceinrelationtodifferentgroupsofpeoplewithepilepsy,identifying
thatthosewithrefractoryepilepsyawaitingsurgeryhavethehighestriskofSUDEPandthosein
remissionthelowestrate.Theydrewthefollowingconclusionsfromtheirreview:
Comparisonofpopulationbasedandcohortstudiesrevealedthatforthosewithsevereepilepsy,
adeathrateof1:200peryearcanbeestimated,whereasonapopulationbasistherateis
TheEpilepsies
503
between1:500and1:1000peryearimplyingthatformildidiopathicepilepsytherateislessthan
1:1,000.Forthoseinremissiontheriskappearstobenegligible.
387
TheEpilepsies
Womenofchildbearingagewithepilepsy
504
13 Womenofchildbearingagewithepilepsy
13.1 Introduction
Mostwomenwithepilepsywhoarereceivingoptimaltreatmentfortheirepilepsy,andwhoarewell
informed,supportedandfullycounselledhaveuncomplicatedpregnancies,normaldeliveries,and
healthychildren.
However,thereareanumberofimportanthealthrelatedissuesrelatingtothediagnosisofepilepsy
andtheuseofAEDsinwomenofchildbearingage.First,boththediseaseanditstreatmentmay
alterthemenstrualcycleandfertility.Second,thereareproblemswithdruginteractions,
particularlywithhormonalcontraceptives.Somemethodsofhormonalcontraceptionmaynotbeas
effectiveinwomentakingAEDS.TheeffectivenesswilldependonwhichAED(s)arebeingtaken.
Effectivecontraceptionhasanadditionalimportanceinwomenwithepilepsybecauseoftherisks
associatedwithanunplannedpregnancytothewomenandthedevelopingfetus.Third,AEDsare
associatedwithteratogeniceffects.Fourth,AEDsanduncontrolledseizurescancauseadverse
effectsduringpregnancy.Conversely,pregnancyandthemenstrualcyclecanaffectseizurecontrol
duetohormonallyinducedalterationoftheseizurethreshold.
396
13.2 Whatinformationandcounsellingshouldbegivenandwhen?
199. Inordertoenableinformeddecisionsandchoice,andtoreducemisunderstandings,women
andgirlswithepilepsyandtheirpartners,asappropriate,mustbegivenaccurateinformation
andcounsellingaboutcontraception,conception,pregnancy,caringforchildrenand
breastfeeding,andmenopause.[2004]
200. Informationaboutcontraception,conception,pregnancy,ormenopauseshouldbegivento
womenandgirlsinadvanceofsexualactivity,pregnancyormenopause,andtheinformation
shouldbetailoredtotheirindividualneeds.Thisinformationshouldalsobegiven,asneeded,
topeoplewhoarecloselyinvolvedwithwomenandgirlswithepilepsy.Thesemayincludeher
familyand/orcarers.[2004]
201. Allhealthcareprofessionalswhotreat,carefor,orsupportwomenandgirlswithepilepsy
shouldbefamiliarwithrelevantinformationandtheavailabilityofcounselling.[2004]
Evidencestatements
Womenwithepilepsywant,andneed,informationandcounsellingaboutissuesrelatingtoAED
therapyanditseffects,contraception,pregnancy,theriskofinheritance,andthemenopause.(III)
Informationispreferredbeforethetimeitisneeded.(III)
Details
Secondaryevidence
NosystematicreviewsofRCTsofinformationprovisionforwomenwithepilepsywereidentified.
Onesystematicreviewofotherevidencewasfound.Couldridgeandcolleaguesreviewedthe
primaryevidence(includingnonRCTstudies)ontheinformationandcounsellingneedsofpeople
withepilepsy,thepreferredformat,timing,anddeliveryofinformationandcounselling,andthe
outcomesofinformationgivingandcounselling.
372
TheEpilepsies
505
Noneofthe40includedstudiesreportedtheroleoreffectsofinformationorcounsellinginwomen
withepilepsyasagroup,althoughsomestudiesdidhavewomeninthestudypopulation.
Primaryevidence
NoRCTsontheeffectivenessofinformationgivingorcounsellingwereidentified.
Sincethepublicationofthesystematicreviewdescribedabove
372
,twolargesurveysofwomenwith
epilepsywerefound.
Crawford1999
397
CrawfordandLeereportedtheresultsofaquestionnairesurveyoffemalemembersoftheBritish
EpilepsyAssociation.1855questionnaires(fromatotalof6000)wereincludedintheresults
(responserate31%).
47%(n=89)ofwomentakingoralcontraceptionfelttheyhadnotbeengivenenoughinformation
abouttheoralcontraceptionpillandtheirAED(s).43%(n=637)reportedreceivingnoinformation
aboutpregnancy,and25%(n=459)haddiscussedpregnancywithnoone.Manywomenintendingto
havechildreninthesubsequenttwoyearsfelttheystillhadunansweredquestions(seeFigure111).
Figure2: Concernsaboutpregnancy
397
ModifiedfromSeizure,8,CrawfordPandLeeP,Gender
differenceinmanagementofepilepsyWhatwomenarehearing,pages1359,Copyright
(1999)withpermissionfromBEATradingLtd.
0
10
20
30
40
50
60
70
80
90
100
Not enough
information
given
Breast feeding Effects of
medication on
child
Increased
seizures
Ability to care
for the child
Effect of
epilepsy on
role as mother
Whether
medication
affects fertility
No previous children (n=117) Previous children (n=52)
TheEpilepsies
506
Overall,womenfelttherewasaneedformoreinformationaboutepilepsyandpregnancy.Thesurvey
concludedthatwomenwithepilepsywanted,andneeded,moreinformationandcounsellingaboutissues
relatingtocontraception,pregnancy,andthemenopause.
397
Crawford2003
398
In2001,theIdealWorldsurveyaimedtoassessthequalityofcurrenttreatmentinformationprovisionto
womenwithepilepsyatdifferentlifestages,andtoidentifytheinformationneedsandwantswithaviewto
ensuringthatallwomenwithepilepsyarecounselledappropriately,inatimelymanner,andareableto
makeinformedchoicesabouttheirtreatment.
Approximately12,000femalemembersofEpilepsyActionweresurveyed,andthequestionnairewasalso
postedontheEpilepsyActionwebsite.2,600questionnairesand90webresponseswerecompleted,and
2000responsesrandomlyselectedforanalysis.
Themostimportantissuesforwomenaged19to44yearswhowereconsideringhavingchildrenwere:
1. riskofepilepsy/medicationaffectingtheunbornchild(87%)
2. effectofpregnancyonseizurecontrol(49%)
3. riskofachilddevelopingepilepsy(42%)
Forwomenaged45yearsormore,themostimportantissueswere:
1. epilepsymedicationandosteoporosis(63%)
2. epilepsymedicationasyougetolder(57%)
3. changesinseizuresduringthemenopause(44%).
Mostwomen(84%)wantedtobebetterinformedabouttreatmentdecisions,and41%wantedtotakea
moreproactiveroleindiscussionsaroundtreatment.43%wantedmoreinformationsotheycouldaskfora
reviewoftheirmedication.57%wantedthelatestinformationonepilepsytreatmentandtheriskofbirth
defectsonanongoingbasis,evenifthedatawereincomplete.
Thepreferredtimingofreceivinginformationcanbeseenin13.2.
HudsonS,Understandingtheinformationneedsofwomenwithepilepsyatdifferentlifestages:
resultsofthe'IdealWorld'survey,pages5027,Copyright(2003)withpermissionfrom
BEATradingLtd.
EffectofEpilepsy
on:
Diagnosis
(%)
Before
Puberty
(%)
At
Puberty
(%)
Before
considering
pregnancy(%)
When
considering
pregnancy(%)
Approaching
menopause
(%)
Periods 35 32 15
Contraception 25 6 30 15 2 1
Pregnancy 17 2 10 42 9 1
Riskofchild
developing
epilepsy
19 1 5 41 15
AEDsand
pregnancyfetal
development
16 1 5 43 13
Menopause 19 58
TheEpilepsies
507
Thesurveyshowedconsistentlythatinformationispreferredbeforethetimeitisneeded.59%
wantedinformationinawrittenformat,and28%throughconversationwithahealthcare
professional.
398
13.3 Whatissuesshouldbeconsideredinwomenwhomaybecome
pregnantorwhoarebreastfeeding?
202. Womenandgirlsshouldbereassuredthatanincreaseinseizurefrequencyisgenerally
unlikelyinpregnancyorinthefirstfewmonthsafterbirth.[2004]
203. Theclinicianshoulddiscusswiththewomanandgirltherelativebenefitsandrisksof
adjustingmedicationtoenablehertomakeaninformeddecision.Whereappropriate,the
womanorgirlsspecialistshouldbeconsulted.[2004]
204. Generally,womenandgirlsmaybereassuredthattheriskofatonicclonicseizureduringthe
labourandthe24hoursafterbirthislow(14%).[2004]
205. Allwomenandgirlswithepilepsyshouldbeencouragedtobreastfeed,exceptinveryrare
circumstances.BreastfeedingformostwomenandgirlstakingAEDsisgenerallysafeand
shouldbeencouraged.However,eachmotherneedstobesupportedinthechoiceoffeeding
methodthatbestssuitsherandherfamily.[2004]
206. PrescribersshouldconsultindividualdrugadviceintheSPCandtheBNF(availableat
http://bnf.org)
gg
whenprescribingAEDsforwomenandgirlswhoarebreastfeeding.The
decisionregardingAEDtherapyandbreastfeedingshouldbemadebetweenthewomanorgirl
andtheprescriber,andbebasedontherisksandbenefitsofbreastfeedingagainstthe
potentialrisksofthedrugaffectingthechild.[2004,amended2012]
EvidenceStatements
Generally,seizurefrequencydoesnotchangeduringpregnancyorintheearlypuerperiuminwomen
withepilepsy.(IIb)
Inaminoritytheremaybeanincreaseinseizurefrequency(15%to37%).Theexplanationofan
increaseinseizurefrequencyisuncertain,butpotentialfactorsmayincludepooradherencewith
treatment,alteredAEDpharmacokineticsandsleepdeprivation.(IIb)
12%ofwomenwithactiveepilepsywillhaveatonicclonicseizureduringlabour,andafurther12%
inthefollowing24hours.(III)
Alltheolderantiepilepticdrugshavebeenassociatedwithmalformations,withsodiumvalproate
beingassociatedwithasignificantlyhigherriskofmalformationsthancarbamazepine.(IaNICE)
Multipledrugtherapyisassociatedwithagreaterrisk,althoughthismayberelatedtotheseverityof
themothersepilepsy.(IaNICE)
NohighqualityevidenceonthepossibleeffectsofAEDtherapywhilebreastfeedingwasfound.
Details
gg
Inthisrecommendation,theoriginalreferraltoappendix5oftheBNFhasbeenremovedandreplacedwithmoreupto
datesourcereferencematerialbecausethisappendixnolongerexistsandhasthereforebecomeobsoletesincethe
TheEpilepsies
508
Issuesare:
increasedriskofseizures
teratogeniceffectsofAEDs
effectiveness
sidesffects(seeSectionononPharmacologicaltreatment)
Evidencestatements,recommendationsandreviewsarepresentedforeachofthefourareasabove.
(Forsideeffects,seeSectiononPharmacologicaltreatment)
13.4 Increasedriskofseizuresduringpregnancyorwhilst
breastfeeding
Secondaryevidence
Nosystematicreviewsofseizurecontrolduringpregnancywereidentified.
Primaryevidence
Prospectivecohortstudiesthatassessedseizurefrequencyduringpregnancyinwomenwithepilepsy
wereincluded.
Fivestudieswereidentifiedthatmeasuredchangesinseizurefrequencyduringpregnancy(see13.3).
Foreachstudydifferentinclusioncriteriawereappliedtoparticipants,differenttimeperiodsand
differentdefinitionsofincreasedordecreasedseizurerateswereused.Ifnodefinitionofseizure
ratechangewasgiven,thestudywasexcluded.
TheEpilepsies
Table29: Seizurefrequencyduringpregnancyandpuerperium
Study Participants
Numberof
participants Definitionofseizureratechange(s) Increased Unchanged Decreased
Bardy1987
399
Womenwhohadat
least2epileptic
seizuresfulfillingthe
criteriaoftheWHO
DictionaryofEpilepsy,
withthefirstseizure
occurringbefore
pregnancy
154pregnanciesin
140women
Increasedifthenumberofseizureswas200%
ormoreduringpregnancyand3monthsafter
thaninthe12monthsbefore
Decreasedifthenumberofseizureswas50%
orlessduringpregnancyand3monthsafter
thaninthe12monthsbefore
32% 54% 15%34
Gjerde1988
400
Womenwhohad
epilepsyandusedone
ormoreAEDsforat
leastoneyearpriorto
pregnancy
78pregnanciesin
66women
Increasediftherewasatleastonemore
seizureduringpregnancythaninthe9month
beforepregnancy
Decreasediftherewasatleastoneless
seizureduringpregnancythaninthe9month
beforepregnancy
17% 67% 17%
Schmidt1983
401
Womenwhohadthree
ormoreverified
epilepticseizureswho
completedthe
pregnancy
136pregnanciesin
122women
Increasedordecreasediftheactualseizure
frequencychanged,ratherthanapercentage
(ieonemoreoronelessseizure)during
pregnancyand3monthsfollowingdelivery
comparedwiththe9monthsbefore
pregnancy
37% 50% 13%
Tanganelli1992
402
Womenwithepilepsy 138pregnanciesin
97women
Increasedordecreasedfrequencydefinedas
a10%ormorechangeduringpregnancy
whencomparedwiththe9monthspriorto
pregnancy
17% 80% 3%
Tomson1994
403
Womenwhowere
treatedwithAEDsfor
epilepsysincethe
beginningofpregnancy
93pregnanciesin
70women
Changeinseizurefrequencywasdefinedasa
movementfromonefrequencycategoryto
another(fivecategoriesrangingfromseizure
freetooneseizureaweekormore)whenthe
rateduringpregnancywascomparedwiththe
15% 61% 24%
34
Percentages may not add to 100% due to rounding errors
TheEpilepsies
Study Participants
Numberof
participants Definitionofseizureratechange(s) Increased Unchanged Decreased
9monthspriortothepregnancy
TheEpilepsies
511
Schmidtandcolleaguesassessedthefactorsassociatedwithincreasedseizuresandfoundthatnon
adherencetomedication,sleepdeprivation,andinadequatetherapyinfluencedseizurerate.
Threestudies
399,401,402
reportedseizurefrequencyinthefirst3monthsafterthebirth.
Bardyfoundastatisticallysignificantincreaseincomplexfocalseizuresduringtheearlypuerperium
(p<0.001).
399
IncreasedseizureswereseeninsixpregnanciesintheSchmidtstudy
401
andnonadherenceandsleep
deprivationwereassociatedwithfiveofthese.
TanganelliandRegesta
402
reportedthatduringthepuerperium,seizurefrequencyreturnedtopre
pregnancylevelsinallbuttwowomen(2%,n=2/97).
Twostudiesreportedseizuresinlabour.In97womenwithepilepsy,noseizuresduringlabour
occurred.Intheotherstudy,
399
seizuresoccurredduringlabourin10cases,anincidenceninetimes
greaterthantheaverage.
Bardy
404
alsoreportedthatageneralisedtonicclonicseizureoccurredinlabourinapproximately1
2%ofwomenwithepilepsy,andwithin24hoursofdeliveryinanother12%.
Therearetwomainsourcesofpossiblebiasinallofthetrialsabove:
1. becausethehistoryofseizurefrequencybeforepregnancyreliesonrecallbythewomanandher
family(andinsomestudies,frommedicalrecords)theremaybeanunderestimateofseizure
frequencybeforepregnancy.
2. becausenoneofthestudiescompareseizureratesinpregnantwomenwiththoseinwomenwho
arenotpregnant,someofthechangesinratemaybeduetorandomfluctuationsintheepilepsy,
ratherthantheeffectofpregnancy.
13.5 TeratogeniceffectsofAEDswhilstpregnant
13.5.1 Introduction
Itisrecognisedthatanunbornchildmaybeputatriskifexposedtotoxins,ofwhichalcoholand
drugs,includingprescribedmedicationareexamples.Exposuretoantiepilepticdrugs(AEDs)during
pregnancyisassociatedwithanincreasedriskofcongenitalmalformations,andmayhaveanadverse
effectonfetalgrowthandpsychomotordevelopment.AlthoughdataonolderAEDsandriskof
congenitalmalformationhasbeenevident,thatonneweragentsisonlyjustbeingaccumulated
throughpregnancyregistries.Further,dataonlongertermeffectsonneurodevelopmentofchildren
exposedinuterocanonlybeobtainedthroughprospectivestudydesign.Itisimportantthat
appropriateaccurateinformationismadeavailabletowomensothatinformedchoicescanbemade.
Forthisreviewweincludedchildrenofpregnantwomenwithepilepsywhowereexposedtooneor
moreAEDspriortodelivery.Comparisongroupsincludedchildrenofwomenwithepilepsywho
werenotexposedtoAEDsandchildrenofwomenfromthegeneralpopulation(withoutepilepsy).
Welookedfordataspecificallyontheproportionofchildrenbornwithmajormalformations,the
proportionofchildrenbornwithminormalformations,theincidenceofmiscarriageand
developmental/cognitiveoutcomes.Wefoundseveralsystematicreviewsforthisreviewand
thereforedidnotperformareviewforindividualstudies.Thesystematicreviewsincluded
prospectivecontrolledcohortsandcasecontrolstudies.
TheEpilepsies
512
Whenthesystematicreviewsprovidedinformationontheindividualsincludedinthestudiesthe
resultsofeachstudywerepresentedseparatelyinthisreview.However,whenthesystematic
reviewspresentedpooleddataandametaanalysiscouldbeperformedtheresultswerepresented
inthisway.Thisevidencereviewisdividedintwosectionsbasedonthetypesofoutcomesreviewed:
Thefirstsectionpresentsevidenceforminor/majormalformationsandmiscarriage:Weuseda
systematicreviewandmetaanalysis(Meador,2008)
405
ofpublishedpregnancyregistriesand
cohortstopresenttheincidenceofminormalformations,majormalformationsandmiscarriage
followinginuteroantiepilepticdrugexposure.Thissystematicreviewincludedstudieswithatleast
100totalpregnanciesorbirths.
Thesecondsectionpresentsevidencefordevelopmental/cognitiveoutcomes:WeusedaCochrane
review(Adab,2004)
406
andametaanalysisofcohortstudies(Banach,2010)
407
forinformationon
thedevelopmental/cognitiveoutcomes.Adab(2004)
406
includedphenobarbital,phenytoin,
carbamazepine,oxcarbazepine,sodiumvalporate,lamotrigine,topiramate,gabapentin,vigabatrin,
tiagabineandzonisamide.TheseAEDswereeithertakenasmonotherapyorpolytherapy.The
Banach(2010)
407
reviewincludedsodiumvalproate.
Table30: Cognitivescales
Fullnameofthe
scale
Scales
abbreviations
Briefdescription Scoring
Bayleyscalesof
development
Anagestandardisedtest
ofinfantdevelopment
betweenonemonthto42
months.Measure
developmentin3
domains;cognitive,motor
andbehavioural.
Significantdelayforscores
with2SDbelowthemean,
e.g.score<70.
Griffithschild
developmentscale
Assess5areasofchildren
development;locomotor,
personal,social,hearing
andspeech,eyeandhand
coordination,
performance.2scalesfor
children02yearsand28
years.
Eachscalescored
independentlyand
summatingallthe
subscalesgiventhetotal
DQ.Globaldelayisa
DQ<70.
Wechsler
Intelligencescale
forchildren
WISC
Ameasureofgeneral
intellectualfunctioningfor
childrenaged616years.
12subsetsassessing2
areasofintelligence:
verbalIQ(VIQ)and
performance(PIQ),
summatedprovidea
compositescore(FSIQ).
Wechslerpreschool
andprimaryscale
intelligence
WIPPSI Ameasureofgeneral
intellectualfunctioningfor
ColumbiaMental
Maturityscale
CMMS
Assessgeneralreasoning
abilityinchildrenaged39
years.
Rawscore,agedeviation
score,percentilerank,
stanineandmaturity
index.
Illinoistestof
psycholinguistic
abilities
ITPA
Ameasureofusedand
acquisitionoflanguagefor
10subsetsand2
supplementarysubsets.
Rawscoresusedtoderive
acompositescore,
TheEpilepsies
513
Fullnameofthe
scale
Scales
abbreviations
Briefdescription Scoring
psycholinguisticagescores
andpsycholinguistic
quotientsforsubtestsand
composite.
Frostigtestofvisual
perception
FTVP
Assessvisualperception
skillsinchildrenaged48
years.
5subsets.Rawscores
obtainedforeachsubset
andconvertedtoage
equivalentsorperceptual
ages(Pas)andScaleScores
(SS);totalscoreexpressed
inPerceptualQuotient.
LincolnOseretzky
testofMotor
Performance
LOS
Ameasureofmotor
performanceforchildren
614years.
36subscales.Scores
presentedaspercentile
ranksforeachagelevel.
McCarthyScales McC
Ameasurementdeviceto
assesstheabilitiesof
preschoolchildren2.58.5
years.
Sixscalescores:verbal,
perceptualperformance,
quantitative,general
cognitive,memory,motor.
Leiterinternational
performancescale
LIPS
Nonverbaltestof
intelligence.Assess
intellectualability,
memoryandattentionfor
thosewhomtraditional
testcouldnotbeused
between220years.
2mainbatteries;
visualisationandreasoning
(VR)andattentionand
memory(AM).Each
batteryprovidesa
measureofIQSCORES.
Neuropsychological
testbattery
adaptedfromLuria
NEPS Astandardizedtest
batteryusedinthe
screeningandevaluation
ofneuropsychologically
impairedindividuals13
yearsoldandolder
Itconsistsof269itemsin
11clinicalscales.Scores
forthreesummaryscales
canalsobecalculated:
pathognomonic,right
hemisphere,andleft
hemisphere.
Schoolcareer
Beingininappropriate
classforageandlearning
disorders
Frequency(proportion)
Dutchtest 3subtests;reading,
spelling,arithmetic.
Proportionofchildren
withscore<10thcentile
13.5.2.1 Incidenceofmalformations
Clinicalevidence
TheEpilepsies
514
Evidencestatements
Congenitalmalformationsstatisticallysignificantresults
Significantlymorechildren(includingthoseofpregnanciesthatdidnotcometoterm)ofwomen
takingthefollowingAEDshadcongenitalmalformationscomparedtogeneralpopulation:
sodiumvalproate
phenobarbitalandoneotherAED
phenytoinandoneotherAED
sodiumvalproateandoneotherAED
phenobarbitalandtwootherAEDs
phenytoinandtwootherAEDs
sodiumvalproateandtwootherAEDs
SignificantlymorechildrenofwomentakingthefollowingAEDswerebornwithcongenital
malformationscomparedtogeneralpopulation:
carbamazepine
sodiumvalproate
Costeffectiveness
NoeconomicevidencecomparingexposuretoanyAEDtononexposureinthegeneralpopulation
wasidentified.
13.5.2.2 Incidenceofcongenitalmalformations/otherpregnancyoutcomesinchildrenexposedinuteroto
monotherapycomparedtogeneralpopulation
Evidencestatements
Congenitalmalformations/otherpregnancyoutcomesstatisticallysignificantresults
Theincidenceofstillbirthwassignificantlyhigherinchildrenexposedinuterotomonotherapywith
antiepilepticmedicationcomparedtochildreningeneralpopulation,howeverthereisuncertainty
overthemagnitudeofitseffect.(VERYLOWQUALITY)^
Theincidenceofspontaneousabortionswassignificantlyhigherinchildreningeneralpopulation
comparedtochildrenexposedinuterotomonotherapy.(VERYLOWQUALITY)^
Theincidenceofelectiveabortionswassignificantlyhigherinchildreningeneralpopulation
comparedtochildrenexposedinuterotomonotherapy.(VERYLOWQUALITY)^
Theincidenceofbirthswithcongenitalmalformationwassignificantlyhigherinchildrenexposedin
uterotomonotherapycomparedtochildreningeneralpopulation.(VERYLOWQUALITY)^
TheEpilepsies
515
Theincidenceofperinataldeathswassignificantlyhigherinchildrenexposedinuteroto
monotherapycomparedtochildreningeneralpopulation.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretoanymonotherapytononexposureinthegeneral
populationwasidentified.
polytherapycomparedtogeneralpopulation
Clinicalevidence
Evidencestatements
Theincidenceofspontaneousabortionswassignificantlyhigherinchildreningeneralpopulation
comparedtochildrenexposedinuterotopolytherapy.(VERYLOWQUALITY)^
Theincidenceofelectiveabortionswassignificantlyhigherinchildreningeneralpopulation
comparedtochildrenexposedinuterotopolytherapy.(VERYLOWQUALITY)^
Theincidenceofelectiveabortionsduetomalformationswassignificantlyhigherinchildrenexposed
inuterotopolytherapycomparedtochildreningeneralpopulation,howeverthereisuncertainty
overthemagnitudeofitseffect.(VERYLOWQUALITY)^
uterotopolytherapycomparedtochildreningeneralpopulation.(VERYLOWQUALITY)^
Theincidenceofcongenitalmalformations(totalevents)wassignificantlyhigherinchildrenexposed
inuterotopolytherapycomparedtochildreningeneralpopulation.(VERYLOWQUALITY)
Theincidenceofperinataldeathswassignificantlyhigherinchildrenexposedinuterotopolytherapy
comparedtochildreningeneralpopulation.(VERYLOWQUALITY)^
Costeffectiveness
Noeconomicevidencecomparingexposuretoanypolytherapytononexposureinthegeneral
monotherapycomparedtopolytherapy
Clinicalevidence
TheEpilepsies
516
Evidencestatements
uterotopolytherapycomparedtochildreninmonotherapy.(VERYLOWQUALITY)
Theincidenceofcongenitalmalformationwassignificantlyhigherinchildrenexposedinuteroto
polytherapycomparedtochildreninmonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretoanypolytherapytoexposuretoanymonotherapywas
identified.
13.5.3 Comparisonbetweenspecificmonotherapiesondevelopmental/cognitiveoutcomes
13.5.3.1 Phenytoinversuscarbamazepine
Clinicalevidence
Evidencestatements
Developmental/Cognitiveoutcomesstatisticallynonsignificantresults
followingdevelopmental/cognitivescales:
Bayleyscale(mental,motor,language,cognitive)(VERYLOWQUALITY)
McCarthyscaleofchildrensabilities(GCIT,verbal,perceptual,quantitative,memory,motor
over30months(VERYLOWQUALITY)
Reynellstandardscores(comprehension,expressive)(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenytoinmonotherapytocarbamazepinemonotherapywas
identified.
13.5.3.2 Phenytoinversusphenobarbital
Clinicalevidence
Evidencestatements
TheEpilepsies
517
Developmental/cognitiveoutcomesstatisticallynonsignificantresults
Nosignificantdifferencebetweenphenytoinmonotherapyandphenobarbitalmonotherapyforthe
followingdevelopmental/cognitivescales:
Geselldevelopmentalschedules(VERYLOWQUALITY)
mentaldevelopment(8months)(VERYLOWQUALITY)
motordevelopment(8months)(VERYLOWQUALITY)
IQ(4years)(VERYLOWQUALITY)
WISC/WPPSI(49years)(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenytoinmonotherapytophenobarbitalmonotherapywas
identified.
Clinicalevidence
Evidencestatements
theDutchtest(nonoptimalschoolcareer,poorreading,poorarthemetic,poorspelling)(VERYLOW
QUALITY).
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalmonotherapytocarbamazepinemonotherapywas
identified.
13.5.3.4 Sodiumvalproateversuscarbamazepine
Clinicalevidence
Evidencestatements
Developmental/cognitiveoutcomesstatisticallysignificantresults
TheEpilepsies
518
Childrenexposedtosodiumvalproatemonotherapyscoredsignificantlylowercomparedtochildren
exposedtocarbamazepinemonotherapyinuterofor:
WPPSI/WISCrevisedverbalIQscale,howeverthereisuncertaintyoverthemagnitudeofthis
effect.(VERYLOWQUALITY)
Bayleyscalesmentalanddifferentialabilityscale,howeverthereisuncertaintyoverthe
magnitudeofthiseffect.(VERYLOWQUALITY)
fortheproportionofchildrenwithmildtoseveredevelopmentaldelay(4mths10years)
forthefollowingdevelopmental/cognitivescales:
WPPSI/WISCrevisednonverbalIQscale(VERYLOWQUALITY)
WPPSI/WISCrevisedfullscale(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytocarbamazepinemonotherapy
wasidentified.
13.5.3.5 Sodiumvalproateversusphenytoin
Clinicalevidence
Evidencestatements
NosignificantdifferenceontheBayleyscaleinchildrenexposedtosodiumvalproateandphenytoin.
(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytophenytoinmonotherapywas
identified.
13.5.3.6 Sodiumvalproateversuslamotrigine
ClinicalEvidence
TheEpilepsies
519
Evidencestatements
ChildrenexposedtosodiumvalproatescoredsignificantlylowerontheBayleyscalecomparedto
childrenexposedtolamotrigine.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytolamotriginemonotherapywas
identified.
13.5.4 Anymonotherapyexposureversusnoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
Childrenexposedtomonotherapyscoredsignificantlylowercomparedtononexposedchildrenin
generalpopulationfor:
WPPSI(performanceandtotalscale)(1020years)(VERYLOWQUALITY)
LOSscale(46years)(VERYLOWQUALITY)
WISCperformanceIQ(1019years)(VERYLOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtomonotherapyandnonexposedchildrenin
generalpopulationfortheproportionofchildrenwithborderlineintelligenceandchildrenwith
learningdisabilities(VERYLOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtomonotherapyandnonexposedchildrenin
generalpopulationforthefollowingdevelopmental/cognitivescales:
BayleyScales(mental,motor)(15months)(VERYLOWQUALITY)
WPPSI(verbal,performance)(46years)(VERYLOWQUALITY)
CMMSscale(46years)(VERYLOWQUALITY)
WPPSI(verbal)(1020years)(VERYLOWQUALITY)
ITPAscale(46years)(VERYLOWQUALITY)
FTVPscale(46years)(VERYLOWQUALITY)
McCarthyTscores(46years)(VERYLOWQUALITY)
WISCscale(verbal,totalIQ)(1019years)(VERYLOWQUALITY)
TheEpilepsies
520
WPPSI(5.5years)(VERYLOWQUALITY)
LIPSscale(5.5years)(VERYLOWQUALITY)
WPPSIR(verbal,nonverbal,fullscale)(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretoanymonotherapytononexposureinthegeneral
13.5.4.1 Carbamazepineexposureversusnoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
Childrenexposedtocarbamazepinescoredsignificantlylowercomparedtononexposedchildrenin
McCarthyGCI,verbal,perceptual,quantitative,memoryandmotorscores(earlyyears)(VERY
LOWQUALITY)
Bayleymentaldevelopmentindex(earlyyears)(VERYLOWQUALITY)^
McCarthyGlobaldevelopmentindex(earlytoschoolyears)(VERYLOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtocarbamazepineandnonexposedchildrenin
ReynellScales(comprehension,expressive)(earlyyears)(VERYLOWQUALITY)
BayleScales(mental,performance,cognitive,language,motor)(earlyyears)(VERYLOW
QUALITY)
Griffithschilddevelopmentscale(earlyyears,earlytoschoolyears)(VERYLOWQUALITY)
McCarthy(earlytoschoolyears)(VERYLOWQUALITY)
Dutchtestforpooroutcomes(reading,spelling,arithmetic,schoolcareer)(earlytoschool
years)(VERYLOWQUALITY)
WPPSIR/WISCR(verbal,nonverbalIQ,fullscale)(earlytoschoolyears)(VERYLOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretocarbamazepinetononexposureinthegeneral
TheEpilepsies
521
13.5.4.2 Phenytoinexposureversusnoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
Childrenexposedtophenytoinscoredsignificantlylowercomparedtononexposedchildrenin
Bayleyscalelanguage(earlytoschoolyears)(LOWQUALITY)
McCarthyscale(GCI,verbal,perceptual,quantitative)((earlytoschoolyears)(LOWUALITY)^
Reynellscale(comprehension,expressive)(earlytoschoolyears)(LOWQUALITY)
IQ(4years)(LOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtophenytoinandnonexposedchildrenin
Griffithschilddevelopmentindex(VERYLOWQUALITY)
Mentalscale(specifictestsnotdetailed)(8months)(VERYLOWQUALITY)
Motorscale(specifictestsnotdetailed)(8months)(VERYLOWQUALITY)
Geselldevelopmentquotient(VERYLOWQUALITY)
Bayleyscales(MDI,PDI,cognitive,language,motor)(VERYLOWQUALITY)
McCarthyscales(memory,motor)(VERYLOWQUALITY)
WISC/WIPPSI(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretophenytointononexposureinthegeneralpopulation
wasidentified.
13.5.4.3 Phenobarbitalexposureversusthosenoexposureingeneralpopulation
Clinicalevidence
TheEpilepsies
522
Evidencestatements
Significantlymorechildrenexposedtophenobarbitalcomparedtononexposedchildreningeneral
populationhadlowscores(<10thcentile)in:
Dutchtestforspelling(LOWQUALITY)
Dutchtestforarithmetic(LOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtophenobarbitalandnonexposedchildrenin
Mentaldevelopmentscale(specifictestsnotdetailed)(VERYLOWQUALITY)
Motordevelopmentscale(specifictestsnotdetailed)(VERYLOWQUALITY)
Geselldevelopmentquotient(VERYLOWQUALITY)
IQtest(notspecified)(VERYLOWQUALITY)
Dutchtestforreading(VERYLOWQUALITY)
Schoolcareer(VERYLOWQUALITY)
WISC/WIPPSI(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretophenobarbitaltononexposureinthegeneral
13.5.4.4 Sodiumvalproateexposureversusnoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
Childrenexposedtosodiumvalproatescoredsignificantlylowerthannonexposedchildreninthe
generalpopulationintheWPPSIR/WISCRverbalIQscale.(VERYLOWQUALITY)
NosignificantdifferencewasfoundoneitherscaleofIQ(performanceandfullscale)between
childrenexposedtosodiumvalproateinuteroandgeneralpopulation(nonexposedchildrenofnon
epilepticmothers)(VERYLOWQUALITY).
TheEpilepsies
523
NosignificantdifferencewasfoundonnonverbalandfullscaleofWPPSIR/WISCRbetweenchildren
exposedtosodiumvalproateinuteroandgeneralpopulation(nonexposedchildrenofnonepileptic
mothers)(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingexposuretosodiumvalproatetononexposureinthegeneral
13.5.4.5 ComparisonofanyAEDversusnoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
ChildrenexposedtoanyAEDcomparedtononexposedchildreningeneralpopulationhad
significantlylowscoresin:
Bayleyscale(motor,homeinventory)(15months)(VERYLOWQUALITY)
Geselldevelopmentscale(1836months)(VERYLOWQUALITY)
Enjohijistest(fundamentalhabits,humanrelationships,speech,languageininfants<24
months)(fundamentalhabits,bodymovement,handmovement,humanrelationships,
speech,languageininfants2453months)(VERYLOWQUALITY)
WPPSIscale(5.5years)(VERYLOWQUALITY)
proportionofchildrenwithspecificcognitivedysfunction(VERYLOWQUALITY)
WPPSIscale(verbal,performance)(46years)(VERYLOWQUALITY)
CMMSscale(VERYLOWQUALITY)
FTVPscale(VERYLOWQUALITY)
LOSscale(VERYLOWQUALITY)
WPPSI/WISCscale(proportionofchildrenwithIQ<90)(49years)(VERYLOWQUALITY)
WPPSI/WISCscale(proportionofchildrenwithlanguagedisability),howeverthereis
uncertaintyoverthemagnitudeofitseffect(49years)(VERYLOWQUALITY)
WPPSI/WISCscale(fullscale)(48years)(VERYLOWQUALITY)
WISCscale(verbal,performance)(48years)(VERYLOWQUALITY)
VMIscale(48years)(VERYLOWQUALITY)
TheEpilepsies
524
NosignificantdifferencebetweenchildrenexposedtoanyAEDandnonexposedchildreningeneral
populationforthefollowingdevelopmental/cognitivescales:
Griffithsdevelopmentscale(VERYLOWQUALITY)
Enjohijistest(body,handmovementininfants<24months)(VERYLOWQUALITY)
Proportionofchildrenwithmentaldeficiency,borderlineintelligence(5.5years)(VERYLOW
QUALITY)
ITPAscale(VERYLOWQUALITY)
McCarthyscale(VERYLOWQUALITY)
WPPSI/WISCscale(proportionofchildrenwithlearningdisabilities)(49years)(VERYLOW
QUALITY)
WPPSI/WISCscale(proportionofchildrenwithspecialeducationneeds)(49years)(VERY
LOWQUALITY)
ITPA(auditoryassociation,grammaticclosure)(48years)(VERYLOWQUALITY)
Griffithsscale(locomotorfunction,personalandsocialbehaviour,hearingandspeech,eye
andhandcoordination,performance,practicalreasoning)(VERYLOWQUALITY)
Dutchtest(reading,spelling,arithmetic)(713years)(VERYLOWQUALITY)
Schoolcareer(713years)(VERYLOWQUALITY)
Costeffectiveness
NoeconomicevidencecomparingexposuretoanyAEDtononexposureinthegeneralpopulation
wasidentified.
13.5.4.6 Anypolytherapyexposureversusthosenoexposureingeneralpopulation
Clinicalevidence
Evidencestatements
Childrenexposedtopolytherapycomparedtononexposedchildreningeneralpopulationhad
BayleyMotorscale(15months)(VERYLOWQUALITY)
CMMSscale(46years)(VERYLOWQUALITY)
WPPSIverbalscale(46years)(VERYLOWQUALITY)
WPPSIperformancescale(46years)(VERYLOWQUALITY)
TheEpilepsies
525
McCarthyscale(46years)(VERYLOWQUALITY)
WPPSIscale(verbal,performance,totalscale)(1020years)(VERYLOWQUALITY)
WPPSIR/WISCRverbalIQscale(VERYLOWQUALITY)
Nosignificantdifferencebetweenchildrenexposedtopolytherapyandnonexposedchildrenin
BayleyMentalscale(15months)(VERYLOWQUALITY)
proportionofchildrenwithmildseveredevelopmentaldelay(earlytoschoolyears)(VERY
LOWQUALITY)
LOSscale(VERYLOWQUALITY)
WISCscale(verbalIQ,performanceIQ,totalIQ)(1019years)(VERYLOWQUALITY)
proportionofchildrenwithborderlineintelligence(VERYLOWQUALITY)
proportionofchildrenwithlearningdisability(VERYLOWQUALITY)
WPPSIR/WISCRscale(nonverbalIQ,totalscale)(VERYLOWQUALITY)
Costeffectiveness
13.5.4.7 AnyAEDexposureinuteroversusnoexposureinchildrenofmotherswithepilepsy
Clinicalevidence
Evidencestatements
Childrenexposedtopolytherapycomparedtononexposedchildreningeneralpopulationhad
WPPSIPerformancescale(46years)(VERYLOWQUALITY)
Bayleyscale(mental,motor,homeinventory)(15months)(VERYLOWQUALITY)
WPPSIscale(5.5years)(VERYLOWQUALITY)
TheEpilepsies
526
Dutchtest(reading,spelling,arithmetic)(VERYLOWQUALITY)
Schoolcareer(713years)(VERYLOWQUALITY)
WPPSIVerbalscale(46years)(VERYLOWQUALITY)
LOSscale(46years)(VERYLOWQUALITY)
McCarthyscale(46years)(VERYLOWQUALITY)
WPPSIscale(verbal,performance,totalIQ)(1020years)(VERYLOWQUALITY)
Costeffectiveness
13.5.4.8 Anymonotherapyexposureversusnoexposureinchildrenofmotherswithepilepsy
Clinicalevidence
Evidencestatements
Dutchtest(reading,spelling,arithmetic)(713years)(VERYLOWQUALITY)
schoolcareer(713years)(VERYLOWQUALITY)
WISCscale(verbal,performance,totalIQ)(1019years)(VERYLOWQUALITY)
WPPSIscale(verbal,performance,totalIQ)(VERYLOWQUALITY)
Costeffectiveness
TheEpilepsies
527
13.5.4.9 Carbamazepineexposureversusnoexposuretochildrenofwomenwithepilepsy
Clinicalevidence
Evidencestatements
NosignificantdifferencewasfoundonanyscaleofWPPSIR/WISCRbetweenchildrenexposedto
carbamazepineinuteroandchildrenofwomenwithepilepsynotexposedtocarbamazepinein
utero.(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingexposuretocarbamazepinetononexposureinwomenwith
epilepsywasidentified.
13.5.4.10 Sodiumvalproateexposureversusnoexposuretochildrenofwomenwithepilepsy
Clinicalevidence
Evidencestatements
Childrenexposedtosodiumvalproatescoredsignificantlylowerthannonexposedchildrenof
womenwithepilepsyin:
WPPSIR/WISCRverbalIQ(VERYLOWQUALITY).
NosignificantdifferencewasfoundonWPPSIR/WISCR(nonverbal,fullscale)betweenchildren
exposedtosodiumvalproateinuteroandnonexposedchildrenofepilepticmothers(VERYLOW
QUALITY).
NosignificantdifferencewasfoundoneitherscaleofIQ(verbal,performanceandfullscale)between
childrenexposedtosodiumvalproateinuteroandnonexposedchildrenofepilepticmothers(VERY
LOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingexposuretosodiumvalproatetononexposureinwomenwith
epilepsywasidentified.
TheEpilepsies
528
Recommendation
207. Discusswithwomenandgirlsofchildbearingpotential
(includingyounggirlswhoarelikelytoneedtreatmentinto
theirchildbearingyears),andtheirparentsand/orcarersif
appropriate,theriskofAEDscausingmalformationsand
possibleneurodevelopmentalimpairmentsinanunborn
child.Assesstherisksandbenefitsoftreatmentwith
individualdrugs.Therearelimiteddataonriskstotheunborn
childassociatedwithnewerdrugs.Specificallydiscusstherisk
ofcontinueduseofsodiumvalproatetotheunbornchild,
beingawarethathigherdosesofsodiumvalproate(more
than800mg/day)andpolytherapy,particularlywithsodium
valproate,areassociatedwithgreaterrisk.[new2012]
outcomes
TheGDGplacedgreaterimportanceontheincidenceofmajor
malformations,miscarriagesandneurodevelopmentaloutcomes
forthechildofamotherwithepilepsy.
benefitsandharms
Theriskofharmtomotherandunbornchildfromseizuresneeds
tobebalancedagainsttheriskofharmfromantiepileptic
effectivenessofAEDsusedtotreatpregnantwomenwith
epilepsy.Noeconomicevaluationhaseverincorporated
teratogenicityintoitsclinicaloutcomes.TheGDGconsideredthat
bothreducedseizurecontrolandpotentialharms(malformations
andneurodevelopmentaldelay)havecostandqualityoflife
implicationsformotherandunbornchild.Drugsanddosesthat
maybecosteffectiveinthegeneralepilepsypopulation,suchas
sodiumvalproate,maynotbeascosteffectiveinthisgroupdue
toitspotentialteratogeniceffect.
Qualityofevidence Evidencecomesfromthreesystematicreviews;onereview
focusedonincidenceofmalformationandtheothertwoonchild
neurodevelopmentaloutcomes.NoindividualRCTswere
reviewed.ThisrecommendationwasalsobasedonGDG
consensusopinion.
Otherconsiderations Thisrecommendationwasupdatedandamendedfromthefirst
editionofthisguideline(2004).
TheEpilepsies
529
Recommendation
208. Beawareofthelatestdataontheriskstotheunbornchild
associatedwithAEDtherapywhenprescribingforwomenand
girlsofpresentandfuturechildbearingpotential.[2012]
outcomes
Seizurefreedomandadverseeventsinthemotherand
malformationsandneurodevelopmentaldelayinthechildwere
benefitsandharms
Risksofseizureexacerbationorrelapsewithreductionindoseof
AEDneedtobebalancedagainsttheriskofharmfrom
antiepilepticmedicationtakenbythemotherinpregnancy.
Noeconomicevaluationhaseverincorporatedteratogenicityinto
itsclinicaloutcomes.TheGDGconsideredthatbothreduced
seizurecontrolandpotentialharms(malformationsand
neurodevelopmentaldelay)havecostandqualityoflife
implicationsformotherandunbornchild.TheGDGfeltthatif
healthcareprofessionalsareawareofthemostuptodatedataon
theteratogenicrisksofdifferentAEDs,thenwellinformed
prescribingdecisionscanbemade.
Qualityofevidence
ThisrecommendationwasbasedonGDGconsensusopinion.
Otherconsiderations Thisrecommendationisunchangedfromthe2004editionofthis
guideline.TheGDGconsideredthisrecommendationtobestill
validinlightofthereviewedevidenceforthe2012update.
TheEpilepsies
530
Recommendation
209. Aimforseizurefreedombeforeconceptionandduring
pregnancy(particularlyforwomenandgirlswithgeneralised
tonicclonicseizures)butconsidertheriskofadverseeffects
ofAEDsandusethelowesteffectivedoseofeachAED,
avoidingpolytherapyifpossible.[new2012]
outcomes
Seizurefreedomandadverseeventsinthemotherand
malformationsandneurodevelopmentaldelayinthechildwere
benefitsandharms
Risksofseizureexacerbation/relapsewithreductionindoseofAED
needtobebalancedagainsttheriskofharmfromantiepileptic
Noeconomicevaluationhaseverincorporatedteratogenicityinto
itsclinicaloutcomes.TheGDGconsideredthatbothreduced
seizurecontrolandpotentialharms(malformationsand
neurodevelopmentaldelay)havecostandqualityoflife
implicationsformotherandunbornchild.Drugsanddosesthat
maybecosteffectiveinthegeneralepilepsypopulation,suchas
sodiumvalproate,maynotbeascosteffectiveinthisgroupdueto
itspotentialteratogeniceffect.
Qualityofevidence
Recommendation
210. Discusswithwomenandgirlswhoaretakinglamotrigine
thatthesimultaneoususeofanyoestrogenbased
contraceptivecanresultinasignificantreductionof
lamotriginelevelsandleadtolossofseizurecontrol.Whena
womanorgirlstartsorstopstakingthesecontraceptives,the
doseoflamotriginemayneedtobeadjusted.[new2012]
outcomes
Seizurefreedom,adverseeffectandeffectivecontraceptivewere
benefitsandharms
Interactionbetweenlamotrigineandanyoestrogenbased
contraceptivemayreducelamotriginesanticonvulsanteffect
becauseofhepaticmetabolism.
Economicconsiderations Therewasnoeconomicevidenceavailableandthistypeof
scenariowasnotincorporatedintotheoriginaleconomicmodels
undertakenfortheguideline.However,theGDGconsideredthat
thelikelyextraresourceuseandcostsassociatedwithadjusting
dosage(extramedicalappointmentsand/orincreasedor
decreaseddailydose)waslikelytobecosteffectiveifithelpsto
maintainseizurecontrol.
Qualityofevidence
TheEpilepsies
531
Recommendation
211. DonotroutinelymonitorAEDlevelsduringpregnancy.If
seizuresincreaseorarelikelytoincrease,monitoringAED
levels(particularlylevelsoflamotrigineandphenytoin,which
maybeparticularlyaffectedinpregnancy)maybeuseful
whenmakingdoseadjustments.[new2012]
outcomes
Seizurefreedomandadverseeffectwereconsideredthemost
importantoutcomes.
benefitsandharms
Risksofseizureexacerbation/relapsewithalterationin
pharmacokineticsofAEDinpregnancyneedtobebalancedagainst
theriskofharmfromantiepilepticmedicationtakenbythemother
inpregnancy.
Economicconsiderations Therewasnoeconomicevidenceavailableonroutinemonitoring
ofAEDlevelsandthiswasnotincorporatedintotheoriginal
economicmodelsundertakenfortheguideline.TheGDG
consideredthatroutinemonitoringofAEDlevelsinpregnancyis
notnecessary.However,itshouldbeborneinmindthatthelevels
ofsomeAEDs,andspecificallylamotrigineandphenytoin,maybe
affectedbypregnancyandmonitoringoftheselevelsmayreduce
theriskofseizuresthatmaycauseharmtothemotherandthe
unbornchild.
Qualityofevidence
Thisrecommendationwasupdatedfromthefirsteditionofthis
guideline(2004).
TheEpilepsies
532
Recommendation
212. IndicationsformonitoringofAEDbloodlevelsare:
detectionofnonadherencetotheprescribedmedication
suspectedtoxicity
adjustmentofphenytoindose
managementofpharmacokineticinteractions(forexample,
changesinbioavailability,changesinelimination,andco
medicationwithinteractingdrugs)
specificclinicalconditions,forexample,statusepilepticus,
organfailureandcertainsituationsinpregnancy(see
recommendation211)[2012]
outcomes
Seizurefreedomandadverseeffectwereconsideredthemost
importantoutcomes.
benefitsandharms
Risksofseizureexacerbation/relapsewithalterationinthe
pharmacokineticsofAEDsinpregnancyneedtobebalanced
againsttheriskofharmfromantiepilepticmedicationtakenbythe
motherinpregnancy.
Economicconsiderations Therewasnoeconomicevidenceavailableonroutinemonitoring
ofAEDlevelsandthiswasnotincorporatedintotheoriginal
economicmodelsundertakenfortheguideline.TheGDG
consideredthattherearesomespecificindicationsformonitoring
ofAEDbloodlevels,suchasdetectionofnonadherencetothe
prescribedmedication,suspendedAEDtoxicity,adjustmentof
phenytoindoseand/ormanagementofpharmacokinetic
interactions.RoutinemonitoringofAEDlevelsinpregnancyisnot
necessary,however,itshouldbeborneinmindthatthelevelsof
someAEDsparticularlylamotrigineandphenytoinmaybeaffected
bypregnancyandmonitoringoftheselevelsmayreducetherisk
ofseizuresthatmaycauseharmtothemotherandtheunborn
child.
Qualityofevidence
Thisrecommendationwasupdatedfromthefirsteditionofthis
guideline(2004).
TheEpilepsies
533
Recommendation
213. RefertotheSPCandBNF(availableathttp://www.bnf.org)
forindividualdrugadviceontheinteractionsbetweenAEDs
andhormonalreplacementandcontraception.[new2012]
outcomes
Seizurefreedom,adverseeffectandeffectivecontraceptivewere
benefitsandharms
Therisksofunplannedpregnancycausedbydruginteraction
betweenAEDsandhormonalcontraceptivesmustbeconsidered,
buttherisksofseizuresrequirethat,whenpossible,themost
effectiveantiepilepticmedicationbeprescribed.
Economicconsiderations Therewasnoeconomicevidenceavailableandconcomitantuseof
AEDsandhormonalcontraceptiveswasnotincorporatedintothe
originaleconomicmodelsundertakenfortheguideline.However,
theGDGconsideredthatinteractionsbetweenAEDsandhormonal
contraceptivesshouldbeborneinmindtoreducetheriskof
unplannedpregnanciesorreducedseizurecontrol.
Qualityofevidence
13.5.6.1 AEDsandpregnancy
Whatisthemalformationrateandlongertermneurodevelopmentaloutcomeofchildrenbornto
motherswhohavetakenAEDsinpregnancy?
Whythisisimportant
PregnancyregistersareincreasingthedatathatareavailableonestablishedAEDs;however,these
registersmaygivemalformationratesbutdonotprovidecontrolledlongtermdataon
neurodevelopmentaloutcome.
measuresofmaternaloutcome,includingseizurefrequencyandqualityoflife
majorandminorratesofcongenitalmalformations
prospectiveneurodevelopmental(includingcognitive)andbehaviouraloutcomesinchildren
borntowomenandgirlswithepilepsy(theseshouldbeundertakenonalongtermbasisand
ideallyusingacohortstudy,followedfrombirthanduntiladultlife).
13.6 DoAEDsinteractwithcontraceptives?
214. Inwomenofchildbearingpotential,thepossibilityofinteractionwithoralcontraceptives
shouldbediscussedandanassessmentmadeastotherisksandbenefitsoftreatmentwith
individualdrugs.[2004]
TheEpilepsies
534
215. Ingirlsofchildbearingpotential,includingyounggirlswhoarelikelytoneedtreatmentinto
theirchildbearingyears,thepossibilityofinteractionwithoralcontraceptivesshouldbe
discussedwiththechildand/orhercarer,andanassessmentmadeastotherisksandbenefits
oftreatmentwithindividualdrugs.[2004]
216. Inwomenandgirlsofchildbearingpotential,therisksandbenefitsofdifferentcontraceptive
methods,includinghormonereleasingIUDs,shouldbediscussed.[2004]
217. IfawomanorgirltakingenzymeinducingAEDschoosestotakethecombinedoral
contraceptivepill,guidanceaboutdosageshouldbesoughtfromtheSPCandcurrenteditionof
218. Theprogestogen
onlypillisnotrecommendedasreliablecontraceptioninwomenandgirls
takingenzymeinducingAEDs.[2004,amended2012]
219. Theprogestogen
gg
implantisnotrecommendedinwomenandgirlstakingenzymeinducing
AEDs.[2004,amended2012]
220. Theuseofadditionalbarriermethodsshouldbediscussedwithwomenandgirlstaking
enzymeinducingAEDsandoralcontraceptionorhavingdepotinjectionsofprogestogen
ii
.
[2004,amended2012]
221. IfemergencycontraceptionisrequiredforwomenandgirlstakingenzymeinducingAEDs,the
typeanddoseofemergencycontraceptionshouldbeinlinewiththeSPCandcurrenteditionof
Evidencestatements
Carbamazepine,phenytoin,oxcarbazepine,topiramateandbarbituratesreducetheeffectivenessof
oralcontraceptives,necessitatingtheuseofalternativemethods,orspecialhighdoseregimensof
oralcontraceptives.Evenwiththisprecaution,theeffectivenessoftheoralcontraceptiveisreduced.
(IaNICE)
HormonereleasingIUDsareeffectiveasamethodofcontraceptioninwomentakingAEDs.(III)
Thereislimitedevidencethatprogesteroneimplants(specificallylevonorgestrel)areineffectivein
womentakingenzymeinducingAEDs.(III)
Thereisnoevidenceontheeffectivenessofemergencycontraceptioninwomentakingenzyme
inducingAEDs.
Details
TheNICEtechnologyappraisalstatedthatoxcarbazepineandtopiramateinteractwithoral
contraceptiveswhilstlamotrigine,gabapentin,levetiracetam,andtiagabinedonot.Detailsof
interactionsforvigabatrinwerenotreported.Oftheolderdrugs,sodiumvalproatedoesnotinteract
withtheoralcontraceptive,butmustbeusedwithcautioninwomenofchildbearingage.
43,408
NosystematicreviewsofRCTsorRCTswereidentifiedthatcompareddifferentmethodsof
contraceptionordifferentdosesoforalcontraception.Inaddition,nocohortstudiesofwomenwith
ii
TheEpilepsies
535
epilepsyandcontraceptionfailurerateswereidentified.Theevidencepresentedbelowistherefore
nonexperimentaldescribingfailureratesofdifferentcontraceptivemethodsinwomenwithepilepsy
whoaretakingAEDsanddruginteractionsbetweenAEDsandhormonalcontraception,orreviewsof
theinteractionsbetweenAEDsandhormonalcontraception.
Hormonalcontraception(general)
Crawford2002
409
InareviewonAEDsandhormonalcontraception,Crawfordreviewedtheliteratureondrug
interactionsbetweenAEDsandoralcontraceptivesandotherhormonalcontraceptivemethods.
RecommendationsoncontraceptionforwomentakingAEDswerethenpresented.Thesewere:
Womentakingphenobarbital,phenytoin,carbamazepine,felbamate,topiramate,or
oxcarbazepineshouldtakeanoralcontraceptivepillcontainingatleast50mcgofoestrogen.
WomentakingotherAEDscantakeanormaldoseoralcontraceptivepill.
(Basedon17studiesandotherreferencessuchastheBNF)
TheprogestogenonlypillislikelytobeunreliableinwomentakingenzymeinducingAEDs.
(BasedontheBNF)
Thefrequencyofinjectionfordepotprogestogenshouldbeincreasedtoevery10weeks
(comparedwiththeusual12weeks)inwomentakingenzymeinducingAEDs.
(Basedonexpertopiniononly)
Progestogenimplants(specificallylevonorgestrelimplants)shouldbenotusedasamethodof
contraceptioninbywomentakingenzymeinducingdrugs.
(Basedoncasereportsandasmallcaseseriesof19women)
TheserecommendationsweresimilartothosepreviouslyreachedbytheWomenwithEpilepsy
GuidelinesDevelopmentGroupbasedonavailableevidenceandexpertjudgementand
experience.
396
Oralcontraception(Thepill)
Coulam1979
410
In1979,CoulamandAnnegerspresentedtheresultsofarecordreviewof82womenwithepilepsy
whowerealsotakingoralcontraception.
410
Intotal,therewere3,233womanmonthsoforal
contraceptionuseinthreesubgroupsofwomen:
41womenusedAEDsandoralcontraceptivesfor955months
30womenweretakingoralcontraceptivesonlyfor828months
31womenwhohadbeenseizurefreeandhadnotbeentakingAEDsfor5yearsweretakingoral
contraceptionfor1,450months.
Theexpectedandobservedratesofcontraceptivefailurewerethencalculated.Threecontraceptive
failuresoccurred,comparedtotheexpectednumberof0.12(relativerisk25,95%CI5to73).All
threeofthewomeninwhomoralcontraceptionfailedweretakingAEDs;twoofthewomenwith
weretakingcombinedoralcontraceptionandonewastakingsequentialcontraception.
TheauthorsthenreviewedtheliteratureonoralcontraceptivefailuresinwomentakingAEDsor
barbiturates.IncludingthewomenabovedescribedbyCoulamandAnnegers,therewere25failures
inwomentakingAEDseitherasmonotherapyorincombination.
TheEpilepsies
536
Mostwomenweretakingtheequivalentof50mcgsofoestrogen,withafewtaking10mcgsof
oestrogen,andonetaking80mcgsofoestrogen.
Theauthorsconcludedthattherateoforalcontraceptivefailureishigheramongwomentaking
AEDs.
410
Back1988
411
TheCommitteeonSafetyofMedicines(CSM)monitorsadversedrugreactionsintheUK.Backand
colleaguessearchedtheCSMadversereactionsregisterfor1968to1984toidentifypregnancies
reportedinwomentakingoralcontraceptivesandAEDs.
43pregnancieswerereportedinwomentakingAEDs;ofthese,25weretakingphenytoin,20
phenobarbital,7primidone,6carbamazepine,4ethosuximide,and1takingsodiumvalproate.Some
ofthewomenweretakingmorethanonedrug.
Ofthese43pregnancies,25weretakinghighoestrogencontraception(50mcg),13weretaking
mediumoestrogencontraception(30mcgto35mcg)and5weretakingothertypesoforal
contraceptive,includingprogesteroneonly,biphasicandtriphasicpreparations.
Theauthorssuggestedthatduetothelowlevelsofreportingofadverseevents(lessthan10%),the
reportedfailureswereafractionoftheactualnumber.
411
Noevidencewasfoundonthemosteffectivedoseoforalcontraception,orthemosteffective
regimen.Arecentguideline
396
onthemanagementofwomenwithepilepsyrecommended,onthe
basisofevidenceandconsensus,that
ForwomenonenzymeinducingAEDs(phenytoin,phenobarbital,primidone,carbamazepine,
topiramate)wishingtotakethecombinedoralcontraceptivepill:
o Startona50mcgethinyloestradioldose
o Ifbreakthroughbleedingoccurs,increasethedoseofethinyloestradiolto75mcgor100mcg
perday,orconsidergivingthreepacksofthepillwithoutabreak(tricycling).
396
Hormonereleasingintrauterinedevices
Bounds2002
412
Theauthorsofthisstudyaimedtodocumentthecontraceptiveeffectivenessofthehormone
releasingIUDMirenainwomentakingAEDsandotherenzymeinducingdrugs.
65womenwererecruitedtothestudy,ofwhich56wereincludedintheanalysis.Ofthese56
participants,49(87.5%)weretakingmedicationforepilepsy.Drugsincludedcarbamazepine,
phenytoin,phenobarbital,primidone,andtopiramate.
Duringthe1,075monthsofexposuretotheriskofpregnancy,twoaccidentalpregnancieswere
reported,bothtowomentakingAEDs(primidoneandphenytoin,andphenytoinonly).Onlyoneof
thesewasassessedasbeingatruefailureevent;theotherfailuremayhavebeenduetoanon
protectedperiodafterremovaloftheIUD.Thefailureratewascalculatedtobe1.1per100woman
years(95%CI0.03to6.25)basedonthetruefailureonly,and2.2per100womanyears(95%CI0.27
to8.07)basedonbothfailures.
Theauthorsstressedthatthiswasapilotstudyonly,butthatthefailurerateof2.2per100woman
yearscomparedwellwithfailureratesforwomenonoralcontraceptionandAEDS(approximately7
per100womanyears
396
,andwasbetterthanratesforbarriermethods(15to20per100woman
years).
396,412
Progesteroneimplants
TheEpilepsies
537
Haukamaa1986
413
Ninewomenwithepilepsyaged16to35yearsparticipatedinthisstudytoassesstheefficacyof
progesteroneimplantsinwomentakingAEDs.Thecontrolgroupwas10womenaged28to44years
withoutepilepsywhoweretakingnomedication.
Nopregnanciesoccurredinthecontrolgroupinthe12monthsofthestudy.Twopregnancies
occurredintheepilepsygroup;bothwomenweretakingphenytoinandtheirplasmalevelsof
levonorgestrelwerelowatthetimeofconception.Inaddition,nineofthecontrolgroupcontinued
tousetheimplantafter12months.Ofthewomenwithepilepsy,onlysixoftheninewomen
continuedtousetheimplantat12months.
Emergencycontraception
FFPRHC2003
414
TheFacultyofFamilyPlanningandReproductiveHealthCareClinicalEffectivenessUnitproduced
evidencebasedguidancefortheuseofemergencycontraceptioninprimaryandsecondarycare.
Druginteractionsrelevanttoemergencycontraceptionwerereviewedandnoevidencewascited
aroundtheinteractionbetweenlevonorgestrelandenzymeinducingAEDs.Theguidance
recommendedthat:
twotablets(1.5mg)arefollowed12hourslaterbyasingletablet(0.75mg),althoughthisis
outsidetheproductlicense.
414
Theuseofanincreaseddosewasalsoproposedinanotherreviewofemergencycontraception,
415
althoughagainthelackofevidencewashighlighted.Similarly,theguidelinesonthemanagementof
womenwithepilepsystatedthattherearenodataonwhetherachangeindoseofthemorning
aftercontraceptivepillisrequiredinwomentakingAEDmedication;somepractitionersuseaslightly
higherdoseinthosewomentakingenzymeinducingdrugs.
396
13.7 Doesepilepsyincreasetheriskofcomplicationsinpregnancy?
222. Womenandgirlswithepilepsyshouldbeinformedthatalthoughtheyarelikelytohave
healthypregnancies,theirriskofcomplicationsduringpregnancyandlabourishigherthanfor
womenandgirlswithoutepilepsy.[2004]
223. Careofpregnantwomenandgirlsshouldbesharedbetweentheobstetricianandthe
specialist.[2004]
224. PregnantwomenandgirlswhoaretakingAEDsshouldbeofferedahighresolutionultrasound
scantoscreenforstructuralanomalies.Thisscanshouldbeperformedat1820weeks
gestationbyanappropriatelytrainedultrasonographer,butearlierscanningmayallowmajor
malformationstobedetectedsooner.[2004]
225. Allpregnantwomenandgirlswithepilepsyshouldbeencouragedtonotifytheirpregnancy,
orallowtheircliniciantonotifythepregnancy,totheUKEpilepsyandPregnancyRegister
(www.epilepsyandpregnancy.co.uk).[2004]
Evidencestatements
Mostwomenwithepilepsyhavehealthypregnancieshowevertheymayhaveanincreasedriskof
complications.(IIa)
Prenatalscreeningcanidentifysomeabnormalities.(IaNICE)
TheEpilepsies
538
13.7.1 Arewomenwithepilepsyatincreasedriskofcomplicationsduringthepregnancyand
labour?
Details
Secondaryevidence
Primaryevidence
Fairgrieve2000
416
Oneprospective,populationbasedstudywasidentified.400notificationsofpregnanciesinwomen
withepilepsywereincluded.Ofthe359(90%)knownpregnancyoutcomes,theobstetric
complicationratewassimilartothatofthebackgroundpopulation,exceptforanexcessof
prematuredeliveries(8.2%).Nostatisticalsignificancewasgiven.
416
Tanganelli1992
402
Anotherprospectivecontrolledstudycompared138pregnanciesin97womenwithepilepsywith
140controlpregnanciesin88womenwhodidnothaveepilepsy.Slightlymorecomplications
occurredinwomenwithepilepsycomparedwithcontrols(23.4%vs15.6%)butthedifferencewas
notstatisticallysignificant.However,inducedlabourandprolongedlabourwereapproximately
twiceaslikelyinwomenwithepilepsy(9.0%vs4.7%and5.7%vs2.3%).
402
Olafsson1998
417
Complicationsofpregnancy,delivery,andoutcomeinwomenwithactiveepilepsywerecompared
withwomenwithoutepilepsyinaretrospectivepopulationstudy.Activeepilepsywasdefinedas
treatmentwithAEDsduringpregnancyorduringthe5yearperiodprecedingthepregnancy.Inthe
19yearstudyperiod,thenumberoflivebirthswas82,483(from81,473pregnancies)ofwhich268
childrenwerebornto157womenwithactiveepilepsy(from266pregnancies).
Althoughthefrequencyofadverseeventsinpregnancyweresimilarinbothgroups,caesarean
sectionwasperformedtwiceasfrequentlyinwomenwithactiveepilepsy(13%,35of266compared
with8.8%,7,139of81,473).Perinatalmortality(11.2in1000comparedwith8,7in1000,OR=1.5,
95%CI0.34.1)andmeanbirthweight(3,601gcomparedwith3,647g,p=0.2)werenotsignificantly
differentfortheoffspringofwomenwithactiveepilepsy.
417
13.7.2 Whenshouldscreeningforstructuralfetalanomaliesbeperformedinpregnantwomen
withepilepsy?
ArecentNICEguidelinereviewedtheevidenceonthedetectionofstructuralfetalabnormalitiesin
healthypregnantwomen.
418
Asystematicreviewassessedtheoverallprevalenceoffetalanomalyto
be2.09%,rangingfrom0.76%to2.45%inindividualstudiesandincludingmajorandminor
anomalies.Overall,44.7%oftheseanomaliesweredetectedusingscreening,witharangeof15.0%
to85.3%asdifferentanomaliesaremoreorlesslikelytobecorrectlyidentified.
Theyfoundthatvariationindetectionrateoccurredwith:
thetypeofanomalybeingscreened
thegestationalageatscanning
theskilloftheoperator
thequalityoftheequipmentbeingused
thetimeallocatedforthescan.
TheEpilepsies
539
Theguidelinerecommendedthatpregnantwomenshouldbeofferedanultrasoundscantoscreen
forstructuralanomalies,ideallybetween18to20weeksofgestation,byanappropriatelytrained
sonographerandwithequipmentofanappropriatestandardasoutlinedbytheNationalScreening
Committee.
418
13.8 Whenshouldfolicacidbestarted?
226. AllwomenandgirlsonAEDsshouldbeoffered5mgperdayoffolicacidbeforeanypossibility
ofpregnancy.[2004]
Evidencestatement
ThereislimitedevidencetoshowthatfolicacidsupplementationreducestheriskofNTDandother
congenitalmalformationsinwomentakingAEDs.(IV)
Details
Folatesandfolicacidhaveamajorroletoplayinthepreventionofneuraltubedefects.
419
Itisalreadyrecommendedthatallwomenwhoareplanningpregnancyshouldbeadvisedtotake
400mcgoffolicacidfromwhentheybegintryingtoconceiveuntilthe12thweekofpregnancyand
thatthosewhosuspecttheyarepregnantandwhohavenotbeentakingsupplementsshouldstart
folicacidsupplementsimmediatelyandcontinueuntilthe12thweekofpregnancy.
419
NoRCTsofdifferentlevels,ordifferenttimingoffolicacidsupplementationinwomenwithepilepsy
wereidentified.
Anarrativereview
420
onneuraltubedefectsandfolicacidsupplementationinwomenwithepilepsy
concludedthat:
Thevalueofpericonceptionalfolicacidsupplementationforwomeninthegeneralpopulationis
accepted.However,itisunclearwhetherfolicacidsupplementationprotectsagainstthe
embryotoxicandteratogeniceffectsofAEDsbecauseanimalandhumanstudiesandcasereports
haveshownvariableresults.Nevertheless,folicacidsupplementationisrecommendedforwomen
withepilepsyasitisforotherwomenofchildbearingage.However,thedoseof400mcgperday
maynotbehighenoughformanywomenwhodonotmetabolisefolateeffectively.
420
13.9 Whatarethedangersofseizuresinwomenwhoarepregnantor
postnatal?
227. Womenandgirlswithepilepsyneedaccurateinformationduringpregnancy,andthe
possibilityofstatusepilepticusandSUDEPshouldbediscussedwithallwomenandgirlswho
plantostopAEDtherapy(seesection10.2.6).[2004]
228. Womenandgirlswithgeneralisedtonicclonicseizuresshouldbeinformedthatthefetusmay
beatrelativelyhigherriskofharmduringaseizure,althoughtheabsoluteriskremainsvery
low,andthelevelofriskmaydependonseizurefrequency.[2004]
TheEpilepsies
540
229. Womenandgirlsshouldbereassuredthatthereisnoevidencethatfocal
jj
,absenceand
myoclonicseizuresaffectthepregnancyordevelopingfetusadverselyunlesstheyfalland
sustainaninjury.[2004,amended2012]
230. Theriskofseizuresduringlabourislow,butitissufficienttowarranttherecommendation
thatdeliveryshouldtakeplaceinanobstetricunitwithfacilitiesformaternalandneonatal
resuscitationandtreatingmaternalseizures.[2004]
231. Advancedplanning,includingthedevelopmentoflocalprotocolsforcare,shouldbe
implementedinobstetricunitsthatdeliverbabiesofwomenandgirlswithepilepsy.[2004]
232. Parentsshouldbereassuredthattheriskofinjurytotheinfantcausedbymaternalseizureis
low.[2004]
233. Parentsofnewbabiesoryoungchildrenshouldbeinformedthatintroducingafewsimple
safetyprecautionsmaysignificantlyreducetheriskofaccidentsandminimiseanxiety.An
approachingbirthcanbeanidealopportunitytoreviewandconsiderthebestandmosthelpful
measurestostarttoensuremaximumsafetyforbothmotherandbaby.[2004]
234. Informationshouldbegiventoallparentsaboutsafetyprecautionstobetakenwhencaring
forthebaby(seeAppendixD)
kk
.[2004]
Evidencestatements
Thereisnoevidencethatsimplefocal,complexfocal,absenceandmyoclonicseizuresadverselyaffect
thepregnancyordevelopingfetus.(IV)
Generalisedtonicclonicseizuresarelikelytoresultinmoreprofoundhypoxiathaninthenongravid
stateduetoincreasedmaternaloxygenrequirements.Thismayhaveadverseaffectsforthefetus.
(IV)
Indirectdeathsfrommedicalconditionsexacerbatedbypregnancyweregreaterthanthosedeaths
fromconditionsdirectlyarisingfrompregnancy.Someofthesedeathswereattributedtoepilepsy.
(III)
Babiesofmotherswithactiveepilepsy,particularlyifthemotherhasjuvenilemyoclonicepilepsy,are
atriskofinjury.Theriskofinjuryisrelatedtoseizuretypeandseverity.Inparticular,thepatternof
seizuresiscrucial.(III)
Details
Effectsofmaternalseizuresonthefetus
AnexpertworkshopconvenedbytheEpilepsyResearchFoundation
421
consideredbothpublished
evidenceandexpertopinionandconcludedthat:
Focalseizuresandnonconvulsivegeneralisedseizuresareunlikelytoexposethefetusto
immediaterisksinutero.
jj
kk
AppendixDprovidesachecklistfortheinformationneedsofwomenandgirlswithepilepsy,andpracticalinformationfor
motherswithepilepsy.
TheEpilepsies
541
Generalisedtonicclonicseizuresmayreducebloodflowtotheuterus,butthatevidencewas
lacking.Ifthewomanfalls,thenthereisariskofuterinecontractionandsubsequentplacental
abruption.
TheevidencesuggestedthatincreasedrateofteratogenesisisduetoAEDsratherthantoseizures
inpregnancy.
Itseemsunlikelythatmaternalseizuresduringpregnancyhaveimportantlongterm
developmentaleffectsonfetaldevelopment.
421
Effectofmaternalseizuresonthewoman
TheConfidentialEnquiresintoMaternalDeathsintheUnitedKingdom
422
foundthat:
Indirectdeaths(n=136)weregreaterthandirectdeaths(n=106).
Ofthoseindirectdeaths,ninewererelatedtoepilepsy.
TheEnquiryrecommendedthatwomenneedspecialistadviceinpregnancy,andthatthepossibility
ofSUDEPshouldbediscussedwithallwomenwhoplantostopAEDtherapy.
422
Effectofmaternalseizuresduringlabour
Theexpertworkshop
421
recommendedthat,asseizuresduringlabourcanaffectthefetus,delivery
forwomenwithepilepsyshouldtakeplaceatobstetricunitswithsufficientfacilities.Nodetailsof
whatsufficientfacilitiesweregiven.
Effectofmaternalseizuresinthepostnatalperiod
Fox1999
423
Anauditof187womenwithepilepsyseeninapreconceptionclinicwasundertakentoassesstherisk
posedtoababyborntoamotherwithactiveepilepsy.Theexperienceofthe187women(Group1)
seenintheclinicandgivencounsellingandinformationaboutsafetywascomparedwith38women
(Group2)whoweregivennocounsellingaboutsafetyprecautions.
Therewere3minorincidentsrecordedinGroup1comparedwith8seriousand4minorincidentsin
Group2.Ofthe15womenrecordinganincident,7hadJME.Apartfromonemotherwhohadher
firstseizurewhilstcarryingherchild,alltheincidentswerepreventable.
423
13.10 Whatistheroleofdrugmonitoringinpregnantwomenwith
epilepsy?
Evidencestatements
ThereisnoclearcutrelationshipbetweenserumlevelsofAEDsandseizurecontrolinnonpregnant
andpregnantwomenwithepilepsy.(IV)
NoevidencetosupporttheuseofroutinebloodmonitoringofAEDlevelswasfound.
Details
NosystematicreviewsorRCTswereidentified.(SeeWhatistheroleofmonitoringinadultsand
childrenwithepilepsy?)
In1993,theILAECommissiononAntiepilepticDrugspublishedguidelinesfortherapeuticmonitoring
ofAEDs.Theyhighlightedthreeareasofconcern:
thelackofstrictcorrelationbetweenefficacyand/ortoxicityofAEDsandtheirbloodlevelsfor
individuals.
TheEpilepsies
542
bloodlevelsjudgedonanindividualsamplingmaybemisleadingwherethereexistswidediurnal
variation.
accuracyofmeasurementsmustbeconsidered.
Inconclusion,theCommissionrecommendedthat
indiscriminateuseofbloodleveldeterminationsisnotrecommended,butthattailored
determinationswithspecificpurposessuchaspregnancymaybehelpful.
148
13.11 ShouldoralorparenteralvitaminKbeused?
235. AllchildrenborntomotherstakingenzymeinducingAEDsshouldbegiven1mgofvitaminK
parenterallyatdelivery.[2004]
Evidencestatement
Thereislimitedevidencetoshowthattheriskofhaemorrhagicdiseaseofthenewbornisnot
increasedinwomentakingenzymeinducingAEDsprovidedthatinfantsreceivethestandard
treatmentof1mgvitaminKparenterally(intramuscularorintravenous)atbirth.(III)
Details
NosystematicreviewsorRCTscomparingoralandparenteralvitaminKwereidentified.Onlyone
prospectivestudywasidentified.
Kaaja2002
424
TheoccurrenceofbleedingcomplicationsinnewbornsexposedtomaternalenzymeinducingAEDs
inuterowasexaminedin662pregnancies(452womenand667offspring).Agroupof1,324
pregnancies(1,334neonates)servedasthecontrolgroup.Noneoftheexposedgrouporthecontrol
receivedvitaminKsupplementationduringpregnancyorlabour.Allnewbornsofmotherswith
epilepsyandcontrolnewbornsreceivedastandarddoseof1mgvitaminKintramuscularlyatbirth.
Fiveexposed(0.7%)andfivecontrol(0.4%)newbornssufferedableedingcomplication.Bleeding
wasassociatedwithbirthatlessthan32weeks(OR=13,95%CI2.764)andalcoholabuse(OR=17,
95%CI1.8to162).NoassociationwasfoundwithexposuretoenzymeinducingAEDs(OR=1.1,
95%CI0.34.6,p=0.8).
Limitationsdescribedbytheauthorsincludedthelowincidenceofneonatalbleedinginbothgroups.
Also,theresultscannotbeextrapolatedtowomenonpolytherapy(only21.3%offetuseswere
exposedtopolytherapy)oronprimidoneorphenobarbital,asthesewereseldomusedbythe
includedwomen.
424
13.12 Whatistheriskofofinheritingepilepsy?
236. Geneticcounsellingshouldbeconsideredifonepartnerhasepilepsy,particularlyifthe
partnerhasidiopathicepilepsyandapositivefamilyhistoryofepilepsy.[2004]
237. Althoughthereisanincreasedriskofseizuresinchildrenofparentswithepilepsy,children,
youngpeopleandadultswithepilepsyshouldbegiveninformationthattheprobabilitythata
childwillbeaffectedisgenerallylow.However,thiswilldependonthefamilyhistory.[2004]
Evidencestatements
TheEpilepsies
543
Foridiopathicgeneralizedepilepsy,theriskofachilddevelopingtheconditionis520%ifthereisone
affectedfirstdegreerelative(includingthemother),andover25%iftwofirstdegreerelativesare
affected.Thustheriskofaindividualwithidiopathicgeneralizedepilepsyhavinganaffectedchildis
about912%,andtheriskis3%inchildrenofthosewithcryptogenic(focal)seizures.(IV)
Thereisahigherriskinthosefamilieswhohavemanyaffectedmembers.(IV)
Details
Foridiopathicgeneralizedepilepsy,theriskofachilddevelopingtheconditionis520%ifthereis
oneaffectedfirstdegreerelative(includingthemother),andover25%iftwofirstdegreerelatives
areaffected.Thustheriskofanindividualwithidiopathicgeneralizedepilepsyhavinganaffected
childisabout912%,andtheriskis3%inchildrenofthosewithcryptogenic(focal)seizures.
396
13.13 Whatistheroleofjointepilepsyandobstetricclinicsinthecare
ofwomenwithepilepsywhoarepregnant?
238. Jointepilepsyandobstetricclinicsmaybeconvenientformothersandhealthcare
professionalsbutthereisinsufficientevidencetorecommendtheirroutineuse.[2004]
239. Itis,however,importantthatthereshouldberegularfollowup,planningofdelivery,liaison
betweenthespecialistorepilepsyteamandtheobstetricianormidwife.[2004]
Evidencestatement
Noevidencefortheeffectivenessofjointepilepsyandobstetricclinicscouldbefound.
Details
NosystematicreviewsorRCTswereidentified.
TheEpilepsies
Children,youngpeopleandadultswithlearningdisabilitiesandepilepsy
544
14 Children,youngpeopleandadultswithlearning
disabilitiesandepilepsy
14.1 Introduction
Theprevalenceoflearningdisabilitiesinthepopulationisapproximately18per1000.Thus,aGP
withalistsizeof2000hasapproximately36individualswithlearningdisabilities,ofwhomaboutsix
willhaveseverelearningdisabilities.Epilepsyandlearningdisabilitiescommonlycoexistandmost
oftendevelopinchildhood.Itisestimatedthatepilepsyhasaprevalenceof15%inpeoplewithmild
learningdisabilitiesand30%inthosewithseverelearningdisabilities.
Peoplewithmildlearningdisabilities(IQ50to70)andnootherconcomitantconditionsareatlowest
risk(57%)ofdevelopingepilepsy.Upto75%ofthosewithadditionaldisabilitiessuchascerebral
palsyorpostnatalbraininjuryhaveepilepsy.Severelearningdisability(IQ20to50)ismorelikelyin
individualswithearlyseizureonset.PeoplewithDownssyndromeandotherchromosomal
conditionscommonlyhaveepilepsy:approximately810%ofsuchpeoplehaveahistoryofseizures.
Manychildrenwithepilepsydonothaveassociatedlearningdisabilities,butsomechildhoodonset
epilepsies,suchasLennoxGastautsyndrome,areassociatedwithlearningdisabilities.
425
Thereareparticularchallengesinprovidinginformationandsupportforthisgroupastheremaybe
occasionswherepeoplewithlearningdisabilitiesandepilepsycannotmaketheirowndecisionsdue
toalackofmentalcapacity.Itisimportantthatdecisionsaremadewithappropriateadvocacyfor
theindividual,asoutlinedinrecentguidancefromtheDepartmentofHealth.
426
Problemsinconductinganevidencebasedreview:
TheKCQsidentifiedbytheGDGwereconvertedintoEBQsandsystematicliteraturesearcheswere
carriedout.Incommonwithotherreviewsinthefield
427
largegapsintheavailableevidencewere
identifiedandmuchofwhatwasidentifiedwasofpoormethodologicalquality.Thelackofplacebo
controlleddoubleblinddrugtrialsinthispopulationissingledoutforcomment.
Wherethereisalackofevidence,thekeyrecommendationsfromarecentconsensusguidelineon
themanagementofepilepsyinadultswithanintellectualdisabilityaresummarized.
427
14.2 Whoshouldmanageandtreatepilepsyinchildren,youngpeople
andadultswithlearningdisabilities?
Evidencestatements
Nostudieswereidentifiedthatcomparedoutcomesforpeoplewithepilepsyandlearningdisabilities
managedbydifferentgroupsofclinicians.Inparticular,therewasnocomparisonofspecialist
versusnonspecialistcare.
Therewasonestudythatsuggestedthatspecialistsmaybebetteratmanaginglearningdisabilities
withepilepsy.(III)
14.2.1 Dopeoplewithlearningdisabilitiesandepilepsywhoreceivecarefromaspecialistin
learningdisabilitiesandepilepsycomparedwithcarefromanonspecialisthave
differencesinprocessesandoutcomesofcare?
Details
TheEpilepsies
545
Secondaryevidence
Primaryevidence
Collacott1989
428
Acohortof215people(meanage38years14years)withlearningdisabilitiesandepilepsywas
followedupforfouryears.TheparticipantswereallresidentsofamentalhandicapunitintheUK.
Theanticonvulsantregimeswerereviewedbyaspecialistinmentalhandicapandaspecialistin
clinicalpharmacology.Ofthe172whoremainedinthestudy,41%wereseizurefreecomparedwith
37%ontheinitialreview(p<0.005).Overall,seizurefrequencywasreducedin48%,increasedin33%
andunchangedin19%.Atthefinalreview,themeannumberofAEDsperindividualwasreduced
from1.41to1.05(p<0.005).
428
AlthoughthisstudysuggeststhatspecialistsarebetteratmanagingPLDandepilepsy,therewasno
descriptionofwhomanagedtheindividualspriortotheassessment.
DeToledo2002
429
VideoEEGsof824institutionalisedadultswithepilepsywerestudiedtoidentifynewseizuretypes
identifiedbystaff(caregivers,teachers,therapists,LPNs,RNs).Ofthe63requestsforanevaluation
ofnewlyidentifiedseizuretypes,epilepsywasconfirmedin4events(6.3%).
429
Thisstudycomparesspecialistswithnonclinicalstaff,notgeneralphysicians.
14.3 Ismakingadiagnosismoredifficultinpeoplewithlearning
disabilities?
240. Itcanbedifficulttodiagnoseepilepsyinchildren,youngpeopleandadultswithlearning
disabilities,andsocareshouldbetakentoobtainafullclinicalhistory.Confusionmayarise
betweenstereotypicorotherbehavioursandseizureactivity.[2004]
241. Itisimportanttohaveaneyewitnessaccountsupplementedbycorroborativeevidence(for
example,avideoaccount),wherepossible.[2004]
242. Clear,unbiasedreportingisessential.Witnessesmayneededucationtodescribetheir
observationsaccurately.[2004]
Evidencestatements
Stereotypicbehaviourandotherabnormalmovementsmaybeconfusedwithseizures.(III)
14.3.1 Aretheratesofmisdiagnosishigherforpeoplewithlearningdisabilitiesandepilepsy
whencomparedwithpeoplewithepilepsywhodonothavelearningdisabilities?
ThisquestionhasalreadybeenconsideredinChapter7.2andnoprimarystudieswereidentifiedthat
answeredthisquestion.
14.3.2 Whatarethepracticaldifficultiesinestablishingthediagnosisinthisgroup?
Details
Secondaryevidence
TheEpilepsies
Children,youngpeopleandadultswith learningdisabilitiesandepilepsy
546
Primaryevidence
DeToledo2002
429
Newseizuretypesininstitutionalisedadultswithepilepsywereidentifiedbystaff,whothen
requestedvideoEEGsforevaluation.Ofthe63requestsforvideoEEG,epilepsywasconfirmedin4
events(6.3%).Episodeslikelytobeconfusedwithseizuresinthosewithseverelearningdisabilities
werestereotypic,repeatedblinkingorswallowing,buccolingualmovements,spontaneoussmilingor
grimacing,periodsofapparentpsychomotorarrest,anddystonicposturing.Inlessimpaired
individuals,themostcommondiagnoseswerestereotypicselfstimulationandselfabusive
behaviours,ataxiawithfalls,andsimulationofconvulsions.
429
14.4 Aretheredifficultiesindoinginvestigationsinthisgroup?
243. Thosewithlearningdisabilitiesmayrequireparticularcareandattentiontotolerate
investigations.[2004]
244. Facilitiesshouldbeavailableforimagingunderanaesthesia,ifnecessary.[2004]
245. Inthechildoryoungpersonpresentingwithepilepsyandlearningdisability,investigations
directedatdetermininganunderlyingcauseshouldbeundertaken.[2004]
Evidencestatements
Nostudieswerefoundthatcomparedeithertheconductorinterpretationofinvestigationsdonein
peoplewithlearningdisabilitiesandepilepsywithpeoplewithepilepsywhodonothavelearning
disabilities.
14.4.1 Aretherea)difficultiesinconductinginvestigations(EEG;neuroimaging);b)difficultiesin
interpretinginvestigations(EEG;neuroimaging)inpeoplewithlearningdisabilityand
epilepsywhencomparedwithpeoplewithepilepsywhodonothavelearningdisabilities?
Details
Secondaryevidence
Primaryevidence
Brodtkorb1994
430
AnEEGrecordingcouldnotbemadein10of63institutionalisedindividualswithlearningdisabilities
duetocooperationproblems.
Consensusguidelinerecommendations
WorkinggroupoftheInternationalAssociationoftheScientificStudyofIntellectualDisability2001
427
Kerrandcolleaguesrecommendedthat:
Facilitiesshouldbeavailableforimagingundergeneralanaesthesia.
TheEpilepsies
547
14.5 Whatarethemainfactorstoassesswhenmakingacareplanfor
anindividualwithlearningdisabilitiesandepilepsy?
246. Inmakingacareplanforachild,youngpersonoradultwithlearningdisabilitiesandepilepsy,
particularattentionshouldbepaidtothepossibilityofadversecognitiveandbehavioural
effectsofAEDtherapy.[2004]
247. Therecommendationsonchoiceoftreatmentandtheimportanceofregularmonitoringof
effectivenessandtolerabilityarethesameforthosewithlearningdisabilitiesasforthegeneral
population.[2004]
Evidencestatements
Thereisnoevidencetosuggestthatdifferentantiepilepticdrugsshouldbeusedforthosewith
learningdisabilitiesthanforthosewithoutlearningdisabilities.(NICE)
Peoplewithlearningdisabilitiesandepilepsyareatincreasedriskofadversecognitiveorbehavioural
sideeffectsfromAEDs.(IV)
14.6 Pharmacologicalmanagementofpeoplewithepilepsyand
learningdisabilities
14.6.1 Introduction
Thereisnoevidencetosuggestthatepilepsyinthelearningdisabledpopulationrequiresany
differentconsiderationwithregardtotreatmentcomparedtothosewithoutlearningdisability.One
couldarguehowever,theymaybemoresusceptibleparticularlytocognitivesideeffectsof
anticonvulsantmedication.Further,theymaybedisadvantagedintheirmanagementbylackofself
advocacy.
Forthisreviewweincludedadultsandchildrenwithlearningdisabilitiesandepilepsy.Peoplewith
LennoxGastautsyndromewereexcludedfromthisevidencereviewandwerereportedinaseparate
evidencereview(seesection10.7).
adultsandchildrenwithepilepsyandlearningdisabilities.Thefollowinginterventionswereincluded
inoursearch;pregabalin,zonisamide,lacosamide,lamotrigine,gababentin,oxcarbazepine,
tiagabine,levetiracetam,topiramate,vigabatrin,phenytoin,phenobarbital,clobazam,felbamate,
acetazolamide,sodiumvalproate,primidoneandcarbamazepine.WelookedforanyRCTstudiesthat
comparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
TheEpilepsies
Placebo
Pregabalin
Zonisamide
Lacosamide
Lamotrigine
Gabapentin 1
431

Oxcarbazepine
Tiagabine
Levetiracetam
Topiramate 1
432

Vigabatrin
Phenytoin
Phenobarbital
Clobazam
Felbamate
Acetazolamide
Sodium
evaporate

Primidone
Carbamazepine
Pla PRE ZNS LCS LTG GBP OXC TGB LEV TPM VGB PHT PBT CLB FBM ACT VPA PRM CBZ
TheEpilepsies
Placebo(Pla)Pregabalin(PRE)Zonisamide(ZNS)Lacosamide(LCS)Lamotrigine(LTG)Gabapentin(GBP)
Oxcarbazepine(OXC)Tiagabine(TGB)Levetiracetam(LEV)Topiramate(TPM)Vigabatrin(VGB)Phenytoin(PHT)
Phenobarbital(PBT)Clobazam(CLB)Felbamate(FBM)Acetazolamide(ACT)Sodiumvalproate(VPA)Primidone(PRM)
Carbamazepine(CBZ)
TheEpilepsies
550
14.6.3.1 Topiramateasadjunctivetherapyversusplacebo
Clinicalevidence
Evidencestatements
Foradultsandchildrenwithepilepsyandlearningdisabilities,therewasnosignificantdifferencefor
theproportionofparticipantsachievingatleast50%reductioninseizurefrequencybetween
topiramateadjunctivetherapyandplacebo.(VERYLOWQUALITY)
Forpeoplewithepilepsyandlearningdisabilities,significantlymorepatientshadthefollowing
adverseeventswithtopiramateadjunctivetherapycomparedtoplacebo:
anorexia,howeverthereisuncertaintyoverthemagnitudeoftheclinicaleffect.(LOW
QUALITY)
somnolence,howeverthereisuncertaintyoverthemagnitudeoftheclinicaleffect.(LOW
QUALITY)
Therewasnosignificantdifferencefortheproportionofparticipantsthatwithdrewduetoadverse
eventsbetweentopiramateadjunctivetherapyandplacebo.(VERYLOWQUALITY)
Therewasnosignificantdifferencebetweentopiramateadjunctivetherapyandplaceboforthe
incidenceof:
asthesia(VERYLOWQUALITY)
hostility(VERYLOWQUALITY)
abnormalgait(VERYLOWQUALITY)
convulsions(VERYLOWQUALITY)
nervousness.(VERYLOWQUALITY)
Nosignificantdifferencewasfoundbetweentopiramateadjunctivetherapyandplaceboonthe
followingdomainsofqualityoflife:
seizures(VERYLOWQUALITY)
TheEpilepsies
551
drugs(VERYLOWQUALITY)
dailylife(VERYLOWQUALITY)
severity(VERYLOWQUALITY)
sideeffects(VERYLOWQUALITY)
behaviour(VERYLOWQUALITY)
mood(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivetopiramatetoplaceboinapopulationofpatientswith
learningdisabilitieswasidentified.
seizurefreedom
timetofirstseizure
timetoexit/withdrawal
14.6.3.2 Gabapentinadjunctivetherapyversuslamotrigineadjunctivetherapy
Clinicalevidence
Healtheconomics
Evidencestatements
Nosignificantdifferencewasfoundbetweengabapentinadjunctivetherapyandlamotrigine
adjunctivetherapyfortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
Nostatisticallysignificantdifferencewasfoundbetweengabapentinadjunctivetherapyand
lamotrigineadjunctivetherapyfortheproportionofparticipantsexperiencingatleasta50%
reductioninseizurefrequency.(VERYLOWQUALITY)
Forpeoplewithlearningdisabilities,nostatisticallysignificantdifferencewasfoundbetween
gabapentinadjunctivetherapyandlamotrigineadjunctivetherapyfortheproportionofparticipants
withdrawnduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivegabapentintoadjunctivelamotrigineinapopulationof
patientswithlearningdisabilitieswasidentified.
TheEpilepsies
552
timetofirstseizure
cognitiveoutcomes
Recommendation
248. Enablechildren,youngpeopleandadultswhohavelearning
disabilities,andtheirfamilyand/orcarerswhereappropriate,
totakeanactivepartindevelopingapersonalisedcareplan
fortreatingtheirepilepsywhiletakingintoaccountany
comorbidities.[new2012]
outcomes
Themanagementofepilepsyinthispatientgroupisnodifferent
thanfromageneralepilepsypopulation.Asforchildren,young
peopleandadultswithoutlearningdisabilities,seizurefreedom,a
reductionofseizuresandavoidanceofadverseeffectsare
importantoutcomes.Therewasnoevidencetosuggestthat
efficacyofdrugsdiffersforthispopulation.
benefitsandharms
Giventheindividualscomplexcomorbidities,adultsandchildren
withlearningdisabilitiesandtheirfamily/carerscouldcontribute
activelytotheestablishmentofsettingprioritiespersonalisedto
individualneeds.
Economicconsiderations TheGDGconsideredthatextratimemayberequiredtoimplement
thisrecommendation,butthatpersonalisedcareplansforthis
groupofpatientsmayhelpimprovethelongtermoutcomesof
treatmentandmayultimatelyreducetheneedforhospital
admissions,outpatientappointmentsandGPconsultations.
Outcomesmaybeimprovedaschoiceofdruganddosecanbe
tailoredmoresuccessfullytothepatient,therebyreducingriskof
discontinuationduetointolerablesideeffects.TheGDG
considereditlikelytobeacosteffectiveuseofresources,although
noevidenceisavailable.
Qualityofevidence
ThisrecommendationwasbasedonGDGexpertise.
Otherconsiderations GDGviewisthatthispatientgrouphastraditionallyreceivedsub
optimalcare,andlessaccesstospecialistepilepsyservices.
TheEpilepsies
553
Recommendation
249. Ensureadequatetimeforconsultationtoachieveeffective
managementofepilepsyinchildren,youngpeopleandadults
withlearningdisabilities.[new2012]
outcomes
peopleandadultswithoutlearningdisabilities,seizurefreedom,a
reductionofseizuresandadverseeffectsareimportantoutcomes.
Therewasnoevidencetosuggestthatefficacyofdrugsdiffersfor
thispopulation,however,theGDGopinionwasthatimportanceis
placedoncognitiveandbehaviouraleffectsofAEDsasitmaybe
moredifficulttoassessandtreatinthispopulation.
benefitsandharms
Communicationwiththepatientandthecarermaybemore
challenginganditmaytakelongerduringtheconsultationto
monitoranysideeffectsandoptimisedrugmanagement,
particularconsideringissuesthatmayariseundertheMental
CapacityAct(2005).
Economicconsiderations TheGDGconsideredthatadditionaltimemayberequiredto
appropriatelyassessandmanagethisgroupofpatients,butthatit
islikelytorepresentacosteffectiveuseofresources.Optimising
theirtreatmentislikelytoimprovetheiroutcomesandmayresult
infewerhospitaladmissions,outpatientappointmentsandGP
consultations.
Qualityofevidence
Otherconsiderations GDGviewisthatthispatientgrouphastraditionallyreceivedsub
optimalcare,andlessaccesstospecialistepilepsyservices.
Recommendation
250. Donotdiscriminateagainstchildren,youngpeopleand
adultswithlearningdisabilities,andofferthesame
services,investigationsandtherapiesasforthegeneral
population.[new2012]
outcomes
peopleandadultswithoutlearningdisabilities,seizurefreedom,
areductionofseizuresandadverseeffectsareimportant
outcomes.
benefitsandharms
GDGviewisthatthispatientgrouphastraditionallyreceived
suboptimalcare,andlessaccesstospecialistservices.
Economicconsiderations None.
Qualityofevidence
TheEpilepsies
554
Otherconsiderations GDGviewisthatthispatientpopulationhastraditionally
receivedsuboptimalcare,andlessaccesstospecialistepilepsy
services.
14.6.5 Isepilepsymoredifficulttotreatinpeoplewithlearningdisabilities?
251. Everytherapeuticoptionshouldbeexploredinchildren,youngpeopleandadultswith
epilepsyinthepresenceorabsenceoflearningdisabilities.[2004]
Evidencestatements
Remissionratesforpeoplewithlearningdisabilitiesandepilepsyarelowerthanthoseforpeoplewith
epilepsywhodonothavelearningdisabilities.(IIb)
Incommunitybasedstudiesofchildrenwithepilepsyandlearningdifficultiesasignificant(3940%)
proportionachieveremission.(IIb)
14.6.6 Likelihoodofremissionofseizures
Details
Onlystudiesofprognosisthatusedacommunitysampleofparticipantswereincludedsoastoavoid
referralbias.
Secondaryevidence
PrimaryPapers
Airaksinen2000
433
151childrenwithlearningdisabilitieswereidentifiedattheagesof8or9yearsfromfourbirth
cohortsinFinland.Bytheageof22years,32(21%)ofthechildrenhaddefinedepilepsy.Four
peoplewithepilepsyhaddiedbyage22,butthecausesofdeathwerenotdirectlyrelatedto
epilepsy.Thecumulativeprobabilityofremissionfromseizures(definedasfor5ormoreyears)at
theagesof10,17,and22yearswas8,25,and32%.Inadditiontothe8(29%)childreninremission,
14%oftheliving28childrenhadbeenseizurefreeforatleast12months.So,although71%ofthe
childrenhadactiveepilepsy(definedashavingseizuresinthepast5years)atage22years,43%had
beenseizurefreeforatleast12months.
433
Annegers1979
434
Inastudyof618individualswithadiagnosisofepilepsy(atleasttwoseizureswithnoapparent
cause),457werefollowedupforatleast5years,328foratleast10years,and141atleast20years.
49ofthesehadneurologicdysfunction(spasticity,hemiparesis,mentalretardation)frombirth.The
percentageofthosewithneurologicdysfunctionhada46%probabilityofremission(seizurefreefor
5years)at20yearsafterdiagnosiscomparedwith74%forthosewhohadnoneurologicdysfunction
andidiopathicepilepsy.Theprobabilityforindividualswithneurologicdeficitsbeinginremission
andoffmedication10yearsafterdiagnosiswaslessthan15%comparedwith36%fortheidiopathic
groupandlessthan20%forthesymptomaticgroup.Theprobabilityforthosewithneurologic
deficitsbeinginremissionandoffmedication20yearsafterdiagnosiswas30%(47%forthe
idiopathicgroupand54%forthesymptomaticgroup).
434
Brorson1987
435
TheEpilepsies
555
Afollowupstudyof195children(aged0to19years)withactiveepilepsy(atleastoneseizureinthe
past3years)inUppsala,Swedenwasundertaken.Ofthe194childrenthatagreedtoparticipate,74
hadsomeneurodeficit.After12years,29ofthe74children(39%)wereinremission,definedas
beingseizurefreefor3consecutiveyears.Theannualremissionratewashigh(12%)onlyinthefirst
fewyearsafteronset,butthenfellto3%.
435
Goulden1991
436
Aprospectivestudyofchildrenwithmentalretardation(MR)wasundertakentoassesstheriskof
seizuresinthispopulation.Ofthe221childrenincluded,11diedpriortoage22,noneasaresultof
seizures.Byage22years,33(15%)hadrepeated,unprovokedseizures.39%ofthesewerein
remission(definedasseizurefreefor5years).Ratesofremissiondifferedbygroup:56%MRonly,
47%MRandcerebralpalsy,11%postnatalinjury.
436
Sillanpaa1975
437
244peoplewithepilepsyagedunder16yearswithrecurrentepilepticseizureswerefollowedupfor
ameanperiodof10.5years(minimum7years).94(28%)wereclassifiedashavingsomedegreeof
motorhandicap(clumsiness,cerebralpalsy,severesecondaryhypotonia).Theriskofpersistent
seizureswas2times,fivetimes,andtentimesthatforthosewithnomotorhandicapforpeoplewith
clumsiness,cerebralpalsy,andseveresecondaryhypotoniarespectively.
437
14.7 Whataretheadditionalmanagementissuesinpeoplewith
learningdisabilities?
252. Healthcareprofessionalsshouldbeawareofthehigherrisksofmortalityforchildren,young
peopleandadultswithlearningdisabilitiesandepilepsyanddiscussthesewiththem,their
253. Allchildren,youngpeopleandadultswithepilepsyandlearningdisabilitiesshouldhavearisk
assessmentincluding:
bathingandshowering
preparingfood
usingelectricalequipment
managingprolongedorserialseizures
theimpactofepilepsyinsocialsettings
SUDEP
thesuitabilityofindependentliving,wheretherightsofthechild,youngpersonoradultare
balancedwiththeroleofthecarer.[2004]
Evidencestatements
Mortalityratesarehigherinpeoplewithlearningdisabilitiesandepilepsythanthoseforpeoplewith
epilepsywhodonothavelearningdisabilities.However,epilepsyisnotthemajorcauseofdeathin
thisgroup.(IIb)
Managementissuesthatareviewedasimportantbyhealthcareprofessionalsandcarersare:
Concernsaboutseizuresandtheirimpactonindividualswithepilepsyandlearningdisabilitiesand
theircarers;
TheEpilepsies
556
Concernsabouttreatmentanditsimpactonindividualswithepilepsyandlearningdisabilitiesand
theircarers;
Concernsabouthowboththecarer(s)andanindividualwithepilepsyandlearningdisabilitiescan
achieveacarebalance;
Concernsaboutthesocialimpactforindividualswithepilepsyandlearningdisabilities.(III)
14.7.1 Isthereincreasedmortalityinpeoplewithlearningdisabilitiesandepilepsy?
Details
Secondaryevidence
Primaryevidence
Brorson1987
435
Afollowupstudyof195children(aged0to19years)withactiveepilepsy(atleastoneseizureinthe
past3years)inUppsala,Swedenwasundertaken.Ofthe194childrenthatagreedtoparticipate,74
hadneurodeficit.After12yearsobservation,8ofthechildrenwithneurodeficitdied,significantly
morethanchildrenwithout(p<0.05).Allhadactiveepilepsy.Onechilddiedsuddenlyand
unexpectedly,andwithoutanywitnesses.Onechilddiedduetoseizures(inSE),threedieddueto
infections,andthreehadunexplaineddeathsininstitutions.
435
Forsgren1996
438
Acohortof1,478peoplewithmentalretardationlivinginaSwedishprovincewasfollowedfor7
yearstostudythepatternofmortality.296peoplehadepilepsy(definedasrecurrent,unprovoked
seizures)andmentalretardation(MR).Duringthe7yearobservationperiod,124peopledied,of
whom30(10.1%)hadepilepsy.TheincreaseddeathratewashighlysignificantforpeoplewithMR
andepilepsy,(SMR5.0,95%CI3.3to7.5)andpeoplewithMR,epilepsyandCP(SMR5.8,95%CI3.4
to9.8).Epilepsywasreportedasthecauseofdeathin1ofthe30cases,andasacontributingcause
in6.Examinationofmedicalfiles,deathcertificates,andnecropsy(11cases)foundtwodeathstobe
probablyseizurerelated(oneafterafallprobablyafteraseizure,onefounddeadinbedwithno
obviouscause)and28deathsnotrelatedtotheepilepsy.
438
Forssman1970
439
Astudyof12,903individualscaredforininstitutionsforthementallydeficientwasundertakenin
1955to1959.12,873(99.8%)werefollowedupuntiltheydiedortoJanuary1st1968.Standard
mortalitywascalculatedfromthelifetablesforthestandardpopulationin19601965.1,784people
diedduringtheperiodofobservation,ofwhom445hadepilepsy.Theoverallreductioninlife
expectancywas5%comparedwith14%forpeoplewithepilepsy.Ofthe1,682withepilepsy,26%
(445)diedandtherelativemortalityratewas7.9timesthestandard(comparedwith3.2overall).
439
Nashef1995
388
Mortalityandsuddendeathrateswerestudiedinacohortof310childrenattendingaschool
specialisingintheeducationofpeoplewithepilepsyandlearningdisability.Childrenwereincludedif
theyattendedatanytimebetween1970and1993.Totaldurationoffollowupwas4,135person
years.Therewere28deaths(meanage19years,range10to28);14wereclassifiedassudden
death.
388
TheEpilepsies
557
14.7.2 Whatmanagementissuesinpeoplewithlearningdisabilitiesdohealthcarepractitioners
andcarersviewasimportant?
Secondaryevidence
Primarypapers
Espie2001
440
The2001paperreportedthedevelopmentandvalidationoftheGlasgowEpilepsyOutcomeScale
(GEOS):ahealthmeasurementscaledevelopedspecificallyforusewithadultswithepilepsyand
learningdisabilities.Intheinitialscaledevelopmentworkaconveniencesampleof48carersand46
healthpractitionersparticipatedinfocusgroupdiscussionstodetermineissuesofconcerninthe
managementofadultswithepilepsyandlearningdisabilities.Thisledtothedevelopmentoffour
subscaleswhicharesummarisedhere:
1) Concernsaboutseizures
Seizurepattern
Seizureseverity
Emergencyrisks
Injuryrisks
Aftereffectsofseizures
2) Concernsabouttreatment
Diagnosticissues
Treatmentdecisions
Medicationforepilepsy
Drugsideeffects
Dependenceonmedication
3) Concernsaboutcaring
Achievingacarebalance(e.g.,freedomversussupervision)
Caredependency(e.g.,carerslosetheirownindependence)
Careexpertise(e.g.,donotknowhowtohelpthepersonduringaseizure)
4) Concernsaboutsocialimpactforpersonwithepilepsy
Lossofindependence
Socialattitudes
Personalskills(e.g.,dangerousforpersontousekitchen,usestairs)
440
TheEpilepsies
Youngpeoplewithepilepsy
558
15 Youngpeoplewithepilepsy
15.1 Introduction
Adolescenceisaperiodoftransitionfromdependencetoindependence,whenadolescentsbeginto
adoptamultitudeofnewsocialandemotionalrolesandlearntocopewithalteredbodilyfunctions.
Adolescentswithachronicillnesssuchasepilepsyareconstantlystrugglingforindependence.Atthe
sametime,theirillnessoftenkeepsthemtiedphysically,emotionallyandfinanciallytotheirfamilies.
Goodmanagementofthistransitionperiodbyhealthcareprofessionalsisvitaltodevelopand
maintaintheselfesteemandconfidenceoftheadolescentwithepilepsy.
441
15.2 Isadifferentapproachtomanagementrequiredinadolescence?
254. Thephysical,psychologicalandsocialneedsofyoungpeoplewithepilepsyshouldalwaysbe
consideredbyhealthcareprofessionals.Attentionshouldbepaidtotheirrelationshipswith
familyandfriends,andatschool.[2004]
255. Healthcareprofessionalsshouldadoptaconsultingstylethatallowstheyoungpersonwith
epilepsytoparticipateasapartnerintheconsultation.[2004]
256. Decisionsaboutmedicationandlifestyleissuesshoulddrawonboththeexpertiseofthe
healthcareprofessionalandtheexperiences,beliefsandwishesoftheyoungpersonwith
epilepsyaswellastheirfamilyand/orcarers.[2004]
257. Duringadolescenceanamedclinicianshouldassumeresponsibilityfortheongoing
managementoftheyoungpersonwithepilepsyandensuresmoothtransitionofcaretoadult
services,andbeawareoftheneedforcontinuingmultiagencysupport.[2004]
Evidencestatement
Nostudieswereidentifiedwhichtestedtheeffectivenessofinterventions(e.g.,educational
interventions)designedtoincreaseadherencewithhealthcareprofessionalsadviceinyoungpeople
withepilepsy.
Details
NosystematicreviewsofRCTsorRCTsofdifferentprocessesofcareforadolescentswithepilepsy
wereidentified.
15.3 Whatarethefactorsthataffectadherencetotreatmentin
adolescentswithepilepsy?
Secondaryevidence
Onesystematicreviewofadherencewithmedicationinpeoplewithepilepsywasidentified.
Althoughthisreviewdidnotfocusonlyonadolescents,itfoundthatbeingateenagerwasassociated
withpooradherencewithmedication
151
.
Theauthorsthenconsideredtheexistingliteratureonadherencetomedicationinadolescentsasa
group.Studiessuggestedthatpooradherencetoprescriptionregimensmaybeinfluencedby:
feelingsofisolation,
feelingsofstigma,
TheEpilepsies
559
threatstoindependenceandabilitytojoininwithpeers,
perceivedlackofunderstandingoftheircondition,and
denialoftheirepilepsy.
Conversely,goodadherencewithtreatmentregimewasfoundtobelinkedwith:
supportfromparents,
supportfromthedoctor,
goodmotivation,
feelingsofepilepsynotbeingathreattosocialwellbeing,and
[good]familyenvironment.
Theauthorsconcludedthattheneedsofadolescentsrequirespecialattention.
151
15.4 Isthereanyevidenceofeffectivenessforanygivenstrategies
proposedtoimproveoutcomesforadolescents?
Thestudiesreportedintheabovesystematicreview
151
arereportedasshowinganassociation
betweencertainhealthcareprofessionalbehavioursandselfreportedadherencewithmedication.It
shouldbenotedthatassociationdoesnotinitselfprovethattherelationshipiscausal,thatis,having
regularhealthcareprofessionalinputleadstoimprovedadherencetothetreatmentplan.
258. Multidisciplinaryservicesprovidedjointlybyadultandpaediatricspecialistshaveakeyrolein
thecareoftheyoungpersonwithepilepsy.Thiscanfacilitatethetransitionfrompaediatricto
adultservicesandaidinthedisseminationofinformation.[2004]
259. Beforethetransitiontoadultservicesismade,diagnosisandmanagementshouldbe
reviewedandaccesstovoluntaryorganisations,suchassupportgroupsandepilepsycharities,
shouldbefacilitated.[2004]
Evidencestatement
Nostudieswereidentifiedwhichcomparedoutcomesforyoungpeopleattendingspecialistteenage
epilepsyasopposedtothoseattendingroutinechildoradultclinics.
Details
Appleton1999
442
Inthispersonalpracticepaper,theauthorsproposedthataspecialistserviceshouldbeprovided
becauseteenagersfeeluncomfortableormayfeelitinappropriatetocontinuetoattendpaediatric
services,andtheyarelikelytoremainonmedicationforalongperiodoftime.Theysuggestedthat
thiscouldbesitedwithinaspecificclinicforteenagers.
Smith2002
443
Thispaperreportstheexperienceofonespecificteenagerepilepsyclinic.Itdoesnotcompare
outcomesforadolescentsattendingspecialistteenageepilepsyasopposedtothoseattending
routinechildoradultclinics.
15.5 Whatarethespecialneedsorinformationrequirementsofthis
group?
260. Theinformationgiventoyoungpeopleshouldcoverepilepsyingeneralanditsdiagnosisand
treatment,theimpactofseizuresandadequateseizurecontrol,treatmentoptionsincluding
sideeffectsandrisks,andtherisksofinjury.Otherimportantissuestobecoveredarethe
TheEpilepsies
560
possibleconsequencesofepilepsyonlifestyleandfuturecareeropportunitiesanddecisions,
drivingandinsuranceissues,socialsecurityandwelfarebenefitissues,suddendeathandthe
importanceofadherencetomedicationregimes.Informationonlifestyleissuesshouldcover
recreationaldrugs,alcohol,sexualactivityandsleepdeprivation(seechapter12).[2004]
Evidencestatements
Thereislittleresearchavailableonthespecificinformationneedsofyoungpeople.(III)
Individualswithepilepsyrequireinformationon:Epilepsyingeneral;Diagnosisandtreatment
options;Medicationandsideeffects;Seizuresandseizurecontrol;Injuryprevention;Psychological
issues;Socialsecurity;Drivingandinsurance;Employment;Prognosis;Lifestyleandsocialissues.(III)
Secondaryevidence
Couldridge2001
372
ThisUKpapersystematicallyreviewedtheinformationandcounsellingneedsofpeoplewith
epilepsy.Itaimedtolocate,appraiseandsynthesiseevidencefromkeyprimaryresearchinthisarea
between1990and2000.Thereviewdidnotfocusspecificallyontheneedsofadolescentsand
epilepsy.Fifteenpapersidentifiedspecificinformationneedsofpeoplewithepilepsy.Resultsfrom
thesestudiessuggestthatpeoplewithepilepsyrequireinformationon:
epilepsyingeneral
seizuresandseizurecontrol
injuryprevention
psychologicalissues
socialsecurity
drivingandinsurance
employment
prognosis
lifestyleandsocialissues
Thereview
372
identifiedonepaperthatdealtspecificallywiththeexperiencesofyoungpeoplewith
epilepsy.
Wilde1996
444
ThisqualitativestudywassetintheEastMidlands(Leicester)andinvolvedindepthinterviewswith
24youngpeople(15females,9males),agedbetween13and25years,allofwhomhadepilepsyand
attendedoutpatientclinics.
Theimportantissuesraisedincludedthefindingthatalargeproportionofthesample(71%)reported
havingbeenthevictimsofprejudice,especiallybullyingandteasingwhiletheywereatsecondary
school.Additionally,manysubjectswerecriticalofthemedicalprofessionandsupportservicesfor
peoplewithepilepsy,complainingthattheywerenotmeetingtheirneedsappropriately.Most
subjectsreportedfeelingsofapprehensionabouttellingothersabouttheirepilepsy,especially
membersoftheoppositesex,andpotentialemployers.Mostdescribedsupportive,positive
elationshipswiththeirfamiliesandclosefriends,andparentaloverprotectionwasrarelyreportedby
themasbeingasignificantproblem.Inaddition,anestimateofsubjects'adjustmenttoepilepsywas
obtainedwhichappearstoindicatethatthemajoritywerecopingwellwiththeircondition,even
thoughitmayhavebeenresentedbysomeofthem.
444
TheEpilepsies
561
15.6 Shouldthediagnosisofepilepsyberevisitedinthisgroup?
261. Thediagnosisandmanagementofepilepsyshouldbereviewedduringadolescence.[2004]
Evidencestatements
Nostudieswereidentifiedwhichcomparedoutcomesforyoungpeoplehavingtheirdiagnosis
reviewed/revisitedattheiroutpatientclinicappointmentasopposedtothosewhodidnothavetheir
diagnosisreviewed/revisited.
Oneuncontrolledcasereviewfoundthat10%ofyoungpeopleattendingsuchaclinicdidnothavea
diagnosisofepilepsyand22%wereonaninappropriateAED.(III)
Itistheopinionofrespectedauthoritiesthatthediagnosisandmanagementofepilepsyshouldbe
revisitedinthisgroup.(IV)
Arevisitisindicatedonthefollowinggrounds:thedifferentialdiagnosisofaseizureinyoungpeople
iswideandcanincludenonepilepticattackdisorder,vasovagalattacksandmigraine.(IV)
Thereisaneedtoclassifytheepilepsysyndrometoensureoptimumtreatmentandaccurate
prognosis.Thechoiceandsideeffectsofantiepilepticdrugs(AEDs)needtobeconsideredintheshort
andlongterm.(IV)
Secondaryevidence
Nosystematicreviewsoftheliteraturethataddressedtheabovequestionwereidentified.
Primaryevidence
Appleton1997
445
ThisUKbasedstudyreportedacaseseriesfromadolescentsattendingadedicatedclinicfor
teenagerswithepilepsy.
In1991,aspecificclinicforteenagerswithepilepsywasestablishedinLiverpooltoaddressthe
uniqueneedsandconcernsofthisagegroupand,importantly,tofacilitateasmoothhandoverof
specialistepilepsycarefrompaediatrictoadultservices.Anadditionalandcrucialbenefitofthis
clinichasbeentoprovideafurther,andhopefullyfinal,screentoconfirm(orrefute)thediagnosisof
epilepsy,tocorroborate,orcorrectlyidentify,thespecificepilepsysyndromeandtoensurethatthe
mostappropriateantiepilepticdrug(AED)isbeingprescribedandwhen,ifpossible,thedrugcanbe
withdrawn.
Of120consecutiveindividualsreferredtotheteenagerclinic,12(10%)didnothaveepilepsy,and26
(22%)werebeingtreatedwithaninappropriateAED.Themainissuesandconcernsvoicedbythe
teenagersincludedchoicesoffurthereducationandcareer,thepossibilityandrisksofwithdrawing
anticonvulsants,drivingregulations,theinheritanceofepilepsyandpregnancy/contraception.
Theyidentifiedthefollowingreasonswhythediagnosisofepilepsyshouldberevisitedinthisgroup:
Thedifferentialdiagnosisofaseizureinadolescentsiswideandcanincludenonepilepticattack
disorder,vasovagalattacksandmigraine;
Thereisaneedtoclassifytheepilepsysyndromegiventheprevalenceofjuvenilemyoclonic
epilepsyinthisgroup;
Poorseizurecontrolduringadolescencecanaffectmaturationduetodisruptionofendocrine
systems;
Thechoiceandsideeffectsofantiepilepticdrugs(AEDs)needtobeconsidered:forboysandgirls:
thecosmeticsideeffectsofAEDs;forgirls:pregnancyandAEDs.
TheEpilepsies
562
Theauthorsrecommendedthatadolescenceisanimportanttimetoreviewthediagnosisof
epilepsy.
445
Expertevidence
Appleton1999
442
AppletonandNevillestatedthattheadolescentperiodwasanimportanttimetoreviewthe
diagnosisofbothepilepsyandtheepilepsysyndrome,andtoconsideranyunderlyingcause.
Reasonsincludedpreviousmisdiagnosis,andparticularlythepotentiallyseriousimplicationsof
misdiagnosisforemployment,driving,andpsychosocialhealth.
TheEpilepsies
Olderpeople
563
16 Olderpeople
16.1 Pharmacologicalmanagementofepilepsyinolderpeople
16.1.1 Introduction
Theelderlyarearapidlygrowingpopulation.Asaconsequence,anincreasingnumberarepresenting
withepilepsy,manytheresultofcerebrovasculardisease.Thereisnoevidencetosuggestthat
seizuresareanymoreresistanttomedicationthantheyoungerpopulation.However,thehighrate
ofotherillnessandcomedication,susceptibilitytosideeffects(egcardiac)aswellastheagingbrain,
suggesttheymayrequireveryspecificconsiderationwithregardtotreatmentchoice.Wehaveused
thedefinitionof65yearsorolderhoweverthisisbasedonthecutoffpointinthemajorityofthe
literature.Itshouldberecognisedthatolderpeoplemaymeansomethingdifferentclinically.
includedolderpeopletakingantiepilepticdrugs.Welookedfordataspecificallyontheincidenceof
adverseevents(10%orabove),cognitiveeffectsandqualityoflife.Onlyvalidatedmeasuresof
cognitiveeffectandoutcomesrelatingtoqualityoflifehavebeeninvestigatedforthepurposesof
thisevidencereview.TheGDGdecidedthatevidenceontheeffectivenessofthevariousdrugsat
reducingnumberofseizureswasbetterexaminedbyconsideringthedatafromgeneralepilepsy
population.Thisdatacanbefoundinothersectionsoftheguideline.
WesearchedforRCTscomparingthetolerabilityofdifferentpharmacologcialinterventionsfor
epilepsyinanolderpopulation.Theinterventionsweincludedinoursearchwerepregabalin,
zonisamide,lacosamide,lamotriginegabapentin,oxcarbazepine,tiagabine,levetiracetam,
topiramate,vigabatrin,phenyoin,phenobarbital,clobazam,clonazepam,felbamate,acetazolamide,
primidone,sodiumvalproateandcarbamazepine.WesearchedforanyRCTstudiesthatcompared
thetolerabilityoftwoormoreofthesetreatments(orplacebo).Belowisamatrixshowingwere
evidencewasidentified.Aboxcontainingafigureindicatesthenumberofstudiesthatwerefound
andthattheevidenceforthiscomparisonhasbeenreviewedinthischapter.Anemptyboxindicates
thatnoevidencewasfound.Inthiscase,nosectiononthiscomparisonisincludedinthechapter.
Placebo
Carbamazepine
Carbamazepine
sustainedrelease

Lamotrigine 3
446,447
164
2
448
450

Sodiumvalproate
Phenytoin 1
451

Gabapentin 1
446
1
446

TheEpilepsies
Olderpeople
564
PCBplaceboCBZcarbamazepineCBZSRcarbamazepinesustainedrelease
LTGlamotrigineVPAsodiumevaporatePHTphenytoin
GBPgabapentin
16.1.3.1 Lamotriginemonotherapyversuscarbamazepinemonotherapy
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsoncarbamazepinecomparedtolamotriginehadseizurefreedom
(MODERATEQUALITY).
Significantlymoreparticipantsoncarbamazepinemonotherapycomparedtolamotrigine
monotherapywithdrewduetoadverseevents(MODERATEQUALITY).
Significantlymoreparticipantsonlamotriginemonotherapycomparedtocarbamazepine
monotherapyhad:
incidenceoftremor(LOWQUALITY)
incidenceofweightloss(MODERATEQUALITY)
Significantlymoreparticipantsoncarbamazepinemonotherapycomparedtolamotrigine
monotherapyhadanincidenceof:
death(LOWQUALITY)
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandcarbamazepine
monotherapyforincidenceof:
poorcoordination(VERYLOWQUALITY)
sedation(VERYLOWQUALITY)
GIproblems(VERYLOWQUALITY)
PCB CBZ CBZ
SR
LTG VPA PHT GBP
TheEpilepsies
Olderpeople
565
weightgain>4lbs(VERYLOWQUALITY)
waterretention(VERYLOWQUALITY)
Nystagmus(VERYLOWQUALITY)
Dysarthria(VERYLOWQUALITY)
gaitproblems(VERYLOWQUALITY)
changeinmoodoraffect(VERYLOWQUALITY)
cognitivedisturbances.(VERYLOWQUALITY)
Therewerenostudiesthatreportedqualityoflifeoutcomes.
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytocarbamazepinemonotherapywas
identified.
16.1.3.2 Lamotriginemonotherapyversussustainedreleasecarbamazepinemonotherapy
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandsustainedrelease
carbamazepinemonotherapyforseizurefreedom(VERYLOWQUALITY).
carbamazepinemonotherapyfortimetoexit/withdrawal(duetoanyevents).(VERYLOW)
Significantlymoreparticipantsonsustainedreleasecarbamazepinemonotherapycomparedto
lamotriginemonotherapyhadwithdrawalduetoadverseevents(LOWQUALITY).
carbamazepinemonotherapyfortheincidenceof:
rash/skinreaction(VERYLOWQUALITY)
carbamazepinemonotherapyonthechangesinSEALSscore.
TheEpilepsies
Olderpeople
566
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytosustainedreleasecarbamazepine
monotherapywasidentified.
16.1.3.3 Sodiumvalproatemonotherapyversusphenytoinmonotherapy
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweensodiumvalproatemonotherapyandphenytoinfor
seizurefreedom.
Therewasnosignificantdifferencebetweensodiumvalproatemonotherapyandphenytoin
monotherapyfor:
withdrawalduetoadverseevents(VERYLOWQUALITY)
incidenceofunsteadiness(VERYLOWQUALITY)
incidenceofsleepiness(VERYLOWQUALITY)
incidenceoftremor(VERYLOWQUALITY)
incidenceofedema(VERYLOWQUALITY)
incidenceofalopecia(VERYLOWQUALITY)
incidenceofdepression(VERYLOWQUALITY)
incidenceofweightgain(VERYLOWQUALITY)
incidenceofcognitivefunction.(MODERATEQUALITY)
Cognitiveeventsstatisticallysignificantresults
Therewassignificantimprovementincancellationtimetestscoresforphenytoinmonotherapy
comparedtosodiumvalproatemonotherapyat6monthsonly.
Cognitiveeventsstatisticallynonsignificantresults
Therewasnosignificantdifferencebetweensodiumvalproatemonotherapyandphenytoin
monotherapyforallothercognitivetestsat6weeks,3months,6monthsand1year.
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytophenytoinmonotherapywas
identified.
TheEpilepsies
Olderpeople
567
16.1.3.4 Gabapentinmonotherapyversuscarbamazepinemonotherapy
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweengabapentinmonotherapyandcarbamazepine
monotherapyforseizurefreedom(VERYLOWQUALITY).
Significantlymoreparticipantsongabapentinmonotherapycomparedtocarbamazepine
monotherapyhadanincidenceof:
weightgain>4lbs(MODERATEQUALITY
waterretention.(MODERATEQUALITY)
Significantlymoreparticipantsoncarbamazepinemonotherapycomparedtogabapentin
monotherapyforwithdrawalduetoadverseevents(LOWQUALITY).
theincidenceof:
dysarthris(VERYLOWQUALITY)
cognitivedisturbances(VERYLOWQUALITY)
incidenceofheadaches(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinggabapentinmonotherapytocarbamazepinemonotherapywas
identified.
TheEpilepsies
Olderpeople
568
16.1.3.5 Lamotriginemonotherapyversusgabapentinmonotherapy
Clinicalevidence
Evidencestatements
Therewasnosignificantdifferencebetweenlamotriginemonotherapyandgabapentinmonotherapy
forseizurefreedom(VERYLOWQUALITY).
Significantlymoreparticipantsonlamotriginemonotherapycomparedtogabapentinmonotherapy
hadahigherincidenceofweightloss.(MODERATEQUALITY)
Significantlymoreparticipantsongabapentinmonotherapycomparedtolamotriginemonotherapy
had:
withdrawalduetoadverseevents(MODERATEQUALITY).
incidenceofweightgain>4lbs(MODERATEQUALITY)
incidenceofwaterretention(MODERATEQUALITY)
Nosignificantdifferencebetweenlamotriginemonotherapyandgabapentinmonotherapyforthe
incidenceof:
hyponatremia(VERYLOWQUALITY)
dysarthria(VERYLOWQUALITY)
cognitivedisturbances(VERYLOWQUALITY)
headaches.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytogabapentinmonotherapywas
identified.
TheEpilepsies
Olderpeople
569
Recommendation
262. Donotdiscriminateagainstolderpeople,andofferthe
sameservices,investigationsandtherapiesasforthegeneral
population.[new2012]
outcomes
Adverseeffectsofdrugsandqualityoflifewereconsideredthe
mostimportantoutcomesforthisreviewasolderpeopleare
moresusceptibletosideeffectsofdrugs.Effectivenessofthe
drugsatreducingnumbersofseizuresisalsoimportantbutis
dealtwithintheotherseizureandepilepsysyndromesectionsof
thisguideline.
benefitsandharms
AEDareassociatedwithpotentiallymoreadversesideeffectsin
thispatientgroup.Thereductioninseizuresfoundinourother
reviewsisassumedtobesimilarforolderpeople.TheGDG
consideredthatthebenefitofreductioninseizuresoutweighed
theadverseeffectsassociatedwithdrugtreatmentinthesame
wayasitdoesforotherpeoplewithepilepsy.
Economicconsiderations TherewasnoeconomicevidencebuttheGDGconsideredthat
treatmentwithAEDswouldbecosteffectiveforolderpeoplejust
asitisforotherpeoplewithepilepsy.
Qualityofevidence Thisrecommendationwasbasedonoutcomedatathatwas
moderatetoverylowqualityandGDGexpertise.
Otherconsiderations
TheGDGwishedtoensurethatolderpeoplehadoptimal
treatmentandhadthesameopportunitiesasotheradultsto
accesstreatmentsandspecialistepilepsyservices.TheGDGwere
concernedthatthisisnotnecessarilycurrentpractice.
TheEpilepsies
Olderpeople
570
Recommendation
263. Payparticularattentiontopharmacokineticand
pharmacodynamicissueswithpolypharmacyandcomorbidity
inolderpeoplewithepilepsy.Considerusinglowerdosesof
AEDsand,ifusingcarbamazepine,offercontrolledrelease
carbamazepinepreparations.[new2012]
outcomes
Incidenceofadverseeventsandcognitiveoutcomeswereclinically
benefitsandharms
Carbamazepinehadsignificantlyhigherincidenceofdeathand
somnolencecomparedtolamotriginebuttherewasnosignificant
differencebetweenthetwodrugswhencarbamazepinewasinthe
sustainedreleaseformulation.Significantlymoreparticipantson
lamotriginehadweightlosswhencomparedtogabapentinand
carbamazepineandhighertremorcomparedtocarbamazepine.
Significantlymoreparticipantsongabapentinhadweightgainand
waterretentionwhencomparedtolamotrigineand
carbamazepine.TheGDGconsideredthatolderpeoplemayhave
equivalentreductioninseizureswithlowerdosesofAEDsandby
reducingthedose,adverseeffectscanbeminimalised.
TheGDGconsideredthatolderpeoplearemorelikelytohave
additionalcomorbiditiesandalsobetakingdrugsfortheseco
morbiditiesthanotheradults.Druginteractionsandcomorbidities
maycauseundesirablepharmacokineticandpharmacodynamic
issues.Whilstitwilltakesomeadditionaltimeduringthe
consultationforhealthcareprofessionalstoconsiderco
morbiditiesandpolypharmacy,theGDGconsideredthatthe
benefitsoutweighedtherisksofnotdoingthis.
Economicconsiderations Noeconomicevidencewasavailabletoinformcosteffectiveness
ofAEDsinolderpeoplespecifically.TheGDGthoughtthatthe
effectivenessofAEDsinthisgroupislikelytobesimilartoother
epilepsypopulationsandthereforecosteffectivenesswaslikelyto
bedrivenbytheincidenceofintolerablesideeffectscausing
withdrawaloftreatment.TheGDGalsoconsideredthatthis
populationmayrespondtolowerdosesofanumberofAEDswhich
couldreducetheburdenofsomesideeffectsaswellasreduce
overallcosts.Theadditionalconsultationtimetakentoconsiderco
morbiditiesandpolypharmacywasconsideredtobeworthwhilein
ordertoreducetheriskofadverseeffectsofdruginteractions.
Finally,controlledreleaseformulationsofcarbamazepinearenot
morecostlythannoncontrolledreleasecarbamazepine.
Qualityofevidence
Thequalityofthestudieswasgenerallygood,howeverthedrop
outratewasextremelyhigh,withdifferencesbetweengroups
whichcouldbiasresults.Asthedifferentialdropoutwasover20%
weconductedasensitivityanalysistoconfirmwhetherthe
differentialdropoutaffectedtherecommendation.Wetestedthe
differenceofusingavailablecaseanalysiscomparedtoITTanalysis
instudieswheretherewasahighdifferentialdropout.The
TheEpilepsies
Olderpeople
571
outcomesthatchangedbyusingavailablecaseanalysiswere
seizurefreedom(fromstatisticallysignificanttononsignificant),
incidenceofpoorcoordination(fromnonstatisticallysignificant
tostatisticallysignificantlyhigherinthecarbamazepinearm)and
incidenceofdizziness(fromnonstatisticallysignificantto
statisticallysignificantlyhigherinthecarbamazepinearm).The
resultsdidnotaffecttherecommendationwhichwasbasedon
adverseeventsratherthanefficacy.Moreadverseeventswere
foundtobestatisticallysignificantfromusingavailablecase
analysis,whichreinforcesthedifferencebetweencarbamazepine
andcarbamazepinecontrolledreleaseformulationsforolder
patients.
Otherconsiderations TheGDGexpertisesupportedthisrecommendationthat
carbamazepinecontrolledreleaseformulationhassimilarefficacy
TheGDGexpressedtheviewthatolderpeoplehavenotingeneral
receivedadequateaccesstospecialistservicesandthereisarisk
thattheyarereceivinglessthanoptimumtreatmentandpoorer
outcomes.Theythereforethoughtitwasimportanttomakethis
recommendationtopayparticularattentiontochoiceofdrugand
doseforolderpeople.
TheEpilepsies
Peoplefromblackandminorityethnicgroups
572
17 Peoplefromblackandminorityethnicgroups
17.1 Introduction
TheUKhasasizeableblackandminorityethnicpopulation.Itisimportantthatthehealthneedsof
individualswithepilepsyfromblackandminorityethnicgroupsareresearchedandtheresearch
findingsdisseminatedtopromoteequityofcare.Todatepublishedresearchinthisareahasbeen
limitedandhasfocusedonsmallprevalencestudiesinparticularethnicgroups.
452
Individualswhohaveepilepsyandwhoareblackorfromaminorityethnicgroupmayencounter
specificdifficultiesthathavethepotentialtoadverselyaffecttheirhealthoutcomes.Theymay
experiencedifficultiesincommunicationandinaccessingappropriatehealthcare,includingreferral
toaspecialisttomakeadiagnosisofepilepsyandstartingandcontinuingappropriatetreatment.
Differentethnicgroupsmayhavedifferenthealthbeliefsinrelationtowhatitmeanstohavea
diagnosisofepilepsy,includingtheextenttowhichtheconditionisstigmatised.Itisimportantthat
healthcareprofessionalsareenabledtodeliverculturallysensitivecaretoindividualswithepilepsy
fromminorityethnicgroups.
17.2 Whataretheinformationandserviceprovisionneedsofpeople
fromblackandminorityethnicgroups?
264. Children,youngpeopleandadultsfromblackandminorityethnicgroupsmayhavedifferent
culturalandcommunicationneedsandtheseshouldbeconsideredduringdiagnosisand
management.Theneedforinterpretationshouldbeconsideredalongsideothermeansof
ensuringthatapersonsneedsareappropriatelymet.[2004]
265. Aninterpretershouldhavebothculturalandmedicalknowledge.Interpretersfromthefamily
aregenerallynotsuitablebecauseofissuessuchasconfidentiality,privacy,personaldignity,
andaccuracyoftranslation.[2004]
266. Information,includinginformationaboutemploymentrightsanddriving,shouldbeavailable
inanappropriateformatorthroughotherappropriatemeansforchildren,youngpeopleand
adultswhodonotspeakorreadEnglish.[2004]
Evidencestatements
SouthAsianswithepilepsywantinformationonallaspectsofepilepsy,includingtreatmentandside
effects,andfurthersourcesofsupport,information,andadvice.(III)
Nootherevidencewasidentifiedabouttheinformationneedsofindividualswithepilepsyand/or
theircarersinotherblackandminorityethnicgroupsintheUK.
Details
NoevidencewasfoundintheMedicinesAlliancereview
151
ortheCouldridgereview
372
relating
specificallytominorityethnicgroups.Oneprimarysourceofevidencewasidentified.
453
Ismailandcolleagues2003
453
ThisqualitativestudyaimedtoexploretheexperiencesofSouthAsianswithepilepsyinrelationto
theirhealthneedsandbeliefsandtheroleofhealthprofessionalsinprovidingappropriate
informationandaccessibleservices.
TheEpilepsies
Peoplefromblackandminorityethnicgroups
573
Individualindepthinterviewswereconductedwithatotalof56people:30peoplewithepilepsyand
16familymembers(carers)and10healthprofessionals.Twofocusgroupswereconductedwith16
membersofthewiderSouthAsiancommunityinBradford.
Theresearchfindingscoveredperceptionsofepilepsy,familysupport,impactonlifestyleand
employment,traditionalSouthAsiantherapiesandserviceprovision.Theimpactofepilepsyon
employmentwasreportednegatively.Fourthemeswereidentifiedinrelationtoserviceprovision:
Lackofinformation.Therewasconcernexpressedaboutthelackofappropriateinformationand
advice.Themajorityofrespondentswantedmoreinformationfromdiagnosisonwards.
Individualsandtheirfamiliesfeltoverwhelmedatdiagnosisandwouldhavelikedmoretimeand
furtherexplanationstohelpadjustment
Languagebarriers.OnethirdoftherespondentswithepilepsywerenotfluentinspokenEnglish.
Therewasverylimiteduseofofficialinterpretersinconsultations.Usuallyfamilymemberstook
onthisrolewiththemajorityofpeoplewithepilepsyexpressingapreferenceforthis.However,
somepeoplefeltembarrassedattheideaofdiscussingpersonalproblemsthroughfamily
members.Alsonotallthecarersinterviewedwerehappyaboutinterpreting;theyadmitted
havingdifficultyintranslatingmedicalterminology.Also,healthprofessionalsexpressedconcerns
aboutimpartialityandconfidentialityissueswithsucharrangements.Thosewhospokelittleorno
Englishwantednontechnicalinformationintheirownlanguage.Writteninformationwasnot
alwaysthepreferredformatassomeindividualswereunabletoread,orfeltthatverbal
communicationwouldbemorebeneficial.
Interactionwithhealthcareprofessionals.Epilepsynurseswereregardedasthemosthelpful
healthprofessionalsduetotheireasyaccessibilityandholisticapproach.Respondentswere
satisfiedwiththeirGPswithaspecialinterestinepilepsyandhospitalspecialists(consultants)but
morethanhalfofrespondentsexpresseddissatisfactionwiththecareprovidedbytheirownGP.
Supportgroups.Alargenumberofrespondentswereopenmindedabouttheideaofattending
supportgroupsbutfacedpracticaldifficultieswithattendance(e.g.,transport,childcare).
TheEpilepsies
Thecareprocessforpeoplewithepilepsy
574
18 Thecareprocessforpeoplewithepilepsy
18.1 Introduction
Itisoutsidethescopeofthischaptertomakerecommendationsonservicedeliveryissuesasthey
relatetotheindividualwithepilepsyand/ortheircarers.Itdoesnotthereforedirectlyaddress
modelsofcare,therolesorcompositionofprimaryorsecondaryhealthcareteamsand
competencies,skillmixortrainingrequirements.
Thecareprocessforindividualswithepilepsyis,however,extremelyimportantandneedstobe
consideredintheguideline.Thischaptermakesrecommendationsontheprocessofcarenecessary
fortheindividualwithepilepsyand/ortheircarertoachievethebestpossiblehealthoutcomes.Itis
thusisspecifiedwhatresourcesindividualswithepilepsyshouldhaveaccesstoattheirconsultation
withaspecialist(forexample,writtenandvisualinformation)buttheguidelinedoesnotrecommend
whatformofserviceconfigurationcanbestprovidetheseresources(forexample,adedicatedfirst
seizureclinic).
18.2 Whatfeaturesofthecareprocessinprimarycare/sharedcare
leadtoimprovedhealthoutcomesforadultsandchildrenwith
epilepsy?
267. Children,youngpeopleandadultswithepilepsyshouldhavearegularstructuredreviewand
beregisteredwithageneralmedicalpractice.[2004]
268. AdultsshouldhavearegularstructuredreviewwiththeirGP,butdependingonthepersons
wishes,circumstancesandepilepsy,thereviewmaybecarriedoutbythespecialist.[2004]
269. Foradults,themaximumintervalbetweenreviewsshouldbe1yearbutthefrequencyof
reviewwillbedeterminedbythepersonsepilepsyandtheirwishes.[2004]
270. Epilepsyspecialistnurses(ESNs)shouldbeanintegralpartofthenetworkofcareofchildren,
youngpeopleandadultswithepilepsy.ThekeyrolesoftheESNsaretosupportbothepilepsy
specialistsandgeneralists,toensureaccesstocommunityandmultiagencyservicesandto
provideinformation,trainingandsupporttothechild,youngpersonoradult,families,carers
and,inthecaseofchildren,othersinvolvedinthechildseducation,welfareandwellbeing.
[2004]
271. Children,youngpeopleandadultswithepilepsyshouldhaveanaccessiblepointofcontact
withspecialistservices.[2004]
272. Allchildren,youngpeopleandadultswithepilepsyshouldhaveacomprehensivecareplan
thatisagreedbetweentheperson,familyand/orcarerswhereappropriate,andprimarycare
andsecondarycareproviders.Thisshouldincludelifestyleissuesaswellasmedicalissues.
[2004]
Evidencestatements
Thereisalackofgoodqualityevidenceofeffectivenessforstructuredannualreviewinprimarycare.
AhighproportionofadultswhodiedofepilepsyintheNationalSentinelClinicalAuditofEpilepsy
relatedDeathhadnothadastructuredreview.Auditsinprimarycarecanimprovetheprocessof
careforpeoplewithepilepsy.(IV)
TheEpilepsies
575
Thereisevidencethatepilepsyspecialistnursesimprovetheprocessofcareforpeoplewithepilepsy
inprimarycare.(Ia)
Thereissomeevidencetoshowthatinformationrecordedisimprovedanddepressionreducedwith
epilepsyspecialistnurses.(Ia)
Thereiscurrentlylimitedevidencethatepilepsyspecialistnursesimproveclinicallyimportant
outcomesforpeoplewithepilepsyinprimarycare.(Ia)
18.2.1 Whatevidenceisthereregardingthequalityofcarecurrentlyprovidedinprimarycare?
Details
Secondaryevidence
Therewerenopublishedhighqualityreviewsidentifiedofthequalityofcareforadultsandchildren
withepilepsyprovidedinprimarycare.Onenarrativereviewhighlightedthelimitedevidencebase
inthisareaandtheneedforfurtherresearch.
454
Primaryevidence
SUDEP2002
18
In2002,theNationalSentinelClinicalAuditofEpilepsywaspublished.TheauditreviewedtheGP
casenotesof285individualswhodied;45whoreceivedtheircareentirelywithingeneralpractice
and241whoalsoreceivedsecondarycare
Afterafirstseizuremostindividuals(84%)werereferredtosecondarycare.Therewasalowlevelof
clinicalinformationrecordinginrelationtoallthosewhodied.Documentedevidenceofindividual,
writtencareplanswaslacking.Intheyearpriortodeath,therehadbeennorecordedreviewof67%
ofpeoplereceivingalltheircareingeneralpractice.78%ofthosewhowerereceivingcombined
carehadbeenreviewedbyeitherthespecialistortheGP.Around29%ofindividualshadbeenseen
bytheirGPfornonepilepsyrelatedproblemsinthemonthbeforedeath.Fourindividualsreceiving
onlyprimarycarehadachangeinseizurefrequency,butwerenotreferred.Ofthosereceiving
combinedprimary/secondarycare,68individualswereconsideredtofulfilthecriteriaforre
assessment,butonly6(9%)wererereferred.
18
ClinicalStandardsAdvisoryGroup(CSAG)2000
11
Individualsperspectivesoncare
TheCSAGpostalsurveyofusersviewsonepilepsyserviceswasconductedacrosstheUKand
involvedpeoplerecruitedfrombothgeneralpractice(communitysample)andsecondarycare
(hospitalsample).Aresponserateof52%(2394/4620)wasachieved.
Overall91%weresatisfiedorfairlysatisfiedwithGPcare.Therewerenomajordifferencesbetween
adultsandchildren,betweencommunitybasedandhospitalbasedsamples,orbetweenthosewho
sufferfromnewonsetcontinuingepilepsyandthosewhohavecontrolledepilepsy.Manypeopledid
notconsulttheirGPregularlyabouttheirepilepsyanddidnotexpecttheirGPtohaveadetailed
knowledgeofepilepsy.Inthe12monthsbeforethesurvey,58%ofthecommunitysamplehadnot
visitedaGPtoconsultabouttheirepilepsy.
Themajorityofadultsinthecommunitysample,mostofwhomhadcontrolledepilepsyandwere
notattendinghospital,consideredtheirGPtobethemainproviderofcare(70%)andexpresseda
preferenceforGPcare(61%).Themajorityofadultsinthehospitalsampleregardedtheirhospital
doctorasthemainproviderofcare(55%).Only17%oftheoverallsampleconsideredtheircareto
besharedbetweentheGPandhospitaldoctor.Children,inbothsamples,preferredcaretobe
eithersharedbetweenprimaryandsecondarycareorprovidedbythehospital.
11
Generalpractitionersperspectivesoncare
CSAGsurveyedGPsintheUKwitha71%responserate(135/189).
ThemajorityofGPsreportedthattheyconsideredthecareofpeoplewithepilepsytobesharedwith
thehospital(57%).AminoritysawtheircareaseitherhospitalbasedwithlittleornoGP
TheEpilepsies
576
involvement(30%;ofwhomthemajorityofGPs,59%,werenothappywiththissituation)orGPled
(GPscompletelyinvolvedinmanagement)(13%).GPsfeltthatbettersharedcarearrangements
andcommunicationandaccesstohospitalwouldimproveclinicalservices.Themostcommon
suggestion(23%)byGPsforimprovingprimarycareepilepsyserviceswastheprovisionofan
epilepsyspecialistnurse.However,only16%oftheGPssurveyedhadaccesstoepilepsyspecialist
nurses(ateitherhospitalorcommunitylevel).
11
Primarycareaudits
Evidenceisavailableonthequalityofcareprovidedingeneralpracticethroughpublishedaudits
conductedinthelasttenyears.
455459
Severaloftheseauditsreportedfindingsfromasmallnumber
ofpracticesand/orreliedonselfselectingvolunteerpractices.Onepublishedauditaddressed
theseproblemsbybeingregionwide,randomlyselectingthegeneralpracticesandhavingahigh
participationrate(87%participated,31/36).
456
Theyfoundthatrecordingofinformationinthe
medicalnoteswasgenerallygood,particularlyinrelationtoinformationondateoffirstseizureand
AEDtherapy.Itwas,however,poorforsomekeyitemsessentialtotheeffectivemanagementofthe
condition.Anumberofrecommendationsaboutprovisionofcareforepilepsywerenotbeingmet,
inparticular,therewaslittleevidenceofanyregularreviewofthecareofpeoplewithepilepsybeing
undertakenbygeneralpractitionersandcounsellingaboutthenonclinicalaspectsofepilepsyoften
appearedinadequate.
Itisdifficulttoreportonthecarespecificallyprovidedtochildrenwithepilepsyinprimarycare.
Althoughadultsandchildrenwithepilepsywereincludedinanumberoftheaudits,onlyaminority
ofthosereviewedwerechildrenundertheageof16(forexample,11%
456
,5%
455
)andtheauditdata
werenotdisaggregatedintoadultsandchildren.
18.2.2 Whatprocessofcarehasbeenproposedtoimproveoutcomesforadultsandchildrenwith
epilepsyinprimarycare?
Structuredannualreview
Sharedcarebetweenprimaryandsecondarycare,forexamplefacilitatedbyepilepsyspecialist
nursesorGPswithaspecialinterest(GPSI)inepilepsy
18.2.2.1 Doadultsandchildrenwithepilepsyattendingprimarycarewhoreceivestructuredannualreview,
whencomparedwiththosewhodonot,havebetterhealthoutcomes?
Details
Aconsistentfindingfromareviewoftheevidenceonthequalityofcareprovidedinprimarycarefor
peoplewithepilepsyisthatcareisoftenreactiveandofvariablequality.TheneedforGPsto
provideastructuredmanagementsystemforepilepsy,alongthelinesofthatprovidedfordiabetes
andasthma,hasbeenproposedbyanumberofauthorities.
11,18
Thiscouldbeachievedbya
structuredannualreview.
Secondaryevidence
Primaryevidence
Norandomisedcontrolledtrialswerefoundevaluatingtheeffectivenessofstructuredreviewinthe
careofpeoplewithepilepsy.
ThestudybyThaparandcolleagues
454
wasexcludedasthisevaluatedtheopportunisticuseofa
promptandremindercardingeneralpracticeasopposedtostructuredannualreview.
TheEpilepsies
577
18.2.2.2 Doadultsandchildrenwithepilepsyattendingprimarycarewhoreceivecarefromaspecialist
epilepsynurse,whencomparedwiththosewhodonot,havebetterhealthoutcomes?
Details
Theneedforsharedcareprotocolsbetweenprimaryandsecondarycarehasbeenproposedbya
numberofauthorities.
11,460
Thedeploymentofnursestrainedinepilepsycare(specialistepilepsy
nurses)workinginprimarycarewhocouldliaisewithsecondarycarehasbeenproposed.
461
Secondaryevidence
Bradley2003
462
ACochranereviewassessedtheeffectivenessofspecialistepilepsynursescomparedtoroutinecare.
AnyRCTsorquasirandomisedtrialsthatcomparedspecialistnurseinterventionscomparedto
routineoralternativecarewereincluded.
Threetrialswereincluded,oneingeneralpracticeandtwoinaneurologycentre.Thethreetrials
onlyincludedindividualsaged15yearsorolder.
Thefindingsfromthetrialbasedingeneralpracticearesummarisedhere.
TheRidsdaleRCT
463
(andthefollowuppaper
464
)wasbasedingeneralpracticeandmostofthe
participantshadestablishedepilepsy.Thestudyincluded251adults(aged15yearsorover).The
interventioninvolvedaninterviewwithaspecialistepilepsynursefollowedupbytwospecialist
nurseinterviewsinadditionto'standardcare'.AconcernraisedintheCochranereview
462
wasthat
participantsintheinterventiongroupweretoldthattheywouldattenda'neurologyclinic',which
mayhavebeeninterpretedasspecialistcare.Potentiallythisbeliefmayhaveimprovedoutcomes
overandabovetheeffectsoftheinterventionfromtheepilepsyspecialistnurse.Thestudykey
outcomevariableswereknowledgeofepilepsy,anddepressionandanxietyscoresatsixmonths
(assessedbyvalidatedquestionnairesgivenbeforeandaftertheintervention)andtherecordingof
keyvariables(driving;drugcompliance;adversedrugeffects;alcohol,andselfhelpgroups)extracted
fromtheclinicalrecords.
Theauthorsreportedanincreaseofadvicerecordedinthenotesofpeoplewithepilepsy(p<0.001).
Theyalsofoundasignificantdecreaseintheriskfordepressionatsixmonths(p=0.024)inthose
individualswhohadnotexperiencedanepilepticseizureinthelastsixmonths(p=0.03).However,
therewasnosignificantdifferencebetweencontrolandinterventiongroupsinthosewhohad
experiencedaseizureinthelastsixmonths(p=0.44).
Inconclusion,thisstudydidnotshowanimprovementinanyclinicallyimportantoutcomes
465
for
peoplewithepilepsymanagedingeneralpracticebyanepilepsyspecialistnurse.Astheauthorsof
thestudythemselvesnotedthisstudywassmallinsizeandscope,focusingonprocessratherthan
outcomesandtheauthorsofthereviewcalledforfurtherresearchinthisarea.
462
Nosystematicreviewsofpaediatricclinicswereidentified.
Primaryevidence
Norandomisedcontrolledtrialswerefoundevaluatingtheeffectivenessofepilepsyspecialistnurses
publishedafterthedateoftheaboveCochraneReview.
18.3 Whatfeaturesofthecareprocessinsecondaryandtertiarycare
leadtoimprovedhealthoutcomesforadultsandchildrenwith
epilepsy?
273. Adultsshouldhaveregularreviews.Inaddition,accesstoeithersecondaryortertiarycare
shouldbeavailabletoensureappropriatediagnosis,investigationandtreatmentiftheperson
orclinicianviewtheepilepsyasinadequatelycontrolled.[2004]
TheEpilepsies
578
274. Adultswithwellcontrolledepilepsymayhavespecificmedicalorlifestyleissues(forexample,
pregnancyordrugcessation)thatmayneedtheadviceofaspecialist.[2004]
275. Childrenandyoungpeopleshouldhavearegularstructuredreviewwithaspecialist.[2004]
276. Forchildrenandyoungpeople,themaximumintervalbetweenreviewsshouldbe1year,but
thefrequencyofreviewsshouldbedeterminedbythechildoryoungperson'sepilepsyand
theirwishesandthoseofthefamilyand/orcarers.Theintervalbetweenreviewsshouldbe
agreedbetweenthechildoryoungperson,theirfamilyand/orcarersasappropriate,andthe
specialist,butislikelytobebetween3and12months.[2004]
277. Atthereview,children,youngpeopleandadultsshouldhaveaccessto:writtenandvisual
information;counsellingservices;informationaboutvoluntaryorganisations;epilepsyspecialist
nurses;timelyandappropriateinvestigations;referraltotertiaryservicesincludingsurgery,
whereappropriate.[2004]
278. Ifthestructuredreviewistobeconductedbythespecialist,thismaybebestprovidedinthe
contextofaspecialistclinic.[2004]
Evidencestatements
Thereisalackofgoodqualityevidenceofeffectivenessofdedicatedepilepsyclinicsinsecondaryand
tertiarycare.(Ia)
Thereissomeevidencethatepilepsyspecialistnursesimproveclinicallyimportantoutcomessuchas
knowledge,anxietyanddepressionforpeoplewithepilepsyinsecondaryandtertiarycare.(III)
18.3.1 Whatevidenceisthereofthequalityofcarecurrentlyprovidedinsecondary/tertiary
care?
Details
Secondaryevidence
Nosystematicreviewswereidentifiedthatsummarisedthequalityofcareinthesecondaryand
tertiarycaresettings.
Primaryevidence
SUDEPreport
18
In2002,theNationalSentinelClinicalAuditofEpilepsywaspublished.180caseswereaudited(158
adultsand22children).Clinicalreviewofthesedeathssuggestedthat60%ofepilepsyrelated
deathswereSUDEPandafurther7%werepossibleSUDEP.However,thesenumberswereestimates
becauseofconcernsaboutinformationavailabletotheauditonthecircumstancesofdeath,the
eventsleadinguptothedeathandtheadequacyofpostmorteminvestigations.
Only3%ofpeoplewhodiedwererecordedasseizurefreeattheirlasthospitalappointment.Most
ofthepaediatricdeathsoccurredinindividualswhohadseizuresthatweredifficulttocontroland/or
hadlearningorphysicaldisabilities.Althoughmostadults(93%)werenotrecordedasseizurefree
foratleastayearbeforedeath,atleast37%ofthesepeoplewerenotseenintheyearbeforethey
died.Thereasonsforthiswereunclearin50%ofcases.Threeindividualswithlearningdisabilities
hadbeenlostinthehandoverfrompaediatrictoadultcare.Around15%ofadultsmissedatleast
oneappointment.
Accesstoappropriatespecialistcarewasaparticularprobleminchildrenandinadultswithspecial
needs.About36%ofchildrenhadinadequateaccesstoaspecialistinepilepsycare.Adultswith
learningdifficultieswerelesslikelytoseeaconsultant.
TheEpilepsies
579
Inadults,seizurefrequencywaseithernotrecordedorunclearin47%ofdeaths.Inchildren,there
wasinadequatedocumentationofclassificationofseizuretypeandsyndromeandconsiderationof
anunderlyingcause,andseizurefrequencywaseithernotrecordedorunclearin41%ofdeaths.
Itappearedthatappropriateinvestigationwaspoorinasignificantpercentageofpeoplewhodied.
Forexample,inadults,32%didnothaveEEGsandofthese43%wereunder25yearsatdiagnosis
andshouldhavehadanEEG.Investigationswereinadequatein32%ofchildren.
Fromareviewoftheauditfindings,theexpertpanelraisedconcernsabouttherapeuticmanagement
andconsideredthatitwasdeficientin20%ofadultsand45%ofchildren.Sixpercentofadultsand
18%ofchildrenhadnotbeenprescribedanyantiepilepticdrug(AED)atthetimeofdeath,insome
casesdespiteongoingseizures,and14%ofadultshaddocumenteddrugadherenceproblems.Issues
relatingtotherapeuticmanagementincludedinappropriatechoiceorcombinationsofAED,sub
optimalorinappropriatedoses,unsupervisedorinappropriatemanagementofAEDtreatment
changes,littleconsiderationofalternativeoradditionalAEDsincasesofongoingseizuresandmajor
drugerrors.
Theexpertpanelconsideredthatsecondarycarehadbeeninadequate(orcontainedatleastone
majorerror)in85adults(54%)and17children(77%).Mostofthesechildrenandmostadultshad
deficienciesinmorethanoneaspectofcare(andinadditiontoanyfindingonprovisionof
informationandsupport).
Themainproblemsinadultsandchildrenwithoverallinadequatecarewereaccesstospecialistcare
(66%ofadultsand47%ofchildren),lackofappropriateinvestigations(25%ofadultsand41%of
children)andtherapeuticmanagement(38%ofadultsand59%ofchildren).Overall,39%ofadult
deathsand59%ofdeathsinchildrenwereconsideredtohavebeenpotentiallyorprobably
avoidable.
18
ClinicalStandardsAdvisoryGroup(CSAG)report2000
11
Usersperspectivesoncare
TheClinicalStandardsAdvisoryGroupwasaskedtoadviseonstandardsofNHSservicesforpeople
withepilepsy.Aspartofthereport,theexperienceofuserswasstudied
466
.Inall,2,394peoplewith
epilepsytookpartinthepostalsurvey;oneintenwerenewlydiagnosed,54%hadcontinuing
epilepsyand37%hadcontrolledepilepsy.In54%ofcases,epilepsywasclassifiedassevere,andin
46%ofcases,asmild.
Therewaslittledifferenceinoverallexperiencebetweenadultsandchildren,orbetweenthosewho
hadnewonsetcontinuingepilepsyandthosewhohadcontrolledepilepsy;thehospitalbased
sampleofadultshadahigherlevelofsatisfactionwithsecondarycarethanthepopulationbased
sample(93%comparedwith83%),butsatisfactionwashighforbothgroupsofchildren(96%).
Inthecommunitybasedsample,only30%ofallpeoplehadattendedasanoutpatientatahospital
inthepreceding12months.Forthoseattendinghospitalclinics,thelevelsofsatisfactionwere
reasonablyhigh:87%foundcommunicationwiththeirhospitaldoctorssatisfactoryorfairly
satisfactory(85%adultsand93%children),and80%feltthattheirhospitaldoctorstooktheirviews
intoaccount.However,73%ofrespondentsattendingthehospitalclinicsreportedseeingthesame
doctorrepeatedly.
Mostindividuals(90%ofthecommunitybasedsampleandallofthehospitalbasedsample)had
beenreferredtoahospitaldoctorattheonsetofsymptoms.Approximatelyathirdwerewaitingfor
sixweeksormorebeforebeingseen.Individualswithestablishedepilepsyhadfarlongerwaiting
timesforrereferralandlongerintervalsbetweenfollowupappointments.
11
Cliniciansperspectivesoncare
CSAG
11
alsosurveyedneurologists(n=220),paediatriciansrunninggeneralpaediatricclinics(n=64),
generalphysicians(n=27),geriatricians(=27),andlearningdisabilitydoctors(n=33)intheUKabout
thequalityofsecondarycareforpeoplewithepilepsy.
TertiaryserviceswereassessedbysystematictelephonesurveyofallappropriateNHSTrustsinthe
UK.
TheEpilepsies
580
Allrespondentsthoughtthatadultswithnewlydiagnosedepilepsyshouldbereferredtoahospital
andthosewithcontinuingepilepsyshouldreceiveongoinghospitalcare.Therewasconcernabout
thelackoffacilitiesingeneralclinics,longwaitingtimes,thelackofclinictimeforindividualsandthe
paucityoflinkswithotherspecialists.Therewasawidelyheldviewthatthereweretoofew
specialiststaff,particularlyneurologists,tomeetthedemandonhospitalservices.Hospital
physicianssupportedtheconceptofsharedcare,asameansofimprovingefficiencyandqualityof
careandensuringthatreferralsareappropriate.
Mostchildrenwereseeningeneralpaediatricclinics;however,mostoftheseclinicslackedstaffwho
hadaspecialinterestinepilepsy.Therewasstrongsupportfortheviewthatsomegeneral
paediatriciansshouldbeencouragedtotakeaspecialinterestinepilepsyandtorunspecialepilepsy
clinicswithingeneralpaediatricservices.Therewasgeneralagreementthatclinicsspecialisingin
epilepsycouldprovidebettercare.Accesstoandfacilitiesforchildreninpaediatricclinicswere
consideredtobebetterthaninadultneurologyclinics.Itwaswidelyagreedthatallchildrenon
medicationforepilepsyshouldreceiveongoinghospitalcare.Theneedforbetteraccesstospecialist
neurologyandspecialistepilepsyserviceswasemphasised.
TheevidenceshowedthattherehadbeenamarkedexpansionofneurologyservicesintheUKduring
thelastdecade.Thereweregeneralimprovementsinmanyaspects,althoughregionaldifferences
stillexisted.Examplesofhighqualityserviceswereencountered,butthelevelofqualityalmost
alwaysdependedontheexceptionalactivitiesofindividuals.Thehubandspokemodelofneurology
serviceshoweverhadacentripetalmomentum,andthisdidnotgenerallyengenderthe
developmentoflocalservices.Epilepsyisacommonneurologicalcondition,withafrequencyand
complexitythatrequiresthefacilitiesofbotharegionalcentreandalocalservice.Itrequires
servicesprovidedatprimary,secondaryandtertiarylevelstobewellintegratedandcoordinated.
Thepoorcorrelationbetweenseverityofepilepsyandaccessto,orlevelof,specialistadvice
indicatedbothalackofclearpurposeinthepatternsofreferralandalsopossiblewastefulnessinthe
useofsecondaryandtertiaryservices.
Theresearchteamconcludedthattherequirementforamoreintegratedservicewouldbebestmet
bythedevelopmentofaspecialepilepsyservice(theEpilepsyCentre)withingeneralneurology,
situatedatalocallevelwhichcouldtakealocalperspectivebutalsohavestronglinkstotheregional
NNC.
11
IndependentReviewofPaediatricNeurologyServicesInLeicester2003
467
ThisreviewintotheprovisionofpaediatricneurologyservicesinLeicesterrecommended:
thatformalappraisalofconsultantmedicalstaffoperatingonasinglehandedbasisshouldensure
thatopportunitiesareinplaceforeffectiveclinicalnetworkingincorporatingpeerreviewandthat
theseopportunitiesareappropriatelyutilised.
thattheappropriateauthoritiesconsiderclarifyingthetrainingrequirementsandqualifications
neededforconsultantmedicalstaffpractisinginspecialityareas,withparticularreferenceto
paediatricneurology.
467
Otherprimaryevidence
Bradley1999
468
Bradleyandcolleaguesconductedaprimarycarebasedauditofepilepsycare,thatevaluatedthe
opinionsofusersandstandardsofcareinbothprimaryandsecondarycare.Auserquestionnaire
wasalsoanalysed.Thedatafrom395clinicalrecordsand211questionnaireswereincluded.Ofthe
individualswhohadhospitalrecords(n=149),only47%(n=70/149)wereconfirmedasseeingan
appropriatespecialist(definedasaneurologist,physicianorpsychiatristwithaninterestinepilepsy,
orpaediatricianwithaninterestinepilepsyasrelevant).99%(n=147/149)hadinvestigationbyEEG,
22%(n=33/149)CTscan,withotherinvestigations(MRI,videotelemetryetc)beinglesscommon.
30%(n=63/211)ofindividualsreportedhavingabloodtesttocheckserumdruglevelsinthe
previous12months.
TheEpilepsies
581
Ingeneral,thestandardofrecordkeepinginhospitalswaslowerthaningeneralpractice.In
particular,thelevelsofrecordingofadvicegivenwerelow,withthoseinhospitallowerthangeneral
practiceinmostcases.
468
Reynders2002
469
ReyndersandBakerundertookaquestionnairesurveytoreviewthecurrentpracticeof
neuropsychologistsworkingwithinepilepsyservicesintheUK.Theyfoundthatalthoughprogress
hadbeenmadetowardsfulfillingtherecommended1991ILAEguidelinesforservices,notallhad
beenimplemented.
Therewasaneedforappropriateandnationallyrecognisedtrainingforneuropsychologistsandthe
establishmentofcentresofexcellence.Thereviewshowedthatmeetingthefullrangeof
psychologicalneedsoftheindividualsandtheirfamiliesremainedunderdeveloped.
469
epilepsyinsecondary/tertiarycare?
Specificepilepsy/seizureclinics
EpilepsyNurseSpecialists
18.3.2.1 Doadultsandchildrenwithepilepsyattendingsecondarycarewhoreceivecareinaspecialist
clinic,whencomparedwiththosewhodonot,havebetterhealthoutcomes
Details
IntheCSAGsurveyofclinicians,therewasgeneralagreementthatclinicsspecialisinginepilepsy
couldprovidebettercare,andindividualsexpressedstrongsupportforsuchservices.
11
Specialised
clinicshavealsobeenproposedbymanyauthorities.
11,460
SecondaryEvidence
Bowley2000
470
Inarecentnarrativeliteraturereviewofepilepsyinpeoplewithlearningdisabilities,noevidenceof
researchinservicedeliverywasidentified.
Bradley2003
471
OneCochranereviewwasidentifiedthatassessedtheeffectivenessofspecialistepilepsyclinics
comparedtoroutinecare.TheselectioncriteriawereanyRCTsorquasirandomisedtrials
consideringspecialistclinicinterventionscomparedtoroutineoralternativecare.Notrialsof
suitablequalitywereidentifiedandthereviewconcludedthatitisnotknownwhethersuchclinics
improveoutcomesforpeoplewithepilepsy
471
.
18.3.2.2 Doadultsandchildrenwithepilepsyattendingsecondarycarewhoreceivecarefromaspecialist
nurse,whencomparedwiththosewhodonot,havebetterhealthoutcomes?
Details
Theroleofthespecialistnurseissupportedbymanyauthorities,
11,460
anddetaileddescriptionsofthe
rolehavebeenproposed.
Secondaryevidence
Bradley2003
462
ACochranereviewassessedtheeffectivenessofspecialistepilepsynursescomparedtoroutinecare.
AnyRCTsorquasirandomisedtrialsthatcomparedspecialistnurseinterventionscomparedto
routineoralternativecarewereincluded.
Threetrialswereincluded,oneingeneralpracticeandtwoinneurologycentres.Thethreetrials
onlyincludedadultsaged15yearsorolder.Thetwotrialsinneurologycentresarepresentedbelow.
TheEpilepsies
582
Ridsdaleandcolleaguesassessedtheeffectofanepilepsynursespecialistonnewlydiagnosedadults'
knowledgeofepilepsy,satisfactionwiththeadviceprovided,andpsychologicalwellbeing
472
.The
trialwasassessedasofadequatequality.Individualsrandomisedtoseethenursespecialistwere
significantlymorelikelytoreportthatenoughadvicehadbeenprovidedonmostepilepsyrelated
topicscomparedwiththecontrolgroup.Therewerenosignificantdifferencesinknowledgeof
epilepsyscores.However,thereweresignificantdifferencesinthegroupwho,atbaseline,had
knowledgescoresinthelowestquartile;thoserandomisedtothenursehadhigherknowledgescores
(42.7vs.37.2;p<0.01).Comparedwithdoctors,thenursewashighlyratedforprovidingclear
explanations.
Thequalityofthetrialbasedintertiarycare
473
wasassessedasunclear.Therewasnosignificant
differencebetweentheinterventionandcontrolgroupforseizurefrequency,levelsofanxietyand
depression,socialfunctioning,overallhealthstatus,orabsencefromwork.However,therewasan
increaseinknowledgeintheinterventiongroup(p=0.035),althoughthereissomeconcernaboutthe
reliabilityofthescaleused(EKPGscale).Thistrialreportedasignificantdecreaseinoutpatientclinic
hospitalattendances(p<0.01)andanonsignificantdecreaseinGPconsultations(p=0.054).The
economicevaluationsuggestedthatspecialistepilepsynursecareischeaperthanstandardcare,but
therewereseveralflaws.However,thereviewstatedthattherewasnoevidencetosuggestthat
specialistnursesweremoreexpensive
462
.
Thereviewconcludedthat,forbothprimaryandsecondary/tertiarycare,therewasnoconvincing
evidencethatspecialistnurseservicesimproveoutcomesforpeoplewithepilepsy,butlowbaseline
knowledgeinindividualswithnewlydiagnosedepilepsymaybeimproved.
Meads2002
474
Meadsandcolleaguesreviewedtheliteratureonbothspecialistepilepsyclinicscomparedtogeneral
neurologyclinicsandspecialistnursescomparedtousualcare.UnliketheCochranereviews
describedabove,studydesignsotherthanRCTswereincluded.
Forepilepsyclinics,theevidencewasofpoorqualitywithpoorlydesignedstudiesandadifferent
casemixbetweenspecialistclinicsandgeneralneurologyclinics.
Forspecialistnurses,theevidencewasofahigherqualitybutshowednodifferencesregarding
seizurefrequencyorseizureseveritybetweenthosereceivingcarefromspecialistnursesorusual
care.However,therewassomeevidencethatincidenceofdepressionwasdecreased(onestudyof
three).Therewasgoodevidencetoshowthattheprocessofcarewasimprovedandthatuser
satisfactionwasimproved.TheoneRCTthatcomparedqualityoflifeshowednodifferencebetween
thegroups.
Theresultsweresummarisedas:
Epilepsyclinicsshowednoevidenceofreducedseizurefrequencyorseverity,noqualityoflife
informationandweremoreexpensive.
Epilepsynurseservicesshowednoevidenceofreducedseizurefrequencyorseverity,noeffecton
qualityoflifebutwerelessexpensive
474
.
Primaryevidence
TherewerenoRCTsidentifiedasbeingpublishedsincethereviewspresentedabove.
Healtheconomics
Meads2002
474
Theobjectivesofthispaperweretosystematicallyreviewtwoaspectsofspecialistepilepsycare
provision:
theevidenceontherelativeeffectivenessandcosteffectivenessofspecialistepilepsyclinics
comparedtogeneralneurologyoutpatientclinics.
theeffectivenessontherelativeeffectivenessandcosteffectivenessofspecialistepilepsynurses
ininpatient,outpatientorGPcarecomparedtousualcarewithoutaspecialistepilepsynurse.
TheEpilepsies
583
Oftheincludedstudiesonspecialistclinics,onlytheRCTincludedaneconomicanalysis,butitwas
poorlydesigned.Thestudyestimatesgaveatotalmeancliniccostperpatientperyearof106.57
fortheepilepsyclinicand106.57fortheneurologyclinic.Thetrialauthorsdidnotreportany
distributioninformationandthecostswerenotnecessarilytypicalofallindividuals.
IntheRCTassessingtheeffectivenessofnursespecialists,thetotalmeanNHScostperpatientper
yearwascalculatedtobe674fortheepilepsynursegroupand858forusualcare;however,this
wasnotastatisticallysignificantreductionandwaslargelyaccountedforbythelowercostforan
epilepsynursestimecomparedtothatforadoctor.TheEUROQOLqualityofliferesultsshowed
thattherewerenosignificantdifferencesbetweenthetwogroupsonbothweightedhealthstatus
andselfratedhealth.
Meadsandcolleaguesconcludedthatmoreresearchwasneededtodeterminethemostclinical
effectivemodelofserviceprovisionforpeoplewithepilepsy.Thelowercostandthefactthatuser
satisfactionandtheprocessofcarewassuperiorwithspecialistepilepsynursessuggestedthat,in
theabsenceofbetterevidence,thiscouldbeanappropriatemethodofdeliveringcare.
474
18.4 WhatfeaturesofthecareprocessinA&Eleadtoimprovedhealth
outcomesforadultsandchildrenwithepilepsy?
279. Attheinitialassessmentforarecentonsetseizure,thespecialistshouldhaveaccessto
appropriateinvestigations.[2004]
280. Children,youngpeopleandadultspresentingtoanAccidentandEmergencydepartment
followingasuspectedseizureshouldbescreenedinitially.Thisshouldbedonebyanadultor
paediatricphysicianwithonwardreferraltoaspecialist
ll
whenanepilepticseizureissuspected
orthereisdiagnosticdoubt.[2004]
281. Protocolsshouldbeinplacethatensureproperassessmentintheemergencysettingfor
children,youngpeopleandadultspresentingwithanepilepticseizure(suspectedor
confirmed).[2004]
Evidencestatement
NoevidenceofeffectivenessforcomponentsofthecareprocessforpeoplewithepilepsyinanA&E
settingwasidentified.
18.4.1 Qualityofcarecurrentlyprovidedinandaccidentandemergencydepartments(A&E)
Details
A&Edepartmentsoftenprovidecaretopeoplewithepilepsyforvariousreasons.Inonestudy,
475
43%ofthestudypopulation(n=1,628)hadattendedanA&Edepartmentonaccountofepilepsy,and
47%requiredhospitaladmission.
Secondaryevidence
NosystematicreviewsofthequalityofcareinA&Ewereidentified.
Primaryevidence
CSAGreport
11
ll
andyoungpeople,aspecialistisdefinedthroughoutasapaediatricianwithtrainingandexpertiseinepilepsy.
TheEpilepsies
584
Thesurveyfoundthat15%ofthecommunitybasedsampleand35%ofthehospitalbasedsample
hadattendedA&Eduringtheprevious12monthsbecauseoftheirepilepsy.Ofthecommunity
basedsample,9%hadbeenadmittedovernightasanemergencycomparedto21%ofthehospital
basedsample.Ofthoseadmittedfrombothgroups,80%stayedinhospitalfor15days.
AlmosthalfoftheindividualswithfirstseizurespresentedtoanA&Edepartmentratherthantoa
GP.
Otherareasofconcernwereidentifiedfromtheresearchliteratureincludingpoorlycontrolled
seizures,poorqualityrecordkeeping,widevariationininvestigationsdone,andhospital
admissions.
11
Otherprimaryevidence
Ryan1998
476
In1998,Ryanandcolleaguespublishedacomparativeinterdepartmentalaudittoassessthequality
anddegreeofcompletenessofdocumentationinA&Erecordsandtodevelopaproformaforthe
documentationofanycasepresentingwithaseizurewhichwouldincorporatemanagement
guidelinesforusebyAandEdoctors.Itwascarriedoutin12A&EdepartmentsintheSouthThames
regioninvolving1200adultswhopresentedtoA&Edepartmentsafteraseizure(retrospective
sampleof100perdepartment).
Importantaspectsofthehistoryandexaminationwerefrequentlyunrecordedinthenotes.The
recordingofvitalsignswasparticularlypoor,forexamplethedocumentationrateofrespiratoryrate
rangedfrom34%to92%,mean63.4%.Adiversityofpracticewasshownbetweenthedepartments
thatwereauditedandthenumberofinvestigationsperformedineachdepartmentvaried
considerably,forexampleglucosewasmeasuredinaround24%ofthesample,range10%to39%..
Hospitaladmissionsforpeoplewithfirstseizuresvariedwidelybetweendepartments,rangingfrom
between34.6%to91.7%ofcases.Ofthoseadmitted,72.5%wereadmittedtoageneralward,and
27.5%toanA&Eshortstayward.Documentationofadvicegiventoindividualsaboutdrivingwas
recordedin0.9%ofcases.
476
Reuber2000
477
ReuberandcolleaguesreviewedtheA&Erecordsofalladultsattendingthecasualtydepartmentat
StJames'sUniversityHospitalwithemergenciesrelatedtoepilepsybetween1Apriland30
September1998.Outofatotalof36024adultsattending,190wereemergenciesrelatingto
epilepsy.
Aproblemrelatingtoapreviouslyrecognizedseizuredisorderwasthecommonestreasonfor
attendance(see18.1).Only20%ofattendanceswereforfirstseizures(38/190).Carewashighly
variableandoftensuboptimal.Descriptionsofseizuresemiologyandexaminationfindingswere
frequentlydeficientwithonly59.4%(113of190)havingadescriptionrecordedand77.4%(147of
190)havingsomeformofneurologicalexamination.Mostwhoattendeddidnotrequireany
treatmentwithanticonvulsantsinA&E.Only19.5%(37of190)ofcasesreceivedanticonvulsants
acutely.Intravenousorrectaldiazepamwasinvariablyusedasfirstlinetreatment.Neurology
SeniorHouseOfficers(SHOs)orregistrarswereonlycontactedaboutaminorityofcases(19.5%,37
of190).59%(112of190)ofallindividualsseenwithemergenciesrelatingtoepilepsywere
dischargedhomefromA&E.20%(3of15)ofadultsfulfillingourdefinitionofstatusepilepticuswere
senthomeafterreceivingemergencytreatmentwithdiazepaminA&E.Onlyaminoritypresenting
withemergenciesrelatedtoepilepsywerereferredforneurologicalfollowup,notedtobeunder
regularspecialistfollowup,oradmittedtotheneurologyward(24.2%,46of190).
477
Figure3: Causesofattendance
477
ModifiedfromSeizure,9,ReuberM,HattinghLand
GoudlingPJ,Epileptologicalemergenciesinaccidentandemergency:asurveyatStJames's
universityhospital,Leeds,pages21620,Copyright(2000)withpermissionfromBEATrading
Ltd.
TheEpilepsies
585
NoevidencewasfoundofthequalityofcareforchildreninA&E.
Oneauditwasidentifiedthatauditedtheuseofaspecifictreatmentprotocolratherthanany
variationincare,sowasexcluded.
478
epilepsyinA&E?
NoproposedprocessofcarewasidentifiedforA&Edepartments.
18.5 Howeffectiveareindividual/selfmanagementplansinadultsand
childrenwithepilepsy?
18.5.1 Introduction
Therehasbeenincreasinginterestintheuseofselfmanagementeducationtoimprovethequality
oflifeofpeoplewithlongtermhealthconditions.Selfmanagementeducationprogrammesshould
employasoundtheoreticalmodelofbehaviourchangeandemploystrategiestoempowerpeopleto
buildontheirexistingknowledge,skillsandselfefficacy(theconfidencethatonecancarryouta
behaviournecessarytoreachadesiredgoal).Theiroverallaimistoencourageindividualstotake
greatercontrolovertheircondition.Researchfromotherchronicdiseasessuchasasthmaand
diabetesshowsthatselfmanagementeducationcanimprovehealthoutcomes.
Epilepsyselfmanagementcanbedefined(ordescribed)asarangeofactionsandskillsthatmayhelp
individualswithepilepsyfeelmoreconfidentaboutmakingdecisionsabouttheircondition,taking
actionaboutseizurecontrol,usingmedication,andlivingwiththeircondition.Goodself
managementincludesworkinginpartnershipwithhealthcareprofessionalstodecidethebest
treatmentandcareplanfortheirepilepsy.Selfmanagementalsoinvolvesdevelopingstrategiesto
managetheemotionalandphysicalchallengesofepilepsy,andwaystolivelifetothefull,despite
thecondition.
51
48
38
31
15
7
0
10
20
30
40
50
60
TheEpilepsies
586
18.5.2 Doadultsandchildrenwithepilepsywhoareeducatedinselfmanagement,when
comparedwiththosewhodonot,havebetterhealthoutcomes?
282. Children,youngpeopleandadultswithepilepsyandtheirfamiliesand/orcarersshouldbe
empoweredtomanagetheirconditionaswellaspossible.[2004]
283. Adultsshouldreceiveappropriateinformationandeducationaboutallaspectsofepilepsy.
Thismaybebestachievedandmaintainedthroughstructuredselfmanagementplans.[2004]
284. Inchildrenandyoungpeople,selfmanagementofepilepsymaybebestachievedthrough
activechildcentredtrainingmodelsandinterventions.[2004]
285. HealthcareprofessionalsshouldhighlighttheExpertPatientsProgramme
(www.expertpatients.co.uk
mm
)tochildren,youngpeopleandadultswithepilepsywhowishto
managetheirconditionmoreeffectively.[2004,amended2012]
Evidencestatements
Selfmanagementeducationforadultswithepilepsycanleadtoanimprovementinseizurefrequency.
Ithasalsobeenshowntoincreaseindividualsunderstandingofepilepsyandtheiradherencewith
medicationanddecreaseindividualsfearofseizuresandhazardousmedicalselfmanagement
strategies.(Ib)
Activeeducationinchildrenwithepilepsycanleadtoanimprovementinseizurefrequency.Ithas
alsobeenshowntodecreasehospitalemergencyroomattendance,schoolabsenteeismand
unnecessaryrestrictionofactivities.(Ib)
Secondaryevidence
NosystematicreviewswerefoundthatansweredthisKCQ.
Primaryevidence
Fourstudiesevaluatedtheuseofselfmanagementprogramsforpeoplewithepilepsy;twoRCTs
includedadultsonlyandtwochildren.
Helgeson1990
479
HelgesonandcolleaguesassessedtheeffectivenessoftheSepulvedaEpilepsyEducationprogram
(SEE)inadults.Thisindividual/familyprogrammeusedapsychoeducationaltreatmentapproachto
deliverpsychosocialhelpandhealtheducation.Theunderlyingbeliefisthatanadequate
understandingofepilepsyleadstomoreeffectivecopingstrategies.
Thirtyeightoutpatientsmatchedaccordingtoseizuretypeandfrequencywereassignedto
treatment(n=20)ortoawaitinglistcontrolgroup(n=18).Thetreatmentgroupshowedasignificant
increaseinoverallunderstandingofepilepsy(F(1,36)=39.74,p<0.0001),asignificantdecreaseinfear
ofseizures(F(1,36)=7.49,p<0.009),andasignificantdecreaseinhazardousselfmanagement
practices(F(1,36)=29.67,p<0.0001).Thetreatmentgroupalsoshowedasignificantincreasein
medicationcompliance(F(1,24)=4.18,p<0.05).
479
May2002
379
TheefficacyoftheMOSESeducationaltreatmentprogrammeforadultswithepilepsywasevaluated
byMayandPfafflin.383adultsovertheageof16yearsfrom22epilepsycentreswererandomly
mm
Thewebaddresshaschangedsincetherecommendationwaspublishedin2004andhasbeenupdated.
TheEpilepsies
587
allocatedtoeitherMOSESorawaitinglistcontrolgroup.Ofthe242thatcompletedboth
questionnaires,113wereallocatedtotheinterventiongroupand129tothecontrolgroup.
Althoughbothgroupsshowedimprovements,theparticipantsinMOSESshowedsignificant
improvementsinknowledge(p<0.001),copingwithepilepsy(p=0.004),seizurefrequency(p=0.041),
andweremoresatisfiedwiththetherapy(bettertolerabilityofAEDs,fewersideeffectsp=0.014)
comparedwiththecontrolgroup.Theparticipantswerealsohighlysatisfiedwiththeprogramme.
However,thereweremanyaspectsofepilepsymeasuresthatwerenotimprovedbytheprogramme,
includingunnecessaryrestrictionofactivities,andepilepsyrelatedfears.
379
Lewis1990
480
andLewis1991
481
LewisandcolleaguesassessedtheimpactoftheChildrensEpilepsyProgramme(CEP)onchildren
withepilepsyandtheirparents.TheCEPisachildcentred,familyfocusedinterventionbasedon
decisionmakingandcommunication.
252childrenaged7to14yearswererandomisedtoeitheractiveeducation(n=123)ortopassive
education(n=113)wherethesameinformationwaspresentedinamoretraditionallectureformat.
Thechildrenandparentswereassessedbothbeforetheinterventionand5monthsafter.
Therewasanincreaseinknowledgeinbothgroupsofchildren,buttheknowledgeofchildreninthe
interventiongroupincreasedsignificantlycomparedtothecontrolgroupinareasrelatedto
managementofseizures(duringseizurenoobjectsinthemouthp=0.002,duringseizuredonot
restrainp=0.001,afterseizureERvisitnotrequiredp=0.001)andunnecessaryrestrictionofactivities
(p=0.001).Therewasasignificantincreaseintheselfperceptionofsocialcompetency(p<0.05)in
theinterventiongroup(n=106)thanthecontrolgroup(n=92)andtheyalsoreportedsignificantly
betterbehaviour(p<0.002).
480
Asforchildren,therewasanincreaseinknowledgeforbothgroupsofparents.However,therewas
asignificantdecreaseinknowledgerelatedtoseizuremanagement(lossofsleepcantriggerseizures
p=0.005)intheinterventiongroup(n=185)comparedtothecontrolgroup(n=180).Parentsinthe
interventiongroup(n=175),andmothersparticularly,weremorelikelytoreportthattheywereless
anxious(p<0.001)andthelevelsofanxietyweredecreased(p<0.01)whencomparedtothecontrol
group(n=176).
481
Tieffenberg2000
482
AnRCToftheACINDESchildcentredtrainingmodelforchildrenwithchronicillnesseswas
conducted.Thisincluded355childrenagedbetween6and15yearsold,withmoderatetosevere
asthmaorepilepsy.167childrenwithepilepsywererandomisedtotheintervention(n=103)or
control(n=64)group.
Childrenintheinterventiongroupshowedsignificantimprovementsinknowledge,belief,attitudes,
andbehaviourscomparedwiththecontrolgroup(probabilityofexperimentalgainovercontrol
=0.69,2=0.007).Parentsofthechildrenalsohadimprovedknowledgeofepilepsy(increasedfrom
22%to56%c.f.control8%to15%,probabilityofexperimentalgainovercontrol=0.62,2=0.0026)
anddecreasedfearofthechildsdeath(decreasedfrom69%to30%c.f.control74%to65%,
probabilityofexperimentalgainovercontrol=0.63,2=0.0026).Theparentsintheintervention
groupallowedtheirchildrentosleepatfriendshomesmoreoften(probabilityofexperimentalgain
overcontrol=0.59,2=0.0026).Ratesofseizures(p=0.026),emergencyvisits(p=0.046),andschool
absenteeism(p=0.011)decreasedsignificantlyintheinterventiongroupcomparedwiththecontrol
group.
482
TheEpilepsies
Glossary
588
19 Glossary
AbsenceSeizure Aseizurecharacterisedbybehaviouralarrestassociatedwith
generalisedspikewaveactivityonEEG.
Absoluteriskreduction
(Riskdifference)
Thedifferenceintheriskofaneventbetweentwogroups(one
subtractedfromtheother)inacomparativestudy.
Abstract Summaryofastudy,whichmaybepublishedaloneorasan
introductiontoafullscientificpaper.
Adherence Theextenttowhichthepatientsbehaviourmatchestheprescribers
recommendations.Adherenceemphasisestheneedforagreement
andthatthepatientisfreetodecidewhetherornottoadheretothe
doctorsrecommendation.
483
Adjunctivetreatment WhereamedicationisaddedtoafirstlineAEDforcombination
therapy.
Adjustment Astatisticalprocedureinwhichtheeffectsofdifferencesin
compositionofthepopulationsbeingcompared(ortreatmentgiven
atthesametime)havebeenminimisedbystatisticalmethods.
Aetiology Thecauseororiginofadiseaseordisorderasdeterminedbymedical
diagnosis.
Algorithm(in
guidelines)
Aflowchartoftheclinicaldecisionpathwaydescribedinthe
guideline,wheredecisionpointsarerepresentedwithboxes,linked
witharrows.
Allocationconcealment Theprocessusedtopreventadvanceknowledgeofgroup
assignmentinaRCT.Theallocationprocessshouldbeimperviousto
anyinfluencebytheindividualmakingtheallocation,bybeing
administeredbysomeonewhoisnotresponsibleforrecruiting
participants.
Antiepilepticdrug
(AED)
Medicationtakendailytopreventtherecurrenceofepileptic
seizures.RefertoAppendixKconcerningthechoiceofdrug,side
effectsandsuitabilitytosyndrome.
Applicability Thedegreetowhichtheresultsofanobservation,studyorreview
arelikelytoholdtrueinaparticularclinicalpracticesetting.
AppraisalofGuidelines
Researchand
Evaluation(AGREE)
Aninternationalcollaborationofresearchersandpolicymakers
whoseaimistoimprovethequalityandeffectivenessofclinical
practiceguidelines(http://www.agreecollaboration.org/).The
AGREEinstrument,developedbythegroup,isdesignedtoassessthe
qualityofclinicalguidelines.
Arm(ofaclinicalstudy) Subsectionofindividualswithinastudywhoreceiveoneparticular
intervention,forexampleplaceboarm.
Association Statisticalrelationshipbetweentwoormoreevents,characteristics
orothervariables.Therelationshipmayormaynotbecausal.
Atonicseizure
Ageneralisedseizurecharacterisedbysuddenonsetoflossof
muscletone.
Attack Anepisodeinthecourseofanillness.
TheEpilepsies
Glossary
589
Audit SeeClinicalaudit.
Baseline Theinitialsetofmeasurementsatthebeginningofastudy(after
runinperiodwhereapplicable),withwhichsubsequentresultsare
compared.
BECTS Benignepilepsywithcentrotemporalspikes.Anepilepsysyndrome
ofchildhood(514years)characterisedbyfocalmotorand/or
secondarilygeneralizedseizures,themajorityfromsleep,inan
otherwisenormalindividual,withcentrotemporalspikesseenonon
EEG.
Bias Systematic(asopposedtorandom)deviationoftheresultsofastudy
fromthetrueresultsthatiscausedbythewaythestudyisdesigned
orconducted.
Blinding(masking) Keepingthestudyparticipants,caregivers,researchersandoutcome
assessorsunawareabouttheinterventionstowhichtheparticipants
havebeenallocatedinastudy.
Borderlineintelligence MinimalIQrequiredtofunctionnormallyandindependentlyinthe
world.
Capitalcosts Costsofpurchasingmajorcapitalassets(usuallyland,buildingsor
equipment).Capitalcostsrepresentinvestmentsatonepointin
time.
Carer(caregiver) Someoneotherthanahealthprofessionalwhoisinvolvedincaring
forapersonwithamedicalcondition.
Casecontrolstudy Comparativeobservationalstudyinwhichtheinvestigatorselects
individualswhohaveexperiencedanevent(forexample,developed
adisease)andotherswhohavenot(controls),andthencollectsdata
todeterminepreviousexposuretoapossiblecause.
Caseseries Reportofanumberofcasesofagivendisease,usuallycoveringthe
courseofthediseaseandtheresponsetotreatment.Thereisno
comparison(control)groupofpatients.
Childhoodabsence
epilepsy
Anepilepsysyndromewithanageofonsetof49years,
characterisedbyfrequentabsenceseizuresassociatedwith3Hzspike
waveactivityonEEG.
Clinicalaudit Aqualityimprovementprocessthatseekstoimprovepatientcare
andoutcomesthroughsystematicreviewofcareagainstexplicit
criteriaandtheimplementationofchange.
Clinicalefficacy Theextenttowhichaninterventionisactivewhenstudiedunder
controlledresearchconditions.
Clinicaleffectiveness Theextenttowhichaninterventionproducesanoverallhealth
benefitinroutineclinicalpractice.
Clinicalimpact Theeffectthataguidelinerecommendationislikelytohaveonthe
treatmentortreatmentoutcomes,ofthetargetpopulation.
Clinicalpresentation Thedescriptionofthehistoryandpresentionoftheclinicalcondition
totheassessingmedicalteam
TheEpilepsies
Glossary
590

Clinicalquestion Inguidelinedevelopment,thistermreferstothequestionsabout
treatmentandcarethatareformulatedtoguidethedevelopmentof
evidencebasedrecommendations.
Clinician Ahealthcareprofessionalprovidingdirectpatientcare,forexample
doctor,nurseorphysiotherapist.
Cluster Acloselygroupedseriesofeventsorcasesofadiseaseorother
relatedhealthphenomenawithwelldefineddistributionpatterns,in
relationtotimeorplaceorboth.Alternatively,agroupedunitfor
randomisation.
CochraneLibrary Aregularlyupdatedelectroniccollectionofevidencebasedmedicine
databasesincludingtheCochraneDatabaseofSystematicReviews.
CochraneReview Asystematicreviewoftheevidencefromrandomisedcontrolled
trialsrelatingtoaparticularhealthproblemorhealthcare
intervention,producedbytheCochraneCollaboration.Available
electronicallyaspartoftheCochraneLibrary.
Cohortstudy Aretrospectiveorprospectivefollowupstudy.Groupsofindividuals
tobefolloweduparedefinedonthebasisofpresenceorabsenceof
exposuretoasuspectedriskfactororintervention.Acohortstudy
canbecomparative,inwhichcasetwoormoregroupsareselected
onthebasisofdifferencesintheirexposuretotheagentofinterest.
Comorbidity Coexistenceofmorethanonediseaseoranadditionaldisease
(otherthanthatbeingstudiedortreated)inanindividual.
Comparability Similarityofthegroupsincharacteristicslikelytoaffectthestudy
results(suchashealthstatusorage).
Compliance Theextenttowhichapersonadherestothehealthadviceagreed
withhealthcareprofessionals.Mayalsobereferredtoasadherence
orconcordance.
483
Concordance Thisisarecenttermwhosemeaninghaschanged.Itwasinitially
appliedtotheconsultationprocessinwhichdoctorandpatient
agreetherapeuticdecisionsthatincorporatetheirrespectiveviews,
butnowincludespatientsupportinmedicinetakingaswellas
prescribingcommunication.Concordancereflectssocialvaluesbut
doesnotaddressmedicinetakingandmaynotleadtoimproved
adherence.
483
Conference
proceedings
Compilationofpaperspresentedataconference.
Confidenceinterval(CI) Arangeofvaluesforanunknownpopulationparameterwitha
statedconfidence(conventionally95%)thatitcontainsthetrue
value.Theintervaliscalculatedfromsampledata,andgenerally
straddlesthesampleestimate.Theconfidencevaluemeansthatif
themethodusedtocalculatetheintervalisrepeatedmanytimes,
thenthatproportionofintervalswillactuallycontainthetruevalue.
Confounding Inastudy,confoundingoccurswhentheeffectofaninterventionon
anoutcomeisdistortedasaresultofanassociationbetweenthe
TheEpilepsies
Glossary
591
populationorinterventionoroutcomeandanotherfactor(the
confoundingvariable)thatcaninfluencetheoutcome
independentlyoftheinterventionunderstudy.
Consensusmethods Techniquesthataimtoreachanagreementonaparticularissue.
FormalconsensusmethodsincludeDelphiandnominalgroup
techniques,andconsensusdevelopmentconferences.Inthe
developmentofclinicalguidelines,consensusmethodsmaybeused
wherethereisalackofstrongresearchevidenceonaparticular
topic.Expertconsensusmethodswillaimtoreachagreement
betweenexpertsinaparticularfield.
Controlgroup Agroupofpatientsrecruitedintoastudythatreceivesnotreatment,
atreatmentofknowneffect,oraplacebo(dummytreatment)in
ordertoprovideacomparisonforagroupreceivinganexperimental
treatment,suchasanewdrug.
Controlledclinicaltrial
(CCT)
Astudytestingaspecificdrugorothertreatmentinvolvingtwo(or
more)groupsofpatientswiththesamedisease.One(the
experimentalgroup)receivesthetreatmentthatisbeingtested,and
theother(thecomparisonorcontrolgroup)receivesanalternative
treatment,aplacebo(dummytreatment)ornotreatment.Thetwo
groupsarefolloweduptocomparedifferencesinoutcomestosee
howeffectivetheexperimentaltreatmentwas.ACCTwherepatients
arerandomlyallocatedtotreatmentandcomparisongroupsiscalled
arandomisedcontrolledtrial.
Convulsivestatus
epilepticus(CSE)
Whenaconvulsiveseizurecontinuesforaprolongedperiod(longer
than5minutes),orwhenconvulsiveseizuresoccuroneafterthe
otherwithnorecoverybetween.Convulsivestatusepilepticusisan
emergencyandrequiresimmediatemedicalattention.
Costbenefitanalysis Atypeofeconomicevaluationwherebothcostsandbenefitsof
healthcaretreatmentaremeasuredinthesamemonetaryunits.If
benefitsexceedcosts,theevaluationwouldrecommendproviding
thetreatment.
Costconsequences
analysis(CCA)
Atypeofeconomicevaluationwherevarioushealthoutcomesare
reportedinadditiontocostforeachintervention,butthereisno
overallmeasureofhealthgain.
Costeffectiveness
analysis(CEA)
Aneconomicstudydesigninwhichconsequencesofdifferent
interventionsaremeasuredusingasingleoutcome,usuallyin
naturalunits(forexample,lifeyearsgained,deathsavoided,heart
attacksavoided,casesdetected).Alternativeinterventionsarethen
comparedintermsofcostperunitofeffectiveness.
Costeffectiveness
model
Anexplicitmathematicalframework,whichisusedtorepresent
clinicaldecisionproblemsandincorporateevidencefromavarietyof
sourcesinordertoestimatethecostsandhealthoutcomes.
Costutilityanalysis
(CUA)
Aformofcosteffectivenessanalysisinwhichtheunitsof
effectivenessarequalityadjustedlifeyears(QALYs).
TheEpilepsies
Glossary
592
Credibleinterval TheBayesianequivalentofaconfidenceinterval.
Crossovertrial
Atrialinwhicheachofthestudygroupswillreceiveeachofthe
treatments,butinarandomisedorder:thatis,theywillstartoffin
onearmofthetrial,butwilldeliberatelycrossovertotheother
arm(s)inturn(HTA).
Cryptogenic Unknowncause.
CSWS Continuousspikewaveduringslowsleep;anepilepsysyndromeof
onsetinchildrencharacterisedbyaplateauandregressionof
cognitiveabilitiesassociatedwithdramaticincreaseinspikewave
activityinslowwavesleep(>85%ofslowsleep).Theremaybefew
seizuresatpresentation.
Decisionanalysis Anexplicitquantitativeapproachtodecisionmakingunder
uncertainty,basedonevidencefromresearch.Thisevidenceis
translatedintoprobabilities,andthenintodiagramsordecisiontrees
whichdirecttheclinicianthroughasuccessionofpossiblescenarios,
actionsandoutcomes.
Decisionproblem Aclearspecificationoftheinterventions,patientpopulationsand
outcomemeasuresandperspectiveadoptedinanevaluation,with
anexplicitjustification,relatingthesetothedecisionwhichthe
analysisistoinform.
Diplopia Doublevision.
Discounting Costsandperhapsbenefitsincurredtodayhaveahighervaluethan
costsandbenefitsoccurringinthefuture.Discountinghealth
benefitsreflectsindividualpreferenceforbenefitstobeexperienced
inthepresentratherthanthefuture.Discountingcostsreflects
individualpreferenceforcoststobeexperiencedinthefuturerather
thanthepresent.
Dominance Aninterventionissaidtobedominatedifthereisanalternative
interventionthatisbothlesscostlyandmoreeffective.
Dosage Theprescribedamountofadrugtobetaken,includingthesizeand
timingofthedoses.
Doubleblind/masked
study
Astudyinwhichneitherthesubject(patient)northeobserver
(investigator/clinician)isawareofwhichtreatmentnorintervention
thesubjectisreceiving.Thepurposeofblinding/maskingisto
protectagainstbias.
TheEpilepsies
Glossary
593
Dravetsyndrome
Previouslyknownasseveremyoclonicepilepsyofinfancy.An
epilepsystndromewithonsetininfancy,characterisedbyinitial
prolonged,typicallylateralised,febrileseizures,subsequent
developmentofmultipleseizuretypesincludingmyoclonic,absence,
focalandgeneralisedtonicclonicseizures,withdevelopmental
plateauorregression.
Dropout
Aparticipantwhowithdrawsfromaclinicaltrialbeforetheend.
Economicevaluation Comparativeanalysisofalternativehealthstrategies(interventions
orprogrammes)intermsofboththeircostsandconsequences.
Effect(asineffect
measure,treatment
effect,estimateof
effect)
Theobservedassociationbetweeninterventionsandoutcomesora
statistictosummarisethestrengthoftheobservedassociation.
Effectsize Thistermisusuallyusedinmetaanalysistodenotetreatmenteffect,
orestimateofeffect.
Italsoreferstostandardisedmeandifference(SMD),obtainedby
dividingthemeandifferencewiththepooledstandarddeviation.
ThisisthemeaningusuallyreferredtoinGRADE.
Effectiveness SeeClinicaleffectiveness.
Efficacy SeeClinicalefficacy.
Electro
encephalography
(EEG)
Aninvestigationthatinvolvesrecordingoftheelectricalactivityof
thebrain.Electrodesareattachedtostandardisedpointsonthe
individualsheadwithcollodion.Recordingsareusuallytakenacross
twopoints.fortheroleofEEGindiagnosisofepilepsyandepilepsy
syndromes.
Epidemiologicalstudy Thestudyofadiseasewithinapopulation,definingitsincidenceand
prevalenceandexaminingtherolesofexternalinfluences(for
example,infection,diet)andinterventions.
Epilepsy Aconditionwhereanindividualispronetorecurrentepileptic
seizures.
Epilepticseizure*
Atransientoccurrenceofsignsand/orsymptoms,theresultofa
primarychangetotheelectricalactivity(abnormallyexcessiveor
synchronous)inthebrain.
EpilepticSpasm Aninvoluntarymusclecontractionofsuddenonset.
Epilepsysyndromes* Distinctivedisordersidentifiableonthebasisofatypicalageof
onset,seizuretypes,specificEEGcharacteristics,andoftenother
features.Identificationofsuchhasimplicationsfortreatment,
managementandprognosis.
Epilepticdisease* Apathologicconditioncausingepilepsywithasinglespecific,well
definedetiology.Thusprogressivemyoclonusepilepsyisa
syndrome,butUnverrichtLundborgisadisease.
TheEpilepsies
Glossary
594
Epileptic
encephalopathy*
Aconditioninwhichtheepileptiformabnormalitiesthemselvesare
believedtocontributetotheprogressivedisturbanceincerebral
function.
Equity Fairdistributionofresourcesorbenefits.
Evidence Informationonwhichadecisionorguidanceisbased.Evidenceis
obtainedfromarangeofsourcesincludingrandomisedcontrolled
trials,observationalstudies,expertopinion(ofclinicalprofessionals
and/orpatients).
Evidencetable Atablesummarisingtheresultsofacollectionofstudieswhich,
takentogether,representtheevidencesupportingaparticular
recommendationorseriesofrecommendationsinaguideline.
Exclusioncriteria
(literaturereview)
Explicitstandardsusedtodecidewhichstudiesshouldbeexcluded
fromconsiderationaspotentialsourcesofevidence.
Exclusioncriteria
(clinicalstudy)
Criteriathatdefinewhoisnoteligibletoparticipateinaclinical
study.
Expertconsensus SeeConsensusmethods.
Extrapolation Indataanalysis,predictingthevalueofaparameteroutsidethe
rangeofobservedvalues.
Focalceizures
Seizurewhichoriginateswithinnetworkslimitedtoonehemisphere,
discretelylocalisedormorewidelydistributed.Replacestheterms
partialseizuresandlocalizationrelatedseizures.
Followup Observationoveraperiodoftimeofanindividual,grouporinitially
definedpopulationwhoseappropriatecharacteristicshavebeen
assessedinordertoobservechangesinhealthstatusorhealth
relatedvariables.
Generalisability Theextenttowhichtheresultsofastudybasedonmeasurementin
aparticularpatientpopulationand/oraspecificcontextholdtruefor
anotherpopulationand/orinadifferentcontext.Inthisinstance,
thisisthedegreetowhichtheguidelinerecommendationis
applicableacrossbothgeographicalandcontextualsettings.For
instance,guidelinesthatsuggestsubstitutingoneformoflabourfor
anothershouldacknowledgethatthesecostsmightvaryacrossthe
country.
Generalisedseizure
Aseizurewhichoriginatesin,andrapidlyengages,bilaterally
distributednetworks.Suchbilateralnetworkscanincludecortical
andsubcorticalstructuresbutdonotnecessarilyincludetheentire
cortex(ILAE2010)
TheEpilepsies
Glossary
595
Generalisedtonic
clonicseizure
Aseizureofsuddenonsetinvolvinggeneralisedstiffeningand
subsequentrhythmicjerkingofthelimbs,theresultofrapid
widespreadengagementofbilateralcorticalandsubcortical
networksinthebrain.
Genetic(withreference
toepilepsy)
Theepilepsyis,asbestasunderstood,thedirectresultofaknownor
presumedgeneticdefect(s)inwhichseizuresarethecoresymptom
ofthedisorder(ILAE2010)
Girlsofchildbearing
age
Girlswhohaveenteredmenarcheandwhoaremenstruating
Goldstandard SeeReferencestandard
Goodnessoffit Howwellastatisticalmodelordistributioncompareswiththe
observeddata.
Gradingof
Recommendations
Assessment,
Developmentand
Evaluation(GRADE)
Asystematicandexplicitapproachtogradingthequalityofevidence
andthestrengthofrecommendations.
Greyliterature Reportsthatareunpublishedorhavelimiteddistribution,andare
notincludedinthecommonbibliographicretrievalsystems.
Harms Adverseeffectsofanintervention.
Healtheconomics Thestudyoftheallocationoflimitedresourcesamongalternative
healthcaretreatments.Healtheconomistsareconcernedwithboth
increasingtheaveragelevelofhealthinthepopulationand
improvingthedistributionofhealth.
Healthrelatedquality
oflife
Acombinationofanindividualsphysical,mentalandsocialwell
being;notmerelytheabsenceofdisease.
Heterogeneity Orlackofhomogeneity.Thetermisusedinmetaanalysesand
systematicreviewswhentheresultsorestimatesofeffectsof
treatmentfromseparatestudiesseemtobeverydifferentinterms
ofthesizeoftreatmenteffectsoreventotheextentthatsome
indicatebeneficialandotherssuggestadversetreatmenteffects.
Suchresultsmayoccurasaresultofdifferencesbetweenstudiesin
termsofthepatientpopulations,outcomemeasures,definitionof
variablesordurationoffollowup.
Homogeneity Thismeansthattheresultsofstudiesincludedinasystematicreview
ormetaanalysisaresimilarandthereisnoevidenceof
heterogeneity.Resultsareusuallyregardedashomogeneouswhen
differencesbetweenstudiescouldreasonablybeexpectedtooccur
bychance.
Hypothesis Asuppositionmadeasastartingpointforfurtherinvestigation.
Ictalphenomenology Descriptionorhistoryofictalevents(seizures).
Idiopathic Asyndromethatisonlyepilepsy,withnounderlyingstructuralbrain
lesionorotherneurologicalsignsorsymptoms.Thesearepresumed
TheEpilepsies
Glossary
596
tobegeneticinaetiologyandareusuallyagedependent(ILAE2001).
Idiopathicepilepsy
syndrome*
Apreviouslyusedtermforasyndromethatinvolvesonlyepilepsy,
withnounderlyingstructuralbrainlesionorotherneurologicsignsor
symptoms.Thesearepresumedtobegeneticandareusuallyage
dependent.Itisnolongerrecommendedthatthisterminologyis
used.
Idopathicgeneralised
epilepsy
Awelldefinedgroupofdisorderscharacterisedbytypicalabsences,
myoclonicandgeneralisedtonicclonicseizures,aloneorinvarying
combinationsinotherwisenormalindividuals.TheEEGisalso
characteristicdemonstratingadistinctpatternofgeneralised
polyspikewavedischargesand/orgeneralisedspikewave.Of
presumedgeneticaetiology.ThenewclassificationoftheILAE2010
suggesteterminologyshouldchangetogeneticgeneralized
epilepsy.
Idiosyncratic Physicalorbehaviouralcharacteristicthatispersonaltothat
individual.
InternationalLeague
AgainstEpilepsy(ILAE)
InternationalLeagueAgainstEpilepsy.TheILAEisaglobal,
professionalandnonprofitinternationalorganisationandanon
governmentalorganisationwithanofficialrelationshipwiththe
WHO(WorldHealthOrganisation).TheILAEsobjectivesare:to
advanceanddisseminateknowledgeaboutepilepsy(having
developedguidelinesfortheclassificationofepilepsyandthedesign
ofinvestigativetrials);topromoteresearch,educationandtraining;
andtoimproveoverallpatientcare.
Imprecision Imprecisionisoneofthequalityelementsconsideredunderthe
GRADEsystem.Resultsareimprecisewhenstudiesincluderelatively
fewpatientsandfeweventsandthushavewideconfidenceintervals
aroundtheestimateoftheeffect.
Inclusioncriteria
(literaturereview)
Explicitcriteriausedtodecidewhichstudiesshouldbeconsideredas
potentialsourcesofevidence.
Incrementalanalysis Theanalysisofadditionalcostsandadditionalclinicaloutcomeswith
differentinterventions.
Incrementalcost Themeancostperpatientassociatedwithaninterventionminusthe
meancostperpatientassociatedwithacomparatorintervention.
Incrementalcost
effectivenessratio
(ICER)
Thedifferenceinthemeancostsinthepopulationofinterestdivided
bythedifferencesinthemeanoutcomesinthepopulationof
interestforonetreatmentcomparedwithanother.
ICER=(Cost
A
Cost
B
)/(Effectiveness
A
Effectiveness
B
).
Inconsistency Inconsistencyisoneoftheelementsofqualityconsideredunderthe
GRADEsystem.Inconsistencyreferstotheunexplained
heterogeneityintheresultsobserved.
TheEpilepsies
Glossary
597
Index Inepidemiologyandrelatedsciences,thiswordusuallymeansa
ratingscale,forexample,asetofnumbersderivedfromaseriesof
observationsofspecifiedvariables.Examplesincludethevarious
healthstatusindices,andscoringsystemsforseverityorstageof
cancer.
Indirectness Indirectnessisoneoftheelementsofqualityconsideredunderthe
GRADEsystem.Indirectnessofevidencereferstothedifferencein
studypopulation,intervention,comparatorandoutcomesbetween
theavailableevidencedandtheclinicalquestionorpopulation
addressedintheguidelinerecommendations.
Indication(specific) ThedefineduseofatechnologyaslicensedbytheMedicinesand
HealthcareproductsRegulatoryAgency(MHRA).
Infantilespasms Aspecificseizuretypepresentinginthefirstyearoflife,most
commonlybetween3and9monthsofage.Spasmsarebriefaxial
movementslasting0.22seconds,mostcommonlyflexorinnature,
involvingflexionofthetrunkwithextensionoftheupperandlower
limbs.Theyareoccasionallyreferredtoassalaamseizures.
Intentiontotreat
analysis(ITTanalysis)
Ananalysisoftheresultsofaclinicalstudyinwhichthedataare
analysedforallstudyparticipantsasiftheyhadremainedinthe
grouptowhichtheywererandomised,regardlessofwhetherornot
theyremainedinthestudyuntiltheend,crossedovertoanother
treatmentorreceivedanalternativeintervention.
Intermediateoutcomes Outcomesthatarerelatedtotheoutcomeofinterestbutmaybe
moreeasilyassessedwithinthecontextofaclinicalstudy.
Internalvalidity Thedegreetowhichtheresultsofastudyarelikelytoapproximate
thetruthfortheparticipantsrecruitedinastudy(thatis,arethe
resultsfreeofbias?).Itreferstotheintegrityofthedesignandisa
prerequisiteforapplicability(externalvalidity)ofastudysfindings.
SeeExternalvalidity.
Intervention Healthcareactionintendedtobenefitthepatient,forexample,drug
treatment,surgicalprocedure,psychologicaltherapy.
Juvenileabsence
epilepsy
Anepilepsysyndromewithanageofonsetof913years
characterisedbyabsenceseizuresassociatedwith34Hzspikewave
onEEG.Generalisedtonicclonicseizuresmayoccur.
Juvenilemyoclonic
epilepsy
Anepilepsysyndromewithanageofonsetof520+years(peak,10
16),characterisedbymyoclonicseizureswhichmostcommonly
occursoonafterwakening.Absenceandgeneralisedtonicclonic
seizuresmayoccurinbetween50and80%ofpeople.EEG
demonstrates36Hzgeneralisedpolyspikeandwaveactivity,with
photosensitivityin>30%.
Ketogenicdiet Aspecificdietwhichishighinfatsbutlowincarbohydratesand
protein.
TheEpilepsies
Glossary
598
LandauKleffner
Syndrome
Averyrareepilepsysyndromewithanageofonsetof36years
characterisedbylossoflanguage(afteraperiodofnormallanguage
development)associatedwithanepilepsyofcentrotemporalorigin,
morespecificallybitemporalspikesonEEGwithenhancementin
sleeporCSWS.
Lateonsetchildhood
occipitalepilepsy
(Gastauttype)
Epilepsywithanageofonsetinmidchildhoodtoadolescencewith
frequentbriefseizurescharacterisedbyinitialvisualhallucinations,
ictalblindness,vomitingandpostictalheadache.EEGtypicallyshows
interictaloccipitalspikesattenuatedbyeyeopening.
Lengthofstay Thetotalnumberofdaysaparticipantstaysinhospital.
LennoxGastaut
syndrome
Anepilepsysyndromewithanageofonsetof310years
characterisedbymultipleseizuretypes(includingatonic,tonic,tonic
clonicandatypicalabsenceseizures),cognitiveimpairmentand
specificEEGfeaturesofdiffuseslowspikeandwave(<2Hz)aswellas
paroxysmalfastactivity(10Hzormore)insleep.
Licence SeeProductlicence.
Lifeyearsgained Meanaverageyearsoflifegainedperpersonasaresultofthe
interventioncomparedwithanalternativeintervention.
Likelihoodratio(LR) Theratiooftheprobabilitythatapersonwithaconditionhasa
specifiedtestresulttotheprobabilitythatapersonwithoutthe
conditionhasthesamespecifiedtestresult.Forpositivetestresults,
thisisreferredtoasLikelihoodratiopositive,LR+.Fornegativetest
result,thisisknownasLikelihoodrationnegative,LR.
Literaturereview Anarticlethatsummarisestheevidencecontainedinanumberof
differentindividualstudiesanddrawsconclusionsabouttheir
findings.Itmayormaynotbesystematicallyresearchedand
developed.
Marketing
authorisation
Anauthorisationthatcoversallthemainactivitiesassociatedwith
themarketingofamedicinalproduct.Medicinesthatmeetthe
standardsofsafety,qualityandefficacysetbytheMedicinesand
HealthcareproductsRegulatoryAgency(MHRA)aregranteda
marketingauthorisation(previouslyaproduct
licence),whichisnormallynecessarybeforetheycanbeprescribed
orsold.
Markovmodel Amethodforestimatinglongtermcostsandeffectsforrecurrentor
chronicconditions,basedonhealthstatesandtheprobabilityof
transitionbetweenthemwithinagiventimeperiod(cycle).
Medicinesand
HealthcareProducts
RegulatoryAgency
(MHRA)
TheExecutiveAgencyoftheDepartmentofHealthprotectingand
promotingpublichealthandpatientsafetybyensuringthat
medicines,healthcareproductsandmedicalequipmentmeet
appropriatestandardsofsafety,quality,performanceand
effectiveness,andareusedsafely.
TheEpilepsies
Glossary
599
Metaanalysis Astatisticaltechniqueforcombining(pooling)theresultsofa
numberofstudiesthataddressthesamequestionandreportonthe
sameoutcomestoproduceasummaryresult.Theaimistoderive
morepreciseandclearinformationfromalargedatapool.Itis
generallymorereliablylikelytoconfirmorrefuteahypothesisthan
theindividualtrials.
Minimalimportant
difference(MID)
Thisisthesmallestchangewhichcanberecognisedbyapatientas
beingclinicallysignificant
Monotherapy Useofasingledrugintreatment.
Multivariatemodel Astatisticalmodelforanalysisoftherelationshipbetweentwoor
morepredictor(independent)variablesandtheoutcome
(dependent)variable.
Myoclonicastatic
epilepsy(MAE)
MyoclonicastaticepilepsyorDoosesyndrome.Anepilepsy
syndromewithanageofonsetof1860months,characterisedby
differentseizuretypeswithmyoclonicandmyoclonicastaticseizures
seeninall,causingchildrentofall.TheEEGshowsgeneralised
spike/polyspikeandwaveactivityat26Hz.
Myoclonicseizures
Suddenbrief(<100ms)andalmostshocklikeinvoluntarysingleor
multiplejerksduetoabnormalexcessiveorsynchronousneuronal
activityandassociatedwithpolyspikesonEEG.
Narrativesummary Summaryoffindingsgivenasawrittendescription.
Negativelikelihood
ratio(LR)
Theratiooftheprobabilitythatapersonwithaconditionhasa
negativetestresulttotheprobabilitythatapersonwithoutthe
conditionhasnegativetestresult.
Likelihoodrationegative,LR=(1sensitivity)/specificity
Seelikelihoodratioandpositivelikelihoodratio.
Negativepredictive
value(NPV)
Proportionofpatientswithanegativetestresultwhodonothave
thedisease=TN/(FP+TN).
Neurologicaldeficit Adeficiencyorimpairmentofthenervoussystem.
Nonconvulsivestatus
epilepticus
Achangeinmentalstatusorbehaviourfrombaseline,associated
withcontinuousseizureactivityonEEG,thatisalsoseentobea
changefrombaseline.
Nonepilepticattack
disorder
(NEAD)
Adisordercharacterisedbyepisodesofchangeinbehaviouror
movement,notcausedbyaprimarychangeinelectricalactivityof
thebrain.Movementsarevaried,andtheattackscanbedifficultto
differentiatefromepilepticseizures.RefertoAppendixAforthe
differentiationsofepilepticattacksfromNEADanditssubgroups.
Nystagmus
Involuntaryrapidmovement(horizontal,vertical,rotatory,ormixed)
oftheeyeballs.
Numberneededto
treat(NNT)
Thenumberofpatientsthatwhoonaveragemustbetreatedto
preventasingleoccurrenceoftheoutcomeofinterest.
Observationalstudy Retrospectiveorprospectivestudyinwhichtheinvestigator
TheEpilepsies
Glossary
600
observesthenaturalcourseofeventswithorwithoutcontrol
groups;forexample,cohortstudiesandcasecontrolstudies.
Oddsratio Ameasureoftreatmenteffectiveness.Theoddsofanevent
happeninginthetreatmentgroup,expressedasaproportionofthe
oddsofithappeninginthecontrolgroup.Theoddsistheratioof
eventstononevents.
Offlabel Adrugordeviceusedtreataconditionordiseaseforwhichitisnot
specificallylicensed.
Olderpeople Wehaveusedthedefinitionof65yearsorolderhoweverthisis
basedonthecutoffpointinthemajorityoftheliterature.
Operatingcosts Ongoingcostsofcarryingoutanintervention,excludingcapitalcosts.
Opportunitycost Theopportunitycostofinvestinginahealthcareinterventionisthe
lossofotherhealthcareprogrammesthataredisplacedbyits
introduction.Thismaybebestmeasuredbythehealthbenefitsthat
couldhavebeenachievedhadthemoneybeenspentonthenext
bestalternativehealthcareintervention.
Outcome Measureofthepossibleresultsthatmaystemfromexposuretoa
preventiveortherapeuticintervention.Outcomemeasuresmaybe
intermediateendpointsortheycanbefinalendpoints.See
Intermediateoutcome.
Pvalue Theprobabilitythatanobserveddifferencecouldhaveoccurredby
chance,assumingthatthereisinfactnounderlyingdifference
betweenthemeansoftheobservations.Iftheprobabilityislessthan
1in20,thePvalueislessthan0.05;aresultwithaPvalueofless
than0.05isconventionallyconsideredtobestatisticallysignificant.
Panayiotopolous
syndrome
Epilepsysyndromepresentinginearlychildhood(mean47yrs)with
rareseizureswhichareprolonged.Characterisedbyautonomic
featuresincludingvomiting,pallor,andsweatingfollowedbytonic
eyedeviation,impairmentofconsciousnesswithpossibleevolution
intosecondarygeneralisation.Prognosisisexcellentandtreatment
oftenunnecessary.
Parasomnia Anybehaviouralabnormalityassociatedwithsleep.Forexample,
headbanging/confusionalarousal/REMsleepdisordernightterrors.
Patientreported
outcomes(PRO)or
patientreported
outcomesmeasures
(PROMS)
Thesetermscoversawholerangeofpotentialtypesof
measurements(e.g.symptomsseverityorbother,healthrelated
qualityoflife,satisfactionwithtreatment)butisusedspecificallyto
refertoquestionnairesdesignedtoobtaintheperspectiveofthe
patientratherthantheperspectiveofcliniciansorcarers.PROdata
maybecollectedviaselfadministeredquestionnairescompletedby
thepatientthemselvesorviaintervieweradministered
questionnaires.Thesequestionnairesshouldbedevelopedand
validatedbeforeuse.
Pharmacokinetics Thewayinwhichadrugisprocessedbythebody,influencing
absorption,metabolism,distributionandexcretion.
TheEpilepsies
Glossary
601
Peerreview Aprocesswhereresearchisscrutinisedbyexpertsthathavenot
beeninvolvedinthedesignorexecutionofthestudies.
Placebo Aninactivebutphysicallyidenticalmedicationorprocedureusedas
acomparatorincontrolledclinicaltrials.Alsosometimesreferredto
asadummytreatment.
Placeboeffect Abeneficial(oradverse)effectproducedbyaplaceboandnotdueto
anypropertyoftheplaceboitself.
Polypharmacy Multipledifferentdrugsusedinapatientstreatment,whichcould
includeAEDs.
Polytherapy Twoormoremedicationsusedincombinationtherapy.The
guidelinespecificallyreferstoAEDs.
Primarycare Healthcaredeliveredtopatientsoutsidehospitals.Primarycare
coversarangeofservicesprovidedbyGPs,nursesandother
healthcareprofessionals,dentists,pharmacistsandopticians.
Primaryresearch Studygeneratingoriginaldataratherthananalysingdatafrom
existingstudies(whichiscalledsecondaryresearch).
Productlicence AnauthorisationfromtheMHRAtomarketamedicinalproduct.A
drugmaybelicensedforseveralconditions.Whenadrugis
referredtoasunlicensedforaparticularindication,thatmeans
thatthedrugmayhaveamarketingauthorisationforother
conditions,butnotfortheconditiondiscussed.Thisisalsoknownas
offlabeluse.
Prognosis Aprobablecourseoroutcomeofadisease.Prognosticfactorsare
patientordiseasecharacteristicsthatinfluencethecourse.Good
prognosisisassociatedwithlowrateofundesirableoutcomes;poor
prognosisisassociatedwithahighrateofundesirableoutcomes
Prospectivestudy Astudyinwhichpeopleareenteredintotheresearchandthen
followedupoveraperiodoftimewithfutureeventsrecordedas
theyhappen.Thiscontrastswithstudiesthatareretrospective.
Provocationtechniques Methodsusedtoprovokeseizuressuchashyperventilation,photic
stimulation,sleepdeprivationandwithdrawalofmedication.
Psychogenicnon
epilepticseizure
(PNES)
Atypeofnonepilepticattackdisorder(NEAD).SeeNEAD.
Puerperium Thetimeafterchildbirth,lastingapproximately6weeks,during
whichtheanatomicandphysiologicchangesbroughtaboutby
pregnancyresolveandawomanadjuststotheneworexpanded
responsibilitiesofmotherhoodandnonpregnantlife.
Qualitativeresearch Researchconcernedwithsubjectiveoutcomesrelatingtosocial,
emotionalandexperientialphenomenainhealthandsocialcare.
Qualityoflife SeeHealthrelatedqualityoflife.
TheEpilepsies
Glossary
602
Qualityadjustedlife
year(QALY)
Anindexofsurvivalthatisadjustedtoaccountforthepatients
qualityoflifeduringthistime.QALYshavetheadvantageof
incorporatingchangesinbothquantity(longevity/mortality)and
quality(morbidity,psychological,functional,socialandotherfactors)
oflife.Usedtomeasurebenefitsincostutilityanalysis.TheQALYs
gainedarethemeanQALYsassociatedwithonetreatmentminusthe
meanQALYsassociatedwithanalternativetreatment.
Quantitativeresearch Researchthatgeneratesnumericaldataordatathatcanbe
convertedintonumbers,forexampleclinicaltrialsorthenational
Censuswhichcountspeopleandhouseholds.
QuickReferenceGuide AnabridgedversionofNICEguidance,whichpresentsthekey
prioritiesforimplementationandsummarisestherecommendations
forthecoreclinicalaudience.
Randomisation Allocationofparticipantsinaresearchstudytotwoormore
alternativegroupsusingachanceprocedure,suchascomputer
generatedrandomnumbers.Thisapproachisusedinanattemptto
ensurethereisanevendistributionofparticipantswithdifferent
characteristicsbetweengroupsandthusreducesourcesofbias.
Randomisedcontrolled
trial(RCT)
Acomparativestudyinwhichparticipantsarerandomlyallocatedto
interventionandcontrolgroupsandfolloweduptoexamine
differencesinoutcomesbetweenthegroups.
RCT SeeRandomisedcontrolledtrial.
Reflexepilepsy
syndromes*
Syndromesinwhichallepilepticseizuresareprecipitatedby
particularsensorystimuli.Reflexseizuresthatoccurinfocaland
generalizedepilepsysyndromesthatalsoareassociatedwith
spontaneousseizuresarelistedasseizuretypes.Isolatedreflex
seizuresalsocanoccurinsituationsthatdonotnecessarilyrequirea
diagnosisofepilepsy.Seizuresprecipitatedbyotherspecial
circumstances,suchasfeveroralcoholwithdrawal,arenotreflex
seizures.
Refractorystatus
epilepticus
Continuedstatusepilepticusdespitetreatmentwithtwo
anticonvulsantsinappropriatedoses.Thiscanoccurinboth
convulsiveandnonconvulsivestatusepilepticus.
Relativerisk(RR) Thenumberoftimesmorelikelyorlesslikelyaneventistohappen
inonegroupcomparedwithanother(calculatedastheriskofthe
eventingroupA/theriskoftheeventingroupB).
Remit ThebriefgivenbytheDepartmentofHealthandWelshAssembly
Governmentatthebeginningoftheguidelinedevelopmentprocess.
Thisdefinescoreareasofcarethattheguidelineneedstoaddress.
Resourceimplication Thelikelyimpactintermsoffinance,workforceorotherNHS
resources.
Retrospectivestudy Aretrospectivestudydealswiththepresent/pastanddoesnot
involvestudyingfutureevents.Thiscontrastswithstudiesthatare
prospective.
TheEpilepsies
Glossary
603
Secondarily
GeneralisedSeizure
Nowreferredtoasafocalseizureevolvingtoabilateralconvulsive
seizure(ILAE2010).
Selectionbias(also
allocationbias)
Asystematicbiasinselectingparticipantsforstudygroups,sothat
thegroupshavedifferencesinprognosisand/ortherapeutic
sensitivitiesatbaseline.Randomisation(withconcealedallocation)
ofpatientsprotectsagainstthisbias.
Selectioncriteria Explicitstandardsusedbyguidelinedevelopmentgroupstodecide
whichstudiesshouldbeincludedandexcludedfromconsiderationas
potentialsourcesofevidence.
Sensitivityanalysis(SA) Ameansofrepresentinguncertaintyintheresultsofeconomic
evaluations.Uncertaintymayarisefrommissingdata,imprecise
estimatesormethodologicalcontroversy.Sensitivityanalysisalso
allowsforexploringthegeneralisabilityofresultstoothersettings.
Theanalysisisrepeatedusingdifferentassumptionstoexaminethe
effectontheresults.
Onewaysimplesensitivityanalysis(univariateanalysis):each
parameterisvariedindividuallyinordertoisolatetheconsequences
ofeachparameterontheresultsofthestudy.
Multiwaysimplesensitivityanalysis(scenarioanalysis):twoormore
parametersarevariedatthesametimeandtheoveralleffectonthe
resultsisevaluated.
Thresholdsensitivityanalysis:thecriticalvalueofparametersabove
orbelowwhichtheconclusionsofthestudywillchangeare
identified.
Probabilisticsensitivityanalysis:probabilitydistributionsare
assignedtotheuncertainparametersandareincorporatedinto
evaluationmodelsbasedondecisionanalyticaltechniques(For
example,MonteCarlosimulation).
Simpleandcomplex
partialepileptic
seizures*
Thesetermsarenolongerrecommended.Theyhavebeengenerally
replacedwiththesingleword,focal.Focalseizuresshouldincludea
cleardescriptionofimpairmentofconsciousness.
Specialist
(asusedinthis
guideline)
Foradults:amedicalpractitionerwithtrainingandexpertisein
epilepsy.
Forchildren:apaediatricianwithtrainingandexpertiseinepilepsy.
Specificcognitive
dysfunction
Definedasperformingbelowthe5thcentileforoneormoreonthe
followingtestsofcognitivefunction
1.visuoconstructivescoreofWIPPSI
2.auditoryphonemicscoreofITPA
3.comprehensionscoreofNEPS
Stakeholder Thosewithaninterestintheuseoftheguideline.Stakeholders
includemanufacturers,sponsors,healthcareprofessionals,and
patientandcarergroups.
Statisticalpower Theabilitytodemonstrateanassociationwhenoneexists.Poweris
relatedtosamplesize;thelargerthesamplesize,thegreaterthe
powerandthelowertheriskthatapossibleassociationcouldbe
TheEpilepsies
Glossary
604
missed.
Statusepilepticus
(convulsive)(CSE)
Seeconvulsivestatusepilepticusabove.
Suddenunexpected(or
unexplained)deathin
epilepsy
(SUDEP)
Sudden,unexplained,witnessedorunwitnessed,nontraumaticand
nondrowningdeathinindividualswithepilepsy,withorwithout
evidenceforaseizure,andexcludingdocumentedstatusepilepticus,
inwhichpostmortemexaminationdoesnotrevealatoxicologicalor
anatomiccausefordeath.
ProvidedbyNashefL.Suddenunexpecteddeathinepilepsy:
Terminologyanddefinitions.Epilepsia1997;38:S20S22.
Symptomaticepilepsy
syndrome*
Previouslyusedtermthatreferstoasyndromeinwhichthe
epilepticseizuresaretheresultofoneormoreidentifiablestructural
lesionsofthebrain.Thisterminologyisnolongerrecommendedfor
use.Seetable9.7.
Syncope
(vasovagalsyncopal
attack)
Abrieflapseinconsciousnesscausedbytransientreductioninblood
flowtothebrain.Maybecausedbymanydifferentfactors,
includingemotionalstress,vagalstimulation,vascularpoolinginthe
legs,diaphoresis,orsuddenchangeinenvironmentaltemperatureor
bodyposition.
Synthesisofevidence Agenerictermtodescribemethodsusedforsummarising
(comparingandcontrasting)evidenceintoaclinicallymeaningful
conclusioninordertoansweradefinedclinicalquestion.Thiscan
includesystematicreview(withorwithoutmetaanalysis),
qualitativeandnarrativesummaries.
Systematicreview Researchthatsummarisestheevidenceonaclearlyformulated
questionaccordingtoapredefinedprotocolusingsystematicand
explicitmethodstoidentify,selectandappraiserelevantstudies,and
toextract,collateandreporttheirfindings.Itmayormaynotuse
statisticalmetaanalysis.
Teratogenic Aneventorprocesswhichinterfereswithnormalprenatal
development,causingthedevelopmentofoneormore
developmentalabnormalitiesinthefetus.
TertiaryEpilepsy
Specialist
Atertiaryepilepsyspecialistisanadultorpaediatricneurologistwho
devotesthemajorityoftheirworkingtimetoepilepsy,whois
workinginamultidisciplinarytertiaryreferralcentrewith
appropriatediagnosticandtherapeuticresourcesandissubjectto
regularpeerreview
Tertiarycentre Specialistcaredeliveryunit,towhichindividualsmaybereferred
fromsecondarycare.
Timehorizon ThetimespanusedintheNICEappraisalwhichreflectstheperiod
overwhichthemaindifferencesbetweeninterventionsinhealth
effectsanduseofhealthcareresourcesareexpectedtobe
experienced,andtakingintoaccountthelimitationsofsupportive
evidence.
Tonicseizures
Anepilepticseizurecharacterisedbyabruptgeneralisedmuscle
stiffeningpossiblycausingafall.Theseizureusuallylastslessthana
minuteandrecoveryisrapid.
TheEpilepsies
Glossary
605
Tonicclonicseizure
Anepilepticseizurecharacterisedbyinitialgeneralisedmuscle
stiffening,followedbyrhythmicaljerkingofthelimbs,usuallylasting
afewminutes.Thepersonmaybitetheirtongueandmaybe
incontinent.Theymayfeelconfusedorsleepyafterwards,andtakea
whiletorecoverfully.
Treatmentallocation Assigningaparticipanttoaparticulararmofthetrial.
Treatmentoptions Thechoicesofinterventionavailable.
Utility Ameasureofthestrengthofanindividualspreferenceforaspecific
healthstateinrelationtoalternativehealthstates.Theutilityscale
assignsnumericalvaluesonascalefrom0(death)to1(optimalor
perfecthealth).Healthstatescanbeconsideredworsethandeath
andthushaveanegativevalue.
Washoutperiod(for
crossoverstudies)
Astageinacrossovertrialafterthefirsttreatmentiswithdrawn,but
beforethesecondtreatmentisstarted.Thewashoutperiodallows
timeforanyactiveeffectsofthefirsttreatmenttowearoffbefore
thenextphasebegins.
Westsyndrome Anepilepsysyndromewithanageofonsetinthefirstyearoflife
(peak,39months)characterisedbyinfantilespasmsandanEEG
patterndescribedashypsarrhythmia.Manychildrenalsoshow
developmentalplateauatpresentation.
Unlessotherwisestated,takenfromMosbysMedical,NursingandAlliedHealthDictionary5th
editionandsupplementedbythetextofthefullguideline(2004Guideline).
*DefinitionsfromILAETaskForceonClassification(updated2010)
TheEpilepsies
606
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PharmacologicalUpdateofClinicalGuideline20

Result defined as a large increase in pre-test to post-test probability

Result defined as a moderate increase in pre-test to post-test probability

126 62(49.2) 51(40.5) 5(8.1) 0(0)

TGB PHB PMD

Minorlimitations Directlyapplicable Decisionanalyticmodel;

8,841 8.8795 At20KperQALYthreshold,probabilitymost

11,327 8.8933 180,137 At20KperQALYthreshold,probabilitymost

TPM 1,930 1.541 Dominate

LTG 2,078(a) 1.563 Dominate

GBP 2,573 1.480 Dominate

10,606 8.302 Dominate

19,922 9.509 Dominate

LEV 20,448 9.523 341,875 At20KperQALYthreshold,

LTG CBZ PHT VPA OXC TPM PHB GBP

9,556 7.738 Dominate

LTG 1,090 120.9 Noanalysisofuncertaintycouldberecreated

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