Guidelines For Epilepsy Nice

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
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
Chairman,Theepilepsiesguideline2012
Update2012
ConsultantPsychiatrist,PrisonMentalHealthInreachTeamandMedicalDirector,Dorset
CommunityHealthServices
ThefirstNICEguidelineonthemanagementofepilepsyinchildrenandadultswaspublishedin2004.
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.
PartialPharmacologicalUpdateofClinicalGuideline20
TheEpilepsies
Preface
Theguidelinehighlightedtheinadequaciesthatexistedintheservices,careandtreatmentfor
peoplewithepilepsy,andmadegreatprogressinaddressingrelevantimportantissues
misdiagnosis,inappropriateorinadequatetreatment,suddenunexpecteddeaththatmighthave
beenprevented,adviceaboutpregnancyandcontraceptionandmanagementofstatusepilepticus.
Revisitingthisguidelineistimely.TheNHSisfacingmajorfinancialchallenges,anditisvitalthata
spotlightiskeptontheneedtofurtherdevelopthestillvariableservicesforpeoplewithepilepsy.
Theplaceofnewlylicenseddrugsforepilepsyalsoneedscarefulconsideration.
Peoplewithepilepsyremainatthecentreofthisguideline,andtheneedforservicestoconsiderthe
needsofeachindividual,tonotdiscriminateinprovisionandtoworkinpartnershipwithpeoplewith
epilepsyandtheircarersisunderlined.
Attentionhasbeenpaidtoensurethattherecommendationsarewritteninclearlanguageandare
accessible,and,wehope,usefultoall.Supportingthewrittenversionisanonlinecarepathway,and
qualitystandardsaresoontobepublished.Weremaincommittedtothecareofpeoplewith
epilepsyandcommendtheseguidelinestoyouinthatlight.
Update2012
Theupdatedguidelineremindsthereaderoftheneedforproperlyresourcedservices,offering
appropriatelevelsofexpertise,whichallowtimelyaccesstoassessmentandtreatmentforpeople
withepilepsy.Theprimaryscopeoftheguidelineswastoconsidertheroleofantiepilepticdrugs,
especiallygiventheimpactofimportant,realworldstudiessuchasSANAD.Theroleofestablished
andnewlylicenseddrugshasbeenconsideredusingnovelstatisticalmethodsallowingcomparison
ofcosteffectivenessaprocessthathasbeenmuchaided,asalways,byarobuststakeholder
reviewprocess.
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
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
2.5
2.4.1
Literaturesearchstrategies.................................................................................32
2.4.2
Healtheconomics................................................................................................34
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
5
TheEpilepsies
Contents
Durationofstudies........................................................................................................................39
Posology........................................................................................................................................39
Typesofoutcomemeasuresanddefinitions................................................................................39
Typeofanalysis.............................................................................................................................41
Useofunpublisheddataintheguideline.....................................................................................41
2.8
Gradingofqualityofevidenceforoutcomes(2012)..........................................................41
Inconsistency.................................................................................................................................42
Indirectness...................................................................................................................................42
Imprecision....................................................................................................................................42
2.9
2.8.1
Healtheconomicsmethods.................................................................................44
2.8.2
Literaturereviewforhealtheconomics..............................................................45
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
Guidance...............................................................................................................................57
4.1.1
Outlineepilepsycarealgorithms.........................................................................82
AuditCriteria.........................................................................................................................85
Principleofdecisionmaking..................................................................................................86
6.1
Whoshouldbeinvolvedinthedecisionmakingprocessforadultsandchildrenwith
epilepsy?.............................................................................................................................86
Diagnosis...............................................................................................................................87
7.1
Introduction........................................................................................................................87
7.2
Establishingthediagnosisofepilepsy.................................................................................87
7.3
Keyfeaturesofthehistoryandexaminationthatallowepilepsytobedifferentiated
fromotherdiagnosesinadultsandchildren......................................................................88
7.4
Whatarethekeyfeaturesofthehistoryandexaminationthatallowanepileptic
6
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Contents
seizuretobedifferentiatedfromothercausesofattackdisorderinadults?....................91
7.5
Theroleofattack/seizurediariesindiagnosisinadults&children...................................91
7.6
Theroleofhomevideorecordinginmakingthediagnosisofepilepsyinadultsand
children?..............................................................................................................................91
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
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
7
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Contents
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
10.3.9
10.3.10 Newresearchrecommendations(forfulllistseesection2.11)........................221
10.4 Therapyforrefractoryfocalseizures................................................................................222
10.4.1
Introduction.......................................................................................................222
10.4.2
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
10.4.9
10.4.10 ResearchRecommendations(forfulllistseesection2.11)..............................283
10.5 GeneralisedTonicClonicSeizures(GTCS).........................................................................284
10.5.1
Introduction.......................................................................................................284
10.5.2
10.5.3
10.5.4
Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresin
adults.................................................................................................................287
10.5.5
Individualpatientdatanetworkmetaanalysisasmonotherapyfor
generalisedtonicclonicepilepsy.......................................................................308
10.5.6
Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresin
children..............................................................................................................310
8
TheEpilepsies
Contents
10.5.7
Adjunctivetherapyforthetreatmentofgeneralisedtonicclonicseizures......310
10.5.8
HealtheconomicevidenceforAEDsusedasadjunctivetherapyinadults
withrefractorygeneralisedtonicclonicseizures..............................................315
10.5.9
10.6 AbsenceSeizures...............................................................................................................322
10.6.1
Introduction.......................................................................................................322
10.6.2
10.6.3
10.6.4
AEDsforthetreatmentofabsenceseizures.....................................................323
10.6.5
10.7 MyoclonicSeizures............................................................................................................329
10.7.1
Introduction.......................................................................................................329
10.7.2
10.7.3
10.7.4
Monotherapyforthetreatmentofmyoclonicseizures....................................330
10.7.5
Adjunctivetherapyforthetreatmentofmyoclonicseizures...........................331
10.7.6
10.8 Tonicoratonicseizures.....................................................................................................340
10.8.1
Introduction.......................................................................................................340
10.8.2
10.8.3
10.8.4
10.9 InfantileSpasms(Westsyndrome)...................................................................................345
10.9.1
Introduction.......................................................................................................345
10.9.2
10.9.3
Matrixoftheevidenceforadjunctivetherapy..................................................345
10.9.4
10.9.5
Newresearchrecommendations(forfulllistseesection2.11)........................356
10.10Dravetsyndrome(SMEI)...................................................................................................357
10.10.1 Introduction.......................................................................................................357
10.10.2 Methodsoftheevidencereview.......................................................................357
10.10.3 Matrixoftheevidence.......................................................................................357
10.10.4 AdjunctivetreatmentofDravetSyndrome(SMEI)............................................358
10.10.5 Newrecommendationsandlinktoevidence....................................................359
10.11LennoxGastautSyndrome................................................................................................363
10.11.1 Introduction.......................................................................................................363
9
TheEpilepsies
Contents
10.11.4 AdjunctivetreatmentforLennoxGastautsyndrome.......................................364
10.11.5 HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildren
withLennoxGastautsyndrome........................................................................369
10.12Benignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeandlate
onsetchildhoodoccipitalepilepsy(Gastauttype)............................................................376
10.12.1 Introduction.......................................................................................................376
10.12.4 MonotherapyforthetreatmentofadultsandchildrenwithBECTS,
Panayiotopoulossyndromeandlateonsetchildhoodoccipitalepilepsy
(Gastauttype)....................................................................................................377
10.13IdiopathicGeneralisedEpilepsy(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
10.13.10Monotherapy/adjunctivetherapyforthetreatmentofjuvenilemyoclonic
epilepsy(JME)....................................................................................................417
10.13.11AdjunctivetreatmentforforthetreatmentofofJuvenileMyoclonic
Epilepsy(JME)....................................................................................................418
10.13.12AEDsforthetreatmentofepilepsywithgeneralisedtonicclonicseizures
only....................................................................................................................419
10.13.13Introduction.......................................................................................................419
10.13.14Methodsoftheevidencereview.......................................................................419
10.13.15Matrixoftheevidence.......................................................................................419
10.13.16Newrecommendationsandlinktoevidence...................................................419
10.14Otherepilepsysyndromes................................................................................................443
10.14.1 Introduction.......................................................................................................443
10
TheEpilepsies
Contents
10.15Prolongedseizuresandconvulsivestatusepilepticus......................................................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
10.15.10Newrecommendationsandlinktoevidence....................................................465
10.15.11Newresearchrecommendations(forfulllistseesection2.11)........................475
10.16Nonconvulsivestatusepilepticus....................................................................................476
10.16.1 Introduction.......................................................................................................476
10.16.3 AEDsforthetreatmentofnonconvulsiveStatusEpilepticus(observational
study).................................................................................................................477
10.16.5 Genericprescribing............................................................................................477
10.17Whenshouldanindividualwithepilepsybereferredforassessmentinatertiary
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
11.3.2
11.3.3
11.3.4
11.3.5
11.3.6
Ketogenicdietinadults.....................................................................................488
11.4 Inpeoplewithdrugresistantepilepsy,isvagusnervestimulation(VNS)effectiveas
anadjunctivetreatment?..................................................................................................488
12 Informationneedsofindividuals,families,andcarers.........................................................493
12.1 Introduction......................................................................................................................493
11
TheEpilepsies
Contents
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
13.5.2
13.5.3
Comparisonbetweenspecificmonotherapiesondevelopmental/cognitive
outcomes...........................................................................................................516
13.5.4
Anymonotherapyexposureversusnoexposureingeneralpopulation..........519
13.5.5
13.5.6
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
13.10Whatistheroleofdrugmonitoringinpregnantwomenwithepilepsy?........................541
13.11ShouldoralorparenteralvitaminKbeused?..................................................................542
13.12Whatistheriskofofinheritingepilepsy?........................................................................542
13.13Whatistheroleofjointepilepsyandobstetricclinicsinthecareofwomenwith
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
12
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Contents
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
14.6.2
14.6.3
14.6.4
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
16.1.2
16.1.3
16.1.4
17 Peoplefromblackandminorityethnicgroups.....................................................................572
17.1 Introduction......................................................................................................................572
17.2 Whataretheinformationandserviceprovisionneedsofpeoplefromblackand
minorityethnicgroups?....................................................................................................572
18 Thecareprocessforpeoplewithepilepsy...........................................................................574
13
TheEpilepsies
Contents
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
18.3.2
andchildrenwithepilepsyinsecondary/tertiarycare?....................................581
18.4 WhatfeaturesofthecareprocessinA&Eleadtoimprovedhealthoutcomesfor
adultsandchildrenwithepilepsy?...................................................................................583
18.4.1
Qualityofcarecurrentlyprovidedinandaccidentandemergency
departments(A&E)............................................................................................583
18.4.2
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
14
TheEpilepsies
Guidelinedevelopmentgroupmembers
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
15
TheEpilepsies
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
16
TheEpilepsies
HeadofEpilepsyNursingService,NHSEasternandCoastalKentCommunityservices
Update
2012
MrsTraceyTruscott
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
ProfessorFrankBesag
17
Update2012
GuidelineDevelopmentGroup(GDG)cooptees(2012)
TheEpilepsies
ConsultantNeuropsychiatristChildrensLearningDisabilityService.TwinwoodsHealthResource
Centre,Bedford.
DrMichaelMarsh
ConsultantinObstetricsandGynaecology,King'sCollegeHospital,London
DrAzaJJAbdulla
ProfessorTonyMarson(ExternalPeerReviewer)
ProfessorofNeurology.UniversityofLiverpoolandCoordinatingEditorCochraneEpilepsyGroup
Update2012
ConsultantPhysicianandGeriatrician.DepartmentofElderlyMedicine,SouthLondonHealthcare
NHSTrust.PrincessRoyalUniversityHospital.Kent
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
DrJenniferHill(untilMarch2011)
GuidelinesOperationsDirector
MsSusanLatchem(fromApril2011)
18
Update2012
NationalClinicalGuidelineCentreProjectteam(2012)
TheEpilepsies
GuidelinesOperationsDirector
MsVanessaDelgadoNunes
SeniorResearchFellowandProjectManager
MsJulieNeilson
SeniorResearchFellow
MsLauraSawyer
SeniorHealthEconomist
DrGrammatiSarri
SeniorResearchFellow
MrCarlosSharpin
SeniorInformationScientistandResearchFellow
19
TheEpilepsies
Acknowledgements
Acknowledgements
2004
TheGuidelineDevelopmentGroupwouldliketothankNancyTurnbullandCharmaineLarmentofthe
NationalCollaboratingCentreforPrimaryCare,RoyalCollegeofGeneralPractitionersforalltheir
hardworkinarrangingGDGmeetingsandsupportingtheguidelinedevelopmentprocess.
TheProjectTeamwouldliketothankMsVickiCluley,UniversityofLeicester,forsecretarialsupport
andDrAliAlGhorrandDrMorayNairn,ScottishIntercollegiateGuidelinesNetwork,Edinburghfor
theirhelpinsharingrelevantsearchesandevidencereviewsontheepilepsiesinadultsandchildren.
TheteamwouldalsoliketothankDrAllanWailloo,UniversityofSheffieldforhisinitialhealth
economicinputandMsNicolaCostinforherhelpwiththeseconddraft.
2012
20
Update2012
TheGuidelineDevelopmentGroupandprojectteamwouldliketothankDrLeeYeeChong,Ms
KatrinaSparrow,MrsFulviaRonchi,MsAbigailJones,MrDavidWonderling,MrTimReason,Ms
ElisabettaFenu,MrsLizAvital,MsHatiZorbaandDrNormaOFlynnforalltheirhelpandsupport
throughouttheguidelinedevelopmentprocess.TheprojectteamwouldalsoliketothankProfessor
TonyMarsonandDrCatrinTudurSmithforprovidingfurtherdatafortheevidenceanalysesandfor
actingasexpertpeerreviewerstotheguidelineupdate.
TheEpilepsies
Introduction
1 Introduction
1.1 Definitionofepilepsy
2004
Anepilepsyisdefinedasaneurologicalconditioncharacterisedbyrecurrentepilepticseizures
unprovokedbyanyimmediatelyidentifiablecause.Anepilepticseizureistheclinicalmanifestation
ofanabnormalandexcessivedischargeofasetofneuronsinthebrain1.
Epilepsyshouldbeviewedasasymptomofanunderlyingneurologicaldisorderandnotasasingle
diseaseentity.Thetermepilepsiesisusedinthetitleoftheguidelinetoreflectthis.
1.2 Clinicalaspects
2004
Theclinicalpresentationdependsonanumberoffactors,chiefly:thepartsofthebrainaffected,the
patternofspreadofepilepticdischargesthroughthebrain,thecauseoftheepilepsyandtheageof
theindividual.2Theclassificationoftheepilepsiesiscontroversialandhastendedtofocusonboth
theclinicalpresentation(typeofepilepticseizure)andontheunderlyingneurologicaldisorder
(epilepsiesandepilepsysyndromes).3
Epilepsyisprimarilyaclinicaldiagnosisbasedonadetaileddescriptionoftheeventsbefore,during
andafteraseizuregivenbythepersonand/orwitness.Electroencephalogram(EEG),magnetic
resonanceimaging(MRI)andcomputedtomography(CT)areusedtoinvestigateindividualswith
knownandsuspectedepilepsy.Thediagnosisofepilepsyrequiresthatseizuretype,epilepsy
syndromeandanyunderlyingcausearedetermined.4Itcanbedifficulttomakeadiagnosisof
epilepsyandmisdiagnosisiscommon.5
TheUKNationalGeneralPracticeStudyofEpilepsyfoundthat60%ofpeoplewithepilepsyhave
convulsiveseizures,ofwhichtwothirdshavefocalepilepsiesandsecondarilygeneralisedseizures
andtheotherthirdwillhavegeneralisedtonicclonicseizures.1,6,7Aboutonethirdofcaseshaveless
thanoneseizureayear,onethirdhavebetweenoneand12seizuresperyearandtheremainder
havemorethanoneseizurepermonth.8
Inadultsandchildrenwithepilepsy,most(70%)willenterremission(beingseizurefreeforfiveyears
onorofftreatment)but30%developchronicepilepsy.9Thenumberofseizuresinthe6months
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
21
TheEpilepsies
Introduction
2012
Ensuringanaccuratediagnosisisimportantforplanningmanagement.Althoughtheprimaryaimis
todiagnosearecognisableelectroclinicalsyndrome,itisrecognisedthismaynotbepossibleinanot
insignificantnumberofindividuals.Theexactsyndromediagnosismaynotbereadilyapparentat
presentation.Moreover,insome,thecausemaybeofequalimportance.Amoredescriptive
approachhasbeenrecommended,retainingtheelectroclinicalsyndromeswherepossiblebutwhere
underlyingaetiologyistakenintoaccount12.Thishasimplicationsfortreatmentinanincreasing
numberofsituations.
Update2012
Since2004,discussionwithregardtotheclassificationoftheepilepsieshascontinued.With
advancesintechnology,particularlyimagingandgenetics,someoftheoldertermininologyeg
idiopathic/symptomatic/cryptogenic,hasbecomeredundantingeneraluse.Furthermore,although
seizuresmaybefocalorgeneralisedinonset,suchterminologycannotbeappliedtosyndromes.The
termspartial,complexandsimplearealsoreplacedsimplybyfocal.
1.3 Epidemiology
2004
TheepilepsiescomprisethemostcommonseriousneurologicaldisordersintheUK.Itaffects
between260,000and416,000peopleinEnglandandWales(AppendixG).13
Theincidenceofepilepsyisabout50per100,000perannum.14Theincidenceishighinchildhood,
decreasesinadulthoodandrisesagaininolderpeople.6Theusualprevalencefiguregivenforactive
epilepsyintheUKis510casesper1,000.11
Epidemiologicalstudiesconsistentlyreportastandardisedmortalityrate(SMR)of24for
epilepsy.15,16Innewlydiagnosedepilepsy,deathislargelyattributabletotheunderlyingdisease(for
example,vasculardisease,tumour).Inchronicepilepsy,however,themaincauseofexcessmortality
isdeathduringaseizure:suddenunexpecteddeathinepilepsy(SUDEP).17SUDEPisestimatedto
accountfor500deathsayearintheUKandhasbeenthesubjectofarecentNationalSentinel
ClinicalAudit.18
Epilepsyisnotalwaysassociatedwithsignificantmorbidity.Manypeoplewithepilepsycontinueto
havehighlyproductiveandfruitfullives,inwhichtheepilepsydoesnotinterferetoagreatextent.
However,thereisanassociatedmorbiditywhichmaybesignificantinsomeindividuals,andmaybe
duetotheeffectsofseizures,theirunderlyingcauseand/ortreatment.Epilepsymaysometimes
resultinsignificantdisability,socialexclusionandstigmatisation.Peoplewithepilepsycommonly
encounterproblemsinthefollowingareas:education;employment;driving;personaldevelopment;
psychiatricandpsychologicalaspectsandsocialandpersonalrelationships.11Inaddition,itis
importanttorecognisethatpeoplewithepilepsymayhavecomorbidities.Forexample,children
withepilepsymayhaveattentionaldifficultiesorlearningdifficulties.19
2012
22
Update2012
AnalysisofdatafromtheQualityandOutcomesFramework(QOF)epilepsydiagnosticcodessuggest
aprevalenceofdiagnosedepilepsyinpeopleaged18andoverof1.15%.Theuseofdatafrom
administrativedatabasessuchastheQOF,however,whichincorporatenonvalidatedepilepsy
diagnosticcodesfortheestimationofprevalenceratesisfraughtwithdifficultyandthereisa
tendencyforsuchdatabasestooverestimateprevalence.Therearenodirectestimatesofthe
epilepsyprevalenceforEngland.Someexistingdatausingvalidatedmethods,suggesttheprevalence
TheEpilepsies
Introduction
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
neurodevelopmentalcompromise20.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,
althoughthepossibilityofmisdiagnosisalsoremainshigh22.Specialconsiderationneedstobegiven
whenprescribinganymedicationwithinthispopulation,notleastbecauseofdruginteractionand
pharmacokineticissues,andthissimilarlyappliestoantiepilepticmedication.Increasinginformation
isalsobeinggatheredontheeffectofantiepilepticdrugstakenbyamotherontheunbornchild;
furtherdatahavetobeaccumulatedtoensureaccurateinformationontreatmentanditspossible
effectsaregiventoawomanpriortoconceptionsosheisabletomakechoices23.
1.4 Costofepilepsy
2004
ThemedicalcosttotheNHSin1992/1993ofnewlydiagnosedepilepsyinthefirstyearofdiagnosis
wascalculatedas18millionandthetotalannualcostofestablishedepilepsyestimatedat2billion
(directandindirectcosts),over69%ofwhichwasduetoindirectcosts(unemploymentandexcess
mortality).24
Thecostsoftreatingepilepsyarelikelytoincreasegiventhenewtrendsinprescribingpatterns
towardsnewerandmoreexpensiveAEDs.Oneofthelateststudiesintheliterature25estimatedthat
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.
23
TheEpilepsies
Introduction
2012
Update2012
Since2004,afurtherfiveAEDshavebecomelicensedforuseintheUKforthetreatmentofepilepsy.
AmorerecentcostanalysisestimatedthetotalcostofepilepsyinEuropein2004was15.5billion
Euros;thecostofantiepilepticdrugusebeing400,00026.Economiccosthoweverisonlyoneaspect
tobeconsideredwhendiscussingthecostofepilepsytotheindividual.Lostemployment,hospital
visitsandoveralllifedisruption/qualityoflifeneedtobecarefullyconsidered.Studiesreviewing
qualityoflifeofindividualswithepilepsyhighlightimportantdeterminantstobeseizurefreedom
andmedicationsideeffectsamongstothers27.Seizurefreedomshouldbestrivedforineach
individualwhopresentswithepilepsy,althoughnotattheexpenseofexcessivesideeffects.Choices
ofantiepilepticmedicationthereforehavetomeasuredandtailoredtotheindividual,informedby
dataavailablefromtheexistingevidencebase.
1.5 HealthServicesforpeoplewithepilepsy
2004
Since1953sixmajorreports11,18,2831havemaderecommendationstoimproveservicesforpeople
withepilepsyintheUK,buttheseservicesremainpatchyandfragmented.13TheDepartmentof
Healthhasrecentlypublishedanactionplan32toimproveservicesforpeoplewithepilepsyin
responsetotheNationalSentinelClinicalAudit(SUDEPreport).18
Akeyaimoftheauditwastoestablishwhetherdeficienciesinthestandardofclinicalmanagement
oroverallpackageofhealthcarecouldhavecontributedtodeaths.TheissuesraisedbytheSUDEP
reportastheyrelatetoprimaryandsecondarycarearesummarisedhere.
2012
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
24
Update2012
Since2004,theclinicalguidelinerecommendationshaveprovidedaframeworkbywhichepilepsy
servicescanbeimproved.Howeverservicesremainpatchy;afurtherreportin2008bytheAllParty
ParliamentaryGrouponepilepsy(wastedmoney,wastedlives)recognisedthatinsomeareasmany
oftherecommendationsaspublishedin2004hadnotbeenimplemented,andthatanearlyreview
wasrequiredastotheprogressofimplementationoftheNICEguidelinesinEngland&Wales.
Furthermore,thewiderneedfortrainingwasalsorecognised.CurrentlyHQIPincollaborationwith
theBritishPaediatricNeurologyAssociationandtheRoyalCollegeofPaediatricsandChildHealth
haveinitiatedanationalauditofchildrensservices(Epilepsy12),measuredagainstvarious
performancemeasuresasdefinedbythe2004guideline,duetopublishin2014.
TheEpilepsies
Introduction
2012
1.5.2
Update2012
Whotakesprimaryresponsibilityforindividualswithepilepsymaydependonlocalnetworksofcare.
Inchildren,responsibilityremainsprimarilywithinsecondarycare.Traininghasbeenstandardised
withcoursesthroughtheBritishPaediatricNeurologyAssociationandothers.Transitionofcareinto
adulthoodmayproveproblematichowever,asdifferinggroupsofindividualadultsmayfallwithin
theremitofdifferingprofessionalgroupsandteamsegadultswithlearningdisability,andthe
elderly.SomePrimaryCareTrustshavedevelopedtheroleoftheGPwithaspecialinterestinthe
epilepsies(GPSIES)whoareresponsibleforindividualswithepilepsy.Definedcarepathwaysfor
individualspresentingwithseizuresarerecommended,frominitialdiagnosistocomplexcare(NICE
2004).
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
Update2012
Criteriabywhichindividualsshouldbereferredintotertiarycarewereincludedinthe2004
guideline.Careofindividualswithepilepsywillbeoptimisedwheretheseguidelinesarefollowedand
carepathwaysareinplace.Auditofcareisyettobeundertakenhowever;HQIPincollaborationwith
BritishPaediatricNeurologyAssociationandtheRoyalCollegeofPaediatricsandChildHealthhave
initiatedanauditof12outcomesfromtheNICEguidelinetobeconductedthroughouttheUKin
children(Epilepsy12)tobecompleteby2014.
1.6 TheSANADtrial
25
Update2012
TheSANADtrialwasapragmatic,randomised,unblinded,parallelgroupclinicaltrialcomprisingtwo
arms(onecomparingnewAEDswithcarbamazepineandtheothercomparingnewerAEDswith
sodiumvalproate).ItwascommissionedandsponsoredbytheNHSR&DHealthTechnology
AssessmentProgramme,butalsosupportedbythepharmaceuticalcompanieswithAEDsincludedin
thestudy,whocontributedapproximately20%ofthetotalcostsofthestudy.Itreceivedappropriate
multicentreandlocalethicsandresearchcommitteeapprovals,andpatientsgaveinformedconsent
toinclusionandtolongtermfollowup.Italsoachievedtheinvolvementofalargenumberof
TheEpilepsies
Introduction
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.
26
TheEpilepsies
Introduction
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
27
TheEpilepsies
Introduction
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.
28
TheEpilepsies
Introduction
2012
ThisguidelineisapartialupdateofTheepilepsies:thediagnosisandmanagementoftheepilepsies
inadultsandchildreninprimaryandsecondarycare(NICEclinicalguideline20,2004).Itupdates
thepharmacologicalmanagementsectionsofthe2004guidelineandalsoincludestheuseofthe
ketogenicdiet.
Threeyearsafterpublicationoftheclinicalguideline,theNCGCandNICEwilldeterminewhetheran
updateiswarranted.
29
TheEpilepsies
Methods
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.
30
TheEpilepsies
Methods
2012
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
31
Update2012
ThemethodologyteamwasledbytheGuidelinesOperationsDirectoroftheNationalClinical
GuidelinesCentre(NCGC),andcomprised:aseniorresearchfellowwhoactedalsoasproject
manager,twosystematicreviewers,onehealtheconomistandtwoinformationscientists.Advice
andguidancewasalsosoughtfromtheclinicaladvisor(ProfessorHelenCross),theappointedChair
oftheGuidelinesDevelopmentGroup(DrNickKosky),andmembersandcoopteesoftheGDG.
TheEpilepsies
Methods
2.3 Developingkeyclinicalquestions(KCQs)
Thefirststepinthedevelopmentoftheguidelinewastorefinetheguidelinescope(seeappendixB)
intoaseriesofkeyclinicalquestions(KCQs)whichreflectedtheclinicalcarepathwayforadultsand
childrenwithepilepsy.TheseKCQsformedthestartingpointforthesubsequentsystematicreview
andasaguidetofacilitatethedevelopmentofrecommendationsbytheGDG.
TheKCQsweredevelopedbytheGDG,withinputasappropriatefromcoopteesandwithassistance
fromthemethodologyteam.TheKCQswererefinedintospecificevidencebasedquestions(EBQs)
bythemethodologyteamandtheseEBQsformedthebasisoftheliteraturesearching,appraisaland
synthesis34.
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
32
Update2012
healthcareindustryandtheseweremadeavailableinthepublicdomain.Detailsofthesecanbeseen
inAppendixU.DeclarationofinterestswereupdatedatthestartofeachGDGmeeting.Arecordof
updateddeclarationsofinterestwasrecordedintheNCGCsdatabaseandminutesofeachmeeting
wereproduced.TheminutesoftheGDGmeetingswerepublishedontheNICEwebsitewithin10
weeksofbeingagreedbytheGDG.
TheEpilepsies
Methods
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.35Nosystematicattemptwas
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
33
TheEpilepsies
Methods
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.
34
TheEpilepsies
Methods
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).37Criticalappraisalwascarriedoutbythesystematicreviewer.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.
35
TheEpilepsies
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2.5.2
2.5.2.1
Methodsfor2012Guideline
Qualityassessementforinterventionstudies
Foreachclinicalquestionthehighestlevelofevidencewassought.Weincludedonlyrandomised
controlledtrialsastheyareconsideredthemostrobusttypeofastudydesignthatcouldproducean
unbiasedestimateoftheinterventioneffects.Whereanappropriaterandomised(doubleblinded,
singleblindedorunblinded)controlledtrialwasidentified,wedidnotsearchforstudiesofaweaker
design.ThequalityassessmentcriteriaaslistedintheNICEGuidelinesManual200936wereusedto
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.
36
TheEpilepsies
Methods
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.
Onehighqualityindividualpatientdatanetworkmetaanalysis38wasidentifiedduringstakeholder
consultation.TheGDGagreedthatthiswasahighqualitystudythatshouldbeincorporatedintothe
evidencereivew.Theindividualpatientdatafor6418patientsfrom20randomisedcontrolledtrials
wasincorporatedintomonotherapyfornewlydiagnosedfocalandgeneralisedtonicclonicseizures
37
TheEpilepsies
Methods
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,200239).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
38
TheEpilepsies
Methods
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:
39
TheEpilepsies
Methods
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
economicevaluation40,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
40
TheEpilepsies
Methods
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
analysis38.
2.8 Gradingofqualityofevidenceforoutcomes(2012)
Afterresultswerepooled,theoverallqualityofevidenceforeachoutcomewasconsideredusingthe
GRADEsystem.ThefollowingistheprocedureadoptedwhenusingGRADE
1. TheevidenceforalloutcomesstartwithaHIGHqualityratingasonlyRCTswereconsidered.
2. Theratingwasthendowngradedforthespecifiedcriteria:Studylimitations,inconsistency,
indirectness,imprecisionandreportingbias.Thesecriteriaaredetailedbelow.
3. Thedowngrademarksarethensummed.Eachqualityelementbeingconsideredashaving
seriousorveryseriousriskofbiaswererateddown1or2pointsrespectively.Allstudies
41
TheEpilepsies
Methods
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
42
TheEpilepsies
Methods
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
43
TheEpilepsies
Methods
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.
44
TheEpilepsies
Methods
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
45
TheEpilepsies
Methods
RemainingstudieswereprioritisedforinclusionbasedontheirrelativeapplicabilitytothecurrentUK
NHSsituationanddevelopmentofthisguideline,andthestudylimitations.Forexample,ifahigh
quality,directlyapplicableUKanalysisisavailableotherlessrelevantstudiesmaynotbeincluded.
Whereexclusionsoccurredonthisbasis,thisisnotedintherelevantevidencesection.
Includedpaperswerecriticallyappraisedbyahealtheconomistusingthequalityandapplicability
checklistoutlinedintheNICEguidelinesmanual200936.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
46
TheEpilepsies
Methods
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.
47
TheEpilepsies
Methods
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:
2.10.2
aprospectiverandomisedcontrolledtrial
allagegroups
subgroupanalysesonseizuretypesandsyndromes
primaryoutcomeofseizurefreedom
secondaryoutcomes,includingseizurereduction,qualityoflifeandcognitiveoutcome
anattempttoobtaindataonpharmacoresistance.
Epilepsysyndromes
WhataretheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswith
onsetinchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome?
Whythisisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidenceonthemost
appropriateinitialoraddonAEDsinthetreatmentoftherarerepilepsies.
multicentrerandomisedcontrolledcomparativetrialswithcentralisednationaldata
collection
theketogenicdietasoneoftherandomisedtreatments
48
TheEpilepsies
Methods
2.10.3
anattempttoobtaindataonpharmacoresistance
thepossibilityofincludingallchildrenwithspecificepilepsysyndromesforconsiderationin
thetrial.
Infantilespasms
Doestreatmentresponserelatetocauseininfantilespasms?Doesearlytreatmentsuccessinseizure
controlandresolutionofthehypsarrhythmicEEGinfluencethelongtermdevelopmentaland
cognitiveoutcomesmorethantheunderlyingcauseofthespasms?
Whythisisimportant
TheUKInfantileSpasmsStudy(UKISS)demonstrated14dayoutcomeefficacyofsteroidsover
vigabatrin,althoughthisexcludedchildrenwithtuberoussclerosis.Thisstudyprovidednospecific
subgroupanalysisbasedonthecauseofthespasms.Therewasalsonoanalysisontheeffectof
treatmentlag(delay)onthestudyfindings.Furtherdataareavailableonbehaviouraloutcomeswith
differenttreatmentsat14monthsand4yearsbutwithnoanalysisbasedoncauseortreatmentlag.
Furtherdevelopmentalandcognitiveoutcomeswouldbeuseful,includingresponsebyspecificcause
andbytreatmentlag.
2.10.4
prospectiverandomiseddesign,includingsubgroupanalysesbasedonbothcauseand
treatmentlag;thiswouldrequirelargenumbersofpatientsandwouldneedtobe
multicentre,possiblyinvolvingWesternEurope
EEGoutcomes
developmentalstatusatpresentation,andatfollowup
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
49
TheEpilepsies
Methods
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.
2.10.6
measuresofmaternaloutcome,includingseizurefrequencyandqualityoflife
majorandminorratesofcongenitalmalformations
prospectiveneurodevelopmental(includingcognitive)andbehaviouraloutcomesinchildren
borntowomenandgirlswithepilepsy(theseshouldbeundertakenonalongtermbasisand
ideallyusingacohortstudy,followedfrombirthuntiladultlife).
Ketogenicdietinadults
Whatistheeffectivenessandtolerabilityoftheketogenicdietinadultswithepilepsy?
Whyisthisimportant?
Therearenodataontheuseoftheketogenicdietinadults.Thismayreflectthefactthatthediet
hasbeenshowntobeineffectiveandtheresultsunpublished,or,asismorelikely,thatthediethas
neverbeenusedinthisagegroup.Inviewofthenumerousanecdotalandrandomisedcontrolled
datademonstratingitseffectivenessandthatthenumberofantiepilepticdrugsprescribedmaybe
reducedasaresultofthisdietaryapproachinthepaediatricepilepsies,itisappropriatetoundertake
arandomisedcontrolledtrialofketogenicdietinadultpatientswithdrugresistantepilepsy.
aninitialpilotstudyofthefeasibilityandacceptabilityoftheketogenicdietinadultswhoare
independentinactivitiesofdailylivingandwhohavenolearningdifficulties
50
TheEpilepsies
Methods
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
guidancetotheNHSinEnglandandWales43(www.nice.org.uk).
Theprojectleadoftheguidelineworkedwiththetechnicalleadonthetechnologyappraisalsto
ensurethatthereleaseofthefinalappraisaldeterminationcoincidedwiththecompletionofthefirst
draftoftheguidelineandthattherewasappropriateexchangeofinformationduringthe
51
TheEpilepsies
Methods
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,44whereasanNSFis
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
52
TheEpilepsies
Methods
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
53
TheEpilepsies
Methods
caseseries
IVExpertcommitteereports,opinionsand/orclinicalexperienceofrespectedauthorities
NICEguidelinesorHealthTechnologyAppraisalprogramme
54
TheEpilepsies
Keyprioritiesforimplementation
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.Administerrectaldiazepamgifpreferredorifbuccalmidazolam
isnotavailable.Ifintravenousaccessisalreadyestablishedandresuscitationfacilitiesareavailable,
administerintravenouslorazepam.[new2012]
Onlyprescribebuccalmidazolamorrectaldiazepamgforuseinthecommunityforchildren,
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
55
TheEpilepsies
Keyprioritiesforimplementation
nurses;timelyandappropriateinvestigations;referraltotertiaryservices,includingsurgeryif
appropriate.[2004]
Ifseizuresarenotcontrolledand/orthereisdiagnosticuncertaintyortreatmentfailure,
children,youngpeopleandadultsshouldbereferredtotertiaryservicessoonforfurther
assessment.[2004]
TheGuidelineDevelopmentGroupconsideredthatsoonmeantbeingseenwithin4weeks.
56
TheEpilepsies
Guidance
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. Itisrecommendedthatalladultshavingafirstseizureshouldbeseenassoonaspossiblebya
specialistinthemanagementoftheepilepsiestoensurepreciseandearlydiagnosisandinitiation
oftherapyasappropriatetotheirneeds.[2004]
5. Itisrecommendedthatallchildrenandyoungpeoplewhohavehadafirstnonfebrileseizure
shouldbeseenassoonaspossiblebyaspecialistinthemanagementoftheepilepsiestoensure
preciseandearlydiagnosisandinitiationoftherapyasappropriatetotheirneeds.[2004]
6. Adetailedhistoryshouldbetakenfromthechild,youngpersonoradultandaneyewitnesstothe
attack,wherepossible,todeterminewhetherornotanepilepticseizureislikelytohaveoccurred.
[2004]
7. Theclinicaldecisionastowhetheranepilepticseizurehasoccurredshouldthenbebasedonthe
combinationofthedescriptionoftheattackanddifferentsymptoms.Diagnosisshouldnotbe
basedonthepresenceorabsenceofsinglefeatures.[2004]
8. Theinformationthatshouldbeobtainedfromtheadultand/orfamilyorcarerafterasuspected
seizureiscontainedinAppendixA.[2004]
TheGuidelineDevelopmentGroupconsideredthatwitharecentonsetsuspectedseizure,referralsshouldbeurgent,
meaningthatpatientsshouldbeseenwithin2weeks.
57
TheEpilepsies
Guidance
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,youngpeopleandadultsrequiringanEEGshouldhavethetestperformedsoonafterit
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.
58
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.
59
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]
60
TheEpilepsies
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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.
61
TheEpilepsies
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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.
62
TheEpilepsies
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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.
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TheEpilepsies
Guidance
90.Offersodiumvalproateasfirstlinetreatmenttochildren,youngpeopleandadultswithnewly
diagnosedGTCseizures.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation
83).[new2012]
91.Offerlamotrigineifsodiumvalproateisunsuitable.Ifthepersonhasmyoclonicseizuresoris
suspectedofhavingjuvenilemyoclonicepilepsy(JME),beawarethatlamotriginemayexacerbate
myoclonicseizures.[new2012]
92.Considercarbamazepineandoxcarbazepinebutbeawareoftheriskofexacerbatingmyoclonic
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.Offerlamotrigineifethosuximideandsodiumvalproateareunsuitable,ineffectiveornot
tolerated.[new2012]
97.IftwofirstlineAEDs(seerecommendations95and96)areineffectiveinchildren,youngpeople
andadultswithabsenceseizures,consideracombinationoftwoofthesethreeAEDsas
adjunctivetreatment:ethosuximide,lamotrigineorsodiumvalproate.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new2012]
98.Ifadjunctivetreatment(seerecommendation97)isineffectiveornottolerated,discusswith,or
referto,atertiaryepilepsyspecialistandconsiderclobazam,clonazepam,levetiracetam,
topiramateorzonisamide.[new2012]
99.Donotoffercarbamazepine,gabapentin,oxcarbazepine,phenytoin,pregabalin,tiagabineor
vigabatrin.[new2012]
Pharmacologicalmanagementofmyoclonicseizures
100.
Offersodiumvalproateasfirstlinetreatmenttochildren,youngpeopleandadultswith
newlydiagnosedmyoclonicseizures,unlessitisunsuitable.Beawareofteratogenicrisksof
64
TheEpilepsies
Guidance
101.
Considerlevetiracetamortopiramateifsodiumvalproateisunsuitableornottolerated.
Beawarethattopiramatehasalessfavourablesideeffectprofilethanlevetiracetamandsodium
valproate.[new2012]
102.
Offerlevetiracetam,sodiumvalproateortopiramateasadjunctivetreatmenttochildren,
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
105.
tonicoratonicseizures.Beawareofteratogenicrisksofsodiumvalproate(seerecommendation
83).[new2012]
106.
Offerlamotrigineasadjunctivetreatmenttochildren,youngpeopleandadultswith
tonicoratonicseizuresiffirstlinetreatmentwithsodiumvalproateisineffectiveornottolerated.
[new2012]
107.
Discusswithatertiaryepilepsyspecialistifadjunctivetreatment(seerecommendation
106)isineffectiveornottolerated.OtherAEDsthatmaybeconsideredbythetertiaryepilepsy
specialistarerufinamideandtopiramate.[new2012]
108.
Donotoffercarbamazepine,gabapentin,oxcarbazepine,pregabalin,tiagabineor
Pharmacologicalmanagementofinfantilespasms
109.
Discusswith,orreferto,atertiarypaediatricepilepsyspecialistwhenaninfantpresents
withinfantilespasms.[new2012]
110.
Offerasteroid(prednisoloneortetracosactide)orvigabatrinasfirstlinetreatmentto
infantswithinfantilespasmsthatarenotduetotuberoussclerosis.Carefullyconsiderthe
riskbenefitra owhenusingvigabatrinorsteroids.[new2012]
111.
Offervigabatrinasfirstlinetreatmenttoinfantswithinfantilespasmsduetotuberous
sclerosis.Ifvigabatrinisineffective,offerasteroid(prednisoloneortetracosactide).Carefully
considertheriskbenefitra owhenusingvigabatrinorsteroids.[new2012]
PharmacologicalmanagementofDravetsyndrome
65
TheEpilepsies
Guidance
112.
Discusswith,orreferto,atertiarypaediatricepilepsyspecialistwhenachildpresents
withsuspectedDravetsyndrome.[new2012]
113.
ConsidersodiumvalproateortopiramateasfirstlinetreatmentinchildrenwithDravet
syndrome.[new2012]
114.
Discusswithatertiaryepilepsyspecialistiffirstlinetreatments(seerecommendation
113)inchildren,youngpeopleandadultswithDravetsyndromeareineffectiveornottolerated,
andconsiderclobazamorstiripentolasadjunctivetreatment.[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.
Onlyofferfelbamateincentresprovidingtertiaryepilepsyspecialistcareandwhen
treatmentwithalloftheAEDslistedinrecommendations119and120hasprovedineffectiveor
nottolerated.[new2012]
Pharmacologicalmanagementofbenignepilepsywithcentrotemporalspikes,Panayiotopoulos
syndromeorlateonsetchildhoodoccipitalepilepsy(Gastauttype)
122.
Discusswiththechildoryoungperson,andtheirfamilyand/orcarers,whetherAED
treatmentforbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlate
onsetchildhoodoccipitalepilepsy(Gastauttype)isindicated.[new2012]
123.
Offercarbamazepineorlamotrigineasfirstlinetreatmenttochildrenandyoung
peoplewithbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlateonset
childhoodoccipitalepilepsy(Gastauttype).[new2012]
124.
LevetiracetamisnotcosteffectiveatJune2011unitcosts.Offerlevetiracetam,
oxcarbazepine,orsodiumvalproate(providedtheacquisitioncostoflevetiracetamfallstoat
Estimatedcostofa1500mgdailydosewas2.74atJune2011.CosttakenfromtheNationalHealthServiceDrugTariff
forEnglandandWales,availableatwww.ppa.org.uk/ppa/edt_intro.htm
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TheEpilepsies
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least50%ofJune2011valuedocumentedintheNationalHealthServiceDrugTariffforEngland
andWales)ifcarbamazepineandlamotrigineareunsuitableornottolerated.IfthefirstAEDtried
isineffective,offeranalternativefromthesefiveAEDs.Beawarethatcarbamazepineand
oxcarbazepinemayexacerbateorunmaskcontinuousspikeandwaveduringslowsleep,which
mayoccurinsomechildrenwithbenignepilepsywithcentrotemporalspikes.Beawareof
teratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
125.
ConsideradjunctivetreatmentifasecondwelltoleratedAEDisineffective(see
recommendations123and124).[new2012]
126.
Offercarbamazepine,clobazam,gabapentin,lamotrigine,levetiracetam,
oxcarbazepine,sodiumvalproateortopiramateasadjunctivetreatmenttochildrenandyoung
peoplewithbenignepilepsywithcentrotemporalspikes,Panayiotopoulossyndromeorlateonset
childhoodoccipitalepilepsy(Gastauttype)iffirstlinetreatments(seerecommendations123and
124)areineffectiveornottolerated.Beawareofteratogenicrisksofsodiumvalproate(see
recommendation83).[new2012]
127.
with,orreferto,atertiaryepilepsyspecialist.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistareeslicarbazepineacetate,lacosamide,phenobarbital,phenytoin,
pregabalin,tiagabine,vigabatrinandzonisamide.Carefullyconsidertheriskbenefitratio
whenusingvigabatrinbecauseoftheriskofanirreversibleeffectonvisualfields.[new2012]
Pharmacologicalmanagementofidiopathicgeneralisedepilepsy
128.
newlydiagnosedIGE,particularlyifthereisaphotoparoxysmalresponseonEEG.Beawareof
129.
Offerlamotrigineifsodiumvalproateisunsuitableornottolerated.Beawarethat
lamotriginecanexacerbatemyoclonicseizures.IfJMEissuspectedseerecommendations134and
135.[new2012]
130.
Considertopiramatebutbeawarethatithasalessfavourablesideeffectprofilethan
sodiumvalproateandlamotrigine.[new2012]
131.
Offerlamotrigine,levetiracetam,sodiumvalproateortopiramateasadjunctive
treatmenttochildren,youngpeopleandadultswithIGEiffirstlinetreatments(see
67
TheEpilepsies
Guidance
recommendations128,129and130)areineffectiveornottolerated.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new2012]
132.
with,orreferto,atertiaryepilepsyspecialistandconsiderclobazam,clonazepamor
133.
Pharmacologicalmanagementofjuvenilemyoclonicepilepsy
134.
newlydiagnosedJME,unlessitisunsuitable.Beawareofteratogenicrisksofsodiumvalproate
135.
Considerlamotrigine,levetiracetam,ortopiramateifsodiumvalproateisunsuitableor
nottolerated.Beawarethattopiramatehasalessfavourablesideeffectprofilethanlamotrigine,
levetiracetamandsodiumvalproate,andthatlamotriginemayexacerbatemyoclonicseizures.
[new2012]
136.
Offerlamotrigine,levetiracetam,sodiumvalproateortopiramateasadjunctive
treatmenttochildren,youngpeopleandadultswithJMEiffirstlinetreatments(see
recommendations134and135)areineffectiveornottolerated.Beawareofteratogenicrisksof
137.
with,orreferto,atertiaryepilepsyspecialistandconsiderclobazam,clonazepamor
138.
Pharmacologicalmanagementofgeneralisedtonicclonicseizuresonly
139.
Offerlamotrigineorsodiumvalproateasfirstlinetreatmenttochildren,youngpeople
andadultswithepilepsywithGTCseizuresonly.Iftheyhavesuspectedmyoclonicseizures,orare
suspectedofhavingJME,offersodiumvalproatefirst,unlessitisunsuitable.Beawareof
140.
Considercarbamazepineandoxcarbazepinebutbeawareoftheriskofexacerbating
myoclonicorabsenceseizures.[new2012]
141.
Offerclobazam,lamotrigine,levetiracetam,sodiumvalproateortopiramateas
adjunctivetreatmenttochildren,youngpeopleandadultswithepilepsywithGTCseizuresonly,if
68
TheEpilepsies
Guidance
firstlinetreatments(seerecommendation139and140)areineffectiveornottolerated.Be
awareofteratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
Pharmacologicalmanagementofchildhoodabsenceepilepsy,juvenileabsenceepilepsyandother
absencesyndromes
142.
Offerethosuximideorsodiumvalproateasfirstlinetreatmenttochildren,youngpeople
andadultswithabsencesyndromes.IfthereisahighriskofGTCseizures,offersodiumvalproate
first,unlessitisunsuitable.Beawareofteratogenicrisksofsodiumvalproate(see
143.
Offerlamotrigineifethosuximideandsodiumvalproateareunsuitable,ineffectiveornot
tolerated.[new2012]
144.
IftwofirstlineAEDs(seerecommendations142and143)areineffectiveinchildren,
youngpeopleandadultswithabsenceepilepsysyndromes,consideracombinationoftwoof
thesethreeAEDsasadjunctivetreatment:ethosuximide,lamotrigineorsodiumvalproate.Be
awareoftheteratogenicrisksofsodiumvalproate(seerecommendation83).[new2012]
145.
with,orreferto,atertiaryepilepsyspecialistandconsiderclobazam,clonazepam,
levetiracetam,topiramateorzonisamide.[new2012]
146.
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]
69
TheEpilepsies
Guidance
154.
Giveimmediateemergencycareandtreatmenttochildren,youngpeopleandadultswho
haveprolonged(lasting5minutesormore)orrepeated(threeormoreinanhour)convulsive
seizuresinthecommunity.[2012]
155.
Onlyprescribebuccalmidazolamorrectaldiazepamforuseinthecommunityfor
children,youngpeopleandadultswhohavehadapreviousepisodeofprolongedorserial
convulsiveseizures.[new2012]
156.
Administerbuccalmidazolamasfirstlinetreatmentinchildren,youngpeopleandadults
withprolongedorrepeatedseizuresinthecommunity.Administerrectaldiazepamifpreferred
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,propofolorthiopentalsodiumtotreatadultswith
refractoryconvulsivestatusepilepticus.Adequatemonitoring,includingbloodlevelsofAEDs,and
70
TheEpilepsies
Guidance
criticallifesystemssupportarerequired.SeealsothesuggestedprotocolsinappendixK.[new
2012]
163.
Administerintravenousmidazolamorthiopentalsodiumtotreatchildrenandyoung
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,
children,youngpeopleandadultsshouldbereferredtotertiaryservicessoonforfurther
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]
71
TheEpilepsies
Guidance
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]
179.
Vagusnervestimulationisindicatedforuseasanadjunctivetherapyinreducingthe
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).
72
TheEpilepsies
Guidance
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]
73
TheEpilepsies
Guidance
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]
198.
Informationshouldbeprovidedtochildren,youngpeopleandadultsandfamiliesand/or
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]
74
TheEpilepsies
Guidance
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.
75
TheEpilepsies
Guidance
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.
Theprogestogenonlypillisnotrecommendedasreliablecontraceptioninwomenand
girlstakingenzymeinducingAEDs.[2004,amended2012]
219.
Theprogestogenimplantisnotrecommendedinwomenandgirlstakingenzyme
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
76
TheEpilepsies
Guidance
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]
77
TheEpilepsies
Guidance
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]
78
TheEpilepsies
Guidance
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]
79
TheEpilepsies
Guidance
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
paediatricphysicianwithonwardreferraltoaspecialistwhenanepilepticseizureissuspectedor
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.
80
TheEpilepsies
Guidance
285.
HealthcareprofessionalsshouldhighlighttheExpertPatientsProgramme
(www.expertpatients.co.uk)tochildren,youngpeopleandadultswithepilepsywhowishto
managetheirconditionmoreeffectively.[2004,amended2012]
Thiswebaddresshaschangedsincetherecommendationwaspublishedin2004andhasbeenupdated.
81
TheEpilepsies
Guidance
4.1.1
Outlineepilepsycarealgorithms
Outlinecarealgorithmforadults
Outlinecarealgorithmforchildren
82
TheEpilepsies
Guidance
83
TheEpilepsies
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
84
TheEpilepsies
AuditCriteria
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.
85
TheEpilepsies
Principleofdecisionmaking
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.
BritishEpilepsyAssociation200045
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
86
TheEpilepsies
Diagnosis
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
shouldbeseenassoonaspossibleibyaspecialistinthemanagementoftheepilepsiesto
ensurepreciseandearlydiagnosisandinitiationoftherapyasappropriatetotheirneeds.
[2004]
Evidencestatement
Diagnosingepilepsyisnoteasy,andmisdiagnosisoccursinaround25%ofcases.(III)
Details
Anadequatediagnosisofepilepsyrequiresdifferentiationbetweenseizuresandothercausesof
transientneurologicaldisturbanceandcollapse;differentiationbetweenacutesymptomaticand
unprovokedepilepticseizures;and,inpeoplewithepilepsy,classificationofthedisorderand
identificationofthecausesoastooptimisetreatment.46
Secondaryevidence
***
TheGuidelineDevelopmentGroupconsideredthatwitharecentonsetsuspectedseizure,referralsshouldbeurgent,
meaningthatpatientsshouldbeseenwithin2weeks.
87
TheEpilepsies
Diagnosis
Nosystematicreviewscomparingratesofdiagnosisbytraining,title,orpositionwerefound.
Primaryevidence
Smith19995
Oneprimarypaperwasidentifiedthatassessedthefrequency,causes,andconsequencesofan
erroneousdiagnosisofepilepsy.Theauthorsfoundanoverallmisdiagnosisrateof26.1%
(n=46/184).Erroneousdiagnosesweremadebyallprofessionalgroups,butthemajorityweremade
bygeneralists.
Scheepers199847
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.
88
TheEpilepsies
Diagnosis
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.48,49Unfortunatelyitisdifficulttoprepareanevidencebasedreviewon
theclinicaldiagnosisofepilepsyforreasonsdiscussedbelow.
Secondaryevidence
AHRQ200150
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
Bergandcolleagues53,54reportedthat609of613childrenwereassignedasyndromicdiagnosison
thebasisofclinicalfeatures.
89
TheEpilepsies
Diagnosis
Arts,Geerts,Brouwer,andcolleagues55reportingon466childrensuggestedthehistoryalone
yieldeda29percentsensitivityand89percentspecificity.
Hoefnagels,Padblerg,Overweg,andcolleagues52notedthatitwasimpossibletofindagold
standardforthediagnosisofepilepsyandthereforedevelopedtheirowntodistinguishepilepsy
fromsyncope.Sensitivityandspecificityofseveralcomponentsofahistorywerecomputed,e.g.,
particularsymptomsbefore,during,andaftertheparoxysmalevent.Thosebeforetheeventhad
thehighestsensitivity(88%to98%),andthoseduringtheevent,thehighestspecificity(64%to
94%).
Camfield,Camfield,Dooleyandcolleagues51reportedthatinaretrospectiveanalysisof168
childrenseenaftertheirfirstseizure,anabnormalneurologicexamination(in30children)was
predictiveofrecurrence,aswasseizuretype(focalseizureassociatedwithincreasedrisk).
Neitherthesleepwakestatusatthefirstseizurenorahistoryoffebrileseizurespredicted
recurrence.Inthreeadditionalretrospectivestudies,theutilityofvariousinterventionsin
diagnosisand/orpredictionofrecurrencewasreported.
Ambrosetto,Giovanardi,andTassinari56reportedonhistory(andEEGfindings)in72individuals
andconcludedthatonlygeneralizedseizuresasthesoleictalphenomenon,andalonginterval
betweenthefirstandsecondseizures,werepredictiveofseizurefrequencysubsequently.
Otherprimarypapers
Sheldon200257
SincetheAHRQreview50,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?
90
TheEpilepsies
Diagnosis
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
recordingsasanaidtothediagnosisofepilepsyinadults58andchildren.59,60Onepaperlookedat
theuseofahandheldvideocamcorderinatertiarycentretoassistintheevaluationofseizures,but
itwasexcludedonthegroundsitdidnotrelatetodirectrecordingofattacksathome.61
Primaryevidence
Newmark198158
Newmarkreportedasinglecasehistoryofa66yearoldwomanwitha21monthhistoryof
undiagnosedattacksinwhomhospitalmonitoringhadbeenunsuccessful.Adiagnosisofsecondarily
generalisedtonicclonicseizureswasmadebyanalysisofthehomevideotape.
Sheth199459
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TheEpilepsies
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ShethandBodensteinerreportedasinglecasehistoryofa2yearoldboywhowasevaluatedbya
paediatricianandaneurologistforstereotypicparoxysmaleventswhichhisparentshadrecorded
withavideocamera.Theneurologistmadeaninitialdiagnosisofseizuresandphenobarbitalwas
prescribed.Theseizurescontinuedandarepeatvideo6weekslaterrevealedthediagnosistobe
infantilemasturbationandtherapywasdiscontinued.
Woody198560
Woodyreportedtwocasesofchildren(10montholdboy&8yearoldgirl)whohadbeenpreviously
investigatedforundiagnosedattacksusingEEGandinpatientassessment.Thehomevideo
recordingswereofsufficientqualitytoallowacorrectdiagnosistobemadeineachcase(complex
focalseizureandreflexmicturitionepilepsy).
Healtheconomics
Thereisalackofhealtheconomicsevidenceontheareasrelatedtodiagnosisinepilepsy.Inthe
presentguidelinemisdiagnosiswasviewedasahugeproblemnotonlyintermsofhumansuffering
butalsointermsofwasteofresourcesfortheNHSandsocietyasawhole.Withthepurposeof
highlightingthemagnitudeoftheproblem,aneconomicanalysiswascarriedouttoestimatethe
costsofmisdiagnosis(seeAppendixG).
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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)
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TheEpilepsies
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Details
Arecentdefinitionofwhatconstitutesastandard/routineinterictalEEGhasbeenprovidedin
guidelinesproducedbytheInternationalLeagueAgainstEpilepsy.62Recommendationsforroutine
EEGinvestigationwerethat:
Themodifiedcombinednomenclaturederivedfromthe1020systemshouldbeusedfor
electrodelocation
Theminimumnumberofelectrodesshouldbe21foradultsand9forchildren
Atleastbipolarmontageswithlongitudinalandtransversechainsshouldbeincluded
Artefactsofeyemovementshouldbeexcludedusingeyeopening,eyeclosing,andblink
procedures
Activationprocedures,suchashyperventilationandphoticstimulation,shouldbeused.62
Secondaryevidence
Linzer199763
InthisUSsystematicreview,theauthorsreviewedtheliteratureondiagnostictestinginsyncopein
ordertoproviderecommendationsforacomprehensive,costeffectiveapproachtoestablishingits
cause.
Theauthorsnotedthatintheearly1980sEEGwascommonlyusedintheUStoinvestigate
individualswithsyncope.However,sixstudiesconclusivelyshowedthatEEGmonitoringisoflittle
useinunselectedindividualswithsyncope.Theauthorsqualitativelysummarizedtheresultsof
thesesixstudies.Intheabsenceofahistoryofseizureactivity,EEGdidnotprovideadiagnosisin
morethan500casesreportedintheliterature.Eightof534individualswerediagnosed(diagnosis
notstated)usingEEG;2ofthese8hadclinicaldataprovided,andbothpeoplehadahistoryof
seizures.
Fowle200064
OneUKpaperusedsystematicliteraturesearchingtoidentifyrelevantprimarystudies.However,
thispaperdidnotmeetsystematicreviewcriteriaasitdidnotaddressaspecificclinicalquestion:it
presentedageneraloverviewoftheusesoftheEEGinepilepsy.
TheauthorsmadetheimportantpointthatEEGisadiagnostictestwithvariablesensitivityand
specificity.64Thus,theEEGmaybeabnormalinnormalpeople(inonestudyofmaleRAFpersonnel
whoareallscreenedusingEEG,0.5%(69/13658),ofthesamplehadepileptiformdischarges65).It
mayalsobenormalinpeoplewithepilepsy.
Gilbert200066
AsystematicreviewoftheuseofEEGafterafirstunprovokedseizureinchildrenidentifiedfour
relevantprimarystudies.Fromthese,thesensitivityandspecificityoftheEEGwascalculatedtobe
atbest61%and71%respectively.
AHRQ200150
AUSsystematicreviewconsideredtheroleoftheEEGinmakingadiagnosisofepilepsy.Theauthors
notedthatitwasdifficulttoprepareanevidencebasedreviewofdiagnosisinepilepsy,includingthe
roleoftheEEG,forthefollowingreasons:
Goldstandardfordiagnosiswaslooselyconstruedandincludedbothaclinicalcomponentand
anEEGcomponent.
Theclinicalrequirementsfordiagnosiswerehighlyvariableandincludedsuchsignsand
symptomsastonic/clonicmovements,withorwithoutpostictalconfusion,tonguebiting,
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sphincterdisturbance,aura,andlossofconsciousness.Somestudiesrequiredtheeventstobe
unprovoked;othersdidnot.Somestudiesrequiredtheeventsbewitnessed;othersdidnot.
Theseizuretypewasusuallydiagnosedbyclinicalfeaturesandtheepilepsysyndrome,byseizure
typeandEEGfindings.
Onlyaminorityofstudiesreferredtoestablishedclassificationschemas,forexample,theILAE.50
Primaryevidence
Theprimarypapersreviewedherehadmethodologicaldeficienciesaccordingtocriteriafor
diagnostictestsproposedbytheEvidenceBasedMedicineWorkingGroup.49,67
Goodin198468
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)
Specificity
0.96(910/948)
Likelihoodratioforpositivetest
13.0
Likelihoodratiofornegativetest
0.5
****
Inthosewithadiagnosisofnonepilepticneurologicalandpsychiatricdisordersonly4%(38/948)had
epileptiformactivityontheinitialEEG.Inthosewithaclinicaldiagnosisofepilepsy52%(397/764)
hadepileptiformactivityontheinitialEEG.
Theresultscanbeinterpretedasfollows.EpileptiformactivityintheEEGisspecific,butnot
sensitive,forthediagnosisofepilepsy.ApositiveinterictalEEGcanbeusedtohelpconfirmthe
diagnosisofepilepsybutanegativeresultcannotbeusedtoruleoutthediagnosisofepilepsy.
Hoefnagels199152
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)
****
95
TheEpilepsies
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orsyncope(62%).TheirfindingsforthetestcharacteristicsofinterictalEEGarepresentedbelow
(presentedinthisforminthepaper).
Table82:ResultsofEEGin118individualsreferredtoaneurologicaldepartmentwithoneormore
episodesoftransientlossofconsciousness
A)ResultsofinterictalEEG
Seizure(n=45)
Syncope(n=73)
Normal
15
55
Localisedepileptiformactivity
10
Generalisedepileptiformactivity
Localisedslowactivity
12
14
B)Diagnosticvalueofepileptiformactivityforaseizure
Sensitivity
0.40(18/45)
0.95(69/73)
Specificity
Likelihoodratioforpositivetest(CI)
7.3(2.620.3)
Likelihoodratiofornegativetest(CI)
0.6(0.50.8)
Theresultscanbeinterpretedasfollows.EpileptiformactivityintheEEGisspecific,butnot
sensitive,forthediagnosisofaseizureasthecauseoftransientlossofconsciousness.Apositive
interictalEEGcanbeusedtoconfirmtheclinicaldiagnosisofaseizurebutanegativeresultcannot
beusedtoruleouttheclinicaldiagnosisofaseizure.
Camfield200069
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).
Jan200270
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
96
TheEpilepsies
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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
Generalisedepileptiformdischarges
12
BackgroundEEGdisturbances(focal&diffuse)
29
Normal
95
39
B)Diagnosticvalueofepileptiformactivityforaseizure
Sensitivity
0.26(40/154)
Specificity
0.98(39/40)
Likelihoodratioforpositivetest
13*****
0.76
Likelihoodratiofornegativetest
Stroink200371
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)
97
TheEpilepsies
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8.2.2
HowgoodistheEEGatdifferentiatingbetweenindividualswhohavedifferentepilepsy
seizuretypesandepilepsysyndromes?
20.AnEEGmaybeusedtohelpdetermineseizuretypeandepilepsysyndromeinchildren,young
peopleandadultsinwhomepilepsyissuspected.Thisenablesthemtobegiventhecorrect
prognosis.[2004]
ThestandardEEGcanhelpclassifyindividualswithaclinicaldiagnosisofanepilepticseizureinto
differentepilepsyseizuretypesandepilepsysyndromes.(III)
Details
Secondaryevidence
Hirtz200072
Anevidencebasedreviewofapproachesforevaluatingafirstnonfebrileseizureinchildrenwas
identified.ThisstatedthatthemajorityofstudiesconfirmedthatanEEGhelpsindeterminationof
seizuretypeandepilepsysyndromeinchildren.
Primaryevidence
King199873
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]
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TheEpilepsies
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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.50,64,74Specificreviewarticlesarediscussedbelow.
8.2.3.1
EarlyrecordingofEEGafterseizure
Secondaryevidence
Nosystematicreviewswereidentified.
Primaryevidence
King199873
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.
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TheEpilepsies
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ThefirstEEGwasperformedwithin12hoursoftheseizurein89(30%)individuals,between1224
hoursin67(22%)individuals,andaftermorethan24hoursin144(48%)individuals.Epileptiform
abnormalitieswereobservedin80(51%)ofthe156whohadanEEGwithinthefirst24hours,
comparedwith49(34%)ofthe144whohadalaterEEG(95%CIfordifferenceinproportions6%
28%).
Sundaram199075
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
Salinsky198776
OneUSstudyretrospectivelyreviewedtheEEGdataon429adultstodeterminetheprobabilityof
findinginterictalepileptiformactivity(IEA)onEEG.Blindingwasnotdocumented.
Thestudypopulationwashighlyselected,comprisingofadultmaleveterans(armypersonnel)with
epilepsy(95%ofwhomhadcomplexfocalseizures).
In50%ofadultswithIEA,theabnormalitywaspresentonthefirstEEG,in84%bythethirdEEGand
in92%bythefourthEEG.
8.2.3.3
SleepandsleepdeprivationEEGs
Anarrativereviewwhichconsideredtheearlierliterature77andarecentcriticalreviewofthe
literature78wereconsulted.Therewasconsensusthatnaturalsleepandsleepdeprivationincrease
thediagnosticyieldofEEGinchildrenandadults.Thefollowingissues,however,wereidentified:
PoorqualityofresearchstudiesaddressingimpactofsleepandsleepdeprivationEEGson
diagnosticyield.Manystudiesareretrospective;notblindedandconfoundtheeffectofrepeat
EEGrecordingswiththeeffectsofsleepandsleepdeprivation;
Uncertaintyastowhethersleepitselforsleepdeprivationcausestheobservedincreased
diagnosticyield;
ConflictingadviceontheroleofsleepandsleepdeprivationEEGsinauthoritativereviewslikely
tobeconsultedbypractitioners.64
100
TheEpilepsies
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Twoprospectivestudiesoftheroleofsleepandsleepdeprivationwereidentified,bothincludedin
theAgencyforHealthcareResearch&Qualitysystematicreview.50
Secondaryevidence
Primaryevidence
Carpay199779
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).
King199873
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).
Schreiner200380
SchreinerandPohlmannEdenaimedtoevaluatethepredictivevalueofstandardEEGandEEGwith
sleepdeprivationforseizurerecurrenceinadultsafterafirstunprovokedseizure.157adultswere
includedandwereagedbetween17and84years.61.8%weremale.AstandardEEGwas
performedwithin48hoursofthefirstseizure.AsleepdeprivedEEGwasperformed3to7daysafter
thefirstseizureforthoseinwhomthestandardEEGwasnormalorwasinconclusive.
46adults(29.3%)hadanormalEEG.Ofthe60whoseinitialEEGwasnormalorwasinconclusive,the
sleepdeprivedEEGshowedabnormalitiesin9adults.Conversely,in10adults,sleepdeprivedEEG
didnotdetectabnormalitiesalreadyidentifiedbythestandardEEG.
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TheEpilepsies
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8.2.3.4
WhatistheroleofmelatoninforchildrenundergoingasleepEEG?
Inchildren,sleepEEGshavetraditionallybeenundertakenbydeprivingchildrenofsleepthenight
beforetheEEGstudy.Thisprocedure,however,hasbeenshowntobeoflimitedacceptabilityto
parentsofchildrenwithepilepsy.81Asanalternative,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
adults83andtwoonthediagnosisofnonepilepticattackdisorders(NEAD).84,85
Secondaryevidence
AHRQ200150
Eightprimarystudies(4prospectiveand4retrospective)oftheroleoflongtermvideoEEGinthe
diagnosisofepilepsywerereviewedintheAgencyforHealthcareResearch&Qualityreview.These
aresummarisedbelow.TheauthorsofthereviewconcludedthatinpatientvideoEEGand
ambulatoryEEGwerediscretionarytestsandthattheevidencewasinconclusiveonthevalueofany
addedinformation.
Prospectivestudies:
AnAustralianstudyreportedacaseseriesof82children(age2months16years,median6
years)whounderwentinpatientEEGvideotelemetry.86Thecommonestreasonforreferralwas
todeterminewhetheraneventwasictal(76%,62/82).Otherreasonsincludedseizurefrequency,
102
TheEpilepsies
Investigations
classificationorlocalisationofonset.Eventsoccurredduringtherecordingin80%(66/82)of
subjects.Ofthese,35%(23/66)werejudgedtobeepilepticandtheseizuretypeidentified.
AUSstudyreportedacaseseriesof100infants,childrenandadolescentswhohadoutpatient
videoEEG.87Ofthe36whowerereferredtodeterminewhethertheeventswereepileptic,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.92The
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)
103
TheEpilepsies
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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.
McGonigal200295
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%).
Bhatia199796
Anotherstudyconsideredtheusefulnessofshorttermrecordingofvideoelectroencephalography
(VEEG)asanoutpatientprocedurewithplaceboinductionandintravenoussalineincasesof
pseudoseizures.
Fiftycasesofsuspectedpseudoseizureswereenrolled.Theyweredividedinto2groups:Group1
consistedofindividualswithfrankpseudoseizures;Group2thosewherediagnosiswasuncertain.
VEEGrecordingwasdoneand10mlofsalineusedforplaceboinduction.Of50cases,24(48%)were
104
TheEpilepsies
Investigations
inGroup1and26(52%)inGroup2.Fifteen(15/50,30%)hadaspontaneouseventduringVEEG.A
further15(15/45,33%)hadaneventonlyonplaceboinduction.
Parra199897
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.
Dericioglu199898
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.
Benbadis200099
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
105
TheEpilepsies
Investigations
Individualspresentingwithafirstunprovokedseizurewhohaveepileptiformactivityontheirinitial
EEGhaveanincreasedriskofseizurerecurrence.(IIbchildren,IIIadults)
ThespecificityofanepileptiformEEGinpredictingfurtherseizuresrangesfrom0.13to0.99,and
sensitivityfrom0.20to0.91.(II)
Details
Secondaryevidence
Foursystematicreviewswereidentified.
Berg1991100
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.
Gilbert200066
Inthisreview,theauthorsaimedtoquantifyandanalysethevalueoftheinformationfromanEEG
afterafirstunprovokedseizureinchildren.
Fourstudiesinvolving831childrenwereincluded.
Thepretestprobabilityofrecurrenceinallstudieswasfoundtobebelowthelowerrangeofthe
rationaltestingregion;thatis,theexpectedvalueoftheinformationgainedfromtheEEGwastoo
lowtoaffecttreatmentrecommendationsinmostchildren.
Hirtz200072
AnevidencebasedpracticeparameterstatedthattheEEGhelpsindeterminationofriskof
recurrenceofseizuresinchildrenafterafirstunprovokedseizure.
106
TheEpilepsies
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Figure8.1Probabilityofseizurerecurrenceafterafirstunprovokedseizureasafunctionofthestandard
EEG101ModifiedwithpermissionfromBergatal2000
Gilbert2003102
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]
107
TheEpilepsies
Investigations
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
AHRQ200150
Ninestudiesdiscussedtheroleofneuroimaginginthediagnosisofepilepsy,andtheevidence
suggestedthattheroleofMRIinfirstdiagnosisisbestestablishedinindividualsinwhomtheCTis
nondiagnostic.
108
TheEpilepsies
Investigations
Hirtz200072
Ninestudiesaddressedtheuseofneuroimaginginchildrenpresentingwithafirstnonfebrile
seizure.TheevidenceconsistentlydemonstratedthatMRIwasmoresensitivethanCTscanning.
However,thestudiesshowedthatonly1.9%ofimagesrevealedclinicallysignificantfindingsthat
contributedtotreatmentormanagement.
Primaryevidence
AsforevidenceonEEG,theprimarypapersreviewedherehavemethodologicaldeficiencies
accordingtocriteriafordiagnostictests.
Diagnosisofepilepsy
Berg2000101
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
fromBergatal2000101
109
TheEpilepsies
Investigations
EpilepsySyndrome*
Total
Any
Neuroimaging
MRI(CT)
N(%)
Abnormal
N(%)
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(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(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.
Bunn2002103
OnestudyaimedtocomparetheclinicalbenefitofCTwithMRIforchildreninvestigatedatadistrict
generalhospital.
110
TheEpilepsies
Investigations
Aretrospectivecasenotereviewoftwooneyearperiods(19921993and19961997)was
undertaken.Allchildrenaged18orunderwhohadaCTscanorMRIofthehead,neck,orspine
requestedbyapaediatricianwereincluded.
AdefinitivediagnosiswasmadewithCTin12%ofchildrenwhopresentedwithseizures,andin27%
withMRI.
Dam1985104
Theaimofthestudywastocomparethediagnosticvalueofthehistory,clinicalexamination,and
EEGwiththeCTscanintheidentificationofpeoplewithbraintumours.
Thecauseofepilepsyin221individualswithlateonsetofepilepsy(25yearsorolder)was
determinedbyhistory,clinicalexamination,EEGrecording,andCTscan.
Braintumour,asdiagnosedbytheCTscan,wasthecauseofepilepsyin16%(n=36).Thecause
(usinghistory,neurologicalexamination,andCT)couldnotbeidentifiedin38%ofindividuals(n=84).
HoltSeitz1999105
Theaetiology,earlymortality,predictorsofprognosis,anddiagnosticyieldsofEEGandCTscansin
newonsetseizuresinolderpeoplewereexaminedinadultsaged60orolder.
ParticipantswereidentifiedbyreviewingrecordsofallEEGrecordingsundertakeninatwoyear
period(Jan1994Dec1995)atasinglehospital.88peoplewithdefiniteorprobableseizurewere
identified,but4refusedtoparticipate.TheinitialEEGwasabnormalin61people(73%).CTwas
performedinallindividualsandwereabnormalin57(68%).Only11individualsunderwentMRI
scanningandabnormalitiesweredetectedin7,threeofwhomhadnoabnormalitydetectedinCT.
Jallon1997106
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.
Kilpatrick1991107
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.
King199873
111
TheEpilepsies
Investigations
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
RamirezLassepas1984108
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.
Roberts1988109
AprospectivestudyofCTscansinadultswithlateonsetepilepsywassetuptosearchforevidence
ofcerebrovasculardisease.
Thecasenotesof132consecutivenewoutpatientswithahistoryofoneormoreepilepticseizures
withageofonset40yearsorolderwerereviewed.Individualswereexcludediftherewereother
neurologicalsymptomsortherewasdoubtaboutthediagnosis.Controlscanswereobtainedfrom
132controlsubjectsofappropriateageandsex.
15ofthosewithepilepsyhadinfarctsonCTcomparedwith2ofthecontrols(p=0.003).However,
therewasnodifferencebetweenthegroupsinthepresenceofrelevantclinicalfeaturesofsystemic
vascularandcardiacdisease.TheCTevidenceofcerebralatrophywasthesameinbothgroups.
Syndromicdiagnosisandclassification
Atakli1998110
Onestudyaimedtoidentifyandanalysepitfallsinthediagnosisofjuvenilemyoclonicepilepsy(JME).
Thenotesof76individualswithwelldocumenteddiagnosesofJME(asassessedusingthe
Panayiotopoulosdiagnosticcriteria)wereretrospectivelyanalysed.
AlloftheCT(n=33)andMRI(n=3)investigationswerenormal.
Harvey1997111
Acommunitybasedcohortofchildrenwithnewonsettemporallobeepilepsy(TLE)wererecruited
tostudythepresentationandnaturalhistoryofthedisorder.
112
TheEpilepsies
Investigations
318childrenwithahistoryof2ormoreunprovokedfocalseizuresofsuspectedTLEoriginwithonset
beforeaged15wererecruited(Jan1991toMar1993).Ofthese,63werediagnosedwithTLE.MRI
wasperformedin58ofthe63(92%)childrenandCTin48ofthe63(76%).Fivechildrendidnot
undergoMRIbecausetheCTwasnormalandtheirparentsdidnotwishthemtoundergoMRI.
MRIrevealedstructuralabnormalitiesofthetemporallobein24ofthe63children(38%).
Jallon2001112
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.
Lee2002113
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%.
113
TheEpilepsies
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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
AHRQ200150
Thissystematicreviewidentifiedtworelevantpapers(Anzola114andNeufeld115discussedbelow).
Primaryevidence
Theprimarypapersreviewedherehavemethodologicaldeficienciesaccordingtocriteriafor
diagnostictestsproposedbytheEvidenceBasedMedicineWorkingGroup.Themainconcernswere
lackofagoldstandardforreference,andlackofblindingofinvestigatorsorassessors.49,67
Diagnosisofepilepsy
Fein1997116
Theutilityofserumandcerebrospinalfluid(CSF)prolactinlevelswasassessedinthediagnosisof
childrenwithseizures.Serumsampleswereanalysedifthesamplesweretakenwithin90minutesof
theseizure,andCSFsampleswithin4hoursoftheseizure.Thecomparisongroupwaschildrenwho
hadnotexperiencedaseizurebutwhootherwiserequiredalumbarpuncture.
Thepositivepredictivevalueofageadjusteddichotomouslevels(elevatedandnormal)ofserum
prolactinwas68%(95%CI4785%)andthenegativepredictivevaluewas76%(95%CI6187%).
Shah2001117
Onestudyaimedtoanalysetherelationshipbetweendifferenttypesofseizuresandnonepileptic
events,seizureduration,timeofsamplingandserumprolactinlevelsandperipheralwhiteblood
count.Seizureclassificationandbaselineplusbothposteventwhitebloodcountandprolactinlevels
wereavailablefor174events.
114
TheEpilepsies
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Serumprolactinlevelincreasedabovetwicethelevelatbaselineafteracomplexfocalseizureora
generalizedseizure.PeripheralWBCcountwaselevatedabovetheupperlimitofnormalin36%of
casesafterageneralizedseizure.Ingeneralizedseizures,thelengthofaseizureispositively
associated,whereasthelapsetimebetweentheseizureonsetandblooddrawisnegatively
correlatedwiththeincreaseinWBCcount.
Tumani1999118
Thetemporalprofileofseriallevelsofneuronspecificenolase(NSE)andserumprolactinwere
comparedin21individualswithsingleseizures.Measurementsweretakenatone,three,sixand24
hoursaftertheevent.
TherewasasignificantdecreaseofNSEandprolactinlevelsovertime(p<0.001).Atonehourafter
theevent,only38%ofindividualshadincreasedNSEcomparedwithabnormalprolactinlevelsin
81%.
Differentialdiagnosisbetweenepilepticandnonepilepticattacks
Alving1998119
Thisstudyaimedtoevaluatethediscriminativepowerofserumprolactinmeasurementsinthe
differentialdiagnosisbetweenepileptic(ES)andpseudoepilepticseizures(PES).Bloodsamples
weretakenfrom58participantsboth15minutesaftertheseizureand2hoursafterthefirstsample.
Sensitivityforthemaximalriseofserumprolactininpseudoseizures(5.5timesbaselinelevel)was
only20%andthenegativepredictivevalue40%.Forthecutoffinabsolutelevel,(1025U/ml),the
figureswere34%and44%respectively.
Epilepsyvssyncope
Anzola1993114
Theclinicalusefulnessofplasmaprolactininthedifferentialdiagnosisbetweenepilepsyandsyncope
wasstudiedin59cases.Plasmaprolactinlevelsweremeasuredassoonaspossibleaftertheevent
(P1),onehourafterP1(P2),andinthemorningforthenexttwodays(P3,P4).
LevelsweresignificantlyincreasedinthosewhohadaseizurewhenP1wassampledwithin60
minutesofanattack.Inpeoplewhohadasyncopalattack,plasmalevelsdidnotincrease.Forthose
assessedwithin60minutesoftheattack,thepositivepredictivevalueofthecutoff(P1exceedingby
+3sdofthemeanofP2,P3,P4)was89%andthenegativepredictivevaluewas61%.
Lusic1999120
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
Neufeld1997115
Theobjectiveofthisstudywastodeterminetheroleofsequentialserumcreatinekinase(CK)levels
indifferentiatingbetweengeneralisedtonicclonicseizuresandvasovagalsyncopeinpeople
presentingwithfirsteventsoflossofconsciousness.Serumlevelsweretakenin16individualson
admission(i.e.withinafewhoursoftheevent)and2426hourslater.
115
TheEpilepsies
Investigations
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.
Zaidi2000121
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
116
TheEpilepsies
Investigations
ThissectionwasnotsubjecttoafullevidencereviewforreasonssetoutinChapter2.
Narrativereviews
Twoexpertreviewswereconsulted.
Buelow2002122
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.
Kwan2001123
Thisreviewconsideredthecauseandneuropathologyofepilepsy,neuronaldischarges,AED
treatmentandtheassociatedeffectsoncognitionandbehaviour.Psychosocialfactorswerealso
discussed.
Theauthorsconcludedthatabetterunderstandingofthecomplexcognitiveandbehavioural
dimensionsofepilepsywouldallowclinicianstoprovideamoreholistic,personcentredapproachto
117
TheEpilepsies
Investigations
management.Theyrecommendedthateachindividualwithepilepsyshouldbeassessedindividually
withrespecttofactorsuniquetotheirseizuredisorderandtreatment.
118
TheEpilepsies
Classificationofseizuresandepilepsysyndromes
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.124HisworkformedthebasisfortheCommissionontheClassification
andTerminologyoftheInternationalLeagueagainstEpilepsy(ILAE)standardisedclassificationsand
119
TheEpilepsies
terminologyforepilepticseizuresandtheepilepsiesandepilepticsyndromesdevelopedinthe1970s
and1980s.125,126(Table9.1,Table).
AlthoughtheILAE1981and1989classificationsremainincommonusetheyhavebeenthesubjectof
criticismanddebate.Theyhavebeencriticisedfor:
beingunsatisfactoryforepidemiologicalresearch3
placingundueemphasisonthetypesofcasereferredtotertiarycentres127
placingundueemphasisontheroleoftheEEGattheexpenseofnewertechniquessuchasMRI3
notclassifyingepilepticseizuresaccordingtowhataindividualoreyewitnessreportshappens
duringaseizure(ictalsemiology).128
InresponsetoconcernsabouttheexistingclassificationsystemstheILAEin1997undertooktomake
arevisionofclassificationapriorityandsetupaTaskForceofexpertsinthefieldtoaddressthis
issue.Thisgroupfirstreportedin2001.4TheTaskForcearguedthatitwasnotpossibletoreplace
thecurrentinternationalclassifications125,126withsimilarrevisedandupdatedclassificationsthat
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.
120
TheEpilepsies
Table9.1Classificationofepilepticseizuresaccordingtoclinicaltype(1981)
1.
2.
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
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
seizures126ReprintedbypermissionofthejournalEpilepsia
121
TheEpilepsies
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
125
classificationofepilepsiesandepilepticsyndromes ReprintedbypermissionofthejournalEpilepsia
Idiopathic:Nounderlyingcauseotherthanapossiblehereditarypredisposition.
Symptomatic:Theconsequenceofaknownorsuspecteddisorderofthecentralnervoussystem.
Cryptogenic:Adisorderwhosecauseishiddenoroccult.Cryptogenicepilepsiesarepresumedtobesymptomatic,buttheaetiologyisnot
known.
122
TheEpilepsies
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
4
classificationandterminology
ReprintedbypermissionofthejournalEpilepsia
Table94a:Classificationofseizures(2010)
Classificationofseizuresa
Generalizedseizures
Tonicclonic(inanycombination)
Absence
Typical
Atypical
Absencewithspecialfeatures
Myoclonicabsence
Eyelidmyoclonia
Myoclonic
Myoclonic
Myoclonicatonic
Myoclonictonic
Clonic
Tonic
Atonic
Focalseizures
Unknown
Epilepticspasms
Seizurethatcannotbeclearlydiagnosedintooneoftheprecedingcategoriesshouldbeconsidered
unclassifieduntilfurtherinformationallowstheiraccuratediagnosis.Thisisnotconsideredaclassification
category,however.
123
TheEpilepsies
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)
Descriptorsoffocalseizuresaccordingtodegreeofimpairmentduringseizurea
Accordingtoseverity
Withoutimpairmentofconsciousnessorawareness
Withobservablemotororautonomiccomponents
Involvingsubjectivesensoryorpsychicphenomenaonly.Withimpairmentofconsciousnessor
awareness.
Evolvingtoabilateral,convulsivebseizure(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
Electroclinicalsyndromesarrangedbyageatonseta
Neonatalperiod
Benignfamilialneonatalepilepsy(BFNE)
Earlymyoclonicencephalopathy(EME)
Ohtaharasyndrome
Infancy
Epilepsyofinfancywithmigratingfocalseizures
Westsyndrome
Myoclonicepilepsyininfancy(MEI)
Benigninfantileepilepsy
Benignfamilialinfantileepilepsy
Dravetsyndrome
Myoclonicencephalopathyinnonprogressivedisorders
124
TheEpilepsies
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
125
TheEpilepsies
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
126
TheEpilepsies
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
127
TheEpilepsies
Table97:Majorchangesinterminologyandconceptsforclassificationoftheepilepsiesand
seizures
Oldtermandconcept
Newtermandconcept
Aetiology
Idiopathic:presumedgenetic
Symptomatic:secondarytoaknownor
Genetic:geneticdefectdirectlycontributestothe
epilepsy,andseizuresarethecoresymptomofthe
disorder
presumeddisorderofthebrain
Structuralmetabolic:causedbyastructuralor
metabolicinsultordisorderofthebrain
Cryptogenic:presumedsymptomatic
Ofunknowncause:thecauseisunknownandmight
begenetic,structural,ormetabolic
Seizures
Generalised:firstchangesindicateinitial
Generalised:arisingwithinandrapidlyengaging
involvementofbothhemispheres
bilaterallydistributednetworks
Focal:firstchangesindicateactivationofa
Focal:originatingwithinnetworkslimitedtoone
systemofneuronslimitedtopartofonecerebral
hemisphere
hemisphere
Additionofepilepticspasms;groupedasunknown
Spasmswerenotacknowledged
owingtoinsufficientevidencetoclassifyasfocal,
generalised,orboth
Complex,simplepartial,secondarilygeneralised
Earliertermabandonedinfavourofprecise
descriptionoffocalseizuresaccordingtoictal
semiology
Epilepsies
128
TheEpilepsies
Generalised:epilepsieswithgeneralisedseizures
Earliertermabandoned
Focal:epilepsieswithfocalseizures
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).
DelgadoEscueta1984129
Inonestudy,43individuals,aged15to69years,werereferredforuncontrolledconvulsiveseizures.
AfterthediagnosisofJMEwasestablished,86%wereeitherseizurefreeorsatisfactorilycontrolled
onvalproatealone,orwithotherAEDs.
Grunewald1992130
InaLondonbasedcaseseries,15definitecasesofJMEwereidentifiedfrom180consecutive
referralstoanepilepsyclinic.Diagnosesonreferralwereusuallyvagueandnonsyndromic.Inmany
cases,thesyndromicfeatureswereaccuratelyrecordedinthenotes,butthereferringphysician
appearedtobeunawareofJMEandacorrectdiagnosisnotmade.FollowingthediagnosisofJME
andoptimisationofdrugtreatments,myoclonicjerksimprovedordisappearedin13ofthe15
individuals.Theauthorssuggestedthatasyndromicclassificationshouldberecordedforallpeople
withepilepsy,andthisshouldberegularlyreviewedparticularlyifseizuresarepoorlycontrolled.
Montalenti2001131
Montalentiandcolleaguesfoundthatonly31.3%ofindividuals(n=20/63)werecorrectlydiagnosed
onreferraltotheEpilepsyService.Theremainderwereeitherclassifiedashavingidiopathic
generalisedepilepsy(n=10),ordiagnosedashavingfocalepilepsy,orwerenotclassified(n=33).The
mostfrequentreasonformisdiagnosiswasanunderestimationormisinterpretationofmyoclonic
jerksbyboththeindividualorthereferringphysician,suggestingthatthecorrectdiagnosisis
dependentontheknowledgeofthephysician.
Thishasalsobeenidentifiedinotherstudies.130,132Anotherfactorassociatedwithmisdiagnosiswas
afailuretoseekahistoryofmyoclonicjerks,againassociatedwiththeknowledgeofthereferring
physicianofthesyndrome.133,134
129
TheEpilepsies
Pharmacologicaltreatmentofepilepsy
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
130
TheEpilepsies
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.135However,
participantsmayhavetriedseveralmonotherapyregimesbeforeinclusion,sothisRCTwasexcluded.
NootherRCTswereidentified.
Otherevidence
Kwan2000136
131
TheEpilepsies
Aprospectivestudyevaluatedtheeffectivenessofsubstitutiontherapyandaddontherapyafter
treatmentwithafirstAEDfailedinindividualwithnewlydiagnosedepilepsy.Individualswere
assessedasseizurefreeiftheyhadnoseizuresforoneyear.
248individuals,bothadultsandchildren,wereincludedinthestudycohort.Ofallindividualswith
inadequateseizurecontrolonthefirsttoleratedAED,42receivedaddontherapyand35received
substitution.Therewerenosignificantdifferencesinseizurefreedom(addon26%,substitution
17%)andincidenceofadverseeventsleadingtowithdrawal(addon12%,substitution26%)between
thetwogroups(p=0.25).
Deckers2003137
Atthe5thEuropeanCongressonEpileptology,thetopicofsubstitutionofalternativemonotherapy
ofaddontherapyinadultswasdiscussed.Aliteraturereviewpreparedforthediscussiongroupwas
prepared.137Ninepaperswerereviewed;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
132
TheEpilepsies
seizuretypeand/orepilepsysyndrome.(IIb)
Treatmentofafirstunprovokedseizurereducestheriskofrecurrenceintheshortterm.(Iachildren,
Ibadults)
Inchildren,treatmentofafirstunprovokedseizuredoesnotalterthelongtermprognosisforseizure
remission.(Ia)
10.2.1.1
Inadultsandchildrenwhopresentwithasingleseizurewhatarethefeatures(fromhistoryand
investigations)whichpredictriskoffurtherseizures?
Secondaryevidence
Berg1991100
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%).
Hirtz2003138
ThispracticeparameteroftheQualityStandardsSubcommitteeoftheAmericanAcademyof
NeurologyandthePracticeCommitteeoftheChildNeurologySocietysystematicallyreviewedthe
publishedliteraturerelevanttothedecisiontobegintreatmentafterachildoradolescent
experiencesafirstunprovokedseizureandpresentsevidencebasedpracticerecommendations(see
below).Theauthorsreviewedtheevidencebaseupto2001.
Howlikelyisasecondseizure?
Theprobabilityofhavingasecondseizurehadbeenexploredinseverallarge,cohortstudieswith
longtermfollowup.Thecumulativeriskofrecurrenceincreasedovertime;however,instudies
133
TheEpilepsies
wheretheinformationwasavailable,themajorityoftherecurrencesoccurredearly(withinthefirst
1to2years).Atanygiventime,thereportedriskofrecurrencewashighlyvariable.Forexample,at
1year,itrangedfromalowof14%toahighof65%.Inallthesecohortstudiestherewasvariability
inthemixofparticipantsandthedistributionsofimportantprognosticfactors.Treatmentwasalso
notrandomised.Somemethodologicaldifferencesinseizureidentification,agerangesincluded,
recruitment,andfollowupofstudyparticipantsmayhavecontributedtothisvariability.138
Aretherefactorsthatincreasetheriskofrecurrence?
TheauthorscitedthefindingsoftheBerg&Shinnarreview100thattheunderlyingaetiologyand
whethertheEEGisnormalorabnormalwereconsistentlyrelatedtotheriskofrecurrence.138
Primaryevidence
Hart1990139
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).
Macdonald200010
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
134
TheEpilepsies
10.2.1.2
Inadultsandchildrenwhopresentwithasingleseizure,doestreatmentwithantiepileptic
medicationreducetheriskoffurtherseizures?
Secondaryevidence
Berg1991100
Asystematicreviewoftheriskofseizurerecurrencefollowingafirstunprovokedseizurewas
undertakenbyBerg&Shinnarin1991.Theirliteraturereviewreviewedallrelevantstudiesupto
1990.TheauthorsidentifiedoneRCT140inwhichtreatmentofafirstseizurewasassociatedwitha
significantreductioninriskofrecurrence.
Hirtz2003138
ThispracticeparameteroftheQualityStandardsSubcommitteeoftheAmericanAcademyof
NeurologyandthePracticeCommitteeoftheChildNeurologySocietysystematicallyreviewedthe
publishedliteraturerelevanttothedecisiontobegintreatmentafterachildoradolescent
experiencesafirstunprovokedseizureandpresentsevidencebasedpracticerecommendations(see
below).Theauthorsreviewedtheevidencebaseupto2001.
Howeffectiveistreatmentafterafirstseizureinpreventionofrecurrences?
Therewerefourrandomisedclinicaltrialsincludingchildrenandadolescentsthatexaminedthe
efficacyoftreatmentafterafirstseizure.Onlyoneofthesestudiesconsistedsolelyofchildren
randomisedtotreatmentversusnotreatmentafterafirstnonfebrileseizure.140Inthisstudywitha
totalof31children,2of14children(14%)treatedwithcarbamazepine(CBZ)experienceda
recurrencecomparedwith9of17(53%)whowerenottreated.Followupwasfor1year,and
compliancewasmonitored.Althoughtherecurrencerateupto1yearwassignificantlylowerinthe
treatedgroup,only6of14(43%)childrenrandomisedtoCBZcompletedtheyearwithnosignificant
sideeffectsorseizurerecurrenceand7of17(41%)assignedtonomedicationhadnoseizure
recurrence.140
Instudiesinvolvingbothchildrenandadults,outcomewasnotprovidedbasedonage.Onestudy141
inwhich228subjectswererandomisedtovalproicacid(VPA)orplaceboincluded33adolescents
betweentheagesof16and19.Thefollowupperiodforthistrialwasbetween9monthsand5
years.Five(4%)ofthetreatedgroupexperiencedarecurrencecomparedwith63(56%)ofthose
treatedwithplacebo.141
However,theseresultswerenotfoundinanotherrandomisedstudy142(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
studies142,143.
Onestudy142had419subjects,ofwhom114werebetween2and16yearsofage.Thisstudy
comparedtheprobabilityofexperiencingaremission,thatis,1or2seizurefreeyears,inthose
135
TheEpilepsies
treatedafterafirstseizureversusinpeopletreatedafterasecondseizure.Followupwasforat
least3yearsoraminimumof2yearsseizurefree.Individualstreatedafterthefirstseizureand
thosetreatedafterasecondseizurehadthesameprobabilityofachievinga1or2yearseizure
remission(68%,n=215versus60%,n=204)(relativerisk1.04,95%CI0.82to1.30).
Anothersmallerstudy143of31childrenrandomisedtoCBZ(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]
136
TheEpilepsies
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.
137
TheEpilepsies
Details
Inadults/childrenwithepilepsy,doesroutinemonitoringof
AEDbloodlevels
sideeffects
drugusage
leadtobetteroutcomes(e.g.seizurerecurrence,sideeffects)whencomparedwiththosewho
receivenomonitoringormonitoringonlywhenclinicallyindicated?
10.2.4.1
Inadultsandchildrenwithepilepsy,doesroutinemonitoringofAEDbloodlevelsleadtobetter
outcomeswhencomparedwiththosewhoreceivenomonitoringormonitoringonlywhen
clinicallyindicated?
Secondaryevidence
AHRQ200150
Thissystematicreviewonthemanagementofpeoplewithnewlydiagnosedepilepsyreviewed24
prospectiveinterventionalstudiesthathadamonitoringcomponent.Noneofthesestudieshadasa
primaryobjectivethetestingofmonitoringinterventionsnecessaryforoptimalcarebutinnearlyall,
thiswasamonitoringinterventiondictatedbyaresearchstudyprotocolandnotoptimalcare.
Therefore,thereviewwasexcluded.
SwedishCouncilonTechnologyAssessmentinHealthcare1998144
Thisassessmentoftherapeuticdrugmonitoringinthetreatmentofepilepsyidentifiedone
prospectiverandomisedstudy.127peoplewithepilepsywererandomisedeithertotreatmentwith
orwithoutthesupportoftherapeuticdrugmonitoring.Samplesweretakenfrombothgroups,but
resultsforthoseinthetreatmentgrouponlywerepresentedtotheattendingphysician.105
individualswerefollowedupafter12months.Nodifferenceswerefoundinseizurecontrol.
However,alargepercentageofallparticipants(equallylargeinbothgroups)showeddruglevels
outsideofthetargetarea.
Onthebasisofthestudyaboveandoneotherretrospectivestudy,thetechnologyassessmentreport
concludedthattherewaspoorevidencetodemonstratethebenefitsoftherapeuticdrug
monitoring.144
Primaryevidence
Jannuzzi2000145
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
138
TheEpilepsies
differencesbetweenthemonitoredgroupandthecontrolgroupwithrespecttoindividualsachieving
12monthremission(60%vs.61%),individualsremainingseizurefreesinceinitiationoftreatment
(38%vs.41%),andtimetofirstseizureor12monthremission.Frequencyofadverseeffectswas
almostidenticalinthetwogroups.WiththeAEDsmostcommonlyusedinthisstudy,early
implementationofserumAEDlevelmonitoringdidnotimproveoveralltherapeuticoutcome,and
themajorityofpeoplecouldbesatisfactorilytreatedbyadjustingdoseonclinicalgrounds.
Froscher1981146
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
Deckers1997147
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:
139
TheEpilepsies
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
140
TheEpilepsies
Concordancereferstoaconsultationprocessbetweenahealthcareprofessionalandanindividual.
Complianceoradherencereferstoaspecificbehaviour:wasthemedicinetakeninaccordancewith
thewishesofthehealthcareprofessional?149Complianceisaproblematicterm.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:Factorsaffectingadherencetomedicationregimensinpeoplewithepilepsy151
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.
141
TheEpilepsies
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
142
TheEpilepsies
Berg1994152
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).
QualityStandardsSubcommitteeoftheAmericanAcademyofNeurology1996153
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
Sirven2003154
ThisCochraneReviewsoughtto:
143
TheEpilepsies
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)
MRCAEDwithdrawalstudygroup1991155
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.
144
TheEpilepsies
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:Influenceofindividualcharacteristicsonseizurerecurrence155
Factor
Relativerisk(95%CI)
(multivariatemodel)
Historyoffocalseizures,nonegeneralized
2.51(1.00,6.30)
Historyofmyoclonicseizures
1.85(1.09,3.12)
Historyoftonicclonicseizures
(primaryorsecondary)
Seizuresafterstartoftreatment
3.40(1.48,7.84)
OnmorethanoneAEDatrandomisation
1.79(1.34,2.39)
Periodseizurefreeatrandomisation(years)
1.57(1.10,2.24)
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.
MRCAEDwithdrawalstudygroup1993156
Theaimofthisstudywastodevelopandtestaprognosticindexfortherecurrenceofseizuresaftera
minimumremissionofseizuresoftwoyearsinpeoplewithahistoryofepilepsy.Thisstudyused
datafromtheRCTreportedabove155toidentifyclinicalandtreatmentfactorsofprognostic
importanceindeterminingtherecurrenceofseizures.Asplitsampleapproachwasusedtotestthe
internalvalidityofpredictionsmadeonthebasisofidentifiedprognosticfactors.
TheCoxproportionalhazardsmodelidentifiedseveralfactorsthatincreasedtheriskofseizures
recurring.Theseincludedbeing16yearsorolder;takingmorethanoneantiepilepticdrug;
experiencingseizuresafterstartingantiepilepticdrugtreatment;ahistoryofprimaryorsecondarily
generalisedtonicclonicseizures;ahistoryofmyoclonicseizures;andhavinganabnormal
electroencephalogram.Therisksofseizuresrecurringdecreasedwithincreasingtimewithout
seizures.Themodelallowedestimationoftheriskofseizuresrecurringinthenextoneandtwo
145
TheEpilepsies
yearsunderthepoliciesofcontinuedAEDtreatmentandslowwithdrawalofdrugs.Splitsample
validationsuggestedthatthemodelwaswellcalibrated.156
Validationwasperformedonasampleofthetrialparticipants.Animportantissuehereisthat
studiesneedtobeconductedtovalidatethesefindingsinabroaderpopulation.
Table10.30presentstheauthorsprognosticindexmodel.ThiswasusedintheSIGNadultguideline
toproduceatableofriskofseizurerecurrencethatcouldeasilybeusedbyclinicians.157
Table1030:Prognosticindexforrecurrenceofseizureswithinoneandtwoyearsaftercontinuing
AEDtreatmentorstartingslowwithdrawal
AdaptedfromMRCAEDDrugWithdrawalGroup1993156andreprintedwithpermissionfromthe
BMJPublishingGroup(BMJ,1993,306,13748)
Startingscore(allindividuals)
Age16orolder
TakingmorethanoneAED
SeizuresafterstartofAEDtreatment
Historyofprimaryorsecondarilygeneralizedtonicclonicseizures
Historyofmyoclonicseizures
EEGinlastyear
notavailable
Abnormal
Periodfreefromseizures(t:no.ofyears)
TOTALSCORE
Dividetotalscoreby100andexponentiate
Probabilityofrecurrenceofseizures:
Continuedtreatment
byoneyear
bytwoyears
Slowwithdrawal
byoneyear
bytwoyears
10.2.6.2
175
Add45
Add50
Add35
Add35
Add50
Add15
Add20
Add200/t
T
z=eT/100
10.89z
10.79z
10.69z
10.60z
InadultsandchildrenwithepilepsyonAEDs,dodifferentratesofwithdrawalleadtodifferingrisks
ofseizurerecurrenceand/orothersideeffectsofstoppingtreatment?
Secondaryevidence
Primaryevidence
Tennisonetal1994158
TheaimofthisunblindedRCTwastocompareasixweek(relativelyshort)periodandaninemonth
(relativelylong)periodofdrugtaperinginagroupofchildrenwithepilepsywhohadhadnoseizures
foreithertwoorfouryears.
Allchildrenreceivingcareatthepaediatricepilepsyclinicsatthetwostudyinstitutionswhohadhad
noseizuresforapproximately18monthswereeligibleforthestudy.Childrenwhohadhadasingle
seizureoronlyfebrileseizureswereexcluded,aswerethosewithneonatalseizuresorinfantile
spasms.
Theauthorsrandomlyassigned149childrentoeitherasixweekoraninemonthperiodofdrug
tapering,afterwhichtherapywasdiscontinued.Eachgroupwascomposedofchildrenwhohad
beenseizurefreeforeithertwoorfouryearsbeforedrugtaperingwasbegun.Mostchildrenwere
146
TheEpilepsies
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.
147
TheEpilepsies
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
148
TheEpilepsies
Recommendation
outcomes
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]
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.
149
TheEpilepsies
TheGDGmemberswereallawareofexamplesofpeoplechanging
brandswithsubsequentrelapseintheirseizures.Theyalso
recognisedthatstressassociatedwithchange(notjustin
medication)canmakepeoplevulnerabletoseizures.
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
150
TheEpilepsies
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
151
TheEpilepsies
positioninafootnotetothisrecommendation.
TheGDGnotedthatchangesinmetabolicfunctionsinolderpeople
arealsoperhapsmoresensitivetosideeffectswhichmayhaveless
noticeableimpactinyoungerpeople,especiallythosewhichaffect
balancewithconsequentproblems.Breakthroughseizuresmay
alsobelessobvioustoanobserverinthisgroup.
TheGDGfeltthatorganisationalstructuresrelatedtomedicines
management,suchasmedicinesmanagementcommittees,should
alsocarefullyconsidertheseissueswhenmakinglocaldecisions.
152
TheEpilepsies
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.
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
153
TheEpilepsies
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.
NoeconomicevidencewasavailabletoinformtheGDGoncost
effectivenessofAEDsusedtotreatpregnantwomenwithepilepsy.
Noeconomicevaluationhaseverincorporatedteratogenicityof
anydrug,includingsodiumvalproate,intoitsclinicaloutcomes.
TheGDGconsideredthatbothreducedseizurecontroland
potentialharms(malformationsandneurodevelopmentaldelay)
havecostandqualityoflifeimplicationsformotherandunborn
child.Drugsanddosesthatmaybecosteffectiveinthegeneral
epilepsypopulation,suchassodiumvalproate,maynotbeascost
effectiveinthisgroupduetoitspotentialteratogeniceffect.
Qualityofevidence
Evidencecomesfromthreesystematicreviews;onereview
focusedonincidenceofmalformationandtheothertwoonchild
neurodevelopmentaloutcomes.NoindividualRCTswerereviewed.
Oneobservationalcohortstudy159thatwaspublishedafterthe
guidelineupdatesearchcutoffwasalsoidentified.Thisstudydid
notmeettheinclusioncriteriafortheevidencereview,butwas
consideredbytheGDGascorroborativeevidencetoinformthis
recommendationparticularlythedosedependentriskwithsodium
valproate.
ThisrecommendationwasalsobasedonGDGconsensusopinion.
Otherconsiderations
Thisrecommendationwasupdatedfromthefirsteditionofthis
guideline(2004).
154
TheEpilepsies
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.
Therewasnoeconomicevidencespecificallyaddressingtheimpact
ofadverseeventsonthecosteffectivenessofdrugsusedinthe
treatmentofindividualswithepilepsy.However,seriousadverse
events(shortandlongterm)canaffectanindividualsqualityof
lifeandleadtoincreasedcoststotheNHS.Heightenedawareness
ofthesepotentialadverseeventsshouldensurethatapatients
treatmentisalteredoradjustedtoreducedecrementstoutility
andminimisethecostofextrahealthcarevisitswhilstmaintaining
seizurecontrol.
Qualityofevidence
Otherconsiderations
*******
TreatmentwithAEDsisassociatedwithasmallriskofsuicidalthoughtsandbehaviour;availabledatasuggestthat
theincreasedriskappliestoallAEDsandmaybeseenasearlyas1weekafterstartingtreatment.Availablefrom
www.mhra.gov.uk/PrintPreview/DefaultSplashPP/CON019574?DynamicListQuery=&DynamicListSortBy=xCreationDate
&DynamicListSortOrder=Desc&DynamicListTitle=&PageNumber=1&Title=Antiepileptics%20&ResultCount=10
155
TheEpilepsies
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.
Onehighqualityindividualpatientdatanetworkmetaanalysis38wasidentifiedduringstakeholder
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.
156
TheEpilepsies
Placebo
Carbamazepine
CarbamazepineCR
Clonazepam
1160;
Gabapentin
2161,162,1
IPD
NMA38
Lamotrigine
1161,1IPD
NMA38
161,163,164,
165,166,166,
1IPD
NMA38;
Levetiracetam
1167
Oxcarbazepine
1161,1
IPDNMA
38
1161,1IPD
NMA38
1161,1IPD
NMA38
Phenytoin
4168,169,170,
171,
1IPD
NMA38
1IPDNMA
38
1172,1IPD
NMA38
1173,1
IPDNMA
38
Sodiumvalproate
2171,174,1
IPDNMA
1IPDNMA
38
1175,1
3
IPDNMA 171,176,177,
38
1IPD
NMA38
38
Topiramate
1161,1
IPDNMA
38
1161,1IPD
NMA38
1161,1IPD
NMA38
1161,1
1IPD
IPDNMA NMA38
38
1IPD
NMA
38
Vigabatrin
178,179,180,
TheEpilepsies
1IPD
NMA38
Tiagabine
Phenobarbital
1170,1
IPDNMA
38
1IPDNMA
38
1IPD
NMA38
1170,1
IPDNMA
38
1IPD
NMA
38
1IPD
NMA
38
Primidone
1170
1170
1170
Pla
CBZ
CBZCR
CLZ
GBP
LTG
LEV
OXC
PHT
VPA
TPM
VGB
TGB
PHB
PMD
TheEpilepsies
PLAPlaceboCBZCarbamazepineCBZCRControlledreleaseCarbamazepineCLZClonazepam
GBPGabapentinLTGLamotrigineLEVLevetiracetamOXCOxcarbazepine
PHTPhenytoinVPASodiumvalproateTPMTopiramateVGBVigabatrin
IPDNMA:individualpatientnetworkmetaanalysis
10.3.4
10.3.4.1
Monotherapyforadultswithnewlydiagnosedfocalseizures
Carbamazepineversuslamotrigine
Clinicalevidence
FordetailsontheclinicalevidencepleaserefertoAppendixN.
IPDmetaanalysis
CarbamazepineandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
analysisofAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.Theresultsof
thisanalysisarepresentedinsection10.3.5.
Healtheconomicevidence
Twoeconomicevaluations161,181ofAEDs,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)
159
TheEpilepsies
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
160
TheEpilepsies
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)
161
TheEpilepsies
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
162
TheEpilepsies
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.
163
TheEpilepsies
10.3.4.4
Carbamazepineversusgabapentin
Clinicalevidence
IPDmetaanalysis
CarbamazepineandgabapentinwereamongAEDsincludedinanindividualpatientdatameta
Oneeconomicevaluation161ofAEDs,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)
164
TheEpilepsies
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
165
TheEpilepsies
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
166
TheEpilepsies
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)
167
TheEpilepsies
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyforthe
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyfortime
tofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandphenytoinmonotherapyfortime
to12monthremission.(IPDmetaanalysis)
Adverseeffectsstatisticallysignificantresults
Significantlyfewerparticipantsinoxcarbazepinemonotherapywithdrewduetoadverseevents
comparedtoparticipantsinphenytoinmonotherapy.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepineandphenytoinwasidentified.
cognitiveoutcomes
10.3.4.8
Oxcarbazepineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Oneeconomicevaluation181ofAEDs,includingoxcarbazepineandsodiumvalproate,usedas
diagnosedfocalseizures.ThecompleteresultsofthisstudyandtheNCGCadultmonotherapymodel
Evidencestatements
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandsodiumvalproatemonotherapy
fortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
fortimetotreatmentfailure.(IPDmetaanalysis)
168
TheEpilepsies
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
169
TheEpilepsies
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.
170
TheEpilepsies
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.
171
TheEpilepsies
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
172
TheEpilepsies
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
173
TheEpilepsies
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
174
TheEpilepsies
Oneeconomicevaluation181ofAEDs,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
175
TheEpilepsies
IPDmetaanalysis
PhenytoinandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Nostudieswereidentifiedintheeconomicliteraturesearch.Sodiumvalproatewasincludedinthe
therapeuticwindow.
Evidencestatements
Nosignificantdifferencebetweensodiumvalproatemonotherapyandphenytoinmonotherapyfor
theproportionofseizurefreeparticipants.(VERYLOWQUALITY)
thetimetotreatmentfailure.(IPDmetaanalysis)
theproportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproateandphenytoinwasidentified.
cognitiveoutcomes
10.3.4.17
Carbamazepineversustopiramate
Clinicalevidence
176
TheEpilepsies
IPDmetaanalysis
CarbamazepineandtopiramatewereamongAEDsincludedinanindividualpatientdatameta
Twoeconomicevaluations161,181ofAEDs,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)
177
TheEpilepsies
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
178
TheEpilepsies
Oneeconomicevaluation181ofAEDs,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
179
TheEpilepsies
Twoeconomicevaluations161,181ofAEDs,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
180
TheEpilepsies
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
Oneeconomicevaluation161ofAEDs,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)
181
TheEpilepsies
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.
182
TheEpilepsies
Oneeconomicevaluationconductedalongsidearandomisedcontrolledtrialshowedlamotrigine
dominatedgabapentin;thatis,treatmentwithlamotriginewasassociatedwithlowercostsand
betterhealthoutcomes(higherQALYsandfewerseizures)thantreatmentwithgabapentin
(partiallyapplicableandpotentiallyseriouslimitations).
Acosteffectivenessanalysisdevelopedfortheguidelinealsoshowedthatlamotriginedominated
gabapentin.Thisconclusionwasconsistentacrossvarioussensitivityanalyses(directlyapplicable
andminorlimitations).
10.3.4.21
Gabapentinversustopiramate
Clinicalevidence
IPDmetaanalysis
GabapentinandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysisof
Oneeconomicevaluation161ofAEDs,includinggabapentinandtopiramate,usedasmonotherapyin
thetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedintheeconomicliterature
developedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocalseizures.The
completeresultsofthisstudyandtheNCGCadultmonotherapymodelarepresentedinsection
10.3.6.
Evidencestatements
rapidlyinparticipantstakingtopiramatemonotherapycomparedtoparticipantstakinggabapentin
Topiramatemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyinprolonging
thetimetofirstseizure.(MODERATEQUALITY).
Topiramatemonotherapyissignificantlymoreeffectivethangabapentinmonotherapyinprolonging
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyforthe
timeto12monthremission.(VERYLOWQUALITY)
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyfortimeto
Nosignificantdifferencebetweengabapentinmonotherapyandtopiramatemonotherapyfortimeto
treatmentfailure.(IPDmetaanalysis)
183
TheEpilepsies
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
184
TheEpilepsies
IPDmetaanalysis
TopiramateandlamotriginewereamongAEDsincludedinanindividualpatientdatametaanalysisof
Twoeconomicevaluations161,181ofAEDs,includinglamotrigineandtopiramate,usedas
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingtopiramate
Topiramatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyinprolonging
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyforthe
timetoexit/withdrawalofallocatedtreatmentduetolackofefficacy.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyfortime
tofirstseizure.(VERYLOWQUALITY)
to12monthremission.(VERYLOWQUALITY)
rapidlyonparticipantstakingtopiramatemonotherapycomparedtoparticipantstakinglamotrigine
Nosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapyforthe
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandtopiramatemonotherapy
in:
185
TheEpilepsies
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
Oneeconomicevaluation161ofAEDs,includingoxcarbazepineandgabapentin,usedasmonotherapy
inthetreatmentofadultswithnewlydiagnosedfocalseizureswasidentifiedintheeconomic
literaturesearch.Astherewerestillgapsintheeconomicevidencebase,anoriginaleconomic
modelwasdevelopedtocompareAEDsusedasmonotherapyinadultswithnewlydiagnosedfocal
seizures.ThecompleteresultsofthisstudyandtheNCGCadultmonotherapymodelarepresented
insection10.3.6.
Evidencestatements
rapidlyinparticipantstakingoxcarbazepinemonotherapycomparedtoparticipantstaking
gabapentinmonotherapy.(MODERATEQUALITY)
186
TheEpilepsies
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
187
TheEpilepsies
10.3.4.24
Lamotrigineversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
Twoeconomicevaluations161,181ofAEDs,includinglamotrigineandoxcarbazepine,usedas
Evidencestatements
Oxcarbazepinemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingthetimetofirstseizure.(IPDmetaanalysis)
Nosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepinemonotherapyforthe
Nosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepinemonotherapyfor
Thereisnosignificantdifferencebetweenlamotriginemonotherapyandoxcarbazepine
monotherapyin:
188
TheEpilepsies
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
Twoeconomicevaluations161,181ofAEDs,includingtopiramateandoxcarbazepine,usedas
Evidencestatements
189
TheEpilepsies
Nosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepinemonotherapyforthe
Nosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepinemonotherapyfor
Thereisnosignificantdifferencebetweentopiramatemonotherapyandoxcarbazepine
monotherapyin:
topiramatemonotherapyandoxcarbazepinemonotherapy.
Costeffectiveness
Availableeconomicevidenceindicatesthattopiramateisnotcosteffectivecomparedto
oxcarbazepine.
Resultsofatrialbasedeconomicevaluationfoundoxcarbazepinedominatedtopiramate;thatis,
(higherQALYsandfewerseizures)thantreatmentwithtopiramate(partiallyapplicableand
OnepublishedcosteffectivenessanalysisundertakenbyHawkinsandcolleaguesshowed
topiramatewastobemorecostlyandmoreeffectivethanoxcarbazepine,butwithan
unacceptablyhighincrementalcosteffectivenessratioof102,933perQALYgained.However,
thisanalysiswasbasedonanowoutofdatesystematicreviewand200203costs(partially
190
TheEpilepsies
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
191
TheEpilepsies
10.3.4.27
Lamotrigineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
SodiumvalproateandlamotriginewereamongAEDsincludedinanindividualpatientdatameta
Oneeconomicevaluation181ofAEDs,includinglamotrigineandsodiumvalproate,usedas
Evidencestatements
Lamotriginemonotherapyissignificantlymoreeffectivethansodiumvalproatemonotherapyin
Nosignificantdifferencebetweenlamotriginemonotherapyandsodiumvalproatemonotherapyfor
Costeffectiveness
Availableeconomicevidenceindicatedthatlamotriginewascosteffectivewhencomparedtosodium
valproate
Acosteffectivenessanalysisundertakenfortheguidelinefoundthatlamotriginedominated
sodiumvalproate;thatis,treatmentwithlamotriginewasassociatedwithlowercostsandbetter
healthoutcomes(higherQALYs)thantreatmentwithsodiumvalproate.Thisconclusionwas
consistentacrossvarioussensitivityanalyses.
ApublishedcosteffectivenessanalysisbyHawkinsandcolleaguesfoundthatsodiumvalproate
dominatedlamotrigine,buttheiranalysiswasbasedonanowoutofdatesystematicreviewand
200203costs.
seizurefreedom
cognitiveoutcomes
192
TheEpilepsies
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
193
TheEpilepsies
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
194
TheEpilepsies
Oneeconomicevaluation181ofAEDs,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
195
TheEpilepsies
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)
196
TheEpilepsies
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.
197
TheEpilepsies
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
198
TheEpilepsies
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)
199
TheEpilepsies
Carbamazepinewasfoundtobesignificantlybetterthansodiumvalproateandgabapentinfortime
to12monthremission.
Timetofirstseizure
Intervention
Comparator
Hazardratio
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
Twostudies161,181assessingthecosteffectivenessofAEDsusedasmonotherapywereincludedin
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)
Partiallyapplicable(c)
Economicevaluationalongside
Marson(2007)after Potentiallyserious
200
TheEpilepsies
Study
June2001161
Limitations
limitations(a,b)
Applicability
OtherComments
randomisedcontrolledtrial;cost
perQALYanalysis;comparators
includedcarbamazepine,
lamotrigine,gabapentin,
topiramateandoxcarbazepine;
2yeartimehorizon;includes
datacollectedafterJune2001
whenoxcarbazepinewas
introduced
Marson(2007)after Potentiallyserious
June2001161
limitations(a,b)
Partiallyapplicable(d)
Economicevaluationalongside
randomisedcontrolledtrial;cost
perseizureavoidedanalysis;
comparatorsincluded
carbamazepine,lamotrigine,
gabapentin,topiramateand
oxcarbazepine;2yeartime
horizon;includesdatacollected
afterJune2001when
oxcarbazepinewasintroduced
Hawkins(2005)181
Partiallyapplicable(f)
comparatorsincluded
carbamazepine,oxcarbazepine,
sodiumvalproate,lamotrigine
andtopiramate;timehorizon15
years;clinicaldatabasedon
networkmetaanalysisthat
includedseveralstudieswith
mixedfocalandgeneralised
epilepsypopulations
Potentiallyserious
limitations(a,c,e)
(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:
AED
LTG
MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofNCGCmodel
Totalcost
()per
patient
8,841
Totaleffects ICER
(/QALY)
(QALYs)
8.8795
201
Uncertainty
At20KperQALYthreshold,probabilitymost
costeffective
Basecase:82%
Allcheapest:61%
CostofmodifiedreleaseCBZ:52%
CostsofgenericLTGandTegretol:51%
TheEpilepsies
AED
Totalcost
()per
patient
Totaleffects ICER
(QALYs)
(/QALY)
Uncertainty
ImprovedtolerabilityofLEV:82%
LEVcost50%and70%reduced:80%and74%
At30KperQALYthreshold:74%
VPA
9,291
8.8391
Dominated
costeffective
Basecase:5%
Allcheapest:1%
LTGandCBZunsuitable:76%
IfLTGandCBZunsuitableandLEVcost50%and
70%reduced:59%and38%
CBZ
9,596
8.8797
3,778,200
(extdom)
costeffective
Basecase:10%
Allcheapest:37%
GBP
9,973
8.7958
Dominated
costeffective
Basecase:0%
Allcheapest:0%
70%reduced:1%and1%
OXC
11,327
8.8933
180,137
costeffective
Basecase:2%
Allcheapest:1%
202
TheEpilepsies
AED
Totalcost
()per
patient
Totaleffects ICER
(QALYs)
(/QALY)
Uncertainty
TPM
11,354
8.8288
Dominated
costeffective
Basecase:0%
Allcheapest:0%
70%reduced:0%and0%
LEV
12,187
8.8622
Dominated
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%.
203
TheEpilepsies
Marson2007161(partiallyapplicable,potentiallyseriouslimitations)
SeeeconomicevidencetableinappendixMforstudydetai
Table3:
MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofMarson
2007161
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
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
204
TheEpilepsies
currentcostsoflamotriginewereused,itwouldbecosteffectivecomparedtoalternativeAEDs
evaluatedasmonotherapy.
Marson2007161(partiallyapplicable,potentiallyseriouslimitations)
SeeeconomicevidencetableinappendixMforstudydetails.
Table4:
MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofMarson
2007161
AED
Totalcost()
perpatient
Totaleffects
(seizures)
ICER
(/
seizure
avoided)
(a)
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%
TPM
2,059
59.4
Dominate
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%
Uncertainty
(a) Nowillingnesstopaythresholdforseizuresavoidedexists.
(b) AcquisitioncostsofLTGandTPMhavedecreasedsignificantlysincethisevaluationwasundertaken.
(c) Inanalysisofentiretrialperiodandthusexcludingoxcarbazepinefromanalysis,LTGmaybecosteffectivecomparedtoCBZ(80per
seizureavoided)
Evidencestatements
OxcarbazepinewouldappeartobethemostcosteffectiveAEDevaluatedasmonotherapy,less
costlyandmoreeffectiveintermsoftotalseizuresexperiencedthangabapentin,lamotrigineand
topiramate.Oxcarbazepineismorecostlyandmoreeffectiveintermsoftotalseizuresexperienced
thancarbamazepine,witheachadditionalseizureavoidedcosting35(partiallyapplicableand
potentiallyseriouslimitations).Withoutanexplicitwillingnesstopayperseizureavoidedthreshold,
itisindeterminableastowhetheroxcarbazepinewouldbeconsideredcosteffectivecomparedto
carbamazepine.
205
TheEpilepsies
Patientstakinggabapentin,lamotrigineandtopiramateexperiencedmoretotalseizuresandincurred
highercoststhanpatientstakingcarbamazepineoroxcarbazepine,indicatingthattheseAEDsmay
notbecosteffective(partiallyapplicableandpotentiallyseriouslimitations).
Hawkins2005181(partiallyapplicable,potentiallyseriouslimitations)
Table5:
MonotherapyforadultswithnewlydiagnosedfocalepilepsyResultsofHawkins
2005181
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY) Uncertainty
CBZ
4,428
9.392
mostcosteffective
Basecase:42%
VPA
4,572
9.404
11,731
mostcosteffective
Basecase:46%
LTG
6,133(a)
9.382
Dominate
d
mostcosteffective
Basecase:0%
OXC
6,294
9.415
Extended
Dominanc
e
mostcosteffective
Basecase:12%
TPM
7,838
9.430
126,519
mostcosteffective
Basecase:0%
(a) AcquisitioncostsofLTGandTPMhavedecreasedsignificantlysincethisevaluationwasundertaken
Evidencestatements
SodiumvalproateisthemostcosteffectiveAEDevaluatedasmonotherapygivenathreshold
willingnesstopayof20,000perQALY(partiallyapplicableandpotentiallyseriouslimitations).
LamotriginewastheleasteffectiveamongAEDsevaluatedasmonotherapyandwasmorecostly
thancarbamazepineandsodiumvalproate(partiallyapplicableandpotentiallyseriouslimitations).
OxcarbazepineandtopiramatearenotcosteffectivecomparedtoalternativeAEDsevaluatedas
10.3.7
10.3.7.1
Monotherapyforchildrenwithnewlydiagnosedfocalepilepsy
Matrixoftheevidenceforchildren
Placebo
Carbamazepine
Phenobarbital
Lamotrigine
1164
Phenytoin
206
TheEpilepsies
Valproate
Oxcarbazepine
1182
Vigabatrin
1183
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.
Oneeconomicevaluation184ofAEDs,includingcarbamazepineandlamotrigine,usedas
monotherapyinthetreatmentofchildrenwithnewlydiagnosedfocalepilepsywasidentifiedinthe
economicmodelwasdevelopedtocompareAEDsusedasmonotherapyinnewlydiagnosedchildren.
ThiswasbasedonclinicalevidencefromNietoBarerra2001164andGuerreiro1997182.Thecomplete
resultsofthisstudyandtheNCGCchildrenmonotherapymodelarepresentedinsection10.3.8.
Evidencestatements
theproportionofseizurefreechildren.(VERYLOWQUALITY)
Significantlymorechildrentakinglamotriginemonotherapyhadaninfectioncomparedtochildren
takingcarbamazepinemonotherapy,althoughthereisuncertaintyoverthemagnitudeofitsclinical
effect.(VERYLOWQUALITY).
Significantlymorechildrentakingcarbamazepinemonotherapyexperienceddizzinesscomparedto
childrentakinglamotriginemonotherapy.(LOWQUALITY).
theproportionofchildrenwithdrawnduetoadverseevents.(VERYLOWQUALITY)
theincidenceofthefollowingadverseevents:
pharyngitis(VERYLOWQUALITY)
Costeffectiveness
207
TheEpilepsies
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedfirstlinetreatmentwith
lamotriginemightbecosteffectivecomparedtofirstlinetreatmentwithcarbamazepine,butthere
wasconsiderableuncertaintyinthisresult(partiallyapplicableandpotentiallyseriouslimitations).
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedlamotriginemonotherapytobe
morecostlyandlesseffectivethancarbamazepinemonotherapy(directlyapplicableandpotentially
seriouslimitations).
timetofirstseizure
cognitiveoutcomes
10.3.7.3
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.
Evidencestatements
Significantlyfewerparticipantsonoxcarbazepinemonotherapywithdrewduetoadverseevents
comparedtophenytoinmonotherapy.(LOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepineandphenytoininchildrenwithnewlydiagnosed
focalepilepsywasidentified.
timetofirstseizure
cognitiveoutcomes
208
TheEpilepsies
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
Onestudy184assessingthecosteffectivenessofAEDsusedasmonotherapywasincludedinthe
economicevidencereview.SeeeconomicevidencetablesinappendixMforstudydetails,including
qualityassessmentofthemethodologyandapplicability.Astherewerestillgapsintheevidence
base,anoriginaleconomicmodelwasdevelopedtocompareAEDsusedasfirstlinemonotherapyin
209
TheEpilepsies
childrenwithnewlydiagnosedfocalepilepsy.ThiswasbasedonclinicalevidencefromNietoBarrera
2001164andGuerreiro1997182.SeeappendixRforfulldetailsandresultsofmodelling.
Table6:
MonotherapyforchildrenwithnewlydiagnosedfocalepilepsyEconomicstudy
characteristics
Study
Limitations
Applicability
OtherComments
NCGCModel
children
monotherapy(see
AppendixRfor
details)
Minorlimitations
Directlyapplicable
comparatorsincluded
carbamazepine,
lamotrigineand
oxcarbazepine;time
horizon15yearsstarting
age2years;clinicaldata
basedonclinicalreview
Frew2007184
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 ICER
(QALYs)
(/QALY)
CBZ
15,170
10.343
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
210
Uncertainty
TheEpilepsies
CarbamazepineisthemosteffectiveandleastcostlyamongtheAEDsevaluatedasmonotherapyin
childrenwithnewlydiagnosedfocalepilepsy(directlyapplicableandminorlimitations).
Lamotrigineandoxcarbazepinearemorecostlyandlesseffectivethancarbamazepine(directly
Frew(2007)184(partiallyapplicable,potentiallyseriouslimitations)
Table8:
MonotherapyforchildrenwithnewlydiagnosedfocalepilepsyResultsofFrew2007184
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.
10.3.9
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
211
TheEpilepsies
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.
TheGDGconsideredallrelevantsourcesofeconomicevidenceand
variousbasecaseandsensitivityanalysesfromtheoriginalNCGC
decisionmodelwhendevelopingtheirrecommendationsforfirst
linetreatmentofindividualswithnewlydiagnosedfocalseizures.
TheresultsoftheNCGCanalysisshowedthathealthbenefitsin
termsofQALYsgainedaresimilaracrossthevariousAEDsandit
showedthattherearesomedifferencesincost,particularly
betweendrugsthatarebeingproducedandprescribedgenerically
andthosethatarenot.Becauseofitslowacquisitioncostand
goodtolerability,theanalysisfoundthatlamotrigineislikelytobe
themostcosteffectiveAED.ResultsfromtheSANADtrialalso
foundlamotriginelikelytobeacosteffectivefirstlineAED,and
givenreductionsinitsunitcost,itmaybeevenmorecosteffective
nowthanwhenthetrialwasundertaken.Basedontheseresults,
theGDGfeltthatlamotriginewaslikelytorepresentgoodvaluefor
NHSresourcesandshouldbeofferedtopatientswithnewly
212
TheEpilepsies
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
213
TheEpilepsies
epilepsy.TheNCGCmodelisnotwithoutlimitations,butitwas
basedonalltheavailableevidence(includingSANAD),thankstoa
networkmetaanalysisundertakenbyTudurSmithand
colleagues38,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,200741
wasalargepragmatictrialwhichinformedmanyofthe
comparisons.Thiswasanunblindedmulticentrestudy.Inchildren,
threestudieswereincluded(NietoBarrera,2001164,Guerreiro,
1997andZamponi1999)themajorityofwhichwereunblinded
withlimitations.
Otherconsiderations
TheGDGfoundnoevidencetorefutetheplaceofdrugslistedas
214
TheEpilepsies
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)inmonotherapyoffocalseizures38.
WeusedtheIPDanalysisassupplementaryevidencetothedirect
evidence.TheGDGconsideredtheIPDanalysisinthedecision
makingprocessalongsidethedirectevidence.
Inrelationtothefindings,commonresultswerefoundinour
directevidenceandtheIPDanalysis38.Inallanalyses,nosingle
drugwassignificantlymoreeffectivethancarbamazepinefortime
to12monthsremission.TheIPDanalysis38foundthatsodium
valproatewassignificantlylesseffectivethancarbamazepinein
achievingtimeto12monthsremissionandhadashortertimeto
firstseizure.Therewasnodirectevidenceforthisdrug
comparison.Othercomparisonswhichhadnodirectevidencebut
hadIPDresultsincludedphenytoinhadashortertimetotreatment
failurethanoxcarbazepineorphenobarbitalandashortertimeto
firstseizurethanphenobarbital.Resultswhichwerenon
significantforthedirectevidencebutsignificantfortheIPD
analysisincludedlamotriginewhichhadashortertimetofirst
seizurethantopiramateoroxcarbazepine.TheGDGconsidered
thatthedifferenceinresultsforsomecomparisonsoriginatedfrom
215
TheEpilepsies
thedifferentstudiescontributingtothedirectevidenceandthe
IPDanalyses.StudiesincludedintheIPDanalyseswereexcluded
fromthedirectevidencemainlyonthebasisthattheydidnot
meetthecutoffpointforexclusionofseizuretypesandtheage
distribution.
TheGDGconsideredthatdifferentpatientsreactdifferentlytothe
differentdrugsandtheremaybeaneedtotrydifferentoptionsto
getthebalancerightbetweenseizurefreedomandadverse
effects.IfthefirstAEDisineffective,asecondAEDshouldbe
addedalongsidetheinitialAEDand,ifseizuresarecontrolled,the
firstAEDmaybewithdrawn,recognisingthatsomepatientswill
prefertoremainontwoAEDsifseizurefree.TheGDGconsidered
thatitisgenerallypreferabletoavoidpolytherapy.
Recommendation
86.LevetiracetamisnotcosteffectiveatJune2011unitcostsz.
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
216
TheEpilepsies
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
217
TheEpilepsies
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,200741
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.
218
TheEpilepsies
(carbamazepine,sodiumvalproate,phenytoin,phenobarbital,
oxcarbazepine,lamotrigine)inmonotherapyoffocalseizures38.
Inrelationtothefindings,commonresultswerefoundinour
directevidenceandtheIPDanalysis38.Inallanalyses,nosingle
drugwassignificantlymoreeffectivethancarbamazepinefortime
to12monthsremission.TheIPDanalysis38foundthatsodium
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
219
TheEpilepsies
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.
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
220
TheEpilepsies
betakenintoconsiderationwhenintroducingorwithdrawing
eithermedication.Onwithdrawalofsodiumvalproate,
lamotriginelevelsmaydropandthismaybethereasonfor
breakthroughseizures.Thereshouldbeconcomitantincreasein
thelamotriginedose.
Thereisincreasedriskofsideeffectswithcarbamazepineinolder
people.Carbamazepinehasbeenassociatedwithahigher
incidenceofprematuredeathinoldpeoplecomparedto
lamotrigine.TheGDGsuggestedtheuseofthecontrolledrelease
preparationofcarbamazepineandtouselowdosesandescalate
verycautiously.Otherwiseuseanalternativefirstlinetherapyin
thispopulation.ItisbettertousenonenzymeinducingAEDsas
thispopulationarelikelytobetakingothermedications.
10.3.10
10.3.10.1
Newresearchrecommendations(forfulllistseesection2.11)
Newlydiagnosedseizures(focal&generalised)monotherapy
diagnosedepilepsy?
Focalseizures:carbamazepine,eslicarbazepineacetate,lacosamide,lamotrigine,
Whythisisimportant
LevetiracetamandotherAEDslicensedforthetreatmentoffocalandgeneralisedseizuressince
publicationoftheoriginalguidelineTheepilepsies(NICEclinicalguideline20)in2004havenotbeen
evaluatedasfirstlinemonotherapy.
aprospectiverandomisedcontrolledtrial
allagegroups
221
TheEpilepsies
10.4 Therapyforrefractoryfocalseizures
10.4.1
Introduction
Focalseizures,asstatedintheprevioussection,originatefromoneareaofthebrain.Theyarethe
mostcommonseizuretypeinadultsandchildren.Althoughseizurefreedomremainsthegoalof
therapy,inthispopulationoptimalseizurecontrolmaybemoreachievable.Treatmentsuccesshas
beenmostrecentlydefinedbytheILAEasaseizurefreedurationthatisatleastthreetimesthe
longestseizurefreeintervalpriortostartingthenewtreatmentwithasustainedresponseover12m
(Kwanetal2009)185.
RecentEMAaadecisionsregardinglicensingofAEDSforuseinchildrenindicatethatforfocal
epilepsiesespeciallycryptogenicandsymptomatic,andidiopathicgeneralisedepilepsies,with
absences,myoclonicand/orgeneralisedconvulsiveseizures,()theefficacyofAEDsseemstobe
comparableinchildhoodandadulthood.Focalepilepsiesinchildrenolderthan4yearsoldhavea
similarclinicalexpressiontofocalepilepsiesinadolescentsandadults.Inrefractoryfocalepilepsies,
theresultsofefficacytrialsperformedinadultscouldtosomeextentbeextrapolatedtochildren
providedthedoseisestablished.Asaresultofthis,andwiththeagreementoftheGDGwehave
combineddataforadultsandchildrenintherefractoryfocalseizuresreview.
10.4.2
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
1186
Oxcarbazepine
1187
aa http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070043.pdf
222
TheEpilepsies
Sodium
valproate
1188
PLA
LTG
TGB
OXC
VPA
223
TheEpilepsies
AdjunctiveAEDtherapyforrefractoryfocalseizures
Placebo
Carbamazepine
Clobazam
1189
Eslicarbazepine 4190193
acetate
Felbamate
1194
Gabapentin
6195199,200
Lacosamide
3201,202,203
Lamotrigine
12204213,214,215
1216
LamotrigineXR 1217
Levetiracetam
12218225,226,227,
228 229
,
1230
Levetiracetam
XR
1231
Oxcarbazepine 2232,233
Phenytoin
Pregabalin
6234238,215
1215
Sodium
valproate
1239
1240
Topiramate
11239,241248,249,250
1251
2239,252
224
TheEpilepsies
Tiagabine
4253256
Vigabatrin
1257,258
1259
2257,258
9206,260263,264266,267
1268
Zonisamide
5269272,273
Primidone
1274
PLC
CBZ
CLB ECBZ FBM GBP
LTG
XR
LEV LEV
XR
Placebo(PLA)
Clobazam(ClB)Eslicarbazepineacetate(ECBZ)
Levetiracetam(LEV) LevetiracetamXR(LEVXR)
Oxcarbazepine(OXC)
LAC LTG
PGB VPA
Felbamate(FBMl) Gabapentin(GBP) Lacosamide(LAC)Lamotrigine(LTG)LamotrigineXR(LTGXR)

Topiramate(TPM)Tiagabine(TGB) Vigabatrin(VGB)Zonisamide(Zon)
OXC PHT
225
TPM TGB
TheEpilepsies
10.4.4
10.4.4.1
SingleAEDtherapyforrefractoryfocalseizures
Directclinicalevidence
Oneeconomicevaluation181oflamotrigine,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
226
TheEpilepsies
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
227
TheEpilepsies
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
Onestudy181assessingthecosteffectivenessofAEDsusedasmonotherapyinadultswithrefractory
focalepilepsywasincludedintheeconomicevidencereview.Seeeconomicevidencetablesin
appendixMforstudydetails,includingqualityassessmentsoftheirmethodologyandapplicability.
Table9:
TherapyinadultswithrefractoryfocalepilepsyEconomicstudycharacteristics
Study
Limitations
181
Hawkins(2005)
Applicability
(a)
(b,c)
228
OtherComments
comparatorsincluded
carbamazepinesodium
valproateand
lamotrigine;timehorizon
TheEpilepsies
Study
Limitations
Applicability
OtherComments
15years;clinicaldata
basedonnetworkmeta
analysisofdatafrom
Gilliam1998188andKerr
2001275
(a) Unitcostsofinterventionsarefrom2002/03andsincethenlamotriginehascomeoffpatentandthenonproprietarypriceis
dramaticallylower.
(b) Effectivenessdatawasderivedfromanetworkmetaanalysisthatincludedatleastoneunpublishedstudythatwasnotreviewedas
partofoursystematicreview.
(c) Costsdiscountedat6%perannum;QALYsdiscountedat1.5%perannum.
SeeeconomicevidencetableinappendixMfordetails.
Table10: SingleAEDtherapyinrefractoryfocalseizuresEconomicsummaryoffindings
Hawkins2005181
AED
Totalcost
()per
patient
Totaleffects ICER
(/QALY)
(QALYs)
CBZ
5,599
8.865
costeffective
Basecase:79%
VPA
5,728
8.856
Dominate
d
costeffective
Basecase:21%
LTG
6,749
8.856
Dominate
d
costeffective
Basecase:0%
Uncertainty
Evidencestatements
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedcarbamazepinetobethemost
effectiveandleastcostly,andthereforemostcosteffectiveAEDusedinthetreatmentofrefractory
focalseizures.Thesameanalysisshowslamotrigineandsodiumvalproatetherapynottobecost
effective.Thisevidenceispartiallyapplicableandhasveryseriouslimitations.
10.4.6
10.4.6.1
Adjunctivetherapyinchildren,youngpeopleandadultswithrefractoryfocalseizures
Lamotrigineversusplacebo
Clinicalevidence
Oneeconomicevaluation181ofAEDsusedasadjunctivetherapyinthetreatmentofadultsandone
economicevaluation184ofAEDsusedinthetreatmentofchildrenandyoungpeoplewithrefractory
focalseizureswereidentifiedintheeconomicliteraturesearch.Astherewerestillgapsinthe
229
TheEpilepsies
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)
230
TheEpilepsies
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
231
TheEpilepsies
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)
232
TheEpilepsies
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
Oneeconomicevaluation181ofAEDs,includinglamotrigineandlevetiracetam,usedasadjunctive
therapyinthetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomic
literaturesearch.NostudiescomparingtheseAEDsinthetreatmentofchildrenandyoungpeople
wereidentified.Astherewerestillgapsintheeconomicevidencebase,twooriginaleconomic
modelsweredevelopedtocompareAEDsusedasadjunctivetherapyinthetreatmentofrefractory
focalseizures:onemodelfortheevaluationoftreatmentforadultsandanotherspecificallyfor
childrenandyoungpeople.ThecompleteresultsofthisstudyandtheNCGCadjunctivetherapy
modelsarepresentedinsections10.4.7and10.4.8.
Evidencestatements
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandlevetiracetamadjunctive
therapyfortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
therapyforwithdrawalduetoadverseevents.(VERYLOWQUALITY)
233
TheEpilepsies
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).
234
TheEpilepsies
Resultsoftheguidelineanlysesindicatedthatonlyiflevetiracetamcanbeacquiredforatleast30
percentlessthanitscurrent2011unitcostisitpotentiallycosteffectivewhencomparedwith
lamotrigine.
timetofirstseizure
10.4.6.4
Lamotrigineversustiagabine
Clinicalevidence
Oneeconomicevaluation181ofAEDs,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.
235
TheEpilepsies
Onepublishedevaluationfoundthatlamotriginedominatedtiagabine;thatis,treatmentwith
adjunctivelamotriginewasassociatedwithlowercostsandbetterhealthoutcomes(higher
QALYs)thantreatmentwithadjunctivetiagabine(partiallyapplicableandpotentiallyserious
limitations).
Thecosteffectivenessanalysisdevelopedfortheguidelinefoundthatadjunctivetiagabinewas
morecostlyandmoreeffectivethanadjunctivelamotrigine,butwithanunacceptablyhigh
incrementalcosteffectivenessratioof131,882perQALY.Thisconclusionwasconsistentacross
arangeofsensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.5
Clinicalevidence
HealthEconomicevidence
and10.4.8.
Evidencestatements
Significantlymoreparticipantsontopiramateadjunctivetherapythanlamotrigineadjunctivetherapy
experiencedseizurefreedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.
(VERYLOWQUALITY)
Significantlymoreparticipantsontopiramateadjunctivetherapycomparedtolamotrigineadjunctive
therapyhadanincidenceofheadache,althoughthereisuncertaintyinthemagnitudeofitsclinical
effect.(VERYLOWQUALITY)
Nosignificantdifferencebetweenlamotrigineadjunctivetherapyandtopiramateadjunctivetherapy
forwithdrawalduetoadverseevents.(VERYLOWQUALITY)
236
TheEpilepsies
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
237
TheEpilepsies
10.4.6.6
Levetiracetamversusplacebo
Clinicalevidence
Oneeconomicevaluation181ofAEDs,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)
238
TheEpilepsies
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
239
TheEpilepsies
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
240
TheEpilepsies
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
241
TheEpilepsies
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)
242
TheEpilepsies
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.
243
TheEpilepsies
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
10.4.6.9
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Adjunctivesodiumvalproatewasnot
includedintheoriginaleconomicmodelasitisnotcommonlyusedasadjunctivetreatment.
Evidencestatements
Nosignificantdifferencebetweentopiramateadjunctivetherapyandsodiumvalproateadjunctive
therapyforwithdrawalduetolackofefficacy.(VERYLOWQUALITY)
244
TheEpilepsies
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
245
TheEpilepsies
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)
246
TheEpilepsies
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
10.4.6.11
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Adjunctivesodiumvalproatewasnot
includedintheoriginaleconomicmodelasitisnotcommonlyusedasadjunctivetreatment.
Evidencestatements
Nosignificantdifferencebetweengabapentinadjunctivetherapyandsodiumvalproateadjunctive
therapyfortheproportionofparticipantsachievingatleasta50%reductioninseizurefrequency
(VERYLOWQUALITY)
therapyfortheproportionofparticipantsachievingseizurefreedom(VERYLOWQUALITY)
247
TheEpilepsies
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.
248
TheEpilepsies
timetofirstseizure
cognitiveoutcomes
10.4.6.13
Gabapentinversuslamotrigine
Clinicalevidence
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)
249
TheEpilepsies
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
Oneeconomicevaluation181ofAEDs,includingtiagabineandplacebo,usedasadjunctivetherapyin
thetreatmentofadultswithrefractoryfocalseizureswasidentifiedintheeconomicliterature
developedtocompareAEDsusedasadjunctivetherapyinadultswithrefractoryfocalseizures.The
completeresultsofthisstudyandtheNCGCadultsadjunctivetherapymodelarepresentedin
section10.4.8.
Evidencestatements
250
TheEpilepsies
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,
251
TheEpilepsies
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
252
TheEpilepsies
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
253
TheEpilepsies
10.4.6.17
Vigabatrinversusplacebo
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch.Vigabatrinwasexcludedfromone
study181owingtoitspotentialtoxicity.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)
254
TheEpilepsies
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
255
TheEpilepsies
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
256
TheEpilepsies
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:
257
TheEpilepsies
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.
258
TheEpilepsies
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:
259
TheEpilepsies
URI(VERYLOWQUALITY)
Costeffectiveness
Availableeconomicevidenceindicatesthatadjunctivelacosamideisnotcosteffectivewhen
oflacosamidewasassociatedwithincreasedcostsandbetterhealthoutcomes(higherQALYs)
lacosamidewastheleasteffectiveandthirdmostcostlyadjunctiveAED.Thisconclusionwas
consistentacrossarangeofsensitivityanalyses(directlyapplicableandminorlimitations).
timetofirstseizure
cognitiveoutcomes
10.4.6.22
Zonisamideversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsonzonisamideadjunctivetherapythanplaceboexperiencedatleast
Nosignificantdifferencebetweenzonisamideadjunctivetherapyandplaceboforseizurefreedom.
(VERYLOWQUALITY)
260
TheEpilepsies
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).
261
TheEpilepsies
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)
262
TheEpilepsies
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)
263
TheEpilepsies
anxiety(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivefelbabamatetoplacebowasidentified.
seizurefreedom
timetofirstseizure
cognitiveoutcomes
10.4.6.25
Oxcarbazepineversusplacebo
Clinicalevidence
and10.4.8.
Evidencestatements
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythanplaceboexperiencedat
least50%reductioninseizurefrequency.(VERYLOWQUALITY)
Significantlymoreparticipantsonoxcarbazepineadjunctivetherapythanplaceboexperienced
seizurefreedom,althoughthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(VERYLOW
QUALITY)
264
TheEpilepsies
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).
265
TheEpilepsies
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
266
TheEpilepsies
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
267
TheEpilepsies
10.4.7
HealtheconomicevidenceofAEDsusedasadjunctivetherapyforadultswithrefractory
focalepilepsy
11studiespublishedsincethesystematicreview40,276ofeconomicstudiesundertakentoinform
TA76andTA79wereidentifiedintheeconomicliteraturesearch.Nineofthesestudies277285were
excludedfromtheeconomicevidencereviewduetopoorapplicabilityorveryseriouslimitations.
FulldetailsofexclusionareincludedinappendixM.
Twostudies181,286assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinadultswith
refractoryfocalepilepsywereincludedintheeconomicevidencereview.Seeeconomicevidence
tablesinappendixMforstudydetails,includingqualityassessmentsoftheirmethodologyand
applicability.Astherewerestillgapsintheeconomicevidencebase,anoriginaleconomicmodel
wasdevelopedtocompareAEDsusedasadjunctivetherapyinadultpatientswithrefractoryfocal
epilepsy.Thiswasbasedonclinicalevidencefrompairwisemetaanalysesofplacebocontrolled
trials(seesection10.4.6).SeeappendixQforfulldetailsandresultsofmodelling.
Table11: AdjunctivetherapyforadultswithrefractoryfocalepilepsyEconomicstudy
characteristics
Study
Limitations
Applicability
OtherComments
NCGCModeladults
adjunctivetherapy
(seeAppendixQfor
details)
Minorlimitations
Directlyapplicable
comparatorsincludedplacebo,
lamotrigine,oxcarbazepine,
gabapentin,topiramate,
levetiracetam,tiagabine,
pregabalin,lacosamide,
eslicarbazepineacetate,
zonisamideandvigabatrin;
databasedonpairwisemeta
analysesofplacebocontrolled
trials
Hawkins(2005)181
Potentiallyserious
limitations(a)
Partiallyapplicable(b,c)
comparatorsincludedplacebo,
lamotrigine,gabapentin,
tiagabine,oxcarbazepine,
topiramate,levetiracetam;
databasedonnetworkmeta
analysisthatincludedsome
studieswithmixedfocaland
generalisedepilepsy
populations
Spackman(2007)286
Potentiallyserious
limitations
Partiallyapplicable(b)
comparatorsincluded
zonisamideandlevetiracetam;
timehorizon15years
(a) Unitcostsofinterventionsarefrom2002/03andsincepublication,lamotriginehascomeoffpatentandthenon
proprietarypriceisdramaticallylower
(b) StudydidnotincludeallcomparatorsconsideredrelevanttotheGDG,namelythenewerAEDs.
(c) Costsandeffectsdiscountedat6%and1.5%perannum,respectively.
268
TheEpilepsies
NCGCadultsadjunctivetherapymodel(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixQ.
Table12: AdjunctivetherapyforadultswithrefractoryfocalseizuresSummaryofNCGCmodel
findings
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY)
Uncertainty
Placebo
8,928
8.197
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
Basecase:31%
Allcheapest:29%
and22%
OXC
10,564
8.314
22,660
Basecase:22%
Allcheapest:17%
and15%
TPM
10,606
8.302
Dominate
d
Basecase:11%
Allcheapest:32%
269
TheEpilepsies
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY)
Uncertainty
and7%
LEV
11,157
8.316
296,500
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
270
TheEpilepsies
Totalcost()
perpatient
AED
Note:
Totaleffects
(QALYs)
ICER
(/QALY)
d
Uncertainty
Basecase:0%
Allcheapest:0%
and0%
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.
Table13: AdjunctivetherapyforadultswithrefractoryfocalepilepsySummaryofHawkins
2005181findings
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY)
Placebo
5,064
8.716
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%
271
Uncertainty
TheEpilepsies
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY)
OXC
6,400
8.794
17,095
LEV
6,984
8.775
Dominated At20KperQALYthreshold,
Basecase:2%
TPM
7,026
8.777
Dominated At20KperQALYthreshold,
Basecase:0%
Uncertainty
Basecase:52%
Evidencestatements
AdjunctiveoxcarbazepineisthemosteffectiveandmostcosteffectiveAEDamongevaluated
adjunctiveAEDs(partiallyapplicableandpotentiallyseriouslimitations).
Adjunctivegabapentin,adjunctivelamotrigineandadjunctivetiagabineareruledoutthrough
extendeddominancebyadjunctiveoxcarbazepineandplacebo(monotherapy)(partiallyapplicable
andpotentiallyseriouslimitations).
Adjunctivelevetiracetamandadjunctivetopiramatearemorecostlyandlesseffectivethan
adjunctiveoxcarbazepine(partiallyapplicableandpotentiallyseriouslimitations).
Spackman2007286(directlyapplicable,potentiallyseriouslimitations)
Table14: AdjunctivetherapyforadultswithrefractoryfocalepilepsySummaryofSpackman
2007286findings
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.
272
TheEpilepsies
10.4.8
HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildrenwithrefractory
focalepilepsy
Onestudy184assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinchildrenwith
refractoryfocalepilepsywasidentifiedintheeconomicliteraturesearchandincludedinthe
economicevidencereview.Astherewerestillgapsintheevidencebase,anoriginaleconomicmodel
wasdevelopedtocompareAEDsusedasadjunctivetherapyinchildrenwithrefractoryfocal
epilepsy.Thiswasbasedonclinicalevidencefrompairwisemetaanalysesofplacebocontrolled
trials(seesection10.4.6).SeeappendixRforfulldetailsandresultsofmodelling.
Table15: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyEconomicstudy
characteristics
Study
Limitations
Applicability
OtherComments
NCGCModel
childrenadjunctive
therapy(see
AppendixRfor
details)
Minorlimitations
Directlyapplicable
comparatorsincluded
placebo,gabapentin,
lamotrigine,
levetiracetam,
oxcarbazepineand
topiramate;timehorizon
15years;clinicaldata
basedonpairwisemeta
analysesofplacebo
controlledtrials.
Frew(2007)184
Potentiallyseriouslimitations Partiallyapplicable(b,
(a)
c)
comparatorswere
treatmentsequences
includinggabapentin,
lamotrigine,
oxcarbazepineand
topiramateaspossible
adjunctivetherapyall
comparedtoabaseline
ofonlyolderAEDs
(carbamazepine,sodium
valproateand
phenytoin);timehorizon
upto15years;clinical
databasedonNieto
Barrera2001164,
Zamponi1999183;
(a) 2002/03UKpounds
(b) Costsdiscountedat6%perannum;Effectsdiscountedat1.5%perannum
(c) AnalysisdidnotincludeallcomparatorsofinteresttotheGDG,namelylevetiracetam.
NCGCModelchildrenadjunctivetherapy(directlyapplicable,minorlimitations)
Forfulldetailsofbasecaseandallsensitivityanalyses,seeappendixR.
273
TheEpilepsies
Table16: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyResultsfromNCGC2010
AED
Totalcost()
perpatient
Totaleffects
(QALYs)
ICER
(/QALY)
Uncertainty
Placebo
18,819
9.409
Basecase:35%
Allcheapest:1%
and34%
Cohortstartingage=10yrs:42%
GBP
19,018
9.462
3,752
Basecase:18%
Allcheapest:20%
and15%
LTG
19,174
9.471
17,291
(extdom)
Basecase:15%
Allcheapest:41%
and12%
OXC
19,764
9.521
12,644
Basecase:19%
Allcheapest:17%
and14%
TPM
19,922
9.509
Dominate
d
Basecase:7%
Allcheapest:17%
and5%
274
TheEpilepsies
AED
LEV
Totalcost()
perpatient
Totaleffects
(QALYs)
20,448
9.523
ICER
(/QALY)
341,875
Uncertainty
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.
Frew2007184(partiallyapplicable,potentiallyseriouslimitations)
Table17: AdjunctivetherapyforchildrenwithrefractoryfocalepilepsyResultsfromFrew
2007184
AED
Baseline(no
newAEDs)
Totalcost
()per
patient
Total
effects
(QALYs)
bedeterminedfrom
thedataprovided
ICER
(/QALY)
Uncertainty
Basecase:0%
TPM(adjunctive Pointestimatescannot
therapy)
bedeterminedfrom
thedataprovided
Morecostlyandpossibly
moreeffective,butICER
cannotbedetermined
fromthedataprovided.
Basecase:30%
OXC(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Likelydominated
Basecase:30%
LTG(secondline Pointestimatescannot
monotherapy)
bedeterminedfrom
Likelydominated
275
TheEpilepsies
AED
Totalcost Total
()per
effects
patient
(QALYs)
thedataprovided
ICER
(/QALY)
Uncertainty
Basecase:23%
LTG(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Likelydominated
Basecase:23%
GBP(adjunctive
therapy)
bedeterminedfrom
thedataprovided
Likelydominated
Basecase:18%
Evidencestatements
CosteffectivenessofadjunctiveAEDsincludinggabapentin,lamotrigine,oxcarbazepineand
topiramatecomparedtoabaselinestrategyofonlyolderAEDsishighlyuncertain.Nodefinitive
conclusionaboutrelativecosteffectivenesscanbedetermined.
10.4.9
Adjunctivetreatmentinchildren,youngpeopleandadultswithrefractoryfocalseizures
NICEhasalsoissuedguidanceontheuseofretigabineasanoptionfortheadjunctivetreatmentof
partial(focalhasbeenusedinthisguideline)onsetseizureswithorwithoutsecondarygeneralisation
inadultsaged18yearsandolderwithepilepsyinRetigabinefortheadjunctivetreatmentofpartial
onsetseizuresinepilepsy(NICEtechnologyappraisalguidance232).
276
TheEpilepsies
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
277
TheEpilepsies
comparedtotoplacebo.
Adecisionmodelwasbuilttoweighuptheclinicalbenefitsofeach
adjunctiveAED,measuredbyseizurecontrolandseizure
reduction,comparedtotheharmsfromadverseeventsas
measuredbywithdrawalsfromtreatmentduetoadverseevents.
Forthedrugsrecommendedhere,thetreatmentbenefits
outweighedtheharmsfortheaveragepatientandtheQALYs
gainedjustifiedtheadditionalcostsoverplacebo(noadjunctive
AED).
Threeeconomicevaluationswereincludedinthesystematic
reviewofpublishedliterature(twoforadultsandoneforchildren),
andoriginaleconomicmodellingwasundertakentoovercome
limitationsofandfillingapsnotcoveredbythepublished
evidence.
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
278
TheEpilepsies
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.
279
TheEpilepsies
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).
280
TheEpilepsies
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
281
TheEpilepsies
opinionwasthatprimidoneisnowrarelyusedininitiating
antiepileptictherapyandisonlyofferedtoindividualsasa
continuingprescription.Itisnotusedinchildrenasafirstline
therapy.
Thedrugsrecommendedforconsiderationherewereeffectiveto
varyingdegress,butthetreatmentbenefits,intermsofQALYs
gained,orinsomecaseslost,didnotjustifiedtheadditionalcosts
overdrugsrecommendedinthepreviousrecommendation
(gabapentin,lamotrigine,oxcarbazepine,topiramate).
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
282
TheEpilepsies
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.
Whyisthisimportant?
LevetiracetamandotherAEDSlicensedforthetreatmentoffocalandgeneralisedseizuressince
publicationoftheoriginalguidelinein2004havenotbeenevaluatedasfirstlinemonotherapy.
283
TheEpilepsies
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.
10.5.2
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereviews.Forthisreviewwe
includedpeopleexperiencinggeneralisedtonicclonicseizures.
10.5.3
Matrixoftheevidence
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
1163,1IPD
NMA38
Phenytoin
1172,1IPD
NMA38
1171,1IPD
NMA38
Sodium
valproate
1(Marson,
2171,288,1
unpublished), IPDNMA38
1IPDNMA38
4171,176,177,289,
1IPDNMA38
284
TheEpilepsies
Oxcarbazepine
1IPDNMA38
1IPDNMA
38
1173,1IPD
NMA38
1175,38
Topiramate
1IPDNMA38
1IPDNMA
38
1IPDNMA38
1(Marson,
unpublished),
1IPDNMA38
Phenobarbital
1IPDNMA38
1290,1IPD
NMA38
1IPDNMA38
1IPDNMA38
1IPD
NMA
38
1IPD
NMA
38
Gabapentin
1IPDNMA38
1IPDNMA
38
1IPDNMA38
1IPDNMA38
1IPD
NMA
38
1IPD
NMA
38
1IPD
NMA
38
LTG
CBZ
PHT
VPA
OXC
TPM
PHB
GBP
Matrixoftheevidenceformonotherapychildren
Placebo
Oxcarbazepine
Phenytoin
1182
Sodium
valproate
Carbamazepine
PCB
OXC
PHT
VPA
CBZ
285
TheEpilepsies
MatrixoftheevidenceforAdjunctivetherapy
Placebo
Clobazam
1291
Lamotrigine
1292
Lamotrigine
XR
1293
Levetiracetam
1294
Topiramate
2295,Barrett
(unpublished
inHTA)40
PCB
CLB LTG LTG

XR
LEV
286
TPM
TheEpilepsies
10.5.4
10.5.4.1
Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresinadults
Lamotrigineversuscarbamazepine
Clinicalevidence
Evidencestatements
Timeto12monthremissionoccurredsignificantlymorerapidlyinparticipantstakingcarbamazepine
monotherapycomparedtoparticipantstakinglamotriginemonotherapyalthoughthereis
uncertaintyinthemagnitudeofclinicaleffect.(IPDmetaanalysis)
Nosignificantdifferencebetweenlamotriginemonotherapyandcarbamazepinemonotherapyinthe
thetimetowithdrawaloftreatment.(IPDmetaanalysis).
Costeffectiveness
Noeconomicevidencecomparinglamotriginemonotherapytocarbamazepinemonotherapyin
patientswithgeneralisedtonicclonicseizureswasidentified.
cognitiveoutcomes
10.5.4.2
Lamotrigineversusphenytoin
Clinicalevidence
Evidencestatements
287
TheEpilepsies
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
10.5.4.3
Clinicalevidence
288
TheEpilepsies
Evidencestatements
timeto12monthremission.(IPDmetaanalysis).
timetoexit/withdrawaloftreatment.(IPDmetaanalysis).
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytophenytoinmonotherapyin
cognitiveoutcomes
10.5.4.4
Oxcarbazepineversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
analysisofAEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonic
seizures.Theresultsofthisanalysisarepresentedinsection10.5.5.
Evidencestatements
289
TheEpilepsies
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytosodiumvalproatemonotherapyin
cognitiveoutcomes
10.5.4.5
Phenytoinversuscarbamazepine
Clinicalevidence
Evidencestatements
Phenytoinmonotherapyismoreeffectivethancarbamazepinemonotherapyinachievingagreater
Nosignificantdifferencebetweenphenytoinmonotherapyandcarbamazepinemonotherapyforthe
timeto12monthremission.(IPDmetaanalysis).
Costeffectiveness
290
TheEpilepsies
Noeconomicevidencecomparingphenytoinmonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
10.5.4.6
Clinicalevidence
Evidencestatements
thetimetoexit/withdrawaloftreatment.(IPDmetaanalysis)
theincidenceofdeath(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalmonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
291
TheEpilepsies
10.5.4.7
Phenytoinversussodiumvalproate
Clinicalevidence
IPDmetaanalysis
PhenytoinandsodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenytoinmonotherapyandsodiumvalproatemonotherapyfor
theproportionofparticipantswithdrawnduetolackofefficacy.(VERYLOWQUALITY)
Significantlymoreparticipantstakingphenytoinmonotherapycomparedtosodiumvalproate
monotherapywithdrewtodueadverseevents,althoughthereisuncertaintyinthemagnitudeof
gastrointestinaldisturbances(VERYLOWQUALITY)
Costeffectiveness
292
TheEpilepsies
Noeconomicevidencecomparingphenytoinmonotherapytosodiumvalproatemonotherapyin
cognitiveoutcomes
10.5.4.8
Sodiumvalproateversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
SodiumvalproateandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Timetotreatmentfailureoccurredsignificantlymorerapidlyinparticipantstakingcarbamazepine
monotherapycomparedtoparticipantstakingsodiumvalproatemonotherapy.(IPDMETAANALYSIS)
Nosignificantdifferencebetweensodiumvalproatemonotherapyandcarbamazepinemonotherapy
Costeffectiveness
Noeconomicevidencecomparingsodiumvalproatemonotherapytocarbamazepinemonotherapyin
cognitiveoutcomes
293
TheEpilepsies
10.5.4.9
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)
294
TheEpilepsies
10.5.4.10
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
295
TheEpilepsies
cognitiveoutcomes
10.5.4.11
LamotrigineversusPhenobarbital
Clinicalevidence
IPDmetaanalysis
LamotrigineandphenobarbitalwereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenlamotriginemonotherapyandphenobarbitalmonotherapyfor
timetoexit/withdrawal.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
outcomesrelatingtoqualityoflife.
10.5.4.12
Clinicalevidence
IPDmetaanalysis
LamotrigineandtopiramatewereamongAEDsincludedinanindividualpatientdatametaanalysisof
AEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonicseizures.The
resultsofthisanalysisarepresentedinsection10.5.5.
296
TheEpilepsies
Timeto12monthremissionoccurredsignificantlymorerapidlyontopiramatemonotherapy
comparedtolamotriginemonotherapy.(IPDmetaanalysis)
Evidencestatements
toexit/withdrawal.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
10.5.4.13
Lamotrigineversusgabapentin
Clinicalevidence
IPDmetaanalysis
LamotrigineandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysisof
Evidencestatements
Nosignificantdifferencebetweenlamotriginemonotherapyandgabapentinmonotherapyfortime
297
TheEpilepsies
seizurefreedom
cognitiveoutcomes
10.5.4.14
LamotrigineversusOxcarbazepine
Clinicalevidence
IPDmetaanalysis
LamotrigineandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
seizurefreedom
cognitiveoutcomes
10.5.4.15
Topiramateversuscarbamazepine
Clinicalevidence
298
TheEpilepsies
IPDmetaanalysis
TopiramateandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandcarbamazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
10.5.4.16
Gabapentinversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
GabapentinandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
299
TheEpilepsies
seizurefreedom
cognitiveoutcomes
10.5.4.17
Oxcarbazepineversuscarbamazepine
Clinicalevidence
IPDmetaanalysis
OxcarbazepineandcarbamazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenoxcarbazepinemonotherapyandcarbamazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
300
TheEpilepsies
10.5.4.18
Phenobarbitalversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenobarbitalmonotherapyandoxcarbazepinemonotherapyfor
seizurefreedom
cognitiveoutcomes
10.5.4.19
Topiramateversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
TopiramateandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
301
TheEpilepsies
seizurefreedom
cognitiveoutcomes
10.5.4.20
Gabapentinversusoxcarbazepine
Clinicalevidence
IPDmetaanalysis
GabapentinandoxcarbazepinewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweengabapentinmonotherapyandoxcarbazepinemonotherapyfor
seizurefreedom
302
TheEpilepsies
cognitiveoutcomes
10.5.4.21
Phenobarbitalversusgabapentin
Clinicalevidence
IPDmetaanalysis
PhenobarbitalandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysis
ofAEDsusedasmonotherapyinadultswithnewlydiagnosedgeneralisedtonicclonicseizures.The
Evidencestatements
seizurefreedom
cognitiveoutcomes
10.5.4.22
Topiramateversusgabapentin
Clinicalevidence
IPDmetaanalysis
TopiramateandgabapentinwereamongAEDsincludedinanindividualpatientdatametaanalysisof
303
TheEpilepsies
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandgabapentinmonotherapyfortimeto
exit/withdrawal.(IPDmetaanalysis)
firstseizure.(IPDmetaanalysis)
seizurefreedom
cognitiveoutcomes
10.5.4.23
TopiramateversusPhenobarbital
Clinicalevidence
IPDmetaanalysis
TopiramateandPhenobarbitalwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandphenobarbitalmonotherapyfor
304
TheEpilepsies
seizurefreedom
cognitiveoutcomes
10.5.4.24
Phenobarbitalversusphenytoin
Clinicalevidence
IPDmetaanalysis
PhenobarbitalversusphenytoinwereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
Nosignificantdifferencebetweenphenobarbitalmonotherapyandphenytoinmonotherapyfortime
seizurefreedom
cognitiveoutcomes
10.5.4.25
Topiramateversusphenytoin
Clinicalevidence
305
TheEpilepsies
IPDmetaanalysis
TopiramateversusphenytoinwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapyandphenytoinmonotherapyfortimeto
seizurefreedom
cognitiveoutcomes
10.5.4.26
Gabapentinversusphenytoin
Clinicalevidence
IPDmetaanalysis
GabapentinversusphenytoinwereamongAEDsincludedinanindividualpatientdatametaanalysis
Evidencestatements
Nosignificantdifferencebetweengabapentinmonotherapyandphenytoinmonotherapyfortimeto
306
TheEpilepsies
seizurefreedom
cognitiveoutcomes
10.5.4.27
Clinicalevidence
IPDmetaanalysis
GabapentinversussodiumvalproatewereamongAEDsincludedinanindividualpatientdatameta
Evidencestatements
seizurefreedom
cognitiveoutcomes
307
TheEpilepsies
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
308
TheEpilepsies
remissionand1765generalisedtonicclonicparticipantsfortimetofirstseizure.Thefollowing
tablesshowtheresultsforthevariousoutcomes,comparingeachAEDwiththecurrentstandard
AED,sodiumvalproate.Thesignificantresultsarehighlightedinbold.
Timetotreatmentfailure
Intervention
Comparator
Hazardratio
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)
Carbamazepine
Sodiumvalproate
1.45(1.07to1.96)
Topiramate
Sodiumvalproate
1.74(1.28to2.36)
Phenobarbital
Sodiumvalproate
1.83(1.07to3.13)
(a) HR<1VPAworse;HR>1VPAbetter
Sodiumvalproatewasfoundtobesignificantlybetterthancarbamazepine,topiramateand
phenobarbitalfortimetotreatmentfailure.
Timeto12monthremission
Intervention
Comparator
Hazardratio
Gabapentin
Sodiumvalproate
0.26(0.04to1.86)
Phenytoin
Sodiumvalproate
0.92(0.72to1.18)
Carbamazepine
Sodiumvalproate
1.00(0.81to1.22)
Topiramate
Sodiumvalproate
1.09(0.86to1.37)
Oxcarbazepine
Sodiumvalproate
1.10(0.73to1.67)
Phenobarbital
Sodiumvalproate
1.28(0.89to1.84)
Lamotrigine
Sodiumvalproate
1.41(1.10to1.80)
Sodiumvalproatewasfoundtobesignificantlybetterthanlamotriginefortimeto12month
remission.
Timetofirstseizure
Intervention
Comparator
Hazardratio
Phenytoin
Sodiumvalproate
0.97(0.77to1.23)
Gabapentin
Sodiumvalproate
1.11(0.16to7.90)
Topiramate
Sodiumvalproate
1.19(0.94to1.51)
Carbamazepine
Sodiumvalproate
1.21(0.99to1.47)
Phenobarbital
Sodiumvalproate
1.28(0.92to1.77)
Oxcarbazepine
Sodiumvalproate
1.32(0.90to1.94)
Lamotrigine
Sodiumvalproate
1.47(1.20to1.80)
Sodiumvalproatewasfoundtobesignificantlybetterthanlamotriginefortimetofirstseizure.
309
TheEpilepsies
10.5.6
10.5.6.1
Monotherapyforthetreatmentofgeneralisedtonicclonicseizuresinchildren
Clinicalevidence
Evidencestatements
Costeffectiveness
Noeconomicevidencecomparingoxcarbazepinemonotherapytophenytoinmonotherapyin
childrenwithgeneralisedtonicclonicseizureswasidentified.
timetofirstseizure
cognitiveoutcomes
10.5.7
10.5.7.1
Adjunctivetherapyforthetreatmentofgeneralisedtonicclonicseizures
Clobazamversusplacebo
Clinicalevidence
Evidencestatements
310
TheEpilepsies
Significantlymoreparticipantstakingclobazamadjunctivetherapywereseizurefreecomparedto
placebo.However,thereisuncertaintyaboutthemagnitudeoftheclinicaleffect.(VERYLOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingclobazamadjunctivetherapytoplacebowasidentified.
timetofirstseizure
cognitiveoutcomes
10.5.7.2
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.
311
TheEpilepsies
timetofirstseizure
cognitiveoutcomes
10.5.7.3
Lamotrigineextendedreleaseversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantstakinglamotrigineextendedreleaseadjunctivetherapywereseizure
freecomparedtoparticipantstakingplacebo.(MODERATEQUALITY)
Significantlymoreparticipantstakinglamotrigineextendedreleaseadjunctivetherapyachievedat
leasta50%reductioninseizurefrequencycomparedtoparticipantstakingplacebo.(MODERATE
QUALITY)
theproportionofparticipantshavingtreatmentwithdrawnduetoadverseevents.(VERYLOW
QUALITY)
headache
vomiting
10.5.7.4
Clinicalevidence
evidencebase,originaleconomicmodellingwasundertakentoevaluateAEDs,including
levetiracetam,usedinthetreatmentofpatientswithrefractorygeneralisedtonicclonicseizures.
FullresultsoftheNCGCGTCSmodelarepresentedinsection10.5.8.
Evidencestatements
312
TheEpilepsies
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
10.5.7.5
Clinicalevidence
Oneeconomicevaluation181wasidentifiedintheeconomicliteraturesearchandincludedinthe
evidencereview.Astherewerestillgapsintheeconomicevidencebase,originaleconomic
313
TheEpilepsies
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.
314
TheEpilepsies
10.5.8
HealtheconomicevidenceforAEDsusedasadjunctivetherapyinadultswithrefractory
generalisedtonicclonicseizures
Onestudy181assessingthecosteffectivenessoftopiramateusedasadjunctivetherapyinpatients
withrefractorygeneralisedtonicclonicseizureswasidentifiedintheeconomicliteraturesearchand
includedintheeconomicevidencereview.Astherewerestillgapsintheevidencebase,anoriginal
economicmodelwasdevelopedtocompareAEDsusedasadjunctivetherapyinpatientswith
refractorygeneralisedtonicclonicseizures.Thiswasbasedonevidenceincludedintheclinical
review292,294,295.SeeappendixSforfulldetailsandresultsofmodelling.
Table18: Adjunctivetherapyforpatientswithrefractorygeneralisedtonicclonicseizures
Study
Limitations
Applicability
OtherComments
NCGCGTCSmodel
(seeappendixSfor
details)
Minorlimitations
Directlyapplicable
15yeartimehorizon;
comparatorsincluded
monotherapy(placebo),
lamotrigine,topiramate
andlevetiracetam;
effectivenessdatafrom
studiesincludedin
clinicalreview292,294,295
Hawkins2005181
Potentiallyserious
limitations(a)
Partiallyapplicable(b,
c)
15yeartimehorizon;
effectivenessdatafrom
Barret1998296andBiton
1999295.
(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)
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.
315
Uncertainty
TheEpilepsies
AED
TPM
Totalcost
()per
patient
Totaleffect
(QALYs)per
patient
9,807
7.562
ICER
(/QALY)
Dominate
d
Uncertainty
IfLTGisexcludedfromtheanalysis:
ICER=14,834andhas74.86%and94.83%
probabilityofbeingoptimalat20Kand30K
/QALY,respectively.
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.
EconomicstudyresultsHawkins2005181
ResultsofHawkins2005181
AED
Totalcost
()per
patient
Totaleffect
(QALYs)per
patient
ICER
(/QALY)
Placebo
5,064
8.737
Atthresholdof30K/QALY,monotherapy
(placebo)has59%probabilityofbeingoptimal
TPM
7,471
8.807
34,417
Atthresholdof30K/QALY,topiramatehasa
41%probabilityofbeingoptimal
Uncertainty
Evidencestatements
Evidencefromonecosteffectivenessanalysisindicatesthattopiramateismorecostlyandmore
effectivethancontinuedmonotherapy,butwithanincrementalcosteffectivenessratiogreaterthan
20,000and30,000perQALYgained,itisunlikelytobeconsideredcosteffectiveinthispatient
group.Thisevidenceispartiallyapplicableandhaspotentiallyseriouslimitations.
316
TheEpilepsies
10.5.9
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
317
TheEpilepsies
makesdosingdifficult.
Sodiumvalproateandhighdoselamotrigineareassociatedwith
increasedriskofneuraltubeandotherdefectsandsothewomen
ofchildbearingageshouldbeinformedofsuchrisks.
TheGDGconsideredthatthebenefitsofreductionofseizures
outweighedtheadverseeffects.
Noeconomicevidencewasidentifiedintheliteratureandno
economicevaluationwasundertakentoinformthecost
effectivenessoffirstlineAEDsusedtotreatnewlydiagnosed
patientsexperiencinggeneralisedtonicclonicseizures.TheGDG
feltthatanextrapolationfromtheSANADstudypopulationwith
generalisedepilepsiestoapopulationwithgeneralisedtonicclonic
seizureswasappropriateandthattherelativecosteffectivenessof
sodiumvalproatewasunlikelytobedifferentbetweenthese
groups.
Sodiumvalproateemergedasthedrugmostlikelytobecost
effectiveinthecostperseizureavoidedanalysisconductedaspart
oftheSANADtrial161.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
318
TheEpilepsies
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.
319
TheEpilepsies
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
intoconsideration.Therewasalackofpowerofstudies
evidencewasverylowwithpoorreportingofrandomisation
studies.
Otherconsiderations
(carbamazepine,gabapentin,lamotrigine,oxcarbazepine,
phenobarbital,phenytoin,sodiumvalproateandtopiramate)
TheGDGconsensusopinionreflectswidespreadclinicalexperience
thatdrugssuchascarbamazepineandoxcarbazepinemay
exacerbatecertainseizurestypes,andspecificallymyoclonicand
absenceseizures.Therefore,theyconcludedthatalthoughthereis
evidencetosupporttheroleofcarbamazepineandoxcarbazepine
inthetreatmentofgeneralisedtonicclonicseizures,theyshould
onlybeconsideredonceotherseizuretypeshavehadtimeto
presentfollowinginitiationoffirstlinedrugs.
320
TheEpilepsies
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.
Qualityofevidence
TheGDGconsideredtheevidencefromtheeconomicevaluation
undertakenfortheguidelineinwhichlamotrigineemergedasa
verycosteffectiveadjunctivetherapyinpatientsexperiencing
refractorygeneralisedtonicclonicseizures.Iflamotriginehad
beentriedpreviously,levetiracetamwasalsolikelytobeacost
effectiveadjunctiveAED.Topiramatewasnotshowntobecost
effective,butintheeventthatotheralternativesfailtoproduce
thedesiredreductioninseizurefrequency,theGDGfeltthatit
shouldbeconsidered.Clobazamwasnotevaluatedaspartofthe
costeffectivenessanalysisbecausetheclinicalstudiesdidnot
reportalloutcomesnecessaryforinclusion.However,theGDG
consideredthatitseffectivenesscomparedtoplaceboanditssmall
unitcostislikelytomakeitcosteffective.
intoconsideration.Therewasalackofpowerinthestudies
particularlywithregardtosideeffects.Theoverallqualityof
evidencewaslow:somehadnodetailsofrandomisationor
allocationconcealment,highdropoutrateoraverysmallsample
size.
321
TheEpilepsies
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.
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
322
TheEpilepsies
areabruptinonsetandoffset,shortinduration(usually<10seconds),andoccurfrequently.
SynchronousspikewaveactivityisseenontheEEGatafrequencyof3Hzorabove.Suchareseenas
partofchildhoodonsetepilepsysyndromessuchaschildhoodabsenceepilepsyandjuvenileabsence
epilepsy.Atypicalabsencesmaynotbeasabruptinonsetoroffset,aretypicallylongerinduration
(>20seconds),andconsciousnessmaynotbetotallylost.FurthertheEEGduringtheattackismore
heterogeneouswithirregularslowerspikewaveactivity(12Hz).Suchmaybeseeninisolation,or
associatedwithotherseizuretypesaspartofanepilepsysyndromeegLennoxGastautsyndrome.
10.6.2
includedpeoplewithmyoclonicseizures.
10.6.3
Matrixoftheevidence
FordetailsonthematrixoftheevidencepleaserefertotheevidencereviewforIGEinsection10.13.
10.6.4
AEDsforthetreatmentofabsenceseizures
Clinicalevidence
FordetailsontheclinicalevidencepleaserefertotheevidencereviewforIGEinsection10.13.For
detailsoneachpaperidentifiedintheliteraturesearchpleaserefertoAppendixL.
323
TheEpilepsies
10.6.5
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.
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.
324
TheEpilepsies
Recommendation
96.Offerlamotrigineifethosuximideandsodiumvalproateare
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.
325
TheEpilepsies
Adjunctivetreatmentinchildren,youngpeopleandadultswithabsenceseizures
Recommendation
97.IftwofirstlineAEDs(seerecommendations95and96)are
ineffectiveinchildren,youngpeopleandadultswithabsence
seizures,consideracombinationoftwoofthesethreeAEDsas
adjunctivetreatment:ethosuximide,lamotrigineorsodium
valproate.Beawareofteratogenicrisksofsodiumvalproate
outcomes
TheGDGconsideredseizurefreedom,reductioninseizure
frequencyandadverseeventstobethemostimportantoutcomes
forthisrecommendation.
benefitsandharms
TheGDGconsideredthatifatleasttwoofthefirstlineAEDshave
failedtoproducethedesiredeffect(seizurefreedom),thenitis
appropriatetotryawelltoleratedcombinationoftwoofthem.
Althoughthereisnoevidenceinthispopulationspecifically,GDG
experienceisthatanyofthethreecanbesafelycombinedand
giventheireffectivenessasindividualdrugs,theexpectationisthat
theyareeffectiveincombination.
Cautionshouldbeusedwithsodiumvalproateingirlsofchild
bearingpotential.
costeffectivenessofanyAEDsusedasmonotherapyoradjunctive
therapytotreatCAE,JAEorgeneralisedabsenceseizures.There
wasnoevidencetosuggestthatanyspecificcombinationof
ethosuximide,lamotrigineandsodiumvalproateisbetterthan
another.Anycombinationisexpectedtobebroadlysimilarin
termsofcostaswell.Therefore,theGDGconsideredthatclinical
judgementandpatientchoiceshouldguidethedecisionforwhich
ofthelikelycosteffectiveAEDcombinationstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasextrapolatedfrom
theevidenceforeachofthesedrugsasmonotherapyinnewly
diagnosedabsenceseizuresandwassupportedbyGDGconsensus.
Otherconsiderations
326
TheEpilepsies
Recommendation
98.Ifadjunctivetreatment(seerecommendation97)isineffective
ornottolerated,discusswith,orreferto,atertiaryepilepsy
specialistandconsiderclobazam,clonazepam,
levetiracetam,topiramateorzonisamide.[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.
327
TheEpilepsies
Recommendation
99.Donotoffercarbamazepine,gabapentin,oxcarbazepine,
phenytoin,pregabalin,tiagabineorvigabatrin.[new2012]
outcomes
Seizurefreedomandadverseeffectswereconsideredtobethe
mostimportantoutcomes.
benefitsandharms
Clinicalpracticesuggeststhatabsenceseizurescanbeaggravated
bythesemedications.TheGDGfeltthatuseofthesemedications
wouldleadtonoclinicalbenefitandcouldcauseharm.
effectivenessoftheseAEDsinthispopulation;however,their
impacthealthrelatedqualityoflifeandincreaseNHSresource
use.
Qualityofevidence
Otherconsiderations
Thereisnoevidenceofbenefitonuseofthesemedications
328
TheEpilepsies
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.
10.7.2
includedpeoplewithmyoclonicseizures.
10.7.3
Matrixoftheevidence
myoclonicseizures.Thefollowinginterventionswereincludedinoursearch:clobazam,clonazepam,
lamotrigine,levetiracetam,piracetam,sodiumvalproate,topiramateandzonisamide.Welookedfor
anyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
Belowisamatrixshowingwhereevidencewasidentified.Aboxcontainingafigureindicatesthe
numberofstudiesthatwerefoundandthattheevidenceforthiscomparisonhasbeenreviewedin
thischapter.Anemptyboxindicatesthatnoevidencewasfound.Inthiscase,nosectiononthis
comparisonisincludedinthechapter.
Placebo
Lamotrigine
1297
Clobazam
Clonazepam
Piracetam
Topiramate
Sodium
Valproate
1165
1298
Zonisamide
Pla
LTG
LEV
CLB
CLN
Levetiracetam
PRC TPM VPA
329
ZNS
TheEpilepsies
10.7.4
10.7.4.1
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
330
TheEpilepsies
Evidencestatements
Nosignificantdifferencebetweentopiramatemonotherapy/adjunctivetherapyandsodium
valproatemonotherapy/adjunctivetherapyfortheproportionofseizurefreeparticipants.(VERY
LOWQUALITY)
valproatemonotherapy/adjunctivetherapyfor50%reductioninseizurefrequency.(VERYLOW
QUALITY)
Costeffectiveness
populationofpatientswithmyoclonicseizureswasidentified.
timetofirstseizure
cognitiveoutcomes
10.7.5
10.7.5.1
Adjunctivetherapyforthetreatmentofmyoclonicseizures
Levetiracetamadjunctivetherapyversusplacebo
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctiveweremyoclonicseizurefree
comparedtoplacebo.However,thereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
331
TheEpilepsies
Significantlymoreparticipantsreceivinglevetiracetamadjunctiveachieved50%orabovereduction
inseizurefrequencycomparedtoplacebo(MODERATEQUALITY).
Thereisnosignificantdifferencebetweenthelevetiracetamadjunctivegroupandtheplacebogroup
ontheincidenceof:
Qualityoflifestatisticallysignificantresults
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadexperienced
improvementinhealthrelatedqualityoflifecomparedtoplacebo(MODERATEQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamadjunctivetherapytoplaceboinapopulationof
patientswithmyoclonicseizureswasidentified.
timetofirstseizure
cognitiveeffects.
332
TheEpilepsies
10.7.6
Firstlinetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
100. Offersodiumvalproateasfirstlinetreatmenttochildren,
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
333
TheEpilepsies
consideredtobethemostimportantclinicaloutcome.
Qualityofevidence
Theevidenceformyoclonicseizureswaslimited.Twounblinded
studiesofverylowqualityevidencewereincludedwithnodetails
onrandomisationandnoallocationconcealment.Onewasasmall
subgroupfromaverysmallpilotstudyofjuvenilemyoclonic
epilepsyandtheotherwasasmallsubgroupwhichtheauthorsdid
notstatisticallycompareduetothesizeandimbalanceof
distribution.Thisrecommendationwasbasedonevidencefor
monotherapyextrapolatedfromJMEpopulations.TheJMEdata
mainlycamefromalargepragmaticunblindedtrial(SANAD).
Otherconsiderations
334
TheEpilepsies
Firstlinetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
101. Considerlevetiracetamortopiramateifsodiumvalproateis
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.
335
TheEpilepsies
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.
Otherconsiderations
336
TheEpilepsies
Adjunctivetreatmentinchildren,youngpeopleandadultswithmyoclonicseizures
Recommendation
102. Offerlevetiracetam,sodiumvalproateortopiramateas
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).
Otherconsiderations
337
TheEpilepsies
Recommendation
103. Ifadjunctivetreatment(seerecommendation102)is
ineffectiveornottolerated,discusswith,orreferto,atertiary
epilepsyspecialistandconsiderclobazam,clonazepam,
piracetamorzonisamide.[new2012]
outcomes
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepam,piracetamor
zonisamidewerepossiblealternativesinaccordancewithtertary
patientswithrefractorygeneralisedseizuretypes.
onthecosteffectivenessofclobazam,clonazepam,piracetamor
zonisamide.
Qualityofevidence
TherewasnoevidenceavailableformyoclonicseizuresorJMEfor
thesedrugssothisrecommendationwasbasedonGDGclinical
expertise.
Otherconsiderations
seizures.
338
TheEpilepsies
Recommendation
104. Donotoffercarbamazepine,gabapentin,oxcarbazepine,
outcomes
benefitsandharms
Clinicalpracticesuggeststhatmyoclonicseizurescanbe
aggravatedbythesemedications.TheGDGfeltthatuseofthese
medicationswouldleadtonoclinicalbenefitandcouldcause
harm.
effectivenessoftheseAEDsinthispopulation;however,their
impacthealthrelatedqualityoflifeandincreaseNHSresourceuse.
Qualityofevidence
Otherconsiderations
339
TheEpilepsies
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.
10.8.2
Pleaseseesection2.8forgeneralmethodsunderpinningtheevidencereviews.Forthisreview
weincludedadultsandchildrenwithtonicoratonicseizures.
10.8.3
Matrixoftheevidence
Noclinicalorcosteffectivenessevidencewasfoundforadultsandchildrenwithtonicoratonic
seizures.
340
TheEpilepsies
10.8.4
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.
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).
341
TheEpilepsies
Adjunctivetreatmentinchildren,youngpeopleandadultswithtonicoratonicseizures
Recommendation
106. Offerlamotrigineasadjunctivetreatmenttochildren,young
peopleandadultswithtonicoratonicseizuresiffirstline
treatmentwithsodiumvalproateisineffectiveornot
tolerated.[new2012]
outcomes
Seizurefreedom,atleast50%reductioninseizurefrequency(all
seizuresanddropattackseizures)andtolerability,asmeasuredby
withdrawalduetoadverseevents,wereconsideredtobethemost
importantoutcomes.
benefitsandharms
review,wherestudiesevaluatedresponseindropattacks.
Lamotrigineadjunctivetreatmentismoreeffectiveinreducing
dropattacksbyatleast50%andhasasimilarsideeffectsprofile
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.
Otherconsiderations
None.
342
TheEpilepsies
Recommendation
107. Discusswithatertiaryepilepsyspecialistifadjunctive
treatment(seerecommendation106)isineffectiveornot
tolerated.OtherAEDsthatmaybeconsideredbythetertiary
epilepsyspecialistarerufinamideandtopiramate.[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.
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
343
TheEpilepsies
adjunctivelamotriginehavebeenineffectiveornottolerated.
Qualityofevidence
Otherconsiderations
EvidencewasextrapolatedfromtheLennoxGastautsyndrome
evidencereview.Theevidenceforbothtopiramateandrufinamide
wasoflowquality.Therewerenoheadtoheadcomparisonsof
rufinamideandtopiramatewithanyotherantiepilepticdrugin
LennoxGastautsyndrome.
Clinicalexperiencewithrufinamideisconsiderablylessthanwith
lamotriginewhichwasshowntobeeffective.
Recommendation
outcomes
benefitandharms
Clinicalpracticesuggeststhatseizurescanbeaggravatedbythese
medications.TheGDGfeltthatuseofthesemedicationswould
leadtonoclinicalbenefitandcouldcauseharm.
potentialtoaggravateseizuresmakesthemveryunlikelytobe
costeffective.Aggravationofseizuresislikelytonegativelyimpact
healthrelatedqualityoflifeandincreaseNHSresourceuse.
Qualityofevidence
ThisrecommendationwasbasedonGDGexpertise.
Otherconsiderations
344
TheEpilepsies
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.
10.9.2
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
1299
Prednisone
2300,301
1302
4299,304
Hydrocortisone
Vigabatrin
1303
345
TheEpilepsies
306
ACTH
PCB VGB ACTH
PNL PNE HYD NPM
1299
1307
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
346
TheEpilepsies
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)
347
TheEpilepsies
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
348
TheEpilepsies
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)
349
TheEpilepsies
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)
350
TheEpilepsies
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.
351
TheEpilepsies
10.9.4
Firstlinetreatmentininfantswithinfantilespasms
Recommendation
109. Discusswith,orreferto,atertiarypaediatricepilepsy
specialistwhenaninfantpresentswithinfantilespasms.[new
2012]
outcomes
benefitsandharms
Infantilespasmsisarareseizuretypewhichrequiresinputfrom
specialistswithexpertiseinthearea.Theadverseeventsprofileof
individualdrugsneedstobeevaluatedandfullydiscussedwith
parents.ThiswasarecommendationbasedontheGDGexpertise
asitisthoughtimportantthatchildrenwithinfantilespasms
shouldsee,orreceiveadvicefrom,aspecialist.Limitedevidence
suggestsearlyresolutionofhypsarrhythmialeadstobetter
prognosis.
Noeconomicevidencewasavailabletoinformrecommendations
aboutthetreatmentofinfantilespasms.However,theGDG
consideredthatdiscussionwith,orreferraltoatertiarypaediatric
specialistandearlyinterventioninthisgroupofpatientsmaylead
toabetterprognosis,preventinglongtermcognitivedeterioration
andassociateddecrementstohealthrelatedqualityoflife.
Qualityofevidence
Therewasnoevidencesoughtforthisrecommendation.The
recommendationwasbasedonGDGexpertise.
Otherconsiderations
Theadverseeventsprofileofindividualmedicinesneedstobe
evaluatedandfullydiscussedwithparents.Theriskofvisualfield
constrictioncausedbyvigabatrinisunknownwithshorttermuse;
theshorttermsideeffectsofhighdosesteroidsincludinghigh
bloodpressure,glucoseintoleranceandimmunosuppression
requiremonitoring.
352
TheEpilepsies
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.
353
TheEpilepsies
Otherconsiderations
Comparedwiththeoriginalguideline(2004),oneadditionalRCT
wasappropriateforconsideration.
354
TheEpilepsies
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.
NoeconomicevidencewasavailabletoinformtheGDGofthe
relativecosteffectivenessofanydrugsusedinthetreatmentof
infantilespasmsassociatedwithtuberoussclerosis.The
populationofchildrenexperiencinginfantilespasmsisquitesmall,
treatmentdurationisshortanditisdifficulttoweighupthe
benefitsandharmsoftreatmentintermsofqualityoflifein
childrensoyoung.Earlydiagnosisandtreatmentareessentialas
thismayimpactonlongertermcognitiveandsocialoutcomes.The
potentialsideeffectsofsteroids(hypertension,irritabilityand
immunosuppressionleadingtopotentiallysevereinfections),pose
additionalcostsintermsofmanagementandmonitoring.
355
TheEpilepsies
Qualityofevidence
Overallnumberandqualityofstudieswaslimited.Heterogeneity
ofcause,dosageofinterventions,anddurationofthetreatment
andfollowup.Allofthestudieswereoflimitedpoweranddonot
excludethepossibilityofsignificantdifferencesbetweenthe
treatments.
Otherconsiderations
10.9.5
10.9.5.1
Infantilespasms
Doestreatmentresponserelatetocauseininfantilespasms?Doesearlytreatmentsuccessinseizure
controlandresolutionofthehypsarrhythmicEEGinfluencethelongtermdevelopmentaland
cognitiveoutcomesmorethantheunderlyingcauseofthespasms?
Whythisisimportant
TheUKInfantileSpasmsStudy(UKISS)bbdemonstrated14dayoutcomeefficacyofsteroidsover
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.
356
TheEpilepsies
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).
10.10.2
includedadultsandchildrenwithDravetsyndrome.
10.10.3
Matrixoftheevidence
epilepsyinapopulationwithseveremyoclonicepilepsyofinfancy.Theinterventionsweincludedin
oursearchwerestiripentol,levetiracetam,topiramate,clobazam,clonazepam,phenobarbitaland
sodiumvalproate.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreof
thesetreatments(orplacebo).Belowisamatrixshowingwereevidencewasidentified.Abox
Placebo
1308
Levetiracetam
Topiramate
Clobazam
Clonazepam
Stiripentol
357
TheEpilepsies
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
10.10.4.1
AdjunctivetreatmentofDravetSyndrome(SMEI)
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)
358
TheEpilepsies
withdrawalduetoadverseevents,
withdrawalduetolackofefficacy,
timetofirstseizure,
cognitiveoutcomes
Costeffectiveness
Noeconomicevidencecomparingadjunctivestiripentoltoplaceboinapopulationofpatientswith
Dravetsyndromewasidentified.
10.10.5
FirstlinetreatmentinchildrenwithDravetsyndrome(SMEI)
Recommendation
outcomes
specialistwhenachildpresentswithsuspectedDravet
syndrome.[new2012]
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
Otherconsiderations
evaluatedandfullydiscussedwithparents.
Recommendation
113. Considersodiumvalproateortopiramateasfirstline
treatmentinchildrenwithDravetsyndrome.[new2012]
359
TheEpilepsies
Recommendation
outcomes
113. Considersodiumvalproateortopiramateasfirstline
treatmentinchildrenwithDravetsyndrome.[new2012]
Seizurefreedomandwithdrawalduetoadverseeventswere
benefitsandharms
NoevidencewasfoundformonotherapytreatmentofDravet
syndrome(SMEI).Onfirstpresentation,thediagnosisofDravet
syndromemaybeunclearoruncertain,andthereforetreatment
choicewillbeinfluencedbythepredominantseizuretype,
typicallygeneralisedtonicclonicormyoclonicseizures.Sodium
valproateandtopiramatehavebeenshowntobeeffectiveinthe
treatmentofothergeneralisedseizuresandepilepsysyndromes.
Thedrugsrecommendedabovearealsolikelytoreducetheriskof
convulsivestatusepilepticus,incontrasttootherdrugsincluding
lamotrigine,whichmayexacerbatemyoclonicseizuresinthisand
otherepilepsysyndromes(BNF).
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
outcomes
114. Discusswithatertiaryepilepsyspecialistiffirstline
treatments(seerecommendation113)inchildren,young
peopleandadultswithDravetsyndromeareineffectiveor
nottolerated,andconsiderclobazamorstiripentolas
adjunctivetreatment.[new2012]
TheGDGconsideredthatthemostimportantoutcomeswerea
greaterthan50%reductioninseizuresandseizurefreedomfor
thisrecommendation,aswellasareductioninepisodesof
convulsivestatusepilepticus(SE).
Onlyonestudywasfoundwhichcomparedstiripentoltoplacebo
benefitsandharms
asadjunctivetreatmenttoclobazamandsodiumvalproateand
360
TheEpilepsies
Recommendation
114. Discusswithatertiaryepilepsyspecialistiffirstline
treatments(seerecommendation113)inchildren,young
peopleandadultswithDravetsyndromeareineffectiveor
nottolerated,andconsiderclobazamorstiripentolas
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.
361
TheEpilepsies
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
10.10.6.1
EpilepsySyndromes
WhatistheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswithonset
inchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome(SMEI)?
Whyisthisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidencebaseforthemost
Researchshouldinclude:
Multicentrerandomisedcontrolledcomparativetrialswithcentralizednationaldatacollection.
Theketogenicdietasoneoftherandomisedtreatments.
Primaryoutcomeseizurefreedom.
Secondaryoutcomemeasuresincludingseizurereduction,qualityoflifeandcognitiveoutcome.
Anattempttoobtainsomedataonpharmacoresistance.
362
TheEpilepsies
Thepossibilitytoincludeallchildrenwithspecificepilepsysyndromestobeconsideredfortrial.
10.11 LennoxGastautSyndrome
10.11.1
Introduction
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.
10.11.2
includedadultsandchildrenwithLennoxGastautSyndrome.
10.11.3
Matrixoftheevidence
LennoxGastautsyndrome.Thefollowinginterventionswereincludedinoursearch;rufinamide,
clobazam,clonazepam,felbamate,ethosuximide,lamotrigine,levetiracetam,sodiumvalproateand
topiramate.WelookedforanyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthese
treatments(orplacebo).
Placebo
Rufinamide
1309
Lamotrigine
1312
1313
2310,311
Topiramate
Levetiracetam
Felbamate
Ethosuximide
Clobazam
Clonazepam
363
TheEpilepsies
Sodium
valproate
Pla
RF
M
LTG
TP
M
LEV
FB
M
ETX
CLB
CLZ VPA
Placebo(Pla)Rufinamide(RFM)Lamotrigine(LTG)Clonazepam(CLZ)
Topiramate(TPM)Levetiracetam(LEV)Felbamate(FBM)Ethosuximide(ETX)
Sodiumvalproate(VPA)Clobazam(CLB)
10.11.4
10.11.4.1
AdjunctivetreatmentforLennoxGastautsyndrome
Clinicalevidence
Oneeconomicevaluation314ofAEDs,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
364
TheEpilepsies
moreintenseseizures(VERYLOWQUALITY)
Costeffectiveness
Oneeconomicevaluationbasedonadecisionanalyticmodelshowedthatadjunctivelamotrigineis
lesscostlyandmoreeffectivethanplacebointhetreatmentoftotalseizuresanddropattack
seizuresinpeoplewithLennoxGastautsyndrome.Thisevidenceispartiallyapplicableandhas
potentiallyseriouslimitations.
timetofirstseizure,
cognitiveoutcomes
10.11.4.2
Clinicalevidence
Evidencestatements
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedatleast50%
reductioninfrequencyofallmajorseizurescomparedtoplacebo,howeverthereisuncertaintyover
themagnitudeofthisclinicaleffect.(LOWQUALITY)
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplacebofortheproportionof
participantsfreefromdropattackseizures.(VERYLOWQUALITY)
Nosignificantdifferencebetweentopiramateadjunctivetherapyandplacebofortheproportionof
participantsexperiencedatleast50%reductionindropattackseizurefrequency(VERYLOW
QUALITY)
Significantlymoreparticipantstakingtopiramateadjunctivetherapyexperiencedsomnolence
comparedtoplacebo,howeverthereisuncertaintyoverthemagnitudeofitsclinicaleffect.(LOW
QUALITY)
365
TheEpilepsies
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)
366
TheEpilepsies
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
367
TheEpilepsies
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
368
TheEpilepsies
10.11.5
HealtheconomicevidenceofAEDsusedasadjunctivetherapyforchildrenwithLennox
Gastautsyndrome
Twostudies314,315assessingthecosteffectivenessofAEDsusedasadjunctivetherapyinchildrenwith
LennoxGastautsyndromewereidentifiedintheeconomicliteraturesearchandincludedinthe
economicevidencereview.SeeappendixMforfullstudydetails.
Onestudy314wasexcludedbecauseitmeasuredoutcomesintermsofadditionalcostper1%
increaseinsuccessfullytreatedpatientandwasthereforeonlypartiallyapplicable.Theotherstudy
315
wasincludedintheeconomicevidencereview.
Table21: AdjunctivetherapyforchildrenwithLennoxGastautsyndromeEconomicstudy
characteristics
Study
Limitations
315
Applicability
Verdian(2010)
Potentiallyseriouslimitations Partiallyapplicable(d)
(a,b,c)
Benedict(2010)314
(a,b)
(e,f)
OtherComments
comparatorsincluded
lamotrigine,rufinamide
andtopiramate;time
horizon3years;clinical
databasedonindirect
treatmentcomparisonof
datapresentedinclinical
review309,311,312
comparatorsincluded
lamotrigine,rufinamide
andtopiramate;time
horizon3years;clinical
databasedonindirect
treatmentcomparisonof
datapresentedinclinical
review309,311,312;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
369
TheEpilepsies
Table22: AdjunctivetherapyforchildrenwithLennoxGastautsyndromeResultsofVerdian
2010315
AED
Totalcost
()per
patient
Totaleffects ICER
(/QALY)
(QALY)
LTG
21,783
1.42
Atthresholdof20Kand30KperQALY,
probabilityofLTGbeingmorecosteffective
thanRUFis92%and85%respectively
TPM
23,360
1.36
Dominated
byLTG
probabilityofTPMbeingmorecosteffective
thanRUFis48%and35%respectively(a)
RUF
24,992
1.44
154,831
comparedto
LTG
probabilityofRUFbeingmorecosteffective
thanLTGis8%and15%respectively.
probabilityofRUFbeingmorecosteffective
thanTPMis52%and65%respectively.
ICERofRUFmostsensitivetochangesin
initialprobabilitiesofresponseat3months.
Uncertainty
(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
370
TheEpilepsies
AED
Totalcost
()per
patient
ICER
Totaleffects (/1%
(%
increasein
successfully successfully
treated
treated
patients)
patients)
RUF
38,828
7.7%
2,151
Uncertainty
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.
10.11.6
Recommendation
outcomes
specialistwhenachildpresentswithsuspectedLennox
Gastautsyndrome.[new2012]
Reductioninseizuresandminimisingadverseeffectswere
benefitsandharms
LennoxGastautsyndromeisarareepilepsysyndromewhich
requiresinputfromspecialistswithexpertiseinthearea.The
adverseeventsprofileofindividualdrugsneedstobeevaluated
andfullydiscussedwithparents.Thiswasarecommendation
basedontheGDGexpertiseasitisthoughtimportantthat
childrenwithLennoxGastautshouldsee,orreceiveadvicefrom,
aspecialistwhohastheappropriateexperience.
EeconomicevidencerelatingtothetreatmentofLennoxGastaut
syndromewasisolatedtodrugoptionsforuseasadjunctive
therapy.TheGDGconsideredthatdiscussionwith,orreferralto
atertiarypaediatricspecialistandappropriateinterventionin
thisgroupofpatientsmayleadtoabetterprognosisforseizure
control,minimiselongtermcognitivedeteriorationand
associateddecrementstohealthrelatedqualityoflife.
Qualityofevidence
Otherconsiderations
evaluatedandfullydiscussedwithparents.
371
TheEpilepsies
FirstlinetreatmentinchildrenwithLennoxGastautsyndrome
Recommendation
outcomes
117. Offersodiumvalproateasfirstlinetreatmenttochildren
withLennoxGastautsyndrome.Beawareofteratogenic
risksofsodiumvalproate(seerecommendation83).[new
2012]
Seizurefreedom,atleast50%reductioninseizurefrequencyand
withdrawalduetoadverseeventswereconsideredtobethe
benefitsandharms
Thepotentialbenefitsofreducingseizuresneedtobebalanced
againstthepotentialforadverseeffects.NoRCTevidencewas
retrievedonsodiumvalproateinthisarea.Thereishowever
evidencethatsodiumvalproateiseffectiveinreducingseizures
inidiopathicgeneralisedepilepsyandtheGDGopinionwasthat
thisevidencecouldbeextrapolatedtochildrenandyoung
peoplewithLennoxGastautsyndrome.
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.
372
TheEpilepsies
Adjunctivetreatmentinchildren,youngpeopleandadultswithLennoxGastautsyndrome
Recommendation
118. Offerlamotrigineasadjunctivetreatmenttochildren,young
peopleandadultswithLennoxGastautsyndromeiffirstline
treatmentwithsodiumvalproateisineffectiveornot
tolerated.[new2012]
outcomes
importantoutcomes.
benefitsandharms
Lamotrigineadjunctivetreatmentismoreeffectiveinreducingat
least50%theseizurefrequencyandhasasimilarsideeffects
profilewhencomparedtoplacebo.
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.
Sodiumvalproateinhibitsmetabolismoflamotrigineandthis
increaseinlamotriginedose.
Otherconsiderations
373
TheEpilepsies
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.
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.
374
TheEpilepsies
Recommendation
outcomes
benefitandharms
Clinicalpracticesuggeststhatseizurescanbeaggravatedbythese
medications,andcancompromisecognitionwithriskofnon
convulsivestatusepilepticus.TheGDGfeltthatuseofthese
harm.
potentialtoaggravateseizuresmakesthemveryunlikelytobe
costeffective.Aggravationofseizuresislikelytonegatively
use.
Qualityofevidence
Otherconsiderations
Recommendation
outcomes
121. Onlyofferfelbamateincentresprovidingtertiaryepilepsy
specialistcareandwhentreatmentwithalloftheAEDslisted
inrecommendations119and120hasprovedineffectiveor
nottolerated.[new2012]
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.
375
TheEpilepsies
10.12 Benignepilepsywithcentrotemporalspikes,Panayiotopoulos
syndromeandlateonsetchildhoodoccipitalepilepsy(Gastaut
type)
10.12.1
Introduction
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.
10.12.2
includedadultsandchildrenwithBECTS,Panayiotopoulossyndromeandlateonsetchildhood
occipitalepilepsy(Gastauttype).
10.12.3
Matrixoftheevidence
epilepsyinapopulationwithbenignfocalepilepsiesofchildhood.Theinterventionsweincludedin
oursearchwerelamotrigine,levetiracetam,topiramate,gabapentin,oxcarbazepine,sulthiame,
sodiumvalproateandcarbamazepine.WelookedforanyRCTstudiesthatcomparedthe
effectivenessoftwoormoreofthesetreatments(orplacebo).Belowisamatrixshowingwere
evidencewasidentified.Aboxcontainingafigureindicatesthenumberofstudiesthatwerefound
andthattheevidenceforthiscomparisonhasbeenreviewedinthischapter.Anemptyboxindicates
thatnoevidencewasfound,inthiscase,nosectiononthiscomparisonisincludedinthechapter.
376
TheEpilepsies
Placebo
Lamotrigine
Levetiracetam
Topiramate
Gabapentin
Oxcarbazepine
1316
Sulthiame
1317
Sodiumvalproate
Carbamazepine
1318
PLA
CBZ
VPA GBP LEV
TPM OXC
SLM LTG
PLAPlaceboLTGLamotrigineLEVLevetiracetam
TPMTopiramateGBPGabapentinOXCOxcarbazepine
SLMSulthiameVPASodiumvalproateCBZCarbamazepine
10.12.4
10.12.4.1
MonotherapyforthetreatmentofadultsandchildrenwithBECTS,Panayiotopoulos
syndromeandlateonsetchildhoodoccipitalepilepsy(Gastauttype)
Sulthiameversusplacebo
Clinicalevidence
Evidencestatements
Significantlymorepatientstakingsulthiamemonotherapywereseizurefreecomparedtoplacebo.
(HIGHQUALITY)
Nosignificantdifferencebetweensulthiamemonotherapyandplaceboforwithdrawaldueto
adverseevents.(HIGHQUALITY)
Nosignificantdifferencebetweensulthiamemonotherapyandplaceboforwithdrawalduetolackof
efficacy.(LOWQUALITY)
Costeffectiveness
377
TheEpilepsies
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.
378
TheEpilepsies
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
379
TheEpilepsies
cognitiveoutcomes
10.12.5
FirstlinetreatmentinchildrenandyoungpeoplewithBECTs,Panayiotopoulossyndromeandlate
onsetchildhoodoccipitalepilepsy(Gastauttype)
Recommendation
outcomes
122. Discusswiththechildoryoungperson,andtheirfamily
and/orcarers,whetherAEDtreatmentforbenignepilepsy
withcentrotemporalspikes,Panayiotopoulossyndromeor
lateonsetchildhoodoccipitalepilepsy(Gastauttype)is
indicated.[new2012]
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.
Noeconomicevidenceinthispopulationwasavailable;
however,thedecisionastowhethertreatmentisindicatedor
notshouldbemadeverycarefullyasthepossiblecostand
qualityoflifeconsequencescouldbesubstantialifapatients
seizuresarepoorlycontrolled.Ifseizureswerepoorly
controlled,thecostsavingsgeneratedbyoptingagainstdrug
treatmentcouldbequicklyoffsetbyhospitaladmissions,
outpatientappointmentsand/orGPconsultations.
380
TheEpilepsies
Recommendation
Qualityofevidence
Otherconsiderations
122. Discusswiththechildoryoungperson,andtheirfamily
and/orcarers,whetherAEDtreatmentforbenignepilepsy
withcentrotemporalspikes,Panayiotopoulossyndromeor
lateonsetchildhoodoccipitalepilepsy(Gastauttype)is
indicated.[new2012]
Thequalityofevidencerangedfromhightoverylowdepending
onoutcomeandtherewasnoevidencecomparingdrug
treatmenttonotreatmentapartfromsulthiameagainstplacebo
butthisisunlicensedintheUK.Thisrecommendationwasbased
onGDGconsensusopinion.
Recommendation
123. Offercarbamazepineorlamotrigineasfirstlinetreatment
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
381
TheEpilepsies
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.
Althoughnoeconomicevidenceontherelativecosteffectiveness
ofAEDswasavailableforthispopulationspecifically,theGDG
consideredtheresultsoftheeconomicmodellingundertakenfor
thetreatmentoffocalepilepsytobeapplicabletothisgroupof
patientsaswell.AschildrenwithBECTS,Panyaiotopoulos
type)arelikelytorespondtothefirstAEDofferedandarelikelyto
experiencespontaneousremissionduringadolescence,these
drugsmaybeevenmorecosteffectiveinthisgroupthaninthe
generalpopulationofpatientswithfocalepilepsy.
OtherAEDslicensedforuseasmonotherapyinfocalepilepsy,
includinggabapentin,levetiracetamandtopiramate,werenot
showntobecosteffectiveatcurrent2011prices.However,as
nonproprietarylevetiracetamisexpectedtocometomarket
withinthenearfutureanditsrelativecosteffectivenesscompared
withtheAEDslistedinthisrecommendationissensitivetochanges
382
TheEpilepsies
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,200741)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
383
TheEpilepsies
incontraceptives.
differentdrugsanddifferentoptionsmayneedtobetriedwiththe
hopeofgettingthebalancerightbetweenseizurefreedomand
sideeffects.IfthefirstAEDisineffective,asecondAEDshouldbe
addedalongsidetheinitialAEDand,ifseizuresarecontrolled,the
firstAEDmaybewithdrawn,recognisingthatsomepatientswill
prefertoremainontwoAEDsifseizurefree.TheGDGconsidered
thatitisgenerallypreferabletoavoidpolytherapy.
384
TheEpilepsies
Recommendation
124. LevetiracetamisnotcosteffectiveatJune2011unitcostscc.
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.
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
385
TheEpilepsies
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
386
TheEpilepsies
childhoodoccipitalepilepsy(Gastauttype)soweextrapolated
fromfocalseizuresfornewlydiagnosedepilepsy.Onetrialwith
highdropoutratesinbotharmsshowedtherewasnosignificant
differencebetweenlevetiracetamandcarbamazepineinthe
proportionofseizurefreeparticipantsandwithdrawaldueto
adverseevents.However,significantlyhigherproportionof
participantsonlevetiracetamwithdrewduetolackofefficacy
comparedtocarbamazepine.
Otherconsiderations
ThisisapartlyGDGconsensusopinionbasedrecommendation.
Levetiracetamisonlylicensedforpeopleover16yearsold.Itis
usefulbecauseitdoesnotinteractwithhormonal
contraception.TheGDGopinionwasthatthelimitedevidence
currentlyavailablesuggeststhatlevetiracetamdoesnotcarryan
387
TheEpilepsies
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.
guidelineindicatesthattheAEDsusedasadjunctivetherapyfor
refractoryfocalseizuresweremoreeffectiveandmorecostlythan
continuingpatientsonmonotherapy.However,adjunctivetherapy
withasubsetofAEDsmaybecosteffectiveattheNICEthreshold
of20,000perQALY.Thereisconsiderableuncertaintyastowhich
AEDrepresentstheoptimaluseofNHSresourcesasmuchdepends
onwhatisappropriatefortheindividualpatientandonhis/her
previoustreatmenthistory.
388
TheEpilepsies
Qualityofevidence
Thisrecommendationwasbasedontheclinicalexpertiseofthe
GDGandviaconsensus.
Otherconsiderations
Sodiumvalproatewouldnotbefirstchoiceinfemalesofpresentor
teratogenicity.
thelamotriginedose.
389
TheEpilepsies
AdjunctivetreatmentinchildrenandyoungpeoplewithBECTs,Panayiotopoulossyndromeand
lateonsetchildhoodoccipitalepilepsy(Gastauttype)
Recommendation
126. Offercarbamazepine,clobazam,gabapentin,
lamotrigine,levetiracetam,oxcarbazepine,sodium
valproateortopiramateasadjunctivetreatmenttochildren
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
390
TheEpilepsies
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).
Weextrapolatedfromtheeconomicconsiderationsforfocal
seizures.
evidence.
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
391
TheEpilepsies
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
392
TheEpilepsies
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.
393
TheEpilepsies
Recommendation
epilepsyspecialist.OtherAEDsthatmaybeconsideredbythe
tertiaryepilepsyspecialistareeslicarbazepineacetate,
lacosamide,phenobarbital,phenytoin,pregabalin,
tiagabine,vigabatrinandzonisamide.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.
394
TheEpilepsies
Thedrugsrecommendedforconsiderationherewereeffectiveto
varyingdegress,butthetreatmentbenefits,intermsofQALYs
gained,orinsomecaseslost,didnotjustifiedtheadditionalcosts
overdrugsrecommendedinthepreviousrecommendation
(gabapentin,lamotrigine,oxcarbazepine,topiramate).
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.
395
TheEpilepsies
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.
396
TheEpilepsies
10.13 IdiopathicGeneralisedEpilepsy(IGE)
10.13.1
Introduction
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
10.13.2
Epilepsysyndrome
Ageofonset
ChildhoodAbsence
Epilepsy
410years
JuvenileAbsence
Epilepsy
Predominant
seizure
types/frequency
EEG
Prognosis
Absence,
many/day
GTCSinfrequent
3Hzgeneralised
spikeandwave
80%remitby
adulthood
913years
Absence
GTCSin80%
Myoclonicjerks
infrequent
34Hzgeneralised
Lifelong;seizure
spikeandwave
controlin7080%
Photosensitivity8%
Juvenile
myoclonic
epilepsy
516years
Myoclonicjerkson
awakeninginall
GTCSinmost
Absencein>30%
(maybeintial
seizuretype)
36Hzgeneralised Lifelong;seizure
polyspikeandwave controlinupto
Photosensitivityin 90%patients
>30%
EpilepsywithGTCS
only
630years
GTCS12hours
afterwaking
Generalised
polyspikewavein
upto50%patients
Lifelong;seizure
controlin90%
MethodsoftheevidencereviewofIGE
Forthisreviewweincludedadultsandchildrenwiththefollowingsyndromes:Absenceseizures
(childhoodabsenceepilepsy,juvenileabsenceepilepsyandotherabsenceepilepsysyndromes),
JuvenileMyoclonicEpilepsyandEpilepsywithTonicClonicSeizuresonly.
397
TheEpilepsies
10.13.3
Matrixoftheevidence
IGE.Thefollowinginterventionswereincludedinoursearch;clobazam,clonazepam,ethosuximide,
lamotrigine,levetiracetam,sodiumvalproatetopiramateandzonisamide.WelookedforanyRCT
studiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
Belowarethematrixshowingwhereevidencewasidentified.Aboxcontainingafigureindicatesthe
398
TheEpilepsies
Placebo
Lamotrigine
1294
Topiramate
141
Oxcarbazepine
Phenytoin
Clobazam
Clonazepam
Phenobarbital
Primidone
141
LEV
TPM
CLB
CZP
PBT
PRM
Levetiracetam
Acetazolamide
Sodium
valproate
Zonisamide
Carbamazepine
241,(Glaxo
SmithKline
unpublishe
dinHTA)40
Pla
LTG
OXC PHT
399
ACT VPA ZN
TheEpilepsies
MatrixoftheevidenceforIGE
Matrixoftheevidenceforchildhoodabsenceepilepsy,juvenileabsenceepilepsyandother
absenceepilepsysyndromes
Placebo
1319
1320
Topiramate
Ethosuximide
1321
Zonisamide
Clobazam
Clonazepam
Sodium
valproate
341,321,
(Marson
unpub.)
1(Marson
unpub.)
4321,322,
ZNS
CLB
CZP
VPA
Lamotrigine
Levetiracetam
323,324
Pla
LTG
LEV
TPM
400
ETX
TheEpilepsies
MatrixoftheevidenceforJuvenileMyoclonicEpilepsy
Placebo
Lamotrigine
Levetiracetam
298
Topiramate
Clobazam
Clonazepam
Zonisamide
Sodium
valproate
1297;
1(Marson,
unpub.)
LEV
TPM
Pla
2,
(Marson,
unpub.)
165,
LTG
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
10.13.4.1
MonotherapyforthetreatmentofIGEinnewlydiagnosedpatients
Clinicalevidence
Twoeconomicevaluations161,181ofAEDs,includinglamotrigineandsodiumvalproate,usedas
monotherapyinthetreatmentofpeoplewithnewlydiagnosedIGEwereidentifiedandincludedin
theeconomicliteraturesearch.Thecompleteresultsofthesestudiesarepresentedinsection
10.13.6.
Evidencestatements
Sodiumvalproatemonotherapyissignificantlymoreeffectivethanlamotriginemonotherapyin
prolongingtimetoexit/withdrawal(MODERATEQUALITY).
Timetofirstseizureoccurredsignificantlymorerapidlyonsodiumvalproatemonotherapycompared
tolamotriginemonotherapy.(MODERATEQUALITY)
401
TheEpilepsies
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.
402
TheEpilepsies
10.13.4.2
Clinicalevidence
Oneeconomicevaluation161ofAEDs,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
403
TheEpilepsies
tobecosteffectivecomparedwithsodiumvalproatewhenusing2010drugcosts(ICER=944per
QALYgained).Thisevidenceisdirectlyapplicablebuthaspotentiallyseriouslimitations.
showsthatinthetreatmentofidiopathicgeneralisedepilepsy,topiramatemonotherapyismore
costly,butlesseffectiveatpreventingseizuresthansodiumvalproatemonotherapy.Thisevidenceis
partiallyapplicablebuthaspotentiallyseriouslimitations.
cognitiveoutcomes.
10.13.4.3
Clinicalevidence
Oneeconomicevaluation161ofAEDs,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.
404
TheEpilepsies
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
10.13.5.1
Adjunctivetherapyinchildren,youngpeopleandadultswithIGE
Clinicalevidence
Nostudieswereidentifiedintheeconomicliteraturesearch,howevertheNCGCmodelevaluating
adjunctiveAEDsinthetreatmentofadultswithrefractorygeneralisedtonicclonicseizuresused
clinicalevidencefromthiscomparison.Forresultsofthisanalysis,seesection10.5.8.
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapywereseizurefree
comparedtoplacebo.(MODERATEQUALITY)
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadatleasta50%
reductioninseizurefrequencycomparedtoplacebo.(MODERATEQUALITY)
405
TheEpilepsies
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
Twoeconomicevaluations161,181assessingthecosteffectivenessofAEDsusedasmonotherapyin
patientswithnewlydiagnosedIGEwereidentifiedintheeconomicliteraturesearchandincludedin
theeconomicevidencereview.SeeappendixMforfullstudydetailsandassessmentsoflimitations
andapplicability.Thesestudieswereconsideredsufficienttoinformrecommendationsinthis
population,thereforenooriginaleconomicmodellingwasundertaken.
Table25: MonotherapyforpatientswithIGEEconomicstudycharacteristics
Study
Limitations
161
Marson(2007)
Applicability
Potentiallyseriouslimitations Directlyapplicable
(a,b)
(c)
406
OtherComments
Economicevaluation
conductedalongsideRCT;
comparatorsincluded
sodiumvalproate,
lamotrigineand
topiramate;2yeartime
TheEpilepsies
Study
Limitations
Applicability
OtherComments
horizon;effectmeasured
asQALYsgained
Marson(2007)161
(a,b)
(c,d)
Economicevaluation
conductedalongsideRCT;
comparatorsincluded
sodiumvalproate,
lamotrigineand
topiramate;2yeartime
horizon;effectmeasured
asseizuresavoided
Hawkins(2005)181
Potentiallyseriouslimitations Partiallyapplicable(h)
(e,f,g)
15yeartimehorizon;
effectivenessdatabased
onanunpublished
study275
(a) SensitivityanalysisincompleteinthatitonlypresentscomparisonsofVPAvLTGandVPAvTPMbutfailstopresent
comparisonofLTGvTPM.
(b) Unitcostsestimatesarefrom2005.
(c) StudypopulationincludedpatientswithIGE(63%)andsomepatientswithanunclassifiedepilepsy(27%).
(d) Analysisofcostperseizuresavoided,notQALYs.
(e) Costsdiscountedat3.5%perannum;QALYsdiscounted1.5%perannum.
(f) Unitcostestimatesarefrom20012002.
275
(g) Treatmenteffectsbasedonresultsofanunpublishedstudy thatwasnotincludedinNCGCsystematicreview.
(h) Didnotincludeallcomparatorsrelevanttotheguidelinereview,namelytopiramate.
Table26: MonotherapyforpatientswithIGEEconomicstudycharacteristics
Totalcost
()per
patient
Totaleffects ICER
perpatient
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
TPMhasa95%probabilityofbeingcost
effectivecomparedtoVPA.Atawillingness
topaythresholdof30,000/QALY,thisfigure
is97%.
LTG
1,906(a)
1.701
Dominated
LTGhasa63%probabilityofbeingcost
effectivecomparedtoVPA.Atawillingness
topaythresholdof30,000/QALY,thisfigure
is68%.
(total
seizures)
(/seizure
avoided)
AED
Costperseizureavoided
analysis
407
TheEpilepsies
AED
Totalcost
()per
patient
Totaleffects ICER
perpatient
VPA
1,136
44.1
willingnesstopaythresholdof1,600/seizure
avoided,VPAhasan84%and99%probability
ofbeingcosteffectivecomparedtoTPMand
LTG,respectively.
TPM
1,568
75.1
Dominated
avoided,TPMhasa16%probabilityofbeing
costeffectivecomparedtoVPA.
LTG
1,761(a)
120.9
Dominated
avoided,LTGhasa1%probabilityofbeing
costeffectivecomparedtoVPA.
Uncertainty
(a) Unitcostsestimatesarefrom2005,andsincethen,unitcostsoflamotrigineandtopiramatehavereducedandmay
changeconclusionsofthecosteffectivenessanalysis.
AstheunitcostsofantiepilepticdrugsusedintheSANADtrialwerefrom2005andtheunitcostsof
lamotrigineandtopiramatehavechangeddramaticallysincethen,itwasconsideredappropriateto
updatetheseandperformanincrementalanalysisbasedoncurrentAEDcosts.Currentunitcostsfor
lamotrigine,sodiumvalproate,andtopiramateweretakenfromtheBNF59325andaweighted
averagecostpermilligramwascalculatedbasedonrelativequantitiesprescribedfromthe
PrescriptionCostAnalysis2008326.Totaldrugcostswerethencombinedwiththehospitalisationand
othercostspublishedinSANADtocalculateamorecurrentaveragecostperpatient.Theupdated
resultsarepresentedintable10.21.
Table27: MonotherapyforpatientswithIGEResultsofMarson2007161
Totalcost
()per
patient(a)
Totaleffects ICER
perpatient
Uncertainty(b)
CostperQALYanalysis
(QALYs)
(/QALY)
LTG
1,090
1.701
Dominated
Noanalysisofuncertaintycouldberecreated
intheupdateofdrugunitcosts.
VPA
1,476
1.648
Dominated
TPM
1,565
1.809
4,402
Costperseizureavoided
analysis
(total
seizures)
(/seizure
avoided)
LTG
1,090
120.9
VPA
1,476
44.1
TPM
1,565
75.1
Dominated
AED
(a) Inthepublishedanalyses,estimatesoftotalcostwereslightlydifferentduetodifferentnumbersofpatientsbeing
includedinthecostperQALYandcostperseizureavoidedanalyses.Inthisrecalculation,theyreassumedtohavebeen
thesame.
(b) Uncertaintyisnotreflectedinthesenewestimates,asbootstrappedestimatescouldnotberecalculatedorcost
effectivenessacceptabilitycurvesreplotted.
(c) Sodiumvalproateismorecostlyandmoreeffectiveinpreventingseizures.Noexplicitwillingnesstopayperseizure
avoidedthresholdexiststoassessthecosteffectivenessofinterventionsonthismeasure.
408
TheEpilepsies
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 ICER
patient
(/QALY)
VPA
4,288
9.814
Atathresholdof30,000perQALY,VPAhasa
95%probabilityofbeingoptimal.
LTG
6,675(a)
9.748
Dominate
d
Atathresholdof30,000perQALY,LTGhasa
5%probabilityofbeingoptimal.
Uncertainty
(a) Theanalysisusedunitcostsfrom200102.Sincethen,thecostofLTGhasreduceddramaticallyandmayaffect
conclusions.
Evidencestatements
Evidencefromacosteffectivenessanalysisindicatesthatlamotriginemonotherapyismorecostly
andlesseffectivethansodiumvalproateintermsoftotalQALYsgained.Theevidenceispartially
applicablebutasitusescostsfrom200102,ithaspotentiallyseriouslimitations.
10.13.7
10.13.7.1
Monotherapyforthetreatmentofchildhoodabsenceepilepsy,juvenileabsenceepilepsy
andotherabsenceepilepsysyndromes
Clinicalevidence
Nostudieswereidentified.
Evidencestatements
Significantlymoreparticipantsinsodiumvalproatemonotherapywereseizurefreeatonemonth
comparedtolamotriginemonotherapy(LOWQUALITY).
409
TheEpilepsies
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.
410
TheEpilepsies
10.13.7.2
Clinicalevidence
Evidencestatements
Sodiumvalproatemonotherapyissignificantlymoreeffectivethantopiramatemonotherapyin
prolongingtimetoexit/withdrawalofallocatedtreatmentat12monthsfollowup(MODERATE).
theincidenceoftiredness,drowsiness,fatigueandlethargyat12monthsfollowup(VERYLOW
QUALITY).
theincidenceofotheradverseevents(forfulllistpleaseseeextractionsinAppendixL)at12months
followup(VERYLOWQUALITY).
Costeffectiveness
patientsandnoothereconomicstudiescomparingtopiramatemonotherapytosodiumvalproate
monotherapyinapopulationofpatientswithCAEorJAEwereidentified.
seizurefreedom
cognitiveoutcomes
411
TheEpilepsies
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
412
TheEpilepsies
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:
413
TheEpilepsies
headache(VERYLOWQUALITY).
Cognitiveeffectstatisticallynonsignificantresults
Nosignificantdifferencebetweenethosuximidemonotherapyandlamotriginemonotherapyin
attentionaldysfunctionat1620weeksfollowup(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingethosuximidemonotherapytolamotriginemonotherapyina
populationofpatientswithCAEorJAEwasidentified.
timetofirstseizure
10.13.7.5
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenlevetiracetamandplaceboforseizurefreedom.(VERYLOW
QUALITY)
Nosignificantdifferencebetweenlevetiracetamandplacebofor50%reductioninseizurefrequency.
(VERYLOWQUALITY)
Nosignificantdifferencebetweenlevetiracetamandplaceboforwithdrawalduetoadverseevents.
(VERYLOWQUALITY)
timetofirstseizure
414
TheEpilepsies
outcomesrelatingtoadverseevents
10.13.8
10.13.8.1
Adjunctivetherapyforthetreatmentofchildhoodabsenceepilepsy,juvenileabsence
epilepsyandotherabsenceepilepsysyndromes
Sodiumvalproateversusethosuximide
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenvalproicacidadjunctiveandethosuximideadjunctiveforthe
proportionofparticipantswithatleast80%reductioninseizurefrequency(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingadjunctivevalproicacidtoadjunctiveethosuximideinapopulation
ofpatientswithCAEorJAEwasidentified.
seizurefrequency
timetofirstseizure
outcomesrelatingtocognitiveeffects
10.13.9
10.13.9.1
MonotherapyforthetreatmentofJuvenileMyoclonicEpilepsy(JME)
Clinicalevidence
415
TheEpilepsies
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.
416
TheEpilepsies
10.13.10
10.13.10.1
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)
417
TheEpilepsies
appetiteincrease(VERYLOWQUALITY)
abnormalvision(VERYLOWQUALITY)
tiredness,drowsiness,fatigueorlethargy(VERYLOWQUALITY)
otheradverseevents(seeevidenceextractionAppendixL)(VERYLOWQUALITY).
Costeffectiveness
Noeconomicevidencecomparingtopiramatemonotherapy/adjunctivetherapytosodiumvalproate
monotherapy/adjunctivetherapyinapopulationofpatientswithJMEwasidentified.
cognitiveoutcomes
outcomesrelatingtoqualityoflife
10.13.11
10.13.11.1
AdjunctivetreatmentforforthetreatmentofofJuvenileMyoclonicEpilepsy(JME)
Clinicalevidence
Evidencestatements
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyweremyoclonicseizure
freecomparedtoplacebo;however,thereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapywereseizurefree(any
seizuresubtype);howeverthereisuncertaintyinthemagnitudeoftheclinicaleffect(LOW
QUALITY).
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyachieved50%orabove
reductioninmyoclonicseizurefrequencycomparedtoplacebo(MODERATEQUALITY).
Thereisnosignificantdifferencebetweenthelevetiracetamadjunctivegroupandtheplacebogroup
ontheincidenceof:
418
TheEpilepsies
Significantlymoreparticipantsreceivinglevetiracetamadjunctivetherapyhadexperienced
improvementinhealthrelatedqualityoflifecomparedtoplacebo(MODERATEQUALITY).
Costeffectiveness
Noeconomicevidencecomparinglevetiracetamadjunctivetherapytoplaceboinapopulationof
patientswithJMEwasidentified.
timetofirstseizure
cognitiveeffects
10.13.12
AEDsforthetreatmentofepilepsywithgeneralisedtonicclonicseizuresonly
10.13.13
Introduction
Epilepsywithgeneralisedtonicclonicseizuresaloneisasdescribed;allindividualshavegeneralised
tonicclonicseizures,1753%12hoursafterawakening.Howeverseizuresmayalsooccurduring
relaxationorleisure,orindeedatothertimes.Ithasanageofonset630years,peak1617years.
InterictalEEGshowsanormalbackgroundwithgeneralisedspikewaveandmultiplespikewave
dischargesof24Hz.Seizuresmaybeprecipitatedbysleepdeprivationandexcessivealcohol
consumption.
10.13.14
includedadultsandchildrenwithepilepsywithgeneralisedtonicclonicseizuresonly.
10.13.15
Matrixoftheevidence
Pleaseseesection10.5inthegeneralizedtonicclonicseizuresevidencereviewforclinicalevidence
relatingtoepilepsywithgeneralisedtonicclonicseizuresonly.
10.13.16
IdiopathicGeneralisedEpilepsy(useforunclassifiedIGEforspecificsyndromessee
below)
FirstLinetreatmentinchildren,youngpeopleandadultswithIGE
419
TheEpilepsies
Recommendation
youngpeopleandadultswithnewlydiagnosedIGE,
particularlyifthereisaphotoparoxysmalresponseonEEG.Be
awareofteratogenicrisksofsodiumvalproate(see
129. Offerlamotrigineddifsodiumvalproateisunsuitableornot
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.
dd
420
TheEpilepsies
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.
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.
Otherconsiderations
CliniciansshouldconsiderthatVPAmayinhibitthehepatic
421
TheEpilepsies
metabolismofotherdrugsandenzymeinducingdrugsmay
enhancethemetabolismofVPA.
422
TheEpilepsies
commendation
130. Considertopiramatebutbeawarethatithasaless
favourablesideeffectprofilethansodiumvalproateand
lamotrigine.[new2012]
outcomes
TheGDGplacedimportanceonefficacyasmeasuredbytimeto
withdrawal,timetofirstseizureandtimeto12monthremission,
adverseeventsandcosteffectivenessinthetrials.
benefitsandharms
Inacomparativetrialofsodiumvalproateveruslamotrigineverus
topiramate,sodiumvalproatewassignificantlybetteratprolonging
thetimetoexitcomparedtotopiramatewhereastopiramatewas
significantlybetteratprolongingtimetofirstseizurethan
lamotrigine,althoughtherewasuncertaintyinthemagnitudeof
clinicaleffect.
Howevertopiramatehasdisadvantagesduetodruginteractions
anditsadverseeventsprofile.
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
Adjunctivetreatmentinchildren,youngpeopleandadultswithIGE
423
TheEpilepsies
Recommendation
outcomes
131. Offerlamotrigine,levetiracetam,sodiumvalproateor
topiramateasadjunctivetreatmenttochildren,young
peopleandadultswithIGEiffirstlinetreatments(see
recommendations128,129and130)areineffectiveornot
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.
424
TheEpilepsies
Recommendation
outcomes
epilepsyspecialistandconsiderclobazam,clonazepamor
outcome.
benefitsandharms
TheGDGconsensuswasthatclobazam,clonazepamorzonisamide
werepossiblealternativesinaccordancewithtertaryepilepsycare.
TheGDGconsidereditimportanttomentionthesedrugsas
potentialoptionstooffertopatientsbetweenthetimeofreferral
toandconsultationwithatertiaryspecialist.Itwasthoughtthat
thesearesomeofthedrugsthatatertiaryspecialistmightuse,
basingthedecisiononclinicalexperiencetreatingpatientswith
refractorygeneralisedseizuretypes.
onthecosteffectivenessofclobazam,clonazepamorzonisamide.
Qualityofevidence
TherewasnoevidenceavailableforIGEforthesedrugssothis
recommendationwasbasedonGDGclinicalexpertise.
Otherconsiderations
seizures.
Recommendation
outcomes
benefitsandharms
Clinicalpracticesuggeststhatmyoclonicseizurescanbe
aggravatedbythesemedications.TheGDGfeltthatuseofthese
harm.
425
TheEpilepsies
Recommendation
potentialtoaggravateIGEmakesthemveryunlikelytobecost
effective.Aggravationofseizuresislikelytonegativelyimpact
Qualityofevidence
Otherconsiderations
JuvenileMyoclonicEpilepsy(JME)
Firstlinetreatmentinchildren,youngpeopleandadultswithJME
Recommendation
outcomes
youngpeopleandadultswithnewlydiagnosedJME,unlessit
isunsuitable.Beawareofteratogenicrisksofsodium
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
426
TheEpilepsies
Recommendation
Otherconsiderations
youngpeopleandadultswithnewlydiagnosedJME,unlessit
isunsuitable.Beawareofteratogenicrisksofsodium
subgroupwhichtheauthorsdidnotanalysestatisticallyduetothe
smallnumberandimbalanceofdistribution.Theotherlarger
unblindedstudy(SANAD)foundonlysodiumvalproatetohave
longertimetofirstseizurethanlamotrigine.
CliniciansshouldconsiderthatVPAmayinhibitthehepatic
metabolismofotherdrugsandenzymeinducingdrugsmay
enhancethemetabolismofVPA.
427
TheEpilepsies
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
428
TheEpilepsies
pregnancy.
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
429
TheEpilepsies
smallnumberandimbalanceofdistribution.Theotherlarger
unblindedstudy(SANAD)foundonlysodiumvalproatetohave
longertimetofirstseizurethanlamotrigine.Datafor
levetiracetamasadjunctivetherapycamefromastudywhereall
participantshadmyoclonicseizuresandahighpercentagehad
juvenilemyoclonicseizures.GDGopinionwasalsousedtoinform
recommendations.
Otherconsiderations
Adjunctivetreatmentinchildren,youngpeopleandadultswithJME
Recommendation
outcomes
peopleandadultswithJMEiffirstlinetreatments(see
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.
430
TheEpilepsies
Recommendation
Otherconsiderations
peopleandadultswithJMEiffirstlinetreatments(see
HowevertherewasonlyonedoubleblindstudyofIGEwith
myoclonicseizureswhere93.4%hadjuvenilemyoclonicepilepsy
and6.6%hadjuvenileabsenceepilepsy.
Recommendation
outcomes
ineffectiveornottolerated,discusswith,orreferto,a
tertiaryepilepsyspecialistandconsiderclobazam,
clonazepamorzonisamide.[new2012]
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.
431
TheEpilepsies
Recommendation
clonazepamorzonisamide.[new2012]
Recommendation
outcomes
benefitsandharms
ClinicalpracticesuggeststhatJMEcanbeaggravatedbythese
medications.TheGDGfeltthatuseofthesemedicationswould
leadtonoclinicalbenefitandcouldcauseharm.
effectivenessoftheseAEDsinthispopulation,howevertheir
potentialtoaggravateJMEmakesthemveryunlikelytobecost
effective.Aggravationofseizuresislikelytonegativelyimpact
Qualityofevidence
Otherconsiderations
432
TheEpilepsies
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.
Noeconomicevidencewasidentifiedintheliteratureandno
economicevaluationwasundertakentoinformthecost
effectivenessoffirstlineAEDsusedtotreatnewlydiagnosed
patientsexperiencinggeneralisedtonicclonicseizures.TheGDG
433
TheEpilepsies
feltthatanextrapolationfromtheSANADstudypopulationwith
generalisedepilepsiestoapopulationwithgeneralisedtonicclonic
seizureswasappropriateandthattherelativecosteffectivenessof
sodiumvalproatewasunlikelytobedifferentbetweenthese
groups.
oftheSANADtrial161.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
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.
434
TheEpilepsies
Furthermore,intheabsenceofsuchevidenceitisimpossibleto
measurelevetiracetamsrelativecosteffectivenesscomparedto
otherdemonstrablycosteffectiveAEDsusedtotreattonicclonic
seizures.Consequently,levetiracetamisrecommendedas
adjunctivetherapy,whereevidenceisavailabletodemonstrateits
clinicalandcosteffectiveness.
TheGDGconsidereditimportanttodirectusersoftheguidelineto
therecommendationsforthetreatmentofmyoclonicseizuresand
juvenilemyoclonicepilepsywhereotherdrugs,including
topiramateandlevetiracetam,maybeconsideredifsodium
valproateorlamotrigineareunsuitable.
Recommendation
outcomes
140. Considercarbamazepineandoxcarbazepinebutbeaware
oftheriskofexacerbatingmyoclonicorabsenceseizures.
[new2012]
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.
Noeconomicevidenceforcarbamazepineoroxcarbazepineina
populationwithepilepsywithgeneralisedtonicclonicseizures
onlyorgeneralisedepilepsywasavailable.TheGDGconsidered
theirrelativecosteffectivenesscomparedtosodiumvalproate
andlamotrigineinpopulationswithfocalepilepsyandconcluded
thatitmightbebroadlysimilar.However,theGDGconsidered
thatcarbamazepineandoxcarbazepinemayaggravateother
seizuretypes,thusnegativelyimpactingpatientqualityoflifeand
potentiallyincreasingNHSresourceuse.Onthisbasis,theyfeltit
wouldbeamoreefficientuseofNHSresourcestoconsiderthese
435
TheEpilepsies
Recommendation
140. Considercarbamazepineandoxcarbazepinebutbeaware
oftheriskofexacerbatingmyoclonicorabsenceseizures.
[new2012]
AEDsonlyafterlamotrigineorsodiumvalproatehavebeentried
andotherseizuretypeshavehadtimetopresent.
Qualityofevidence
intoconsideration.Therewasalackofpowerofstudies
evidencewasverylowwithpoorreportingofrandomisation
studies.
Otherconsiderations
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
TheGDGconsideredtheevidencefromtheeconomicevaluation
undertakenfortheguidelineinwhichlamotrigineemergedasa
verycosteffectiveadjunctivetherapyinpatientsexperiencing
refractorygeneralisedtonicclonicseizures.Iflamotriginehad
beentriedpreviously,levetiracetamwasalsolikelytobeacost
effectiveadjunctiveAED.Topiramatewasnotshowntobecost
effective,butintheeventthatotheralternativesfailtoproduce
436
TheEpilepsies
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.
437
TheEpilepsies
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
438
TheEpilepsies
Recommendation
143. Offerlamotrigineifethosuximideandsodiumvalproateare
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.
439
TheEpilepsies
Adjunctivetreatmentinchildren,youngpeopleandadultswithchildhoodabsence
epilepsy,juvenileabsenceepilepsyandotherabsenceepilepsysyndromes
Recommendation
144. IftwofirstlineAEDs(seerecommendations142and143)are
ineffectiveinchildren,youngpeopleandadultswithabsence
epilepsysyndromes,consideracombinationoftwoofthese
threeAEDsasadjunctivetreatment:ethosuximide,
lamotrigineorsodiumvalproate.Beawareoftheteratogenic
2012]
outcomes
TheGDGconsideredseizurefreedom,reductioninseizure
frequencyandadverseeventstobethemostimportantoutcomes
benefitsandharms
TheGDGconsideredthatifatleasttwoofthefirstlineAEDshave
failedtoproducethedesiredeffect(seizurefreedom),thenitis
appropriatetotryawelltoleratedcombinationoftwoofthem.
Althoughthereisnoevidenceinthispopulationspecifically,GDG
experienceisthatanyofthethreecanbesafelycombinedand
giventheireffectivenessasindividualdrugs,theexpectationisthat
theyareeffectiveincombination.
Cautionshouldbeusedwithsodiumvalproateingirlsofchild
bearingpotential.
costeffectivenessofanyAEDsusedasmonotherapyoradjunctive
therapytotreatCAE,JAEorgeneralisedabsenceseizures.There
wasnoevidencetosuggestthatanyspecificcombinationof
ethosuximide,lamotrigineandsodiumvalproateisbetterthan
another.Anycombinationisexpectedtobebroadlysimilarin
termsofcostaswell.Therefore,theGDGconsideredthatclinical
judgementandpatientchoiceshouldguidethedecisionforwhich
ofthelikelycosteffectiveAEDcombinationstooffer.
Qualityofevidence
Theevidencebaseforthisrecommendationwasextrapolatedfrom
theevidenceforeachofthesedrugsasmonotherapyinnewly
diagnosedabsenceseizuresandwassupportedbyGDGconsensus.
440
TheEpilepsies
Recommendation
outcomes
clonazepam,levetiracetam,topiramateorzonisamide.
[new2012]
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.
441
TheEpilepsies
Recommendation
outcomes
benefitsandharms
Clinicalpracticesuggeststhatabsenceseizurescanbeaggravated
bythesemedications,andcancompromisecognitionwithriskof
nonconvulsivestatusepilepticus.TheGDGfeltthatuseofthese
harm.
use.
Qualityofevidence
Otherconsiderations
442
TheEpilepsies
10.14 Otherepilepsysyndromes
10.14.1
Introduction
Thereremainfurtherepilepsysyndromeswithrecognizablecharacteristicelectroclinicalfeaturesin
whichnaturalhistoryandprognosisareknown.Manyofthesesyndromesarerareandevidence
basewithregardtotheirmanagementlacking.Inviewofthis,inmanyindividualsmanagementmay
becontinuedundertertiarypaediatricneurologycare.
Clinicalevidence
Noevidencewasretrievedforotherepilepsysyndromes.
10.14.2
147. Refertoatertiarypaediatricepilepsyspecialistallchildren
andyoungpeoplewithcontinuousspikeandwaveduring
slowsleep,LandauKleffnersyndromeormyoclonicastatic
epilepsy.[new2012]
Manychildrenwiththesesyndromesareveryunlikelytoachieve
seizurefreedom.Thechildrenusuallyhaveadditionallearning
disabilities.Optimalseizurecontrolwithoutunacceptableside
effectswasthereforethemostimportantoutcomeforthis
recommendation.
Recommendation
outcomes
benefitsandharms
NoRCTstudieswerefoundandthereforethisrecommendationis
basedontheconsensusopinionoftheGDG.Thesesyndromes,if
untreated,canleadtosignificantcognitiveimpairmentand
reducededucationalpotential,withahighriskofcomorbidities.
TheGDGfeltthatitwasimportantthatthesechildrenbereferred
toatertiaryepilepsyspecialisttomanagetheircare.
ingroupswithCSWS,LKSorMAE.
Qualityofevidence
NoRCTdatawasavailableforanyofthesesyndromes.This
recommendationisbasedonGDGconsensusopinion.
Otherconsiderations
None.
443
TheEpilepsies
10.14.3
10.14.3.1
EpilepsySyndromes
WhataretheinitialandaddonAEDsofchoiceinthetreatmentoftheepilepsysyndromeswith
onsetinchildhood,forexample,myoclonicastaticepilepsyandDravetsyndrome?
Whythisisimportant
Despitetheneedtodiagnoseindividualepilepsysyndromes,thereislittleevidenceforthemost
multicentrerandomisedcontrolledcomparativetrialswithcentralisednationaldata
collection
theketogenicdietasoneoftherandomisedtreatments
anattempttoobtaindataonpharmacoresistance
thepossibilityofincludingallchildrenwithspecificepilepsysyndromesforconsiderationin
thetrial.
10.15 Prolongedseizuresandconvulsivestatusepilepticus
10.15.1
Introduction
Generalisedseizures(TC,tonic,clonic)
Inthepast,statusepilepticus(SE)wasdefinedasaseizurelastinglongerthan30minutesortwoor
moreseizureswithin30minuteswithoutareturntothebaselinelevelofconsciousnessbetween
seizures.Morerecently,thedefinitionevolvedtobeaseizurelongerthan5minutesortwoormore
seizureswithoutareturnofconsciousnessbetweenseizures327.Serialseizuresaredefinedas3or
moretonicclonicseizuresinanhour.
SEcanbedividedintoanumberofsubtypes,eitherbyseizuretypeorbyresponsetotreatment.
ClinicalSEcanbeeitherfocalorgeneralised,andeachofthesetypescanbedividedbyduration:
earlySE(530minutes)
establishedSE(>30minutes)
refractorySE(seizurespersistdespitetreatmentwithadequatedosesoftwoorthreeinitial
anticonvulsantmedications)327.
TheBNFstatesthat:immediatemeasurestomanagestatusepilepticusincludepositioningthe
patienttoavoidinjury,supportingrespirationincludingtheprovisionofhighflowoxygen,
maintainingbloodpressure,andthecorrectionofanyhypoglycaemia.Parenteralthiamineshouldbe
consideredifalcoholabuseissuspected;pyridoxineshouldbegivenifthestatusepilepticusiscaused
bypyridoxinedeficiency.
444
TheEpilepsies
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.
10.15.2
Forthisreviewweincludedpeoplewithprolongedseizuresandconvulsivestatusepilepticus.
10.15.3
Matrixoftheevidence
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
1328
445
TheEpilepsies
Intravenous
diazepam
1328
1328
Pla
RIV
LZP
IVDZP
RIV
DZP
Rectal/Intravenou
sdiazepam
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinchildren(community)
Placebo
Buccal/intranasal
midazolam
Rectal/Intravenous
diazepam
4329331,332
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
1335
Intravenous
diazepamand
phenytoin
Intravenous
phenytoin
1336
1336
1336
446
TheEpilepsies
Intravenous
phenobarbital
1336
1336
1337
2*338,
339
IVDZP
IVDZP,
PHT
IV
PBT
IVPBT,
PHT
IV
VPA
1336
Intravenous
phenobarbital
andphenytoin
Intravenous
sodiumvalproate
Pla
IVLZP
IV
PHT
Matrixoftheevidenceforthetreatmentofconvulsivestatusepilepticusinchildren(initial
treatmentinER)
Placebo
Buccal/intranasal
midazolam
Rectal/Intravenous
diazepam
3329331
Intramuscular
midazolam
Intravenous
diazepam
1340
Intranasal
lorazepam
Intramuscular
paraldehyde
1341
RIV
DZP
IMMDM
IV
DZP
INLZP
IM
PLH
Pla
BINMDM
Matrixoftheevidenceforthetreatmentofrefractorystatusepilepticusinchildren
Placebo
Intravenous
diazepam
Intranasal
lorazepam
Sodium
valproate
infusion
1342
447
TheEpilepsies
Midazolam
infusion
Diazepam
infusion
1343
1344
Intravenous
lidocaine
1345
Intravenous
propofol
1346
Pla
IVDZP
IN
LZP
VPA
IF
MDMIF
DZP
IF
RVPA
IV
MDM
IVLID
IVPRF
Rectalsodium
evaporate
Intravenous
Midazolam
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
448
TheEpilepsies
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
449
TheEpilepsies
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
10.15.5.1
Treatmentofprolongedseizuresandconvulsivestatusepilepticusinchildren(community)
Buccalmidazolamversusrectaldiazepam
Clinicalevidence
Evidencestatements
450
TheEpilepsies
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
451
TheEpilepsies
incidenceofadverseevents.
10.15.6
10.15.6.1
Treatmentofacuterepetitiveseizures(childrenandadults)
Diazepamgelversusplacebo
Clinicalevidence
Evidencestatements
Nosignificantdifferencewasfoundbetweendiazepamgelandplacebofortheproportionofseizure
freeparticipants.(LOWQUALITY)
Significantlymoreparticipantsreceivingdiazepamgelexperiencedsomnolencethanplacebo.(LOW
QUALITY)
Costeffectiveness
Noeconomicevidencecomparingdiazepamgeltoplaceboinpatientswithacuterepetitiveseizures
wasidentified.
10.15.7
10.15.7.1
Treatmentofconvulsivestatusepilepticusinadultsinhospitals
Intravenousdiazepamandphenytoinversusintravenousphenobarbital
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenintravenousdiazepamwithphenytoinand
phenobarbitalinachievingseizurefreedom.(VERYLOWQUALITY)
452
TheEpilepsies
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.
453
TheEpilepsies
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)
454
TheEpilepsies
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoIVdiazepaminpatientswithconvulsivestatus
Therewerenostudiesthatreportedincidenceofadverseevents.
10.15.7.5
IVlorazepamversusIVdiazepamplusphenytoin
Clinicalevidence
Evidencestatements
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamand
phenytoininachievingseizurefreedom.(VERYLOWQUALITY)
Nostatisticallysignificantdifferencebetweenintravenouslorazepamandintravenousdiazepamand
phenytoinfortheincidenceof:
Costeffectiveness
NoeconomicevidencecomparingIVlorazepamtoIVdiazepamandphenytoininpatientswith
10.15.7.6
IVlorazepamversusIVphenytoin
Clinicalevidence
Evidencestatements
455
TheEpilepsies
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
456
TheEpilepsies
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.
Fourcostminimisationstudies347350comparingintravenousphenytointointravenousfosphenytoin
wereindentifiedintheeconomicliteraturesearch.Allfourwereexcludedfromthehealtheconomic
evidencereviewduetothefactthattheyhadpoorapplicabilityandpotentiallyserious
methodologicallimitations.SeeeconomicevidencetableinappendixMfordetails.
Despitethepoorapplicabilityandpotentiallyseriouslimitationsofthesestudies,theyhighlight
importanteconomicconsiderations.Thestudiesassumethatphenytoinandfosphenytoinare
bioequivalentandhaveequivalentefficacy,thereforethereshouldbenobetweendrugdifferences
intermsoftheproportionofpatientsachievingseizurecontrol.Thus,differencesintreatment
relatedcostsbetweenthedrugsarelikelytobedrivenbythetimespentintheemergency
departmentandthemanagementofdrugrelatedadverseevents.Thestudiesassertthat
fosphenytoincanbeadministeredmorerapidlyandthatithasalowerincidenceofadverseevents
457
TheEpilepsies
thanphenytoin.Consequently,costdifferencesbasedontheseoutcomesmayfavourfosphenytoin.
However,withoutpublishedevidencespecificallycomparingfosphenytoinwithphenytoininpatients
withconvulsivestatusepilepticus,anyextrapolationoftheresultsconductedinotherpatientgroups
mustbetreatedwithcaution.
10.15.8
10.15.8.1
Treatmentofconvulsivestatusepilepticusinchildren
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)
458
TheEpilepsies
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
459
TheEpilepsies
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)
460
TheEpilepsies
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
461
TheEpilepsies
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)
462
TheEpilepsies
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.
463
TheEpilepsies
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)
464
TheEpilepsies
Costeffectiveness
NoeconomicevidencecomparingIVmidazolamtorectalsodiumvalproateinchildrenwith
10.15.9.6
IVMidazolamversusIVpropofol
Clinicalevidence
Evidencestatements
Nosignificantdifferencebetweenintravenousmidazolaminfusionandintravenouspropofolforthe
Nosignificantdifferencebetweenintravenousmidazolaminfusionandintravenouspropofolforthe
incidenceof:
elevatedserumcreatinephosphokinase(VERYLOWQUALITY)
serumtriglyceridecholesterol(VERYLOWQUALITY)
apnoea(VERYLOWQUALITY).
Costeffectiveness
NoeconomicevidencecomparingIVmidazolamtoIVpropofolinchildrenwithrefractorystatus
10.15.10
465
TheEpilepsies
Firstlinetreatmentforchildren,youngpeopleandadultswithprolongedorrepeated
generalised,convulsive(tonicclonic,tonicorclonic)seizuresinthecommunity
Recommendation
outcomes
154. Giveimmediateemergencycareandtreatmenttochildren,
youngpeopleandadultswhohaveprolonged(lasting5
minutesormore)orrepeated(threeormoreinanhour)
convulsiveseizuresinthecommunity.[2012]
Cessationofseizuresisthemostimportantoutcome.Allevidence
hasusedthecriterionthataprolongedseizureisonethat
continuesforlongerthan5minutes.
benefitsandharms
Thereisariskofseriousimmediateandlongtermmorbidityand
mortalityifconvulsiveseizurenotterminatedby30minutesand
thereforetreatmentisrequiredurgently.
Urgentandappropriatecarewithconsequentsuccessful
treatmentdeliveredinthecommunityislikelytoreducevisitsto
A+Eandsubsequenthospitalisation.Earlycontrolofseizuresmay
alsoreducethemortalityandmorbidityrisksassociatedwith
prolongedtonicclonicseizures.
Qualityofevidence
Thisrecommendationwasbasedontheconsensusopinionofthe
GDG.
Otherconsiderations
Nofurtherevidencehasbeenpublishedtooverturnthe
recommendationfromthepreviouseditionofthisguideline
(2004).TheGDGrecognisesthatinsomesituationsapersonalised
careplanmaydifferfromtheabove.
466
TheEpilepsies
Recommendation
outcomes
155. Onlyprescribebuccalmidazolamorrectaldiazepamfor
useinthecommunityforchildren,youngpeopleandadults
whohavehadapreviousepisodeofprolongedorserial
convulsiveseizures.[new2012]
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.
467
TheEpilepsies
Recommendation
156. Administerbuccalmidazolamasfirstlinetreatmentin
children,youngpeopleandadultswithprolongedorrepeated
seizuresinthecommunity.Administerrectaldiazepamif
preferredorifbuccalmidazolamisnotavailable.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
468
TheEpilepsies
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
Promptandeffectivetreatmentofprolongedandrepeated
seizuresislikelytoleadtolessandshorterdurationof
hospitalisation.
Qualityofevidence
Thereisnoclinicalevidence.Thisrecommendationwasbasedon
theconsensusopinionoftheGDG.
Otherconsiderations
Thisrecommendationisamodificationofoneinthefirsteditionof
thisguideline(2004),astheviewoftheGDGwasthatfurther
clarificationwasrequiredaspartofthemanagementofconvulsive
statusepilepticus.
469
TheEpilepsies
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.
Noeconomicdatawasavailabletoinformontherelativecost
effectivenessofemergencymeasures.Howeverbasicresuscitative
proceduresarerecommendedtoreduceintensivecareadmission
andlongertermmorbidity.
Qualityofevidence
Thisrecommendationwasbasedontheconsensusopinionofthe
GDG.
Otherconsiderations
Modifiedrecommendationfromoriginalguideline(GPP),asthe
viewoftheGDGwasthatfurtherclarificationwasrequiredaspart
ofthemanagementofconvulsivestatusepilepticus.
470
TheEpilepsies
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.
471
TheEpilepsies
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.
Otherconsiderations
472
TheEpilepsies
Refractoryconvulsivestatusepilepticus
Recommendation
161. FollowthesuggestedprotocolsinappendixKfortreating
refractoryconvulsivestatusepilepticusinsecondarycare.
[2012]
outcomes
Notapplicable.
benefitsandharms
Statusepilepticusisamedicalemergencyandmustbetreatedas
soonaspossibletostoptheseizuresinordertoavoidbrain
damageandinsomecasesdeath.Refractoryconvulsivestatus
epilepticusiswhereseizureshavenotbeencontrolledwithinitial
treatment,thereforetheneedtostoptheseizuresisveryurgent.
Notapplicable.
Qualityofevidence
ThisrecommendationwasbasedonGDGconsensus.The
childrensprotocolwasproducedbytheBritishPaediatric
NeurologyAssociationandtheadultsprotocolwascompiledbythe
firstepilepsyguidelinedevelopmentgroupin2004.Theadults
protocolhasfurtherbeenupdatedbythecurrentepilepsy
guidelinedevelopmentgroup.
Otherconsiderations
TheGDGconsideredtheneedforemergencyprotocolstobein
placetoensurepatientsreceivethecorrectmedicationtostopthe
seizuresasquicklyaspossible.
473
TheEpilepsies
Recommendation
162. Administerintravenousmidazolam,propofolorthiopental
sodiumtotreatadultswithrefractoryconvulsivestatus
epilepticus.Adequatemonitoring,includingbloodlevelsof
AEDs,andcriticallifesystemssupportarerequired.Seealso
thesuggestedprotocolsinappendixK.[new2012]
outcomes
TheGDGconsideredcessationofseizuresandtimetocessationof
seizuresasthemostimportantoutcomes.
benefitsandharms
Useofthiopentalsodiumrequiresadequatecriticalcaresupport
withcontinuous(oratleastdaily)EEGmonitoringtoensureseizure
cessation.Continualreviewrequiredofdurationoftreatmentvers
usseizurecessationwithpropofolorthiopental.
Noeconomicdatawasavailabletoinformcosteffectivenessof
treatment.Shorterdurationofstatusepilepticuslikelytoreduce
longtermintensivecareadmissionandlongtermsequelae.
Qualityofevidence
NoRCTevidencewasfoundforadultrefractorypopulation.The
recommendationonpropofolandthiopentalwasbasedonGDG
expertiseandtherecommendationonmidazolamwasbasedon
evidencederivedfromchildrenpopulation.
Otherconsiderations
TheGDGstatedthatnofurtherpublishedevidenceoverturnsthe
originalrecommendation.
Inlinewithnormalstandardsinemergencycare.
474
TheEpilepsies
Recommendation
163. Administerintravenousmidazolamorthiopentalsodiumto
treatchildrenandyoungpeoplewithrefractoryconvulsive
statusepilepticus.Adequatemonitoring,includingblood
levelsofAEDs,andcriticallifesystemssupportarerequired.
SeealsothesuggestedprotocolsinappendixK.[2012]
outcomes
TheGDGconsideredcessationofseizuresandtimetocessationof
seizuresasthemostimportantoutcome.
benefitsandharms
Useofthiopentalsodiumrequiresadequatecriticalcaresupport
withcontinuous(oratleastdaily)EEGmonitoringtoensureseizure
cessation.Continualreviewrequiredofdurationoftreatmentvs
seizurecessation.Propofolnotrecommendedfortreatmentof
statusepilepticusinchildren.
Noeconomicdatawasavailabletoinformcosteffectivenessof
treatment.Shorterdurationofstatusepilepticuslikelytoreduce
longtermintensivecareadmissionandlongtermsequelae.
Qualityofevidence
Therecommendationofmidazolamwasretrievedfrom5un
blindedRCTsofpoorquality.Therecommendationofthiopental
wasbasedonGDGexpertiseandconsensus,includingBritish
PaediatricNeurologyAssociationpreparedguidelines(appendixC)
Otherconsiderations
TheGDGstatedthatnofurtherpublishedevidenceoverturnsthe
originalrecommendation.
10.15.11
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
475
TheEpilepsies
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]
10.16.1
Introduction
Nonconvulsivestatusepilepticusisanunderdiagnosedsyndromewherebyclinicallysubtleseizures
resultinadepressedlevelofconsciousness.Nonconvulsivestatusepilepticusisdividedintotwo
mainsubgroups:generalisednonconvulsivestatusandfocalstatus.Nonconvulsivestatusepilepticus
isatermusedtodenotearangeofconditionsinwhichelectrographicseizureactivityisprolonged
andresultsinnonconvulsiveclinicalsymptomsincludingchangeinbehaviorandor
awarenesss.SubtlegeneralisedconvulsivestatuswasdefinedinthestudyconductedbyTreimanetal
336
asthestageofgeneralisedconvulsivestatuswhenthepatientisincontinuouscomabutonly
subtlemotorconvulsionsareseen.Tomsonetal351definednonconvulsivestatusepilepticusasa
stateofimpairedconsciousnessorresponsivenesswithoutconvulsionslastingatleast60minutes.
Forthisclinicalquestion,weadditionallysearchedforanyobservationalstudiesasitwasinitially
thoughtthatnorandomisedevidenceonnonconvulsivestatusepilepticuswasavailable.
TheBNFstatesthat:theurgencytotreatnonconvulsivestatusepilepticusdependsuponthe
severityofthepatientscondition.Ifthereisincompletelossofawareness,usualoralantiepileptic
therapyshouldbecontinuedorrestarted.Patientswhofailtorespondtooralantiepileptictherapy
orhavecompletelackofawarenesscanbetreatedinthesamewayasforconvulsivestatus
epilepticus,althoughanaesthesiaisrarelyneeded.
10.16.2
NoRCTs(blindedorunblinded)werefoundforthisevidencereviewsoobservationalstudieswere
includedasastudydesignprovidinglowerqualityofevidence.
476
TheEpilepsies
Forthisreviewweincludedadultsandchildrenwithnonconvulsivestatusepilepticus.Theonly
outcomemeasuresincludedinthisreviewwere:theproportionofparticipantswhoseseizurewas
stopped(seizurefree),durationoftimetocessationofseizure,andincidenceofadverseevents.
10.16.3
10.16.3.1
AEDsforthetreatmentofnonconvulsiveStatusEpilepticus(observationalstudy)
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.
10.16.4
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?
10.17.1
Introduction
Individualswithpoorlycontrolledepilepsymaybenefitfromreferraltoatertiarycentreandfurther
assessment,whichmayincludeassessmentforepilepsysurgery.Theexactnumberofindividuals
whomaybenefitfromsuchareferralisunclear.Thereis,however,evidencethatepilepsysurgery
477
TheEpilepsies
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,
children,youngpeopleandadultsshouldbereferredtotertiaryservicessooneeforfurther
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
contraindicationforreferraltoatertiaryserviceff.[2004]
Evidencestatement
ee
ff
Inthisrecommendation,centrehasbeenreplacedwithserviceforconsistencyacrosstherecommendations.
478
TheEpilepsies
Intemporallobeepilepsy,surgeryissuperiortoprolongedmedicaltherapy.(Ib)
Details
ThissectionwasnotsubjecttoafullevidencereviewforreasonsgiveninChapterTwo.
Chilcott1999354
Onesystematicreviewwasidentified.OneRCT(comparingdifferentformsofsurgery)and6case
serieswereincludedinthisreview.Noquantitativeanalysiswaspossible,butanarrativesummary
waspresented.
Theauthorsconcludedthattherearestrongargumentsforensuringthatallyoungpeoplewith
medicallyrefractoryseizuresareevaluatedbyaneurologist/paediatricianorotherspecialistwithan
interestinepilepsy,sothatallsuitablepatientsareidentifiedandmaybeofferedsurgery.Surgery
hasahighchanceofcontrollingepilepsyforthesepeople,allowingthemtocompletetheir
education,integratesocially,achieveemploymentandavoidalifetimeofantiepilepticdrugsand
hospitalattendance.354
Wiebe2001355
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.
Chilcottandcolleagues1999354
Theobjectiveofthissystematicreviewistoassesstheeffectivenessofsurgeryforepilepsyin
childrenandadultswithrefractoryepilepsy.
Theauthorsidentifiedfourstudiesinvestigatingtheeconomicsofsurgeryforrefractoryepilepsy,but
theydidnotidentifyanypublishedstudyconcerningthecostandeffectivenessofsurgeryfor
epilepsyintheUK.
Thestudyreported:
thecostsofevaluationandassessmentofcandidatesforsurgery,andthecostsofsurgery
479
TheEpilepsies
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.
480
TheEpilepsies
Theroleofnondrugtreatmentsinthemanagementoftheepilepsies
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]
481
TheEpilepsies
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.
11.3.2
includedadultsandchildrenwithepilepsy.Norandomiseddatawasfoundforadults.
11.3.3
Matrixoftheevidence
WesearchedforRCTscomparingtheeffectivenessofdifferentvariantsoftheketogenicdietandno
changeindiet.Thefollowinginterventionswereincludedinoursearch;ketogenicdiet,ketogenic
dietplusglucose,MediumChainTriglyceridesDiet(MCT)andmodifiedAtkinsdiet.Welookedfor
anyRCTstudiesthatcomparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
thischapter.Anemptyboxindicatesthatnoevidencewasfound,andinthiscase,nosectiononthis
Normal
diet
(without
dietetic
input)
Ketogenic
diet
1359
Ketogenic
dietplus
glucose
1360
482
TheEpilepsies
MCT
ketogenic
diet
1361
Normal Ketogenic Ketogenic

MCT
diet
diet
dietplus ketogenic
(without
glucose
diet
dietetic
input)
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.
483
TheEpilepsies
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
484
TheEpilepsies
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
485
TheEpilepsies
11.3.4
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.
TheGDGrecognisedthatimplementationoftheketogenicdiet
wouldrepresentanadditionalcostcomparedwithnodietary
change,butbasedontheclinicalevidencewouldalsoreduce
seizurefrequencyforsomepatients.Intheabsenceofafull
economicevaluationtoassessthepotentialcosteffectivenessof
theketogenicdiet,theGDGconsideredsomeofthesubstantial
costsofimplementingthediet,particularlythoserelatedto
initiationandfollowup.Initiationofthedietrequiressubstantial
dieteticinputintermsofteachingfamiliesaboutthediet,
followingupandmakingadjustmentsduringthefirstseveral
weeksandmonthsandliaisingwithotherhealthprofessionals
involvedinthechildscare.GDGmemberswithexperienceof
administeringtheketogenicdietestimatedthatintermsofa
dieticianstime,initiatingthedietwouldrequireroughlyeight
486
TheEpilepsies
hourstosetupandtwohoursperweekoffollowupforthefirst
severalmonths.AccordingtothePSSRU362,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.
487
TheEpilepsies
11.3.5
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?
178. Vagusnervestimulationisindicatedforuseasanadjunctivetherapyinreducingthe
frequencyofseizuresinadultswhoarerefractorytoantiepilepticmedicationbutwhoarenot
suitableforresectivesurgery.Thisincludesadultswhoseepilepticdisorderisdominatedby
focalseizures(withorwithoutsecondarygeneralisation)orgeneralisedseizures.[2004,
amended2012]
179. Vagusnervestimulationisindicatedforuseasanadjunctivetherapyinreducingthe
frequencyofseizuresinchildrenandyoungpeoplewhoarerefractorytoantiepileptic
medicationbutwhoarenotsuitableforresectivesurgery.Thisincludeschildrenandyoung
peoplewhoseepilepticdisorderisdominatedbyfocalseizures(withorwithoutsecondary
generalisation)orgeneralisedseizures.[2004,amended2012]
Evidencestatement
EvidencefromVagusnervestimulationforrefractoryepilepsyinchildren,NICEinterventionalprocedureguidance50
(2004).
488
TheEpilepsies
TheevidenceshowsthatVNSappearstobeaneffectiveandwelltoleratedtreatmentfordrug
resistantfocalseizures.Stimulationusingthehighstimulationparadigmissignificantlybetterthan
lowstimulation.(Ia)
Details
SecondaryEvidence
OneCochranereview363andonetechnologyappraisal364wereidentifiedthataddressedtheuseof
VNSinthemanagementoffocalseizuresanddrugresistantepilepsyrespectively.
Inaddition,guidanceontheuseofVNSasaninterventionalprocedureinchildren365waspublished
byNICEin2004.Theguidanceisincludedintheguidelinerecommendationsabove.
Privitera2003363
PriviteraandcolleaguesreviewedtheevidenceontheeffectsofVNShighlevelstimulation
comparedtolowlevel(presumedsubtherapeuticdose)stimulationinpeoplewithdrugresistant
focalseizures.Randomised,doubleblindcontrolledtrialsofVNScomparinghighandlow
stimulationparadigmsinadultsorchildrenwereincluded.
Thefollowingoutcomeswereassessed:
a.
50%orgreaterreductionintotalseizurefrequency;
b.
treatmentwithdrawal(anyreason);
c.
adverseeffects.
Primaryanalyseswereintentiontotreat.Sensitivitybestandworstcaseanalyseswerealso
undertaken.Summaryoddsratios(ORs)wereestimatedforeachoutcome.
Thetwoincludedstudies366,367wereparalleltrials,sponsoredbyCyberonicsaspartoftheirpre
approvalprogramforVNS.EachtrialtestedtwostimulationparadigmsforVNS.Allparticipants
wereimplantedwithastimulator,butthecontrolgroupreceivedlessfrequentandlowerintensity
stimulation.Inaddition,participantsinthecontrolgroupdidnotreceiveanyelectricalcurrentwhen
thedevicewasactivatedbythehandheldmagnet.Atotalof312individualswererandomisedto
treatment.
StimulationparametersintheE03trial366were:current0.5to3.0mA(activeandcontrol);frequency
20to50Hz(control1to2);pulsewidth500(control130);ontime30to90seconds(control30
seconds);offtime5minutes(control90minutes).
StimulationparametersintheE05trial367were: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
489
TheEpilepsies
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
Bryant1998368
ThistechnologyassessmentwaspublishedpriortothepublicationoftheE05trialsoconclusions
abouteffectivenessarenotpresented.(SeeCochranereviewabove)
Corabian2001364
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.
Raeburn2003369
ThecostutilityofVNSinmedicallyrefractoryepilepsywasestimatedbasedonametaanalysisof
twoRCTs.However,oneofthepublicationsusedreportedpreliminaryresultsfromatrialpublished
infulllater.Thismetaanalysiswasthereforeexcluded.
Fisher1999370
AreportoftheTherapeuticsandTechnologyAssessmentSubcommitteeoftheAmericanAcademyof
NeurologyassessedtheeffectivenessofVNSforepilepsy.ThesametwoRCTswereevaluatedasin
theCochranereviewbyPriviteraandcolleagues.363
490
TheEpilepsies
Thereportconcludedthatthedegreeofimprovementinseizurecontrolremainscomparabletothat
ofnewAEDs,butislowerthanthatofmesialtemporallobectomyinsuitableresectioncandidates.
ThecommitteerecommendedthatVNSwasindicatedforadultsandadolescentsovertheageof12
yearswithmedicallyrefractoryfocalseizureswhoarenotcandidatesforpotentiallycurativesurgical
resections.
Primaryevidence
NoRCTswereidentifiedasbeingpublishedsincetheHTA(2000onwards).
Healtheconomics
Bryant1998368
ThistechnologyappraisalassessedthehealtheconomicevidencerelatedtoVNS.
Aslongtermeffectivenessisunknown,thecosteffectivenessanalysiswaslimitedtothefirstyear.
Thecostperseizuresavedwasintherange246to410.OnestudyofthecostbenefitratioofVNS
concludedthatthecostofVNScouldbeexpectedtobepaidbackbysavingsindirectmedicalcosts
after2years.
TheauthorsconcludedthattherestillremainedquestionsonthecostbenefitofVNS.
Boon1999371
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.
491
TheEpilepsies
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
492
TheEpilepsies
Informationneedsofindividuals,families,andcarers
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
493
TheEpilepsies
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.
494
TheEpilepsies
ItwasagreedwiththeindividualpatientrepresentativesontheGDGthattherecommendationson
informationneedsshouldbemappedtokeypointsonthecarepathwayratherthansummarisedina
separatesectionoftheguideline.
Asfarastheevidencebaseisconcernedthefocuswasonpublishedstudiesthatreportedthe
informationneedsofpeoplewithepilepsyandtheirfamiliesorcarers.Publishedstudiesthathave
surveyedorinterviewedpeoplewithepilepsyand/ortheircarers/familyandreportedspecificallyon
informationneedswereincluded.Evidencethatreportedhealthcareprofessionalsviewsastowhat
individualsinformationneedsareandstudieslookingmoregenerallyattheexperienceofadultsand
childrenlivingwithepilepsywereexcluded.
In2001,LynetteCouldridgeandcolleaguespublishedasystematicreview372ontheinformationand
counsellingneedsofpeoplewithepilepsy.AllthepapersreferencedintheCouldridgereviewwere
reviewed,andasimilarstrategywasusedtoidentifyanyrelevantpaperspublishedsince.The
knowledgeandexperienceoftheGDGwereusedtohelpintheidentificationofgreyliteratureand
surveysthatcontributedtotheevidencebase.
InthisreviewthefindingsoftheCouldridgereview372werepresentedwithresearchidentifying
specificinformationneedsatspecificpointsonthecarepathwaywassummarised.
Secondaryevidence
Couldridge2001372
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.
495
TheEpilepsies
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
McNelis1998374
TheChildReportofPsychosocialCareScalewasusedtomeasurechildren'ssatisfactionwith
healthcarereceived,needforinformationandsupportandseizurerelatedconcernsandfearsin
childrenwithnewonsetseizures.Thesampleof63children(33girlsand30boys),814years,
completedthescaletwotimes,3monthsand6monthsaftertheirfirstseizure.Resultsindicated
thatchildrenwantedinformationrelatedtotheseizurecondition,especiallymanagingtheir
condition,andsupport,intheformoftalkingtootherchildrenwithseizures.
Investigations
Thisshouldrelatetoinitialoutpatientappointmentwiththeappropriatespecialist/epilepsyspecialist
nurseandanysubsequentfollowupappointments.
190. Informationshouldbeprovidedtochildren,youngpeopleandadultsandfamiliesand/or
carersasappropriateonthereasonsfortests,theirresultsandmeaning,therequirementsof
specificinvestigations,andthelogisticsofobtainingthem.[2004]
Evidencestatement
Adultswantinformationaboutthereasonsfortests,theresultsandmeaningoftheseresults.(III)
Details
Dilorio1993375
AUSstudyof59adultswithepilepsy(mean39.3years,range19to60years)foundthatindividuals,
nurses,anddoctorssimilarlyrankedmajorareasoflearningneed.Howeverthereweredifferences
intherankingofindividuallearningneeds.375
496
TheEpilepsies
Althoughthisstudydidnotrelatethelearningneedtotiming,boththeresultsoftestsandthe
reasonsforsuchtestswererankedhigherbyindividualsthanbyhealthcareproviders,anditcouldbe
arguedthatthisinformationwouldbebestprovidedwhentestsareordered/performedandresults
arediscussed.
Ridsdale2002376
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
Averis1996377
InanAustralianquestionnairesurveyof200adultswithepilepsywhoattendedaspecialistclinic,
confirmationofthediagnosiswasratedasthesecondmostimportantfactorinthemanagementof
497
TheEpilepsies
epilepsy(afteravailabilityofthedoctorattimeofneed).Thestaffoftheclinicbelievedthat
educationshouldbeginatdiagnosisandcovertopicsastheybecomerelevanttotheindividual.
CSAG200011
TheCSAGreportstatedthatmanyolderpeoplewouldhavelikedcounsellingandmoretimewiththe
doctorornurseatthetimeofdiagnosis.
Goldstein1997378
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.
May2002379
InanRCTtoevaluatetheuseofaneducationalpackagetoimproveadults'knowledgeand
understandingoftheirepilepsy,therewasnodifferenceinthelevelsofimprovementbetweenthose
withalongandshortdurationofepilepsy(<=5yearsvs>5years).However,theauthorssuggested
thatitwasreasonabletoofferaneducationalprogramassoonaspossibleafterdiagnosis.
Buck1996380
InaUKcommunitybasedsurveyof677adultswithepilepsy,thedurationofepilepsyinfluencedthe
likelihoodthatindividualswoulddiscusssocialimplications;79%ofthosewithareporteddurationof
lessthanoneyearcomparedwithonly59%ofthosewithadurationofmorethan10years
(differenceinproportions11,95%CI2to20).Theauthorssuggestedthatthismaybebecause
individualscometoacceptthesocialimplicationsofepilepsyintime,orthatdoctorsassumethisto
bethecase.Anotherreasonofferedwasthatindividualsbelievethatitislessappropriatetodiscuss
socialissues(asopposedtoclinicalissues)whentherearetimeconstraintsintheconsultation.
Ridsdale2002376
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.
Ridsdale1999381
Inaninterviewstudyofadultswithepilepsy(meanage47years,range18to75years)individuals
feltthatinformationaboutthediagnosiswasextremelyimportant.Specifically3individualswhohad
498
TheEpilepsies
beenchildrenwhentheywerediagnosedreportedthatexplanationsweregiventotheirparents,but
nottothem.
Austin2002382
Inabeforeandafterstudyofanpsychoeducationalinterventionstudy,commentsfromthe10
participantfamiliesofchildrenwithepilepsyindicatedthattheinterventionwouldbemost
effectivelyadministeredearlyinthecourseofthedisorder.Thetailoredinterventionincluded
provisionofinformation,addressingconcernsandconcernsandfears,andprovidingemotional
support.
Kennelly2002383
Inaninterviewstudyof78semistructuredinterviewswiththebereavedrelativesofindividualswith
epilepsywhohaddiedofSUDEP,severalissuesaroundtheprovisionofinformationwereidentified.
Therelativeswantedinformationonepilepsytobeprovidedautomaticallytotheindividualeither
onorsoonafterdiagnosis.Theyalsostressedtheneedforinformationtobegiventocarersaswell
astheindividualwithepilepsytoenablethemtohelpthemmanagetheircondition,aswellasto
interveneeffectivelywhentheyareunabletohelpthemselves.
Elwyn2003384
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
499
TheEpilepsies
Kennelly2002383
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
Mills1997385
AUKquestionnairesurveyfoundthatin394adultswithepilepsy,peoplewhohadhadanattackin
thepast12monthsweremorelikelytowantdiscussionoftopics(causes,sideeffects,lawsetc),
500
TheEpilepsies
significantlysoforhospitalattendersbutnotforGPattenders.However,theperceivedadequacyof
informationwassimilarforbothsettings.
RefractoryEpilepsyandSurgery
198. Informationshouldbeprovidedtochildren,youngpeopleandadultsandfamiliesand/or
carersasappropriateaboutthereasonsforconsideringsurgery.Thebenefitsandrisksofthe
surgicalprocedureunderconsiderationshouldbefullyexplainedbeforeinformedconsentis
obtained.[2004]
Evidencestatement
Individualswantaccurateandbalancedinformationonsurgery.(III)
Swarztrauber2003386
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.
TheliteraturereviewonSUDEPfromtheSUDEPReport18ispresentedandafurtherreviewarticle
wasidentifiedthatsummarizedtheavailableevidenceonthemortalityassociatedwithepilepsyup
to1996.387
Secondaryevidence
TheNationalSentinelClinicalAuditofEpilepsyRelatedDeath18
Inchronicepilepsy,SUDEPisthemaincauseofexcessmortality,andinthisgroupofpeoplethe
mortalityratehasbeenfoundtobe4.5timeshigherthanexpected,withmorethanhalfattributed
toSUDEP.17IntheUKitisestimatedthat500deathsperannumareSUDEP.Youngpeoplewith
501
TheEpilepsies
severeepilepsyandlearningdisabilitymaybeatevenhigherriskofSUDEP,withonerecentstudy
showingadeathrate15.9timesgreaterthanexpected.388
SUDEPisdefined389as:sudden,unexpected,witnessedorunwitnessed,nontraumaticand
nondrowningdeathinindividualswithepilepsy,withorwithoutevidenceforaseizure,andexcluding
documentedstatusepilepticus,inwhichpostmortemexaminationdoesnotrevealatoxicologicalor
anatomiccausefordeath.
CasecontrolstudieshavebeenusedtodeterminepossibleriskfactorsforSUDEP.Reportedrisk
factors390forSUDEPinclude:
youngage
generalisedtonicclonicseizures
uncontrolledepilepsy
learningdisability
seizuresoccurringduringsleep
unwitnessedseizuresandpooradherencetoantiepilepticdrugregimen.
Themostsignificantriskfactorshownbycasecontrolledstudies,however,istheoccurrenceof
seizures,andtheriskofSUDEPappearstobedirectlyrelatedtothefrequencyofseizures.391Indeed,
mostoftheexcessmortalityofepilepsyisrelatedtoseizurefrequency.Inarecentcasecontrol
study,Nilssonandcolleaguesreportedthatpeoplewhohadnotbeenseizurefreeduringtheyear
hada23foldincreasedofSUDEPcomparedtopeoplewithfullycontrolledseizures.391Tomson,392in
areviewofpublishedstudies,concludedthattheriskofSUDEPis40timeshigherinpeoplewho
continuetohaveseizures.Sperlingandcolleaguesfoundthateliminationofseizuresaftersurgery
reducedthemortalityrateinpeoplewithepilepsytoalevelindistinguishablefromthatofthe
generalpopulation.393Theysuggestedthatuncontrolledseizuresareamajorriskfactorforexcess
mortalityinepilepsy.ThereasonforthisrelationshipseemstobethatmostSUDEPsareseizure
related.390,391,394,395
Inlinewithotherstudiesofriskitisimportantthattherelativeriskisnotusedaloneasthisdoesnot
indicatehowcommonoruncommontheconditionisinthepopulationunderstudy.Itisimportant
thatanindicationoftheabsoluteriskofSUDEPisgivenindifferentpopulationgroupswithepilepsy.
ODonoghue1997387
Thisnarrativereviewclearlysetsoutthemethodologicalproblemsassociatedwiththeepidemiology
ofepilepsymortality.ThreestrategieshavebeenusedtostudytheincidenceofSUDEP:
1)
ratesofdeathinlargepopulationusingdeathcertificatesandcoronersreports;
2)
antiepilepticdrugprescriptionasasurrogateforthediagnosisofepilepsyand
3)
followupofacohortofpeoplewithepilepsyforadefinedperiodoftime.
Approaches1&2haveparticularproblemsrelatingtotheaccuracyandcompletenessof
ascertainmentofthenumberofdeathsandthesizeofthepopulationstudied.Approach3isprone
toselectionbiasasthecohortstudiedmaybeattendeesatspecialisttertiarycentersratherthanthe
wholepopulationofpeoplewithepilepsy.
Theauthorsdiscussedtheevidenceinrelationtodifferentgroupsofpeoplewithepilepsy,identifying
thatthosewithrefractoryepilepsyawaitingsurgeryhavethehighestriskofSUDEPandthosein
remissionthelowestrate.Theydrewthefollowingconclusionsfromtheirreview:
Comparisonofpopulationbasedandcohortstudiesrevealedthatforthosewithsevereepilepsy,
adeathrateof1:200peryearcanbeestimated,whereasonapopulationbasistherateis
502
TheEpilepsies
between1:500and1:1000peryearimplyingthatformildidiopathicepilepsytherateislessthan
1:1,000.Forthoseinremissiontheriskappearstobenegligible.387
503
TheEpilepsies
Womenofchildbearingagewithepilepsy
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
504
TheEpilepsies
Noneofthe40includedstudiesreportedtheroleoreffectsofinformationorcounsellinginwomen
withepilepsyasagroup,althoughsomestudiesdidhavewomeninthestudypopulation.
Primaryevidence
NoRCTsontheeffectivenessofinformationgivingorcounsellingwereidentified.
Sincethepublicationofthesystematicreviewdescribedabove372,twolargesurveysofwomenwith
epilepsywerefound.
Crawford1999397
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: Concernsaboutpregnancy397ModifiedfromSeizure,8,CrawfordPandLeeP,Gender
differenceinmanagementofepilepsyWhatwomenarehearing,pages1359,Copyright
(1999)withpermissionfromBEATradingLtd.
100
90
80
70
60
50
40
30
20
10
0
Not enough
information
given
Breast feeding
Effects of
medication on
child
Increased
seizures
No previous children (n=117)
505
Ability to care
for the child
Effect of
Whether
epilepsy on
medication
role as mother affects fertility
Previous children (n=52)
TheEpilepsies
Overall,womenfelttherewasaneedformoreinformationaboutepilepsyandpregnancy.Thesurvey
concludedthatwomenwithepilepsywanted,andneeded,moreinformationandcounsellingaboutissues
relatingtocontraception,pregnancy,andthemenopause.397
Crawford2003398
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
30
15
Pregnancy
17
10
42
Riskofchild
developing
epilepsy
19
41
15
AEDsand
pregnancyfetal
development
16
43
13
Menopause
19
58
506
TheEpilepsies
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)ggwhenprescribingAEDsforwomenandgirlswhoarebreastfeeding.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
507
TheEpilepsies
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.
508
TheEpilepsies
Table29: Seizurefrequencyduringpregnancyandpuerperium
Study
Participants
399
Numberof
participants
Definitionofseizureratechange(s)
Increased
Unchanged
Decreased
Bardy1987
Womenwhohadat
least2epileptic
seizuresfulfillingthe
criteriaoftheWHO
DictionaryofEpilepsy,
withthefirstseizure
occurringbefore
pregnancy
154pregnanciesin
140women
Increasedifthenumberofseizureswas200%
ormoreduringpregnancyand3monthsafter
thaninthe12monthsbefore
Decreasedifthenumberofseizureswas50%
orlessduringpregnancyand3monthsafter
thaninthe12monthsbefore
32%
54%
15%34
Gjerde1988400
Womenwhohad
epilepsyandusedone
ormoreAEDsforat
leastoneyearpriorto
pregnancy
78pregnanciesin
66women
Increasediftherewasatleastonemore
seizureduringpregnancythaninthe9month
beforepregnancy
Decreasediftherewasatleastoneless
seizureduringpregnancythaninthe9month
beforepregnancy
17%
67%
17%
Schmidt1983401
Womenwhohadthree
ormoreverified
epilepticseizureswho
completedthe
pregnancy
136pregnanciesin
122women
Increasedordecreasediftheactualseizure
frequencychanged,ratherthanapercentage
(ieonemoreoronelessseizure)during
pregnancyand3monthsfollowingdelivery
comparedwiththe9monthsbefore
pregnancy
37%
50%
13%
Tanganelli1992402
Womenwithepilepsy
138pregnanciesin
97women
Increasedordecreasedfrequencydefinedas
a10%ormorechangeduringpregnancy
whencomparedwiththe9monthspriorto
pregnancy
17%
80%
3%
Tomson1994403
Womenwhowere
treatedwithAEDsfor
epilepsysincethe
beginningofpregnancy
93pregnanciesin
70women
Changeinseizurefrequencywasdefinedasa 15%
movementfromonefrequencycategoryto
another(fivecategoriesrangingfromseizure
freetooneseizureaweekormore)whenthe
rateduringpregnancywascomparedwiththe
61%
24%
34
Percentages may not add to 100% due to rounding errors
TheEpilepsies
Study
Participants
Numberof
participants
Definitionofseizureratechange(s)
9monthspriortothepregnancy
Increased
Unchanged
Decreased
TheEpilepsies
Schmidtandcolleaguesassessedthefactorsassociatedwithincreasedseizuresandfoundthatnon
adherencetomedication,sleepdeprivation,andinadequatetherapyinfluencedseizurerate.
Threestudies399,401,402reportedseizurefrequencyinthefirst3monthsafterthebirth.
Bardyfoundastatisticallysignificantincreaseincomplexfocalseizuresduringtheearlypuerperium
(p<0.001).399
IncreasedseizureswereseeninsixpregnanciesintheSchmidtstudy401andnonadherenceandsleep
deprivationwereassociatedwithfiveofthese.
TanganelliandRegesta402reportedthatduringthepuerperium,seizurefrequencyreturnedtopre
pregnancylevelsinallbuttwowomen(2%,n=2/97).
Twostudiesreportedseizuresinlabour.In97womenwithepilepsy,noseizuresduringlabour
occurred.Intheotherstudy,399seizuresoccurredduringlabourin10cases,anincidenceninetimes
greaterthantheaverage.
Bardy404alsoreportedthatageneralisedtonicclonicseizureoccurredinlabourinapproximately1
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.
13.5.2
Forthisreviewweincludedchildrenofpregnantwomenwithepilepsywhowereexposedtooneor
moreAEDspriortodelivery.Comparisongroupsincludedchildrenofwomenwithepilepsywho
werenotexposedtoAEDsandchildrenofwomenfromthegeneralpopulation(withoutepilepsy).
Welookedfordataspecificallyontheproportionofchildrenbornwithmajormalformations,the
proportionofchildrenbornwithminormalformations,theincidenceofmiscarriageand
developmental/cognitiveoutcomes.Wefoundseveralsystematicreviewsforthisreviewand
thereforedidnotperformareviewforindividualstudies.Thesystematicreviewsincluded
prospectivecontrolledcohortsandcasecontrolstudies.
511
TheEpilepsies
Whenthesystematicreviewsprovidedinformationontheindividualsincludedinthestudiesthe
resultsofeachstudywerepresentedseparatelyinthisreview.However,whenthesystematic
reviewspresentedpooleddataandametaanalysiscouldbeperformedtheresultswerepresented
inthisway.Thisevidencereviewisdividedintwosectionsbasedonthetypesofoutcomesreviewed:
Thefirstsectionpresentsevidenceforminor/majormalformationsandmiscarriage:Weuseda
systematicreviewandmetaanalysis(Meador,2008)405ofpublishedpregnancyregistriesand
cohortstopresenttheincidenceofminormalformations,majormalformationsandmiscarriage
followinginuteroantiepilepticdrugexposure.Thissystematicreviewincludedstudieswithatleast
100totalpregnanciesorbirths.
Thesecondsectionpresentsevidencefordevelopmental/cognitiveoutcomes:WeusedaCochrane
review(Adab,2004)406andametaanalysisofcohortstudies(Banach,2010)407forinformationon
thedevelopmental/cognitiveoutcomes.Adab(2004)406includedphenobarbital,phenytoin,
carbamazepine,oxcarbazepine,sodiumvalporate,lamotrigine,topiramate,gabapentin,vigabatrin,
tiagabineandzonisamide.TheseAEDswereeithertakenasmonotherapyorpolytherapy.The
Banach(2010)407reviewincludedsodiumvalproate.
Table30: Cognitivescales
Fullnameofthe
Scales
scale
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
Wechslerpreschool
andprimaryscale
intelligence
WIPPSI
Ameasureofgeneral
12subsetsassessing2
intellectualfunctioningfor areasofintelligence:
childrenaged616years. verbalIQ(VIQ)and
performance(PIQ),
Ameasureofgeneral
intellectualfunctioningfor summatedprovidea
compositescore(FSIQ).
childrenaged616years.
ColumbiaMental
Maturityscale
CMMS
Assessgeneralreasoning
Rawscore,agedeviation
abilityinchildrenaged39 score,percentilerank,
years.
stanineandmaturity
index.
Illinoistestof
psycholinguistic
abilities
ITPA
Ameasureofusedand
10subsetsand2
acquisitionoflanguagefor supplementarysubsets.
childrenaged48years.
Rawscoresusedtoderive
acompositescore,
512
TheEpilepsies
Fullnameofthe
scale
Scales
abbreviations
Briefdescription
Scoring
psycholinguisticagescores
andpsycholinguistic
quotientsforsubtestsand
composite.
Frostigtestofvisual FTVP
perception
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
513
TheEpilepsies
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)^
514
TheEpilepsies
Theincidenceofperinataldeathswassignificantlyhigherinchildrenexposedinuteroto
monotherapycomparedtochildreningeneralpopulation.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretoanymonotherapytononexposureinthegeneral
populationwasidentified.
13.5.2.3
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
13.5.2.4
monotherapycomparedtopolytherapy
Clinicalevidence
515
TheEpilepsies
Evidencestatements
uterotopolytherapycomparedtochildreninmonotherapy.(VERYLOWQUALITY)
Theincidenceofcongenitalmalformationwassignificantlyhigherinchildrenexposedinuteroto
polytherapycomparedtochildreninmonotherapy.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingexposuretoanypolytherapytoexposuretoanymonotherapywas
identified.
13.5.3
13.5.3.1
Comparisonbetweenspecificmonotherapiesondevelopmental/cognitiveoutcomes
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
516
TheEpilepsies
Developmental/cognitiveoutcomesstatisticallynonsignificantresults
Nosignificantdifferencebetweenphenytoinmonotherapyandphenobarbitalmonotherapyforthe
followingdevelopmental/cognitivescales:
Geselldevelopmentalschedules(VERYLOWQUALITY)
mentaldevelopment(8months)(VERYLOWQUALITY)
motordevelopment(8months)(VERYLOWQUALITY)
IQ(4years)(VERYLOWQUALITY)
WISC/WPPSI(49years)(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingphenytoinmonotherapytophenobarbitalmonotherapywas
identified.
13.5.3.3
Clinicalevidence
Evidencestatements
theDutchtest(nonoptimalschoolcareer,poorreading,poorarthemetic,poorspelling)(VERYLOW
QUALITY).
Costeffectiveness
Noeconomicevidencecomparingphenobarbitalmonotherapytocarbamazepinemonotherapywas
identified.
13.5.3.4
Sodiumvalproateversuscarbamazepine
Clinicalevidence
Evidencestatements
Developmental/cognitiveoutcomesstatisticallysignificantresults
517
TheEpilepsies
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
518
TheEpilepsies
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)
519
TheEpilepsies
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
520
TheEpilepsies
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
521
TheEpilepsies
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).
522
TheEpilepsies
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)
523
TheEpilepsies
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)
524
TheEpilepsies
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)
525
TheEpilepsies
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
526
TheEpilepsies
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.
527
TheEpilepsies
13.5.5
Recommendation
outcomes
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]
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).
528
TheEpilepsies
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.
529
TheEpilepsies
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
Otherconsiderations
None.
Recommendation
210. Discusswithwomenandgirlswhoaretakinglamotrigine
thatthesimultaneoususeofanyoestrogenbased
contraceptivecanresultinasignificantreductionof
lamotriginelevelsandleadtolossofseizurecontrol.Whena
womanorgirlstartsorstopstakingthesecontraceptives,the
doseoflamotriginemayneedtobeadjusted.[new2012]
outcomes
Seizurefreedom,adverseeffectandeffectivecontraceptivewere
benefitsandharms
Interactionbetweenlamotrigineandanyoestrogenbased
contraceptivemayreducelamotriginesanticonvulsanteffect
becauseofhepaticmetabolism.
Therewasnoeconomicevidenceavailableandthistypeof
scenariowasnotincorporatedintotheoriginaleconomicmodels
undertakenfortheguideline.However,theGDGconsideredthat
thelikelyextraresourceuseandcostsassociatedwithadjusting
dosage(extramedicalappointmentsand/orincreasedor
decreaseddailydose)waslikelytobecosteffectiveifithelpsto
maintainseizurecontrol.
Qualityofevidence
530
TheEpilepsies
Otherconsiderations
None.
Recommendation
211. DonotroutinelymonitorAEDlevelsduringpregnancy.If
seizuresincreaseorarelikelytoincrease,monitoringAED
levels(particularlylevelsoflamotrigineandphenytoin,which
maybeparticularlyaffectedinpregnancy)maybeuseful
whenmakingdoseadjustments.[new2012]
outcomes
Seizurefreedomandadverseeffectwereconsideredthemost
importantoutcomes.
benefitsandharms
Risksofseizureexacerbation/relapsewithalterationin
pharmacokineticsofAEDinpregnancyneedtobebalancedagainst
theriskofharmfromantiepilepticmedicationtakenbythemother
inpregnancy.
Therewasnoeconomicevidenceavailableonroutinemonitoring
ofAEDlevelsandthiswasnotincorporatedintotheoriginal
economicmodelsundertakenfortheguideline.TheGDG
consideredthatroutinemonitoringofAEDlevelsinpregnancyis
notnecessary.However,itshouldbeborneinmindthatthelevels
ofsomeAEDs,andspecificallylamotrigineandphenytoin,maybe
affectedbypregnancyandmonitoringoftheselevelsmayreduce
theriskofseizuresthatmaycauseharmtothemotherandthe
unbornchild.
Qualityofevidence
guideline(2004).
Otherconsiderations
None.
531
TheEpilepsies
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.
Therewasnoeconomicevidenceavailableonroutinemonitoring
ofAEDlevelsandthiswasnotincorporatedintotheoriginal
economicmodelsundertakenfortheguideline.TheGDG
consideredthattherearesomespecificindicationsformonitoring
ofAEDbloodlevels,suchasdetectionofnonadherencetothe
prescribedmedication,suspendedAEDtoxicity,adjustmentof
phenytoindoseand/ormanagementofpharmacokinetic
interactions.RoutinemonitoringofAEDlevelsinpregnancyisnot
necessary,however,itshouldbeborneinmindthatthelevelsof
someAEDsparticularlylamotrigineandphenytoinmaybeaffected
bypregnancyandmonitoringoftheselevelsmayreducetherisk
ofseizuresthatmaycauseharmtothemotherandtheunborn
child.
Qualityofevidence
guideline(2004).
Otherconsiderations
None.
532
TheEpilepsies
Recommendation
13.5.6
13.5.6.1
213. RefertotheSPCandBNF(availableathttp://www.bnf.org)
forindividualdrugadviceontheinteractionsbetweenAEDs
andhormonalreplacementandcontraception.[new2012]
outcomes
Seizurefreedom,adverseeffectandeffectivecontraceptivewere
benefitsandharms
Therisksofunplannedpregnancycausedbydruginteraction
betweenAEDsandhormonalcontraceptivesmustbeconsidered,
buttherisksofseizuresrequirethat,whenpossible,themost
effectiveantiepilepticmedicationbeprescribed.
Therewasnoeconomicevidenceavailableandconcomitantuseof
AEDsandhormonalcontraceptiveswasnotincorporatedintothe
originaleconomicmodelsundertakenfortheguideline.However,
theGDGconsideredthatinteractionsbetweenAEDsandhormonal
contraceptivesshouldbeborneinmindtoreducetheriskof
unplannedpregnanciesorreducedseizurecontrol.
Qualityofevidence
Otherconsiderations
None.
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]
533
TheEpilepsies
215. Ingirlsofchildbearingpotential,includingyounggirlswhoarelikelytoneedtreatmentinto
theirchildbearingyears,thepossibilityofinteractionwithoralcontraceptivesshouldbe
discussedwiththechildand/orhercarer,andanassessmentmadeastotherisksandbenefits
oftreatmentwithindividualdrugs.[2004]
216. Inwomenandgirlsofchildbearingpotential,therisksandbenefitsofdifferentcontraceptive
methods,includinghormonereleasingIUDs,shouldbediscussed.[2004]
217. IfawomanorgirltakingenzymeinducingAEDschoosestotakethecombinedoral
contraceptivepill,guidanceaboutdosageshouldbesoughtfromtheSPCandcurrenteditionof
218. Theprogestogenonlypillisnotrecommendedasreliablecontraceptioninwomenandgirls
takingenzymeinducingAEDs.[2004,amended2012]
219. Theprogestogenggimplantisnotrecommendedinwomenandgirlstakingenzymeinducing
AEDs.[2004,amended2012]
220. Theuseofadditionalbarriermethodsshouldbediscussedwithwomenandgirlstaking
enzymeinducingAEDsandoralcontraceptionorhavingdepotinjectionsofprogestogenii.
[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
534
TheEpilepsies
epilepsyandcontraceptionfailurerateswereidentified.Theevidencepresentedbelowistherefore
nonexperimentaldescribingfailureratesofdifferentcontraceptivemethodsinwomenwithepilepsy
whoaretakingAEDsanddruginteractionsbetweenAEDsandhormonalcontraception,orreviewsof
theinteractionsbetweenAEDsandhormonalcontraception.
Hormonalcontraception(general)
Crawford2002409
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)
Coulam1979410
In1979,CoulamandAnnegerspresentedtheresultsofarecordreviewof82womenwithepilepsy
whowerealsotakingoralcontraception.410Intotal,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.
535
TheEpilepsies
Mostwomenweretakingtheequivalentof50mcgsofoestrogen,withafewtaking10mcgsof
oestrogen,andonetaking80mcgsofoestrogen.
Theauthorsconcludedthattherateoforalcontraceptivefailureishigheramongwomentaking
AEDs.410
Back1988411
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.Arecentguideline396onthemanagementofwomenwithepilepsyrecommended,onthe
basisofevidenceandconsensus,that
ForwomenonenzymeinducingAEDs(phenytoin,phenobarbital,primidone,carbamazepine,
topiramate)wishingtotakethecombinedoralcontraceptivepill:
o Startona50mcgethinyloestradioldose
o Ifbreakthroughbleedingoccurs,increasethedoseofethinyloestradiolto75mcgor100mcg
perday,orconsidergivingthreepacksofthepillwithoutabreak(tricycling).396
Hormonereleasingintrauterinedevices
Bounds2002412
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
per100womanyears396,andwasbetterthanratesforbarriermethods(15to20per100woman
years).396,412
Progesteroneimplants
536
TheEpilepsies
Haukamaa1986413
Ninewomenwithepilepsyaged16to35yearsparticipatedinthisstudytoassesstheefficacyof
progesteroneimplantsinwomentakingAEDs.Thecontrolgroupwas10womenaged28to44years
withoutepilepsywhoweretakingnomedication.
Nopregnanciesoccurredinthecontrolgroupinthe12monthsofthestudy.Twopregnancies
occurredintheepilepsygroup;bothwomenweretakingphenytoinandtheirplasmalevelsof
levonorgestrelwerelowatthetimeofconception.Inaddition,nineofthecontrolgroupcontinued
tousetheimplantafter12months.Ofthewomenwithepilepsy,onlysixoftheninewomen
continuedtousetheimplantat12months.
Emergencycontraception
FFPRHC2003414
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)
537
TheEpilepsies
13.7.1
Arewomenwithepilepsyatincreasedriskofcomplicationsduringthepregnancyand
labour?
Details
Secondaryevidence
Primaryevidence
Fairgrieve2000416
Oneprospective,populationbasedstudywasidentified.400notificationsofpregnanciesinwomen
withepilepsywereincluded.Ofthe359(90%)knownpregnancyoutcomes,theobstetric
complicationratewassimilartothatofthebackgroundpopulation,exceptforanexcessof
prematuredeliveries(8.2%).Nostatisticalsignificancewasgiven.416
Tanganelli1992402
Anotherprospectivecontrolledstudycompared138pregnanciesin97womenwithepilepsywith
140controlpregnanciesin88womenwhodidnothaveepilepsy.Slightlymorecomplications
occurredinwomenwithepilepsycomparedwithcontrols(23.4%vs15.6%)butthedifferencewas
notstatisticallysignificant.However,inducedlabourandprolongedlabourwereapproximately
twiceaslikelyinwomenwithepilepsy(9.0%vs4.7%and5.7%vs2.3%).402
Olafsson1998417
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.418Asystematicreviewassessedtheoverallprevalenceoffetalanomalyto
be2.09%,rangingfrom0.76%to2.45%inindividualstudiesandincludingmajorandminor
anomalies.Overall,44.7%oftheseanomaliesweredetectedusingscreening,witharangeof15.0%
to85.3%asdifferentanomaliesaremoreorlesslikelytobecorrectlyidentified.
Theyfoundthatvariationindetectionrateoccurredwith:
thetypeofanomalybeingscreened
thegestationalageatscanning
theskilloftheoperator
thequalityoftheequipmentbeingused
thetimeallocatedforthescan.
538
TheEpilepsies
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.
Anarrativereview420onneuraltubedefectsandfolicacidsupplementationinwomenwithepilepsy
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]
539
TheEpilepsies
229. Womenandgirlsshouldbereassuredthatthereisnoevidencethatfocaljj,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
AnexpertworkshopconvenedbytheEpilepsyResearchFoundation421consideredbothpublished
evidenceandexpertopinionandconcludedthat:
Focalseizuresandnonconvulsivegeneralisedseizuresareunlikelytoexposethefetusto
immediaterisksinutero.
jj
kk
AppendixDprovidesachecklistfortheinformationneedsofwomenandgirlswithepilepsy,andpracticalinformationfor
motherswithepilepsy.
540
TheEpilepsies
Generalisedtonicclonicseizuresmayreducebloodflowtotheuterus,butthatevidencewas
lacking.Ifthewomanfalls,thenthereisariskofuterinecontractionandsubsequentplacental
abruption.
TheevidencesuggestedthatincreasedrateofteratogenesisisduetoAEDsratherthantoseizures
inpregnancy.
Itseemsunlikelythatmaternalseizuresduringpregnancyhaveimportantlongterm
developmentaleffectsonfetaldevelopment.421
Effectofmaternalseizuresonthewoman
TheConfidentialEnquiresintoMaternalDeathsintheUnitedKingdom422foundthat:
Indirectdeaths(n=136)weregreaterthandirectdeaths(n=106).
Ofthoseindirectdeaths,ninewererelatedtoepilepsy.
TheEnquiryrecommendedthatwomenneedspecialistadviceinpregnancy,andthatthepossibility
ofSUDEPshouldbediscussedwithallwomenwhoplantostopAEDtherapy.422
Effectofmaternalseizuresduringlabour
Theexpertworkshop421recommendedthat,asseizuresduringlabourcanaffectthefetus,delivery
forwomenwithepilepsyshouldtakeplaceatobstetricunitswithsufficientfacilities.Nodetailsof
whatsufficientfacilitiesweregiven.
Effectofmaternalseizuresinthepostnatalperiod
Fox1999423
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.
541
TheEpilepsies
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.
Kaaja2002424
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
542
TheEpilepsies
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.
543
TheEpilepsies
Children,youngpeopleandadultswithlearningdisabilitiesandepilepsy
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.Incommonwithotherreviewsinthefield427largegapsintheavailableevidencewere
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
544
TheEpilepsies
Secondaryevidence
Primaryevidence
Collacott1989428
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.
DeToledo2002429
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
545
TheEpilepsies
Children,youngpeopleandadultswith learningdisabilitiesandepilepsy
Primaryevidence
DeToledo2002429
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
Brodtkorb1994430
AnEEGrecordingcouldnotbemadein10of63institutionalisedindividualswithlearningdisabilities
duetocooperationproblems.
Consensusguidelinerecommendations
WorkinggroupoftheInternationalAssociationoftheScientificStudyofIntellectualDisability2001
427
Kerrandcolleaguesrecommendedthat:
Facilitiesshouldbeavailableforimagingundergeneralanaesthesia.
546
TheEpilepsies
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.
14.6.2
Forthisreviewweincludedadultsandchildrenwithlearningdisabilitiesandepilepsy.Peoplewith
LennoxGastautsyndromewereexcludedfromthisevidencereviewandwerereportedinaseparate
evidencereview(seesection10.7).
14.6.3
Matrixoftheevidence
adultsandchildrenwithepilepsyandlearningdisabilities.Thefollowinginterventionswereincluded
inoursearch;pregabalin,zonisamide,lacosamide,lamotrigine,gababentin,oxcarbazepine,
tiagabine,levetiracetam,topiramate,vigabatrin,phenytoin,phenobarbital,clobazam,felbamate,
acetazolamide,sodiumvalproate,primidoneandcarbamazepine.WelookedforanyRCTstudiesthat
comparedtheeffectivenessoftwoormoreofthesetreatments(orplacebo).
547
TheEpilepsies
Placebo
Pregabalin
Zonisamide
Lacosamide
Lamotrigine
Gabapentin
1431
Oxcarbazepine
Tiagabine
Levetiracetam
1432
Topiramate
Vigabatrin
Phenytoin
Phenobarbital
Clobazam
Felbamate
Acetazolamide
Sodium
evaporate
Primidone
Carbamazepine
ZNS
LCS
LTG
GBP
OXC
TGB
LEV
TPM
VGB
PHT
PBT
CLB
VPA
PRM
CBZ
Pla
PRE
FBM ACT
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
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)
550
TheEpilepsies
drugs(VERYLOWQUALITY)
dailylife(VERYLOWQUALITY)
severity(VERYLOWQUALITY)
sideeffects(VERYLOWQUALITY)
behaviour(VERYLOWQUALITY)
mood(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivetopiramatetoplaceboinapopulationofpatientswith
learningdisabilitieswasidentified.
14.6.3.2
seizurefreedom
timetofirstseizure
timetoexit/withdrawal
Gabapentinadjunctivetherapyversuslamotrigineadjunctivetherapy
Clinicalevidence
Healtheconomics
Evidencestatements
Nosignificantdifferencewasfoundbetweengabapentinadjunctivetherapyandlamotrigine
adjunctivetherapyfortheproportionofseizurefreeparticipants.(VERYLOWQUALITY)
Nostatisticallysignificantdifferencewasfoundbetweengabapentinadjunctivetherapyand
lamotrigineadjunctivetherapyfortheproportionofparticipantsexperiencingatleasta50%
reductioninseizurefrequency.(VERYLOWQUALITY)
Forpeoplewithlearningdisabilities,nostatisticallysignificantdifferencewasfoundbetween
gabapentinadjunctivetherapyandlamotrigineadjunctivetherapyfortheproportionofparticipants
withdrawnduetoadverseevents.(VERYLOWQUALITY)
Costeffectiveness
Noeconomicevidencecomparingadjunctivegabapentintoadjunctivelamotrigineinapopulationof
patientswithlearningdisabilitieswasidentified.
551
TheEpilepsies
14.6.4
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.
TheGDGconsideredthatextratimemayberequiredtoimplement
thisrecommendation,butthatpersonalisedcareplansforthis
groupofpatientsmayhelpimprovethelongtermoutcomesof
treatmentandmayultimatelyreducetheneedforhospital
admissions,outpatientappointmentsandGPconsultations.
Outcomesmaybeimprovedaschoiceofdruganddosecanbe
tailoredmoresuccessfullytothepatient,therebyreducingriskof
discontinuationduetointolerablesideeffects.TheGDG
considereditlikelytobeacosteffectiveuseofresources,although
noevidenceisavailable.
Qualityofevidence
Otherconsiderations
GDGviewisthatthispatientgrouphastraditionallyreceivedsub
optimalcare,andlessaccesstospecialistepilepsyservices.
552
TheEpilepsies
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).
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.
None.
Qualityofevidence
553
TheEpilepsies
Otherconsiderations
14.6.5
GDGviewisthatthispatientpopulationhastraditionally
receivedsuboptimalcare,andlessaccesstospecialistepilepsy
services.
Isepilepsymoredifficulttotreatinpeoplewithlearningdisabilities?
251. Everytherapeuticoptionshouldbeexploredinchildren,youngpeopleandadultswith
epilepsyinthepresenceorabsenceoflearningdisabilities.[2004]
Evidencestatements
Remissionratesforpeoplewithlearningdisabilitiesandepilepsyarelowerthanthoseforpeoplewith
epilepsywhodonothavelearningdisabilities.(IIb)
Incommunitybasedstudiesofchildrenwithepilepsyandlearningdifficultiesasignificant(3940%)
proportionachieveremission.(IIb)
14.6.6
Likelihoodofremissionofseizures
Details
Onlystudiesofprognosisthatusedacommunitysampleofparticipantswereincludedsoastoavoid
referralbias.
Secondaryevidence
PrimaryPapers
Airaksinen2000433
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
Annegers1979434
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
Brorson1987435
554
TheEpilepsies
Afollowupstudyof195children(aged0to19years)withactiveepilepsy(atleastoneseizureinthe
past3years)inUppsala,Swedenwasundertaken.Ofthe194childrenthatagreedtoparticipate,74
hadsomeneurodeficit.After12years,29ofthe74children(39%)wereinremission,definedas
beingseizurefreefor3consecutiveyears.Theannualremissionratewashigh(12%)onlyinthefirst
fewyearsafteronset,butthenfellto3%.435
Goulden1991436
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
Sillanpaa1975437
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;
555
TheEpilepsies
Concernsabouttreatmentanditsimpactonindividualswithepilepsyandlearningdisabilitiesand
theircarers;
Concernsabouthowboththecarer(s)andanindividualwithepilepsyandlearningdisabilitiescan
achieveacarebalance;
Concernsaboutthesocialimpactforindividualswithepilepsyandlearningdisabilities.(III)
14.7.1
Isthereincreasedmortalityinpeoplewithlearningdisabilitiesandepilepsy?
Details
Secondaryevidence
Primaryevidence
Brorson1987435
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
Forsgren1996438
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
Forssman1970439
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
Nashef1995388
Mortalityandsuddendeathrateswerestudiedinacohortof310childrenattendingaschool
specialisingintheeducationofpeoplewithepilepsyandlearningdisability.Childrenwereincludedif
theyattendedatanytimebetween1970and1993.Totaldurationoffollowupwas4,135person
years.Therewere28deaths(meanage19years,range10to28);14wereclassifiedassudden
death.388
556
TheEpilepsies
14.7.2
Whatmanagementissuesinpeoplewithlearningdisabilitiesdohealthcarepractitioners
andcarersviewasimportant?
Secondaryevidence
Primarypapers
Espie2001440
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
557
TheEpilepsies
Youngpeoplewithepilepsy
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
withpooradherencewithmedication151.
Theauthorsthenconsideredtheexistingliteratureonadherencetomedicationinadolescentsasa
group.Studiessuggestedthatpooradherencetoprescriptionregimensmaybeinfluencedby:
feelingsofisolation,
feelingsofstigma,
558
TheEpilepsies
threatstoindependenceandabilitytojoininwithpeers,
perceivedlackofunderstandingoftheircondition,and
denialoftheirepilepsy.
Conversely,goodadherencewithtreatmentregimewasfoundtobelinkedwith:
supportfromparents,
supportfromthedoctor,
goodmotivation,
feelingsofepilepsynotbeingathreattosocialwellbeing,and
[good]familyenvironment.
Theauthorsconcludedthattheneedsofadolescentsrequirespecialattention.151
15.4 Isthereanyevidenceofeffectivenessforanygivenstrategies
proposedtoimproveoutcomesforadolescents?
Thestudiesreportedintheabovesystematicreview151arereportedasshowinganassociation
betweencertainhealthcareprofessionalbehavioursandselfreportedadherencewithmedication.It
shouldbenotedthatassociationdoesnotinitselfprovethattherelationshipiscausal,thatis,having
regularhealthcareprofessionalinputleadstoimprovedadherencetothetreatmentplan.
258. Multidisciplinaryservicesprovidedjointlybyadultandpaediatricspecialistshaveakeyrolein
thecareoftheyoungpersonwithepilepsy.Thiscanfacilitatethetransitionfrompaediatricto
adultservicesandaidinthedisseminationofinformation.[2004]
259. Beforethetransitiontoadultservicesismade,diagnosisandmanagementshouldbe
reviewedandaccesstovoluntaryorganisations,suchassupportgroupsandepilepsycharities,
shouldbefacilitated.[2004]
Evidencestatement
Nostudieswereidentifiedwhichcomparedoutcomesforyoungpeopleattendingspecialistteenage
epilepsyasopposedtothoseattendingroutinechildoradultclinics.
Details
Appleton1999442
Inthispersonalpracticepaper,theauthorsproposedthataspecialistserviceshouldbeprovided
becauseteenagersfeeluncomfortableormayfeelitinappropriatetocontinuetoattendpaediatric
services,andtheyarelikelytoremainonmedicationforalongperiodoftime.Theysuggestedthat
thiscouldbesitedwithinaspecificclinicforteenagers.
Smith2002443
Thispaperreportstheexperienceofonespecificteenagerepilepsyclinic.Itdoesnotcompare
outcomesforadolescentsattendingspecialistteenageepilepsyasopposedtothoseattending
routinechildoradultclinics.
15.5 Whatarethespecialneedsorinformationrequirementsofthis
group?
260. Theinformationgiventoyoungpeopleshouldcoverepilepsyingeneralanditsdiagnosisand
treatment,theimpactofseizuresandadequateseizurecontrol,treatmentoptionsincluding
sideeffectsandrisks,andtherisksofinjury.Otherimportantissuestobecoveredarethe
559
TheEpilepsies
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
Couldridge2001372
ThisUKpapersystematicallyreviewedtheinformationandcounsellingneedsofpeoplewith
epilepsy.Itaimedtolocate,appraiseandsynthesiseevidencefromkeyprimaryresearchinthisarea
between1990and2000.Thereviewdidnotfocusspecificallyontheneedsofadolescentsand
epilepsy.Fifteenpapersidentifiedspecificinformationneedsofpeoplewithepilepsy.Resultsfrom
thesestudiessuggestthatpeoplewithepilepsyrequireinformationon:
epilepsyingeneral
seizuresandseizurecontrol
injuryprevention
psychologicalissues
socialsecurity
drivingandinsurance
employment
prognosis
lifestyleandsocialissues
Thereview372identifiedonepaperthatdealtspecificallywiththeexperiencesofyoungpeoplewith
epilepsy.
Wilde1996444
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
560
TheEpilepsies
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
Appleton1997445
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.
561
TheEpilepsies
Theauthorsrecommendedthatadolescenceisanimportanttimetoreviewthediagnosisof
epilepsy.445
Expertevidence
Appleton1999442
AppletonandNevillestatedthattheadolescentperiodwasanimportanttimetoreviewthe
diagnosisofbothepilepsyandtheepilepsysyndrome,andtoconsideranyunderlyingcause.
Reasonsincludedpreviousmisdiagnosis,andparticularlythepotentiallyseriousimplicationsof
misdiagnosisforemployment,driving,andpsychosocialhealth.
562
TheEpilepsies
Olderpeople
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.
16.1.2
includedolderpeopletakingantiepilepticdrugs.Welookedfordataspecificallyontheincidenceof
adverseevents(10%orabove),cognitiveeffectsandqualityoflife.Onlyvalidatedmeasuresof
cognitiveeffectandoutcomesrelatingtoqualityoflifehavebeeninvestigatedforthepurposesof
thisevidencereview.TheGDGdecidedthatevidenceontheeffectivenessofthevariousdrugsat
reducingnumberofseizureswasbetterexaminedbyconsideringthedatafromgeneralepilepsy
population.Thisdatacanbefoundinothersectionsoftheguideline.
16.1.3
Matrixoftheevidence
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
3446,447
164
448
450
Sodiumvalproate
Phenytoin
1451
Gabapentin
1446
1446
563
TheEpilepsies
Olderpeople
PCB CBZ
CBZ
SR
LTG
VPA PHT
GBP
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)
564
TheEpilepsies
Olderpeople
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.
565
TheEpilepsies
Olderpeople
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.
566
TheEpilepsies
Olderpeople
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.
567
TheEpilepsies
Olderpeople
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.
568
TheEpilepsies
Olderpeople
16.1.4
Recommendation
outcomes
262. Donotdiscriminateagainstolderpeople,andofferthe
sameservices,investigationsandtherapiesasforthegeneral
population.[new2012]
Adverseeffectsofdrugsandqualityoflifewereconsideredthe
mostimportantoutcomesforthisreviewasolderpeopleare
moresusceptibletosideeffectsofdrugs.Effectivenessofthe
drugsatreducingnumbersofseizuresisalsoimportantbutis
dealtwithintheotherseizureandepilepsysyndromesectionsof
thisguideline.
benefitsandharms
AEDareassociatedwithpotentiallymoreadversesideeffectsin
thispatientgroup.Thereductioninseizuresfoundinourother
reviewsisassumedtobesimilarforolderpeople.TheGDG
consideredthatthebenefitofreductioninseizuresoutweighed
theadverseeffectsassociatedwithdrugtreatmentinthesame
wayasitdoesforotherpeoplewithepilepsy.
TherewasnoeconomicevidencebuttheGDGconsideredthat
treatmentwithAEDswouldbecosteffectiveforolderpeoplejust
asitisforotherpeoplewithepilepsy.
Qualityofevidence
Thisrecommendationwasbasedonoutcomedatathatwas
moderatetoverylowqualityandGDGexpertise.
Otherconsiderations
TheGDGwishedtoensurethatolderpeoplehadoptimal
treatmentandhadthesameopportunitiesasotheradultsto
accesstreatmentsandspecialistepilepsyservices.TheGDGwere
concernedthatthisisnotnecessarilycurrentpractice.
569
TheEpilepsies
Olderpeople
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.
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
570
TheEpilepsies
Olderpeople
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.
571
TheEpilepsies
Peoplefromblackandminorityethnicgroups
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
NoevidencewasfoundintheMedicinesAlliancereview151ortheCouldridgereview372relating
specificallytominorityethnicgroups.Oneprimarysourceofevidencewasidentified.453
Ismailandcolleagues2003453
ThisqualitativestudyaimedtoexploretheexperiencesofSouthAsianswithepilepsyinrelationto
theirhealthneedsandbeliefsandtheroleofhealthprofessionalsinprovidingappropriate
informationandaccessibleservices.
572
TheEpilepsies
Peoplefromblackandminorityethnicgroups
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).
573
TheEpilepsies
Thecareprocessforpeoplewithepilepsy
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)
574
TheEpilepsies
Thereisevidencethatepilepsyspecialistnursesimprovetheprocessofcareforpeoplewithepilepsy
inprimarycare.(Ia)
Thereissomeevidencetoshowthatinformationrecordedisimprovedanddepressionreducedwith
epilepsyspecialistnurses.(Ia)
Thereiscurrentlylimitedevidencethatepilepsyspecialistnursesimproveclinicallyimportant
outcomesforpeoplewithepilepsyinprimarycare.(Ia)
18.2.1
Whatevidenceisthereregardingthequalityofcarecurrentlyprovidedinprimarycare?
Details
Secondaryevidence
Therewerenopublishedhighqualityreviewsidentifiedofthequalityofcareforadultsandchildren
withepilepsyprovidedinprimarycare.Onenarrativereviewhighlightedthelimitedevidencebase
inthisareaandtheneedforfurtherresearch.454
Primaryevidence
SUDEP200218
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)200011
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
575
TheEpilepsies
involvement(30%;ofwhomthemajorityofGPs,59%,werenothappywiththissituation)orGPled
(GPscompletelyinvolvedinmanagement)(13%).GPsfeltthatbettersharedcarearrangements
andcommunicationandaccesstohospitalwouldimproveclinicalservices.Themostcommon
suggestion(23%)byGPsforimprovingprimarycareepilepsyserviceswastheprovisionofan
epilepsyspecialistnurse.However,only16%oftheGPssurveyedhadaccesstoepilepsyspecialist
nurses(ateitherhospitalorcommunitylevel).11
Primarycareaudits
Evidenceisavailableonthequalityofcareprovidedingeneralpracticethroughpublishedaudits
conductedinthelasttenyears.455459Severaloftheseauditsreportedfindingsfromasmallnumber
ofpracticesand/orreliedonselfselectingvolunteerpractices.Onepublishedauditaddressed
theseproblemsbybeingregionwide,randomlyselectingthegeneralpracticesandhavingahigh
participationrate(87%participated,31/36).456Theyfoundthatrecordingofinformationinthe
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.11,18Thiscouldbeachievedbya
structuredannualreview.
Secondaryevidence
Primaryevidence
Norandomisedcontrolledtrialswerefoundevaluatingtheeffectivenessofstructuredreviewinthe
careofpeoplewithepilepsy.
ThestudybyThaparandcolleagues454wasexcludedasthisevaluatedtheopportunisticuseofa
promptandremindercardingeneralpracticeasopposedtostructuredannualreview.
576
TheEpilepsies
18.2.2.2
Doadultsandchildrenwithepilepsyattendingprimarycarewhoreceivecarefromaspecialist
epilepsynurse,whencomparedwiththosewhodonot,havebetterhealthoutcomes?
Details
Theneedforsharedcareprotocolsbetweenprimaryandsecondarycarehasbeenproposedbya
numberofauthorities.11,460Thedeploymentofnursestrainedinepilepsycare(specialistepilepsy
nurses)workinginprimarycarewhocouldliaisewithsecondarycarehasbeenproposed.461
Secondaryevidence
Bradley2003462
ACochranereviewassessedtheeffectivenessofspecialistepilepsynursescomparedtoroutinecare.
AnyRCTsorquasirandomisedtrialsthatcomparedspecialistnurseinterventionscomparedto
routineoralternativecarewereincluded.
Threetrialswereincluded,oneingeneralpracticeandtwoinaneurologycentre.Thethreetrials
onlyincludedindividualsaged15yearsorolder.
Thefindingsfromthetrialbasedingeneralpracticearesummarisedhere.
TheRidsdaleRCT463(andthefollowuppaper464)wasbasedingeneralpracticeandmostofthe
participantshadestablishedepilepsy.Thestudyincluded251adults(aged15yearsorover).The
interventioninvolvedaninterviewwithaspecialistepilepsynursefollowedupbytwospecialist
nurseinterviewsinadditionto'standardcare'.AconcernraisedintheCochranereview462wasthat
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,thisstudydidnotshowanimprovementinanyclinicallyimportantoutcomes465for
peoplewithepilepsymanagedingeneralpracticebyanepilepsyspecialistnurse.Astheauthorsof
thestudythemselvesnotedthisstudywassmallinsizeandscope,focusingonprocessratherthan
outcomesandtheauthorsofthereviewcalledforfurtherresearchinthisarea.462
Nosystematicreviewsofpaediatricclinicswereidentified.
Primaryevidence
Norandomisedcontrolledtrialswerefoundevaluatingtheeffectivenessofepilepsyspecialistnurses
publishedafterthedateoftheaboveCochraneReview.
18.3 Whatfeaturesofthecareprocessinsecondaryandtertiarycare
leadtoimprovedhealthoutcomesforadultsandchildrenwith
epilepsy?
273. Adultsshouldhaveregularreviews.Inaddition,accesstoeithersecondaryortertiarycare
shouldbeavailabletoensureappropriatediagnosis,investigationandtreatmentiftheperson
orclinicianviewtheepilepsyasinadequatelycontrolled.[2004]
577
TheEpilepsies
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
SUDEPreport18
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.
578
TheEpilepsies
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)report200011
Usersperspectivesoncare
TheClinicalStandardsAdvisoryGroupwasaskedtoadviseonstandardsofNHSservicesforpeople
withepilepsy.Aspartofthereport,theexperienceofuserswasstudied466.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
CSAG11alsosurveyedneurologists(n=220),paediatriciansrunninggeneralpaediatricclinics(n=64),
generalphysicians(n=27),geriatricians(=27),andlearningdisabilitydoctors(n=33)intheUKabout
thequalityofsecondarycareforpeoplewithepilepsy.
TertiaryserviceswereassessedbysystematictelephonesurveyofallappropriateNHSTrustsinthe
UK.
579
TheEpilepsies
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
IndependentReviewofPaediatricNeurologyServicesInLeicester2003467
ThisreviewintotheprovisionofpaediatricneurologyservicesinLeicesterrecommended:
thatformalappraisalofconsultantmedicalstaffoperatingonasinglehandedbasisshouldensure
thatopportunitiesareinplaceforeffectiveclinicalnetworkingincorporatingpeerreviewandthat
theseopportunitiesareappropriatelyutilised.
thattheappropriateauthoritiesconsiderclarifyingthetrainingrequirementsandqualifications
neededforconsultantmedicalstaffpractisinginspecialityareas,withparticularreferenceto
paediatricneurology.467
Otherprimaryevidence
Bradley1999468
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.
580
TheEpilepsies
Ingeneral,thestandardofrecordkeepinginhospitalswaslowerthaningeneralpractice.In
particular,thelevelsofrecordingofadvicegivenwerelow,withthoseinhospitallowerthangeneral
practiceinmostcases.468
Reynders2002469
ReyndersandBakerundertookaquestionnairesurveytoreviewthecurrentpracticeof
neuropsychologistsworkingwithinepilepsyservicesintheUK.Theyfoundthatalthoughprogress
hadbeenmadetowardsfulfillingtherecommended1991ILAEguidelinesforservices,notallhad
beenimplemented.
Therewasaneedforappropriateandnationallyrecognisedtrainingforneuropsychologistsandthe
establishmentofcentresofexcellence.Thereviewshowedthatmeetingthefullrangeof
psychologicalneedsoftheindividualsandtheirfamiliesremainedunderdeveloped.469
18.3.2
epilepsyinsecondary/tertiarycare?
Specificepilepsy/seizureclinics
EpilepsyNurseSpecialists
18.3.2.1
Doadultsandchildrenwithepilepsyattendingsecondarycarewhoreceivecareinaspecialist
clinic,whencomparedwiththosewhodonot,havebetterhealthoutcomes
Details
IntheCSAGsurveyofclinicians,therewasgeneralagreementthatclinicsspecialisinginepilepsy
couldprovidebettercare,andindividualsexpressedstrongsupportforsuchservices.11Specialised
clinicshavealsobeenproposedbymanyauthorities.11,460
SecondaryEvidence
Bowley2000470
Inarecentnarrativeliteraturereviewofepilepsyinpeoplewithlearningdisabilities,noevidenceof
researchinservicedeliverywasidentified.
Bradley2003471
OneCochranereviewwasidentifiedthatassessedtheeffectivenessofspecialistepilepsyclinics
comparedtoroutinecare.TheselectioncriteriawereanyRCTsorquasirandomisedtrials
consideringspecialistclinicinterventionscomparedtoroutineoralternativecare.Notrialsof
suitablequalitywereidentifiedandthereviewconcludedthatitisnotknownwhethersuchclinics
improveoutcomesforpeoplewithepilepsy471.
18.3.2.2
Doadultsandchildrenwithepilepsyattendingsecondarycarewhoreceivecarefromaspecialist
nurse,whencomparedwiththosewhodonot,havebetterhealthoutcomes?
Details
Theroleofthespecialistnurseissupportedbymanyauthorities,11,460anddetaileddescriptionsofthe
rolehavebeenproposed.
Secondaryevidence
Bradley2003462
ACochranereviewassessedtheeffectivenessofspecialistepilepsynursescomparedtoroutinecare.
AnyRCTsorquasirandomisedtrialsthatcomparedspecialistnurseinterventionscomparedto
routineoralternativecarewereincluded.
Threetrialswereincluded,oneingeneralpracticeandtwoinneurologycentres.Thethreetrials
onlyincludedadultsaged15yearsorolder.Thetwotrialsinneurologycentresarepresentedbelow.
581
TheEpilepsies
Ridsdaleandcolleaguesassessedtheeffectofanepilepsynursespecialistonnewlydiagnosedadults'
knowledgeofepilepsy,satisfactionwiththeadviceprovided,andpsychologicalwellbeing472.The
trialwasassessedasofadequatequality.Individualsrandomisedtoseethenursespecialistwere
significantlymorelikelytoreportthatenoughadvicehadbeenprovidedonmostepilepsyrelated
topicscomparedwiththecontrolgroup.Therewerenosignificantdifferencesinknowledgeof
epilepsyscores.However,thereweresignificantdifferencesinthegroupwho,atbaseline,had
knowledgescoresinthelowestquartile;thoserandomisedtothenursehadhigherknowledgescores
(42.7vs.37.2;p<0.01).Comparedwithdoctors,thenursewashighlyratedforprovidingclear
explanations.
Thequalityofthetrialbasedintertiarycare473wasassessedasunclear.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
specialistnursesweremoreexpensive462.
Thereviewconcludedthat,forbothprimaryandsecondary/tertiarycare,therewasnoconvincing
evidencethatspecialistnurseservicesimproveoutcomesforpeoplewithepilepsy,butlowbaseline
knowledgeinindividualswithnewlydiagnosedepilepsymaybeimproved.
Meads2002474
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
qualityoflifebutwerelessexpensive474.
Primaryevidence
TherewerenoRCTsidentifiedasbeingpublishedsincethereviewspresentedabove.
Healtheconomics
Meads2002474
Theobjectivesofthispaperweretosystematicallyreviewtwoaspectsofspecialistepilepsycare
provision:
theevidenceontherelativeeffectivenessandcosteffectivenessofspecialistepilepsyclinics
comparedtogeneralneurologyoutpatientclinics.
theeffectivenessontherelativeeffectivenessandcosteffectivenessofspecialistepilepsynurses
ininpatient,outpatientorGPcarecomparedtousualcarewithoutaspecialistepilepsynurse.
582
TheEpilepsies
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
paediatricphysicianwithonwardreferraltoaspecialistllwhenanepilepticseizureissuspected
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
CSAGreport11
ll
andyoungpeople,aspecialistisdefinedthroughoutasapaediatricianwithtrainingandexpertiseinepilepsy.
583
TheEpilepsies
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
Ryan1998476
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
Reuber2000477
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:
Causesofattendance477ModifiedfromSeizure,9,ReuberM,HattinghLand
GoudlingPJ,Epileptologicalemergenciesinaccidentandemergency:asurveyatStJames's
universityhospital,Leeds,pages21620,Copyright(2000)withpermissionfromBEATrading
Ltd.
584
TheEpilepsies
60
50
40
51
48
38
30
20
31
15
10
NoevidencewasfoundofthequalityofcareforchildreninA&E.
Oneauditwasidentifiedthatauditedtheuseofaspecifictreatmentprotocolratherthanany
variationincare,sowasexcluded.478
18.4.2
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.
585
TheEpilepsies
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.ukmm)tochildren,youngpeopleandadultswithepilepsywhowishto
managetheirconditionmoreeffectively.[2004,amended2012]
Evidencestatements
Selfmanagementeducationforadultswithepilepsycanleadtoanimprovementinseizurefrequency.
Ithasalsobeenshowntoincreaseindividualsunderstandingofepilepsyandtheiradherencewith
medicationanddecreaseindividualsfearofseizuresandhazardousmedicalselfmanagement
strategies.(Ib)
Activeeducationinchildrenwithepilepsycanleadtoanimprovementinseizurefrequency.Ithas
alsobeenshowntodecreasehospitalemergencyroomattendance,schoolabsenteeismand
unnecessaryrestrictionofactivities.(Ib)
Secondaryevidence
NosystematicreviewswerefoundthatansweredthisKCQ.
Primaryevidence
Fourstudiesevaluatedtheuseofselfmanagementprogramsforpeoplewithepilepsy;twoRCTs
includedadultsonlyandtwochildren.
Helgeson1990479
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
May2002379
TheefficacyoftheMOSESeducationaltreatmentprogrammeforadultswithepilepsywasevaluated
byMayandPfafflin.383adultsovertheageof16yearsfrom22epilepsycentreswererandomly
mm
Thewebaddresshaschangedsincetherecommendationwaspublishedin2004andhasbeenupdated.
586
TheEpilepsies
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
Lewis1990480andLewis1991481
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
Tieffenberg2000482
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
587
TheEpilepsies
Glossary
19 Glossary
AbsenceSeizure
Aseizurecharacterisedbybehaviouralarrestassociatedwith
generalisedspikewaveactivityonEEG.
Absoluteriskreduction Thedifferenceintheriskofaneventbetweentwogroups(one
(Riskdifference)
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.
Aflowchartoftheclinicaldecisionpathwaydescribedinthe
guideline,wheredecisionpointsarerepresentedwithboxes,linked
witharrows.
Algorithm(in
guidelines)
Allocationconcealment Theprocessusedtopreventadvanceknowledgeofgroup
assignmentinaRCT.Theallocationprocessshouldbeimperviousto
anyinfluencebytheindividualmakingtheallocation,bybeing
administeredbysomeonewhoisnotresponsibleforrecruiting
participants.
Antiepilepticdrug
(AED)
Applicability
Medicationtakendailytopreventtherecurrenceofepileptic
seizures.RefertoAppendixKconcerningthechoiceofdrug,side
effectsandsuitabilitytosyndrome.
Thedegreetowhichtheresultsofanobservation,studyorreview
arelikelytoholdtrueinaparticularclinicalpracticesetting.
AppraisalofGuidelines Aninternationalcollaborationofresearchersandpolicymakers
Researchand
whoseaimistoimprovethequalityandeffectivenessofclinical
Evaluation(AGREE)
practiceguidelines(http://www.agreecollaboration.org/).The
AGREEinstrument,developedbythegroup,isdesignedtoassessthe
qualityofclinicalguidelines.
Arm(ofaclinicalstudy) Subsectionofindividualswithinastudywhoreceiveoneparticular
intervention,forexampleplaceboarm.
Association
Statisticalrelationshipbetweentwoormoreevents,characteristics
orothervariables.Therelationshipmayormaynotbecausal.
Atonicseizure
Ageneralisedseizurecharacterisedbysuddenonsetoflossof
muscletone.
Anepisodeinthecourseofanillness.
Attack
588
TheEpilepsies
Glossary
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
589
TheEpilepsies
Glossary
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
590
TheEpilepsies
Glossary
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)
Costbenefitanalysis
Whenaconvulsiveseizurecontinuesforaprolongedperiod(longer
than5minutes),orwhenconvulsiveseizuresoccuroneafterthe
otherwithnorecoverybetween.Convulsivestatusepilepticusisan
emergencyandrequiresimmediatemedicalattention.
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).
591
TheEpilepsies
Glossary
Credibleinterval
Crossovertrial
Cryptogenic
TheBayesianequivalentofaconfidenceinterval.
Atrialinwhicheachofthestudygroupswillreceiveeachofthe
treatments,butinarandomisedorder:thatis,theywillstartoffin
onearmofthetrial,butwilldeliberatelycrossovertotheother
arm(s)inturn(HTA).
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.
592
TheEpilepsies
Glossary
Dravetsyndrome
Dropout
Previouslyknownasseveremyoclonicepilepsyofinfancy.An
epilepsystndromewithonsetininfancy,characterisedbyinitial
prolonged,typicallylateralised,febrileseizures,subsequent
developmentofmultipleseizuretypesincludingmyoclonic,absence,
focalandgeneralisedtonicclonicseizures,withdevelopmental
plateauorregression.
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.
Thestudyofadiseasewithinapopulation,definingitsincidenceand
prevalenceandexaminingtherolesofexternalinfluences(for
example,infection,diet)andinterventions.
Epidemiologicalstudy
Epilepsy
Epilepticseizure*
EpilepticSpasm
Epilepsysyndromes*
Epilepticdisease*
Aconditionwhereanindividualispronetorecurrentepileptic
seizures.
Atransientoccurrenceofsignsand/orsymptoms,theresultofa
primarychangetotheelectricalactivity(abnormallyexcessiveor
synchronous)inthebrain.
Aninvoluntarymusclecontractionofsuddenonset.
Distinctivedisordersidentifiableonthebasisofatypicalageof
onset,seizuretypes,specificEEGcharacteristics,andoftenother
features.Identificationofsuchhasimplicationsfortreatment,
managementandprognosis.
Apathologicconditioncausingepilepsywithasinglespecific,well
definedetiology.Thusprogressivemyoclonusepilepsyisa
syndrome,butUnverrichtLundborgisadisease.
593
TheEpilepsies
Glossary
Epileptic
encephalopathy*
Equity
Aconditioninwhichtheepileptiformabnormalitiesthemselvesare
believedtocontributetotheprogressivedisturbanceincerebral
function.
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
Followup
Generalisability
Generalisedseizure
Seizurewhichoriginateswithinnetworkslimitedtoonehemisphere,
discretelylocalisedormorewidelydistributed.Replacestheterms
partialseizuresandlocalizationrelatedseizures.
Observationoveraperiodoftimeofanindividual,grouporinitially
definedpopulationwhoseappropriatecharacteristicshavebeen
assessedinordertoobservechangesinhealthstatusorhealth
relatedvariables.
Theextenttowhichtheresultsofastudybasedonmeasurementin
aparticularpatientpopulationand/oraspecificcontextholdtruefor
anotherpopulationand/orinadifferentcontext.Inthisinstance,
thisisthedegreetowhichtheguidelinerecommendationis
applicableacrossbothgeographicalandcontextualsettings.For
instance,guidelinesthatsuggestsubstitutingoneformoflabourfor
anothershouldacknowledgethatthesecostsmightvaryacrossthe
country.
Aseizurewhichoriginatesin,andrapidlyengages,bilaterally
distributednetworks.Suchbilateralnetworkscanincludecortical
andsubcorticalstructuresbutdonotnecessarilyincludetheentire
cortex(ILAE2010)
594
TheEpilepsies
Glossary
Generalisedtonic
clonicseizure
Aseizureofsuddenonsetinvolvinggeneralisedstiffeningand
subsequentrhythmicjerkingofthelimbs,theresultofrapid
widespreadengagementofbilateralcorticalandsubcortical
networksinthebrain.
Genetic(withreference Theepilepsyis,asbestasunderstood,thedirectresultofaknownor
toepilepsy)
presumedgeneticdefect(s)inwhichseizuresarethecoresymptom
ofthedisorder(ILAE2010)
Girlsofchildbearing
Girlswhohaveenteredmenarcheandwhoaremenstruating
age
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).
Asyndromethatisonlyepilepsy,withnounderlyingstructuralbrain
lesionorotherneurologicalsignsorsymptoms.Thesearepresumed
Idiopathic
595
TheEpilepsies
Glossary
Idiopathicepilepsy
syndrome*
Idopathicgeneralised
epilepsy
Idiosyncratic
tobegeneticinaetiologyandareusuallyagedependent(ILAE2001).
Apreviouslyusedtermforasyndromethatinvolvesonlyepilepsy,
withnounderlyingstructuralbrainlesionorotherneurologicsignsor
symptoms.Thesearepresumedtobegeneticandareusuallyage
dependent.Itisnolongerrecommendedthatthisterminologyis
used.
Awelldefinedgroupofdisorderscharacterisedbytypicalabsences,
myoclonicandgeneralisedtonicclonicseizures,aloneorinvarying
combinationsinotherwisenormalindividuals.TheEEGisalso
characteristicdemonstratingadistinctpatternofgeneralised
polyspikewavedischargesand/orgeneralisedspikewave.Of
presumedgeneticaetiology.ThenewclassificationoftheILAE2010
suggesteterminologyshouldchangetogeneticgeneralized
epilepsy.
Physicalorbehaviouralcharacteristicthatispersonaltothat
individual.
InternationalLeague
InternationalLeagueAgainstEpilepsy.TheILAEisaglobal,
AgainstEpilepsy(ILAE)
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.
Inconsistency
ICER=(CostACostB)/(EffectivenessAEffectivenessB).
Inconsistencyisoneoftheelementsofqualityconsideredunderthe
GRADEsystem.Inconsistencyreferstotheunexplained
heterogeneityintheresultsobserved.
596
TheEpilepsies
Glossary
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.
597
TheEpilepsies
Glossary
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
Markovmodel
Medicinesand
HealthcareProducts
RegulatoryAgency
(MHRA)
Anauthorisationthatcoversallthemainactivitiesassociatedwith
themarketingofamedicinalproduct.Medicinesthatmeetthe
standardsofsafety,qualityandefficacysetbytheMedicinesand
HealthcareproductsRegulatoryAgency(MHRA)aregranteda
marketingauthorisation(previouslyaproduct
licence),whichisnormallynecessarybeforetheycanbeprescribed
orsold.
Amethodforestimatinglongtermcostsandeffectsforrecurrentor
chronicconditions,basedonhealthstatesandtheprobabilityof
transitionbetweenthemwithinagiventimeperiod(cycle).
TheExecutiveAgencyoftheDepartmentofHealthprotectingand
promotingpublichealthandpatientsafetybyensuringthat
medicines,healthcareproductsandmedicalequipmentmeet
appropriatestandardsofsafety,quality,performanceand
effectiveness,andareusedsafely.
598
TheEpilepsies
Glossary
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
Nonconvulsivestatus
epilepticus
Adeficiencyorimpairmentofthenervoussystem.
Achangeinmentalstatusorbehaviourfrombaseline,associated
withcontinuousseizureactivityonEEG,thatisalsoseentobea
changefrombaseline.
Adisordercharacterisedbyepisodesofchangeinbehaviouror
movement,notcausedbyaprimarychangeinelectricalactivityof
thebrain.Movementsarevaried,andtheattackscanbedifficultto
differentiatefromepilepticseizures.RefertoAppendixAforthe
differentiationsofepilepticattacksfromNEADanditssubgroups.
Nonepilepticattack
disorder
(NEAD)
Nystagmus
Numberneededto
treat(NNT)
Involuntaryrapidmovement(horizontal,vertical,rotatory,ormixed)
oftheeyeballs.
Thenumberofpatientsthatwhoonaveragemustbetreatedto
preventasingleoccurrenceoftheoutcomeofinterest.
Observationalstudy
Retrospectiveorprospectivestudyinwhichtheinvestigator
599
TheEpilepsies
Glossary
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
Parasomnia
Epilepsysyndromepresentinginearlychildhood(mean47yrs)with
rareseizureswhichareprolonged.Characterisedbyautonomic
featuresincludingvomiting,pallor,andsweatingfollowedbytonic
eyedeviation,impairmentofconsciousnesswithpossibleevolution
intosecondarygeneralisation.Prognosisisexcellentandtreatment
oftenunnecessary.
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.
600
TheEpilepsies
Glossary
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.
601
TheEpilepsies
Glossary
Qualityadjustedlife
year(QALY)
Quantitativeresearch
Anindexofsurvivalthatisadjustedtoaccountforthepatients
qualityoflifeduringthistime.QALYshavetheadvantageof
incorporatingchangesinbothquantity(longevity/mortality)and
quality(morbidity,psychological,functional,socialandotherfactors)
oflife.Usedtomeasurebenefitsincostutilityanalysis.TheQALYs
gainedarethemeanQALYsassociatedwithonetreatmentminusthe
meanQALYsassociatedwithanalternativetreatment.
Researchthatgeneratesnumericaldataordatathatcanbe
convertedintonumbers,forexampleclinicaltrialsorthenational
Censuswhichcountspeopleandhouseholds.
QuickReferenceGuide AnabridgedversionofNICEguidance,whichpresentsthekey
prioritiesforimplementationandsummarisestherecommendations
forthecoreclinicalaudience.
Randomisation
Allocationofparticipantsinaresearchstudytotwoormore
alternativegroupsusingachanceprocedure,suchascomputer
generatedrandomnumbers.Thisapproachisusedinanattemptto
ensurethereisanevendistributionofparticipantswithdifferent
characteristicsbetweengroupsandthusreducesourcesofbias.
Randomisedcontrolled Acomparativestudyinwhichparticipantsarerandomlyallocatedto
trial(RCT)
interventionandcontrolgroupsandfolloweduptoexamine
differencesinoutcomesbetweenthegroups.
RCT
SeeRandomisedcontrolledtrial.
Reflexepilepsy
syndromes*
Syndromesinwhichallepilepticseizuresareprecipitatedby
particularsensorystimuli.Reflexseizuresthatoccurinfocaland
generalizedepilepsysyndromesthatalsoareassociatedwith
spontaneousseizuresarelistedasseizuretypes.Isolatedreflex
seizuresalsocanoccurinsituationsthatdonotnecessarilyrequirea
diagnosisofepilepsy.Seizuresprecipitatedbyotherspecial
circumstances,suchasfeveroralcoholwithdrawal,arenotreflex
seizures.
Continuedstatusepilepticusdespitetreatmentwithtwo
anticonvulsantsinappropriatedoses.Thiscanoccurinboth
convulsiveandnonconvulsivestatusepilepticus.
Thenumberoftimesmorelikelyorlesslikelyaneventistohappen
inonegroupcomparedwithanother(calculatedastheriskofthe
eventingroupA/theriskoftheeventingroupB).
Refractorystatus
epilepticus
Relativerisk(RR)
Remit
ThebriefgivenbytheDepartmentofHealthandWelshAssembly
Governmentatthebeginningoftheguidelinedevelopmentprocess.
Thisdefinescoreareasofcarethattheguidelineneedstoaddress.
Resourceimplication
Thelikelyimpactintermsoffinance,workforceorotherNHS
resources.
Retrospectivestudy
Aretrospectivestudydealswiththepresent/pastanddoesnot
involvestudyingfutureevents.Thiscontrastswithstudiesthatare
prospective.
602
TheEpilepsies
Glossary
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*
Specialist
(asusedinthis
guideline)
Thesetermsarenolongerrecommended.Theyhavebeengenerally
replacedwiththesingleword,focal.Focalseizuresshouldincludea
cleardescriptionofimpairmentofconsciousness.
Foradults:amedicalpractitionerwithtrainingandexpertisein
epilepsy.
Forchildren:apaediatricianwithtrainingandexpertiseinepilepsy.
Specificcognitive
dysfunction
Definedasperformingbelowthe5thcentileforoneormoreonthe
followingtestsofcognitivefunction
1.visuoconstructivescoreofWIPPSI
Stakeholder
Statisticalpower
2.auditoryphonemicscoreofITPA
3.comprehensionscoreofNEPS
Thosewithaninterestintheuseoftheguideline.Stakeholders
includemanufacturers,sponsors,healthcareprofessionals,and
patientandcarergroups.
Theabilitytodemonstrateanassociationwhenoneexists.Poweris
relatedtosamplesize;thelargerthesamplesize,thegreaterthe
powerandthelowertheriskthatapossibleassociationcouldbe
603
TheEpilepsies
Glossary
missed.
Statusepilepticus
(convulsive)(CSE)
Suddenunexpected(or
unexplained)deathin
epilepsy
(SUDEP)
Symptomaticepilepsy
syndrome*
Syncope
(vasovagalsyncopal
attack)
Synthesisofevidence
Seeconvulsivestatusepilepticusabove.
Sudden,unexplained,witnessedorunwitnessed,nontraumaticand
nondrowningdeathinindividualswithepilepsy,withorwithout
evidenceforaseizure,andexcludingdocumentedstatusepilepticus,
inwhichpostmortemexaminationdoesnotrevealatoxicologicalor
anatomiccausefordeath.
ProvidedbyNashefL.Suddenunexpecteddeathinepilepsy:
Terminologyanddefinitions.Epilepsia1997;38:S20S22.
Previouslyusedtermthatreferstoasyndromeinwhichthe
epilepticseizuresaretheresultofoneormoreidentifiablestructural
lesionsofthebrain.Thisterminologyisnolongerrecommendedfor
use.Seetable9.7.
Abrieflapseinconsciousnesscausedbytransientreductioninblood
flowtothebrain.Maybecausedbymanydifferentfactors,
includingemotionalstress,vagalstimulation,vascularpoolinginthe
legs,diaphoresis,orsuddenchangeinenvironmentaltemperatureor
bodyposition.
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
Specialistcaredeliveryunit,towhichindividualsmaybereferred
fromsecondarycare.
Tertiarycentre
Timehorizon
Tonicseizures
ThetimespanusedintheNICEappraisalwhichreflectstheperiod
overwhichthemaindifferencesbetweeninterventionsinhealth
effectsanduseofhealthcareresourcesareexpectedtobe
experienced,andtakingintoaccountthelimitationsofsupportive
evidence.
Anepilepticseizurecharacterisedbyabruptgeneralisedmuscle
stiffeningpossiblycausingafall.Theseizureusuallylastslessthana
minuteandrecoveryisrapid.
604
TheEpilepsies
Glossary
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)
Westsyndrome
Astageinacrossovertrialafterthefirsttreatmentiswithdrawn,but
beforethesecondtreatmentisstarted.Thewashoutperiodallows
timeforanyactiveeffectsofthefirsttreatmenttowearoffbefore
thenextphasebegins.
Anepilepsysyndromewithanageofonsetinthefirstyearoflife
(peak,39months)characterisedbyinfantilespasmsandanEEG
patterndescribedashypsarrhythmia.Manychildrenalsoshow
developmentalplateauatpresentation.
Unlessotherwisestated,takenfromMosbysMedical,NursingandAlliedHealthDictionary5th
editionandsupplementedbythetextofthefullguideline(2004Guideline).
*DefinitionsfromILAETaskForceonClassification(updated2010)
605
TheEpilepsies
20 Referencelist
1 SanderJW,ShorvonSD.Epidemiologyoftheepilepsies.JournalofNeurology,Neurosurgery,
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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

CI- confidence interval

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

PHB LTG PHT

VPA OXC VGB

CLB ECBZ FBM GBP

Felbamate(FBMl) Gabapentin(GBP) Lacosamide(LAC)Lamotrigine(LTG)LamotrigineXR(LTGXR)

CLB LTG LTG

PRC TPM VPA

PCB VGB ACTH

PNL PNE HYD NPM

VPA GBP LEV

CLB CZP ZNS VPA

Normal Ketogenic Ketogenic

No previous children (n=117)

Previous children (n=52)

Percentages may not add to 100% due to rounding errors

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