17/06/2015

Harrison'sPrinciplesofInternalMedicine,19e>

445:SeizuresandEpilepsy
DanielH.Lowenstein

INTRODUCTION
Aseizure(fromtheLatinsacire,totakepossessionof)isaparoxysmaleventduetoabnormalexcessiveorsynchronousneuronalactivityinthebrain.Dependingonthe
distributionofdischarges,thisabnormalbrainactivitycanhavevariousmanifestations,rangingfromdramaticconvulsiveactivitytoexperientialphenomenanotreadily
discerniblebyanobserver.Althoughavarietyoffactorsinfluencetheincidenceandprevalenceofseizures,~510%ofthepopulationwillhaveatleastoneseizure,with
thehighestincidenceoccurringinearlychildhoodandlateadulthood.

Themeaningofthetermseizureneedstobecarefullydistinguishedfromthatofepilepsy.Epilepsydescribesaconditioninwhichapersonhasrecurrentseizuresdueto
achronic,underlyingprocess.Thisdefinitionimpliesthatapersonwithasingleseizure,orrecurrentseizuresduetocorrectableoravoidablecircumstances,doesnot
necessarilyhaveepilepsy.Epilepsyreferstoaclinicalphenomenonratherthanasinglediseaseentity,becausetherearemanyformsandcausesofepilepsy.However,
amongthemanycausesofepilepsytherearevariousepilepsysyndromesinwhichtheclinicalandpathologiccharacteristicsaredistinctiveandsuggestaspecific
underlyingetiology.

Usingthedefinitionofepilepsyastwoormoreunprovokedseizures,theincidenceofepilepsyis~0.30.5%indifferentpopulationsthroughouttheworld,andthe
prevalenceofepilepsyhasbeenestimatedat530personsper1000.

CLASSIFICATIONOFSEIZURES
Determiningthetypeofseizurethathasoccurredisessentialforfocusingthediagnosticapproachonparticularetiologies,selectingtheappropriatetherapy,and
providingpotentiallyvitalinformationregardingprognosis.TheInternationalLeagueagainstEpilepsy(ILAE)CommissiononClassificationandTerminology,20052009
hasprovidedanupdatedapproachtoclassificationofseizures(Table4451).Thissystemisbasedontheclinicalfeaturesofseizuresandassociated
electroencephalographicfindings.Otherpotentiallydistinctivefeaturessuchasetiologyorcellularsubstratearenotconsideredinthisclassificationsystem,althoughthis
willundoubtedlychangeinthefutureasmoreislearnedaboutthepathophysiologicmechanismsthatunderliespecificseizuretypes.

TABLE4451ClassificationofSeizures

1. Focalseizures
(Canbefurtherdescribedashavingmotor,sensory,autonomic,cognitive,orotherfeatures)
2. Generalizedseizures
a. Absence
Typical
Atypical
b. Tonicclonic
c. Clonic
d. Tonic
e. Atonic
f. Myoclonic
3. Maybefocal,generalized,orunclear
Epilepticspasms

Afundamentalprincipleisthatseizuresmaybeeitherfocalorgeneralized.Focalseizuresoriginatewithinnetworkslimitedtoonecerebralhemisphere(notethattheterm
partialseizuresisnolongerused).Generalizedseizuresarisewithinandrapidlyengagenetworksdistributedacrossbothcerebralhemispheres.Focalseizuresare
usuallyassociatedwithstructuralabnormalitiesofthebrain.Incontrast,generalizedseizuresmayresultfromcellular,biochemical,orstructuralabnormalitiesthathavea
morewidespreaddistribution.Thereareclearexceptionsinbothcases,however.

FOCALSEIZURES

Focalseizuresarisefromaneuronalnetworkeitherdiscretelylocalizedwithinonecerebralhemisphereormorebroadlydistributedbutstillwithinthehemisphere.With
thenewclassificationsystem,thesubcategoriesofsimplefocalseizuresandcomplexfocalseizureshavebeeneliminated.Instead,dependingonthepresenceof
cognitiveimpairment,theycanbedescribedasfocalseizureswithorwithoutdyscognitivefeatures.Focalseizurescanalsoevolveintogeneralizedseizures.Inthepast
thiswasreferredtoasfocalseizureswithsecondarygeneralization,butthenewsystemreliesonspecificdescriptionsofthetypeofgeneralizedseizuresthatevolvefrom
thefocalseizure.

Theroutineinterictal(i.e.,betweenseizures)electroencephalogram(EEG)inpatientswithfocalseizuresisoftennormalormayshowbriefdischargestermedepileptiform
spikes,orsharpwaves.Becausefocalseizurescanarisefromthemedialtemporallobeorinferiorfrontallobe(i.e.,regionsdistantfromthescalp),theEEGrecorded
duringtheseizuremaybenonlocalizing.However,theseizurefocusisoftendetectedusingsphenoidalorsurgicallyplacedintracranialelectrodes.

FocalSeizuresWithoutDyscognitiveFeatures

Focalseizurescancausemotor,sensory,autonomic,orpsychicsymptomswithoutimpairmentofcognition.Forexample,apatienthavingafocalmotorseizurearising
fromtherightprimarymotorcortexneartheareacontrollinghandmovementwillnotetheonsetofinvoluntarymovementsofthecontralateral,lefthand.These
movementsaretypicallyclonic(i.e.,repetitive,flexion/extensionmovements)atafrequencyof~23Hzpuretonicposturingmaybeseenaswell.Sincethecortical
regioncontrollinghandmovementisimmediatelyadjacenttotheregionforfacialexpression,theseizuremayalsocauseabnormalmovementsofthefacesynchronous
withthemovementsofthehand.TheEEGrecordedwithscalpelectrodesduringtheseizure(i.e.,anictalEEG)mayshowabnormaldischargesinaverylimitedregion
overtheappropriateareaofcerebralcortexiftheseizurefocusinvolvesthecerebralconvexity.Seizureactivityoccurringwithindeeperbrainstructuresissometimesnot
detectedbythestandardEEG,however,andmayrequireintracranialelectrodesforitsdetection.

Threeadditionalfeaturesoffocalmotorseizuresareworthnoting.First,insomepatients,theabnormalmotormovementsmaybegininaveryrestrictedregionsuchas
thefingersandgraduallyprogress(oversecondstominutes)toincludealargerportionoftheextremity.Thisphenomenon,describedbyHughlingsJacksonandknown

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 1/19
17/06/2015
asaJacksonianmarch,representsthespreadofseizureactivityoveraprogressivelylargerregionofmotorcortex.Second,patientsmayexperiencealocalizedparesis
(Toddsparalysis)forminutestomanyhoursintheinvolvedregionfollowingtheseizure.Third,inrareinstances,theseizuremaycontinueforhoursordays.This
condition,termedepilepsiapartialiscontinua,isoftenrefractorytomedicaltherapy.

Focalseizuresmayalsomanifestaschangesinsomaticsensation(e.g.,paresthesias),vision(flashinglightsorformedhallucinations),equilibrium(sensationoffallingor
vertigo),orautonomicfunction(flushing,sweating,piloerection).Focalseizuresarisingfromthetemporalorfrontalcortexmayalsocausealterationsinhearing,olfaction,
orhighercorticalfunction(psychicsymptoms).Thisincludesthesensationofunusual,intenseodors(e.g.,burningrubberorkerosene)orsounds(crudeorhighly
complexsounds),oranepigastricsensationthatrisesfromthestomachorchesttothehead.Somepatientsdescribeodd,internalfeelingssuchasfear,asenseof
impendingchange,detachment,depersonalization,djvu,orillusionsthatobjectsaregrowingsmaller(micropsia)orlarger(macropsia).Thesesubjective,internal
eventsthatarenotdirectlyobservablebysomeoneelsearereferredtoasauras.

FocalSeizureswithDyscognitiveFeatures

Focalseizuresmayalsobeaccompaniedbyatransientimpairmentofthepatientsabilitytomaintainnormalcontactwiththeenvironment.Thepatientisunableto
respondappropriatelytovisualorverbalcommandsduringtheseizureandhasimpairedrecollectionorawarenessoftheictalphase.Theseizuresfrequentlybeginwith
anaura(i.e.,afocalseizurewithoutcognitivedisturbance)thatisstereotypicforthepatient.Thestartoftheictalphaseisoftenasuddenbehavioralarrestormotionless
stare,whichmarkstheonsetoftheperiodofimpairedawareness.Thebehavioralarrestisusuallyaccompaniedbyautomatisms,whichareinvoluntary,automatic
behaviorsthathaveawiderangeofmanifestations.Automatismsmayconsistofverybasicbehaviorssuchaschewing,lipsmacking,swallowing,orpickingmovements
ofthehands,ormoreelaboratebehaviorssuchasadisplayofemotionorrunning.Thepatientistypicallyconfusedfollowingtheseizure,andthetransitiontofull
recoveryofconsciousnessmayrangefromsecondsuptoanhour.Examinationimmediatelyfollowingtheseizuremayshowananterogradeamnesiaor,incases
involvingthedominanthemisphere,apostictalaphasia.

Therangeofpotentialclinicalbehaviorslinkedtofocalseizuresissobroadthatextremecautionisadvisedbeforeconcludingthatstereotypicepisodesofbizarreor
atypicalbehaviorarenotduetoseizureactivity.Insuchcasesadditional,detailedEEGstudiesmaybehelpful.

EVOLUTIONOFFOCALSEIZURESTOGENERALIZEDSEIZURES

Focalseizurescanspreadtoinvolvebothcerebralhemispheresandproduceageneralizedseizure,usuallyofthetonicclonicvariety(discussedbelow).Thisevolutionis
observedfrequentlyfollowingfocalseizuresarisingfromafocusinthefrontallobe,butmayalsobeassociatedwithfocalseizuresoccurringelsewhereinthebrain.A
focalseizurethatevolvesintoageneralizedseizureisoftendifficulttodistinguishfromaprimarygeneralizedonsettonicclonicseizure,becausebystanderstendto
emphasizethemoredramatic,generalizedconvulsivephaseoftheseizureandoverlookthemoresubtle,focalsymptomspresentatonset.Insomecases,thefocal
onsetoftheseizurebecomesapparentonlywhenacarefulhistoryidentifiesaprecedingaura.Often,however,thefocalonsetisnotclinicallyevidentandmaybe
establishedonlythroughcarefulEEGanalysis.Nonetheless,distinguishingbetweenthesetwoentitiesisextremelyimportant,becausetheremaybesubstantial
differencesintheevaluationandtreatmentofepilepsiesassociatedwithfocalversusgeneralizedseizures.

GENERALIZEDSEIZURES

Generalizedseizuresarethoughttoariseatsomepointinthebrainbutimmediatelyandrapidlyengageneuronalnetworksinbothcerebralhemispheres.Severaltypes
ofgeneralizedseizureshavefeaturesthatplacethemindistinctivecategoriesandfacilitateclinicaldiagnosis.

TypicalAbsenceSeizures

Typicalabsenceseizuresarecharacterizedbysudden,brieflapsesofconsciousnesswithoutlossofposturalcontrol.Theseizuretypicallylastsforonlyseconds,
consciousnessreturnsassuddenlyasitwaslost,andthereisnopostictalconfusion.Althoughthebrieflossofconsciousnessmaybeclinicallyinapparentorthesole
manifestationoftheseizuredischarge,absenceseizuresareusuallyaccompaniedbysubtle,bilateralmotorsignssuchasrapidblinkingoftheeyelids,chewing
movements,orsmallamplitude,clonicmovementsofthehands.

Typicalabsenceseizuresareassociatedwithagroupofgeneticallydeterminedepilepsieswithonsetusuallyinchildhood(ages48years)orearlyadolescenceandare
themainseizuretypein1520%ofchildrenwithepilepsy.Theseizurescanoccurhundredsoftimesperday,butthechildmaybeunawareoforunabletoconveytheir
existence.Becausetheclinicalsignsoftheseizuresaresubtle,especiallytoparentswhomaynothavehadpreviousexperiencewithseizures,itisnotsurprisingthatthe
firstcluetoabsenceepilepsyisoftenunexplaineddaydreamingandadeclineinschoolperformancerecognizedbyateacher.

Theelectrophysiologichallmarkoftypicalabsenceseizuresisageneralized,symmetric,3Hzspikeandwavedischargethatbeginsandendssuddenly,superimposedon
anormalEEGbackground.Periodsofspikeandwavedischargeslastingmorethanafewsecondsusuallycorrelatewithclinicalsigns,buttheEEGoftenshowsmany
morebriefburstsofabnormalcorticalactivitythanweresuspectedclinically.Hyperventilationtendstoprovoketheseelectrographicdischargesandeventheseizures
themselvesandisroutinelyusedwhenrecordingtheEEG.

AtypicalAbsenceSeizures

Atypicalabsenceseizureshavefeaturesthatdeviatebothclinicallyandelectrophysiologicallyfromtypicalabsenceseizures.Forexample,thelapseofconsciousnessis
usuallyoflongerdurationandlessabruptinonsetandcessation,andtheseizureisaccompaniedbymoreobviousmotorsignsthatmayincludefocalorlateralizing
features.TheEEGshowsageneralized,slowspikeandwavepatternwithafrequencyof2.5persecond,aswellasotherabnormalactivity.Atypicalabsenceseizures
areusuallyassociatedwithdiffuseormultifocalstructuralabnormalitiesofthebrainandthereforemayaccompanyothersignsofneurologicdysfunctionsuchasmental
retardation.Furthermore,theseizuresarelessresponsivetoanticonvulsantscomparedtotypicalabsenceseizures.

Generalized,TonicClonicSeizures

Generalizedonsettonicclonicseizuresarethemainseizuretypein~10%ofallpersonswithepilepsy.Theyarealsothemostcommonseizuretyperesultingfrom
metabolicderangementsandarethereforefrequentlyencounteredinmanydifferentclinicalsettings.Theseizureusuallybeginsabruptlywithoutwarning,althoughsome
patientsdescribevaguepremonitorysymptomsinthehoursleadinguptotheseizure.Thisprodromeisdistinctfromthestereotypicaurasassociatedwithfocalseizures
thatgeneralize.Theinitialphaseoftheseizureisusuallytoniccontractionofmusclesthroughoutthebody,accountingforanumberoftheclassicfeaturesoftheevent.
Toniccontractionofthemusclesofexpirationandthelarynxattheonsetwillproducealoudmoanorictalcry.Respirationsareimpaired,secretionspoolinthe
oropharynx,andcyanosisdevelops.Contractionofthejawmusclesmaycausebitingofthetongue.Amarkedenhancementofsympathetictoneleadstoincreasesin
heartrate,bloodpressure,andpupillarysize.After1020s,thetonicphaseoftheseizuretypicallyevolvesintotheclonicphase,producedbythesuperimpositionof
periodsofmusclerelaxationonthetonicmusclecontraction.Theperiodsofrelaxationprogressivelyincreaseuntiltheendoftheictalphase,whichusuallylastsnomore
than1min.Thepostictalphaseischaracterizedbyunresponsiveness,muscularflaccidity,andexcessivesalivationthatcancausestridorousbreathingandpartialairway
obstruction.Bladderorbowelincontinencemayoccuratthispoint.Patientsgraduallyregainconsciousnessoverminutestohours,andduringthistransition,thereis
typicallyaperiodofpostictalconfusion.Patientssubsequentlycomplainofheadache,fatigue,andmuscleachethatcanlastformanyhours.Thedurationofimpaired
consciousnessinthepostictalphasecanbeextremelylong(i.e.,manyhours)inpatientswithprolongedseizuresorunderlyingcentralnervoussystem(CNS)diseases
suchasalcoholiccerebralatrophy.

TheEEGduringthetonicphaseoftheseizureshowsaprogressiveincreaseingeneralizedlowvoltagefastactivity,followedbygeneralizedhighamplitude,polyspike
discharges.Intheclonicphase,thehighamplitudeactivityistypicallyinterruptedbyslowwavestocreateaspikeandwavepattern.ThepostictalEEGshowsdiffuse
slowingthatgraduallyrecoversasthepatientawakens.

Thereareanumberofvariantsofthegeneralizedtonicclonicseizure,includingpuretonicandpureclonicseizures.Brieftonicseizureslastingonlyafewsecondsare
especiallynoteworthysincetheyareusuallyassociatedwithspecificepilepticsyndromeshavingmixedseizurephenotypes,suchastheLennoxGastautsyndrome

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 2/19
17/06/2015
(discussedbelow).

AtonicSeizures

Atonicseizuresarecharacterizedbysuddenlossofposturalmuscletonelasting12s.Consciousnessisbrieflyimpaired,butthereisusuallynopostictalconfusion.A
verybriefseizuremaycauseonlyaquickheaddropornoddingmovement,whereasalongerseizurewillcausethepatienttocollapse.Thiscanbeextremelydangerous,
becausethereisasubstantialriskofdirectheadinjurywiththefall.TheEEGshowsbrief,generalizedspikeandwavedischargesfollowedimmediatelybydiffuseslow
wavesthatcorrelatewiththelossofmuscletone.Similartopuretonicseizures,atonicseizuresareusuallyseeninassociationwithknownepilepsysyndromes.

MyoclonicSeizures

Myoclonusisasuddenandbriefmusclecontractionthatmayinvolveonepartofthebodyortheentirebody.Anormal,commonphysiologicformofmyoclonusisthe
suddenjerkingmovementobservedwhilefallingasleep.Pathologicmyoclonusismostcommonlyseeninassociationwithmetabolicdisorders,degenerativeCNS
diseases,oranoxicbraininjury(Chap.330).Althoughthedistinctionfromotherformsofmyoclonusisimprecise,myoclonicseizuresareconsideredtobetrueepileptic
eventsbecausetheyarecausedbycortical(versussubcorticalorspinal)dysfunction.TheEEGmayshowbilaterallysynchronousspikeandwavedischarges
synchronizedwiththemyoclonus,althoughthesecanbeobscuredbymovementartifact.Myoclonicseizuresusuallycoexistwithotherformsofgeneralizedseizuresbut
arethepredominantfeatureofjuvenilemyoclonicepilepsy(discussedbelow).

CURRENTLYUNCLASSIFIABLESEIZURES

Notallseizuretypescanbedesignatedasfocalorgeneralized,andtheyshouldthereforebelabeledasunclassifiableuntiladditionalevidenceallowsavalid
classification.Epilepticspasmsaresuchanexample.Thesearecharacterizedbyabrieflysustainedflexionorextensionofpredominantlyproximalmuscles,including
truncalmuscles.TheEEGinthesepatientsusuallyshowshypsarrhythmias,whichconsistofdiffuse,giantslowwaveswithachaoticbackgroundofirregular,multifocal
spikesandsharpwaves.Duringtheclinicalspasm,thereisamarkedsuppressionoftheEEGbackground(theelectrodecrementalresponse).Theelectromyogram
(EMG)alsorevealsacharacteristicrhomboidpatternthatmayhelpdistinguishspasmsfrombrieftonicandmyoclonicseizures.Epilepticspasmsoccurpredominantlyin
infantsandlikelyresultfromdifferencesinneuronalfunctionandconnectivityintheimmatureversusmatureCNS.

EPILEPSYSYNDROMES
Epilepsysyndromesaredisordersinwhichepilepsyisapredominantfeature,andthereissufficientevidence(e.g.,throughclinical,EEG,radiologic,orgenetic
observations)tosuggestacommonunderlyingmechanism.Threeimportantepilepsysyndromesarelistedbelowadditionalexampleswithaknowngeneticbasisare
showninTable4452.

TABLE4452ExamplesofGenesAssociatedwithEpilepsySyndromesa

Gene
FunctionofGene ClinicalSyndrome Comments
(Locus)

Nicotinicacetylcholine
receptorsubunitmutations
causealterationsinCa2+flux
CHRNA4
throughthereceptorthis
(20q13.2)
mayreduceamountof
GABAreleaseinpresynaptic
terminals
RarefirstidentifiedinalargeAustralian
Autosomaldominantnocturnalfrontallobeepilepsy
familyotherfamiliesfoundtohave
(ADNFLE)childhoodonsetbrief,nighttimeseizures
mutationsinCHRNA2orCHRNB2,and
withprominentmotormovementsoftenmisdiagnosed
somefamiliesappeartohavemutations
asprimarysleepdisorder
atotherloci

Voltagegatedpotassium
channelsubunitsmutationin
poreregionsmaycausea
KCNQ2
2040%reductionof
(20q13.3)
potassiumcurrents,which
willleadtoimpaired
repolarization
Rareotherfamiliesfoundtohave
mutationsinKCNQ3oraninversionin
Benignfamilialneonatalseizures(BFNS)autosomal
chromosomal5sequenceand
dominantinheritanceonsetin1stweekoflifeininfants
functionalhomologytoKCNQ1,
whoareotherwisenormalremissionusuallywithin
mutationsofwhichcauselongQT
weekstomonthslongtermepilepsyin1015%
syndromeandacardiacauditory
syndrome

Subunitofavoltagegated Generalizedepilepsywithfebrileseizuresplus(GEFS+) IncidenceuncertainGEFS+identifiedin

sodiumchannelnumerous autosomaldominantinheritancepresentswithfebrile otherfamilieswithmutationsinother
mutationsaffectingsodium seizuresatmedian1year,whichmaypersist>6years, sodiumchannelsubunits(SCN2Band
SCN1A currentsthatcauseeither thenvariableseizuretypesnotassociatedwithfever SCN2A)andGABAAreceptorsubunit
(2q24.3) gainorlossoffunction numerousothersyndromes,includingalmost80%of (GABRG2andGABRA1)significant
networkeffectsappear patientswithDravetssyndrome(severemyoclonic phenotypicheterogeneitywithinsame
relatedtoexpressionin epilepsyofinfancy)andsomecasesofLennoxGastaut family,includingmemberswithfebrile
excitatoryorinhibitorycells syndrome seizuresonly

Leucinerichglioma
inactivated1geneprevious Mutationsfoundinupto50%offamilies
Autosomaldominantpartialepilepsywithauditory
evidenceforroleinglial containingtwoormoresubjectswith
features(ADPEAF)aformofidiopathiclateraltemporal
LGI1 tumorprogressionrecent idiopathiclocalizationrelatedepilepsy
lobeepilepsywithauditorysymptomsoraphasiaasa
(10q24) studiessuggestaninfluence withictalauditorysymptoms,suggesting
majorfocalseizuremanifestationageofonsetusually
inthepostnataldevelopment thatatleastoneothergenemay
between10and25years
ofglutamatergiccircuitsin underliethissyndrome.
thehippocampus

Disheveled,Egl10and
Autosomaldominantfamilialfocalepilepsywithvariable Studyoffamilieswithlimitednumberof
pleckstrindomaincontaining
foci(FFEVF)familymembershaveseizuresoriginating affectedmembersrevealedmutationsin
protein5exertsaninhibitory
DEPDC5 fromdifferentcorticalregionsneuroimagingusually approximately12%offamiliesthusmay
effectonmammaliantarget
(22q12.2) normalbutmayharborsubtlemalformationsrecent bearelativelycommoncauseoflesion
ofrapamycin(mTOR)
studiesalsosuggestassociationwithbenignepilepsy negativefocalepilepsieswithsuspected
mediatedprocesses,suchas
withcentrotemporalspikes geneticbasis
cellgrowthandproliferation

CystatinB,anoncaspase
cysteineproteaseinhibitor
normalproteinmayblock
CSTB
neuronalapoptosisby
(21q22.3)
inhibitingcaspasesdirectly
orindirectly(viacathepsins),
http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+
Overallrare,butrelativelycommonin
Progressivemyoclonusepilepsy(PME)(Unverricht
FinlandandWesternMediterranean(>1
Lundborgdisease)autosomalrecessiveinheritance
in20,000)preciseroleofcystatinBin
ageofonsetbetween6and15years,myoclonic
humandiseaseunknown,althoughmice
seizures,ataxia,andprogressivecognitivedeclinebrain
withnullmutationsofcystatinBhave
showsneuronaldegeneration
3/19
17/06/2015
orcontrollingproteolysis similarsyndrome

Laforin,aproteintyrosine
phosphatase(PTP)involved
EPM2A
inglycogenmetabolismand
(6q24)
mayhaveantiapoptotic
activity
MostcommonPMEinSouthernEurope,
Progressivemyoclonusepilepsy(Laforasdisease)
MiddleEast,NorthernAfrica,andIndian
autosomalrecessiveinheritanceageofonset619
subcontinentgeneticheterogeneity
years,deathwithin10yearsbraindegeneration
unknownwhetherseizurephenotype
associatedwithpolyglucosanintracellularinclusion
duetodegenerationordirecteffectsof
bodiesinnumerousorgans
abnormallaforinexpression

Doublecortin,expressed
primarilyinfrontallobes
Doublecortin
directlyregulates
(Xq2124)
microtubulepolymerization
andbundling
aThefirstfivesyndromeslistedinthetable(ADNFLE,BFNC,GEFS+,ADPEAF,andFFEVF)areexamplesofidiopathicepilepsiesassociatedwithidentifiedgene
Relativelyrarebutofuncertain
Classiclissencephalyassociatedwithseveremental
incidencerecentincreased
retardationandseizuresinmalessubcorticalband
ascertainmentduetoimprovedimaging
heterotopiawithmoresubtlefindingsinfemales
techniquesrelationshipbetween
(presumablyduetorandomXinactivation)Xlinked
migrationdefectandseizurephenotype
dominant
unknown

mutations.ThelastthreesyndromesareexamplesofthenumerousMendeliandisordersinwhichseizuresareonepartofthephenotype.

Abbreviations:GABA,aminobutyricacidPME,progressivemyoclonusepilepsy.

JUVENILEMYOCLONICEPILEPSY

Juvenilemyoclonicepilepsy(JME)isageneralizedseizuredisorderofunknowncausethatappearsinearlyadolescenceandisusuallycharacterizedbybilateral
myoclonicjerksthatmaybesingleorrepetitive.Themyoclonicseizuresaremostfrequentinthemorningafterawakeningandcanbeprovokedbysleepdeprivation.
Consciousnessispreservedunlessthemyoclonusisespeciallysevere.Manypatientsalsoexperiencegeneralizedtonicclonicseizures,anduptoonethirdhave
absenceseizures.Althoughcompleteremissionisrelativelyuncommon,theseizuresusuallyrespondwelltoappropriateanticonvulsantmedication.Thereisoftena
familyhistoryofepilepsy,andgeneticlinkagestudiessuggestapolygeniccause.

LENNOXGASTAUTSYNDROME

LennoxGastautsyndromeoccursinchildrenandisdefinedbythefollowingtriad:(1)multipleseizuretypes(usuallyincludinggeneralizedtonicclonic,atonic,andatypical
absenceseizures)(2)anEEGshowingslow(<3Hz)spikeandwavedischargesandavarietyofotherabnormalitiesand(3)impairedcognitivefunctioninmostbutnot
allcases.LennoxGastautsyndromeisassociatedwithCNSdiseaseordysfunctionfromavarietyofcauses,includingdenovomutations,developmentalabnormalities,
perinatalhypoxia/ischemia,trauma,infection,andotheracquiredlesions.Themultifactorialnatureofthissyndromesuggeststhatitisanonspecificresponseofthebrain
todiffuseneuralinjury.Unfortunately,manypatientshaveapoorprognosisduetotheunderlyingCNSdiseaseandthephysicalandpsychosocialconsequencesof
severe,poorlycontrolledepilepsy.

MESIALTEMPORALLOBEEPILEPSYSYNDROME

Mesialtemporallobeepilepsy(MTLE)isthemostcommonsyndromeassociatedwithfocalseizureswithdyscognitivefeaturesandisanexampleofanepilepsy
syndromewithdistinctiveclinical,electroencephalographic,andpathologicfeatures(Table4453).Highresolutionmagneticresonanceimaging(MRI)candetectthe
characteristichippocampalsclerosisthatappearstobeessentialinthepathophysiologyofMTLEformanypatients(Fig.4451).Recognitionofthissyndromeis
especiallyimportantbecauseittendstoberefractorytotreatmentwithanticonvulsantsbutrespondswelltosurgicalintervention.Advancesintheunderstandingofbasic
mechanismsofepilepsyhavecomethroughstudiesofexperimentalmodelsofMTLE,discussedbelow.

TABLE4453CharacteristicsoftheMesialTemporalLobeEpilepsySyndrome

History

Historyoffebrileseizures Raregeneralizedseizures

Familyhistoryofepilepsy Seizuresmayremitandreappear

Earlyonset Seizuresoftenintractable

ClinicalObservations

Auracommon Postictaldisorientation

Behavioralarrest/stare Memoryloss

Complexautomatisms Dysphasia(withfocusindominanthemisphere)

Unilateralposturing

LaboratoryStudies

UnilateralorbilateralanteriortemporalspikesonEEG

HypometabolismoninterictalPET

HypoperfusiononinterictalSPECT

Materialspecificmemorydeficitsonintracranialamobarbital(Wada)test

MRIFindings

SmallhippocampuswithincreasedsignalonT2weightedsequences

Smalltemporallobe

Enlargedtemporalhorn

PathologicFindings

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 4/19
17/06/2015
Highlyselectivelossofspecificcellpopulationswithinhippocampusinmostcases
Abbreviations:EEG,electroencephalogramMRI,magneticresonanceimagingPET,positronemissiontomographySPECT,singlephotonemissioncomputed
tomography.

FIGURE4451
Mesialtemporallobeepilepsy.Theelectroencephalogramandseizuresemiologywereconsistentwithalefttemporallobefocus.ThiscoronalhighresolutionT2
weightedfastspinechomagneticresonanceimageobtainedat3teslaisatthelevelofthehippocampalbodies,andshowsabnormalhighsignalintensity,blurringof
internallaminararchitecture,andreducedsizeofthelefthippocampus(arrow)relativetotheright.Thistriadofimagingfindingsisconsistentwithhippocampalsclerosis.

THECAUSESOFSEIZURESANDEPILEPSY
SeizuresarearesultofashiftinthenormalbalanceofexcitationandinhibitionwithintheCNS.Giventhenumerouspropertiesthatcontrolneuronalexcitability,itisnot
surprisingthattherearemanydifferentwaystoperturbthisnormalbalance,andthereforemanydifferentcausesofbothseizuresandepilepsy.Threeclinical
observationsemphasizehowavarietyoffactorsdeterminewhycertainconditionsmaycauseseizuresorepilepsyinagivenpatient.

1. Thenormalbrainiscapableofhavingaseizureundertheappropriatecircumstances,andtherearedifferencesbetweenindividualsinthesusceptibilityorthreshold
forseizures.Forexample,seizuresmaybeinducedbyhighfeversinchildrenwhoareotherwisenormalandwhoneverdevelopotherneurologicproblems,including
epilepsy.However,febrileseizuresoccuronlyinarelativelysmallproportionofchildren.Thisimpliestherearevariousunderlyingendogenousfactorsthatinfluence
thethresholdforhavingaseizure.Someofthesefactorsaregenetic,asafamilyhistoryofepilepsyhasaclearinfluenceonthelikelihoodofseizuresoccurringin
otherwisenormalindividuals.Normaldevelopmentalsoplaysanimportantrole,becausethebrainappearstohavedifferentseizurethresholdsatdifferent
maturationalstages.

2. Thereareavarietyofconditionsthathaveanextremelyhighlikelihoodofresultinginachronicseizuredisorder.Oneofthebestexamplesofthisissevere,
penetratingheadtrauma,whichisassociatedwithuptoa45%riskofsubsequentepilepsy.Thehighpropensityforseveretraumaticbraininjurytoleadtoepilepsy
suggeststhattheinjuryresultsinalonglastingpathologicchangeintheCNSthattransformsapresumablynormalneuralnetworkintoonethatisabnormally
hyperexcitable.Thisprocessisknownasepileptogenesis,andthespecificchangesthatresultinaloweredseizurethresholdcanbeconsideredepileptogenicfactors.
Otherprocessesassociatedwithepileptogenesisincludestroke,infections,andabnormalitiesofCNSdevelopment.Likewise,thegeneticabnormalitiesassociated
withepilepsylikelyinvolveprocessesthattriggertheappearanceofspecificsetsofepileptogenicfactors.

3. Seizuresareepisodic.Patientswithepilepsyhaveseizuresintermittentlyand,dependingontheunderlyingcause,manypatientsarecompletelynormalformonthsor
evenyearsbetweenseizures.Thisimpliesthereareimportantprovocativeorprecipitatingfactorsthatinduceseizuresinpatientswithepilepsy.Similarly,precipitating
factorsareresponsibleforcausingthesingleseizureinsomeonewithoutepilepsy.Precipitantsincludethoseduetointrinsicphysiologicprocessessuchas
psychologicalorphysicalstress,sleepdeprivation,orhormonalchangesassociatedwiththemenstrualcycle.Theyalsoincludeexogenousfactorssuchasexposure
totoxicsubstancesandcertainmedications.

Theseobservationsemphasizetheconceptthatthemanycausesofseizuresandepilepsyresultfromadynamicinterplaybetweenendogenousfactors,epileptogenic
factors,andprecipitatingfactors.Thepotentialroleofeachneedstobecarefullyconsideredwhendeterminingtheappropriatemanagementofapatientwithseizures.
Forexample,theidentificationofpredisposingfactors(e.g.,familyhistoryofepilepsy)inapatientwithfebrileseizuresmayincreasethenecessityforcloserfollowupand
amoreaggressivediagnosticevaluation.Findinganepileptogeniclesionmayhelpintheestimationofseizurerecurrenceanddurationoftherapy.Finally,removalor
modificationofaprecipitatingfactormaybeaneffectiveandsafermethodforpreventingfurtherseizuresthantheprophylacticuseofanticonvulsantdrugs.

CAUSESACCORDINGTOAGE

Inpractice,itisusefultoconsidertheetiologiesofseizuresbasedontheageofthepatient,becauseageisoneofthemostimportantfactorsdeterminingboththe
incidenceandthelikelycausesofseizuresorepilepsy(Table4454).Duringtheneonatalperiodandearlyinfancy,potentialcausesincludehypoxicischemic
encephalopathy,trauma,CNSinfection,congenitalCNSabnormalities,andmetabolicdisorders.Babiesborntomothersusingneurotoxicdrugssuchascocaine,heroin,
orethanolaresusceptibletodrugwithdrawalseizuresinthefirstfewdaysafterdelivery.Hypoglycemiaandhypocalcemia,whichcanoccurassecondarycomplicationsof
perinatalinjury,arealsocausesofseizuresearlyafterdelivery.Seizuresduetoinbornerrorsofmetabolismusuallypresentonceregularfeedingbegins,typically23
daysafterbirth.Pyridoxine(vitaminB6)deficiency,animportantcauseofneonatalseizures,canbeeffectivelytreatedwithpyridoxinereplacement.Theidiopathicor
inheritedformsofbenignneonatalconvulsionsarealsoseenduringthistimeperiod.

TABLE4454CausesofSeizures

Perinatalhypoxiaandischemia
Intracranialhemorrhageandtrauma
CNSinfection
Metabolicdisturbances(hypoglycemia,hypocalcemia,hypomagnesemia,pyridoxinedeficiency)
Neonates(<1month)

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 5/19
17/06/2015
Drugwithdrawal
Developmentaldisorders
Geneticdisorders

Febrileseizures
Geneticdisorders(metabolic,degenerative,primaryepilepsysyndromes)
Infantsandchildren(>1monthand<12 CNSinfection
years)
Developmentaldisorders
Trauma

Trauma
Geneticdisorders

Adolescents(1218years) Infection
Illicitdruguse
Braintumor

Youngadults(1835years) Trauma

Alcoholwithdrawal

Illicitdruguse

Braintumor

Autoantibodies

Olderadults(>35years) Cerebrovasculardisease

Braintumor

Alcoholwithdrawal

Metabolicdisorders(uremia,hepaticfailure,electrolyteabnormalities,hypoglycemia,
hyperglycemia)

AlzheimersdiseaseandotherdegenerativeCNSdiseases

Autoantibodies
Abbreviation:CNS,centralnervoussystem.

Themostcommonseizuresarisinginlateinfancyandearlychildhoodarefebrileseizures,whichareseizuresassociatedwithfeversbutwithoutevidenceofCNSinfection
orotherdefinedcauses.Theoverallprevalenceis35%andevenhigherinsomepartsoftheworldsuchasAsia.Patientsoftenhaveafamilyhistoryoffebrileseizures
orepilepsy.Febrileseizuresusuallyoccurbetween3monthsand5yearsofageandhaveapeakincidencebetween18and24months.Thetypicalscenarioisachild
whohasageneralized,tonicclonicseizureduringafebrileillnessinthesettingofacommonchildhoodinfectionsuchasotitismedia,respiratoryinfection,or
gastroenteritis.Theseizureislikelytooccurduringtherisingphaseofthetemperaturecurve(i.e.,duringthefirstday)ratherthanwellintothecourseoftheillness.A
simplefebrileseizureisasingle,isolatedevent,brief,andsymmetricinappearance.Complexfebrileseizuresarecharacterizedbyrepeatedseizureactivity,duration>15
minutes,orbyfocalfeatures.Approximatelyonethirdofpatientswithfebrileseizureswillhavearecurrence,but<10%havethreeormoreepisodes.Recurrencesare
muchmorelikelywhenthefebrileseizureoccursinthefirstyearoflife.Simplefebrileseizuresarenotassociatedwithanincreaseintheriskofdevelopingepilepsy,while
complexfebrileseizureshaveariskof25%otherriskfactorsincludethepresenceofpreexistingneurologicdeficitsandafamilyhistoryofnonfebrileseizures.

Childhoodmarkstheageatwhichmanyofthewelldefinedepilepsysyndromespresent.Somechildrenwhoareotherwisenormaldevelopidiopathic,generalizedtonic
clonicseizureswithoutotherfeaturesthatfitintospecificsyndromes.Temporallobeepilepsyusuallypresentsinchildhoodandmayberelatedtomesialtemporallobe
sclerosis(aspartoftheMTLEsyndrome)orotherfocalabnormalitiessuchascorticaldysgenesis.Othertypesoffocalseizures,includingthosethatevolveinto
generalizedseizures,maybetherelativelylatemanifestationofadevelopmentaldisorder,anacquiredlesionsuchasheadtrauma,CNSinfection(especiallyviral
encephalitis),orveryrarelyaCNStumor.

Theperiodofadolescenceandearlyadulthoodisoneoftransitionduringwhichtheidiopathicorgeneticallybasedepilepsysyndromes,includingJMEandjuvenile
absenceepilepsy,becomelesscommon,whileepilepsiessecondarytoacquiredCNSlesionsbegintopredominate.Seizuresthatariseinpatientsinthisagerangemay
beassociatedwithheadtrauma,CNSinfections(includingparasiticinfectionssuchascysticercosis),braintumors,congenitalCNSabnormalities,illicitdruguse,or
alcoholwithdrawal.AutoantibodiesdirectedagainstCNSantigenssuchaspotassiumchannelsorglutamatereceptorsareanewlyrecognizedcauseofepilepsythatalso
beginstoappearinthisagegroup(althoughcasesofautoimmunityarebeingincreasinglydescribedinthepediatricpopulation),includingpatientswithoutanidentifiable
cancer.Thisetiologyshouldbesuspectedwhenapreviouslynormalindividualpresentswithaparticularlyaggressiveseizurepatterndevelopingoverweekstomonths
andcharacterizedbyincreasinglyfrequentandprolongedseizurescombinedwithcognitivedecline(Chap.122).

Headtraumaisacommoncauseofepilepsyinadolescentsandadults.Theheadinjurycanbecausedbyavarietyofmechanisms,andthelikelihoodofdeveloping
epilepsyisstronglycorrelatedwiththeseverityoftheinjury.Apatientwithapenetratingheadwound,depressedskullfracture,intracranialhemorrhage,orprolonged
posttraumaticcomaoramnesiahasa3050%riskofdevelopingepilepsy,whereasapatientwithaclosedheadinjuryandcerebralcontusionhasa525%risk.
Recurrentseizuresusuallydevelopwithin1yearafterheadtrauma,althoughintervalsof>10yearsarewellknown.Incontrolledstudies,mildheadinjury,definedasa
concussionwithamnesiaorlossofconsciousnessof<30min,wasfoundtobeassociatedwithonlyaslightlyincreasedlikelihoodofepilepsy.Nonetheless,most
epileptologistsknowofpatientswhohavefocalseizureswithinhoursordaysofamildheadinjuryandsubsequentlydevelopchronicseizuresofthesametypesuch
casesmayrepresentrareexamplesofchronicepilepsyresultingfrommildheadinjury.

Thecausesofseizuresinolderadultsincludecerebrovasculardisease,trauma(includingsubduralhematoma),CNStumors,anddegenerativediseases.
Cerebrovasculardiseasemayaccountfor~50%ofnewcasesofepilepsyinpatientsolderthanage65.Acuteseizures(i.e.,occurringatthetimeofthestroke)areseen
moreoftenwithembolicratherthanhemorrhagicorthromboticstroke.Chronicseizurestypicallyappearmonthstoyearsaftertheinitialeventandareassociatedwithall
formsofstroke.

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 6/19
17/06/2015
Metabolicdisturbancessuchaselectrolyteimbalance,hypoorhyperglycemia,renalfailure,andhepaticfailuremaycauseseizuresatanyage.Similarly,endocrine
disorders,hematologicdisorders,vasculitides,andmanyothersystemicdiseasesmaycauseseizuresoverabroadagerange.Awidevarietyofmedicationsandabused
substancesareknowntoprecipitateseizuresaswell(Table4455).

TABLE4455DrugsandOtherSubstancesThatCanCauseSeizures

Alkylatingagents(e.g.,busulfan,chlorambucil)

Antimalarials(chloroquine,mefloquine)

Antimicrobials/antivirals

lactamandrelatedcompounds

Quinolones

Acyclovir

Isoniazid

Ganciclovir

Anestheticsandanalgesics

Meperidine

Fentanyl

Tramadol

Localanesthetics

Dietarysupplements

Ephedra(mahuang)

Gingko

Immunomodulatorydrugs

Cyclosporine

OKT3(monoclonalantibodiestoTcells)

Tacrolimus

Interferons

Psychotropics

Antidepressants(e.g.,bupropion)

Antipsychotics(e.g.,clozapine)

Lithium

Radiographiccontrastagents

Drugwithdrawal

Alcohol

Baclofen

Barbiturates(shortacting)

Benzodiazepines(shortacting)

Zolpidem

Drugsofabuse

Amphetamine

Cocaine

Phencyclidine

Methylphenidate

Flumazenila
aInbenzodiazepinedependentpatients.

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 7/19
17/06/2015

BASICMECHANISMS
MECHANISMSOFSEIZUREINITIATIONANDPROPAGATION

Focalseizureactivitycanbegininaverydiscreteregionofcortexandthenslowlyinvadethesurroundingregions.Thehallmarkofanestablishedseizureistypicallyan
electrographicspikeduetointensenearsimultaneousfiringofalargenumberoflocalexcitatoryneurons,resultinginanapparenthypersynchronizationofthe
excitatoryburstsacrossarelativelylargecorticalregion.Theburstingactivityinindividualneurons(theparoxysmaldepolarizationshift)iscausedbyarelativelylong
lastingdepolarizationoftheneuronalmembraneduetoinfluxofextracellularcalcium(Ca2+),whichleadstotheopeningofvoltagedependentsodium(Na+)channels,
influxofNa+,andgenerationofrepetitiveactionpotentials.Thisisfollowedbyahyperpolarizingafterpotentialmediatedbyaminobutyricacid(GABA)receptorsor
potassium(K+)channels,dependingonthecelltype.ThesynchronizedburstsfromasufficientnumberofneuronsresultinasocalledspikedischargeontheEEG.

Thespreadingseizurewavefrontisslowedandultimatelyhaltedbyintacthyperpolarizationandasurroundinhibitioncreatedbyfeedforwardactivationofinhibitory
neurons.Withsufficientactivation,thereisarecruitmentofsurroundingneuronsviaanumberofsynapticandnonsynapticmechanisms,including:(1)anincreasein
extracellularK+,whichbluntshyperpolarizationanddepolarizesneighboringneurons(2)accumulationofCa2+inpresynapticterminals,leadingtoenhanced
neurotransmitterrelease(3)depolarizationinducedactivationoftheNmethyldaspartate(NMDA)subtypeoftheexcitatoryaminoacidreceptor,whichcausesadditional
Ca2+influxandneuronalactivationand(4)ephapticinteractionsrelatedtochangesintissueosmolarityandcellswelling.Therecruitmentofasufficientnumberof
neuronsleadstothepropagationofexcitatorycurrentsintocontiguousareasvialocalcorticalconnectionsandtomoredistantareasvialongcommissuralpathwayssuch
asthecorpuscallosum.

Manyfactorscontrolneuronalexcitability,andthustherearemanypotentialmechanismsforalteringaneuronspropensitytohaveburstingactivity.Mechanismsintrinsic
totheneuronincludechangesintheconductanceofionchannels,responsecharacteristicsofmembranereceptors,cytoplasmicbuffering,secondmessengersystems,
andproteinexpressionasdeterminedbygenetranscription,translation,andposttranslationalmodification.Mechanismsextrinsictotheneuronincludechangesinthe
amountortypeofneurotransmitterspresentatthesynapse,modulationofreceptorsbyextracellularionsandothermolecules,andtemporalandspatialpropertiesof
synapticandnonsynapticinput.Nonneuralcells,suchasastrocytesandoligodendrocytes,haveanimportantroleinmanyofthesemechanismsaswell.

Certainrecognizedcausesofseizuresareexplainedbythesemechanisms.Forexample,accidentalingestionofdomoicacid,whichisananalogueofglutamate(the
principalexcitatoryneurotransmitterinthebrain),causesprofoundseizuresviadirectactivationofexcitatoryaminoacidreceptorsthroughouttheCNS.Penicillin,which
canlowertheseizurethresholdinhumansandisapotentconvulsantinexperimentalmodels,reducesinhibitionbyantagonizingtheeffectsofGABAatitsreceptor.The
basicmechanismsofotherprecipitatingfactorsofseizuressuchassleepdeprivation,fever,alcoholwithdrawal,hypoxia,andinfection,arenotaswellunderstoodbut
presumablyinvolveanalogousperturbationsinneuronalexcitability.Similarly,theendogenousfactorsthatdetermineanindividualsseizurethresholdmayrelatetothese
propertiesaswell.

Knowledgeofthemechanismsresponsibleforinitiationandpropagationofmostgeneralizedseizures(includingtonicclonic,myoclonic,andatonictypes)remains
rudimentaryandreflectsthelimitedunderstandingoftheconnectivityofthebrainatasystemslevel.Muchmoreisunderstoodabouttheoriginofgeneralizedspikeand
wavedischargesinabsenceseizures.Theseappeartoberelatedtooscillatoryrhythmsnormallygeneratedduringsleepbycircuitsconnectingthethalamusandcortex.
ThisoscillatorybehaviorinvolvesaninteractionbetweenGABABreceptors,TtypeCa2+channels,andK+channelslocatedwithinthethalamus.Pharmacologicstudies
indicatethatmodulationofthesereceptorsandchannelscaninduceabsenceseizures,andthereisgoodevidencethatthegeneticformsofabsenceepilepsymaybe
associatedwithmutationsofcomponentsofthissystem.

MECHANISMSOFEPILEPTOGENESIS

Epileptogenesisreferstothetransformationofanormalneuronalnetworkintoonethatischronicallyhyperexcitable.Thereisoftenadelayofmonthstoyearsbetween
aninitialCNSinjurysuchastrauma,stroke,orinfectionandthefirstseizure.Theinjuryappearstoinitiateaprocessthatgraduallylowerstheseizurethresholdinthe
affectedregionuntilaspontaneousseizureoccurs.Inmanygeneticandidiopathicformsofepilepsy,epileptogenesisispresumablydeterminedbydevelopmentally
regulatedevents.

Pathologicstudiesofthehippocampusfrompatientswithtemporallobeepilepsyhaveledtothesuggestionthatsomeformsofepileptogenesisarerelatedtostructural
changesinneuronalnetworks.Forexample,manypatientswithMTLEhaveahighlyselectivelossofneuronsthatmaycontributetoinhibitionofthemainexcitatory
neuronswithinthedentategyrus.Thereisalsoevidencethat,inresponsetothelossofneurons,thereisreorganizationorsproutingofsurvivingneuronsinawaythat
affectstheexcitabilityofthenetwork.Someofthesechangescanbeseeninexperimentalmodelsofprolongedelectricalseizuresortraumaticbraininjury.Thus,aninitial
injurysuchasheadinjurymayleadtoaveryfocal,confinedregionofstructuralchangethatcauseslocalhyperexcitability.Thelocalhyperexcitabilityleadstofurther
structuralchangesthatevolveovertimeuntilthefocallesionproducesclinicallyevidentseizures.Similarmodelshaveprovidedstrongevidenceforlongtermalterations
inintrinsic,biochemicalpropertiesofcellswithinthenetworksuchaschronicchangesinglutamateorGABAreceptorfunction.Recentworkhassuggestedthatinduction
ofinflammatorycascadesmaybeacriticalfactorintheseprocessesaswell.

GENETICCAUSESOFEPILEPSY

Themostimportantrecentprogressinepilepsyresearchhasbeentheidentificationofgeneticmutationsassociatedwithavarietyofepilepsysyndromes(Table4452).
Althoughmostofthemutationsidentifiedtodatecauserareformsofepilepsy,theirdiscoveryhasledtoextremelyimportantconceptualadvances.Forexample,it
appearsthatmanyoftheinherited,idiopathicepilepsies(i.e.,therelativelypureformsofepilepsyinwhichseizuresarethephenotypicabnormalityandbrainstructure
andfunctionareotherwisenormal)areduetomutationsaffectingionchannelfunction.Thesesyndromesarethereforepartofthelargergroupofchannelopathies
causingparoxysmaldisorderssuchascardiacarrhythmias,episodicataxia,periodicweakness,andfamilialhemiplegicmigraine.Incontrast,genemutationsobservedin
symptomaticepilepsies(i.e.,disordersinwhichotherneurologicabnormalitiessuchascognitiveimpairmentcoexistwithseizures)areprovingtobeassociatedwith
pathwaysinfluencingCNSdevelopmentorneuronalhomeostasis.Denovomutationsmayexplainasignificantproportionofthesesyndromes,especiallythosewithonset
inearlychildhood.Acurrentchallengeistoidentifythemultiplesusceptibilitygenesthatunderliethemorecommonformsofidiopathicepilepsies.Recentstudiessuggest
thationchannelmutationsandcopynumbervariantsmaycontributetocausationinasubsetofthesepatients.

MECHANISMSOFACTIONOFANTIEPILEPTICDRUGS

Antiepilepticdrugsappeartoactprimarilybyblockingtheinitiationorspreadofseizures.Thisoccursthroughavarietyofmechanismsthatmodifytheactivityofion
channelsorneurotransmitters,andinmostcases,thedrugshavepleiotropiceffects.ThemechanismsincludeinhibitionofNa+dependentactionpotentialsina
frequencydependentmanner(e.g.,phenytoin,carbamazepine,lamotrigine,topiramate,zonisamide,lacosamide,rufinamide),inhibitionofvoltagegatedCa2+channels
(phenytoin,gabapentin,pregabalin),facilitatingtheopeningofpotassiumchannels(ezogabine),attenuationofglutamateactivity(lamotrigine,topiramate,felbamate),
potentiationofGABAreceptorfunction(benzodiazepinesandbarbiturates),increaseintheavailabilityofGABA(valproicacid,gabapentin,tiagabine),andmodulationof
releaseofsynapticvesicles(levetiracetam).Thetwomosteffectivedrugsforabsenceseizures,ethosuximideandvalproicacid,probablyactbyinhibitingTtypeCa2+
channelsinthalamicneurons.

Incontrasttotherelativelylargenumberofantiepilepticdrugsthatcanattenuateseizureactivity,therearecurrentlynodrugsknowntopreventtheformationofaseizure
focusfollowingCNSinjury.Theeventualdevelopmentofsuchantiepileptogenicdrugswillprovideanimportantmeansofpreventingtheemergenceofepilepsyfollowing
injuriessuchasheadtrauma,stroke,andCNSinfection.

APPROACHTOTHEPATIENT:Seizure

Whenapatientpresentsshortlyafteraseizure,thefirstprioritiesareattentiontovitalsigns,respiratoryandcardiovascularsupport,andtreatmentofseizuresifthey
resume(seeTreatment:SeizuresandEpilepsy).LifethreateningconditionssuchasCNSinfection,metabolicderangement,ordrugtoxicitymustberecognizedand

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 8/19
17/06/2015
managedappropriately.

Whenthepatientisnotacutelyill,theevaluationwillinitiallyfocusonwhetherthereisahistoryofearlierseizures(Fig.4452).Ifthisisthefirstseizure,thentheemphasis
willbeto:(1)establishwhetherthereportedepisodewasaseizureratherthananotherparoxysmalevent,(2)determinethecauseoftheseizurebyidentifyingriskfactors
andprecipitatingevents,and(3)decidewhetheranticonvulsanttherapyisrequiredinadditiontotreatmentforanyunderlyingillness.

Inthepatientwithpriorseizuresoraknownhistoryofepilepsy,theevaluationisdirectedtoward:(1)identificationoftheunderlyingcauseandprecipitatingfactors,and
(2)determinationoftheadequacyofthepatientscurrenttherapy.

FIGURE4452
Evaluationoftheadultpatientwithaseizure.CBC,completebloodcountCNS,centralnervoussystemCT,computedtomographyEEG,electroencephalogram
MRI,magneticresonanceimaging.

HISTORYANDEXAMINATION

Thefirstgoalistodeterminewhethertheeventwastrulyaseizure.Anindepthhistoryisessential,becauseinmanycasesthediagnosisofaseizureisbasedsolelyon
clinicalgroundstheexaminationandlaboratorystudiesareoftennormal.Questionsshouldfocusonthesymptomsbefore,during,andaftertheepisodeinorderto
differentiateaseizurefromotherparoxysmalevents(seeDifferentialDiagnosisofSeizuresbelow).Seizuresfrequentlyoccuroutofhospital,andthepatientmaybe
unawareoftheictalandimmediatepostictalphasesthus,witnessestotheeventshouldbeinterviewedcarefully.

Thehistoryshouldalsofocusonriskfactorsandpredisposingevents.Cluesforapredispositiontoseizuresincludeahistoryoffebrileseizures,earlieraurasorbrief
seizuresnotrecognizedassuch,andafamilyhistoryofseizures.Epileptogenicfactorssuchaspriorheadtrauma,stroke,tumor,orCNSinfectionshouldbeidentified.In
children,acarefulassessmentofdevelopmentalmilestonesmayprovideevidenceforunderlyingCNSdisease.Precipitatingfactorssuchassleepdeprivation,systemic
diseases,electrolyteormetabolicderangements,acuteinfection,drugsthatlowertheseizurethreshold(Table4455),oralcoholorillicitdruguseshouldalsobe
identified.

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 9/19
17/06/2015
Thegeneralphysicalexaminationincludesasearchforsignsofinfectionorsystemicillness.Carefulexaminationoftheskinmayrevealsignsofneurocutaneous
disorderssuchastuberoussclerosisorneurofibromatosis,orchronicliverorrenaldisease.Afindingoforganomegalymayindicateametabolicstoragedisease,andlimb
asymmetrymayprovideacluetobraininjuryearlyindevelopment.Signsofheadtraumaanduseofalcoholorillicitdrugsshouldbesought.Auscultationoftheheartand
carotidarteriesmayidentifyanabnormalitythatpredisposestocerebrovasculardisease.

Allpatientsrequireacompleteneurologicexamination,withparticularemphasisonelicitingsignsofcerebralhemisphericdisease(Chap.437).Carefulassessmentof
mentalstatus(includingmemory,languagefunction,andabstractthinking)maysuggestlesionsintheanteriorfrontal,parietal,ortemporallobes.Testingofvisualfields
willhelpscreenforlesionsintheopticpathwaysandoccipitallobes.Screeningtestsofmotorfunctionsuchaspronatordrift,deeptendonreflexes,gait,andcoordination
maysuggestlesionsinmotor(frontal)cortex,andcorticalsensorytesting(e.g.,doublesimultaneousstimulation)maydetectlesionsintheparietalcortex.

LABORATORYSTUDIES

Routinebloodstudiesareindicatedtoidentifythemorecommonmetaboliccausesofseizuressuchasabnormalitiesinelectrolytes,glucose,calcium,ormagnesium,and
hepaticorrenaldisease.Ascreenfortoxinsinbloodandurineshouldalsobeobtainedfromallpatientsinappropriateriskgroups,especiallywhennoclearprecipitating
factorhasbeenidentified.Alumbarpunctureisindicatedifthereisanysuspicionofmeningitisorencephalitis,anditismandatoryinallpatientsinfectedwithHIV,evenin
theabsenceofsymptomsorsignssuggestinginfection.Testingforautoantibodiesintheserumandcerebrospinalfluid(CSF)shouldbeconsideredinpatientspresenting
withaseeminglyaggressiveformofepilepsyassociatedwithotherabnormalitiessuchascognitivedisturbances.

ELECTROPHYSIOLOGICSTUDIES

AllpatientswhohaveapossibleseizuredisordershouldbeevaluatedwithanEEGassoonaspossible.DetailsabouttheEEGarecoveredinChap.442e.

Intheevaluationofapatientwithsuspectedepilepsy,thepresenceofelectrographicseizureactivityduringtheclinicallyevidentevent(i.e.,abnormal,repetitive,rhythmic
activityhavingadiscreteonsetandtermination)clearlyestablishesthediagnosis.Theabsenceofelectrographicseizureactivitydoesnotexcludeaseizuredisorder,
however,becausefocalseizuresmayoriginatefromaregionofthecortexthatcannotbedetectedbystandardscalpelectrodes.TheEEGisalwaysabnormalduring
generalizedtonicclonicseizures.Becauseseizuresaretypicallyinfrequentandunpredictable,itisoftennotpossibletoobtaintheEEGduringaclinicalevent.Continuous
monitoringforprolongedperiodsinvideoEEGtelemetryunitsforhospitalizedpatientsortheuseofportableequipmenttorecordtheEEGcontinuouslyfor24hin
ambulatorypatientshasmadeiteasiertocapturetheelectrophysiologicaccompanimentsofclinicalevents.Inparticular,videoEEGtelemetryisnowaroutineapproach
fortheaccuratediagnosisofepilepsyinpatientswithpoorlycharacterizedeventsorseizuresthataredifficulttocontrol.

TheEEGmayalsobehelpfulintheinterictalperiodbyshowingcertainabnormalitiesthatarehighlysupportiveofthediagnosisofepilepsy.Suchepileptiformactivity
consistsofburstsofabnormaldischargescontainingspikesorsharpwaves.Thepresenceofepileptiformactivityisnotspecificforepilepsy,butithasamuchgreater
prevalenceinpatientswithepilepsythaninnormalindividuals.However,eveninanindividualwhoisknowntohaveepilepsy,theinitialroutineinterictalEEGmaybe
normalupto60%ofthetime.Thus,theEEGcannotestablishthediagnosisofepilepsyinmanycases.

TheEEGisalsousedforclassifyingseizuredisordersandaidingintheselectionofanticonvulsantmedications.Forexample,episodicgeneralizedspikewaveactivityis
usuallyseeninpatientswithtypicalabsenceepilepsyandmaybeseenwithothergeneralizedepilepsysyndromes.Focalinterictalepileptiformdischargeswouldsupport
thediagnosisofafocalseizuredisordersuchastemporallobeepilepsyorfrontallobeseizures,dependingonthelocationofthedischarges.

TheroutinescalprecordedEEGmayalsobeusedtoassesstheprognosisofseizuredisordersingeneral,anormalEEGimpliesabetterprognosis,whereasan
abnormalbackgroundorprofuseepileptiformactivitysuggestsapooroutcome.Unfortunately,theEEGhasnotprovedtobeusefulinpredictingwhichpatientswith
predisposingconditionssuchasheadinjuryorbraintumorwillgoontodevelopepilepsy,becauseinsuchcircumstancesepileptiformactivityiscommonlyencountered
regardlessofwhetherseizuresoccur.

Magnetoencephalography(MEG)providesanotherwayoflookingnoninvasivelyatcorticalactivity.Insteadofmeasuringelectricalactivityofthebrain,itmeasuresthe
smallmagneticfieldsthataregeneratedbythisactivity.ThesourceofepileptiformactivityseenonMEGcanbeanalyzed,anditssourceinthebraincanbeestimated
usingavarietyofmathematicaltechniques.ThesesourceestimatescanthenbeplottedonananatomicimageofthebrainsuchasanMRI(discussedbelow),to
generateamagneticsourceimage(MSI).MSIcanbeusefultolocalizepotentialseizurefoci.

BRAINIMAGING

Almostallpatientswithnewonsetseizuresshouldhaveabrainimagingstudytodeterminewhetherthereisanunderlyingstructuralabnormalitythatisresponsible.The
onlypotentialexceptiontothisruleischildrenwhohaveanunambiguoushistoryandexaminationsuggestiveofabenign,generalizedseizuredisordersuchasabsence
epilepsy.MRIhasbeenshowntobesuperiortocomputedtomography(CT)forthedetectionofcerebrallesionsassociatedwithepilepsy.Insomecases,MRIwillidentify
lesionssuchastumors,vascularmalformations,orotherpathologiesthatneedurgenttherapy.TheavailabilityofnewerMRImethodssuchas3teslascanners,parallel
imagingwithmultichannelheadcoils,threedimensionalstructuralimagingatsubmillimeterresolution,andwidespreaduseofpulsesequencessuchasfluidattenuated
inversionrecovery(FLAIR),hasincreasedthesensitivityfordetectionofabnormalitiesofcorticalarchitecture,includinghippocampalatrophyassociatedwithmesial
temporalsclerosis,aswellasabnormalitiesofcorticalneuronalmigration.Insuchcases,thefindingsmaynotleadtoimmediatetherapy,buttheydoprovidean
explanationforthepatientsseizuresandpointtotheneedforchronicantiepilepticdrugtherapyorpossiblesurgicalresection.

InthepatientwithasuspectedCNSinfectionormasslesion,CTscanningshouldbeperformedemergentlywhenMRIisnotimmediatelyavailable.Otherwise,itisusually
appropriatetoobtainanMRIstudywithinafewdaysoftheinitialevaluation.Functionalimagingproceduressuchaspositronemissiontomography(PET)andsingle
photonemissioncomputedtomography(SPECT)arealsousedtoevaluatecertainpatientswithmedicallyrefractoryseizures(discussedbelow).

DIFFERENTIALDIAGNOSISOFSEIZURES
DisordersthatmaymimicseizuresarelistedinTable4456.Inmostcases,seizurescanbedistinguishedfromotherconditionsbymeticulousattentiontothehistoryand
relevantlaboratorystudies.Onoccasion,additionalstudiessuchasvideoEEGmonitoring,sleepstudies,tilttableanalysis,orcardiacelectrophysiology,mayberequired
toreachacorrectdiagnosis.Twoofthemorecommonnonepilepticsyndromesinthedifferentialdiagnosisaredetailedbelow.

TABLE4456DifferentialDiagnosisofSeizures

Syncope
Vasovagalsyncope
Transientischemicattack(TIA)
Cardiacarrhythmia
BasilararteryTIA
Valvularheartdisease
Sleepdisorders
Cardiacfailure
Narcolepsy/cataplexy
Orthostatichypotension
Benignsleepmyoclonus
Psychologicaldisorders
Movementdisorders
Psychogenicseizure
Tics
Hyperventilation
Nonepilepticmyoclonus
Panicattack

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 10/19
17/06/2015
Metabolicdisturbances Paroxysmalchoreoathetosis
Alcoholicblackouts Specialconsiderationsinchildren
Deliriumtremens Breathholdingspells
Hypoglycemia Migrainewithrecurrentabdominalpainandcyclicvomiting
Hypoxia Benignparoxysmalvertigo
Psychoactivedrugs Apnea
(e.g.,hallucinogens) Nightterrors
Migraine Sleepwalking
Confusionalmigraine
Basilarmigraine

SYNCOPE

(SeealsoChap.27)Thediagnosticdilemmaencounteredmostfrequentlyisthedistinctionbetweenageneralizedseizureandsyncope.Observationsbythepatientand
bystandersthatcanhelpdifferentiatebetweenthetwoarelistedinTable4457.Characteristicsofaseizureincludethepresenceofanaura,cyanosis,unconsciousness,
motormanifestationslasting>15s,postictaldisorientation,musclesoreness,andsleepiness.Incontrast,asyncopalepisodeismorelikelyiftheeventwasprovokedby
acutepainoranxietyoroccurredimmediatelyafterarisingfromthelyingorsittingposition.Patientswithsyncopeoftendescribeastereotypedtransitionfrom
consciousnesstounconsciousnessthatincludestiredness,sweating,nausea,andtunnelingofvision,andtheyexperiencearelativelybrieflossofconsciousness.
Headacheorincontinenceusuallysuggestsaseizurebutmayonoccasionalsooccurwithsyncope.Abriefperiod(i.e.,110s)ofconvulsivemotoractivityisfrequently
seenimmediatelyattheonsetofasyncopalepisode,especiallyifthepatientremainsinanuprightpostureafterfainting(e.g.,inadentistschair)andthereforehasa
sustaineddecreaseincerebralperfusion.Rarely,asyncopalepisodecaninduceafulltonicclonicseizure.Insuchcases,theevaluationmustfocusonboththecauseof
thesyncopaleventaswellasthepossibilitythatthepatienthasapropensityforrecurrentseizures.

TABLE4457FeaturesThatDistinguishGeneralizedTonicClonicSeizurefromSyncope

Features Seizure Syncope

Immediateprecipitatingfactors Usuallynone Emotionalstress,Valsalva,orthostatichypotension,cardiacetiologies

Premonitorysymptoms Noneoraura(e.g.,oddodor) Tiredness,nausea,diaphoresis,tunnelingofvision

Postureatonset Variable Usuallyerect

Transitiontounconsciousness Oftenimmediate Gradualoversecondsa

Durationofunconsciousness Minutes Seconds

Durationoftonicorclonicmovements 3060s Nevermorethan15s

Facialappearanceduringevent Cyanosis,frothingatmouth Pallor

Disorientationandsleepinessafterevent Manyminutestohours <5min

Achingofmusclesafterevent Often Sometimes

Bitingoftongue Sometimes Rarely

Incontinence Sometimes Sometimes

Headache Sometimes Rarely

aMaybesuddenwithcertaincardiacarrhythmias.

PSYCHOGENICSEIZURES

Psychogenicseizuresarenonepilepticbehaviorsthatresembleseizures.Theyareoftenpartofaconversionreactionprecipitatedbyunderlyingpsychologicaldistress.
Certainbehaviorssuchassidetosideturningofthehead,asymmetricandlargeamplitudeshakingmovementsofthelimbs,twitchingofallfourextremitieswithoutloss
ofconsciousness,andpelvicthrustingaremorecommonlyassociatedwithpsychogenicratherthanepilepticseizures.Psychogenicseizuresoftenlastlongerthan
epilepticseizuresandmaywaxandwaneoverminutestohours.However,thedistinctionissometimesdifficultonclinicalgroundsalone,andtherearemanyexamplesof
diagnosticerrorsmadebyexperiencedepileptologists.Thisisespeciallytrueforpsychogenicseizuresthatresemblefocalseizureswithdyscognitivefeatures,because
thebehavioralmanifestationsoffocalseizures(especiallyoffrontallobeorigin)canbeextremelyunusual,andinbothcases,theroutinesurfaceEEGmaybenormal.
VideoEEGmonitoringisveryusefulwhenhistoricfeaturesarenondiagnostic.GeneralizedtonicclonicseizuresalwaysproducemarkedEEGabnormalitiesduringand
aftertheseizure.Forsuspectedfocalseizuresoftemporallobeorigin,theuseofadditionalelectrodesbeyondthestandardscalplocations(e.g.,sphenoidalelectrodes)
mayberequiredtolocalizeaseizurefocus.Measurementofserumprolactinlevelsmayalsohelptodistinguishbetweenorganicandpsychogenicseizures,because
mostgeneralizedseizuresandsomefocalseizuresareaccompaniedbyrisesinserumprolactin(duringtheimmediate30minpostictalperiod),whereaspsychogenic
seizuresarenot.Thediagnosisofpsychogenicseizuresdoesnotexcludeaconcurrentdiagnosisofepilepsy,becausethetwooftencoexist.

TREATMENTSeizuresandEpilepsy

Therapyforapatientwithaseizuredisorderisalmostalwaysmultimodalandincludestreatmentofunderlyingconditionsthatcauseorcontributetotheseizures,
avoidanceofprecipitatingfactors,suppressionofrecurrentseizuresbyprophylactictherapywithantiepilepticmedicationsorsurgery,andaddressingavarietyof
psychologicalandsocialissues.Treatmentplansmustbeindividualized,giventhemanydifferenttypesandcausesofseizuresaswellasthedifferencesinefficacyand
toxicityofantiepilepticmedicationsforeachpatient.Inalmostallcases,aneurologistwithexperienceinthetreatmentofepilepsyshoulddesignandoversee
implementationofthetreatmentstrategy.Furthermore,patientswithrefractoryepilepsyorthosewhorequirepolypharmacywithantiepilepticdrugsshouldremainunder
theregularcareofaneurologist.

TREATMENTOFUNDERLYINGCONDITIONS
Ifthesolecauseofaseizureisametabolicdisturbancesuchasanabnormalityofserumelectrolytesorglucose,thentreatmentisaimedatreversingthemetabolic
problemandpreventingitsrecurrence.Therapywithantiepilepticdrugsisusuallyunnecessaryunlessthemetabolicdisordercannotbecorrectedpromptlyandthe
patientisatriskofhavingfurtherseizures.Iftheapparentcauseofaseizurewasamedication(e.g.,theophylline)orillicitdruguse(e.g.,cocaine),thenappropriate

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 11/19
17/06/2015
therapyisavoidanceofthedrugthereisusuallynoneedforantiepilepticmedicationsunlesssubsequentseizuresoccurintheabsenceoftheseprecipitants.

SeizurescausedbyastructuralCNSlesionsuchasabraintumor,vascularmalformation,orbrainabscessmaynotrecurafterappropriatetreatmentoftheunderlying
lesion.However,despiteremovalofthestructurallesion,thereisariskthattheseizurefocuswillremaininthesurroundingtissueordevelopdenovoasaresultofgliosis
andotherprocessesinducedbysurgery,radiation,orothertherapies.Mostpatientsarethereforemaintainedonanantiepilepticmedicationforatleast1year,andan
attemptismadetowithdrawmedicationsonlyifthepatienthasbeencompletelyseizurefree.Ifseizuresarerefractorytomedication,thepatientmaybenefitfromsurgical
removaloftheepilepticbrainregion(seebelow).

AVOIDANCEOFPRECIPITATINGFACTORS
Unfortunately,littleisknownaboutthespecificfactorsthatdeterminepreciselywhenaseizurewilloccurinapatientwithepilepsy.Somepatientscanidentifyparticular
situationsthatappeartolowertheirseizurethresholdthesesituationsshouldbeavoided.Forexample,apatientwhohasseizuresinthesettingofsleepdeprivation
shouldobviouslybeadvisedtomaintainanormalsleepschedule.Manypatientsnoteanassociationbetweenalcoholintakeandseizures,andtheyshouldbe
encouragedtomodifytheirdrinkinghabitsaccordingly.Therearealsorelativelyrarecasesofpatientswithseizuresthatareinducedbyhighlyspecificstimulisuchasa
videogamemonitor,music,oranindividualsvoice(reflexepilepsy).Becausethereisoftenanassociationbetweenstressandseizures,stressreductiontechniques
suchasphysicalexercise,meditation,orcounselingmaybehelpful.

ANTIEPILEPTICDRUGTHERAPY
Antiepilepticdrugtherapyisthemainstayoftreatmentformostpatientswithepilepsy.Theoverallgoalistocompletelypreventseizureswithoutcausinganyuntoward
sideeffects,preferablywithasinglemedicationandadosingschedulethatiseasyforthepatienttofollow.Seizureclassificationisanimportantelementindesigningthe
treatmentplan,becausesomeantiepilepticdrugshavedifferentactivitiesagainstvariousseizuretypes.However,thereisconsiderableoverlapbetweenmany
antiepilepticdrugssuchthatthechoiceoftherapyisoftendeterminedmorebythepatientsspecificneeds,especiallyhisorherassessmentofsideeffects.

WhentoInitiateAntiepilepticDrugTherapy
Antiepilepticdrugtherapyshouldbestartedinanypatientwithrecurrentseizuresofunknownetiologyoraknowncausethatcannotbereversed.Whethertoinitiate
therapyinapatientwithasingleseizureiscontroversial.PatientswithasingleseizureduetoanidentifiedlesionsuchasaCNStumor,infection,ortrauma,inwhichthere
isstrongevidencethatthelesionisepileptogenic,shouldbetreated.Theriskofseizurerecurrenceinapatientwithanapparentlyunprovokedoridiopathicseizureis
uncertain,withestimatesrangingfrom31to71%inthefirst12monthsaftertheinitialseizure.Thisuncertaintyarisesfromdifferencesintheunderlyingseizuretypesand
etiologiesinvariouspublishedepidemiologicstudies.Generallyacceptedriskfactorsassociatedwithrecurrentseizuresincludethefollowing:(1)anabnormalneurologic
examination,(2)seizurespresentingasstatusepilepticus,(3)postictalToddsparalysis,(4)astrongfamilyhistoryofseizures,or(5)anabnormalEEG.Mostpatientswith
oneormoreoftheseriskfactorsshouldbetreated.Issuessuchasemploymentordrivingmayinfluencethedecisionwhethertostartmedicationsaswell.Forexample,a
patientwithasingle,idiopathicseizurewhosejobdependsondrivingmayprefertakingantiepilepticdrugsratherthanriskaseizurerecurrenceandthepotentiallossof
drivingprivileges.

SelectionofAntiepilepticDrugs
AntiepilepticdrugsavailableintheUnitedStatesareshowninTable4458,andthemainpharmacologiccharacteristicsofcommonlyuseddrugsarelistedinTable445
9.Worldwide,oldermedicationssuchasphenytoin,valproicacid,carbamazepine,phenobarbital,andethosuximidearegenerallyusedasfirstlinetherapyformost
seizuredisordersbecause,overall,theyareaseffectiveasrecentlymarketeddrugsandsignificantlylessexpensiveoverall.Mostofthenewdrugsthathavebecome
availableinthepastdecadeareusedasaddonoralternativetherapy,althoughmanyarenowbeingusedasfirstlinemonotherapy.

Inadditiontoefficacy,factorsinfluencingthechoiceofaninitialmedicationincludetheconvenienceofdosing(e.g.,oncedailyversusthreeorfourtimesdaily)and
potentialsideeffects.Inthisregard,anumberofthenewerdrugshavetheadvantageofreduceddrugdruginteractionsandeasierdosing.Almostallofthecommonly
usedantiepilepticdrugscancausesimilar,doserelatedsideeffectssuchassedation,ataxia,anddiplopia.Longtermuseofsomeagentsinadults,especiallytheelderly,
canleadtoosteoporosis.Closefollowupisrequiredtoensurethesesideeffectsarepromptlyrecognizedandreversed.Mostoftheolderdrugsandsomeofthenewer
onescanalsocauseidiosyncratictoxicitysuchasrash,bonemarrowsuppression,orhepatotoxicity.Althoughrare,thesesideeffectsshouldbeconsideredduringdrug
selection,andpatientsmustbeinstructedaboutsymptomsorsignsthatshouldsignaltheneedtoalerttheirhealthcareprovider.Forsomedrugs,laboratorytests(e.g.,
completebloodcountandliverfunctiontests)arerecommendedpriortotheinstitutionoftherapy(toestablishbaselinevalues)andduringinitialdosingandtitrationofthe
agent.Importantly,studieshaveshownthatAsianindividualscarryingthehumanleukocyteantigenallele,HLAB*1502,areatparticularlyhighriskofdevelopingserious
skinreactionsfromcarbamazepineandphenytoin.Asaresult,racialbackgroundandgenotypeareadditionalfactorstoconsiderindrugselection.

ANTIEPILEPTICDRUGSELECTIONFORFOCALSEIZURES
Carbamazepine(orarelateddrug,oxcarbazepine),lamotrigine,phenytoin,andlevetiracetamarecurrentlythedrugsofchoiceapprovedfortheinitialtreatmentoffocal
seizures,includingthosethatevolveintogeneralizedseizures.Overalltheyhaveverysimilarefficacy,butdifferencesinpharmacokineticsandtoxicityarethemain
determinantsforuseinagivenpatient.Forexample,anadvantageofcarbamazepine(whichisalsoavailableinanextendedreleaseform)isthatitsmetabolismfollows
firstorderpharmacokinetics,whichallowsforalinearrelationshipbetweendrugdose,serumlevels,andtoxicity.Carbamazepinecancauseleukopenia,aplasticanemia,
orhepatotoxicityandwouldthereforebecontraindicatedinpatientswithpredispositionstotheseproblems.Oxcarbazepinehastheadvantageofbeingmetabolizedina
waythatavoidsanintermediatemetaboliteassociatedwithsomeofthesideeffectsofcarbamazepine.Oxcarbazepinealsohasfewerdruginteractionsthan
carbamazepine.Lamotriginetendstobewelltoleratedintermsofsideeffects.However,patientsneedtobeparticularlyvigilantaboutthepossibilityofaskinrashduring
theinitiationoftherapy.ThiscanbeextremelysevereandleadtoStevensJohnsonsyndromeifunrecognizedandifthemedicationisnotdiscontinuedimmediately.This
riskcanbereducedbytheuseoflowinitialdosesandslowtitration.Lamotriginemustbestartedatlowerinitialdoseswhenusedasaddontherapywithvalproicacid,
becausevalproicacidinhibitslamotriginemetabolismandresultsinasubstantiallyprolongedhalflife.Phenytoinhasarelativelylonghalflifeandofferstheadvantageof
onceortwicedailydosingcomparedtotwoorthreetimesdailydosingformanyoftheotherdrugs.However,phenytoinshowspropertiesofnonlinearkinetics,suchthat
smallincreasesinphenytoindosesaboveastandardmaintenancedosecanprecipitatemarkedsideeffects.Thisisoneofthemaincausesofacutephenytointoxicity.
Longtermuseofphenytoinisassociatedwithuntowardcosmeticeffects(e.g.,hirsutism,coarseningoffacialfeatures,gingivalhypertrophy)andeffectsonbone
metabolism.Duetothesesideeffects,phenytoinisoftenavoidedinyoungpatientswhoarelikelytorequirethedrugformanyyears.Levetiracetamhastheadvantageof
havingnoknowndrugdruginteractions,makingitespeciallyusefulintheelderlyandpatientsonothermedications.However,asignificantnumberofpatientstaking
levetiracetamcomplainofirritability,anxiety,andotherpsychiatricsymptoms.Topiramatecanbeusedforbothfocalandgeneralizedseizures.Similartosomeofthe
otherantiepilepticdrugs,topiramatecancausesignificantpsychomotorslowingandothercognitiveproblems.Additionally,itshouldnotbeusedinpatientsatriskforthe
developmentofglaucomaorrenalstones.

Valproicacidisaneffectivealternativeforsomepatientswithfocalseizures,especiallywhentheseizuresgeneralize.Gastrointestinalsideeffectsarefewerwhenusing
thedelayedreleaseformulation(Depakote).Laboratorytestingisrequiredtomonitortoxicitybecausevalproicacidcanrarelycausereversiblebonemarrowsuppression
andhepatotoxicity.Thisdrugshouldgenerallybeavoidedinpatientswithpreexistingbonemarroworliverdisease.Irreversible,fatalhepaticfailureappearingasan
idiosyncraticratherthandoserelatedsideeffectisarelativelyrarecomplicationitsriskishighestinchildren<2yearsold,especiallythosetakingotherantiepilepticdrugs
orwithinbornerrorsofmetabolism.

Zonisamide,tiagabine,gabapentin,lacosamide,andezogabineareadditionaldrugscurrentlyusedforthetreatmentoffocalseizureswithorwithoutevolutioninto
generalizedseizures.Phenobarbitalandotherbarbituratecompoundswerecommonlyusedinthepastasfirstlinetherapyformanyformsofepilepsy.However,the
barbituratesfrequentlycausesedationinadults,hyperactivityinchildren,andothermoresubtlecognitivechangesthus,theiruseshouldbelimitedtosituationsinwhich
noothersuitabletreatmentalternativesexist.

ANTIEPILEPTICDRUGSELECTIONFORGENERALIZEDSEIZURES
Lamotrigineandvalproicacidarecurrentlyconsideredthebestinitialchoiceforthetreatmentofprimarygeneralized,tonicclonicseizures.Topiramate,zonisamide,
phenytoin,carbamazepine,andoxcarbazepinearesuitablealternatives.Valproicacidisalsoparticularlyeffectiveinabsence,myoclonic,andatonicseizures.Itis

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 12/19
17/06/2015
thereforethedrugofchoiceinpatientswithgeneralizedepilepsysyndromeshavingmixedseizuretypes.Importantly,carbamazepine,oxcarbazepine,andphenytoincan
worsencertaintypesofgeneralizedseizures,includingabsence,myoclonic,tonic,andatonicseizures.Ethosuximideisaparticularlyeffectivedrugforthetreatmentof
uncomplicatedabsenceseizures,butitisnotusefulfortonicclonicorfocalseizures.Periodicmonitoringofbloodcellcountsisrequiredsinceethosuximiderarelycauses
bonemarrowsuppression.Lamotrigineappearstobeparticularlyeffectiveinepilepsysyndromeswithmixed,generalizedseizuretypessuchasJMEandLennoxGastaut
syndrome.Topiramate,zonisamide,andfelbamatemayhavesimilarbroadefficacy.

InitiationandMonitoringofTherapy
Becausetheresponsetoanyantiepilepticdrugisunpredictable,patientsshouldbecarefullyeducatedabouttheapproachtotherapy.Thegoalistopreventseizuresand
minimizethesideeffectsoftreatmentdeterminationoftheoptimaldoseisoftenamatteroftrialanderror.Thisprocessmaytakemonthsorlongerifthebaselineseizure
frequencyislow.Mostantiepilepticdrugsneedtobeintroducedrelativelyslowlytominimizesideeffects.Patientsshouldexpectthatminorsideeffectssuchasmild
sedation,slightchangesincognition,orimbalancewilltypicallyresolvewithinafewdays.Startingdosesareusuallythelowestvaluelistedunderthedosagecolumnin
Table4459.Subsequentincreasesshouldbemadeonlyafterachievingasteadystatewiththepreviousdose(i.e.,afteranintervaloffiveormorehalflives).

Monitoringofserumantiepilepticdruglevelscanbeveryusefulforestablishingtheinitialdosingschedule.However,thepublishedtherapeuticrangesofserumdrug
concentrationsareonlyanapproximateguidefordeterminingtheproperdoseforagivenpatient.Thekeydeterminantsaretheclinicalmeasuresofseizurefrequency
andpresenceofsideeffects,notthelaboratoryvalues.Conventionalassaysofserumdruglevelsmeasurethetotaldrug(i.e.,bothfreeandproteinbound).However,itis
theconcentrationoffreedrugthatreflectsextracellularlevelsinthebrainandcorrelatesbestwithefficacy.Thus,patientswithdecreasedlevelsofserumproteins(e.g.,
decreasedserumalbuminduetoimpairedliverorrenalfunction)mayhaveanincreasedratiooffreetobounddrug,yettheconcentrationoffreedrugmaybeadequate
forseizurecontrol.Thesepatientsmayhaveasubtherapeuticdruglevel,butthedoseshouldbechangedonlyifseizuresremainuncontrolled,notjusttoachievea
therapeuticlevel.Itisalsousefultomonitorfreedruglevelsinsuchpatients.Inpractice,otherthanduringtheinitiationormodificationoftherapy,monitoringof
antiepilepticdruglevelsismostusefulfordocumentingadherence.

Ifseizurescontinuedespitegradualincreasestothemaximumtolerateddoseanddocumentedcompliance,thenitbecomesnecessarytoswitchtoanotherantiepileptic
drug.Thisisusuallydonebymaintainingthepatientonthefirstdrugwhileaseconddrugisadded.Thedoseoftheseconddrugshouldbeadjustedtodecreaseseizure
frequencywithoutcausingtoxicity.Oncethisisachieved,thefirstdrugcanbegraduallywithdrawn(usuallyoverweeksunlessthereissignificanttoxicity).Thedoseofthe
seconddrugisthenfurtheroptimizedbasedonseizureresponseandsideeffects.Monotherapyshouldbethegoalwheneverpossible.

WhentoDiscontinueTherapy
Overall,about70%ofchildrenand60%ofadultswhohavetheirseizurescompletelycontrolledwithantiepilepticdrugscaneventuallydiscontinuetherapy.Thefollowing
patientprofileyieldsthegreatestchanceofremainingseizurefreeafterdrugwithdrawal:(1)completemedicalcontrolofseizuresfor15years(2)singleseizuretype,
eitherfocalorgeneralized(3)normalneurologicexamination,includingintelligenceand(4)normalEEG.Theappropriateseizurefreeintervalisunknownand
undoubtedlyvariesfordifferentformsofepilepsy.However,itseemsreasonabletoattemptwithdrawaloftherapyafter2yearsinapatientwhomeetsalloftheabove
criteria,ismotivatedtodiscontinuethemedication,andclearlyunderstandsthepotentialrisksandbenefits.Inmostcases,itispreferabletoreducethedoseofthedrug
graduallyover23months.Mostrecurrencesoccurinthefirst3monthsafterdiscontinuingtherapy,andpatientsshouldbeadvisedtoavoidpotentiallydangerous
situationssuchasdrivingorswimmingduringthisperiod.

TreatmentofRefractoryEpilepsy
Approximatelyonethirdofpatientswithepilepsydonotrespondtotreatmentwithasingleantiepilepticdrug,anditbecomesnecessarytotryacombinationofdrugsto
controlseizures.Patientswhohavefocalepilepsyrelatedtoanunderlyingstructurallesionorthosewithmultipleseizuretypesanddevelopmentaldelayareparticularly
likelytorequiremultipledrugs.Therearecurrentlynoclearguidelinesforrationalpolypharmacy,althoughintheoryacombinationofdrugswithdifferentmechanismsof
actionmaybemostuseful.Inmostcases,theinitialcombinationtherapycombinesfirstlinedrugs(i.e.,carbamazepine,oxcarbazepine,lamotrigine,valproicacid,
levetiracetam,andphenytoin).Ifthesedrugsareunsuccessful,thentheadditionofotherdrugssuchastopiramate,zonisamide,lacosamide,ortiagabineisindicated.
Patientswithmyoclonicseizuresresistanttovalproicacidmaybenefitfromtheadditionofclonazepamorclobazam,andthosewithabsenceseizuresmayrespondtoa
combinationofvalproicacidandethosuximide.Thesameprinciplesconcerningthemonitoringoftherapeuticresponse,toxicity,andserumlevelsformonotherapyapply
topolypharmacy,andpotentialdruginteractionsneedtoberecognized.Ifthereisnoimprovement,athirddrugcanbeaddedwhilethefirsttwoaremaintained.Ifthereis
aresponse,thelesseffectiveorlesswelltoleratedofthefirsttwodrugsshouldbegraduallywithdrawn.

SURGICALTREATMENTOFREFRACTORYEPILEPSY
Approximately2030%ofpatientswithepilepsycontinuetohaveseizuresdespiteeffortstofindaneffectivecombinationofantiepilepticdrugs.Forsome,surgerycanbe
extremelyeffectiveinsubstantiallyreducingseizurefrequencyandevenprovidingcompleteseizurecontrol.Understandingthepotentialvalueofsurgeryisespecially
importantwhenapatientsseizuresarenotcontrolledwithinitialtreatment,assuchpatientsoftendonotrespondtosubsequentmedicationtrials.Ratherthansubmitting
thepatienttoyearsofunsuccessfulmedicaltherapyandthepsychosocialtraumaandincreasedmortalityassociatedwithongoingseizures,thepatientshouldhavean
efficientbutrelativelybriefattemptatmedicaltherapyandthenbereferredforsurgicalevaluation.

Themostcommonsurgicalprocedureforpatientswithtemporallobeepilepsyinvolvesresectionoftheanteromedialtemporallobe(temporallobectomy)oramore
limitedremovaloftheunderlyinghippocampusandamygdala(amygdalohippocampectomy).Focalseizuresarisingfromextratemporalregionsmaybeabolishedbya
focalneocorticalresectionwithpreciseremovalofanidentifiedlesion(lesionectomy).LocalizedneocorticalresectionwithoutaclearlesionidentifiedonMRIisalso
possiblewhenothertests(e.g.MEG,PET,SPECT)implicateafocalcorticalregionasaseizureonsetzone.Whenthecorticalregioncannotberemoved,multiplesubpial
transection,whichdisruptsintracorticalconnections,issometimesusedtopreventseizurespread.Hemispherectomyormultilobarresectionisusefulforsomepatients
withsevereseizuresduetohemisphericabnormalitiessuchashemimegalencephalyorotherdysplasticabnormalities,andcorpuscallosotomyhasbeenshowntobe
effectivefordisablingtonicoratonicseizures,usuallywhentheyarepartofamixedseizuresyndrome(e.g.,LennoxGastautsyndrome).

Presurgicalevaluationisdesignedtoidentifythefunctionalandstructuralbasisofthepatientsseizuredisorder.InpatientvideoEEGmonitoringisusedtodefinethe
anatomiclocationoftheseizurefocusandtocorrelatetheabnormalelectrophysiologicactivitywithbehavioralmanifestationsoftheseizure.Routinescalporscalp
sphenoidalrecordingsandahighresolutionMRIscanareusuallysufficientforlocalizationoftheepileptogenicfocus,especiallywhenthefindingsareconcordant.
FunctionalimagingstudiessuchasSPECT,PET,andMEGareadjunctiveteststhatmayhelptorevealorverifythelocalizationofanapparentepileptogenicregion.Once
thepresumedlocationoftheseizureonsetisidentified,additionalstudies,includingneuropsychologicaltesting,theintracarotidamobarbitaltest(Wadatest),and
functionalMRImaybeusedtoassesslanguageandmemorylocalizationandtodeterminethepossiblefunctionalconsequencesofsurgicalremovaloftheepileptogenic
region.Insomecases,standardnoninvasiveevaluationisnotsufficienttolocalizetheseizureonsetzone,andinvasiveelectrophysiologicmonitoring,suchasimplanted
depthorsubduralelectrodes,isrequiredformoredefinitivelocalization.Theexactextentoftheresectiontobeundertakencanalsobedeterminedbyperformingcortical
mappingatthetimeofthesurgicalprocedure,allowingforatailoredresection.Thisinvolveselectrocorticographicrecordingsmadewithelectrodesonthesurfaceofthe
braintoidentifytheextentofepileptiformdisturbances.Iftheregiontoberesectediswithinornearbrainregionssuspectedofhavingsensorimotororlanguagefunction,
electricalcorticalstimulationmappingisperformedontheawakepatienttodeterminethefunctionofcorticalregionsinquestioninordertoavoidresectionofsocalled
eloquentcortexandtherebyminimizepostsurgicaldeficits.

Advancesinpresurgicalevaluationandmicrosurgicaltechniqueshaveledtoasteadyincreaseinthesuccessofepilepsysurgery.Clinicallysignificantcomplicationsof
surgeryare<5%,andtheuseoffunctionalmappingprocedureshasmarkedlyreducedtheneurologicsequelaeduetoremovalorsectioningofbraintissue.Forexample,
about70%ofpatientstreatedwithtemporallobectomywillbecomeseizurefree,andanother1525%willhaveatleasta90%reductioninseizurefrequency.Marked
improvementisalsousuallyseeninpatientstreatedwithhemispherectomyforcatastrophicseizuredisordersduetolargehemisphericabnormalities.Postoperatively,
patientsgenerallyneedtoremainonantiepilepticdrugtherapy,butthemarkedreductionofseizuresfollowingresectivesurgerycanhaveaverybeneficialeffecton
qualityoflife.

Notallmedicallyrefractorypatientsaresuitablecandidatesforresectivesurgery.Forexample,somepatientshaveseizuresarisingfrommorethanonelocation,making

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 13/19
17/06/2015
theriskofongoingseizuresorpotentialharmfromthesurgeryunacceptablyhigh.Vagusnervestimulation(VNS)hasbeenusedinsomeofthesecases,althoughthe
resultsarelimitedanditisdifficulttopredictwhowillbenefit.Anewimplantabledevicethatcandetecttheonsetofaseizure(insomeinstancesbeforetheseizure
becomesclinicallyapparent)anddeliveranelectricalstimulation(ResponsiveNeuroStimulation)hasrecentlybeenapprovedandmaybeofbenefitinselectedpatients.
Studiesarecurrentlyevaluatingtheefficacyofstereotacticradiosurgery,laserthermoablation,anddeepbrainstimulation(DBS)asotheroptionsforsurgicaltreatmentof
refractoryepilepsy.

TABLE4458SelectionofAntiepilepticDrugs

Typical
GeneralizedOnsetTonicClonic Focal AtypicalAbsence,Myoclonic,Atonic
Absence

FirstLine

Lamotrigine Lamotrigine Valproicacid Valproicacid

Valproicacid Carbamazepine Ethosuximide Lamotrigine

Oxcarbazepine
Phenytoin Lamotrigine Topiramate
Levetiracetam

Alternatives

Topiramate
Zonisamidea Zonisamidea
Phenytoin Valproicacid
Carbamazepine Tiagabinea Clonazepam
Oxcarbazepine Gabapentina Lamotrigine Felbamate
Topiramate Lacosamidea Clonazepam Clobazam
Phenobarbital Exogabinea Rufinamide
Primidone Phenobarbital
Felbamate Primidone
Felbamate

aAsadjunctivetherapy.

TABLE4459DosageandAdverseEffectsofCommonlyUsedAntiepilepticDrugs

Typical AdverseEffects
Dose Therapeutic Drug
HalfLife
Trade Principal Dose Range Interactions
GenericName Neurologic Systemic
Name Uses Interval

Level
decreasedby
Aplasticanemia enzyme
6001800
1017h inducing
mg/d(15 Ataxia Leukopenia
Tonic (variabledue drugsb
35mg/kg,
clonic to Dizziness Gastrointestinal
child)bid Level
Carbamazepine Tegretolc autoinduction: 412g/mL irritation
Focal (capsules Diplopia increasedby
complete35
onset ortablets), Hepatotoxicity erythromycin
wkafter Vertigo
tidqid(oral propoxyphene,
initiation) Hyponatremia
suspension) isoniazid,
cimetidine,
fluoxetine

Fatigue
1040mg/d
(520mg/d 3642h(71 Sedation Constipation Level
Lennox
forpatients 82hforless Not Ataxia Anorexia increasedby
Clobazam Onfi Gastaut
<30kg active established CYP2C19
syndrome Aggression Skinrash
body metabolite) inhibitors
weight)bid Insomnia

Absence Level
Ataxia
Atypical decreasedby
112mg/d Sedation
Clonazepam Klonopin absence 2448h 1070ng/mL Anorexia enzyme
qdtid
Lethargy inducing
Myoclonic drugsb

Level
Gastrointestinal decreasedby
Ataxia irritation enzyme
7501250
60h,adult inducing
mg/d(2040 Lethargy Skinrash
Ethosuximide Zarontin Absence 40100g/mL drugsb
mg/kg)qd 30h,child
Headache Bonemarrow
http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 14/19
17/06/2015
bid suppression Level
increasedby
valproicacid

Retinal
Dizziness
abnormalities
Fatigue
Skindiscoloration Level
Sedation decreasedby
Focal 8001200 Not Cardiac
Ezogabine Potiga 711h enzyme
onset mg/dtid established Confusion conduction(QT
inducing
interval
Vertigo drugsb
prolongation)
Tremor
Urinaryretention

Focal
onset Aplasticanemia
Insomnia Increases
Lennox Hepaticfailure phenytoin,
24003600 Dizziness
Gastaut valproicacid,
Felbamate Felbatol mg/d,tid 1622h 3060g/mL Weightloss
syndrome Sedation active
qid
Gastrointestinal carbamazepine
Tonic Headache
irritation metabolite
clonic

Sedation Gastrointestinal
9002400 Dizziness irritation Noknown
Focal
Gabapentin Neurontin mg/dtid 59h 220g/mL Weightgain significant
onset Ataxia
qid interactions
Fatigue Edema

Gastrointestinal
Dizziness
irritation Level
Ataxia decreasedby
Focal 200400 Not Cardiac
Lacosamide Vimpat 13h enzyme
onset mg/dbid established Diplopia conduction(PR
inducing
interval
Vertigo drugsb
prolongation)

150500
mg/dbid
(immediate
Focal release),
onset daily
Level
(extended
Tonic Dizziness decreasedby
release) 25h
clonic enzyme
(lowerdaily Diplopia
14h(with Skinrash inducing
Atypical dosefor
enzyme Sedation drugsbandoral
Lamotrigine Lamictalc absence regimens 2.520g/mL StevensJohnson
inducers),59 contraceptives
with Ataxia syndrome
Myoclonic h(with
valproic Level
valproicacid) Headache
Lennox acidhigher increasedby
Gastaut dailydose valproicacid
syndrome for
regimens
withan
enzyme
inducer)

10003000 Sedation
mg/dbid
Fatigue
(immediate Anemia Noknown
Focal
Levetiracetam Kepprac release), 68h 545g/mL Incoordination significant
onset Leukopenia
daily interactions
Mood
(extended
changes
release)

Fatigue
Level
Ataxia decreasedby
Focal
9002400 enzyme
onset 1017h(for Dizziness
mg/d(30 See inducing
Oxcarbazepinec Trileptal active 1035g/mL
Tonic 45mg/kg, Diplopia carbamazepine drugsb
metabolite)
clonic child)bid
Vertigo Mayincrease
phenytoin
Headache

Sedation
Ataxia
Tonic
Confusion Level
clonic
60180 increasedby
Phenobarbital Luminal Focal 90h 1040g/mL Dizziness Skinrash valproicacid,
mg/dqdtid
onset Decreased phenytoin

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 15/19
17/06/2015
libido
Depression

Level
increasedby
Gingival isoniazid,
Dizziness hyperplasia sulfonamides,
300400
Tonic mg/d(36 Lymphadenopathy fluoxetine
24h(wide Diplopia
clonic mg/kg, Level
Phenytoin variation, Ataxia Hirsutism
Dilantin adult48 1020g/mL decreasedby
(diphenylhydantoin) Focal dose
mg/kg, Incoordination Osteomalacia enzyme
onset dependent)
child)qd inducing
Confusion Facialcoarsening
tid drugsb
Skinrash
Alteredfolate
metabolism

Level
increasedby
valproicacid
Tonic Primidone,8 Primidone,4
clonic 7501000 15h 12g/mL Level
Sameas
Primidone Mysoline mg/dbid decreasedby
Focal Phenobarbital, Phenobarbital, phenobarbital
tid phenytoin
onset 90h 1040g/mL
(increased
conversionto
phenobarbital

Level
Sedation decreasedby
Gastrointestinal
enzyme
Fatigue irritation
inducing
Lennox 3200mg/d Dizziness Leukopenia drugsb
Not
Rufinamide Banzel Gastaut (45mg/kg, 610h Cardiac Level
established Ataxia
syndrome child)bid conduction(QT increasedby
Headache interval valproicacid
Diplopia shortening)
Mayincrease
phenytoin

Confusion

3256 Sedation
mg/dbid Depression
25h(with
qid(as Level
enzyme Dizziness
adjunctto decreasedby
Focal inducer),79 Not Gastrointestinal
Tiagabine Gabitril enzyme Speechor enzyme
onset h(without established irritation
inducing language inducing
enzyme
antiepileptic problems drugsb
inducer)
drug
regimen) Paresthesias
Psychosis

Psychomotor Renalstones
Focal slowing (avoidusewith
onset 200400 othercarbonic
mg/dbid 20h Sedation Level
Tonic anhydrase
(immediate (immediate Speechor inhibitors) decreasedby
Topiramate Topamax clonic release), release),30h 220g/mL enzyme
language
Lennox daily (extended problems Glaucoma inducing
Gastaut (extended release) drugsb
Fatigue Weightloss
syndrome release)
Paresthesias Hypohidrosis

Tonic
clonic 7502000 Hepatotoxicity
mg/d(20
Absence 60mg/kg) Thrombocytopenia
bidqid Ataxia Level
Atypical Gastrointestinal
Valproicacid Depakene (immediate decreasedby
absence Sedation irritation
(valproatesodium, and 15h 50125g/mL enzyme
Depakotec
divalproexsodium) Myoclonic delayed Tremor Weightgain inducing
release), drugsb
Focal Transientalopecia
daily
onset
(extended Hyperammonemia
Atonic release)

Sedation
Focal Dizziness Anorexia Level
onset 200400 decreasedby
Zonisamide Zonegran mg/dqd 5068h 1040g/mL Confusion Renalstones enzyme
http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 16/19
17/06/2015
Tonic bid Headache Hypohidrosis inducing
clonic drugsb
Psychosis

aExamplesonlypleaserefertoothersourcesforcomprehensivelistingsofallpotentialdrugdruginteractions.

bPhenytoin,carbamazepine,phenobarbital.

cExtendedreleaseproductavailable.

STATUSEPILEPTICUS

Statusepilepticusreferstocontinuousseizuresorrepetitive,discreteseizureswithimpairedconsciousnessintheinterictalperiod.Statusepilepticushasnumerous
subtypes,includinggeneralizedconvulsivestatusepilepticus(GCSE)(e.g.,persistent,generalizedelectrographicseizures,coma,andtonicclonicmovements)and
nonconvulsivestatusepilepticus(e.g.,persistentabsenceseizuresorfocalseizureswithconfusionorpartiallyimpairedconsciousness,andminimalmotorabnormalities).
Thedurationofseizureactivitysufficienttomeetthedefinitionofstatusepilepticushastraditionallybeenspecifiedas1530min.However,amorepracticaldefinitionisto
considerstatusepilepticusasasituationinwhichthedurationofseizurespromptstheacuteuseofanticonvulsanttherapy.ForGCSE,thisistypicallywhenseizureslast
beyond5min.

GCSEisanemergencyandmustbetreatedimmediately,becausecardiorespiratorydysfunction,hyperthermia,andmetabolicderangementscandevelopasa
consequenceofprolongedseizures,andthesecanleadtoirreversibleneuronalinjury.Furthermore,CNSinjurycanoccurevenwhenthepatientisparalyzedwith
neuromuscularblockadebutcontinuestohaveelectrographicseizures.ThemostcommoncausesofGCSEareanticonvulsantwithdrawalornoncompliance,metabolic
disturbances,drugtoxicity,CNSinfection,CNStumors,refractoryepilepsy,andheadtrauma.

GCSEisobviouswhenthepatientishavingovertconvulsions.However,after3045minofuninterruptedseizures,thesignsmaybecomeincreasinglysubtle.Patients
mayhavemildclonicmovementsofonlythefingersorfine,rapidmovementsoftheeyes.Theremaybeparoxysmalepisodesoftachycardia,hypertension,andpupillary
dilation.Insuchcases,theEEGmaybetheonlymethodofestablishingthediagnosis.Thus,ifthepatientstopshavingovertseizures,yetremainscomatose,anEEG
shouldbeperformedtoruleoutongoingstatusepilepticus.ThisisobviouslyalsoessentialwhenapatientwithGCSEhasbeenparalyzedwithneuromuscularblockadein
theprocessofprotectingtheairway.

ThefirststepsinthemanagementofapatientinGCSEaretoattendtoanyacutecardiorespiratoryproblemsorhyperthermia,performabriefmedicalandneurologic
examination,establishvenousaccess,andsendsamplesforlaboratorystudiestoidentifymetabolicabnormalities.Anticonvulsanttherapyshouldthenbeginwithout
delayatreatmentapproachisshowninFig.4453.

FIGURE4453
Pharmacologictreatmentofgeneralizedtonicclonicstatusepilepticus(SE)inadults.CLZ,clonazepamECT,electroconvulsivetherapyLCM,lacosamideLEV,
levetiracetamLZP,lorazepamMDZ,midazolamPGB,pregabalinPHT,phenytoinorfosphenytoinPRO,propofolPTB,pentobarbitalrTMS,repetitivetranscranial
magneticstimulationTHP,thiopentalTPM,topiramateVNS,vagusnervestimulationVPA,valproicacid.(FromAORossetti,DHLowenstein:LancetNeurol10:922,
2011.)

ThetreatmentofnonconvulsivestatusepilepticusisthoughttobelessurgentthanGCSE,becausetheongoingseizuresarenotaccompaniedbytheseveremetabolic
disturbancesseenwithGCSE.However,evidencesuggeststhatnonconvulsivestatusepilepticus,especiallythatcausedbyongoing,focalseizureactivity,isassociated
withcellularinjuryintheregionoftheseizurefocusthereforethisconditionshouldbetreatedaspromptlyaspossibleusingthegeneralapproachdescribedforGCSE.

BEYONDSEIZURES:OTHERMANAGEMENTISSUES
INTERICTALBEHAVIOR

Theadverseeffectsofepilepsyoftengobeyondclinicalseizures,andtheextentoftheseeffectslargelydependsontheetiologyofepilepsy,seizurefrequencyand
severity,andsideeffectsfromantiepileptictherapy.Manyepilepsypatientsarecompletelynormalbetweenseizuresandlivehighlysuccessfulandproductivelives.In
contrast,patientswithseizuressecondarytodevelopmentalabnormalitiesoracquiredbraininjurymayhaveimpairedcognitivefunctionandotherneurologicdeficits.

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 17/19
17/06/2015
FrequentinterictalEEGabnormalitiesareassociatedwithsubtledysfunctionofmemoryandattention.Patientswithmanyseizures,especiallythoseemanatingfromthe
temporallobe,oftennoteanimpairmentofshorttermmemorythatmayprogressovertime.

Patientswithepilepsyareatriskofdevelopingavarietyofpsychiatricproblems,includingdepression,anxiety,andpsychosis.Thisriskvariesconsiderablydependingon
manyfactors,includingtheetiology,frequency,andseverityofseizuresandthepatientsageandpreviouspersonalorfamilyhistoryofpsychiatricdisorder.Depression
occursin~20%ofpatients,andtheincidenceofsuicideishigherinpatientswithepilepsythaninthegeneralpopulation.Depressionshouldbetreatedthroughcounseling
ormedication.Theselectiveserotoninreuptakeinhibitors(SSRIs)typicallyhaveminimaleffectonseizures,whereastricyclicantidepressantsmaylowertheseizure
threshold.Anxietycanbeaseizuresymptom,andanxiousorpsychoticbehaviorcanoccurduringapostictaldelirium.Postictalpsychosisisararephenomenonthat
typicallyoccursafteraperiodofincreasedseizurefrequency.Thereisusuallyabrieflucidintervallastinguptoaweek,followedbydaystoweeksofagitated,psychotic
behavior.Thepsychosisusuallyresolvesspontaneouslybutfrequentlywillrequireshorttermtreatmentwithantipsychoticoranxiolyticmedications.

Thereisongoingcontroversyastowhethersomepatientswithepilepsy(especiallytemporallobeepilepsy)haveastereotypicalinterictalpersonality.Thepredominant
viewisthatatypicalpersonalitytraitsoccurindiverseepilepsies(e.g.,generalizedandfrontallobeepilepsy)andmayresultfromanunderlyingstructuralbrainlesion,
antiepilepticdrugeffects,andpsychosocialfactorsrelatedtosufferingfromachronicdisease,aswellastheepilepsyitself.

MORTALITYOFEPILEPSY

Patientswithepilepsyhaveariskofdeaththatisroughlytwotothreetimesgreaterthanexpectedinamatchedpopulationwithoutepilepsy.Mostoftheincreased
mortalityisduetotheunderlyingetiologyofepilepsy(e.g.,tumorsorstrokesinolderadults).However,asignificantnumberofpatientsdiefromaccidents,status
epilepticus,andasyndromeknownassuddenunexpecteddeathinepilepsy(SUDEP),whichusuallyaffectsyoungpeoplewithconvulsiveseizuresandtendstooccurat
night.ThecauseofSUDEPisunknownitmayresultfrombrainstemmediatedeffectsofseizuresonpulmonary,cardiac,andarousalfunctions.Recentstudiessuggest
that,insomecases,ageneticmutationmaybethecauseofbothepilepsyandacardiacconductiondefectthatgivesrisetosuddendeath.

PSYCHOSOCIALISSUES

Therecontinuestobeaculturalstigmaaboutepilepsy,althoughitisslowlydeclininginsocietieswitheffectivehealtheducationprograms.Manypatientswithepilepsy
harborfearssuchasthefearofbecomingmentallyretardedordyingduringaseizure.Theseissuesneedtobecarefullyaddressedbyeducatingthepatientabout
epilepsyandbyensuringthatfamilymembers,teachers,fellowemployees,andotherassociatesareequallywellinformed.http://www.epilepsyfoundation.orgAuseful
sourceofeducationalmaterialistheWebsitewww.epilepsy.com.

EMPLOYMENT,DRIVING,ANDOTHERACTIVITIES

Manypatientswithepilepsyfacedifficultyinobtainingormaintainingemployment,evenwhentheirseizuresarewellcontrolled.Federalandstatelegislationisdesigned
topreventemployersfromdiscriminatingagainstpatientswithepilepsy,andpatientsshouldbeencouragedtounderstandandclaimtheirlegalrights.Patientsinthese
circumstancesalsobenefitgreatlyfromtheassistanceofhealthproviderswhoactasstrongpatientadvocates.

Lossofdrivingprivilegesisoneofthemostdisruptivesocialconsequencesofepilepsy.Physiciansshouldbeveryclearaboutlocalregulationsconcerningdrivingand
epilepsy,becausethelawsvaryconsiderablyamongstatesandcountries.Inallcases,itisthephysiciansresponsibilitytowarnpatientsofthedangerimposedon
themselvesandotherswhiledrivingiftheirseizuresareuncontrolled(unlesstheseizuresarenotassociatedwithimpairmentofconsciousnessormotorcontrol).In
general,moststatesallowpatientstodriveafteraseizurefreeinterval(onoroffmedications)ofbetween3monthsand2years.

Patientswithincompletelycontrolledseizuresmustalsocontendwiththeriskofbeinginothersituationswhereanimpairmentofconsciousnessorlossofmotorcontrol
couldleadtomajorinjuryordeath.Thus,dependingonthetypeandfrequencyofseizures,manypatientsneedtobeinstructedtoavoidworkingatheightsorwith
machineryortohavesomeoneclosebyforactivitiessuchasbathingandswimming.

SPECIALISSUESRELATEDTOWOMENANDEPILEPSY
CATAMENIALEPILEPSY

Somewomenexperienceamarkedincreaseinseizurefrequencyaroundthetimeofmenses.Thisisbelievedtobemediatedbyeithertheeffectsofestrogenand
progesteroneonneuronalexcitabilityorchangesinantiepilepticdruglevelsduetoalteredproteinbindingormetabolism.Somepatientsmaybenefitfromincreasesin
antiepilepticdrugdosagesduringmenses.Naturalprogestinsorintramuscularmedroxyprogesteronemaybeofbenefittoasubsetofwomen.

PREGNANCY

Mostwomenwithepilepsywhobecomepregnantwillhaveanuncomplicatedgestationanddeliveranormalbaby.However,epilepsyposessomeimportantriskstoa
pregnancy.Seizurefrequencyduringpregnancywillremainunchangedin~50%ofwomen,increasein30%,anddecreasein20%.Changesinseizurefrequencyare
attributedtoendocrineeffectsontheCNS,variationsinantiepilepticdrugpharmacokinetics(suchasaccelerationofhepaticdrugmetabolismoreffectsonplasmaprotein
binding),andchangesinmedicationcompliance.Itisusefultoseepatientsatfrequentintervalsduringpregnancyandmonitorserumantiepilepticdruglevels.
Measurementoftheunbounddrugconcentrationsmaybeusefulifthereisanincreaseinseizurefrequencyorworseningofsideeffectsofantiepilepticdrugs.

Theoverallincidenceoffetalabnormalitiesinchildrenborntomotherswithepilepsyis56%,comparedto23%inhealthywomen.Partofthehigherincidenceisdueto
teratogeniceffectsofantiepilepticdrugs,andtheriskincreaseswiththenumberofmedicationsused(e.g.,1020%riskofmalformationswiththreedrugs)andpossibly
withhigherdoses.Ametaanalysisofpublishedpregnancyregistriesandcohortsfoundthatthemostcommonmalformationsweredefectsinthecardiovascularand
musculoskeletalsystem(1.41.8%).Valproicacidisstronglyassociatedwithanincreasedriskofadversefetaloutcomes(720%).Recentfindingsfromalarge
pregnancyregistrysuggestthat,otherthantopiramate,thenewerantiepilepticdrugsarefarsaferthanvalproicacid.

Becausethepotentialharmofuncontrolledconvulsiveseizuresonthemotherandfetusisconsideredgreaterthantheteratogeniceffectsofantiepilepticdrugs,itis
currentlyrecommendedthatpregnantwomenbemaintainedoneffectivedrugtherapy.Whenpossible,itseemsprudenttohavethepatientonmonotherapyatthelowest
effectivedose,especiallyduringthefirsttrimester.Forsomewomen,however,thetypeandfrequencyoftheirseizuresmayallowforthemtosafelyweanoffantiepileptic
drugspriortoconception.Patientsshouldalsotakefolate(14mg/d),becausetheantifolateeffectsofanticonvulsantsarethoughttoplayaroleinthedevelopmentof
neuraltubedefects,althoughthebenefitsofthistreatmentremainunprovedinthissetting.

Enzymeinducingdrugssuchasphenytoin,carbamazepine,oxcarbazepine,topiramate,phenobarbital,andprimidonecauseatransientandreversibledeficiencyof
vitaminKdependentclottingfactorsin~50%ofnewborninfants.Althoughneonatalhemorrhageisuncommon,themothershouldbetreatedwithoralvitaminK(20mg/d,
phylloquinone)inthelast2weeksofpregnancy,andtheinfantshouldreceiveintramuscularvitaminK(1mg)atbirth.

CONTRACEPTION

Specialcareshouldbetakenwhenprescribingantiepilepticmedicationsforwomenwhoaretakingoralcontraceptiveagents.Drugssuchascarbamazepine,phenytoin,
phenobarbital,andtopiramatecansignificantlydecreasetheefficacyoforalcontraceptivesviaenzymeinductionandothermechanisms.Patientsshouldbeadvisedto
consideralternativeformsofcontraception,ortheircontraceptivemedicationsshouldbemodifiedtooffsettheeffectsoftheantiepilepticmedications.

BREASTFEEDING

Antiepilepticmedicationsareexcretedintobreastmilktoavariabledegree.Theratioofdrugconcentrationinbreastmilkrelativetoserumrangesfrom~5%(valproic
acid)to300%(levetiracetam).Giventheoverallbenefitsofbreastfeedingandthelackofevidenceforlongtermharmtotheinfantbybeingexposedtoantiepileptic
drugs,motherswithepilepsycanbeencouragedtobreastfeed.Thisshouldbereconsidered,however,ifthereisanyevidenceofdrugeffectsontheinfantsuchas

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 18/19
17/06/2015
lethargyorpoorfeeding.

CopyrightMcGrawHillGlobalEducationHoldings,LLC.
Allrightsreserved.
YourIPaddressis58.27.19.239

http://accessmedicine.mhmedical.com.libezp.utar.edu.my/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2&q=seizures+and+epilepsy+ 19/19