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11/17/2016

EpilepsyandSeizures:PracticeEssentials,Background,Pathophysiology

Thissiteisintendedforhealthcareprofessionals

EpilepsyandSeizures
Updated:Jul12,2016
Author:DavidYKo,MDChiefEditor:SelimRBenbadis,MDmore...

OVERVIEW

PracticeEssentials
Epilepsyisdefinedasabraindisordercharacterizedbyanenduringpredispositiontogenerate
epilepticseizuresandbytheneurobiologic,cognitive,psychological,andsocialconsequencesofthis
condition.[1]

Signsandsymptoms
Theclinicalsignsandsymptomsofseizuresdependonthelocationoftheepilepticdischargesinthe
cerebralcortexandtheextentandpatternofthepropagationoftheepilepticdischargeinthebrain.A
keyfeatureofepilepticseizuresistheirstereotypicnature.
Questionsthathelpclarifythetypeofseizureincludethefollowing:
Wasanywarningnotedbeforethespell?Ifso,whatkindofwarningoccurred?
Whatdidthepatientdoduringthespell?
Wasthepatientabletorelatetotheenvironmentduringthespelland/ordoesthepatienthave
recollectionofthespell?
Howdidthepatientfeelafterthespell?Howlongdidittakeforthepatienttogetbackto
baselinecondition?
Howlongdidthespelllast?
Howfrequentdothespellsoccur?
Areanyprecipitantsassociatedwiththespells?
Hasthepatientshownanyresponsetotherapyforthespells?
SeeClinicalPresentationformoredetail.

Diagnosis
Thediagnosisofepilepticseizuresismadebyanalyzingthepatient'sdetailedclinicalhistoryandby
performingancillarytestsforconfirmation.Physicalexaminationhelpsinthediagnosisofspecific
epilepticsyndromesthatcauseabnormalfindings,suchasdermatologicabnormalities(eg,patients
withintractablegeneralizedtonicclonicseizuresforyearsarelikelytohaveinjuriesrequiring
stitches).
Testing
Potentiallyusefullaboratorytestsforpatientswithsuspectedepilepticseizuresincludethefollowing:

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Prolactinlevelsobtainedshortlyafteraseizuretoassesstheetiology(epilepticvsnonepileptic)
ofaspelllevelsaretypicallyelevated3or4foldandmorelikelytooccurwithgeneralized
tonicclonicseizuresthanwithotherseizuretypeshowever,theconsiderablevariabilityof
prolactinlevelshasprecludedtheirroutineclinicaluse
Serumlevelsofanticonvulsantagentstodeterminebaselinelevels,potentialtoxicity,lackof
efficacy,treatmentnoncompliance,and/orautoinductionorpharmacokineticchange
CSFexaminationinpatientswithobtundationorinpatientsinwhommeningitisorencephalitisis
suspected
Imagingstudies
Thefollowing2imagingstudiesmustbeperformedafteraseizure:
Neuroimagingevaluation(eg,MRI,CTscanning)
EEG
TheclinicaldiagnosiscanbeconfirmedbyabnormalitiesontheinterictalEEG,butthese
abnormalitiescouldbepresentinotherwisehealthyindividuals,andtheirabsencedoesnotexclude
thediagnosisofepilepsy.
VideoEEGmonitoringisthestandardtestforclassifyingthetypeofseizureorsyndromeorto
diagnosepseudoseizures(ie,toestablishadefinitivediagnosisofspellswithimpairmentof
consciousness).Thistechniqueisalsousedtocharacterizethetypeofseizureandepileptic
syndrometooptimizepharmacologictreatmentandforpresurgicalworkup.
SeeWorkupformoredetail.

Management
Pharmacotherapy
Thegoaloftreatmentistoachieveaseizurefreestatuswithoutadverseeffects.Monotherapyis
important,becauseitdecreasesthelikelihoodofadverseeffectsandavoidsdruginteractions.
Standardofcareforasingle,unprovokedseizureisavoidanceoftypicalprecipitants(eg,alcohol,
sleepdeprivation).Noanticonvulsantsarerecommendedunlessthepatienthasriskfactorsfor
recurrence.
Specialsituationsthatrequiretreatmentincludethefollowing:
Recurrentunprovokedseizures:Themainstayoftherapyisananticonvulsantifapatienthas
hadmorethan1seizure,administrationofananticonvulsantisrecommended
HavinganabnormalsleepdeprivedEEGthatincludesepileptiformabnormalitiesandfocal
slowing,diffusebackgroundslowing,andintermittentdiffuseintermixedslowing
Selectionofananticonvulsantmedicationdependsonanaccuratediagnosisoftheepileptic
syndrome.Althoughsomeanticonvulsants(eg,lamotrigine,topiramate,valproicacid,zonisamide)
havemultiplemechanismsofaction,andsome(eg,phenytoin,carbamazepine,ethosuximide)have
onlyoneknownmechanismofaction,anticonvulsantagentscanbedividedintolargegroupsbased
ontheirmechanisms,asfollows:
Blockersofrepetitiveactivationofthesodiumchannel:Phenytoin,carbamazepine,
oxcarbazepine,lamotrigine,topiramate
Enhancerofslowinactivationofthesodiumchannel:Lacosamide,rufinamide
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Gammaaminobutyricacid(GABA)Areceptorenhancers:Phenobarbital,benzodiazepines,
clobazam
NMDAreceptorblockers:Felbamate
AMPAreceptorblockers:Perampanel,topiramate
Tcalciumchannelblockers:Ethosuximide,valproate
NandLcalciumchannelblockers:Lamotrigine,topiramate,zonisamide,valproate
Hcurrentmodulators:Gabapentin,lamotrigine
Blockersofuniquebindingsites:Gabapentin,levetiracetam
Carbonicanhydraseinhibitors:Topiramate,zonisamide
Neuronalpotassiumchannel(KCNQ[Kv7])opener:Ezogabine
Nonpharmacologictherapy
Thefollowingare2nonpharmacologicmethodsinmanagingpatientswithseizures:
Aketogenicdiet
Vagalnervestimulation
Surgicaloptions
The2majorkindsofbrainsurgeryforepilepsyarepalliativeandpotentiallycurative.Theuseofa
vagalnervestimulator(VNS)forpalliativetherapyinpatientswithintractableatonicseizureshas
reducedtheneedforanteriorcallosotomy.Lobectomyandlesionectomyareamongseveralpossible
curativesurgeries.
SeeTreatmentandMedicationformoredetail.

Background
Epilepticseizuresareonlyonemanifestationofneurologicormetabolicdiseases.Epilepticseizures
havemanycauses,includingageneticpredispositionforcertaintypesofseizures,headtrauma,
stroke,braintumors,alcoholordrugwithdrawal,repeatedepisodesofmetabolicinsults,suchas
hypoglycemia,andotherconditions.Epilepsyisamedicaldisordermarkedbyrecurrent,unprovoked
seizures.Therefore,repeatedseizureswithanidentifiedprovocation(eg,alcoholwithdrawal)donot
constituteepilepsy.
AsproposedbytheInternationalLeagueAgainstEpilepsy(ILAE)andtheInternationalBureaufor
Epilepsy(IBE)in2005,epilepsyisdefinedasabraindisordercharacterizedbyanenduring
predispositiontogenerateepilepticseizuresandbytheneurobiologic,cognitive,psychological,and
socialconsequencesofthiscondition.[1]
Traditionally,thediagnosisofepilepsyrequirestheoccurrenceofatleast2unprovokedseizures.
Somecliniciansalsodiagnoseepilepsywhen1unprovokedseizureoccursinthesettingofa
predisposingcause,suchasafocalcorticalinjury,orageneralizedinterictaldischargeoccursthat
suggestsapersistentgeneticpredisposition.(SeeClinicalPresentation.)
Seizuresarethemanifestationofabnormalhypersynchronousorhyperexcitabledischargesofcortical
neurons.Theclinicalsignsorsymptomsofseizuresdependonthelocationoftheepilepticdischarges
inthecerebralcortexandtheextentandpatternofthepropagationoftheepilepticdischargeinthe
brain.Thus,seizuresymptomsarehighlyvariable,butformostpatientswith1focus,thesymptoms
areusuallyverystereotypic.
Itshouldnotbesurprisingthatseizuresareacommon,nonspecificmanifestationofneurologicinjury
anddisease,becausethemainfunctionofthebrainisthetransmissionofelectricalimpulses.The
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lifetimelikelihoodofexperiencingatleast1epilepticseizureisabout9%,andthelifetimelikelihoodof
receivingadiagnosisofepilepsyisalmost3%.However,theprevalenceofactiveepilepsyisonly
about0.8%.(SeeEpidemiology.)
Thisarticlereviewstheclassifications,pathophysiology,clinicalmanifestations,andtreatmentof
epilepticseizuresandsomecommonepilepticsyndromes.(SeePathophysiology,Presentation,DDx,
andTreatment.)
Formoreinformationregardingseizuretypesandotherconditions,seethefollowingtopics:
AbsenceSeizures
ComplexPartialSeizures
GeneralizedTonicClonicSeizures
PsychogenicNonepilepticSeizures
PediatricFirstSeizure
EpilepsiaPartialisContinua
StatusEpilepticus
Preeclampsia
Eclampsia
Seethefollowingarticlesformoreinformationregardingepilepticsyndromesandepilepsytreatment:
BenignChildhoodEpilepsy
BenignNeonatalConvulsions
EEGinCommonEpilepsySyndromes
PediatricFebrileSeizures
NeonatalSeizures
FrontalLobeEpilepsy
TemporalLobeEpilepsy
JuvenileMyoclonicEpilepsy
LennoxGastautSyndrome
PosttraumaticEpilepsy
ReflexEpilepsy
VagusNerveStimulation
Women'sHealthandEpilepsy
PartialEpilepsies
PediatricStatusEpilepticus
MyoclonicEpilepsyBeginninginInfancyorEarlyChildhood

Historicalinformation
Epilepticseizureshavebeenrecognizedformillennia.Oneoftheearliestdescriptionsofasecondary
generalizedtonicclonicseizurewasrecordedover3000yearsagoinMesopotamia.Theseizurewas
attributedtothegodofthemoon.Epilepticseizuresweredescribedinotherancientcultures,
includingthoseofChina,Egypt,andIndia.AnancientEgyptianpapyrusdescribedaseizureinaman
whohadpreviousheadtrauma.
Hippocrateswrotethefirstbookaboutepilepsyalmost2500yearsago.Herejectedideasregarding
thedivineetiologyofepilepsyandconcludedthatthecausewasexcessivephlegmleadingto
abnormalbrainconsistency.Hippocraticteachingswereforgotten,anddivineetiologiesagain
dominatedbeliefsaboutepilepticseizuresduringmedievaltimes.
Evenattheturnofthe19thcentury,excessivemasturbationwasconsideredacauseofepilepsy.This
hypothesisiscreditedasleadingtotheuseofthefirsteffectiveanticonvulsant(ie,bromides).
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ModerninvestigationoftheetiologyofepilepsybeganwiththeworkofFritsch,Hitzig,Ferrier,and
Catoninthe1870s.Theseresearchersrecordedandevokedepilepticseizuresinthecerebralcortex
ofanimals.In1929,Bergerdiscoveredthatelectricalbrainsignalscouldberecordedfromthehuman
headbyusingscalpelectrodesthisdiscoveryledtotheuseofelectroencephalography(EEG)to
studyandclassifyepilepticseizures.
Gibbs,Lennox,Penfield,andJasperfurtheradvancedtheunderstandingofepilepsyanddeveloped
thesystemofthe2majorclassesofepilepticseizurescurrentlyused:localizationrelatedsyndromes
andgeneralizedonsetsyndromes.Anexcellenthistoricalreviewofseizuresandepilepsy,writtenby
E.Goldensohn,waspublishedinthejournalEpilepsiatocommemoratethe50thanniversaryofthe
creationoftheAmericanEpilepsySocietyin1997.Adecadelater,anotherreviewinEpilepsia
discussedthefoundationofthisprofessionalsociety.[4]

Pathophysiology
Seizuresareparoxysmalmanifestationsoftheelectricalpropertiesofthecerebralcortex.Aseizure
resultswhenasuddenimbalanceoccursbetweentheexcitatoryandinhibitoryforceswithinthe
networkofcorticalneuronsinfavorofasuddenonsetnetexcitation.
Thebrainisinvolvedinnearlyeverybodilyfunction,includingthehighercorticalfunctions.Ifthe
affectedcorticalnetworkisinthevisualcortex,theclinicalmanifestationsarevisualphenomena.
Otheraffectedareasofprimarycortexgiverisetosensory,gustatory,ormotormanifestations.The
psychicphenomenonofdjvuoccurswhenthetemporallobeisinvolved.
Thepathophysiologyoffocalonsetseizuresdiffersfromthemechanismsunderlyinggeneralized
onsetseizures.Overall,cellularexcitabilityisincreased,butthemechanismsofsynchronization
appeartosubstantiallydifferbetweenthese2typesofseizureandarethereforediscussedseparately.
Forareview,seetheepilepsybookofRho,Sankar,andCavazos.[5]Foramorerecentreview,see
KramerandCash.[6]

Pathophysiologyoffocalseizures
Theelectroencephalographic(EEG)hallmarkoffocalonsetseizuresisthefocalinterictalepileptiform
spikeorsharpwave.Thecellularneurophysiologiccorrelateofaninterictalfocalepileptiform
dischargeinsinglecorticalneuronsistheparoxysmaldepolarizationshift(PDS).
ThePDSischaracterizedbyaprolongedcalciumdependentdepolarizationthatresultsinmultiple
sodiummediatedactionpotentialsduringthedepolarizationphase,anditisfollowedbyaprominent
afterhyperpolarization,whichisahyperpolarizedmembranepotentialbeyondthebaselineresting
potential.Calciumdependentpotassiumchannelsmostlymediatetheafterhyperpolarizationphase.
WhenmultipleneuronsfirePDSsinasynchronousmanner,theextracellularfieldrecordingshowsan
interictalspike.
Ifthenumberofdischargingneuronsismorethanseveralmillion,theycanusuallyberecordedwith
scalpEEGelectrodes.Calculationsshowthattheinterictalspikesneedtospreadtoabout6cm2of
cerebralcortexbeforetheycanbedetectedwithscalpelectrodes.
Severalfactorsmaybeassociatedwiththetransitionfromaninterictalspiketoanepilepticseizure.
Thespikehastorecruitmoreneuraltissuetobecomeaseizure.Whenanyofthemechanismsthat
underlieanacuteseizurebecomesapermanentalteration,thepersonpresumablydevelopsa
propensityforrecurrentseizures(ie,epilepsy).

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Thefollowingmechanisms(discussedbelow)maycoexistindifferentcombinationstocausefocal
onsetseizures:
Decreasedinhibition
Defectiveactivationofgammaaminobutyricacid(GABA)neurons
Increasedactivation
Ifthemechanismsleadingtoanetincreasedexcitabilitybecomepermanentalterations,patientsmay
developpharmacologicallyintractablefocalonsetepilepsy.
Currentlyavailablemedicationswerescreenedusingacutemodelsoffocalonsetorgeneralized
onsetconvulsions.Inclinicaluse,theseagentsaremosteffectiveatblockingthepropagationofa
seizure(ie,spreadfromtheepilepticfocustosecondarygeneralizedtonicclonicseizures).Further
understandingofthemechanismsthatpermanentlyincreasenetworkexcitabilitymayleadto
developmentoftrueantiepilepticdrugsthatalterthenaturalhistoryofepilepsy.

Decreasedinhibition
ThereleaseofGABAfromtheinterneuronterminalinhibitsthepostsynapticneuronbymeansof2
mechanisms:(1)directinductionofaninhibitorypostsynapticpotential(IPSP),whichaGABAA
chloridecurrenttypicallymediates,and(2)indirectinhibitionofthereleaseofexcitatory
neurotransmitterinthepresynapticafferentprojection,typicallywithaGABABpotassiumcurrent.
Alterationsormutationsinthedifferentchlorideorpotassiumchannelsubunitsorinthemolecules
thatregulatetheirfunctionmayaffecttheseizurethresholdorthepropensityforrecurrentseizures.
Mechanismsleadingtodecreasedinhibitionincludethefollowing:
DefectiveGABAAinhibition
DefectiveGABABinhibition
DefectiveactivationofGABAneurons
Defectiveintracellularbufferingofcalcium
NormalGABAAinhibitoryfunction
GABAisthemaininhibitoryneurotransmitterinthebrain,anditbindsprimarilyto2majorclassesof
receptors:GABAAandGABAB.GABAAreceptorsarecoupledtochloride(negativeanion)
channels,andtheyareoneofthemaintargetsmodulatedbytheanticonvulsantagentsthatare
currentlyinclinicaluse.
Thereversalpotentialofchlorideisaboutnegative70mV.Thecontributionofchloridechannels
duringrestingpotentialinneuronsisminimal,becausethetypicalrestingpotentialisnear70mV,and
thusthereisnosignificantelectromotiveforcefornetchlorideflux.However,chloridecurrents
becomemoreimportantatmoredepolarizedmembranepotentials.
Thesechannelsmakeitdifficulttoachievethethresholdmembranepotentialnecessaryforanaction
potential.Theinfluenceofchloridecurrentsontheneuronalmembranepotentialincreasesasthe
neuronbecomesmoredepolarizedbythesummationoftheexcitatorypostsynapticpotentials
(EPSPs).Inthismanner,thechloridecurrentsbecomeanotherforcethatmustbeovercometofirean
actionpotential,decreasingexcitability.
PropertiesofthechloridechannelsassociatedwiththeGABAAreceptorareoftenclinically
modulatedbyusingbenzodiazepines(eg,diazepam,lorazepam,clonazepam),barbiturates(eg,
phenobarbital,pentobarbital),ortopiramate.Benzodiazepinesincreasethefrequencyofopeningsof
chloridechannels,whereasbarbituratesincreasethedurationofopeningsofthesechannels.
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Topiramatealsoincreasesthefrequencyofchannelopenings,butitbindstoasitedifferentfromthe
benzodiazepinereceptorsite.
Alterationsinthenormalstateofthechloridechannelsmayincreasethemembranepermeabilityand
conductanceofchlorideions.Intheend,thebehaviorofallindividualchloridechannelssumupto
formalargechloridemediatedhyperpolarizingcurrentthatcounterbalancesthedepolarizingcurrents
createdbythesummationofEPSPsinducedbyactivationoftheexcitatoryinput.
TheEPSPsarethemainformofcommunicationbetweenneurons,andthereleaseoftheexcitatory
aminoacidglutamatefromthepresynapticelementmediatesEPSPs.Threemainreceptorsmediate
theeffectofglutamateinthepostsynapticneuron:NmethylDasparticacid(NMDA),alphaamino3
hydroxy5methyl4isoxazolepropionicacid(AMPA)/kainate,andmetabotropic.Thesearecoupledby
meansofdifferentmechanismstoseveraldepolarizingchannels.
IPSPstempertheeffectsofEPSPs.IPSPsaremediatedmainlybythereleaseofGABAinthe
synapticcleftwithpostsynapticactivationofGABAAreceptors.
Allchannelsinthenervoussystemaresubjecttomodulationbyseveralmechanisms,suchas
phosphorylationand,possibly,achangeinthetridimensionalconformationofaproteininthechannel.
Thechloridechannelhasseveralphosphorylationsites,oneofwhichtopiramateappearsto
modulate.Phosphorylationofthischannelinducesachangeinnormalelectrophysiologicbehavior,
withanincreasedfrequencyofchannelopeningsbutforonlycertainchloridechannels.
Eachchannelhasamultimericstructurewithseveralsubunitsofdifferenttypes.Chloridechannels
arenoexceptiontheyhaveapentamericstructure.Thesubunitsaremadeupofmolecularlyrelated
butdifferentproteins.
TheheterogeneityofelectrophysiologicresponsesofdifferentGABAAreceptorsresultsfromdifferent
combinationsofthesubunits.Inmammals,atleast6alphasubunitsand3betaandgammasubunits
existfortheGABAAreceptorcomplex.AcompleteGABAAreceptorcomplex(which,inthiscase,is
thechloridechannelitself)isformedfrom1gamma,2alpha,and2betasubunits.Thenumberof
possiblecombinationsoftheknownsubunitsisalmost1000,butinpractice,onlyabout20ofthese
combinationshavebeenfoundinthenormalmammalianbrain.
DefectiveGABAAinhibition
SomeepilepsiesmayinvolvemutationsorlackofexpressionofthedifferentGABAAreceptor
complexsubunits,themoleculesthatgoverntheirassembly,orthemoleculesthatmodulatetheir
electricalproperties.Forexample,hippocampalpyramidalneuronsmaynotbeabletoassemble
alpha5beta3gamma3receptorsbecauseofdeletionofchromosome15(ie,Angelmansyndrome).
ChangesinthedistributionofsubunitsoftheGABAAreceptorcomplexhavebeendemonstratedin
severalanimalmodelsoffocalonsetepilepsy,suchastheelectricalkindling,chemicalkindling,and
pilocarpinemodels.Inthepilocarpinemodel,decreasedconcentrationsofmRNAforthealpha5
subunitofthesurvivinginterneuronswereobservedintheCA1regionoftherathippocampus.[7]
DefectiveGABABinhibition
TheGABABreceptoriscoupledtopotassiumchannels,formingacurrentthathasarelativelylong
durationofactioncomparedwiththechloridecurrentevokedbyactivationoftheGABAAreceptor.
Becauseofthelongdurationofaction,alterationsintheGABABreceptorarethoughttopossiblyplay
amajorroleinthetransitionbetweentheinterictalabnormalityandanictalevent(ie,focalonset
seizure).ThemolecularstructureoftheGABABreceptorcomplexconsistsof2subunitswith7
transmembranedomainseach.
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Gproteins,asecondmessengersystem,mediatecouplingtothepotassiumchannel,explainingthe
latencyandlongdurationoftheresponse.Inmanycases,GABABreceptorsarelocatedinthe
presynapticelementofanexcitatoryprojection.

DefectiveactivationofGABAneurons
GABAneuronsareactivatedbymeansoffeedforwardandfeedbackprojectionsfromexcitatory
neurons.These2typesofinhibitioninaneuronalnetworkaredefinedonthebasisofthetimeof
activationoftheGABAergicneuronrelativetothatoftheprincipalneuronaloutputofthenetwork,as
seenwiththehippocampalpyramidalCA1cell.
Infeedforwardinhibition,GABAergiccellsreceiveacollateralprojectionfromthemainafferent
projectionthatactivatestheCA1neurons,namely,theSchaffercollateralaxonsfromtheCA3
pyramidalneurons.ThisfeedforwardprojectionactivatesthesomaofGABAergicneuronsbeforeor
simultaneouslywithactivationoftheapicaldendritesoftheCA1pyramidalneurons.
ActivationoftheGABAergicneuronsresultsinanIPSPthatinhibitsthesomaoraxonhillockofthe
CA1pyramidalneuronsalmostsimultaneouslywiththepassivepropagationoftheexcitatorypotential
(ie,EPSP)fromtheapicaldendritestotheaxonhillock.Thefeedforwardprojectionthusprimesthe
inhibitorysysteminamannerthatallowsittoinhibit,inatimelyfashion,thepyramidalcell's
depolarizationandfiringofanactionpotential.
FeedbackinhibitionisanothersystemthatallowsGABAergiccellstocontrolrepetitivefiringin
principalneurons,suchaspyramidalcells,andtoinhibitthesurroundingpyramidalcells.Recurrent
collateralsfromthepyramidalneuronsactivatetheGABAergicneuronsafterthepyramidalneurons
fireanactionpotential.
Experimentalevidencehasindicatedthatsomeotherkindofinterneuronmaybeagatebetweenthe
principalneuronsandtheGABAergicneurons.Inthedentategyrus,themossycellsofthehilar
polymorphicregionappeartogateinhibitorytoneandactivateGABAergicneurons.Themossycells
receivebothfeedbackandfeedforwardactivation,whichtheyconveytotheGABAergicneurons.
Incertaincircumstances,themossycellsappearhighlyvulnerabletoseizurerelatedneuronalloss.
Aftersomeofthemossycellsarelost,activationofGABAergicneuronsisimpaired.[8]
Synapticreorganizationisaformofbrainplasticityinducedbyneuronalloss,perhapstriggeredbythe
lossofthesynapticconnectionsofthedyingneuron,aprocesscalleddeafferentation.Formationof
newsproutedcircuitsincludesexcitatoryandinhibitorycells,andbothformsofsproutinghavebeen
demonstratedinmanyanimalmodelsoffocalonsetepilepsyandinhumanswithintractabletemporal
lobeepilepsy.
Mostoftheinitialattemptsofhippocampalsproutingarelikelytobeattemptstorestoreinhibition.As
theepilepsyprogresses,however,theoverwhelmingnumberofsproutedsynapticcontactsoccurs
withexcitatorytargets,creatingrecurrentexcitatorycircuitriesthatpermanentlyalterthebalance
betweenexcitatoryandinhibitorytoneinthehippocampalnetwork.
Defectiveintracellularbufferingofcalcium
Inrodents,recurrentseizuresinducedbyavarietyofmethodsresultinapatternofinterneuronlossin
thehilarpolymorphicregion,withstrikinglossoftheneuronsthatlackthecalciumbindingproteins
parvalbuminandcalbindin.Inrathippocampalsections,theseinterneuronsdemonstratea
progressiveinabilitytomaintainahyperpolarizedrestingmembranepotentialeventually,the
interneuronsdie.
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Inanexperiment,researchersusedmicroelectrodescontainingthecalciumchelatorBAPTAand
demonstratedreversalofthedeteriorationinthemembranepotentialasthecalciumchelatorwas
allowedtodiffuseintheinterneuron.[9]Thesefindingsshowedthecriticalroleofadequate
concentrationsofcalciumbindingproteinsforneuronalsurvivalinsettingswithsustainedrisesof
intracellularcalcium,suchasinstatusepilepticusandotherbraininsults.Thismechanismmay
contributetomedicalintractabilityinsomeepilepsypatients.
Thevulnerabilityofinterneuronstohypoxiaandotherinsultsalsocorrelatestotherelativepresence
ofthesecalciumbindingproteins.Theprematurelossofinterneuronsaltersinhibitorycontroloverthe
localneuronalnetworkinfavorofnetexcitation.Thiseffectmayexplain,forexample,why2patients
whohaveasimilarevent(ie,simplefebrileconvulsion)mayhaveremarkablydissimilaroutcomes
thatis,onemayhavecompletelynormaldevelopment,andtheothermayhaveintractablefocalonset
epilepsyafterafewyears.

Increasedactivation
Mechanismsleadingtoincreasedexcitationincludethefollowing:
IncreasedactivationofNMDAreceptors
Increasedsynchronybetweenneuronsduetoephapticinteractions
Increasedsynchronyand/oractivationduetorecurrentexcitatorycollaterals
IncreasedactivationofNMDAreceptors
Glutamateisthemajorexcitatoryneurotransmitterinthebrain.Thereleaseofglutamatecausesan
EPSPinthepostsynapticneuronbyactivatingtheglutaminergicreceptorsAMPA/kainateandNMDA
andthemetabotropicreceptor.
Fastneurotransmissionisachievedwiththeactivationofthefirst2typesofreceptors.The
metabotropicreceptoralterscellularexcitabilitybymeansofasecondmessengersystemwithlater
onsetbutaprolongedduration.Themajorfunctionaldifferencebetweenthe2fastreceptorsisthat
theAMPA/kainatereceptoropenschannelsthatprimarilyallowthepassageofmonovalentcations(ie,
sodiumandpotassium),whereastheNMDAtypeiscoupledtochannelsthatalsoallowpassageof
divalentcations(ie,calcium).
Calciumisacatalystformanyintracellularreactionsthatleadtochangesinphosphorylationandgene
expression.Thus,itisinitselfasecondmessengersystem.NMDAreceptorsaregenerallyassumed
tobeassociatedwithlearningandmemory.TheactivationofNMDAreceptorsisincreasedinseveral
animalmodelsofepilepsy,suchaskindling,kainicacid,pilocarpine,andotherfocalonsetepilepsy
models.
Somepatientswithepilepsymayhaveaninheritedpredispositionforfastorlonglastingactivationof
NMDAchannelsthatalterstheirseizurethreshold.Otherpossiblealterationsincludetheabilityof
intracellularproteinstobuffercalcium,increasingthevulnerabilityofneuronstoanykindofinjurythat
otherwisewouldnotresultinneuronaldeath.
Increasedsynchronybetweenneuronscausedbyephapticinteractions
Electricalfieldscreatedbysynchronousactivationofpyramidalneuronsinlaminarstructures,suchas
thehippocampus,mayincreasefurthertheexcitabilityofneighboringneuronsbynonsynaptic(ie,
ephaptic)interactions.Changesinextracellularionicconcentrationsofpotassiumandcalciumare
anotherpossiblenonsynapticinteraction,asisincreasedcouplingofneuronsduetopermanent
increasesinthefunctionalavailabilityofgapjunctions.Thislastmaybeamechanismthat
predisposestoseizuresorstatusepilepticus.
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Increasedsynchronyand/oractivationfromrecurrentexcitatorycollaterals
Neuropathologicstudiesofpatientswithintractablefocalonsetepilepsyhaverevealedfrequent
abnormalitiesinthelimbicsystem,particularlyinthehippocampalformation.Acommonlesionis
hippocampalsclerosis,whichconsistsofapatternofgliosisandneuronallossprimarilyaffectingthe
hilarpolymorphicregionandtheCA1pyramidalregion.Thesechangesareassociatedwithrelative
sparingoftheCA2pyramidalregionandanintermediateseverityofthelesionintheCA3pyramidal
regionanddentategranuleneurons.
Prominenthippocampalsclerosisisfoundinabouttwothirdsofpatientswithintractabletemporallobe
epilepsy.Animalmodelsofstatusepilepticushavereproducedthispatternofinjuryhowever,animals
withmorethan100briefconvulsionsinducedbykindlingseizureshadasimilarpattern,suggesting
thatrepeatedtemporallobeseizuresmaycontributetothedevelopmentofhippocampalsclerosis.[10]
Moresubtleandapparentlymorecommonthanoverthippocampalsclerosisismossyfibersprouting.
[11] Themossyfibersaretheaxonsofthedentategranuleneurons,andtheytypicallyprojectintothe
hilarpolymorphicregionandtowardtheCA3pyramidalneurons.Astheneuronsinthehilar
polymorphicregionareprogressivelylost,theirsynapticprojectionstothedentategranuleneurons
degenerate.
Denervationresultingfromlossofthehilarprojectioninducessproutingoftheneighboringmossyfiber
axons.Thenetconsequenceofthisphenomenonistheformationofrecurrentexcitatorycollaterals,
whichincreasethenetexcitatorydriveofdentategranuleneurons.
Recurrentexcitatorycollateralshavebeendemonstratedinhumantemporallobeepilepsyandinall
animalmodelsofintractablefocalonsetepilepsy.Theeffectofmossyfibersproutingonthe
hippocampalcircuitryhasbeenconfirmedincomputerizedmodelsoftheepileptichippocampus.
Otherneuralpathwaysinthehippocampus,suchastheprojectionfromCA1tothesubiculum,have
beenshowntoalsoremodelintheepilepticbrain.
Forfurtherreading,areviewbyMastrangeloandLeuzziaddresseshowgenesleadtoanepileptic
phenotypefortheearlyageencephalopathies.[12]

Pathophysiologyofgeneralizedseizures
Thebestunderstoodexampleofthepathophysiologicmechanismsofgeneralizedseizuresisthe
thalamocorticalinteractionthatmayunderlietypicalabsenceseizures.Thethalamocorticalcircuithas
normaloscillatoryrhythms,withperiodsofrelativelyincreasedexcitationandperiodsofrelatively
increasedinhibition.Itgeneratestheoscillationsobservedinsleepspindles.Thethalamocortical
circuitryincludesthepyramidalneuronsoftheneocortex,thethalamicrelayneurons,andtheneurons
inthenucleusreticularisofthethalamus(NRT).
Alteredthalamocorticalrhythmsmayresultinprimarygeneralizedonsetseizures.Thethalamicrelay
neuronsreceiveascendinginputsfromthespinalcordandprojecttotheneocorticalpyramidal
neurons.Cholinergicpathwaysfromtheforebrainandtheascendingserotonergic,noradrenergic,and
cholinergicbrainstempathwaysprominentlyregulatethiscircuitry.[13]
Thethalamicrelayneuronscanhaveoscillationsintherestingmembranepotential,whichincreases
theprobabilityofsynchronousactivationoftheneocorticalpyramidalneuronduringdepolarization
andwhichsignificantlylowerstheprobabilityofneocorticalactivationduringrelativehyperpolarization.
Thekeytotheseoscillationsisthetransientlowthresholdcalciumchannel,alsoknownasTcalcium
current.

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Inanimalstudies,inhibitoryinputsfromtheNRTcontroltheactivityofthalamicrelayneurons.NRT
neuronsareinhibitoryandcontainGABAastheirmainneurotransmitter.Theyregulatetheactivation
oftheTcalciumchannelsinthalamicrelayneurons,becausethosechannelsmustbedeinactivated
toopentransitorily.
Tcalciumchannelshave3functionalstates:open,closed,andinactivated.Calciumentersthecells
whentheTcalciumchannelsareopen.Immediatelyafterclosing,thechannelcannotopenagainuntil
itreachesastateofinactivation.
ThethalamicrelayneuronshaveGABABreceptorsinthecellbodyandreceivetonicactivationby
GABAreleasedfromtheNRTprojectiontothethalamicrelayneuron.Theresultisahyperpolarization
thatswitchestheTcalciumchannelsawayfromtheinactivestateintotheclosedstate,whichisready
foractivationwhenneeded.Theswitchtoclosedstatepermitsthesynchronousopeningofalarge
populationoftheTcalciumchannelsevery100millisecondsorso,creatingtheoscillationsobserved
intheEEGrecordingsfromthecerebralcortex.
Findingsinseveralanimalmodelsofabsenceseizures,suchaslethargicmice,havedemonstrated
thatGABABreceptorantagonistssuppressabsenceseizures,whereasGABABagonistsworsen
theseseizures.[14]Anticonvulsantsthatpreventabsenceseizures,suchasvalproicacidand
ethosuximide,suppresstheTcalciumcurrent,blockingitschannels.
AclinicalproblemisthatsomeanticonvulsantsthatincreaseGABAlevels(eg,tiagabine,vigabatrin)
areassociatedwithanexacerbationofabsenceseizures.AnincreasedGABAlevelisthoughtto
increasethedegreeofsynchronizationofthethalamocorticalcircuitandtoenlargethepoolofT
calciumchannelsavailableforactivation.

Etiology
Inasubstantialnumberofcases,thecauseofepilepsyremainsunknown.Identifiedcausestendto
varywithpatientage.Inheritedsyndromes,congenitalbrainmalformations,infection,andhead
traumaareleadingcausesinchildren.Headtraumaisthemostcommonknowncauseinyoung
adults.Strokes,tumors,andheadtraumabecomemorefrequentinmiddleage,withstrokebecoming
themostcommoncauseintheelderly,alongwithAlzheimerdiseaseandotherdegenerative
conditions.
Thegeneticcontributiontoseizuredisordersisnotcompletelyunderstood,butatthepresenttime,
hundredsofgeneshavebeenshowntocauseorpredisposeindividualstoseizuredisordersof
varioustypes.Seizuresarefrequentlyseeninpatientsthatarereferredtoageneticsclinic.Insome
cases,theseizuresareisolatedinanotherwisenormalchild.Inmanycases,seizuresarepartofa
syndromethatmayalsoincludeintellectualdisability,specificbrainmalformations,orahostof
multiplecongenitalanomalies.
Forthesakeofbrevityandclarity,geneticdisordersthatcancauseseizureswillbebrokenintothe
followingcategories:
Syndromesinwhichseizuresarecommon
Chromosomaldeletionorduplicationsyndromesthatcauseseizures
Metabolicdiseases
Mitochondrialdiseases
Seizuredisorderscausedbysinglegenemutations

Geneticsyndromeswithseizuredisorder
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Anumberofgeneticsyndromesareknowntocausesseizurestherefore,thislistisnotmeanttobe
authoritative.However,anumberofmorecommonsyndromesshouldbeconsideredinthepatient
whopresentswithseizuresandotherfindings.
Angelmansyndrome
Angelmansyndromeisaninheriteddisorderthatismostfrequently(68%)causedbyadeletioninthe
maternallyinheritedregionofchromosome15q11.2q13.Approximately7%ofcasesarecausedby
paternaldisomyofthesameregion.Anadditional11%ofcasesofAngelmansyndromearedueto
sequencevariantsinthematernallyinheritedUBE3Agene.
PatientswithAngelmansyndromegenerallyhaveanormalprenatalandbirthhistory,withthefirst
evidenceofdevelopmentaldelayoccurringbetween6and12monthsofage.Seizuresoccurinover
80%ofpatientswithAngelmansyndrome,withonsetbeforeage3years.
Patientsgenerallyhavedecelerationofheadgrowth,resultinginmicrocephalybyearlychildhood.
Dysmorphicfaciesaretypicalandincludeaprotrudingtongue,prognathia,andawidemouthwith
widelyspacedteeth.Patientswithadeletionalsohavehypopigmentation.Intellectualimpairments
aretypicallysevereandspeechimpairmentisquitesevere,withmostpatientshavingfeworno
words.Patientsalsohaveataxiaandfrequentlaughterwithahappydemeanor.
Rettsyndrome
RettsyndromeinitsclassicalformiscausedbymutationsintheMECP2gene,althoughothersimilar
formscausedbydifferentgenesaredescribed.Additionally,althoughRettsyndromehasgenerally
beendescribedonlyinfemalepatients(withthesuppositionthatthiswouldbealethaldiseasein
males),rarecaseshavebeendescribedinmales.
PatientswithRettsyndromehaveanormalprenatalandbirthhistoryandnormalpsychomotor
developmentforthefirst6months,followedbydecelerationofheadgrowthinmostpatients,lossof
handskillsoverthefirst23yearsoflife,handstereotypies,socialwithdrawal,communication
dysfunction,lossofacquiredspeech,cognitiveimpairment,andimpairmentofmovement.[15]
Seizuresarereportedingreaterthan90%offemaleswithRettsyndrome.Seizuresmaybeofany
type,butgeneralizedtonicclonicandcomplexpartialseizuresarethemostcommon.[16]
PittHopkinssyndrome
PittHopkinssyndromeisclassicallycausedbymutationsintheTCF4gene,althoughseveralformsof
PittHopkinslikesyndromehavebeendescribed.PatientswithPittHopkinssyndromehavesevere
intellectualdisability,microcephaly,andlittleornospeech.Theyalsohaveanunusualbreathing
patterncharacterizedbyintermittenthyperventilationfollowedbyperiodsofapnea.
PatientswithPittHopkinsalsohavedistinctivefacies,whichmaynotbeapparentinearlychildhood.
Thesefeaturesincludemicrocephalywithacoarsefacialappearance,deeplyseteyes,upslanting
palpebralfissures,abroadandbeakednasalbridgewithadownturnednasaltip,awidemouthand
fleshylips,andwidelyspacedteeth.Thereisalsoatendencytowardprognathism.
Seizuresareseeninthissyndrome,withonestudyreportingafrequencyof20%.[17]Earlierstudies
suggestedthataround50%ofpatientswithPittHopkinshaveseizures.
Tuberoussclerosis
TuberoussclerosiscomplexiscausedbymutationsintheTSC1orTSC2genes.Majorfeaturesof
thisdiseaseincludethefollowing[18]:
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Facialangiofibromata
Ungualorperiungualfibromas
Hypopigmentedmacules
Connectivetissuenevi
Retinalhamartomas
Corticaltubers
Subependymalnodulesorgiantcellastrocytomas
Cardiacrhabdomyomas
Lymphangiomyomatosis
Renalangiomyolipomas
Minorfeaturesincludethefollowing:
Dentalenamelpits
Rectalhamartomas
Bonecysts
Cerebralwhitemattermigrationlines
Gingivalfibromas
Nonrenalhamartomas
Retinalachromicpatches
Confettiskinlesions
Renalcysts
Adefinitediagnosisoftuberoussclerosisrequires2majorfeaturesor1majorand2minorfeatures.A
probablediagnosisoftuberoussclerosisrequires1majorand1minorfeature.
Morethan80%ofpatientswithtuberoussclerosisarereportedtohaveseizures,althoughthismaybe
anoverestimate.However,thisdiagnosisshouldalwaysbestronglyconsideredinthecaseofinfantile
spasms.
PraderWillisyndrome
PraderWillisyndromeismostfrequently(70%)causedbyadeletioninthepaternalinheritedportion
ofchromosome15q11.2q13.Theremainderofcasesarecausedbymaternaluniparentaldisomyof
chromosome15,complexchromosomalrearrangements,ordefectsinspecificimprintingcenters.
PatientswithPraderWillisyndromehaveneonatalhypotoniaandfailuretothriveduringinfancy.
Patientshavehyperphagia,andonsetofweightgainoccursbetweenage1and6years.Affected
individualsalsohavemildmoderateintellectualimpairment,hypogonadism,andcharacteristicfacies
consistingofanarrowbifrontaldiameter,almondshapedeyes,aroundface,anddownturnedcorners
ofthemouth.Handsandfeetwilltendtobesmallforsize.Seizuresoccurinapproximately1020%of
patients.
SturgeWebersyndrome
SturgeWebersyndromehasanunknowncauseandappearstooccurinasporadicfashion.This
disorderischaracterizedbyintracranialvascularanomaliescalledarteriovenousmalformationsand
portwinestainsontheface.PatientswithSturgeWebersyndromealsohaveseizuresandglaucoma.
Theseizurescanbeverydifficulttocontrolinsomeofthesepatients.

Chromosomaldeletionorduplicationsyndromeswithseizures
Chromosomal22qdeletionsyndromeisaspectrumoffindingscausedbyadeletiononchromosome
22q11.2.Thisdisorderhaspreviouslybeenknownbyavarietyofnames,includingDiGeorge
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syndrome,velocardiofacialsyndrome,Shprintzensyndrome,OpitzG/BBBsyndrome,andCayler
asymmetricalcryingfacies,amongothers.Themostcommonfeaturesofthissyndromeare
congenitalheartdisease,palateanomalies,hypocalcemia,immunedeficiencies,andlearning
difficulties.Seizuresoccurin7%ofpatientswithchromosomal22qdeletionsyndrome.[19]
WolfHirschhornsyndromeiscausedbydeletionsofchromosome4p16.3.Typicalfaciesinthese
patientsincludeabroadnasalbridgecontinuingtotheforehead(theGreekwarriorhelmet
appearance),microcephaly,highforehead,hypertelorism,andhighlyarchedeyebrows.Themouth
tendstobeturneddownward.Growthretardationisseen,asisavariabledegreeofintellectual
disability.Althoughseizuresarepresentinbetween50100%ofpatientswithWolfHirschhorn
syndrome,theytendtoimprovewithage.[20]
Chromosomal1p36deletionsyndromeischaracterizedbydysmorphicfacies,includingstraight
eyebrows,deeplyseteyes,alongphiltrum,andmicrocephaly.Allpatientswiththissyndromehave
developmentaldelayandhypotonia,and4458%haveseizures.[21]

Metabolicdisordersthatcancauseseizures
Manydifferentmetabolicdisorderscancauseseizures,someasaresultofametabolicdisturbance
suchashypoglycemiaoracidosisandsomeasaprimarymanifestationoftheseizuredisorder.Some
seizuresareresponsivetoadministrationofcertainvitamins(eg,pyridoxineresponsiveorfolinicacid
responsiveseizures).
Peroxisomalbiogenesisdisorders,whichcancauseseizures,resultfromhomozygosityformutationin
oneofthemanyPEXgenes.Oneofthesedisorders,Zellwegersyndrome,presentsintheneonatal
periodashypotonia,seizures,andhepaticdysfunction.Deathtypicallyoccursfromrespiratoryfailure
withinthefirstyearoflife.
Congenitaldisordersofglycosylationareagroupofdisordersthat(astheirnamesuggests)involve
malfunctioninoneofthemanyenzymesinvolvedinthepathwaythatattachescertain
oligosaccharidestoproteins.Thesedisordersvarysignificantlyintheirseverityandcharacteristic
manifestations.Hypotonia,intellectualdisability,failuretothrive/feedingdifficulties,andunusualfat
distributionarecommon.Seizuresoccurinsomecases.
Otherrarediseasesalsocommonlycauseseizures,includingthefollowing:
Neuronalceroidlipofuscinosis
Disordersofmetalandmetalcofactordeficiency
Disordersofneurotransmittermetabolism
Lysosomalstoragediseases

Mitochondrialdiseases
Mitochondrialdisordersareunderdiagnosedbutofteninvolveseizuresandotherneurologic
manifestations.Mitochondrialencephalomyopathy,lacticacidosis,andstrokelikeepisodes(MELAS)
syndromeisamitochondrialdisorderthatisassociatedwithseizuresoften,seizuresarethe
presentingmanifestation.Patientscanalsohaverecurrentheadacheandvomiting.
Myoclonicepilepsywithraggedredfibers(MERRF)ischaracterizedbymyoclonus,seizures,and
ataxiamyopathy,hearingloss,andvisionlosscanalsooccur.Genetictestsareavailableforthese
disorders.

Seizuredisorderscausedbysinglegenemutations
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AutosomaldominantnocturnalfrontallobeepilepsyiscausedbymutationsintheCHRNA4,
CHRNB2,orCHRNA2genes.Itischaracterizedbynocturnalmotorseizures.Theseverityof
autosomaldominantnocturnalfrontallobeepilepsycanbevariable,canincludeawakeningepisodes,
andcanresultinimpressivedystoniceffects.Affectedindividualsaregenerallyotherwisenormal,and
theattackstendtobecomelessseverewithage.
Autosomaldominantjuvenilemyoclonicepilepsyiscausedbyamutationinoneofanumberof
genes.Patientsreportmyoclonicjerks,mostcommonlyinthemorning,buttheycanalsohaveboth
generalizedtonicclonicseizuresandabsenceseizures.Theonsetofthisdisorderistypicallyinlate
childhoodorearlyadolescence.
BenignfamilialneonatalseizuresarecausedbymutationsintheKCNQ2orKCNQ3genesandare
inheritedinanautosomaldominantmanner.Neonateswiththisdisorderwillexperiencetonicclonic
seizuresafewdaysafterbirth,andtheseseizureswillremitwithin1month.Mostinfantswillhave
normaldevelopment,butthereisa1015%riskofseizuredisorderlaterinlife.
Mutationsinothergenes,suchasSCN1A,cancausearangeofseizuresyndromes.Atthemildend
ofthisspectrum,patientsmayhavefamilialfebrileseizuresandmayotherwisebenormal.Atthe
severeend,patientsmayhaveseveremyoclonicepilepsyofinfancy(alsoknownasDravet
syndrome).
MutationsinSCN2AandSCN1Bareknowntocausegeneralizedepilepsywithfebrileseizures.
MutationsinSCN9A,GPA6,andGPR98areknowntocausefamilialfebrileseizures.
MutationinGABRG2isknowntocausegeneralizedepilepsywithfebrileseizures,andfamilialfebrile
seizures.

Epidemiology
Hauserandcollaboratorsdemonstratedthattheannualincidenceofrecurrentnonfebrileseizuresin
OlmstedCounty,Minnesota,wasabout100casesper100,000personsaged01year,40per
100,000personsaged3940years,and140per100,000personsaged7980years.Bytheageof75
years,thecumulativeincidenceofepilepsyis3400per100,000men(3.4%)and2800per100,000
women(2.8%).[22]
Studiesinseveraldevelopedcountrieshaveshownincidencesandprevalencesofseizuressimilarto
thoseintheUnitedStates.Insomecountries,parasiticinfectionsaccountforanincreasedincidence
ofepilepsyandseizures.

Prognosis
Thepatient'sprognosisfordisabilityandforarecurrenceofepilepticseizuresdependsonthetypeof
epilepticseizureandtheepilepticsyndromeinquestion.Impairmentofconsciousnessduringa
seizuremayunpredictablyresultinmorbidityorevenmortality.
Regardingmorbidity,traumaisnotuncommonamongpeoplewithgeneralizedtonicclonicseizures.
Injuriessuchasecchymosishematomasabrasionstongue,facial,andlimblacerationsandeven
shoulderdislocationcandevelopasaresultoftherepeatedtonicclonicmovements.Atonicseizures
arealsofrequentlyassociatedwithfacialinjuries,aswellasinjuriestotheneck.Worldwide,burnsare
themostcommonseriousinjuryassociatedwithepilepticseizures.

SUDEP
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Regardingmortality,seizurescausedeathinasmallproportionofindividuals.Mostdeathsare
accidentalandresultfromimpairedconsciousness.However,sudden,unexpecteddeathinepilepsy
(SUDEP)isariskinpersonswithepilepsy,anditmayoccurevenwhenpatientsarerestingina
protectedenvironment(ie,inabedwithrailguardsorinthehospital).
TheincidenceofSUDEPislow,about2.3timeshigherthantheincidenceofsuddendeathinthe
generalpopulation.Theincreasedriskofdeathisseenmostlyinpeoplewithlongstandingfocal
onsetepilepsy,butitisalsopresentinindividualswithprimarygeneralizedepilepsy.Theriskof
SUDEPincreasesinthesettingofuncontrolledseizuresandinpeoplewithpoormedication
compliance.Theriskincreasesfurtherinpeoplewithuncontrolledsecondarygeneralizedtonicclonic
seizures.
ThemechanismofdeathinSUDEPiscontroversial,butsuggestionsincludecardiacarrhythmias,
neurogenicpulmonaryedema,andsuffocationduringanepilepticseizurewithimpairmentof
consciousness.Treatmentwithanticonvulsantsdecreasesthelikelihoodofanaccidentalseizure
relateddeath,andsuccessfulepilepsysurgerydecreasestheriskofSUDEPtothatofthegeneral
population.
In2011,theNationalInstitutesofHealth(NIH)convenedaworkshoponSUDEPtofocusresearch
effortsandtodeterminebenchmarksforfurtherstudy.[23]Asummaryoftheirreportcanbefoundat:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115809/.

PatientEducation
Topreventinjury,provideeducationaboutseizureprecautionstopatientswhohavelapsesof
consciousnessduringwakefulnessandinwhomseizuresaresuspected.Mostaccidentsoccurwhen
patientshaveimpairedconsciousness.Thisisoneofthereasonsforrestrictionsondriving,
swimming,takingunsupervisedbaths,workingatsignificantheights,andtheuseoffireandpower
toolsforpeoplewhohaveepilepticseizuresandotherspellsofsuddenonsetseizures.
Therestrictionsdifferforeachpatientbecauseoftheindividualfeaturesoftheseizures,thedegreeof
seizurecontrol,and,intheUnitedStates,statelaws.Othercountrieshavemorepermissiveormore
restrictivelawsregardingdriving.Checkstatedrivinglawsbeforemakingrecommendations.
EpilepsyFoundationofAmericahasalargelibraryofeducationalmaterialsthatareavailableto
healthcareprofessionalsandthegeneralpublic.TheAmericanEpilepsySocietyisaprofessional
organizationforpeoplewhotakecareofpatientswithepilepsy.TheirWebsiteprovidesalarge
amountofcredibleinformation.
Forpatienteducationinformation,seetheBrainandNervousSystemCenter,aswellasEpilepsyand
SeizuresEmergencies.
ClinicalPresentation
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Author
DavidYKo,MDAssociateProfessorofClinicalNeurology,AssociateDirector,USCAdultEpilepsy
Program,KeckSchoolofMedicineoftheUniversityofSouthernCalifornia
DavidYKo,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofNeurology,
AmericanEpilepsySociety,AmericanHeadacheSociety,AmericanClinicalNeurophysiologySociety
Disclosure:ReceivedhonorariafromUCBforspeakingandteachingReceivedconsultingfeefrom
LundbeckforconsultingReceivedconsultingfeefromWestwardforconsultingReceivedconsulting
feefromEsaiforconsultingReceivedconsultingfeefromSupernusforconsultingReceived
consultingfeefromSunovionforspeakingandteaching.
ChiefEditor
SelimRBenbadis,MDProfessor,DirectorofComprehensiveEpilepsyProgram,Departmentsof
NeurologyandNeurosurgery,TampaGeneralHospital,UniversityofSouthFloridaMorsaniCollegeof
Medicine
SelimRBenbadis,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyof
Neurology,AmericanAcademyofSleepMedicine,AmericanClinicalNeurophysiologySociety,
AmericanEpilepsySociety,AmericanMedicalAssociation
Disclosure:Serve(d)asadirector,officer,partner,employee,advisor,consultantortrusteefor:
CyberonicsEisaiLundbeckSunovionUCBUpsherSmith<br/>Serve(d)asaspeakeroramember
ofaspeakersbureaufor:Cyberonics(Livanova)EisaiLundbeckSunovionUCB<br/>Received
researchgrantfrom:Cyberonics(Livanova)GW,LundbeckSunovionUCBUpsherSmith.
Acknowledgements
JoseECavazos,MD,PhD,FAAN,FANA,FACNSProfessorwithTenure,DepartmentsofNeurology,
Pharmacology,andPhysiology,AssistantDeanfortheMD/PhDProgram,ProgramDirectorofthe
ClinicalNeurophysiologyFellowship,UniversityofTexasSchoolofMedicineatSanAntonioCo
Director,SouthTexasComprehensiveEpilepsyCenter,UniversityHospitalSystemDirector,San
AntonioVeteransAffairsEpilepsyCenterofExcellenceandNeurodiagnosticCenters,AudieLMurphy
VeteransAffairsMedicalCenter

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JoseECavazos,MD,PhD,FAAN,FANA,FACNSisamemberofthefollowingmedicalsocieties:
AmericanAcademyofNeurology,AmericanClinicalNeurophysiologySociety,AmericanEpilepsy
Society,AmericanNeurologicalAssociation,andSocietyforNeuroscience
Disclosure:LGCH,IncOwnershipinterestConsulting
RamonDiazArrastia,MD,PhDProfessor,DepartmentofNeurology,UniversityofTexas
SouthwesternMedicalCenteratDallas,SouthwesternMedicalSchoolDirector,NorthTexasTBI
ResearchCenter,ComprehensiveEpilepsyCenter,ParklandMemorialHospital
RamonDiazArrastia,MD,PhDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,
AmericanAcademyofNeurology,NewYorkAcademyofSciences,andPhiBetaKappa
Disclosure:Nothingtodisclose.
MarkSpitz,MDProfessor,DepartmentofNeurology,UniversityofColoradoHealthSciencesCenter
MarkSpitz,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofNeurology,
AmericanClinicalNeurophysiologySociety,andAmericanEpilepsySociety
Disclosure:pfizerHonorariaSpeakingandteachingucbHonorariaSpeakingandteachinglumdbeck
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FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedical
CenterCollegeofPharmacyEditorinChief,MedscapeDrugReference
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