Epilepsy and Seizures.docx
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Epilepsy and Seizures Author: David Y Ko, MD; Chief Editor: Seli Selim m R Benbadis
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Pratie Essentials E!ile!s" is defined as a brain disorder harateri#ed b" an endurin$ !redis!osition to $enerate e!ile!ti sei#ures and b" the neurobiolo$i, o$nitive, !s"holo$ial, and soial onse%uenes of this ondition& '()
Essential update: Study suggests epilepsy surgery during childhood can protect memory development *n a stud" of + hildren -ith for mediation.resistant e!ile!s" -ho under-ent unilateral tem!oral lobe resetions durin$ hildhood and -ere ree/amined as "oun$ adults, S0irro- et al found that sur$er" redued hroni sei#ures and !roteted memor" develo!ment&', 1) After an avera$e avera$e follo-.u! follo-.u! of 2 "ears, "ears, sei#ure sei#ures s had om!l om!letel" etel" sto!!ed in 345 of !atients, !atients, and the the '1) ma6orit" -ere no lon$er ta0in$ e!ile!s" mediation& Com!ared -ith (( !atients -ith e!ile!s" -ho had not had sur$er", !atients -ho had had sur$er" sho-ed si$nifiant im!rovements in reolletion of events and fatual information and in both verbal and visual memor"& 7he best memor" outomes -ere observed amon$ hildren -ho had the least amount of brain tissue removed&
Signs and symptoms 7he linial si$ns and s"m!toms of sei#ures de!end on the loation of the e!ile!ti dishar$es in the erebral orte/ and the e/tent and !attern of the !ro!a$ation of the e!ile!ti dishar$e in the brain& A 0e" feature of e!ile!ti sei#ures is their stereot"!i nature& 8uestions that hel! larif" the t"!e of sei#ure inlude the follo-in$: • • •
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9as an" -arnin$ noted before the s!ell *f so, -hat 0ind of -arnin$ ourred 9hat did the !atient do durin$ the s!ell 9as the !atient able to relate to the environment durin$ the s!ell andor does the !atient have reolletion of the s!ell <o- did the !atient feel after the s!ell <o- lon$ did it ta0e for the !atient to $et ba0 to baseline ondition <o- lon$ did the s!ell last <o- fre%uent do the s!ells our Are an" !rei!itants !rei!itants assoiated assoiated -ith the s!ells <as the !atient sho-n an" res!onse to thera!" for the s!ells Presentation n for more detail& See Clinial Presentatio See
Diagnosis 7he dia$nosis of e!ile!ti sei#ures is made b" anal"#in$ the !atient=s detailed linial histor" and b" !erformin$ anillar" tests for onfirmation& Ph"sial e/amination hel!s in the dia$nosis of s!eifi e!ile!ti s"ndromes that ause abnormal findin$s, suh as dermatolo$i abnormalities >e$, !atients -ith intratable $enerali#ed toni.loni sei#ures for "ears are li0el" to have in6uries re%uirin$ stithes?& Testing Potentiall" useful laborator" laborator" tests for !atients -ith sus!eted e!ile!ti sei#ures inlude the follo-in$: •
Prolatin levels obtained shortl" after a sei#ure to assess the etiolo$" >e!ile!ti vs none!ile!ti? of a s!ell; levels are t"!iall" elevated 1. or +.fold and more li0el" to our -ith $enerali#ed toni.loni sei#ures than -ith other sei#ure t"!es; ho-ever, the onsiderable variabilit" of !rolatin levels has !reluded their routine linial use
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Serum levelsnonom!liane, of antionvulsant a$ents to determine levels, !otential effia", treatment andor autoindution orbaseline !harmao0ineti han$eto/iit", la0 of
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CS@ e/amination in !atients -ith obtundation or in !atients in -hom menin$itis or ene!halitis is sus!eted Imaging studies 7he follo-in$ ima$in$ studies must be !erformed after a sei#ure:
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euroima$in$ evaluation >e$, MR*, C7 sannin$? EE 7he linial dia$nosis an be onfirmed b" abnormalities on the interital EE, but these abnormalities ould be !resent in other-ise health" individuals, and their absene does not e/lude the dia$nosis of e!ile!s"& ideo.EE monitorin$ is the standard test for lassif"in$ the t"!e of sei#ure or s"ndrome or to dia$nose !seudosei#ures >ie, to establish a definitive dia$nosis of s!ells -ith im!airment of onsiousness?& 7his tehni%ue is also used to harateri#e the t"!e of sei#ure and e!ile!ti s"ndrome to o!timi#e !harmaolo$i treatment and for !resur$ial -or0u!& 9or0u! for for more detail& See 9or0u! See
Management Pharmacotherapy 7he $oal of treatment is to ahieve a sei#ure.free status -ithout adverse effets& Monothera!" is im!ortant, beause it dereases the li0elihood of adverse effets and avoids dru$ interations& Standard of are for a sin$le, un!rovo0ed sei#ure is avoidane of t"!ial !rei!itants >e$, alohol, slee! de!rivation?& o antionvulsants are reommended unless the !atient has ris0 fators for reurrene& S!eial situations that re%uire treatment inlude the follo-in$: •
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Reurrent un!rovo0ed sei#ures: 7he mainsta" of thera!" is an antionvulsant; if a !atient has had more than ( sei#ure, administration of an antionvulsant is reommended <avin$ an abnormal slee!.de!rived EE that inludes e!ile!tiform abnormalities and foal slo-in$, diffuse ba0$round slo-in$, and intermittent diffuse intermi/ed slo-in$ Seletion of an antionvulsant mediation de!ends on an aurate dia$nosis of the e!ile!ti s"ndrome& Althou$h some antionvulsants >e$, lamotri$ine, to!iramate, val!roi aid, #onisamide? have multi!le mehanisms of ation, and some >e$, !hen"toin, arbama#e!ine, ethosu/imide? have onl" one 0no-n mehanism of ation, antionvulsant a$ents an be divided into lar$e $rou!s based on their mehanisms, as follo-s: Blo0ers of re!etitive ativation of the sodium hannel: Phen"toin, arbama#e!ine, o/arba#e!ine, lamotri$ine, to!iramate Enhaner of slo- inativation of the sodium hannel: aosamide, rufinamide amma aminobut"ri aid >ABA?A ree!tor enhaners: Phenobarbital, ben#odia#e!ines, loba#am MDA ree!tor blo0ers: @elbamate AMPA ree!tor blo0ers: blo0ers: Peram!anel, Peram!anel, to!iramate to!iramate 7.alium hannel blo0ers: Ethosu/imide, val!roate . and .alium hannel blo0ers: amotri$ine, to!iramate, #onisamide, val!roate <.urrent modulators: aba!entin, lamotri$ine Blo0ers of uni%ue bindin$ sites: aba!entin, levetiraetam Carboni anh"drase inhibitors: 7o!iramate, #onisamide euronal !otassium hannel >KC8 'KvF)? o!ener: E#o$abine Nonpharmacologic therapy 7he follo-in$ are non!harmaolo$i methods in mana$in$ !atients -ith sei#ures:
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A 0eto$eni 0eto$eni die diett a$al nerve stimulation
Surgical options 7he ma6or 0inds of brain sur$er" for e!ile!s" are !alliative and !otentiall" urative& 7he use of a va$al nerve stimulator >S? for !alliative thera!" in !atients -ith intratable atoni sei#ures has redued the need for anterior allosotom"& obetom" and lesionetom" are amon$ several !ossible urative sur$eries& 7reatment and and Mediation Mediation for more detail& See 7reatment See
Ba0$round E!ile!ti sei#ures are onl" one manifestation of neurolo$i or metaboli diseases& E!ile!ti sei#ures have man" auses, inludin$ a $eneti !redis!osition for ertain t"!es of sei#ures, head trauma, trauma, stro0e, brain tumors, alohol or dru$ -ithdra-al, re!eated e!isodes of metaboli insults, suh as h"!o$l"emia, and other onditions& E!ile!s" is a medial disorder mar0ed b" reurrent, un!rovo0ed sei#ures& 7herefore, re!eated sei#ures -ith an identified !rovoation >e$, alohol -ithdra-al? do not onstitute e!ile!s"& As !ro!osed !ro!osed b" the *nternational *nternational ea$ue ea$ue A$ainst A$ainst E!ile!s" >*AE? >*AE? and the *nternational *nternational Bureau Bureau for E!ile!s" >*BE? in GGH, e!ile!s" is defined as a brain disorder harateri#ed b" an endurin$ !redis!osition to $enerate e!ile!ti sei#ures and b" the neurobiolo$i, o$nitive, !s"holo$ial, and soial onse%uenes of this ondition& '() 7raditionall", the dia$nosis of e!ile!s" re%uires the ourrene of at least un!rovo0ed sei#ures& Some liniians also dia$nose e!ile!s" -hen ( un!rovo0ed sei#ure ours in the settin$ of a !redis!osin$ ause, suh as a foal ortial in6ur", or a $enerali#ed interital dishar$e ours that su$$ests a !ersistent $eneti !redis!osition& >See Clinial Presentation&? Sei#ures are the manifestation of abnormal h"!ers"nhronous or h"!ere/itable dishar$es of ortial neurons& 7he linial si$ns or s"m!toms of sei#ures de!end on the loation of the e!ile!ti dishar$es in the erebral orte/ and the e/tent and !attern of the !ro!a$ation of the e!ile!ti dishar$e in the brain& 7hus, sei#ure s"m!toms are hi$hl" variable, but for most !atients -ith ( fous, the s"m!toms are usuall" ver" stereot"!i& *t should not be sur!risin$ that sei#ures are a ommon, nons!eifi manifestation of neurolo$i in6ur" and disease, beause the main funtion of the brain is the transmission of eletrial im!ulses& 7he lifetime li0elihood of e/!erienin$ at least ( e!ile!ti sei#ure is about 25, and the lifetime li0elihood of reeivin$ a dia$nosis of e!ile!s" is almost 15& <o-ever, the !revalene of ative e!ile!s" is onl" about G&35& >See E!idemiolo$"&? 7his artile revie-s the lassifiations, !atho!h"siolo$", linial manifestations, and treatment of e!ile!ti sei#ures and some ommon e!ile!ti s"ndromes& >See Patho!h"siolo$", Presentation, DD/, and 7reatment&? @or more information re$ardin$ sei#ure t"!es and other onditions, see the follo-in$ to!is: • • • • • • • • •
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Absene Sei Sei#ures #ures Com!le/ Partial Sei#ures enerali#ed 7oni.Cloni Sei#ures Ps"ho$eni one!ile!ti Sei#ures Pediatri @irst Sei#ure E!ile!sia Partialis Continua Status E!ile!tius Preelam!sia Elam!sia See the follo-in$ artiles for more information re$ardin$ e!ile!ti s"ndromes and e!ile!s" treatment: Beni$n Childhood E!ile!s" Beni$n eonatal Convulsions EE in Common E!ile!s" S"ndromes Pediatri @ebrile Sei#ures
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eonatal Sei#ures @rontal obe E!ile!s" 7em!oral obe E!ile!s" Iuvenile M"oloni E!ile!s" enno/.astaut S"ndrome Posttraumati Posttraumati E!ile!s" Refle/ E!ile!s" a$us erve Stimulation 9omen=s <ealth and E!ile!s" Partial E!ile!sies Pediatri Status E!ile!tius M"oloni E!ile!s" Be$innin$ in *nfan" or Earl" Childhood Historical information E!ile!ti sei#ures have been reo$ni#ed for millennia& Jne of the earliest desri!tions of a seondar" $enerali#ed toni.loni sei#ure -as reorded over 1GGG "ears a$o in Meso!otamia& 7he sei#ure -as attributed to the $od of the moon& E!ile!ti sei#ures -ere desribed in other anient ultures, inludin$ those of China, E$"!t, and *ndia& An anient E$"!tian !a!"rus desribed a sei#ure in a man -ho had !revious head trauma& <i!!orates -rote the first boo0 about e!ile!s" almost HGG "ears a$o& <e re6eted ideas re$ardin$ the divine etiolo$" of e!ile!s" and onluded that the ause -as e/essive !hle$m leadin$ to abnormal brain onsisten"& <i!!orati teahin$s -ere for$otten, and divine etiolo$ies a$ain dominated beliefs about e!ile!ti sei#ures durin$ medieval times& Even at the turn of the (2th entur", e/essive masturbation -as onsidered a ause of e!ile!s"& 7his h"!othesis is redited as leadin$ to the use of the first effetive antionvulsant >ie, bromides?& Modern investi$ation of the etiolo$" of e!ile!s" be$an -ith the -or0 of @ritsh, <it#i$, @errier, and Caton in the (3FGs& 7hese researhers reorded and evo0ed e!ile!ti sei#ures in the erebral orte/ of animals& *n (22, Ber$er disovered that eletrial brain si$nals ould be reorded from the human head b" usin$ sal! eletrodes; this disover" led to the use of eletroene!halo$ra!h" >EE? to stud" and lassif" e!ile!ti sei#ures& ibbs, enno/, Penfield, and Ias!er further advaned the understandin$ of e!ile!s" and develo!ed the s"stem of the ma6or lasses of e!ile!ti sei#ures urrentl" used: loali#ation.related s"ndromes and $enerali#ed.onset s"ndromes& An e/ellent historial revie- of sei#ures and e!ile!s", -ritten b" E& oldensohn, -as !ublished in the 6ournal Epilepsia Epilepsia to to ommemorate the HGth anniversar" of the Soiet" in (22F& A deade later, another reviereation of the Amerian the Amerian E!ile!s" E!ile!s" Soiet" in Epilepsia Epilepsia disussed disussed the foundation of this !rofessional soiet"& '+)
Patho!h"siolo$" Sei#ures are !aro/"smal manifestations of the eletrial !ro!erties of the erebral orte/& A sei#ure results -hen a sudden imbalane ours bet-een the e/itator" and inhibitor" fores -ithin the net-or0 of ortial neurons in favor of a sudden.onset net e/itation& 7he brain is involved in nearl" ever" bodil" funtion, inludin$ the hi$her ortial funtions& *f the affeted ortial net-or0 is in the visual orte/, the linial manifestations are visual !henomena& Jther affeted areas of !rimar" orte/ $ive rise to sensor", $ustator", or motor manifestations& 7he !s"hi !henomenon of d6L.vu ours -hen the tem!oral lobe is involved& 7he !atho!h"siolo$" of foal.onset sei#ures differs from the mehanisms underl"in$ $enerali#ed. onset sei#ures& Jverall, ellular e/itabilit" is inreased, but the mehanisms of s"nhroni#ation a!!ear to substantiall" differ bet-een these t"!es of sei#ure and are therefore disussed se!aratel"& @or a revie-, see the e!ile!s" boo0 of Rho, San0ar, and Cava#os& 'H) @or a more reent revie-, see Kramer and Cash&'4)
Pathophysiology of focal seizures
7he eletroene!halo$ra!hi >EE? hallmar0 of foal.onset sei#ures is the foal interital e!ile!tiform s!i0e or shar! -ave& 7he ellular neuro!h"siolo$i orrelate of an interital foal e!ile!tiform dishar$e in sin$le ortial neurons is the !aro/"smal de!olari#ation shift >PDS?& 7he PDS is harateri#ed b" a !rolon$ed alium.de!endent de!olari#ation that results in multi!le sodium.mediated ation !otentials durin$ the de!olari#ation !hase, and it is follo-ed b" a !rominent after.h"!er!olari#ation, -hih is a h"!er!olari#ed membrane !otential be"ond the baseline restin$ !otential& Calium.de!endent !otassium hannels mostl" mediate the after.h"!er!olari#ation !hase& 9hen multi!le neurons fire PDSs in a s"nhronous manner, the e/traellular field reordin$ sho-s an interital s!i0e& *f the number of dishar$in$ neurons is more than several million, the" an usuall" be reorded -ith sal! EE eletrodes& Calulations sho- that the interital s!i0es need to s!read to about 4 m of erebral orte/ before the" an be deteted -ith sal! eletrodes& Several fators ma" be assoiated -ith the transition from an interital s!i0e to an e!ile!ti sei#ure& 7he s!i0e has to reruit more neural tissue to beome a sei#ure& 9hen an" of the mehanisms that underlie an aute sei#ure beomes a !ermanent alteration, the !erson !resumabl" develo!s a !ro!ensit" for reurrent sei#ures >ie, e!ile!s"?& 7he follo-in$ mehanisms >disussed belo-? ma" oe/ist in different ombinations to ause foal. onset sei#ures: • • •
Dereased inhibition Defetive ativation of $amma.aminobut"ri aid >ABA? neurons *nreased ativation *f the mehanisms leadin$ to a net inreased e/itabilit" beome !ermanent alterations, !atients ma" develo! !harmaolo$iall" intratable foal.onset e!ile!s"& Currentl" available mediations -ere sreened usin$ aute models of foal.onset or $enerali#ed. onset onvulsions& *n linial use, these a$ents are most effetive at blo0in$ the !ro!a$ation of a sei#ure >ie, s!read from the e!ile!ti fous to seondar" $enerali#ed toni.loni sei#ures?& @urther understandin$ of the mehanisms that !ermanentl" inrease net-or0 e/itabilit" ma" lead to develo!ment of true antie!ile!ti dru$s that alter the natural histor" of e!ile!s"&
Decreased inhibition 7he release of ABA from the interneuron terminal inhibits the !osts"na!ti neuron b" means of mehanisms: >(? diret indution of an inhibitor" !osts"na!ti !otential >*PSP?, -hih a ABA.A hloride urrent t"!iall" mediates, and >? indiret inhibition of the release of e/itator" neurotransmitter in the !res"na!ti afferent !ro6etion, t"!iall" -ith a ABA.B !otassium urrent& Alterations or mutations in the different different hlor hloride ide or !ota !otassium ssium hann hannel el subunits or or in the moleules moleules that re$ulate their funtion ma" affet the sei#ure threshold or the !ro!ensit" for reurrent sei#ures& Mehanisms leadin$ to dereased inhibition inlude the follo-in$: • • • •
Defetive ABA.A inhibition Defetive ABA.B inhibition Defetive ativation of ABA neurons Defetive intraellular bufferin$ of alium Normal GABA-A inhibitory function ABA is the main inhibitor" neurotransmitter in the brain, and it binds !rimaril" to ma6or lasses of ree!tors: ABA.A and ABA.B& ABA.A ree!tors are ou!led to hloride >ne$ative anion? hannels, and the" are one of the main tar$ets modulated b" the antionvulsant a$ents that are urrentl" in linial use& 7he reversal !otential of hloride is about ne$ative FG m& 7he ontribution of hloride hannels durin$ restin$ !otential in neurons is minimal, beause the t"!ial restin$ !otential is near .FG m, and thus there is no si$nifiant eletromotive fore for net hloride flu/& <o-ever, hloride urrents beome more im!ortant at more de!olari#ed membrane !otentials&
7hese hannels ma0e it diffiult to ahieve the threshold membrane !otential neessar" for an ation !otential& 7he influene of hloride urrents on the neuronal membrane !otential inreases as the neuron beomes more de!olari#ed b" the summation of the e/itator" !osts"na!ti !otentials >EPSPs?& *n this manner, the hloride urrents beome another fore that must be overome to fire an ation !otential, dereasin$ e/itabilit"& Pro!erties of the hloride hannels assoiated -ith the ABA.A ree!tor are often liniall" modulated b" usin$ ben#odia#e!ines >e$, dia#e!am, lora#e!am, lona#e!am?, barbiturates >e$, !henobarbital, !entobarbital?, or to!iramate& Ben#odia#e!ines inrease the fre%uen" of o!enin$s of hloride hannels, -hereas barbiturates inrease the duration of o!enin$s of these hannels& 7o!iramate also inreases the fre%uen" of hannel o!enin$s, but it binds to a site different from the ben#odia#e!ine.ree!tor site& Alterations in the normal normal state of the hloride h hannels annels ma" inrease inrease the membrane membrane !ermeabilit" !ermeabilit" and ondutane of hloride ions& *n the end, the behavior of all individual hloride hannels sum u! to form a lar$e hloride.mediated h"!er!olari#in$ urrent that ounterbalanes the de!olari#in$ urrents reated b" the summation of EPSPs indued b" ativation of the e/itator" in!ut& 7he EPSPs are the main form of ommuniation bet-een neurons, and the release of the e/itator" amino aid $lutamate from the !res"na!ti element mediates EPSPs& 7hree main ree!tors mediate the effet of $lutamate in the !osts"na!ti neuron: N .meth"l.D.as!arti .meth"l.D.as!arti aid >MDA?, al!ha.amino.1. h"dro/".H.meth"l.+.iso/a#ole !ro!ioni aid >AMPA?0ainate, and metabotro!i& 7hese are ou!led b" means of different mehanisms to several de!olari#in$ hannels& *PSPs tem!er the effets of EPSPs& *PSPs are mediated mainl" b" the release of ABA in the s"na!ti left -ith !osts"na!ti ativation of ABA.A re ree!tors& e!tors& All hannels hannels in the nervous nervous s"stem are sub6et to mo modulation dulation b" several mehanisms, mehanisms, suh as !hos!hor"lation and, !ossibl", a han$e in the tridimensional onformation of a !rotein in the hannel& 7he hloride hannel has several !hos!hor"lation sites, one of -hih to!iramate a!!ears to modulate& Phos!hor"lation of this hannel indues a han$e in normal eletro!h"siolo$i behavior, -ith an inreased fre%uen" of hannel o!enin$s but for onl" ertain hloride hannels& Eah hannel has a multimeri struture -ith several subunits of different t"!es& Chloride hannels are no e/e!tion; the" have a !entameri struture& 7he subunits are made u! of moleularl" related but different !roteins& 7he hetero$eneit" of eletro!h"siolo$i res!onses of different ABA.A ree!tors results from different ombinations of the subunits& *n mammals, at least 4 al!ha subunits and 1 beta and $amma subunits e/ist for the ABA.A ree!tor om!le/& A om!lete ABA.A ree!tor om!le/ >-hih, in this ase, is the hloride hannel itself? is formed from ( $amma, al!ha, and beta subunits& 7he number of !ossible ombinations of the 0no-n subunits is almost (GGG, but in !ratie, onl" about G of these ombinations have been found in the normal mammalian brain& Defectie GABA-A inhibition Some e!ile!sies ma" involve mutations or la0 of e/!ression of the different ABA.A ree!tor om!le/ subunits, the moleules that $overn their assembl", or the moleules that modulate their eletrial !ro!erties& @or e/am!le, hi!!oam!al !"ramidal neurons ma" not be able to assemble al!ha H beta 1 $amma 1 ree!tors beause of deletion of hromosome (H >ie, An$elman s"ndrome?& Chan$es in the distribution of subunits of the ABA.A ree!tor om!le/ have been demonstrated in several animal models of foal.onset e!ile!s", suh as the eletrial.0indlin$, hemial.0indlin$, and !iloar!ine models& *n the !iloar!ine model, dereased onentrations of mRA for the al!ha H subunit of the survivin$ interneurons -ere observed in the CA( re$ion of the rat hi!!oam!us& 'F) Defectie GABA-B inhibition 7he ABA.B ree!tor is ou!led to !otassium hannels, formin$ a urrent that has a relativel" lon$ duration of ation om!ared -ith the hloride urrent evo0ed b" ativation of the ABA.A ree!tor& Beause of the lon$ duration of ation, alterations in the ABA.B ree!tor are thou$ht to !ossibl" !la" a ma6or role in the transition bet-een the interital abnormalit" and an ital event >ie, foal.onset
sei#ure?& 7he moleular struture of the ABA.B ree!tor om!le/ onsists of subunits -ith F transmembrane domains eah& !roteins, a seond messen$er s"stem, mediate ou!lin$ to the !otassium hannel, e/!lainin$ the laten" and lon$ duration of the res!onse& *n man" ases, ABA.B ree!tors are loated in the !res"na!ti element of an e/itator" !ro6etion&
Defective activation of GAA G AA neurons ABA neurons are ativated b" means of feedfor-ard and feedba0 !ro6etions from e/itator" neurons& 7hese t"!es of inhibition in a neuronal net-or0 are defined on the basis of the time of ativation of the ABAer$i neuron relative to that of the !rini!al neuronal out!ut of the net-or0, as seen -ith the hi!!oam!al !"ramidal CA( ell& *n feedfor-ard inhibition, ABAer$i ells reeive a ollateral !ro6etion from the main afferent !ro6etion that ativates the CA( neurons, namel", the Shaffer ollateral a/ons from the CA1 !"ramidal neurons& 7his feedfor-ard !ro6etion ativates the soma of ABAer$i neurons before or simultaneousl" -ith ativation of the a!ial dendrites of the CA( !"ramidal neurons& Ativation of the the ABAer$i ABAer$i neurons results in an *PSP that inh inhibits ibits the soma soma or a/on hillo0 hillo0 of the CA( !"ramidal neurons almost simultaneousl" -ith the !assive !ro!a$ation of the e/itator" !otential >ie, EPSP? from the a!ial dendrites to the a/on hillo0& 7he feedfor-ard !ro6etion thus !rimes the inhibitor" s"stem in a manner that allo-s it to inhibit, in a timel" fashion, the !"ramidal ell=s de!olari#ation and firin$ of an ation !otential& @eedba0 inhibition is another s"stem that allo-s ABAer$i ells to ontrol re!etitive firin$ in !rini!al neurons, suh as !"ramidal ells, and to inhibit the surroundin$ !"ramidal ells& Reurrent ollaterals from the !"ramidal neurons ativate the ABAer$i neurons after the !"ramidal neurons fire an ation !otential& E/!erimental evidene has indiated that some other 0ind of interneuron ma" be a $ate bet-een the !rini!al neurons and the ABAer$i neurons& *n the dentate $"rus, the moss" ells of the hilar !ol"mor!hi re$ion a!!ear to $ate inhibitor" tone and ativate ABAer$i neurons& 7he moss" ells reeive both feedba0 and feedfor-ard ativation, -hih the" onve" to the ABAer$i neurons& *n ertain irumstanes, the moss" ells a!!ear hi$hl" vulnerable to sei#ure.related neuronal loss& After some of of the moss" ells are are lost, ativation ativation of ABAe ABAer$i r$i neur neurons ons is im!aired& im!aired&'3) S"na!ti reor$ani#ation is a form of brain !lastiit" indued b" neuronal loss, !erha!s tri$$ered b" the loss of the s"na!ti onnetions of the d"in$ neuron, a !roess alled deafferentation& @ormation of ne- s!routed iruits inludes e/itator" and inhibitor" ells, and both forms of s!routin$ have been demonstrated in man" animal models of foal.onset e!ile!s" and in humans -ith intratable tem!oral. lobe e!ile!s"& Most of the initial attem!ts of hi!!oam!al s!routin$ are li0el" to be attem!ts to restore inhibition& As the e!ile!s" !ro$resses, ho-ever, the over-helmin$ number of s!routed s"na!ti ontats ours -ith e/itator" tar$ets, reatin$ reurrent e/itator" iruitries that !ermanentl" alter the balane bet-een e/itator" and inhibitor" tone in the hi!!oam!al net-or0& Defectie intracellular buffering of calcium *n rodents, reurrent sei#ures indued b" a variet" of methods result in a !attern of interneuron loss in the hilar !ol"mor!hi re$ion, -ith stri0in$ loss of the neurons that la0 the alium.bindin$ !roteins !arvalbumin and albindin& *n rat hi!!oam!al setions, these interneurons demonstrate a !ro$ressive inabilit" to maintain a h"!er!olari#ed restin$ membrane !otential; eventuall", the interneurons die& *n an e/!eriment, researhers used miroeletrodes ontainin$ the alium helator BAP7A and demonstrated reversal of the deterioration in the membrane !otential as the alium helator -as allo-ed to diffuse in the interneuron& '2)7hese findin$s sho-ed the ritial role of ade%uate onentrations of alium.bindin$ !roteins for neuronal survival in settin$s -ith sustained rises of intraellular alium, suh as in status e!ile!tius and other brain insults& 7his mehanism ma" ontribute to medial intratabilit" in some e!ile!s" !atients&
7he vulnerabilit" of interneurons to h"!o/ia and other insults also orrelates to the relative !resene of these alium.bindin$ !roteins& 7he !remature loss of interneurons alters inhibitor" ontrol over the loal neuronal net-or0 in favor of net e/itation& 7his effet ma" e/!lain, for e/am!le, -h" !atients -ho have a similar event >ie, sim!le febrile onvulsion? ma" have remar0abl" dissimilar outomes; that is, one ma" have om!letel" normal develo!ment, and the other ma" have intratable foal.onset e!ile!s" after a fe- "ears&
!ncreased activation Mehanisms leadin$ to inreased e/itation inlude the follo-in$: • • •
*nreased ativation of MDA ree!tors *nreased s"nhron" bet-een neurons due to e!ha!ti interations *nreased s"nhron" andor ativation due to reurrent e/itator" ollaterals Increased actiation of N!DA receptors lutamate is the ma6or e/itator" neurotransmitter in the brain& 7he release of $lutamate auses an EPSP in the !osts"na!ti neuron b" ativatin$ the $lutaminer$i ree!tors AMPA0ainate and MDA and the metabotro!i ree!tor& @ast neurotransmission is ahieved -ith the ativation of the first t"!es of ree!tors& 7he metabotro!i ree!tor alters ellular e/itabilit" b" means of a seond.messen$er s"stem -ith later onset but a !rolon$ed duration& 7he ma6or funtional differene bet-een the fast ree!tors is that the AMPA0ainate ree!tor o!ens hannels that !rimaril" allo- the !assa$e of monovalent ations >ie, sodium and !otassium?, -hereas the MDA t"!e is ou!led to hannels that also allo- !assa$e of divalent ations >ie, alium?& Calium is a atal"st for man" intraellular reations that lead to han$es in !hos!hor"lation and $ene e/!ression& 7hus, it is in itself a seond.messen$er s"stem& MDA ree!tors are $enerall" assumed to be assoiated -ith learnin$ and memor"& 7he ativation of MDA ree!tors is inreased in several animal models of e!ile!s", suh as 0indlin$, 0aini aid, !iloar!ine, and other foal.onset e!ile!s" models& Some !atients -ith e!ile!s" ma" have an inherited !redis!osition for fast or lon$.lastin$ ativation of MDA hannels that alters their sei#ure threshold& Jther !ossible alterations inlude the abilit" of intraellular !roteins to buffer alium, inreasin$ the vulnerabilit" of neurons to an" 0ind of in6ur" that other-ise -ould not result in neuronal death& Increased synchrony bet"een neurons caused by ephaptic interactions Eletrial fields reated b" s"nhronous ativation of !"ramidal neurons in laminar strutures, suh as the hi!!oam!us, ma" inrease further the e/itabilit" of nei$hborin$ neurons b" nons"na!ti >ie, e!ha!ti? interations& Chan$es in e/traellular ioni onentrations of !otassium and alium are another !ossible nons"na!ti interation, as is inreased ou!lin$ of be neurons due to !ermanent inreases in the funtional availabilit" of $a! 6untions& 7his last ma" a mehanism that !redis!oses !redis!os es to sei#ures or status e!ile!tius& Increased synchrony and#or actiation from recurrent e$citatory collaterals euro!atholo$i studies of !atients -ith intratable foal.onset e!ile!s" have revealed fre%uent abnormalities in the limbi s"stem, !artiularl" in the hi!!oam!al formation& A ommon lesion is hi!!oam!al slerosis, -hih onsists of a !attern of $liosis and neuronal loss !rimaril" affetin$ the hilar !ol"mor!hi re$ion and the CA( !"ramidal re$ion& 7hese han$es are assoiated -ith relative s!arin$ of the CA !"ramidal re$ion and an intermediate severit" of the lesion in the CA1 !"ramidal re$ion and dentate $ranule neurons& Prominent hi!!oam!al slerosis is found in about t-o thirds of !atients -ith intratable tem!oral.lobe e!ile!s"& Animal models of status e!ile!tius have re!rodued this !attern of in6ur"; ho-ever, animals -ith more than (GG brief onvulsions indued b" 0indlin$ sei#ures had a similar !attern, su$$estin$ that re!eated tem!oral lobe sei#ures ma" ontribute to the develo!ment of hi!!oam!al slerosis& '(G) More subtle and a!!arentl" more ommon than overt hi!!oam!al slerosis is moss".fiber s!routin$& '(() 7he moss" fibers are the a/ons of the dentate $ranule neurons, and the" t"!iall" !ro6et into the
hilar !ol"mor!hi re$ion and to-ard the CA1 !"ramidal neurons& As the neurons in the hilar !ol"mor!hi re$ion are !ro$ressivel" lost, their s"na!ti !ro6etions to the dentate $ranule neurons de$enerate& Denervation resultin$ from loss of the hilar !ro6etion indues s!routin$ of the nei$hborin$ moss" fiber a/ons& 7he net onse%uene of this !henomenon is the formation of reurrent e/itator" ollaterals, -hih inrease the net e/itator" drive of dentate $ranule neurons& Reurrent e/itator" ollaterals have been demonstrated in human tem!oral lobe e!ile!s" and in all animal models of intratable foal.onset e!ile!s"& 7he effet of moss".fiber s!routin$ on the hi!!oam!al iruitr" has been onfirmed in om!uteri#ed models of the e!ile!ti hi!!oam!us& Jther neural !ath-a"s in the hi!!oam!us, suh as the !ro6etion from CA( to the subiulum, have been sho-n to also remodel in the e!ile!ti brain& @or further readin$, a revie- b" Mastran$elo and eu##i addresses ho- $enes lead to an e!ile!ti !henot"!e for the earl" a$e ene!halo!athies& ene!halo!athies&'()
Pathophysiology of generalized seizures 7he best.understood e/am!le of the !atho!h"siolo$i mehanisms of $enerali#ed sei#ures is the thalamoortial interation that ma" underlie t"!ial absene sei#ures& 7he thalamoortial iruit has normal osillator" rh"thms, -ith !eriods of relativel" inreased e/itation and !eriods of relativel" inreased inhibition& *t $enerates the osillations observed in slee! s!indles& 7he thalamoortial iruitr" inludes the !"ramidal neurons of the neoorte/, the thalami rela" neurons, and the neurons in the nuleus retiularis of the thalamus >R7?& Altered thalamoortia thalamoortiall rh"thms ma" result in !ri !rimar" mar" $ener $enerali#ed.on ali#ed.onset set sei#ures& sei#ures& 7he thalami thalami rela" neurons reeive asendin$ in!uts from the s!inal ord and !ro6et to the neoortial !"ramidal neurons& Choliner$i !ath-a"s from the forebrain and the asendin$ serotoner$i, noradrener$i, and holiner$i brainstem !ath-a"s !rominentl" re$ulate this iruitr"& iruitr"&'(1) 7he thalami rela" neurons an have osillations in the restin$ membrane !otential, -hih inreases the !robabilit" of s"nhronous ativation of the neoortial !"ramidal neuron durin$ de!olari#ation and -hih si$nifiantl" lo-ers the !robabilit" of neoortial ativation durin$ relative h"!er!olari#ation& 7he 0e" to these osillations is the transient lo-.threshold alium hannel, also 0no-n as 7.alium urrent& *n animal studies, inhibitor" in!uts from the R7 ontrol the ativit" of thalami rela" neurons& R7 neurons are inhibitor" and ontain ABA as their main neurotransmitter& 7he" re$ulate the ativation of the 7.alium hannels in thalami rela" neurons, beause those hannels must be de.inativated to o!en transitoril"& 7.alium hannels have 1 funtional states: o!en, losed, and inativated& Calium enters the ells -hen the 7.alium hannels are o!en& *mmediatel" after losin$, the hannel annot o!en a$ain until it reahes a state of inativation& 7he thalami rela" neurons have ABA.B ree!tors in the ell bod" and reeive toni ativation b" ABA released from the R7 !ro6etion to the thalami rela" neuron& 7he result is a h"!er!olari#ation that s-ithes the 7.alium hannels a-a" from the inative state into the losed state, -hih is read" for ativation -hen needed& 7he s-ith to losed state !ermits the s"nhronous o!enin$ of a lar$e !o!ulation of the 7.alium hannels ever" (GG milliseonds or so, reatin$ the osillations observed in the EE reordin$s from the erebral orte/& @indin$s in several animal models of absene sei#ures, suh as lethar$i mie, have demonstrated that ABA.B ree!tor anta$onists su!!ress absene sei#ures, -hereas ABA.B a$onists -orsen Antionvulsants nts that !rev !revent ent absen absene e sei#ures, su suh h as val!roi val!roi aid and these sei#ures&'(+) Antionvulsa ethosu/imide, su!!ress the 7.alium urrent, blo0in$ its hannels& A linial linial !roblem !roblem is that some antionvulsan antionvulsants ts that inrea inrease se ABA levels >e$, >e$, tia$abine, vi$abatrin? vi$abatrin? are assoiated -ith an e/aerbation of absene sei#ures& An inreased ABA level is thou$ht to inrease the de$ree of s"nhroni#ation of the thalamoortial iruit and to enlar$e the !ool of 7. alium hannels available for ativation&
Etiolo$" *n a substantial number of ases, the ause of e!ile!s" remains un0no-n& *dentified auses tend to var" -ith !atient a$e& *nherited s"ndromes, on$enital brain malformations, infetion, and head trauma are leadin$ auses in hildren& <ead trauma is the most ommon 0no-n ause in "oun$ adults& Stro0es, tumors, and head trauma beome more fre%uent in middle a$e, -ith stro0e beomin$ the most ommon ause in the elderl", alon$ -ith Al#heimer disease and other de$enerative onditions& 7he $eneti ontribution to sei#ure disorders is not om!letel" understood, but at the !resent time, hundreds of $enes have been sho-n to ause or !redis!ose individuals to sei#ure disorders of various t"!es& Sei#ures are fre%uentl" seen in !atients that are referred to a $enetis lini& *n some ases, the sei#ures are isolated in an other-ise normal hild& *n man" ases, sei#ures are !art of a s"ndrome that ma" also inlude intelletual disabilit", s!eifi brain malformations, or a host of multi!le on$enital anomalies& @or the sa0e of brevit" and larit", $eneti disorders that an ause sei#ures -ill be bro0en into the follo-in$ ate$ories: • • • • •
S"ndromes in -hih sei#ures are ommon Chromosomal deletion or du!liation s"ndromes that ause sei#ures Metaboli diseases Mitohondrial diseases Sei#ure disorders aused b" sin$le.$ene mutations Genetic syndromes "ith seizure disorder A number number of $eneti $eneti s"ndromes s"ndromes are 0no-n 0no-n to ause auses s sei#ures; the therefore, refore, this this list is not meant meant to be authoritative& <o-ever, a number of more ommon s"ndromes should be onsidered in the !atient -ho !resents -ith sei#ures and other findin$s& Angelman Angelma n syndrome An$elman s"ndrome is an inherited inherited disorde disorderr that is most fr fre%uentl" e%uentl" >435? >435? aused b" b" a deletion deletion in the maternall" inherited re$ion of hromosome (H%((&.%(1& A!!ro/imatel" F5 of ases are aused b" !aternal disom" of the same re$ion& An additional ((5 of ases of An$elman s"ndrome are due to se%uene variants in the maternall" inherited %BE&A %BE&A $ene& $ene& Patients -ith An$elman s"ndrome $enerall" have a normal !renatal and birth histor", -ith the first evidene of develo!mental dela" ourrin$ bet-een 4 and ( months of a$e& Sei#ures our in over 3G5 of !atients -ith An$elman s"ndrome, -ith onset before a$e 1 "ears& Patients $enerall" have deeleration of head $ro-th, resultin$ in miroe!hal" b" earl" hildhood& D"smor!hi faies are t"!ial and inlude a !rotrudin$ ton$ue, !ro$nathia, and a -ide mouth -ith -idel".s!aed teeth&and Patients -ith a deletionisalso h"!o!i$mentation& *ntelletual im!airments are t"!iall" severe s!eeh im!airment %uitehave severe, -ith most !atients havin$ feor no -ords& Patients also have ata/ia and fre%uent lau$hter -ith a ha!!" demeanor& 'ett syndrome s"ndrome in in its lassial form is aused b" mutations in the !E(P) $ene, $ene, althou$h other similar Rett s"ndrome forms aused b" different $enes are desribed& Additionall", althou$h Rett s"ndrome has $enerall" been desribed onl" in female !atients >-ith the su!!osition that this -ould be a lethal disease in males?, rare ases have been desribed in males& Patients -ith Rett s"ndrome have a normal !renatal and birth histor" and normal !s"homotor develo!ment for the first 4 months, follo-ed b" deeleration of head $ro-th in most !atients, loss of hand s0ills over the first .1 "ears of life, hand stereot"!ies, soial -ithdra-al, ommuniation d"sfuntion, loss of a%uired s!eeh, o$nitive im!airment, and im!airment of movement& '(H) Sei#ures are re!orted in $reater than 2G5 of females -ith Rett s"ndrome& Sei#ures ma" be of an" '(4)
t"!e, but $enerali#ed toni.loni and om!le/ !artial sei#ures are the most ommon& Pitt-*op+ins syndrome
Pitt.<o!0ins s"ndrome s"ndrome is lassiall" aused b" mutations in the T(, T(, $ene, $ene, althou$h several forms of Pitt.<o!0insli0e s"ndrome have been desribed& Patients -ith Pitt.<o!0ins s"ndrome have severe intelletual disabilit", miroe!hal", and little or no s!eeh& 7he" also have an unusual breathin$ !attern harateri#ed b" intermittent h"!erventilation follo-ed b" !eriods of a!nea& Patients -ith Pitt.<o!0ins also have distintive faies, -hih ma" not be a!!arent in earl" hildhood& 7hese features inlude miroe!hal" -ith a oarse faial a!!earane, dee!l" set e"es, u!slantin$ !al!ebral fissures, a broad and bea0ed nasal brid$e -ith a do-nturned nasal ti!, a -ide mouth and flesh" li!s, and -idel" s!aed teeth& 7here is also a tenden" to-ard !ro$nathism& Sei#ures are seen in this s"ndrome, -ith one stud" re!ortin$ a fre%uen" of G5& '(F) Earlier studies su$$ested that around HG5 of !atients -ith Pitt.<o!0ins have sei#ures& Tuberous sclerosis 7uberous slerosis om!le/ is aused b" mutations in the TS(. TS(. or or TS() $enes& $enes& Ma6or features of '(3) this disease inlude the follo-in$ : • • • • • • • • • •
• • • • • • • • •
@aial an$iofibromata n$ual or !eriun$ual fibromas <"!o!i$mented maules Connetive tissue nevi Retinal hamartomas Cortial tubers Sube!end"mal nodules or $iant ell astro"tomas Cardia rhabdom"omas "m!han$iom"omatosis Renal an$iom"oli!omas Minor features inlude the follo-in$: Dental enamel !its Retal hamartomas Bone "sts Cerebral -hite matter mi$ration lines in$ival fibromas onrenal hamartomas Retinal ahromi !athes Confetti s0in lesions Renal "sts A definite definite dia$nosis dia$nosis of tuberous tuberous slerosis re%uires re%uires ma6or features features or ( ma6or ma6or and minor features& features& A !robable dia$nosis of tuberous slerosis re%uires ( ma6or and ( minor feature& More than 3G5 of !atients -ith tuberous slerosis are re!orted to have sei#ures, althou$h this ma" be an overestimate& <o-ever, this dia$nosis should al-a"s be stron$l" onsidered in the ase of infantile s!asms& Prader-/illi syndrome Prader.9illi s"ndrome s"ndrome is most fre%uentl" >FG5? aused b" a deletion in the !aternal inherited !ortion of hromosome (H%((&.%(1& 7he remainder of ases are aused b" maternal uni!arental disom" of hromosome (H, om!le/ hromosomal rearran$ements, or defets in s!eifi im!rintin$ enters& Patients -ith Prader.9illi s"ndrome have neonatal h"!otonia and failure to thrive durin$ infan"& Patients have h"!er!ha$ia, and onset of -ei$ht $ain ours bet-een a$e ( and 4 "ears& Affeted individuals also have mild.moderate intelletual im!airment, h"!o$onadism, and harateristi faies onsistin$ of a narro- bifrontal diameter, almond.sha!ed e"es, a round fae, and do-nturned orners of the mouth& <ands and feet -ill tend to be small for si#e& Sei#ures our in a!!ro/imatel" (G.G5 of !atients& Sturge-/eber syndrome
Stur$e.9eber s"ndrome has s"ndrome has an un0no-n ause and a!!ears to our in a s!oradi fashion& 7his disorder is harateri#ed b" intraranial vasular anomalies alled arteriovenous malformations and !ort.-ine stains on the fae& Patients -ith Stur$e.9eber s"ndrome also have sei#ures and $lauoma& 7he sei#ures an be ver" diffiult to ontrol in some of these !atients&
#hromosomal deletion or duplication syndromes "ith seizures Chromosomal % deletion s"ndrome s"ndrome is a s!etrum of findin$s aused b" a deletion on hromosome %((&& 7his disorder has !reviousl" been 0no-n b" a variet" of names, inludin$ Dieor$e s"ndrome, veloardiofaial s"ndrome, Sh!rint#en s"ndrome, J!it# BBB s"ndrome, and Ca"ler as"mmetrial r"in$ faies, amon$ others& 7he most ommon features of this s"ndrome are on$enital heart disease, !alate anomalies, h"!oalemia, immune defiienies, and learnin$ diffiulties& Sei#ures our in F5 of !atients -ith hromosomal % deletion s"ndrome& '(2) 9olf.<irshhorn s"ndrome is aused b" deletions of hromosome +!(4&1& 7"!ial faies in these !atients inlude a broad nasal brid$e ontinuin$ to the forehead >the Nree0 -arrior helmetO a!!earane?, miroe!hal", hi$h forehead, h"!ertelorism, and hi$hl" arhed e"ebro-s& 7he mouth tends to be turned do-n-ard& ro-th retardation is seen, as is a variable de$ree of intelletual disabilit"& Althou$h sei#ures are !resent in bet-een HG.(GG5 of !atients -ith 9olf.<irshhorn s"ndrome, the" tend to im!rove -ith a$e& 'G) Chromosomal (!14 deletion s"ndrome is harateri#ed b" d"smor!hi faies, inludin$ strai$ht e"ebro-s, dee!l" set e"es, a lon$ !hiltrum, and miroe!hal"& All !atients -ith this s"ndrome have develo!mental dela" and h"!otonia, and ++.H35 have sei#ures& '()
Metabolic disorders that can cause seizures Man" different metaboli disorders an ause sei#ures, some as a result of a metaboli disturbane suh as h"!o$l"emia or aidosis and some as a !rimar" manifestation of the sei#ure disorder& Some sei#ures are res!onsive to administration of ertain vitamins >e$, !"rido/ine.res!onsive or folini aid. res!onsive sei#ures?& Pero/isomal bio$enesis disorders, -hih an ause sei#ures, result from homo#"$osit" for mutation in one of the man" PE0 $enes& $enes& Jne of these disorders, ell-e$er s"ndrome, !resents in the neonatal !eriod as h"!otonia, sei#ures, and he!ati d"sfuntion& Death t"!iall" ours from res!irator" failure -ithin the first "ear of life& Con$enital disorders of $l"os"lation are a $rou! of disorders that >as their name su$$ests? involve malfuntion in one of the man" en#"mes involved in the !ath-a" that attahes ertain oli$osaharides to !roteins& 7hese disorders var" si$nifiantl" in their severit" and harateristi manifestations& <"!otonia, intelletual disabilit", failure to thrivefeedin$ diffiulties, and unusual fat distribution are ommon& Sei#ures our in some ases& Jther rare diseases also ommonl" ause sei#ures, inludin$ the follo-in$: • • • •
euronal eroid li!ofusinosis Disorders of metal and metal ofator defiien" Disorders of neurotransmitter metabolism "sosomal stora$e diseases Mitochondrial diseases Mitohondrial disorders are underdia$nosed but often involve sei#ures and other neurolo$i manifestations& Mitohondrial ene!halom"o!ath", lati aidosis, and stro0eli0e e!isodes >MEAS? s"ndrome is a mitohondrial disorder that is assoiated -ith sei#ures; often, sei#ures are the !resentin$ manifestation& Patients an also have reurrent headahe and vomitin$& M"oloni e!ile!s" -ith ra$$ed red fibers >MERR@? is harateri#ed b" m"olonus, sei#ures, and ata/ia; m"o!ath", hearin$ loss, and vision loss an also our& eneti tests are available for these disorders&
Seizure disorders caused by single$gene mutations
Autosomal dominant dominant noturnal noturnal frontal frontal lobe e e!ile!s" !ile!s" is aus aused ed b" mutati mutations ons in the(*'NA the(*'NA,, (*'NB) , or (*'NA) $enes& $enes& *t is harateri#ed b" noturnal motor sei#ures& 7he severit" of autosomal dominant noturnal frontal lobe e!ile!s" an be variable, an inlude a-a0enin$ e!isodes, and an result in im!ressive d"stoni effets& Affeted individuals are $enerall" other-ise normal, and the atta0s tend to beome less severe -ith a$e& Autosomal dominant dominant 6uvenile 6uvenile m"oloni m"oloni e!ile!s" is aused b" a mutation in one one of a number number of $enes& Patients re!ort m"oloni 6er0s, most ommonl" in the mornin$, but the" an also have both $enerali#ed toni.loni sei#ures and absene sei#ures& 7he onset of this disorder is t"!iall" in late hildhood or earl" adolesene& Beni$n familial neonatal sei#ures are aused b" mutations in the 1(N2) or or 1(N2& $enes 1(N2& $enes and are inherited in an autosomal dominant manner& eonates -ith this disorder -ill e/!eriene toni.loni sei#ures a fe- da"s after birth, and these sei#ures -ill remit -ithin ( month& Most infants -ill have normal develo!ment, but there is a (G.(H5 ris0 of sei#ure disorder later in life& Mutations in other $enes, suh as S(N.A S(N.A,, an ause a ran$e of sei#ure s"ndromes& At the mild end of this s!etrum, !atients ma" have familial febrile sei#ures and ma" other-ise be normal& At the severe end, !atients ma" have severe m"oloni e!ile!s" of infan" >also 0no-n as Dravet s"ndrome?& Mutations in S(N)A S(N)A and and S(N.B S(N.B are are 0no-n to ause $enerali#ed e!ile!s" -ith febrile sei#ures& Mutations in S(N3A S(N3A,, GPA4 , and GP'35 are are 0no-n to ause familial febrile sei#ures& Mutation in GAB'G) is is 0no-n to ause $enerali#ed e!ile!s" -ith febrile sei#ures, and familial febrile sei#ures&
E!idemiolo$" <auser and ollaborators demonstrated that the annual inidene of reurrent nonfebrile sei#ures in Jlmsted Count", Minnesota, -as about (GG ases !er (GG,GGG !ersons a$ed G.( "ear, +G !er (GG,GGG !ersons a$ed 12.+G "ears, and (+G !er (GG,GGG !ersons a$ed F2.3G "ears& B" the a$e of FH "ears, the umulative inidene of e!ile!s" is 1+GG !er (GG,GGG men >1&+5? and 3GG !er (GG,GGG -omen >&35?&') Studies in several develo!ed ountries have sho-n inidenes and !revalenes of sei#ures similar to those in the nited States& *n some ountries, !arasiti infetions aount for an inreased inidene of e!ile!s" and sei#ures&
Pro$nosis 7he !atient=s !ro$nosis for disabilit" and for a reurrene of e!ile!ti sei#ures de!ends on the t"!e of e!ile!ti sei#ure and the e!ile!ti s"ndrome in %uestion& *m!airment of onsiousness durin$ a sei#ure ma" un!reditabl" result in morbidit" or even mortalit"& Re$ardin$ morbidit", trauma is not unommon amon$ !eo!le -ith $enerali#ed toni.loni sei#ures& *n6uries suh as eh"mosis; hematomas; abrasions; ton$ue, faial, and limb laerations; and even shoulder disloation an develo! as a result of the re!eated toni.loni movements& Atoni sei#ures are also fre%uentl" assoiated -ith faial in6uries, as -ell as in6uries to the ne0& 9orld-ide, burns are the most ommon serious in6ur" assoiated -ith e!ile!ti sei#ures&
S%DEP Re$ardin$ mortalit", sei#ures ause death in a small !ro!ortion of individuals& Most deaths are aidental and result from im!aired onsiousness& <o-ever,sudden, <o-ever, sudden, une/!eted death in e!ile!s" >SDEP? e!ile!s" >SDEP? is a ris0 in !ersons -ith e!ile!s", and it ma" our even -hen !atients are restin$ in a !roteted environment >ie, in a bed -ith rail $uards or in the hos!ital?& 7he inidene of SDEP is lo-, about &1 times hi$her than the inidene of sudden death in the $eneral !o!ulation& 7he inreased ris0 of death is seen mostl" in !eo!le -ith lon$.standin$ foal. onset e!ile!s", but it is also !resent in individuals -ith !rimar" $enerali#ed e!ile!s"& 7he ris0 of SDEP inreases in the settin$ of unontrolled sei#ures and in !eo!le -ith !oor mediation
om!liane& 7he ris0 inreases further in !eo!le -ith unontrolled seondar" $enerali#ed toni.loni sei#ures& 7he mehanism of death in SDEP is ontroversial, but su$$estions inlude ardia arrh"thmias, neuro$eni !ulmonar" edema, and suffoation durin$ an e!ile!ti sei#ure -ith im!airment of onsiousness& 7reatment -ith antionvulsants dereases the li0elihood of an aidental sei#ure. related death, and suessful e!ile!s" sur$er" dereases the ris0 of SDEP to that of the $eneral !o!ulation& *n G((, the ational *nstitutes of <ealth >*<? onvened a -or0sho! on SDEP to fous researh summar" of their their re!ort an an be found found efforts and to determine benhmar0s for further stud"& stud"&'1) A summar" at:htt!:---&nbi&nlm&nih&$ov!martilesPMC1((H3G2 at:htt!:---&nbi&nlm&nih&$ov!martilesPMC1((H3G2 &
Patient Eduation 7o !revent in6ur", !rovide eduation about sei#ure !reautions to !atients -ho have la!ses of onsiousness durin$ -a0efulness and in -hom sei#ures are sus!eted& Most aidents our -hen !atients have im!aired onsiousness& 7his is one of the reasons for restritions on drivin$, s-immin$, ta0in$ unsu!ervised baths, -or0in$ at si$nifiant hei$hts, and the use of fire and !o-er tools for !eo!le -ho have e!ile!ti sei#ures and other s!ells of sudden.onset sei#ures& 7he restritions differ for eah !atient beause of the individual features of the sei#ures, the de$ree of sei#ure ontrol, and, in the nited States, state la-s& Jther ountries have more !ermissive or more restritive la-s re$ardin$ drivin$& Che0 state drivin$ la-s before ma0in$ reommendations& Ameria has a lar$e librar" of eduational materials that are available to E!ile!s" @oundation of Ameria has Soiet" is a !rofessional healthare !rofessionals and the $eneral !ubli& 7he Amerian 7he Amerian E!ile!s" Soiet" or$ani#ation for !eo!le -ho ta0e are of !atients -ith e!ile!s"& 7heir 9ebsite !rovides a lar$e amount of redible information& @or !atient eduation information, see the Brain and ervous S"stem Center , as -ell as as E!ile!s" E!ile!s" and and Sei#ures Emer$enies Emer$enies&&
