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1 Epilepsy & Behvior 15 (2009) Contents lists vilble t ScienceDirect Epilepsy & Behvior journl homepge: Drug tretment of epilepsy: Options nd limittions Dieter Schmidt * Epilepsy Reserch Group, Goethestrsse 5, D Berlin, Germny rticle info bstrct Article history: Received 18 Februry 2009 Accepted 19 Februry 2009 Avilble online 21 Februry 2009 Keywords: Adverse drug effects Strting AEDs Choice of AEDs Drug-resistnt epilepsy Psychitric comorbidity Stopping AEDs The modern ntiepileptic drug (AED) er spnning period of more thn 150 yers from the first use of bromide in 1857 to 2008 hs seen the introduction into clinicl prctice of diverse group of effective nd sfe drugs. These AEDs hve provided considerble benefits for those fflicted with epilepsy of ll kinds. In s mny s 60 70% of newly treted ptients, current AEDs led to stisfctory control of seizures nd fvorble risk benefit blnce for the gret mjority of ptients, lbeit with considerble differences in response depending on the type of seizure nd epilepsy syndrome nd rre serious dverse events. Unfortuntely, in 20 30% of ptients, epilepsy cnnot be controlled. Ptients with drug-resistnt epilepsy often hve serious comorbidity, including injury, depression, nxiety, nd incresed mortlity. The im of ntiepileptic tretment should be to control seizures s quickly s possible with no or miniml side effects nd with no negtive impct on the qulity of life. Improved seizure control is likely to reduce the morbidity nd incresed mortlity ssocited with uncontrolled epilepsy. In this short overview, the options nd the limittions of treting ptients with epilepsy re briefly summrized. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Antiepileptic drugs provide stisfctory control of seizures for most ptients with epilepsy. Seizures in bout 65% of ptients with new-onset epilepsy respond, seizure recurrence occurs in 5%, nd 35% hve uncontrolled epilepsy. Seizure precipittion cn be voided by lifestyle chnges, prticulrly in dolescents with idiopthic generlized epilepsy. If two or three drug regimens hve not brought complete seizure control, the dignosis of epilepsy nd of the epilepsy syndrome should be reevluted, nd if refrctory epilepsy is confirmed, surgicl options should be considered in suitble cndidtes. In this short overview, the options nd the limittions of treting ptients with epilepsy re briefly summrized. For extensive discussion nd detiled references, see textbooks nd monogrphs [1 3]. 2. Currently used ntiepileptic drugs The following ntiepileptic drugs (AEDs) hve been pproved by regultory gencies in the United Sttes nd Europe: cetzolmide, crbmzepine, clonzepm, clorzepte, ethosuximide, ethotoin, felbmte, gbpentin, lcosmide, lmotrigine, levetircetm, mephenytoin, methsuximide, oxcrbzepine, phenobrbitl, phenytoin, pregblin, primidone, tigbine, topirmte, trimethdione, vlprote, vigbtrin, nd zonismide. The following dditionl gents re used minly for the cute therpy * Fx: E-mil ddress: [email protected] of sttus epilepticus: dizepm, fosphenytoin, lorzepm, midzolm, nd propofol. Prgmticlly, the choice of AED mong firstline gents needs to be individulized minly on the bsis of the ptient profile, including the efficcy for the seizure or the epilepsy syndrome, tolerbility, sfety, ese of use, phrmcokinetics (in considertion of the current or likely future need for concomitnt mediction for comorbidity), nd finlly cost. AEDs provide stisfctory control of seizures for most ptients with epilepsy. About 65% of ptients with new-onset epilepsy respond, seizure recurrence occurs in 5%, nd 35% hve uncontrolled epilepsy. Seizure precipittion cn be voided by lifestyle chnges, prticulrly in dolescents. If two or three drug regimens hve not brought complete seizure control, the dignosis of epilepsy nd of the epilepsy syndrome should be reevluted, nd if refrctory epilepsy is confirmed, surgicl options should be considered in suitble cndidtes. 3. Strting tretment The decision to strt drug tretment in ptient with unquestionble epilepsy requires creful individul risk benefit ssessment. Although AEDs re ble to prevent further seizures nd reduce the severity of seizures, nd tretment is recommended in ll persons with high risk of seizure recurrence, the side effects of AEDs need to be considered. High-risk fetures for seizure recurrence re symptomtic epilepsy with generlized tonic clonic seizures (GCTS), complex or simple prtil seizures, nd idiopthic generlized epilepsies. Erly tretment fter first GTCS hs, however, not been shown to improve long-term prognosis or lower /$ - see front mtter Ó 2009 Elsevier Inc. All rights reserved. doi: /j.yebeh

2 D. Schmidt / Epilepsy & Behvior 15 (2009) mortlity or the risk of injury [4]. A number of ptients with good prognoses (e.g., uncomplicted febrile seizures, often benign idiopthic prtil epilepsies) my not even require drug tretment. Also, dverse events of AEDs, including centrl nervous system toxicity nd hypersensitivity rections, hve to be blnced ginst the potentil benefit. Psychosocil consequences in cse of nother seizure (e.g., driver s license or n otherwise seizure-sensitive socil setting) my weigh in fvor of drug tretment in some ptients. Drug tretment is usully not indicted if the dignosis of epilepsy is uncertin, if provoked seizures occur tht cn be prevented without drugs, if seizures re rre, nd, lst not lest, if the informed ptient or cregiver does not wnt drug tretment. Recommendtion: Drug tretment of epilepsy is generlly dvisble if disbling seizures occur or cn be resonbly expected to recur sufficiently frequently to dversely ffect the individul more thn the dverse effects of AEDs. The decision to strt tretment fter single seizure needs to be individulized. Even when blocking seizures, AEDs do not seem to fvorbly ffect the course of the underlying epilepsy, which is serious limittion of current AED tretment. 4. Phrmcokinetics of ntiepileptic drugs From clinicl perspective, the idel AED does not require monitoring of plsm concentrtions, is metboliclly inert nd is not involved in dverse drug interctions, nd cn be conveniently given once or twice dy [5]. Unfortuntely, number of currently used clssic AEDs induce or, less commonly, inhibit the cytochrome p450 system, such s crbmzepine (CBZ), phenobrbitl (PHB), nd phenytoin (PHT), or inhibit enzymes involved in glucuronidtion, such s vlprote (VPA) [6]. Fortuntely, modern AEDs re vilble tht re less enzyme inducing, such s oxcrbzepine, or re not metbolized by the oxidtive cytochrome p450 system t ll, such s gbpentin (GBP), levetircetm (LEV), lcosmide (LCM), lmotrigine (LTG), pregblin (PGN), topirmte (TPM), nd zonismide (ZNS), nd therefore re less likely to be involved in drug interctions bsed on enzyme induction. In ddition, VPA nd LTG inhibit metbolic steps involving glucuronidtion nd cn thus be involved in drug interctions (Tble 1). The bsence of drug interctions is very importnt dvntge for n AED. Most ptients with epilepsy re treted for severl yers, nd the mjority need to tke AEDs for their life. The longterm consequences must therefore be tken into ccount. For exmple, girl my wish to use orl contrceptives t some time in the future, or n dult my become overweight or comorbid with depression, nxiety disorders, migrine, or common serious disorders such s crdiovsculr disese, dibetes, nd cncer nd require dditionl mediction. The incresing incidence of epilepsy in the elderly who commonly hve multimorbidity lso requires AEDs tht do not interct. Finlly, one in three ptients with new-onset epilepsy requires combintion or succession of AEDs over her or his lifetime for optiml seizure control. In ddition, AEDs tht interct with other drugs, for exmple, through enzyme induction or enzyme inhibition, will lso disdvntgeously ffect endogenous sexul nd other hormone metbolism, nd my contribute to dverse events. Tking enzyme-inducing CBZ, OXC, PHB, PHT, nd primidone (PRM) my, in contrst to GBP, LTG, nd TPM, below 200 mg/dy, led to reduced efficcy of comediction including orl contrceptives, AEDs, nd other mediction. Adding n orl contrceptive my lower the plsm concentrtions nd efficcy of LTG. Vlprote is not involved in interctions with orl contrceptives, but my, however, inhibit glucuronidtion of, for exmple, LTG. Fewer cliniclly relevnt interctions with drugs or endogenous substnces occur with OXC, TPM, nd VPA insted of clssic enzyme-inducing AEDs, which re the lest dvntgeous gents in tht respect. Finlly, mny clssic AEDs shre the disdvntge of both cusing cliniclly relevnt interctions nd being ffected by other drugs. For ll these resons, bsence of enzyme induction or enzyme inhibition is plus for ny AED. Up to one in three ptients with new-onset epilepsy requires combintion of different AEDs for seizure control. In uncommon cses, even more thn two AEDs my be needed. During combintion therpy, number of drug interctions my rise with clssic AEDs. Drug interctions my interfere with drug efficcy. A prototypic exmple is the combintion of CBZ nd VPA. When VPA is dded to CBZ, dequte VPA plsm concentrtions cnnot be chieved in most cses becuse CBZ lowers the plsm concentrtion of VPA. However, drug interctions my lso increse the plsm concentrtions to toxic levels, for exmple, of LTG in the presence of VPA. Although this combintion is beneficil for mny ptients, tremor my develop nd the combintion hs been shown to be more tertogenic thn LTG lone or in combintion with nother AED, except VPA. However, modern AEDs such s GBP, LEV, LCM, PGN, nd tigbine (TGB) re much better suited for combintion therpy s they re much less or not involved t Tble 1 Simplified synopsis of drug interction properties of common AEDs. Antiepileptic drug Enzyme inducer (CYP) Enzyme inhibitor (CYP, UGT) Effect of drug on disposition of other AEDs Clobzm (CLB) No No No relevnt chnge Felbmte (FBM) No No No relevnt chnge Gbpentin (GBP) No No No relevnt chnge Levetircetm (LEV) No No No relevnt chnge Lcosmide (LCM) No No No relevnt chnge Zonismide (ZNS) No No No relevnt chnge Topirmte (TPM) No (<200 mg/dy) No No relevnt chnge Crbmzepine (CBZ) Yes No LTG, TGB, VPA (..) Ethosuximide (ETS) No No PHT, VPA (N), CBZ (.) Lmotrigine (LTG) Yes Yes No relevnt chnge Oxcrbzepine (OXC) Yes No OXC doses >900 mg (.); CBZ, LTG, PHT, TGB, VPA (..) Phenobrbitl (PHB) Yes No CBZ, LTG, OXC, PHT, TGB, VPA (..) Phenytoin (PHT) Yes No CBZ, LTG, PHT, TGB, VPA (..) Pregblin (PGN) No No No relevnt chnge Primidone (PRM) Yes No see PHB Vlprote (VPA) No Yes CBZ-E, LTG, PB, free PHT (N) Vigbtrin (VGB) No No PHT (.), other AEDs (JI) Note. CYP, Cytochrome p450 System; UGT, Uridine diphosphte-glucuronyl Trnsferse System; CBZ-E, Crbmzepine epoxide; JI, no relevnt chnge; N, increse in plsm concentrtion;., decrese in plsm concentrtion;.., mjor decrese in plsm concentrtion. Source. Modified from Refs. [6,9].

3 58 D. Schmidt / Epilepsy & Behvior 15 (2009) ll in drug interctions mong AEDs. Strting epilepsy tretment with modern nonintercting AEDs cn prevent such complictions. A lrge number of ptients with epilepsy rely on dditionl mediction other thn AEDs for birth control or mngement of disorders. Depression, nxiety disorders, nd migrine re common in ptients with epilepsy. Ptients with epilepsy re not protected from common diseses such s stroke, myocrdil infrction, leukemi, nd cncer, which ll require mediction tht my be interfered with by clssic enzyme-inducing AEDs. Ptients my require tretment with ntibiotics, which increses plsm concentrtion of AEDs nd my thus cuse toxicity. Inititing epilepsy tretment with modern nonintercting AEDs cn prevent such complictions. Recommendtion: Adverse drug interctions cn be minimized by voiding enzyme-inducing or -inhibiting clssic AEDs nd using beneficil combintions of AEDs, if needed, for seizure control. 5. Adverse effects of ntiepileptic drugs Possible dverse effects of AEDs re listed in Tble 2 [7 9]. The min dvntges of some of the modern AEDs include bsence of hypersensitivity rections, weight problems, nd drug interctions tht cuse centrl nervous system toxicity. There is no need for routine lbortory monitoring nd sfety is improved with bsence of life-thretening orgn dmge. Ptients receiving crbmzepine should hve CBC once month for the first yer of therpy. If the white or red blood cell count decreses significntly, the drug should be discontinued immeditely. Ptients receiving vlprote should hve liver function tests every 3 months for 1 yer; if serum trnsminse or mmoni levels increse significntly (to >2 times the upper limit of norml), the drug should be discontinued. An increse in mmoni up to 1.5 times the upper limit of norml cn be tolerted sfely. When n overdose rection occurs, the mount of drug is reduced until the rection subsides. When more serious cute poisoning occurs, the ptient is given ipecc syrup or, if obtunded, lvged. After emesis or lvge, ctivted chrcol is dministered, followed by sline cthrtic (e.g., mgnesium citrte). Hemodilysis my be considered. The suspect drug should be discontinued nd new nticonvulsnt strted simultneously. Recommendtion: Adverse effects of AED tretment cn be minimized by slow-dose escltion up to verge dily mintennce doses (unless increments re needed for seizure control), by voiding enzyme-inducing gents nd polytherpy, if possible, nd by using pproprite well-tolerted modern AEDs for both new-onset cses nd refrctory epilepsy. 6. Choice of ntiepileptic drug Prgmticlly, the choice of AED mong first-line gents needs to be individulized, minly on the bsis of the ptient profile, including efficcy for the seizure or epilepsy syndrome, tolerbility, sfety, ese of use, phrmcokinetics (including current or likely future need for concomitnt mediction for comorbidity), nd finlly cost (Tble 3) Prtil seizures A number of AEDs re recommended on the bsis of their benefit risk blnce (Tble 3) [10,11]. The modern AEDs for therpy of previously untreted dolescents nd dults with prtil epilepsy such s GBP, LTG, LEV, OXC, nd TPM hve number of dvntges compred with clssic AEDs such s CBZ, PHB, PHT, PRM, nd VPA. The new AEDs show brodly similr efficcy, with the possible exception of GBP, which seems to be less efficcious thn CBZ nd t lest s tolerble or more tolerble t dequte dosges thn clssic AEDs for ptients with prtil epilepsy. However, none of Tble 2 Overview of dverse effects of AEDs. CBZ CLB ETS FBM GBP LCM LEV LTG OXC PGN PHB PHT TGB TPM VPA VGB ZNS Erly-onset dverse events Somnolence Dizziness Seizure ggrvtion Gstrointestinl (+) (+) Liver filure + + Hypersensitivity (SJS/TEN ) Rsh Lte-onset dverse events Sedtion (+) Encephlopthy Depression Behviorl problems Psychotic episodes (+) ++ (+) + (+) (+) (+) (+) (+) (+) ++ Leukopeni (+) + + Aplstic nemi Thrombopeni + ++ Megloblstic nemi (+) + + Pncretitis (+) + Nephrolithisis (+) + Osteoporosis (+) + + (+) Hypontremi (+) + Weight gin Weight loss + Cognition impired Tertogenicity ++ Note. (+), Minimlly incresed risk in clinicl use; +, risk higher thn for AEDs without +; ++, highest risk mong AEDs. In generl, lthough exposure to some modern AEDs is still limited, tretment with number of modern AEDs ppers to be dvntgeous compred with tretment with some of the clssic AEDs (see summry of risks). It should, however, be noted tht the incidence of mny erly dverse events shown here cn be lowered by using slow titrtion nd voiding bove-verge dosges nd combintion therpy, if possible. For definitions of AEDs see Tble 1. Source. Modified from Ref. [9]. Stevens Johnson syndrome/toxic epiderml necrolysis.

4 D. Schmidt / Epilepsy & Behvior 15 (2009) Tble 3 Preferred first-line AEDs for new-onset nd refrctory epilepsy in dults. New-onset prtil epilepsies Crbmzepine Gbpentin Lmotrigine Levetircetm Oxcrbzepine Topirmte Vlprote New-onset idiopthic generlized epilepsies Lmotrigine Topirmte Vlprote the modern AEDs ws more efficcious thn CBZ or VPA in their respective comprison groups [12,13]. The first AED leds to complete seizure control in bout 50% of ptients; subsequent regimens with combintion or substitution chieve control in up to 10 15%. One in three ptients remins with uncontrolled prtil seizures. In ddition to the AEDs mentioned, efficcious second-line AEDs such s lcosmide, pregblin, nd zonismide re vilble for combintion if first tretment filed to control seizures. If severl single-drug or combintion regimens with these drugs hve filed, surgicl options should be considered. If not, third-line gents re vilble; these re clobzm, phenobrbitl, phenytoin, primidone, nd tigbine. Less often used gents with either tolerbility or sfety problems or no Clss I evidence for efficcy (cetzolmide, bromide, felbmte, sulthime, vigbtrin) should be used s lst resort. Given their similr efficcy for prtil seizure control, the choice of AED mong first-line gents needs to be individulized bsed minly on the ptient profile including the epilepsy syndrome, tolerbility, gender issues, phrmcokinetics (including current or likely future need for concomitnt mediction for comorbidity), nd cost Generlized seizures Refrctory prtil epilepsies Lcosmide Pregblin Zonismide Clobzm Refrctory idiopthic generlized epilepsies Clobzm Levetircetm Note. For refrctory cses, ll first-line AEDs for new-onset cses re lso considered unless they hve filed during previous tretment. Source. Modified from Refs. [10,11]. A number of AEDs re recommended on the bsis of their benefit risk blnce (Tble 3). Despite requiring different tretment strtegies, typicl bsence seizures nd juvenile myoclonic epilepsy nd relted idiopthic generlized epileptic syndromes re often erroneously grouped with prtil nd other epilepsies under the brod term epilepsy. Furthermore, AEDs re tested nd licensed minly for prtil epilepsies nd there my be inpproprite generliztions for their use in epilepsy. This is exemplified by GBP, CBZ, OXC, nd PHT, which induce myoclonic seizures, nd VBG nd TGB, which induce bsences; they re contrindicted in idiopthic generlized epilepsy, which constitutes more thn one-third of epilepsy. VPA is still the drug of first choice for ptients with idiopthic nd symptomtic generlized epilepsy despite its disdvntges, prticulrly weight gin nd tertogenicity, becuse the efficcy of VPA is unsurpssed by ny modern suitble AED such s LTG nd TPM [4,13] or LEV. Although LTG nd TPM re used for previously untreted dolescents nd dults with generlized or unclssified epilepsies, the efficcy of LTG is inferior to tht of VPA. Absence seizures re fundmentlly different from ny other type of seizures nd, therefore, unique in terms of phrmcologicl tretment. Typicl bsence seizures re often esy to dignose nd tret. VPA, ethosuximide, nd LTG, lone or in combintion, re first-line gents. VPA controls bsences in 75% of ptients nd lso GTCS (70%) nd myoclonic jerks (75%); however, it my be undesirble for some women. Similrly, LTG my control bsences nd GTCS in possibly 50 to 60% of ptients, but my worsen myoclonic jerks; skin rshes re common. Ethosuximide controls 70% of bsences, but it is unsuitble s monotherpy if other generlized seizure types coexist. A combintion of ny of these three drugs my be needed for resistnt cses. Low dosges of LTG dded to VPA my hve drmtic beneficil effect. Clobzm, prticulrly in bsences with myoclonic components, nd cetzolmide my be useful djunctive drugs. Generlized myoclonic seizures re different phrmcologiclly from bsence seizures. If VPA hs filed to control myoclonic seizures, LEV is well-tolerted nd effective dd-on mediction [14]. LEV hs, however, not been tested for tretment of previously untreted juvenile myoclonic epilepsy or other idiopthic generlized epilepsies. PRM nd PHB, which my be lst resort for tretment of refrctory juvenile myoclonic epilepsy, re ineffective nd my even worsen bsence seizures. The epilepsy syndrome my lso ply role. For exmple, LTG, which is effective in children with typicl bsence seizures, my worsen myoclonic seizures in infnts with severe myoclonic epilepsy. Children re, in generl, more vulnerble. Controlled studies of new AEDs in peditric popultions re significntly behind those for dults; consequently, such gents re initilly licensed for dults only. Peditricins hve to lern by success or filure in dily prctice Advntges of modern AEDs The most modern AEDs re less enzyme inducing thn CBZ, PHT, or brbiturtes or less enzyme inhibiting thn VPA, or do not influence heptic enzyme systems t ll. This is why, in generl, tretment with the new AEDs cuses fewer dverse drug interctions. During long-term exposure to some of the newer AEDs, fewer hormonl metbolic disturbnces cn resonbly be expected. Bsed on current evidence, the mjor mlformtion rte ssocited with the use of LTG is similr to tht seen during CBZ tretment or in untreted women with epilepsy nd is lower thn tht observed with VPA tretment. A second, very importnt dvntge of some of the modern AEDs is the bsence of hypersensitivity rections. These dt suggest, in our view, tht modern AED should be preferred over clssic AED when strting drug tretment in ptient with new-onset epilepsy. In ddition, the choice of n AED is lso influenced by the individul s chrcteristics. When first-line AEDs hve brought insufficient results, number of second- nd thirdline AEDs re vilble: As these drugs ll hve quite significnt limittions, with respect to either evidence of efficcy or, t lest in prt, sfety concerns (see Section 5), they re recommended only in cses of disbling refrctory epilepsy. Recommendtion: The choice of AED mong first-line gents needs to be individulized bsed minly on the ptient profile, including the efficcy for the seizure or epilepsy syndrome, tolerbility, sfety, ese of use, phrmcokinetics (including current or likely future need for concomitnt mediction for comorbidity), nd finlly cost nd physicin preference. 7. Finding the optiml dose of n ntiepileptic drug The drug of choice for prticulr type of epilepsy is titrted to the lowest effective dose. If seizures continue, the dily dose is incresed by smll increments to the verge effective dose [9 11]. Except in n emergency, there is no need for rpid titrtion. Most modern AEDs work within severl dys to week of strting tretment. Rpid titrtion is not only unnecessry, but my even be hrmful. It increses the risk of cutneous hypersensitivity rections, for exmple, with CBZ, LTG, nd PHT, nd dds voidble centrl nervous system toxicity, prticulrly during erly PRM therpy. In recent yers it ws determined tht the verge effective dose

5 60 D. Schmidt / Epilepsy & Behvior 15 (2009) chieves seizure control in bout 70 80% of those who respond t ll doses, including bove-verge doses. As consequence, dose increment is useful for only bout 20 30% of those whose seizures re not controlled by well-tolerted verge dose. If seizure control cnnot be chieved with the mximum tolerted dose, dose reduction to the previous verge dose is recommended. If toxic symptoms or high plsm concentrtions indicte n incresed risk of toxicity before seizures re controlled, second AED is dded, gin gurding ginst toxicity. Interction between drugs cn interfere with their rte of metbolic degrdtion. If the ptient does not respond sufficiently, the initil, filed nticonvulsnt is then withdrwn grdully nd trnsfer to monotherpy with the recently dded AED is n option. If the ptient responds well, the combintion of drugs is usully mintined unless side effects require downtitrtion to lower the totl drug lod. Dily dosge for dults nd children is summrized in Tbles 4 nd 5. The time to rech verge dily dosges vries considerbly mong AEDs (Tble 4). Recommendtion: Slow titrtion up to verge mintennce doses is generlly dvisble, becuse rpid dose escltion nd higher-thn-verge dosges cuse dverse events. Higher-thnverge doses re more likely to improve seizure control in only n dditionl 20 30% of ll responders. If the therpeutic benefit is not seen fter further dose escltion, returning to the previous dose will void unnecessry toxicity. 8. Single-drug versus dd-on therpy Once single-drug therpy is not ble to control seizures, ddition of second drug nd substitution monotherpy re common options. When the initilly prescribed AED fils to produce seizure freedom, trnsfer to monotherpy with n lterntive gent (substitution) will led to seizure control in s mny s 15 30% of cses [15,16].Two rndomized controlled trils with mostly old, enzymeinducing AEDs hve compred substitution with combintion therpy nd obtined rther similr outcome [17,18]. There re no conclusive dt fvoring either substitution monotherpy or ddon tretment. Except for ptients with severe idiosyncrtic rections, where substitution is clerly preferble, prgmtic choice is to evlute the combintion first nd to slowly tper nd finlly discontinue the first drug. This my prevent the substitution of prtilly efficcious drug with nonefficcious drug. Reduction of the first drug prevents unnecessry drug exposure in cse of dverse effects. The second drug should be chosen on the bsis of which first drug filed. The use of newer-genertion AEDs tht do not interct with other drugs my possibly provide better outcome for dd-on tretment, which is more vulnerble to dverse drug interctions thn substitution monotherpy. The min dvntges of substitution versus combintion include simplicity llowing cler ttribution of observed clinicl effect, no unnecessry drug lod (overtretment) s in combintion therpy, no detrimentl drug interctions, nd no dverse effects of specific combintions, for exmple, incresed tertogenicity with combintion of VPA nd LTG. Furthermore, trnsfer to monotherpy hs been shown to be useful when combintion therpy hs filed to provide sufficient seizure control. A sfe nd well-communicted trnsfer schedule is s essentil s the choice of optiml gent for the success of either combintion or substitution. Recommendtion: Except for ptients with severe idiosyncrtic rections, where substitution is clerly preferble, prgmtic choice is to evlute the combintion first nd to slowly tper nd finlly discontinue the first drug if the response to the combintion is not impressive. Combining my prevent the substitution of n insufficiently efficcious drug with nonefficcious drug. Reduction of the first drug prevents unnecessry drug exposure in cse of dverse effects. In the decision on the next drug, drugs tht hve filed in the pst should be voided nd modern AEDs tht re better suited for combintion therpy becuse of the bsence of dverse drug interctions should be considered. 9. Monitoring tretment with ntiepileptic drugs Trget plsm AED concentrtions re vilble for number of drugs [see 9]. However, plsm AED concentrtions re less useful to follow thn the clinicl course. Some ptients hve toxic symptoms t low concentrtions, wheres others tolerte higher concentrtions without pprent clinicl symptoms. Some ptients Tble 4 Dosges nd effective plsm concentrtions of often used AEDs for dults. AED Suggested titrtion Suggested rnge of verge trget dose (totl mg/dy; frequency of dosing) Time to rech verge dose (weeks) Trget plsm concentrtion (mg/l) Crbmzepine 200 mg every 3 dys bid or tid Clobzm 10 mg per dy bid 1 Felbmte 300 mg every 7 dys bid, tid Gbpentin 300 mg every 1-3 dys bid, tid 3 Lmotrigine Monotherpy: 25 mg for 2 weeks, 50 mg for the next 2 weeks, then increses qd, bid of mg/week. Add-on in the presence of VPA: 25 mg every other dy for 2 weeks, 25 mg/dy for the next 2 weeks, then increses of mg/week. Add-on in the presence of enzyme-inducing AEDs: 50 mg for 2 weeks, 100 mg for the next 2 weeks, then increses of mg/week. Levetircetm 500 mg every 1 3 dys bid 2 Oxcrbzepine 150 mg every 3 7 dys bid, tid (MHD) Phenobrbitl 50 mg every 7 dys qd, bid Phenytoin mg every 3 5 dys; beyond 200 mg in mg steps bid, tid Pregblin mg every 3 7 dys Primidone mg every 7 dys tid (PHB) Tigbine 6 mg every 5 7 dys tid 5 Topirmte 25 mg for 1 2 weeks; beyond 100 mg, mg per week bid 4 6 Vigbtrin 500 mg every 7 dys bid 2 Vlprote 500 mg every 3 7 dys bid slow relese, tid Zonismide 25 mg Note. qd, once dy; bid, two times per dy; tid, three times per dy; qid, four times per dy. Source. Modified from Ref. [9]. Irrelevnt.

6 D. Schmidt / Epilepsy & Behvior 15 (2009) Tble 5 Dosges of AEDs for children. AED Bromide Acetzolmide Crbmzepine Clonzepm Ethosuximide Felbmte Gbpentin Lmotrigine Levetircetm Oxcrbzepine Phenobrbitl Phenytoin Pregblin Primidone Tigbine Topirmte Vigbtrin Vlprote Zonismide Totl dily dosge, frequency of dosing, titrtion 300-mg strting dose, verge dose (mg/dy up to 2100 mg); time to rech verge dose is 8 weeks 8 30 mg/kg in dily divided doses; not to exceed 750 mg/dy <6 yers old: initilly 5 mg/kg, divided bid, tid, qid; incresed every 5 7 dys up to 20 mg/kg 6 12 yers old: initilly 10 mg/kg bid, mximum 200 mg; incresed by 100 mg/dy t weekly intervls up to mg/kg Initilly mg/kg, mximum 0.05 mg/kg bid, tid; incresed by mg/kg every 3 dys until seizures re controlled or dverse effects occur; for mintennce, mg/kg tid <6 yers old: initilly 15 mg/kg divided bid, mximum 500 mg; incresed every 4 7 dys; for mintennce, mg/kg bid, mximum 1500 mg >6 yers old: initilly 250 mg bid; incresed by 250 mg bid s needed every 4 7 dys; for mintennce, usully mg/kg bid, mximum 1500 mg 4 14 yers old: strt with mg/kg per dy bid or tid; lower dose of PHT nd VPA comediction by 20 30%; increse dose by 7.5 mg/kg per dy every 2 weeks, if needed; do not exceed totl dily dose of 45 mg/kg or 3600 mg mg/kg tid, qid <12 yers old Add-on with ei-aed, no VPA: initilly 0,6 mg/kg/dy for 2 weeks, then 1.2 mg/kg/dy for 2 weeks, mximum15 mg/kg/dy or 400 mg/dy Add-on with ei-aed nd VPA: initilly, 0.3 mg/kg/dy for 2 weeks, then 0.6 mg/kg/dy for 2 weeks, then 1.2 mg/kg/dy in one or two doses,; mximum 5 mg/kg/dy or 200 mg/dy Add-on with VPA, no ei-aeds: initilly, 0.15 mg/kg/dy for 2 weeks, then 0.3 mg/kg/dy for 2 weeks, then 0.6 mg/kg/dy, mximum 5 mg/kg/dy or 200 mg/dy Children ged 4 11/dolescents ged weighing <50 kg: initil therpeutic dose 10 mg/kg bid; dose cn be incresed to 30 mg/kg bid; dose chnges should not exceed 10 mg/kg every 2 weeks; children 620 kg should preferbly strt the tretment with 100 mg/ml orl solution; strting dose of 10 mg/kg dily corresponds to 150, 200, nd 250 mg bid for children weighing 15, 20, nd 25 kg, respectively; mximum dose of 30 mg/kg bid trnsltes to 450, 600, nd 750 mg bid for children weighing 15, 20, nd 25 kg, respectively; dosge in children P50 kg is the sme s for dults P6 yers old: initilly 8 10 mg/kg/dy, incresed every week by 10 mg/kg/dy, mximum 46 mg/kg/dy, given bid Neontes: 3 4 mg/kg, then incresed Infnts: 5 6 mg/kg in one or two divided doses Neontes: initilly 5 mg/kg, bid; for mintennce, usully 5 8 mg/kg bid, tid Use in ptients <17 yers old is not recommended (EMEA SPC) <8 yers: initilly mg t bedtime, incresed by mg/dy every 3 7 dys; for mintennce, usully mg/kg tid, qid Use in ptients <12 yers old is not recommended Initilly mg/kg, incresed mg/kg bid weekly or biweekly; for mintennce, usully 3 6 mg/kg in monotherpy, 5 9 mg/kg in combintion, bid Monotherpy for tretment of West syndrome: strt with 50 mg/kg per dy; up to 150 mg/kg per dy hs been tolerted Initilly mg/kg bid, tid, incresed by 5 10 mg/kg/dy t weekly intervls; for mintennce, usully mg/kg bid, tid Use in ptients <18 yers old is not recommended (EMEA SPC) Note. For trget plsm concentrtions, see Tble 4. ei-aed, enzyme-inducing AED; qd, once dy; bid, two times per dy; tid, three times per dy; qid, four times per dy. Source. Modified from Ref. [9]. respond t very low concentrtions; others do not respond even to very high concentrtions. If tretment is ineffective, monitoring of concentrtion my unmsk irregulr drug complince; conversely, high concentrtion my indicte tht higher dose increment is not likely to led to better response nd, in ddition, involves higher risk of drug toxicity. In ptient with unexplined centrl nervous system toxicity, high plsm AED concentrtions my be useful for dignosis nd mngement of the intoxiction. Except for PHT, for which monitoring is strongly recommended, prticulrly t concentrtions bove 20 mg/l becuse of the nonliner sturtion dose kinetics, monitoring of other AED plsm concentrtions is optionl nd should be individulized. Recommendtion: Except for PHT, for which monitoring is strongly recommended, prticulrly t concentrtions bove 20 mg/l becuse of the nonliner sturtion dose kinetics, monitoring of other AED plsm concentrtions is optionl nd should be individulized (e.g., poor drug complince or dverse events). 10. Mngement of drug-resistnt epilepsy The definition of drug resistnce is elusive. In the brodest sense, ll epilepsy is drug resistnt, becuse drugs re pllitive tretment preventing the clinicl expression of seizures but cnnot ffect the underlying pthologicl stte. In lrge study of ptients evluted nd treted in Glsgow, Scotlnd, Kwn nd Brodie [16] found tht of 470 ptients who hd never before received n AED, 301 (64%) becme seizure free for t lest 12 months during tretment. Of the 248 ptients uncontrolled by the first drug, 113 discontinued the first drug becuse of lck of efficcy; 69 becuse of intolerble side effects; 29 becuse of idiosyncrtic rections; nd 37 for other resons. Only 79 of these 248 ptients (32%) subsequently becme seizure free. The outcome mong these ptients ws strongly ssocited with the reson for filure of tretment with the first drug. Another 12 (11%) ptients in whom tretment with the first drug ws ineffective subsequently becme seizure free. Only 4% dequtely responded to third drug. Similrly, only 3% of ptients responded to two drugs. However, new evidence from severl studies hs suggested tht the results of Kwn nd Brodie [16] my hve been too pessimistic. Long-term observtions indicte tht s mny s 20 30% with pprent drug-resistnt seizures will eventully enter remission fter chnge in drug regimen [see, e.g., 19]. The response to newly dministered AEDs ws highly dependent on pst tretment history. The seizure-free rtes decresed from 61.8% for the first AED to 41.7, 16.6, nd 0% fter one, two to five, nd six or seven AEDs proved inefficient [19]. Although reltive drug-resistnt epilepsy cn be dignosed fter filure of two AEDs, bsolute drug resistnce requires filure of six AEDs, s significnt minority of ptients (16.6%) re rendered seizure free by ddition of newly dministered AEDs even fter filure of two to five ntiepileptic drugs [19]. The good outcome in s mny s one of five ptients indicted tht there is hope, even fter mny yers of hving uncontrolled epilepsy. If epilepsy is considered drug resistnt if tretment for P12 months does not chieve seizure freedom, for whtever reson, s mny s 36% of newly treted ptients re drug resistnt [16]. However, if the definition of frequent nd severe seizures despite optiml tretment is used so tht lterntive therpies including surgery might be indicted, only 5 10% of newly dignosed ptients re estimted to be drug resistnt [20]. The proportion of uncontrolled epilepsy (seizure frequency t lest one per month for 18 months, dopted from [21]) ws 15.6%, corresponding to prevlence of 0.94 per 1000 [22]. There re multiple resons why ptients my be resistnt to AED therpy. An incorrect dignosis my led to ineffective tret-

7 62 D. Schmidt / Epilepsy & Behvior 15 (2009) ment. For exmple, use of CBZ in ptient with bsence seizures nd generlized spike wve ctivity could excerbte seizures. Likewise, treting ptient with complex prtil seizures with ethosuximide is unlikely to be helpful. Certin AEDs such s GBP, PGB, VGB, nd LTG cn excerbte myoclonic seizures. It hs been suggested tht ltered drug permebility cross the blood brin brrier (BBB) my be involved in phrmcoresistnce to AEDs [23]. ATP-dependent multidrug trnsporters such s P-glycoprotein re found in the luminl membrnes of brin cpillry endothelil cells nd re known to ply role in BBB function by limiting drug penetrtion into the brin. Reduced trget sensitivity of use-dependent blockde of voltge-dependent N + chnnels in CBZ-resistnt ptients is nother novel mechnism underlying the development of drug-resistnt epilepsy. Current theories on drug resistnce in epilepsy include the drug trnsporter hypothesis, the drug trget hypothesis, nd novel pproch clled the inherent severity model of epilepsy, which posits tht the severity of the disese determines its reltive response to mediction. Vluble s ech of these hypotheses is, none is currently stnd-lone theory tht is ble to convincingly explin drug resistnce in humn epilepsy. As consequence, it my be of interest to updte nd integrte the vrious hypotheses of drug resistnce nd to explore possible links to the severity of epilepsy. The observtion tht high frequency of seizures prior to onset of tretment is prognostic of incresed severity nd future drug refrctoriness suggests tht common neurobiologicl fctors my underlie both disese severity nd phrmcoresistnce. Such link hs been proposed for depression; however, the evidence for direct mechnistic link, genetic or otherwise, between drug response nd severity of humn epilepsy remins elusive. Although emerging dt from experimentl studies suggest tht ltertions in GABA A receptors my represent one exmple of mechnistic link, clerly more work is needed to explore whether common neurobiologicl fctors my underlie both epilepsy severity nd drug refrctoriness [23]. It is now cler tht lthough the new-genertion AEDs re very useful, they re not ble to reverse drug-resistnt epilepsy in the vst mjority of ptients [24]. The medicl, socil, nd economic consequences of poorly controlled seizures cn be enormous. Recurrent seizures re ssocited with significnt risks for deth, physicl injury, cognitive impirment, nd psychosocil problems. Frequent seizures not only influence qulity of life, morbidity, nd mortlity in epilepsy, but lso significntly increse costs. Recommendtion: Although the exct mechnism(s) of drug resistnce remins elusive, we know tht chnge in regimen in pprently refrctory epilepsy will eventully led to seizure freedom in s mny s one in five ptients. Avoiding resigntion on the side of the ptient nd complcency on the side of the physicin is essentil to the success of medicl tretment. Drug-resistnt epilepsy is ssocited with significnt risks for deth, physicl injury, cognitive impirment, nd psychosocil problems. Erly referrl for exploring surgicl tretment is dvisble; two-thirds of ptients respond to AEDs fter surgery, nd one-third remin seizure-free fter AEDs hve been withdrwn. If surgery is not n option, chnge in medicl regimens nd pllitive vgus nerve stimultion re good options. 11. Limittions of current drug tretment Prophylctic tretment Hed injuries with skull frctures, intrcrnil hemorrhges, focl neurologicl deficits, nd mnesi cuse posttrumtic epilepsy in 25 to 75% of cses. Prophylctic tretment with nticonvulsnt drugs fter the hed injury reduces the probbility of erly posttrumtic seizures during the first few weeks fter the injury, but does not prevent the development of permnent posttrumtic epilepsy months or yers lter. Erly tretment fter second tonic clonic seizure does not improve the long-term outcome of the epilepsy. It is now cler tht lthough the new-genertion AEDs re very useful, mny ptients in whom previous drug regimens were ineffective will not respond to the drugs. A chllenge for the scientific community is to determine the cuses of these drug filures nd circumvent obstcles to seizure control by developing novel tretment strtegies Seizure ggrvtion Seizure ggrvtion is n importnt limittion of current AEDs. Idiopthic generlized epilepsies (IGEs) re prticulrly prone to phrmcodynmic ggrvtion: typicl bsences re consistently incresed by CBZ, VGB, TGB, nd GBP, wheres PHT is less ggrvting. Juvenile myoclonic epilepsy is ggrvted often by CBZ nd less frequently by PHT nd other AEDs. The GTCS tht occur in IGEs my respond to AEDs tht ggrvte the other seizure types. Nonconvulsive sttus epilepticus hs been ssocited with TGB. GBP-ssocited myoclonus ppers to be reltively frequent. It is usully mild nd cn esily be overlooked. Discontinution of therpy is not necessry in most cses. Ptients with symptomtic generlized epilepsies often hve severl seizure types tht respond differently to AEDs: myoclonis re generlly ggrvted by the sme drugs tht ggrvte IGEs; tonic seizures in the Lennox Gstut syndrome respond to CBZ, which, however, my ggrvte typicl bsences. In severe myoclonic epilepsy of infncy, LTG hs nerly constnt ggrvting effect. In some ptients with benign Rolndic epilepsy, cler ggrvtion my be produced by CBZ, with occurrence of negtive myoclonis, typicl bsences, drop ttcks, nd, t the mximum evolution, stte of electricl sttus epilepticus during sleep. Only few medictions cn control IGEs without potentilly cusing seizure ggrvtion. Brod-spectrum AEDs such s VPA, LTG, nd TPM re extremely effective t controlling vriety of seizures without cusing excessive seizure ggrvtion. Among these drugs, VPA hs the longest clinicl experience history nd the lrgest body of published dt Loss of effect (tolernce) Development of tolernce (i.e., reduction in response to drug fter repeted dministrtion) is n dptive response of the body to prolonged exposure to the drug, nd tolernce to AEDs is no exception. Tolernce develops to some drug effects much more rpidly thn to others. The extent of tolernce depends on the drug nd individul (genetic?) fctors. Tolernce my led to ttenution of side effects but lso to loss of efficcy of AEDs nd is reversible fter discontinution of drug tretment. Different experimentl pproches re used to study tolernce in lbortory nimls. Development of tolernce depends on the experimentl model, drug, drug dosge, nd durtion of tretment, so tht bttery of experimentl protocols re needed to evlute fully whether tolernce to effect occurs. Two mjor types of tolernce re known. Phrmcokinetic (metbolic) tolernce, resulting from induction of AED-metbolizing enzymes, hs been shown for most first-genertion AEDs nd is esy to overcome by incresing dosge. Phrmcodynmic (functionl) tolernce is due to dpttion of AED trgets (e.g., by loss of receptor sensitivity) nd hs been shown experimentlly for ll AEDs tht lose ctivity during prolonged tretment. Functionl tolernce my led to complete loss of AED ctivity nd cross-tolernce to other AEDs. Convincing experimentl evidence indictes tht lmost ll first-, second-, nd third-genertion AEDs lose their ntiepileptic ctivity during prolonged tretment, lthough to different extents. Becuse of diverse confounding fctors, detecting tolernce in ptients with

8 D. Schmidt / Epilepsy & Behvior 15 (2009) epilepsy is more difficult, but cn be done with creful ssessment of decline during long-term individul ptient response. After exclusion of confounding fctors, tolernce to ntiepileptic effect for most modern nd old AEDs cn be shown in smll subgroups of responders by ssessing individul or group response. Development of tolernce to the ntiepileptic ctivity of n AED my be n importnt reson for filure of drug tretment. Knowledge of tolernce to AED effects s mechnism of drug resistnce in previous responders is importnt for ptients, physicins, nd scientists [25] Unpredictbility of effects Drug tretment of epilepsy is chrcterized by unpredictbility of efficcy, dverse drug rections, nd optiml doses in individul ptients, which, t lest in prt, is consequence of genetic vrition. Since genetic vribility in drug metbolism ws reported to ffect tretment with PHT more thn 25 yers go, the ultimte gol of phrmcogenetics hs been to use the genetic mkeup of n individul to predict drug response nd efficcy, s well s potentil dverse drug events. However, determining the prcticl relevnce of phrmcogenetic vrints remins difficult, in prt becuse of problems with study design nd repliction. This rticle reviews the published work with prticulr emphsis on phrmcogenetic ltertions tht my ffect the efficcy, tolerbility, nd sfety of AEDs, including vrition in genes encoding drug trget (SCN1A), drug trnsport (ABCB1), drug metbolism (CYP2C9, CYP2C19), nd humn leukocyte ntigen (HLA) proteins. Although the current studies ssociting prticulr genes nd their vrints with seizure control or dverse events hve inherent weknesses nd hve not provided unifying conclusions, severl results, for exmple, tht Asin ptients with prticulr HLA llele, HLA- B * 1502, re t higher risk of developing Stevens Johnson syndrome when using CBZ, re helpful in incresing our knowledge of how genetic vrition ffects the tretment of epilepsy. Although genetic testing rises ethicl nd socil issues, better understnding of genetic influences on epilepsy outcome is key to developing the much needed new therpeutic strtegies for individuls with epilepsy [26]. Recommendtion: Although AED tretment is beneficil for most ptients, AEDs do not prevent epilepsy in persons t risk or drugresistnt epilepsy even when given erly. Aggrvtion of mostly myoclonic or bsence seizures by drugs for prtil seizures is nother problem. Unpredictbility of effect nd loss of effect during prolonged tretment re further issues in drug tretment. 12. Avoidble tretment errors Overtretment The most common voidble tretment errors stem from misdignosis nd indvertent overtretment. Common forms of misdignosis occur erly in the mngement of ptient who is thought to hve epilepsy, but in fct hs syncope with myocloni or psychogenic nonepileptic seizures. Subsequent AED use provides no benefit, even t higher doses, which invribly result in dverse events. Overtretment my, however, lso occur in ptients with unequivocl epileptic seizures. Although complete seizure control is the ultimte gol of phrmcologicl therpy, it should not be sought t ll costs, nd no ptient with epilepsy should suffer more from the side effects of tretment thn from the consequences of the underlying disese. Overtretment is not uncommon in ptients tking AEDs, nd it my occur in mny forms nd by vriety of mechnisms. Long-term use (or continution) of AED therpy in situtions where it is not indicted (e.g., in children with simple febrile seizures or in seizure-free ptients who hve undergone brin surgery) constitutes n overt cse of overtretment. Other forms of overtretment include the use of unnecessrily rpid dose escltion rtes, which my expose the ptient to potentilly serious or severe side effects, or the prescription of unnecessrily high mintennce dosges. The ltter my result from indequte understnding of dose response reltionships, from misinterprettion of serum drug concentrtions (e.g., trgeting concentrtions within the rnge in ptients who re well controlled t lower concentrtions), or, less often, from filure to recognize prdoxicl increse in seizure frequency s sign of drug toxicity. The most common form of overtretment, however, involves the unnecessry use of combintion therpy (polyphrmcy) in ptients who could be treted optimlly with single drug. Adverse effects ssocited with polyphrmcy often result from undesirble drug drug interctions. Although phrmcokinetic interctions re somewht predictble nd cn be minimized or controlled by monitoring serum drug concentrtions nd/or dose djustment, phrmcodynmic interctions leding to enhnced neurotoxicity (s seen, e.g., in some ptients given combintion of LTG nd CBZ) cn be identified only by creful clinicl observtion. There is evidence tht not ll AED combintions re eqully dverse, nd tht the combined use of specific drugs (e.g., LTG nd VPA) my even exhibit n improved therpeutic index in some ptients compred with either gent given lone, provided pproprite dose djustments re mde. In women of childbering potentil, however, the sme combintion is ssocited more often with fetl mlformtions thn either drug lone. Unless nd until we better understnd the complexities of drug combintions, single-drug therpy my void indvertent overtretment ssocited with polyphrmcy Undertretment Unfortuntely, tretment of ptients with uncontrolled epilepsy with suboptiml doses my prevent seizure remission. In every ptient with uncontrolled epilepsy dose increment should be considered unless the ptient hs symptoms nd signs of incipient centrl nervous system or other orgn drug toxicity. It hs been shown tht in s mny s one in three ptients presenting with uncontrolled seizures, incresing the dose led to seizure remission [27]. Recommendtion: Keep it simple; void unnecessry dignostic or therpeutic interventions with n unfvorble risk benefit blnce. It is dvisble to withhold drug tretment until the dignosis of epilepsy is certin. Avoid combintion therpy nd enzymeinducing gents if possible. Both overtretment nd undertretment with AEDs should be voided. 13. Specil tretment needs One of the stndrds of good clinicl cre is to individulize the tretment of epilepsy to the specil needs of the individul with epilepsy. Here we focus on the elderly nd those with mentl helth problems. Other importnt ptient groups re discussed elsewhere [9] The elderly The chnge in phrmcokinetics nd higher sensitivity to dverse events of mny AEDs usully require more cutious dosing in the elderly. In ddition, high comorbidity in the elderly often requires dditionl mediction. To void disturbing drug interctions, AED monotherpy nd the use of modern AEDs tht re not involved or subject to drug interctions, such s GBP [28], low-dose TPM [29], nd LEV (no evidence clss I study vilble), re preferble. Complince my be more difficult in the elderly

9 64 D. Schmidt / Epilepsy & Behvior 15 (2009) with cognitive decline. Multimorbidity with mny comedictions is common. The elderly my hve n incresed susceptibility for dverse events, especilly when treted with CBZ. Atxi my be more frequent in the elderly, nd discontinution of AEDs becuse of dverse events is more common in the elderly thn in younger dults. Lower doses of AEDs re often sufficient becuse tretment response my be better in the elderly. Lower glomerulr filtrtion rtes in the elderly require much lower doses of renlly excreted AEDs; body ft, lbumin, nd cytochrome p450 chnges lso occur in the elderly, nd OXC-relted hypontremi my be more frequent in the elderly. Osteoporosis should not be overlooked in the elderly with epilepsy who re on enzyme-inducing AEDs or VPA. Elderly women with epilepsy present severl unique mngement chllenges. They hve n elevted risk for osteoporotic frcture becuse of the dverse effects of AEDs on bone metbolism, combined with the chnce of trum during seizures nd the subtle effects of AEDs on coordintion tht promote flling. Recommendtion: Epilepsy in the elderly is incresing lthough specilists see surprisingly few elderly ptients with epilepsy. It is dvisble to prefer non-metbolized, non-enzyme inducing new AEDs such s GBP nd LTG in the elderly insted of clssic enzyme-inducing CBZ, if possible. Slow dose escltion nd lowerthn- verge dosges re recommended; AED combintion therpy should be voided, nd cler written instructions re importnt Ptients with mentl helth disorders The lifetime community-bsed prevlence of depression, suicidl idetion, nd generlized nxiety disorder is twofold higher in ptients with epilepsy thn in the generl popultion [30] (Tble 6). Suicide is leding cuse of deth in ptients with refrctory epilepsy. Depression nd, less well known, nxiety disorders re the leding cuses of suicidl deth in epilepsy. Severity of depression (not seizure frequency) seems to be the most importnt correlte for qulity of life. Serotonin reuptke inhibitors cn be given for depression in persons treted with AEDs for epilepsy without worsening of seizure control. Tretment of depression does not seem to ffect seizure control either wy. Reboxetine nd citloprm re good cndidte ntidepressnts for people with epilepsy. Anxiety cn be treted with nxiolytic gents such s buspirone (10 20 mg/dy) [31]. In ptients with uncontrolled epilepsy nd nxiety who require chnge in AED regimen, dd-on tretment with n nxiolytic AED such s PGB my be considered. In ptients with dysthymi nd mood instbility, mood-stbilizing AEDs such s lmotrigine nd vlprote should be considered, prticulrly when chnge in regimen is considered to improve seizure control. Conversely, tretment with PHT or PHB hs been shown to be ssocited with depression in some ptients, even when tretment hs resulted in seizure freedom. In cse both seizure control nd mood stbility re proving resistnt to AEDs, vgus nerve stimultion should be considered. Vgus nerve stimultion hs been Tble 6 Psychitric comorbidity in people with epilepsy nd the generl popultion. Psychitric disorder (lifetime) Percentge (95% CI) Epilepsy, N = 253 No epilepsy N = 36,717 Mjor depressive disorder 17.4% ( ) 10.7% ( ) Mood disorder 24.4% ( ) 13.2% ( ) Anxiety disorder 14.1% ( ) 11.2% ( ) Mood disorder/nxiety disorder/dysthymi 34.2% ( ) 19.6% ( ) Pnic disorder/gorphobi 6.6% ( ) 3.6% ( ) Suicidl idetion 25.0% ( ) 13.3% ( ) Any mentl helth disorder 35.5% ( ) 20.7% ( ) Source. Modified from Ref. [30]. shown to improve seizure control nd mood, prticulrly postictl mood chnges. In ptients undergoing resective surgery for refrctory epilepsy, prticulrly refrctory temporl lobe epilepsy, those becoming seizure free fter surgery often report improved mentl well-being. It is difficult to sy t present if the improvement in mood is specific effect of surgery or if it lso occurs when chnge in AED regimen hs led to seizure freedom in pprently refrctory prtil epilepsy. Recommendtion: Depression nd prticulrly nxiety re often underdignosed in ptients with epilepsy, prticulrly drug-resistnt epilepsy. Tretment with selective serotonin reuptke inhibitors nd nxiolytic gents such s buspirone re s sfe nd effective s in ptient without epilepsy. It is dvisble to void clssic AEDs such s PHT nd PHB, which my contribute to depressive mood, nd to prefer new, mood-stbilizing AEDs such s LTG or nxiolytic AEDS such s PGB. Vgus nerve stimultion should be considered if seizures nd depression prove to be drug resistnt. 14. Stopping therpy with ntiepileptic drugs Strting n AED is much esier thn stopping tretment. The possibility tht the ptient my hve developed serious or cognitive dverse events is n rgument in fvor of discontinuing AEDs. On the other hnd, seizure relpse my hve grve socil consequences, prticulrly in n dult. Drug discontinution fter seizure freedom results in relpse in one-third of ptients. Reinstitution of mediction tht worked for yers fils to chieve control in one of four ptients. These risks need to be considered, lthough there is no evidence tht discontinution is responsible for the poor prognosis of tretment of seizure recurrence in some ptients [32]. However, women in their childbering yers who re seizure free should lso be encourged to stop mediction tht my cuse mlformtions. Studies hve shown tht the risk of seizure recurrence becomes lower with the durtion of prior seizure remission [33]. Ptients who hd been in remission for t lest 2 yers were prospectively rndomized into group tht continued drug tretment nd nother group in which drugs were grdully withdrwn. Two yers fter the study commenced, 78% who continued tretment remined seizure free compred with 59% who hd stopped tretment. However, 5 yers fter withdrwl, there were no differences in seizure relpse rte between the withdrwl nd no withdrwl groups. A met-nlysis of severl studies suggests tht this figure my be s low s 30% [34]. The MRC study identified ge over 16, concurrent therpy with one or more AEDs, seizures fter strting AED therpy, history of secondrily generlized seizures or myoclonic seizures, short period of freedom from seizures, nd bnorml EEG s significnt fctors predicting recurrence. Etiology is importnt, nd ptients with brin lesions or cerebrl plsy my be more prone to recurrence. Although there is no clss I evidence, most ptients with juvenile myoclonic epilepsy re dvised to continue mediction for life. It is probbly dvisble to wit until seizures hve been in remission for t lest 3 yers in remission before considering withdrwl of AED therpy. However, in children with benign epilepsies tht hve welldefined nturl histories, such s those with centrotemporl spikes, shorter periods my be sufficient. Withdrwl of AED therpy should be plnned, grdul, nd lwys one drug t time. Sttus epilepticus is possible, lthough uncommon, with brupt cesstion. No cler guidnce is vilble s to how fst AEDs should be withdrwn. It hs been suggested tht cesstion of therpy over period less thn 6 months results in higher rtes of relpse [35]. However, recent studies hve shown tht more rpid tpering over periods s short s 6 weeks [36] my be just s sfe s slow withdrwls over 6 or more months.

10 D. Schmidt / Epilepsy & Behvior 15 (2009) Conclusion The mjority of ptients with epilepsy will chieve lsting remission on drug tretment. Of those who do not, significnt risks of mortlity nd morbidity exist due to uncontrolled seizures. Seizure freedom is therefore very importnt. Severl new drugs hve been dded to the rmmentrium nd these should be tried in ech refrctory ptient. These re not lwys effective, however, nd surgicl options should be explored. References [1] Levy RH, Mttson RH, Meldrum B, Perucc E, editors. Antiepileptic drugs. Phildelphi: Lippincott, Willims & Wilkins; [2] Shorvon S. Hndbook of epilepsy tretment. Oxford: Blckwell Science; [3] Engel Jr J, Pedley T, editors. Epilepsy: comprehensive textbook, 2nd ed., vols Phildelphi: Wolters Kluwer/Lippincott Willims & Wilkins; [4] Mrson A, Jcoby A, Johnson A, et l. Immedite versus deferred ntiepileptic drug tretment for erly epilepsy nd single seizures: rndomised controlled tril. Lncet 2005;365: [5] Ptslos PN, Perucc E. 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