Choosing Among Antiepileptic Drugs.9

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CHOOSING AMONG

ANTIEPILEPTIC DRUGSNathan B. Fountain

ABSTRACT

Selecting an antiepileptic drug (AED) for treatment of seizures is daunting becausethere are now 20 from which to choose. Following simple principles allows a sys-tematic approach to drug selection. Efficacy studies provide limited information. Forinitial monotherapy of partial seizures, high-level evidence exists for the efficacy oflamotrigine, carbamazepine, oxcarbazepine, and topiramate. For initial monother-apy of generalized seizures, high-level evidence is available for valproate, lamotrigine,

topiramate, and oxcarbazepine. For initial monotherapy of absence seizures, high-level evidence exists for valproate, lamotrigine, and ethosaximide. All second-generation AEDs have efficacy as adjunctive therapy for partial seizures. AEDs areoften useful for comorbid conditions or have properties that should be avoided insome groups. Thus, AEDs should usually be selected on the basis of comorbidconditions, including depression, migraine, chronic pain, obesity, and nephrolithia-sis, or patient characteristics, especially for women of childbearing potential andolder adults.

Continuum Lifelong Learning Neurol 2010;16(3):121135.

GENERAL PRINCIPLESSelecting among antiepileptic drugs(AEDs) is intimidating because there arenow more than 20 AEDs from which tochoose (Table 6-1). However, use of afew basic principles allows a simplesystematic approach to selecting themost appropriate drug. This is facili-tated greatly by the fact that mostsecond-generation AEDs have simplepharmacokinetics and few drug inter-actions compared to the complexity of

conventional AEDs. The foundation ofselecting a proper drug is correctly di-agnosing the problem through a care-ful history and evaluation to ensurethat the spells in question are seizuresand to characterize the seizure typeproperly and determine the etiologyor epilepsy syndrome.

The first principle of AED use is to

select the most efficacious AED for theseizure type or epilepsy syndrome pres-ent. With regard to AED use, seizuresare fundamentally grouped into partialonset (including simple partial, complexpartial, and secondarily generalized),primary generalized tonic clonic, myo-clonic, atonic, and absence becausethese are the categories that share ef-

ficacy for specific drugs. All partial-onset seizure types can be grouped

together because AEDs useful for onetype are useful for another. It is im-portant to also consider infantile spasmsand neonatal seizures in young chil-dren, but this chapter deals with sei-

zures in adults and older children.The second principle is to consider

the side effect profile of each drug and

121

Relationship Disclosure: Dr Fountain has received research support from NeuroPace, Inc., Medtronic, Inc.,Johnson and Johnson, and UCB.Unlabeled Use of Products/Investigational Use Disclosure: Dr Fountain discusses the unlabeled use of someantiepileptic drugs as initial monotherapy. These instances are disclosed.

Copyright # 2010, American Academy of Neurology. All rights reserved.

KEY POINT

A The first principle

of prescribing

an antiepileptic

drug (AED) isto select the

most efficacious

AED for the

seizure type

or epilepsy

syndrome

present.


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the patients unique characteristics. AEDs

should be avoided if they have sideeffects that would be problematic for aspecific patient. The most importantdeterminants are whether the patientbelongs to a special population, suchas older adults, children, or women ofchildbearing potential. Important comor-bid conditions that take advantage of

AED side effects or can be treated byan AED include depression, migraineheadache, chronic pain, and obesity.

When patients fit into one of these

categories, then selecting an AED is of-ten straightforward because only oneor a few AEDs are appropriate.

The third principle is to considerconvenience. Drugs dosed twice perday or less lead to better compliancethan drugs dosed more frequently. Theuse of extended-release preparations ofcarbamazepine, lamotrigine, and valpro-ate allow dosing twice daily, or poten-tially once daily, and zonisamide andphenobarbital can often be dosed onceper day. Some people must use or pre-fer liquid or sprinkle forms, so selectinga drug available in these formulations is

logical. All conventional AEDs are avail-able in liquid preparations as are gaba-pentin, levetiracetam,and oxcarbazepine.

The fourth principle is to select thelowest-cost AED, an increasingly impor-tant consideration. Conventional drugsare least expensive, especially in genericforms. Phenobarbital is the least expen-sive at less than $20 per month and isonly dosed once per day, so it can be ap-propriate for indigent patients withoutinsurance who tolerate it. Conventional

AEDs cost $50 to $100 per month; newergeneric AEDs, $200 to $300 per month;and brand-name second-generation

AEDs, $300 to $600 per month.

Starting and stopping an AED shouldbe done in a specific, simple manner.The titration schedule recommendedfor AEDs by the manufacturer is de-termined from clinical trials, typicallyfrom forced titration studies. In gen-eral, AEDs are better tolerated when

started slower. Therefore, the adageof start low and go slow is best ap-plied. Most people find dose-escalationschedules to be confusing. Many sched-ules recommend increasing the doseevery 3 days. This is problematic be-cause 3-day increments are not logi-cal and it is inconvenient for patients

who fill a 7-day pill box. It is mucheasier for patients to remember tochange doses each week, on a specificday of the week or on the day they fill

122

TABLE 6-1 AntiepilepticDrugs Approvedin the United

States

" Conventional

Carbamazepine

Clonazepam

Clorazepate

Diazepam

Ethosuximide

Phenobarbital

Phenytoin

Primidone

Valproic acid

" Second-Generation

Felbamate

Gabapentin

Lacosamide

Lamotrigine

Levetiracetam

Oxcarbazepine

Pregabalin

Rufinamide

Tiagabine

Topiramate

Vigabatrin

Zonisamide

Continuum Lifelong Learning Neurol 2010;16(3)

KEY POINTS

A The second

principle of

prescribing an

AED is toconsider the

side effect

profile of each

drug and

the patients

unique

characteristics,

eg, depression,

migraine, pain,

obesity, woman

of childbearing

potential,

older adult.

A The third

principle of

selecting an

AED for a

patient is to

consider

convenience

and dosing.

Drugs dosed

twice per day

or less lead

to bettercompliance

than drugs

dosed more

frequently.

A The fourth

principle of

prescribing an

AED is to select

the lowest-cost

AED.

Traditional

drugs are leastexpensive,

especially in

generic forms.

A Starting and

stopping an

AED should be

done in a

specific, simple

manner.

"CHOOSING AMONG AEDs


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their pill box. It may take longer toreach a target dose if an AED is esca-lated by one pill each week, but it is

more likely that it will be tolerated andthe proper dose will be achieved.Monotherapy is recommended when-

ever possible because use of more AEDsincreases the risk of side effects. Drugsshould be overlapped when transition-ing from one to another, but then thefirst drug should be withdrawn to avoidaccumulating unnecessary drugs. Thenew drug should be added and in-creased to the target dose to see that itis effective and tolerated before the first

drug is withdrawn. Before a new AED isadded, the physician should be surethe existing drug is ineffective. The onlymeans to determine that the drug isineffective is to increase the AED doseuntileither seizures come under controlor side effects occur. When side effectsare induced, the dose should be re-duced to the maximum well-tolerateddose. Levetiracetam and gabapentin areexceptions to this rule because manypatients can tolerate extremely largedoses so the maximum tolerated dosemay never be achieved. Levetiracetam isUS Food and Drug Administration (FDA)approved up to 3000 mg/d, but somepatients get benefit from doses up to4000 mg/d or rarely 5000 mg/d. Largerdoses are rarely useful. Gabapentin isFDA approved to 1800 mg/d, but dosesof up to 3600 mg/d are often needed;larger doses rarely induce side effectsbut seem to be no more effective,

possibly because absorption is saturated.If no benefit is seen from these AEDs atthese doses, it is not usually useful toincrease them even if side effects havenot occurred.

COMPARATIVEEFFECTIVENESS STUDIES:INITIAL MONOTHERAPY

The first and most logical question inselecting any drug for any condition is,Which drug is most effective? Un-

fortunately, for AEDs the answer is un-known for initial monotherapy of sei-zures because the question has not

been investigated sufficiently. FDA-approved indications (Table 6-2) donot provide much guidance becausemany drugs that are not approved formonotherapy are nonetheless clearlyuseful in everyday practice. A study isneeded to compare all available AEDs forinitial monotherapy in a single, very large,randomized, blinded controlled trial,looking separately at patients withpartial-onset seizures and those withgeneralized tonic-clonic seizures. Al-

though there is also a need for studiesin absence seizures and all other sei-

zure types, the need is most acute forseizures of partial-onset or unknowntype because this is the largest popu-lation of new-onset epilepsy. Unfortu-nately, such studies do not exist. Instead,

we must rely on: (1) individual efficacystudies, (2) small comparative trials, and

(3) open-label comparative trials.Individual efficacy studies of AEDs

for initial monotherapy ofpartial-onsetseizures have been reviewed and theevidence categorized in an AAN prac-tice parameter.1 These studies are use-ful in understanding which AEDs havebeen studied for specific indicationsbut are not very useful in selectingamong AEDs because the data arelimited for two main reasons. (1) Some

AEDs only have class II monotherapystudies or only have efficacy studies foradjunctive therapy but yet are clearly

useful as monotherapy. In fact, what isthe rationale for suggesting that a drugwould be useful in the difficult circum-stance of adjunctive therapy but yet

would not be useful as initial mono-therapy? (2) Results from one efficacystudy cannot be directly compared toanother, even for identical study de-

signs, because the small variability in-troduced in different studies is likely tomask the small difference in efficacybetween AEDs.

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KEY POINT

A Monotherapy is

recommended

whenever

possiblebecause use

of more AEDs

increases

the risk of

side effects.


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A few studies have compared tradi-tional AEDs as initial monotherapy forpartial seizures. Two Department of Vet-

erans Affairs (VA) Cooperative Trials areseminal studies of traditional AEDs. Thefirst study compared carbamazepine,

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TABLE 6-2 US Food and Drug Administration 2009 ApprovedIndications

Antiepileptic Drug Seizure Types Age (y) Monotherapy

Carbamazepine CPS, GTC, mixed

Clonazepam LGS, akinetic, MYO, ABS Yes

Clorazepate Partial No

Diazepam Convulsive disorders No

Ethosuximide ABS

Phenobarbital NS

Phenytoin CPS, GTC (neurosurgery)

Pregabalin Partial onset Adult No

Primidone NS NS

Valproic acid CPS, ABS Yes

Multiple including ABS No

Felbamate Partial Adults Yes

Partial and generalizedin LGS

Children No

Gabapentin Partial >3 No

Lamotrigine Partial, generalized inLGS, PGTC

>1 Conversion tomonotherapy(>16 years old)

Lacosamide Partial >16 No

Levetiracetam Partial, MYO, PGTC(>6 years old)

>4 No

Oxcarbazepine Partial >2 Yes (>4)

Rufinamide LGS >3 No

Tiagabine Partial >12 No

Topiramate Partial, PGTC, LGS >2 Yes (>10)

Zonisamide Partial Adults No

Vigabatrin Infantile spasms Children Yes

Refractory CPS Adults No

CPS = complex partial seizures; GTC = generalized tonic-clonic seizures;LGS = Lennox-Gastaut syndrome; MYO = myoclonic seizures; ABS = absence seizures;NS = not specified; PGTC = primary generalized tonic-clonic seizures.

Adapted with permission from Fountain NB. Manual of antiepileptic drug therapy. West Islip, NY: ProfessionalPublications, Inc., 2010.



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phenytoin, phenobarbital, and primi-done as initial monotherapy in 622adults.2 Drug failure was defined as

failure to control seizures after 2 yearsor the occurrence of unacceptable sideeffects. As in most studies that use anintent-to-treat analysis, the drug is calleda failure if it causes unacceptable sideeffects even if it controls seizures sothat efficacy is a combination of sei-zure control and tolerability. This studyfound carbamazepine and phenytointo be statistically more efficacious thanprimidone; phenobarbital was interme-diate. The authors concluded that car-

bamazepine and phenytoin are drugsof first choice for partial-onset seizures.This study guided therapy from thetime it was published in 1985 until theapproval of second-generation AEDs be-ginning in 1995.

The second VA Cooperative Trialwas published in 1993 and comparedvalproate to carbamazepine in 206 pa-tients with complex partial and 237patients with secondarily generalizedtonic-clonic seizures.3 Carbamazepinehad better efficacy than valproate forcomplex partial seizures, but no differ-ence was found for control of second-arily generalized seizures. A compositescore that combined efficacy and sideeffects also favored carbamazepine. Thisstudy supported the popular notionthat carbamazepine is preferable to val-proate for complex partial seizures.

Topiramate at doses of 100 mg/d and200 mg/d were compared to standard

drug therapy of new-onset epilepsy ina randomized controlled trial.4 Patientswere assigned to one of two treatmentgroups depending on whether understandard clinical circumstances they

would have been given carbamazepine(presumably for partial-onset seizures)or valproate (presumably for generalized

seizures) No differences were found in avariety of outcomes for the 390 patientsassigned to the group comparing car-bamazepine 600 mg/d to the two topi-

ramate doses. Similarly, no differencewas found in efficacyfor the 223 patientsassigned to valproate 1250 mg/d com-

pared to the two topiramate doses. Al-though the overall number of subjects isrelatively large, the number assigned toeach group is relatively small given thesmall difference expected between treat-ments. Nevertheless, it would seem thattopiramate is at least as effective as thesetraditional agents.

Carbamazepine has been comparedto lamotrigine in five blinded, random-ized clinical trials in new-onset epilepsy,

which were combined in a systematic

meta-analysis.5

The meta-analysis in-cluded 1384 subjects and found thatlamotrigine had the longest time totreatment failure and carbamazepinehad better time to first seizure and rateof seizure freedom at 6 months. In gen-eral, carbamazepine was more likely tobe withdrawn for side effects. There-fore, lamotrigine seems to be bettertolerated than carbamazepine, but amongthose who tolerate carbamazepine, theefficacy is similar to lamotrigine.

The Standard and New AntiepilepticDrugs (SANAD) study was a two-partstudy conducted in the United King-dom to examine the outcome from theuse of common AEDs as initial mono-therapy in the manner employed inclinical practice. Therefore, it was notblinded. One part of the study ran-domized 1721 patients to compare car-bamazepine to four other commonlyused AEDs in patients for whom carba-

mazepine would be selected as the usualstandard therapy.6 Subjects were ran-domized, but the dose titration and finaldose was left up to investigators. Sub-jects who could tolerate the drugs endedup on average daily doses of 249-mglamotrigine, 662-mg carbamazepine,1496-mg gabapentin, 1019-mg oxcarba-

zepine, or 181-mg topiramate. Lamotri-gine had the longest time to treatmentfailure, and carbamazepine had theshortest time to a 12-month remission.

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KEY POINTS

A The first VA

Cooperative

Trial concluded

carbamazepineand phenytoin

were more

efficacious

than primidone

and better

tolerated than

phenobarbital.

A The second VA

Cooperative

Trial found

carbamazepine

was moreefficacious

than valproate

for complex

partial seizures.

A Lamotrigine

is better

tolerated than

carbamazepine,

but among

those who

tolerate

carbamazepine,the efficacy is

similar to

lamotrigine.


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The authors interpret the results tosuggest that lamotrigine is superiorto carbamazepine, as well as superior

to the other drugs tested. There doesseem to be sufficient evidence to sug-gest that lamotrigine and carbamaze-pine are superior to the other drugs.However, the differences between la-motrigine and carbamazepine are smallfor almost all measures, and there is nodifference in the drugs when analysis isconfined to the period when subjects

were on monotherapy with just the drugto which they were randomized. Thismakes it difficult to know whether the

statistical differences are clinically mean-ingful. The open-label nature of thestudy should probably cause us to de-mand a greater difference in outcomesbefore widely changing practice.

Overall, it can be concluded thatclass I evidence is not available todemonstrate that any one AED is clearlymore efficacious than another for initialmonotherapy of partial-onset seizures.Carbamazepine has been the preferredfirst drug, but evidence suggests thatlamotrigine is more efficacious and bet-ter tolerated than carbamazepine, gaba-pentin, and possibly oxcarbazepine.Some evidence also suggests that top-iramate is as efficacious as carbamaze-pine, but analyses have not includedlevetiracetam and other newer drugs.Thus, little evidence compels the choiceof one AED over another for treatment ofpartial seizures. Other unique drug andpatient characteristics are likely to be

helpful in selecting an AED, as will bediscussed later.Initial AED monotherapies for gen-

eralized seizureshave not received thesame attention as for the treatment ofpartial-onset seizures. Generalized mo-tor seizures, principally generalized tonic-clonic seizures, have been studied insome cases, but most new-onset studiesinclude generalized seizures with sei-zures of unknown type or sometimes

with partial seizures on the theory that it

is difficult to determine whether seizuresare partial or generalized early in thediagnosis. The previously mentioned

AAN practice parameter has reviewedindividual efficacy studies of specificdrugs as initial monotherapy for gen-eralized seizures.1 The parameter con-cludes that lamotrigine, topiramate,and oxcarbazepine are efficacious asinitial monotherapy for a population ofmixed partial and generalized seizuresbased on efficacy studies in mixed pop-ulations. Subsequently, a study dem-onstrated the efficacy of levetiracetamin idiopathic generalized epilepsy, but

for adjunctive therapy rather than ini-tial therapy.7

The second part of the SANAD studycompared valproate, lamotrigine, andtopiramate for generalized or unclassi-fied new-onset seizures in 716 patients.8

Valproate had the greatest efficacy forgeneralized seizures because of a longertime to treatment failure than topir-amate and shorter time to a 1-yearremission than lamotrigine. Thus, theauthors concluded that valproate is thepreferred drug for treatment of gener-alized seizures.

Absence seizures were historicallytreated with ethosuximide and morerecently with valproate. In 1982, a smalldouble-blind comparativecross-over studyof valproate versus ethosuximide in amixed population of 41 patients withnew-onset or refractory absence sei-zures found valproate to be as effectiveas ethosuximide.9 It was not powered suf-

ficiently to find superiority of either drug,though. The efficacy of lamotrigine fornew-onset absence seizures was dem-onstrated in a prospective withdrawalprotocol.10 A very recently publishedprospective comparative efficacy studycompared valproate, ethosuximide, andlamotrigine for new-onset absence sei-

zures.11Ethosuximide and valproateweremore efficacious than lamotrigine, andethosuximide had less effect on atten-tion. This suggests that ethosuximide is

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KEY POINTS

A The SANAD

study found

lamotrigine and

carbamazepinesuperior to

gabapentin,

oxcarbazepine,

and topiramate,

but it was an

open-label study

so the results are

questionable.

A Overall, it can be

concluded that

class I evidence

is not availableto demonstrate

that any one

AED is more

efficacious

than another

for initial

monotherapy

of partial-onset

seizures.

A The SANAD

study found

better efficacyfor valproate

than for

lamotrigine

or topiramate

for presumed

generalized

seizures.



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the drug of choice for new-onset absenceseizures. However, it is important toremember that ethosuximide is not

effective against motor seizures, so val-proate is usually the drug of choice whenboth absence and generalized tonic-clonic seizures are present. In addition,ethosuximide, like valproate, requiresregular surveillance blood tests, whilelamotrigine does not.

COMPARATIVE EFFECTIVENESSSTUDIES: ADJUNCTIVE THERAPY

Comparative efficacy studies of adjunc-tive therapy for seizures suffer from

the same limitations as initial mono-therapy studies. No large double-blindplacebo-controlled comparative clini-cal trials of all available AEDs exist.Thus, we are again left with examiningdata from individual efficacy studies,meta-analyses, and open-label compar-ative studies.

Individual efficacy studies compar-ing the AEDs to placebo for partial-onset seizures have been performedfor all second-generation and most tra-ditional AEDs because such studies arerequired for FDA approval (Table 6-2).These are double-blind, randomized,placebo-controlled trials as adjunctivetherapy in patients with establishedepilepsy who are taking one to three

AEDs. The efficacy of adding a singleexperimental drug is compared to add-ing placebo. Established epilepsy islogically the first population in whichto study the efficacy of a potential AED

because this population has the great-est need and the potential benefit out-weighs the risk. The usual format is todetermine whether seizure frequencyis reduced more in patients random-ized to the experimental drug than tothe placebo group. Seizure frequency istypically established in a 2-month base-line phase, and patients with at leasttwo (or sometimes at least four) sei-zures per month are randomized toreceive the study drug or placebo in a

3-month treatment phase. Seizure fre-quency typically decreases in a clinicaltrial of AEDs, even in the placebo

group. The usual outcome measure isto determine whether seizure frequen-cy is reduced more in the drug-treatedgroup than the placebo group.

An AAN practice parameter has eval-uated individual efficacy studies foradjunctive therapy of partial seizuressimilar to that reviewed for initialmonotherapy discussed above.12 Notsurprisingly, it concludes that there isevidence of efficacy for all available

AEDs for partial-onset seizures com-

pared to placebo. For generalized sei-zures, data supported only the efficacyof adjunctive topiramate and lack ofefficacy for gabapentin. The practiceparameter does not review compara-tive trials or make any conclusionsabout which AED is more efficacious.

Meta-analyses or comparisons of re-sults from individual efficacy trials ofsimilar design have not found differ-ences that significantly inform practicebecause there are no clear winners.

A seminal careful consideration of meta-analyses of gabapentin, lamotrigine,tiagabine, topiramate, vigabatrin, andzonisamide found each to demon-strate superiority to placebo but noclear demonstration that any one drug

was superior to another.13 Compari-son of meta-analyses of levetiracetam,oxcarbazepine, zonisamide, and rema-cemide appropriately found that rema-cemide alone was not likely to be

effective but did not inform practiceabout drug superiority.14 A combinedmethod of assessing seizure controland side effects of second-generation

AEDs reached a similar conclusion.15

Many Cochrane systematic reviews ofindividual AEDs or paired compari-sons have yielded similar results.

An accepted summary of the efficacydata from adjunctive therapy of partialand generalized seizures is that nocompelling data suggest that one AED

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KEY POINT

A There is evidence

of efficacy

of all second-

generationAEDs for

treatment of

partial-onset

seizures, but

there is not

compelling

evidence that

one is more

efficacious than

another.


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is better than another. If efficacy stud-ies are not particularly useful in select-ing an AED, then what is? The AAN

practice parameter and most expertsrecommend considering unique patientcharacteristics to guide AED selection,such as patient age, concomitant medi-cations, AED tolerability, safety, andefficacy.

The discussion of efficacy for AEDsis complicated by the common occur-rence of significant side effects, whichare especially common and cumber-some for the conventional AEDs. Com-parative efficacy studies take this into

account by use of an intent-to-treatanalysis. This method logically consid-ers a subject a treatment failure ifthe drug is inadequate to control sei-zures. The straightforward situation is

when subjects persist in having sei-zures despite reaching the target doseof the drug. However, subjects wouldalso be considered a treatment failureif they could not tolerate the drugbecause of side effects. Thus, the effi-cacy measure is always a combinationof the drugs ability to control seizuresand its tolerability. A drug may appearbetter because it actually controls sei-zures better or because it has moretolerable side effects.

It is clear that some drugs morecommonly induce side effects thanothers. For example, in the second VACooperative Study, weight gain, hairloss, and tremor were more commonin the valproate-treated group, while

rash was much more common withcarbamazepine.Otherstudies havefoundthat carbamazepine-treated patients havemore side effects than lamotrigine-treated patients.16,17 This might leadto the conclusion that lamotrigine ispreferable to carbamazepine. However,the intent-to-treat analysis compensates

for this and only when a drug wins inthe analysis is it actually better for a

whole population, regardless of whetherit is better tolerated. The situation is

different when selecting drugs for indi-vidual patients where the unique char-acteristics of the patient and the drug

can be taken into account. Each AEDhas common side effects that will not bediscussed in detail here except in re-lation to AED selection in the followingsection.

UNIQUE PATIENT ANDANTIEPILEPTIC DRUGCHARACTERISTICS

Unique patient characteristics usefulin selecting an AED include the pres-ence of comorbidities or being a mem-

ber of a special population (Table 6-3)(Case 6-1). Patients with epilepsy havemany comorbidities, such as depres-sion, migraine, chronic pain, and obe-sity, which can be treated with an AEDfor dual purposes. The presence or pre-disposition to some comorbidities sug-gests that some AEDs should be avoidedbecause their side effects might beparticularly problematic for a particularpatient; for example, the presence ofa history of kidney stones suggeststopiramate and zonisamide should beavoided. Similarly, if a patient is a mem-ber of a special population, such as

women of childbearing potential or

older adults, AEDs can be selected thatare known to be useful in this groupor AEDs can be avoided when theycause problems unique to these groups.

Depression is very common in epi-lepsy, especially temporal lobe epilepsy.Lamotrigine has demonstrated benefi-

cial effects for patients with epilepsy.Lamotrigine reduces depression in pro-spective randomized trials when addedto existing AED therapy and reducesanger, hostility, and depression betterthan levetiracetam.18,19 Valproate hasbeen historically associated with treat-ing comorbid psychiatric disease be-

cause of its use in acute mania. Evi-dence suggests, however, that lamotriginemore effectively improves depressionthan valproate does.20 Nevertheless, if

128


KEY POINTS

A An AED may

appear more

efficacious

in anintent-to-treat

analysis

because it

controls

seizures better

or because

it is better

tolerated.

A Select an AED

based on the

presence of

depression,migraine,

chronic pain,

obesity, woman

of childbearing

potential, or

older age.

A Lamotrigine has

the best

evidence for

efficacy in

treating

depression inpatients with

epilepsy.



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coincidental bipolar disorder is pres-ent, then lamotrigine and valproate aregood choices. Oxcarbazepine reduceddepression in an uncontrolled studyand is also useful in bipolar disorder,

similar to carbamazepine, so it is also areasonable consideration in this cir-cumstance.21

Levetiracetam can cause irritability andanger with psychiatric adverse events

occurring in 10% of patients in a retro-spective review.22 However, the actualrate of levetiracetam-induced psychiat-ric side effects is not known becauseplacebo-controlled clinical trials did

not specifically investigate these typesof side effects, so they may havegone unnoticed. In studies used forFDA registration, irritability did notemerge as a very common event in

129

TABLE 6-3 Antiepileptic Drug Preferences in Special Circumstances

Patient Characteristics Antiepileptic Drug Preferences

Depression Lamotrigine, oxcarbazepine

Migraine Topiramate, valproate

Chronic pain Pregabalin, gabapentin, oxcarbazepine,carbamazepine, lacosamide

Obesity Topiramate, zonisamide

Avoid pregabalin, gabapentin, valproate

Woman of childbearingpotential

Avoid valproate

Older adult Lamotrigine, gabapentin, topiramate

Asian Avoid carbamazepine

Nephrolithiasis Avoid topiramate and zonisamide

Atopic (rash prone) Avoid lamotrigine, carbamazepine

Case 6-1A 30-year-old male construction worker presented with new-onset complexpartial seizures and focal left temporal sharp waves and normal MRI.Which AED should be prescribed?

Comment. Any conventional AED could be selected, except

ethosuximide, which is useful only for absence seizures, or almost anysecond-generation AED. This patient has few unique characteristics thatsuggest one drug is more appropriate than another, based on theinformation available. It would be important to ask specifically aboutcomorbid conditions that would influence drug choice. If he has migraineheadaches, then topiramate would be appropriate unless he has ahistory of kidney stones. If he has depression, then consider lamotrigine.If mood instability is an issue, then consider oxcarbazepine. If cost is anissue, then consider a conventional AED, especially carbamazepine; orconsider phenobarbital if compliance is likely to be an issue. Levetiracetamis not FDA approved for initial monotherapy but is often prescribedbecause it is easy to use, well tolerated, and has a wide therapeutic index.



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levetiracetam-treated patients, but thistype of symptom is unlikely to be cap-tured during routine efficacy trials and

is probably not a very high-frequencyevent. Although the overall rate ofirritability is seemingly low, it can besignificant when it occurs. Therefore, itseems prudent to avoid levetiracetam inpatients for whom irritability would beparticularly problematic. Topiramate hasbeen reported to cause depression, pos-sibly dependent on the dose-escalationrate, but is also being investigated forthe treatment of resistant depression,so its role in treating comorbid depres-

sion is minimal.23

Migraine is common in patients withepilepsy. Valproate has been the histori-cal mainstay for migraine prophylaxis,including in patients with epilepsy. How-ever, valproate is teratogenic and car-ries the risk of hepatitis and other sideeffects that necessitate routine blood

work. Topiramate also has efficacy inmigraine prophylaxis, but because itlacks the end-organ toxicity and appar-ently the teratogenicity of valproate,it is often preferred over valproate

when no other mitigating circum-stances are present. Open-label or single-blind studies have suggested improvedheadache control with zonisamide,24

pregabalin,25 and gabapentin,26 ashasacase series of levetiracetam,27 butdouble-blind placebo-controlled stud-ies for these drugs are lacking. Oxcarba-zepine was not effective for migraineprophylaxis in a placebo-controlled

trial.28

Lamotrigine was less efficaciousfor migraine than topiramate in a smalldouble-blind placebo-controlled trialand only marginally better than pla-cebo,29 confirming the general clinicalimpression that lamotrigine has low ef-ficacy for migraine.

Chronic and neuropathic pain is

not particularly common in patientswith epilepsy, but it is relatively com-mon in the general population, soepilepsy patients with comorbid pain

syndromes are seen somewhat fre-quently. Some AEDs have clearly dem-onstrated utility for pain, while others

lack data. Pain syndromes found tobe responsive to AEDs include diabeticneuropathy, postherpetic neuralgia, tri-geminal neuralgia, spinal cord injurypain, phantom limb pain, fibromyalgia,and cancer pain. Somewhat consistentefficacy across pain syndromes has beenfound for carbamazepine, oxcarbaze-pine, gabapentin, and pregabalin, withlittle effect of topiramate and inconsis-tent effect of lamotrigine, as outlined inan evidence-based review.30 Gabapentin

and pregabalin have been particularlywell studied, especially for postherpeticneuralgia, and pregabalin for fibromy-algia. Peripheral neuropathy pain hastraditionally been treated with carba-mazepine, but randomized controlledtrials demonstrate efficacy of gabapentin,pregabalin, and lacosamide, althoughnot all of these drugs have regulatoryapproval for this indication. Topiramatehas not generally been efficacious forpain syndromes.

Obesity is a common problem, es-pecially in people with epilepsy whoare less active. Pregabalin, gabapentin,and valproate can cause weight gainand should be avoided when that pos-sibility is a problem. Topiramate andzonisamide can cause weight loss, sothis characteristic may be useful forobese patients. Conversely, it meansthat these drugs should be avoided incachectic patients.

Women of childbearing potentialhave several considerations in selectingan AED. The most important issue isthe avoidance of highly teratogenic

AEDs. Pregnancy registries have dem-onstrated that valproate is associated

with a major congenital malformationrate of approximately 10%, especially athigh doses.31 The risk of birth defectsin the general population is approxi-mately 2%. Lamotrigine is probably notassociated with an increase in the overall

130


KEY POINT

A Topiramate and

valproate have

the best

evidence forefficacy against

migraine

headache in

patients with

epilepsy.



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risk of birth defects, but among the birthdefects that develop, cleft lip and pal-ate are more common. Surprisingly

little systematic data have been col-lected on older AEDS,32 but it appearscarbamazepine is not associated with asignificant increase in teratogenicity.The risk for other AEDs is not wellknown because registries have not yetaccumulated enough pregnancies. How-ever, the risk does not appear to be highfor topiramate and levetiracetam. Therates for phenobarbital and phenytoinare still relatively unknown using con-temporary study methods. Overall, it is

reasonable to avoid valproate in wom-en of childbearing potential and con-sider using lamotrigine, which has aknown, but low, rate of malformation(Case 6-2).

Elderly patients constitute a specialpopulation because they are morelikely to be on multiple medications,have other systemic illnesses, and tol-erate drugs less well than younger pa-tients with epilepsy. Carbamazepinehas been the traditional drug of choice,but like phenytoin and phenobarbital,it induces hepatic enzymes, which isa particular problem in older adultsbecause of potential drug interactions.In addition, these drugs have a narrowtherapeutic index. Some randomizedcontrolled trials in older adults have

not found lamotrigine to have greaterefficacy than carbamazepine or gaba-pentin, but lamotrigine is better toler-

ated, leading some to conclude that itis preferable.16,33 A placebo-controlledstudy of low-dose topiramate (50 mg)and high-dose topiramate (200 mg) inolder adults found them to be equallyefficacious as initial monotherapy, butthe higher dose was more efficaciousas adjunctive therapy.34 These data in-dicate that topiramate is better thanplacebo but do not indicate whether itis better than lamotrigine or alternativedrugs. Other AEDs have not had con-

trolled comparative trials in older adults.Thus, lamotrigine, gabapentin, topira-mate, and carbamazepine are efficaciousin older adults and reasonable consid-erations. Which of these drugs is betterremains unknown, but the second-generation agents, especially lamotrigineand topiramate, are better tolerated(Case 6-3).

A few drugs have idiosyncratic sideeffects that occasionally influence drugchoice. Topiramate and zonisamide areassociated with kidney stones. Althoughit is not known whether a history ofkidney stones predisposes to develop-ing them again in patients treated withthese drugs, it is prudent to avoidthese drugs in patients with a historyof kidney stones.

131


Case 6-2A 21-year-old woman presented with the recent onset of generalizedtonic-clonic seizures after a week of sleep deprivation during springbreak. She also had occasional early morning arm jerks, and her EEGdemonstrated generalized polyspike-and-wave discharges, suggesting thatshe has juvenile myoclonic epilepsy.

Comment. Valproate should be avoided because she is likely to needlong-term AED use and valproate is significantly teratogenic. Lamotriginehas an established low risk of teratogenicity and is often selected.However, lamotrigine has a very long dose-escalation phase to avoid rash.Topiramate is useful although the low teratogenic risk is not as wellestablished. Levetiracetam is efficacious but has only been studied asadjunctive therapy, and the teratogenic risk is also not well established.

KEY POINTS

A Valproate,

gabapentin,

and pregabalin

can causeweight gain,

and topiramate

and zonisamide

can cause

weight loss.

A Conventional

enzyme-inducing

AEDs, such as

phenytoin and

carbamazepine,

should be

avoided inolder adults.


12/15

Rashes in patients with epilepsy areusually mild and, indeed, are probably

most often unrelated to an AED. Thesedrugs, however, can cause serious rash,such as Steven-Johnson syndrome ortoxic epidermal necrolysis. Lamotrigine

was commonly associated with rash inclinical trials (1:50 children), but theincidence has decreased dramatically

with the practice of starting at lowdoses and using slow dose escalation.No reliable risk factors have beenidentified that will predict who willdevelop rash, but it is prudent to avoidlamotrigine in atopic patients. If suchpatients are treated with lamotrigineand do develop a rash, it will be dif-ficult to determine whether lamo-trigine is responsible. Carbamazepineis associated with rash, particularlyin patients with a human leukocyteantigen-B1502 genotype. This geno-type is particularly common in the

Asian population. Therefore, it has beenrecommended to check this laboratory

test prior to starting carbamazepine inAsian patients or to avoid carbamaze-pine in this group.

A few AEDs should not be selectedas initial monotherapy and are proba-bly best prescribed by epilepsy spe-cialists because of potential problems.

Vigabatrin is associated with progres-sive visual field loss. Felbamate wasassociated with hepatitis and aplasticanemia within 1 year of its approval,although no additional cases have been

reported since then. Rufinamide is notknown to be associated with any par-

ticular problems and is approved forLennox-Gastaut syndrome. It has ef-ficacy for refractory partial seizuresbut is best reserved for treatment ofrefractory epilepsy until enough pa-tients have been treated to determine

whether rare significant side effects willoccur.

CONCLUSION

The few comparative efficacy studiesof AEDs for the treatment of par-tial onset seizures do not convincinglydemonstrate that one drug is clearlymore efficacious than others for ini-tial monotherapy in this seizure type.

Although lamotrigine has received themost attention and appears to bebetter tolerated than carbamazepine,other drugs have not been examinedcarefully. Thus, an AED should be se-lected on the basis of comorbid condi-tions or patient characteristics. Similar

issues exist for generalized seizures.Although valproate, topiramate, andlamotrigine have been most widelycompared, the presence of comorbidconditions and special circumstancesare likely to be more useful in guid-ing selection of an AED. Taking timeto learn the principles outlined here

will considerably simplify the selectionof an AED and allow the neurologistto approach selection of an AEDsystematically.

132


Case 6-3A 67-year-old man presents with new-onset complex partial seizures dueto cryptogenic epilepsy. Which AED should be prescribed?

Comment. Lamotrigine is well tolerated and likely to have few druginteractions. Topiramate, oxcarbazepine, pregabalin, and levetiracetamare also often selected for similar reasons although levetiracetam has notbeen studied as initial monotherapy. Carbamazepine is a considerationif cost is an issue, but the patient will also incur the cost of blood workthat would be avoided with the second-generation medications notedpreviously. Phenytoin should be avoided because of potential for druginteractions and it is poorly tolerated in older adults.



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