Advancements in the Treatment of...

ANRV334-ME59-18 ARI 13 September 2007 19:51

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Advancements in theTreatment of EpilepsyB.A. Leeman and A.J. ColeEpilepsy Service, Massachusetts General Hospital, Boston, Massachusetts 02114;email: [email protected]; [email protected]

Annu. Rev. Med. 2008. 59:257–77

The Annual Review of Medicine is online athttp://med.annualreviews.org

This article’s doi:10.1146/annurev.med.58.071105.110848

Copyright c© 2008 by Annual Reviews.All rights reserved

0066-4219/08/0218-0257$20.00

Key Words

seizures, neuroimaging, anticonvulsants, epilepsy surgery

AbstractDiagnostic tools and treatment options for epilepsy have expandedin recent years. Imaging techniques once confined to research lab-oratories are now routinely used for clinical purposes. Medicationsthat were unavailable a few years ago are now first-line agents. Pa-tients with refractory seizures push for earlier surgical intervention,consider treatment with medical devices, and actively seek nonphar-macologic alternatives. We review some of these recent advances inthe management of epilepsy.

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First published online as a Review in Advance on September 20, 2007

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EEG/fMRI:concurrent elec-troencephalographyand functionalmagnetic resonanceimaging

MEG: magnetoen-cephalography

PET: positronemissiontomography

INTRODUCTION

Epilepsy, operationally defined as having orbeing at risk of having recurrent unprovokedseizures, affects an estimated 1.1–2.3 millionpeople in the United States. The diagno-sis of epilepsy confers a greater likelihoodof injury and sudden unexplained death, aswell as a loss of independence and perceivedstigmatization. Patients with epilepsy reportpoorer overall health-related quality of life,and exhibit activity limitations, psychiatric co-morbidities, increased unemployment rates,and lower educational attainment and incomethan those without seizures (1–3). The goal oftreatment is to attain seizure freedom with-out side effects and return patients to normal,healthy lifestyles.

The past several years have brought newdiagnostic aids, medication options, and de-vices for the treatment of seizures. It is not justthe armamentarium that has changed but alsothe way it is used. Imaging techniques onceconfined to research laboratories are now rou-tinely used in clinics. Medications that werenew and unfamiliar a few years ago are nowfirst-line treatments. Patients and physicianspush for earlier surgical intervention to treatrefractory seizures and actively seek alterna-tives in diets and implantable devices. This isan exciting time in epileptology, and below weshare some of the recent developments.

DIAGNOSIS

Successful treatment requires a precise diag-nosis. Recent advances in imaging technologyhelp to identify subtle lesions that may repre-sent epileptogenic foci. Magnetic resonanceimaging, for example, now with phased arraysurface coils (PA MRI) and field strengths of3 Tesla (3T), has signal-to-noise ratios 6 to8 times that of conventional 1.5T scans. PAMRI better defines the gray-white junctionand creates a more uniform signal intensityof normal cortex, allowing better visualizationof abnormalities such as cortical dysplasias. Astudy of 3T PA MRI detected brain lesions

in 65% of patients with focal epilepsy and re-portedly normal standard 1.5T scans. In addi-tion, in 33% of patients with lesions revealedby 1.5T scans, abnormalities were better de-fined on the 3T images (4). A greater ability todetect or characterize subtle lesions may altertreatment strategies.

Although still largely a research tool,concurrent EEG and functional MRI(EEG/fMRI) is now used for clinical pur-poses at some centers. Functional MRI usesblood oxygenation level dependent (BOLD)pulse sequences, which map cerebral bloodflow with millisecond temporal resolution(5). With simultaneous EEG, it is possible tocorrelate areas of altered blood flow with theoccurrence of interictal or ictal discharges (6).This may help to identify foci or networksthat are functionally abnormal during spikesand sharp waves, although they may not berecognized as structural lesions on standardMRI scans (7).

Whereas EEG detects electrical poten-tials, magnetoencephalography (MEG) sensesmagnetic fields created by activity of apicaldendrites, providing a novel technique for thelocalization of ictal and interictal epileptiformactivity (8). An advantage of MEG is the rel-ative lack of signal attenuation by the skulland scalp compared with EEG. MEG, how-ever, only measures those fields tangential tothe scalp. It is most sensitive to discharges inthe neocortical convexities and relatively poorat detecting more mesial sources. AlthoughMEG may identify epileptiform dischargesmissed by routine scalp EEG, its utility con-tinues to be debated.

Nuclear imaging modalities have alsogained popularity, as a growing number ofcenters now have access to this technol-ogy. Positron emission tomography (PET)scanning, for example, is commonly used toaid in localization of seizure foci. Interictalinjection with a radio-labeled tracer, mostoften fluorodeoxyglucose-18 (FDG), mayreveal regions of cellular hypometabolismthat signify underlying abnormal, potentiallyepileptogenic, brain tissue. In contrast, ictal

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single-photon emission computed tomogra-phy (SPECT) uses injection of a technetium-99-labeled tracer at the start of a seizure.This lipophilic tracer is 90% extracted onfirst pass into lipid-rich tissue including brainin proportion to local perfusion. Uptake ofthe tracer by a brain region with actively fir-ing cells, evident on the scan as a focal areaof hyperperfusion, may indicate the regionof seizure onset. SISCOM, a technique inwhich SPECT images obtained during ic-tal and interictal periods are subtracted andcoregistered with MRI, further improves lo-calization. The utility of ictal SPECT may belimited, however, by the logistics of appropri-ately timing the injection and by the sensitivityof various tracers. Nevertheless, this methodis often useful in settings in which the MRI isunrevealing (9).

The availability of minimally invasivetechniques provides additional tools forseizure localization. Older methods for fo-cus identification, such as foramen ovale elec-trodes and epidural pegs, have seen resur-gence. Foramen ovale electrodes are placedpercutaneously through the foramen so thatthey lie along the inferomesial aspect of thetemporal lobe. This allows recordings to beobtained from deep medial structures withoutthe need for surgical placement of depth elec-trodes into brain tissue. Epidural pegs providea method for obtaining recordings over theconvexities through small burr holes, whicheliminates the muscle artifact that may con-taminate scalp leads. This technique may beused to plan for the optimal placement ofgrids or strips, or it may potentially obviatethe need for further invasive recording. Thesemethods, either separately or in conjunction,have been helpful in many cases in which scalpEEG data have been inconclusive (8).

MEDICATIONS

Historically, treatment options for epilepsyhave been limited. Major pharmacologic op-tions included carbamazepine, phenobarbi-tal, phenytoin, primidone, ethosuximide, and

SPECT:single-photonemission computedtomography

AAN: AmericanAcademy ofNeurology

AES: AmericanEpilepsy Society

valproic acid. Though often effective, rel-atively affordable, and familiar, these oldermedications carry the risks of hepatic dys-function, drug interactions, and other signif-icant side effects. Between 1978, when val-proic acid was introduced, and 1993, whenfelbamate was approved, no new anticonvul-sants were approved by the US Food andDrug Administration (FDA). In contrast, inthe past decade, eight new anticonvulsantshave been approved in the United States.These agents typically offer equal efficacy butmay have fewer adverse effects and drug inter-actions than the older generation of medica-tions (9a, 9b). Newer anticonvulsants (listedin reverse order of FDA approval) includepregabalin, oxcarbazepine, zonisamide, leve-tiracetam, tiagabine, topiramate, lamotrigine,gabapentin, and felbamate.

What may be more striking than thenumber of new medications, however, ishow quickly these drugs have become first-line therapies. In 2005, Karceski et al. (10)surveyed 43 epileptologists regarding theirprescribing practices. Lamotrigine was con-sidered a first-line treatment for idiopathicprimary generalized tonic-clonic, absence,simple partial, and secondarily generalizedtonic-clonic seizures, and it was the treat-ment of choice for complex partial seizures.Topiramate was a first-line medication fortreatment of idiopathic primary generalizedtonic-clonic seizures. Oxcarbazepine had be-come the treatment of choice for simple par-tial and secondarily generalized tonic-clonicseizures, and levetiracetam was also an ac-ceptable initial option for treatment of thesepartial-onset seizure types. The survey alsomarked a shift in thinking from as little as fiveyears earlier, when lamotrigine, topiramate,and levetiracetam were often considered tobe second-line agents.

With new treatments, however, oftencomes confusion and a lack of consensus re-garding prescribing practices. The AmericanAcademy of Neurology (AAN) and AmericanEpilepsy Society (AES) have published rec-ommendations for use of many of the newer

www.annualreviews.org • Treatment of Epilepsy 259

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medications (11–13). The choice in a givenpatient, however, continues to be guided byseizure type, patient characteristics and sideeffect profiles. Below we summarize the in-dications, associated adverse events, mech-anisms and pharmacokinetic properties ofthe more recently approved anticonvulsants.These drugs are discussed in the reverse or-der of their approval in the United States(Table 2).

Pregabalin

Pregabalin is the newest anticonvulsant. Itis structurally similar to gabapentin but hasa slightly longer half-life. Although struc-turally related to gamma-amino-butyric acid(GABA), the drug does not have GABA-ergicactivity. Pregabalin binds to the alpha2-deltasubunit of voltage-gated calcium channels, re-ducing calcium influx and thereby decreasingrelease of several neurotransmitters, includ-ing glutamate.

Clinical experience with pregabalin is lim-ited because it was only approved by theFDA in June 2005. The drug is currentlyindicated for adjunctive treatment of partial-onset seizures in adults, on the basis of studiesdemonstrating seizure frequency reductionup to 47.8%–54% in this population (14–16).Our experience suggests that pregabalin mayworsen idiopathic generalized epilepsy.

Initial studies suggest a few potential ad-vantages of pregabalin. The drug is reason-ably well tolerated at starting doses up to600 mg/day (14), although many patientscomplain of dizziness at initial doses above100–150 mg/day. In urgent situations, steadystate can be achieved in as little as 48 h. Pre-gabalin is renally excreted, so it is suitable forpatients with hepatic disease. A lack of hepaticenzyme induction or inhibition is also advan-tageous in that the drug poses little risk forinteraction with other medications.

In addition, pregabalin is generally safe.Serious adverse events included a macu-lopapular rash in one patient, which resolvedafter discontinuation of the drug, as well as

isolated reports of cholestatic jaundice. Thereis no known association of pregabalin withcardiovascular dysfunction; cases of periph-eral edema have been reported, but detailedcardiac testing of those patients has not beendescribed (16). These adverse events are typi-cally dose-related. They tend to occur shortlyafter the medication is started, often withinone week of initiation, and are generallyself-limited, even if the drug is continued.Weight gain has been reported in a substantialfraction of patients chronically treated withpregabalin.

Oxcarbazepine

Oxcarbazepine is FDA approved for use asmonotherapy and adjunctive treatment inchildren (17, 18) and adults (19–21) with par-tial seizures. Oxcarbazepine has rapidly be-come a first-line agent for those with partialseizures and is often preferred in patientswith psychiatric comorbidities because ofits apparent mood-stabilizing effects. Studiescomparing oxcarbazepine monotherapy withphenytoin (22, 23), valproic acid (24), andcarbamazepine (25) demonstrate equivalentrates of seizure freedom in populations withboth partial-onset and primary generalizedtonic-clonic seizures. The AAN/AES guide-lines suggest that although oxcarbazepinemonotherapy is appropriate inpopulationsthat include patients with newly diagnosedpartial and/or generalized seizure disorders,there is insufficient evidence to determineefficacy for those with primary generalizedseizures alone.

The drug was developed as a structuralvariant of carbamazepine, designed to elim-inate the carbamazepine epoxide metabolitethought to cause side effects. Carbamazepineand oxcarbazepine are distinct drugs, withseparate metabolic pathways and somewhatdifferent modes of action and side effectprofiles (26).

Oxcarbazepine exerts much of its ef-fect through 10-monohydroxy metabolite(MHD), an active metabolite not present

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with carbamazepine. Oxcarbazepine blocksvoltage-sensitive sodium channels, stabilizingneuronal membranes and inhibiting repeti-tive firing at lower concentrations than thatrequired by carbamazepine. Increased potas-sium conductance and modulation of voltage-activated calcium channels may also play a rolein its anticonvulsant effect. The interactionoccurs at the N-, P-, and R-type calcium chan-nels rather than the L-type channels affectedby carbamazepine.

Metabolites of oxcarbazepine, unlike thoseof carbamazepine, are excreted in the urine, sodosing must be adjusted in patients with renaldisease. The effect on P-450 hepatic enzymesubtypes is minimal, causing only limited druginteractions (see Table 1). Of particular con-cern, however, is the induction of CYP3A4and CYP3A5 enzymes, which may reduceconcentrations of oral contraceptives. Never-theless, oxcarbazepine is associated with fewerhepatic enzyme and drug interactions thancarbamazepine or other older agents.

In general, oxcarbazepine carries lowerrisk of adverse events than the prior gener-ation of anticonvulsants. Clinical experience,however, suggests that oxcarbazepine doeshave adverse effects, often causing headache(26a). Side effects are typically dose-related,and slow titration is recommended to mini-mize risk. Serious side effects include rash andhyponatremia. Rash, when it occurs, gener-ally appears within one month of use. Becausecross reactivity of allergic reactions occurs inup to 27% of patients, those with exfoliativedermatitis from use of carbamazepine shouldnot receive oxcarbazepine. The incidence ofhyponatremia is greater with oxcarbazepinethan with carbamazepine, and is of particularconcern in the elderly and those on sodium-wasting agents. The hyponatremia is mostoften chronic and asymptomatic, developinggradually over the first six weeks of treatment.Sodium levels typically normalize with reduc-tion or cessation of oxcarbazepine treatmentand may respond to fluid restriction. Sodiumlevels should be obtained prior to initiatingtreatment and should be monitored during

the first three months of use in those at risk.No consensus exists as to a threshold for dis-continuation of the drug, although levels lessthan 128 mEq/L and a continuing downwardtrend are worrisome.

Zonisamide

Zonisamide is FDA approved for adjunc-tive treatment of partial seizures in patients16 years of age and older (27, 28). Althoughsome studies demonstrate efficacy in childrenwith partial and generalized epilepsy (29), in-cluding infantile spasms (30) and myoclonicseizures (31), AAN/AES guidelines cautionthat there is insufficient evidence to recom-mend use of zonisamide in children or pa-tients with primary generalized seizures. Fur-ther data are also required to confirm utilityas monotherapy, although zonisamide is oftenused as such for treatment of partial seizuresin adults.

Zonisamide contains a sulfonamide chem-ical structure, precluding its use in patientswith a sulfa allergy. It produces its anticon-vulsant effect by blockade of sodium andT-type calcium channels, thereby stabilizingneuronal membranes. Zonisamide also hasweak carbonic anhydrase–inhibiting activity,but this does not appear to substantially con-tribute to its antiseizure properties.

The medication offers several advantages.First, although the drug undergoes primar-ily hepatic elimination, it does not alter hep-atic metabolism. Hence, zonisamide has fewerdrug interactions than older medications do.Second, estimates of the half-life are as greatas 24–60 h. This long duration enables once-per-day administration, improving compli-ance. Third, the drug may cause weight loss, asopposed to weight gain caused by many alter-native medications. The drug is now availableas a generic formulation, potentially making itmore affordable. Finally, open-label data andanecdotal experience suggest that zonisamidemay have antimigraine properties, providinga reasonable option for those with comorbidheadaches.


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Table 1 Properties of new anticonvulsantsa

Medication Half-life Mechanism Clearance

Hepaticenzymeeffects

Notable druginteractions Cautions

Pregabalin 6 h Likely related toeffects atvoltage-gatedcalcium channels

Renal None None None

Oxcarbazepine 4–9 h Sodium channelblockade; possiblecontribution ofeffect onpotassium andcalcium channels

Renal andhepatic

Minimalinductionandinhibitionofsubtypes

Decreases levels of:carbamazepinedihydropyridines oralcontraceptiveslamotrigine (?)

Increases levels of:phenobarbitalphenytoin

MHD decreased by:verapamilcarbamazepinephenobarbitalphenytoin valproate

Crossreactivity ofhypersensi-tivity tocarba-mazepine;risk of hy-ponatremia

Zonisamide 24–60 h Sodium andcalcium channelblockade

Hepatic morethan Renal

None Levels decreased byhepaticenzyme-inducingmedications:carbamazepinephenytoinphenobarbital

Do not use ifpatient hassulfa allergyor history ofnephrolithi-asis

Levetiracetam 6–8 h Binding at SV2Asynaptic vesicleprotein andhigh-voltagecalcium channels,modulation ofGABA andglycine receptors

Renal,hydrolysis

None None Risk ofpsychiatricside effects

Tiagabine 4–9 h Inhibition ofGABA reuptake

Hepatic None Levels decreased byhepaticenzyme-inducingmedications:carbamazepinephenytoinphenobarbital

Risk of“spike-wave”stupor

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Table 1 (Continued )

Medication Half-life Mechanism Clearance

Hepaticenzymeeffects

Notable druginteractions Cautions

Topiramate 15–23 h Blockade ofvoltage-dependentsodium channels,inhibition ofcarbonicanhydrase,antagonizesAMPA/kainateglutamatereceptors, andmodulatesGABAa-mediatedchloride activity

Renal morethan hepatic

Inductionandinhibition

Decreases levels of: oralcontraceptives (no effectwith topiramate doses<200 mg/d) lithiumdigoxin valproate

Increases levels of:haloperidol phenytoin

Levels decreased byhepaticenzyme-inducingmedications:carbamazepinephenytoin valproate

Do not use ifpatient hassulfa allergyor history ofnephrolithi-asis

Potential sideeffectsincludecognitiveimpairment,open-angleglaucoma,metabolicacidosis,weight loss

Lamotrigine 15–35 h Likely related toinhibition ofvoltage-sensitivesodium channels

Hepatic Minimalinduction

Decreases levels of:valproate oralcontraceptives

Levels decreased by:phenytoin oralcontraceptives

Levels increased by:valproate

Risk of rash,particularlywithconcurrentuse ofvalproate

Gabapentin 4–6 h Unknown; may berelated tovoltage-activatedcalcium channels

Renal None Levels decreased by:Maalox-TC

None

Felbamate 20–23 h Antagonist ofglycinerecognition site ofNMDA receptor

Renal andhepatic

Inductionandinhibition

Increases levels of:valproate phenytoincarbamazepine epoxideb

phenobarbitalDecreases levels of:carbamazepine oralcontraceptives

Levels increased by:valproate

Levels decreased by:phenytoincarbamazepine

Risk ofaplasticanemia,hepaticfailure, andrash

aAbbreviations: MHD, 10-monohydroxy metabolite; GABA, gamma-amino-butyric acid.bElevated levels of the epoxide may cause toxicity.


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Table 2 FDA-approved indications for new anticonvulsants

Medication

Use in partialseizures(simple,complex,

secondarilygeneralized)—

adjunctive

Use inpartial

seizures(simple,complex,

secondarilygeneralized)—monotherapy

Use inabsence

seizures—monotherapy

Use inprimarygeneral-

izedtonic-clonic

seizures—adjunctive

Use inprimary

generalizedtonic-clonicseizures—

monotherapy

Use inLennox-Gastaut

(tonic/atonicand

tonic-clonicseizures)—adjunctive

Use inmyoclonicseizures of

JMEa—adjunctive

pregabalin adultsoxcarbazepine adults,

children ≥2 years of age

adults,children ≥4years of age

zonisamide adultslevetiracetam adults,

children ≥4 years of age

adults,children≥6 yearsof age


tiagabine adults,children ≥12 years ofage

topiramate adults,children ≥2 years of age

adultsb,children ≥10years of ageb


adultsb,children≥10 yearsof ageb

adults,children ≥2years of age

lamotrigine adults,children ≥2 years of age

adultsc,(d) (children) adults,children≥2 yearsof age

(adultsd) adults,children ≥2years of age

gabapentin adults,children ≥3 years ofage, ≥12years of age ifsecondarygeneraliza-tion

(adults andadolescentsb)

felbamatee adults adults adults,children ≥2years of age(≥4 yearsper AAN)

aJuvenile myoclonic epilepsy.bFor initial monotherapy.cOnly FDA approved for conversion to monotherapy in patients receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, orvalproate.dFor initial monotherapy of partial and mixed (partial and generalized) seizure types.eAccording to AAN guidelines, children with partial or generalized epilepsies and patients with Lennox-Gastaut syndrome under age 4 years who areunresponsive or intolerant to first-line agents may also consider use in certain situations when risk/benefit ratio unclear; data limited.( ) = Appropriate for use based on AAN/AES guidelines but not FDA approved for this indication.

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Adverse reactions are typically dose-dependent. Most commonly, patients reportcognitive clouding. Nephrolithiasis may beassociated with zonisamide use. Concomitantadministration of other carbonic anhydraseinhibitors, such as acetazolamide or topira-mate, may increase the risk for renal stoneformation. The drug should be avoided in pa-tients with a history of nephrolithiasis, andthose taking the medication should be encour-aged to drink sufficient amounts of water. An-other serious risk is that of hypohydrosis withresultant hyperthermia, a rare side effect thatoccurs primarily in children. Zonisamide mayalso cause a rash and, rarely, Stevens-Johnsonsyndrome.

Levetiracetam

Levetiracetam is indicated for adjunctivetreatment of partial epilepsy in adults (32,33) and children aged 4 years and older (34,35) with refractory seizures. Data also sup-port conversion to monotherapy in patientswith refractory partial epilepsy (36). In clini-cal practice, levetiracetam is often prescribedas monotherapy on the basis of its successas an add-on treatment. Use as monother-apy, however, is not currently FDA ap-proved or AAN/AES recommended owingto insufficient data regarding efficacy. Lev-etiracetam is indicated for add-on ther-apy of myoclonic seizures in patients aged12 years and older with juvenile myoclonicepilepsy (37, 38). Most recently, levetiracetamalso received FDA approval for adjunctivetreatment of primary generalized tonic-clonic seizures in adults and children aged6 years and older with idiopathic generalizedepilepsy.

Levetiracetam has rapidly gained popular-ity owing to its ease of administration. Takenorally twice per day, the drug is at steady statewithin three doses and can be rapidly titratedto therapeutic levels. A new intravenous for-mulation is available, indicated for adjunc-tive treatment of partial seizures in adults andas an alternative when oral administration is

temporarily prohibited. Access to intravenouslevetiracetam may increase its off-label usein acute situations, as case reports have in-dicated benefit in status epilepticus (39). Be-cause it has no hepatic effects, levetiracetamis a first-line medication for those with liverdysfunction. The lack of hepatic effects alsominimizes the potential for drug interactions,making levetiracetam a preferred agent forpatients taking multiple medications, such asthose who are elderly, HIV-positive, or onchemotherapy.

Levetiracetam’s mechanism of action is un-known. It does not act at the receptors typ-ically affected by antiepileptic medications.The drug binds to a presynaptic protein,SV2A, located on synaptic vesicles. The pro-tein is probably involved in vesicle fusion tothe presynaptic membrane and may reduceneurotransmitter release, but the relation-ships between SV2A binding and anticon-vulsant properties are unclear. The anticon-vulsant effect of levetiracetam may also berelated to other atypical mechanisms, such asreduction of current through neuron-specifichigh voltage–activated calcium channels andmodulation of the effects of zinc and beta-carbolines on inhibitory GABAa and glycinereceptors.

No serious adverse reactions to levetirac-etam have been reported. Common sideeffects include irritability and behavioralchanges, and in some patients these adverseeffects may be treatment limiting.

Levetiracetam has a particularly wide ther-apeutic range. Hence, levetiracetam levels aretypically not clinically useful, except to deter-mine compliance.

Tiagabine

Tiagabine exerts its anticonvulsant effectvia a novel mechanism involving inhibi-tion of GABA reuptake into neurons andglia. The medication is indicated as adjunc-tive therapy in patients aged 12 years andolder for the treatment of partial seizures(40–42). However, little evidence supports


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its use as monotherapy, in younger chil-dren, or for treatment of generalized-onsetseizures.

There are four reasons why tiagabine isnot commonly prescribed. First, the drugmay not be as effective as others (40–42).Although it is not possible to directly com-pare trials owing to differences in studypopulations, dosages, and design, tiagabineseems to have somewhat lower responderrates than the other newer medications. Sec-ond, tiagabine undergoes hepatic elimination.This makes it a less desirable option for pa-tients with liver disease. Tiagabine itself doesnot alter hepatic enzyme function, but itsmetabolism may be affected by enzyme in-ducers and inhibitors, which raises concernabout drug interactions. Third, the medica-tion takes several weeks to titrate to a ther-apeutic dosage. Fourth and most important,the drug carries the potential for serious sideeffects.

Use of tiagabine may cause a paradoxi-cal increase in seizure activity. New seizuretypes may develop, along with an increasedincidence of nonconvulsive status epilepticus(NCSE) or so-called spike-wave stupor. Ina recent retrospective study of patients withrefractory partial seizures, 7.8% of thosetreated with tiagabine experienced episodes ofNCSE, confirmed by spike- and polyspike-wave discharges on EEG that resolved af-ter discontinuation of the drug (43). In fact,the FDA has issued a safety alert in responseto reports of new-onset seizures and statusepilepticus in patients without epilepsy whowere prescribed tiagabine for other indica-tions. Some patients on tiagabine have devel-oped an encephalopathy that is probably re-lated to seizure activity. These effects do notappear to be dose-related and may developmore than three months after treatment isinitiated. Assertions that frontal lobe epilepsyincreases these risks are controversial and notwell documented in the literature. The mech-anism for development of encephalopathy isuncertain, but is probably related to GABA-mediated pathways.

Topiramate

Topiramate blocks voltage-dependent sodiumchannels, inhibits carbonic anhydrase, actsas an antagonist of 2-(aminomethyl) pheny-lacetic acid (AMPA)/kainate glutamate recep-tors, and modulates GABAa-mediated chlo-ride activity. The mode of action underlyingits anticonvulsant effect, however, remainsunknown.

Topiramate is approved by the FDA as ini-tial monotherapy for partial-onset or primarygeneralized tonic-clonic seizures in patients10 years of age and older. Studies supportingthis indication have shown that patients withpartial (44) and primary generalized tonic-clonic (45) seizures randomized to higherdoses of topiramate had significantly greaterrates of seizure freedom than those on lowerdoses of the drug. Topiramate is also approvedas adjunctive therapy for patients 2 years ofage and older with refractory partial seizures,primary generalized tonic-clonic seizures,and Lennox-Gastaut syndrome. Randomizeddouble-blind add-on studies support its usein these populations, demonstrating greaterreduction in partial-onset seizures (46), pri-mary generalized tonic-clonic seizures (47),and drop attacks (48) compared to placebo.Efficacy and safety of conversion from an-other antiepileptic medication to topira-mate monotherapy have not been adequatelystudied.

Topiramate is advantageous in its broadrange of efficacy. It may also help prevent mi-graines and is at times favored for patientswith comorbid headaches and seizures. Themedication also has mood-stabilizing effects.Topiramate may be less preferable as a first-line agent, however, owing to its long list ofpotential side effects.

Common adverse reactions to topiramateinclude cognitive dysfunction, often associ-ated with word-finding difficulties. Paresthe-sias of fingertips and toes may occur shortlyafter the medication is initiated, probably re-lated to carbonic anhydrase inhibition. Pares-thesias are typically self-limited, resolving

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over weeks. If bothersome or prolonged, iso-lated case reports indicate that potassium sup-plementation at 20–40 mEq per day may behelpful (49), although no placebo-controlledtrials have been published to date. Seriousside effects include nephrolithiasis in 1%–5%of patients, and the drug should be avoidedin those with a history of renal stones. Theacute onset of diminished visual acuity orocular pain should prompt concern aboutopen-angle glaucoma associated with topi-ramate use, typically occurring within thefirst month of treatment. Other possible sideeffects include hypohydrosis, particularly inchildren, and a hyperchloremic, nonanion gapmetabolic acidosis. Transient but significantweight loss may also occur. The risk of theabove side effects appears to be dose-relatedand may be minimized by slow titration. De-spite the mood-stabilizing properties of topi-ramate, there are reports of rare topiramate-induced suicidality. In addition, the drug is asulfa derivative and is contraindicated in pa-tients with sulfa allergies.

Lamotrigine

Lamotrigine has rapidly become a first-lineagent for many seizure types and patientpopulations. It is currently FDA approvedas adjunctive therapy for partial (50–53)and primary generalized tonic-clonic (54)seizures, as well as generalized seizures ofLennox-Gastaut syndrome (55), in patients2 years of age and older. Lamotrigine isalso indicated for conversion to monother-apy in adults with partial seizures receiv-ing treatment with carbamazepine, pheny-toin, phenobarbital, primidone, or valproate(56). Conversion to monotherapy from otheranticonvulsants or from multiple anticonvul-sants is not currently approved. Nor is thedrug approved for initial monotherapy, al-though there is evidence of efficacy in thissituation (57–59). In practice, lamotrigine isoften used as initial monotherapy for partial-onset and primary generalized tonic-clonicseizures. The AAN/AES guidelines also in-

dicate that lamotrigine is effective for newlydiagnosed absence seizures in children (60),although it is not FDA approved for this indi-cation. Anecdotal reports suggest that in somepatients, lamotrigine may worsen myoclonicjerks (61).

Lamotrigine has become a preferred agentfor women planning pregnancy. In multiplepregnancy registries, the rate of fetal malfor-mations in children born to mothers on lam-otrigine monotherapy has been low, 2.5%–2.9%. A single report suggests that within thatrate, there may be an overrepresentation of aspecific malformation, cleft lip or palate (62).Because this finding has not been confirmedin other pregnancy registries, many epileptol-ogists consider lamotrigine to be a first-lineagent in pregnancy. This issue is likely to gen-erate further discussion as additional data be-come available.

Lamotrigine offers several advantages.The drug is considered to be effective andgenerally well tolerated. Although it is me-tabolized by the liver, lamotrigine elicits littlehepatic enzyme induction and no enzyme in-hibition. Hence, there are relatively few druginteractions, making lamotrigine a reasonableoption for the elderly, patients with HIV, andpatients with other underlying medical prob-lems in whom polypharmacy is an issue. Ow-ing to its mood-stabilizing effects, the drughas also become a popular choice for patientswith comorbid depression or bipolar disorder.Lamotrigine is a first-line agent for patientswith renal or hepatic dysfunction, as well. Al-though its metabolism may be affected by hep-atic disease, the drug itself causes little renalor hepatic toxicity.

A few notable drug interactions, however,do exist. Lamotrigine causes a modest re-duction in levonorgestrel levels, and ethinylestradiol may decrease lamotrigine levels. Ad-equate lamotrigine levels may be difficultto attain in the presence of phenytoin, asthis drug induces the metabolism of lam-otrigine. Very high dosages of lamotriginemay be required to yield therapeutic bloodlevels with concomitant phenytoin use. In


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contrast, valproate may significantly increaselamotrigine blood levels. When converting tolamotrigine monotherapy from these anticon-vulsants, lamotrigine levels should be moni-tored carefully. The therapeutic range beginsat 4–6 mcg/ml. Some patients may benefitfrom higher levels, although our clinical ex-perience suggests that levels in the teens posea greater risk for side effects.

Although the drug is typically well tol-erated, a few potential side effects deservemention. Use of lamotrigine carries a riskof rash. The risk appears similar to that as-sociated with phenytoin and carbamazepine,but if a lamotrigine associated rash occurs,it may be very serious and patients shouldbe encouraged to contact a physician imme-diately. Cases of Stevens-Johnson syndromeand toxic epidermal necrolysis have been re-ported. The risk is highest for children andthose on concurrent valproate. Uncommonside effects also include cough and insomnia.

Risks are minimized by slow titration. Ittakes several weeks to properly attain a ther-apeutic dosage; the titration schedule may beconfusing for some patients, and various blis-ter starter packets are available to simplifythe regimen. An even slower titration sched-ule should be employed for those also takingvalproate, and separate starter packets areavailable for that purpose.

The chemical structure of lamotrigine isunrelated to those of the other anticonvul-sants. The mechanism underlying lamotrig-ine’s anticonvulsant effect is uncertain. Thedrug is postulated to act by inhibiting use- andvoltage-sensitive sodium channels, therebystabilizing neuronal membranes and modu-lating release of excitatory neurotransmitterssuch as glutamate.

Gabapentin

Although gabapentin is structurally relatedto GABA, the drug does not act via GABA-ergic mechanisms. The mechanism of its an-ticonvulsant activity is unknown. Animal datasuggest that it binds to a subunit of voltage-

activated calcium channels, but the functionalimportance of this is unclear.

Gabapentin is FDA approved as adjunctivetherapy for partial seizures in patients aged3 years and older and for seizures with sec-ondary generalization in those aged 12 yearsand older. These indications are supported bydouble-blind randomized placebo-controlledstudies (63–65). According to the AAN/AESevidence-based guidelines, gabapentin is alsoa reasonable option as initial monotherapyfor adolescents and adults with newly diag-nosed partial-onset seizures (66), although itis not yet FDA approved for this indication.Insufficient evidence exists to support its useas monotherapy in those with refractory par-tial seizures. The drug has not been shown tobe effective for primary generalized epilepsiesand may in fact worsen myoclonic jerks (67),absence, and primary generalized tonic-clonicseizures.

Gabapentin is typically quite well toleratedwith few drug interactions. Our clinical expe-rience suggests, however, that it is less effica-cious than other available anticonvulsants.

Felbamate

Felbamate, an N-methyl-D-aspartate(NMDA) receptor antagonist, was approvedby the FDA in 1993 for use as adjunctivetreatment (68) or monotherapy (69–71) inadults with partial-onset seizures, and asadjunctive treatment for seizures associatedwith Lennox-Gastaut syndrome in patients2 years of age and older (72). In addition,limited data suggest efficacy as add-on treat-ment for typical and atypical absence seizures(73, 74), partial seizures in children (75), andgeneralized tonic-clonic seizures in adults(76). Although one study demonstrated effi-cacy as monotherapy or adjunctive treatmentfor myoclonic, typical absence, and gener-alized tonic-clonic seizures associated withjuvenile myoclonic epilepsy in adolescentsand adults (77), the results must be inter-preted with caution given the small samplesize.

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The drug appeared to be well toleratedand to cause less sedation than other anti-convulsants. In 1994, however, a “Dear Doc-tor” letter proposed that physicians discon-tinue use of the drug owing to cases of aplasticanemia, with recent estimates suggesting aprevalence of 27–209 cases per million. Thecourse of aplastic anemia depends on theseverity of bone marrow suppression. Reportsalso identified instances of hepatic failure andrash, including Stevens-Johnson syndromeand toxic epidermal necrolysis, associatedwith felbamate use. Although rare, these reac-tions were serious and prompted many physi-cians to discontinue felbamate therapy in theirpatients.

In light of these findings, the AAN issueda guideline for felbamate use (78). The guide-line suggests that felbamate may be an ap-propriate choice for patients over age 4 withLennox-Gastaut syndrome, and for patientsover age 18 with partial seizures refractory tofirst-line anticonvulsants. One may also con-sider use of felbamate in certain situations forchildren with partial or generalized epilep-sies and patients with Lennox-Gastaut syn-drome under age 4 who are unresponsive to orintolerant of first-line agents. Data suggesteda better risk/benefit ratio for treatment withmonotherapy and for continuation in pa-tients who have taken the drug for more than18 months.

The AAN guideline notes that therisk/benefit ratio should be examined care-fully in each patient, however, and that pa-tients should be counseled regarding possi-ble side effects and the recommendations formonitoring. Routine laboratory studies hadnot been shown to be useful, but the man-ufacturer and FDA do recommend liver func-tion tests and blood counts. Because the riskof aplastic anemia declines after one year oftreatment, the value of routine monitoringafter this time period is less clear. The drugshould not be used in patients with a his-tory of hematologic abnormalities, liver dis-ease or systemic lupus erythematosus, patientswho cannot comply with close follow-up, or

patients and guardians unable to provide in-formed consent. Should physicians choose toprescribe felbamate, they are encouraged toregister their patients in the Felbatol Registry(http://www.guideline.gov, 78a).

Vigabatrin

Vigabatrin is a derivative of the inhibitoryneurotransmitter GABA and irreversibly in-hibits GABA transaminase, preventing break-down of the neurotransmitter. The drug wasinitially intended to treat partial seizures inadults. Used in Europe since the late 1980s, itwas found to be effective, particularly as ad-junctive therapy for complex partial seizuresand partial seizures with secondary general-ization (79, 80). The medication appeared tobe relatively well tolerated with minor sideeffects. After several years on the market inEurope, however, it was discovered that vi-gabatrin caused visual field defects in up tonearly 50% of adults (81), with additional casereports in children (82). Some patients alsodeveloped diminished visual acuity, deficits incolor vision, and other retinal abnormalities(81). When FDA approval was sought in 2004,it was denied because of these potential visualeffects. As a recent AAN practice parametersuggests, however, the drug may be effectivefor treatment of infantile spasms, includingspasms in the setting of tuberous sclerosis, forwhich there are few other treatment options(83). Many physicians and parents of these pa-tients obtain the drug from outside the UnitedStates despite the potentially serious sideeffects.

Drugs in Development

Several new compounds are currently indevelopment, and the following drugs arequickly moving along the pipeline (84).Brivaracetam, an SV2A ligand related to leve-tiracetam, recently acquired orphan drug sta-tus for symptomatic myoclonus and is un-dergoing evaluation for add-on treatmentof partial seizures and Unverricht-Lundborg


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disease. Eslicarbazepine acetate, structurallyrelated to carbamazepine and oxcarbazepine,is in phase III clinical trials for the adjunctivetreatment of partial seizures in adults, with re-sults expected this year. Lacosamide, in bothintravenous and oral formulations, is underphase III investigation for the treatment ofpartial seizures. Thought to be effective inpartial-onset seizures, ritigabine and carisba-mate are also in phase III trials (85). A NewDrug Application has been submitted to theFDA for rufinamide, a compound believed tobe efficacious for adults and adolescents withrefractory partial seizures as well as for adultsand children with Lennox-Gastaut syndrome.Each new drug provides additional hope forseizure freedom in patients with epilepsy.

Drug Monitoring

Routine monitoring of anticonvulsant lev-els is not recommended except during preg-nancy, when an increased volume of dis-tribution causes levels to fall and changesin dosage are often required. Levels shouldbe used to address specific concerns, e.g.,to document compliance, assess for toxicity,or aid in management when changing drugregimens or when breakthrough seizuresoccur.

ALTERNATIVES TOPHARMACOLOGICMANAGEMENT

A 2001 study of patients with newly diagnosedepilepsy found that 47% become seizure-freewith the first anticonvulsant prescribed (86).The probability of successful treatment di-minishes with successive trials of differentmedications. Typically patients are consideredto be refractory to medications when theyhave failed three or more anticonvulsants.Failure is defined as breakthrough seizures ofany frequency, often quantified in the liter-ature as at least one seizure within the pastyear. For these patients, ∼30% of those with

epilepsy, alternatives to pharmacologic man-agement should be considered.

The utilization of surgical approaches forrefractory epilepsy has increased. Resectionis an effective treatment with little associatedmorbidity. In the first randomized controlledtrial of epilepsy surgery, 64% of those whounderwent anteromesial temporal lobectomyfor refractory complex partial seizures werefree of seizures that impaired consciousness,compared to 8% of those who received medi-cal management alone. Moreover, 42% of thesurgical patients were completely seizure-free(87). A review of the literature regarding an-teromesial temporal lobectomy and neocorti-cal resections yielded similar results (88). Onthe basis of these data, the practice parameterset by the AAN and AES in 2003 states that re-ferral to a surgical center should be consideredfor patients with refractory, disabling, com-plex partial temporal lobe seizures. A morerecent report demonstrated even more im-pressive statistics, with 73% of those un-dergoing resection for mesial temporal lobeepilepsy rendered seizure-free (89). Unfortu-nately, many potential surgical candidates arenot referred for evaluation or are referred af-ter long delays.

The appropriate timing of surgical inter-vention remains in question. A trial to assessoutcomes of early surgery (the Early Ran-domized Surgical Epilepsy Trial, or ERSET)was unable to recruit a sufficient number ofsubjects. Anecdotal reports and small case se-ries suggest a role for urgent resection inrefractory status epilepticus, although ran-domized controlled trials have not been per-formed. This highlights the need for studiesof treatment strategies for medically refrac-tory seizures.

Implantable devices are an alternative forpatients who are not candidates for, or donot desire, resection. Vagus nerve stimulation(VNS) was the first implantable device de-veloped for treatment of seizures. Its mech-anism of action remains unknown. Electrodeswrap around the left vagus nerve and connectto a generator placed subcutaneously in the

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chest wall. The stimulator delivers prepro-grammed intermittent electrical pulses to thevagus nerve. It may also be activated by theswipe of a magnet to abort a seizure. Duringstimulation, however, patients may experiencecough, hoarseness, or throat pain. Moreover,VNS requires surgical implantation, a costlyprocedure that poses a risk of injury to thenerve and carotid sheath. Very few adult pa-tients (only isolated case reports) are renderedseizure-free by the device, and the risks mustbe weighed against the low probability of sig-nificant benefit. Overall, VNS is not believedto be useful in adults, although some successhas been reported in children with refractoryseizures. The AAN practice guidelines statethat VNS is indicated for those aged 12 yearsand older with refractory partial seizures whoare not candidates for resection (90).

VNS has, however, paved the way for newdevice-driven therapies. A trial is under wayto assess the efficacy of responsive or “closedloop” stimulators. These devices, implantedin the epileptogenic focus, detect epilepti-form activity. They then deliver electricalstimulation to abort the abnormal discharges,thereby preventing the evolution of a clinicalseizure. Some centers are also investigatinguse of deep brain stimulation for the treat-ment of epilepsy. Deep brain stimulation de-livers “scheduled” or “open loop” stimulationto structures such as the thalamus, cerebellum,and hippocampus (91).

The implantation of any device poses asmall risk of infection and hemorrhage. It alsorequires rigorous work-up, as would a surgi-cal resection. For example, one must know theprecise location of seizure onset in order toplan the placement of a closed-loop stimu-lator. This may require invasive EEG moni-toring with recording grids, strips, or depthelectrodes.

Dietary treatments provide an alternative,noninvasive approach for patients with re-fractory seizure disorders. The classic keto-genic diet, developed in the 1920s, recentlygained popularity (92). It involves low carbo-hydrate and high fat intake, with resultant ke-

tosis. The mechanism of action underlying itsefficacy, however, remains unclear. Approxi-mately 20% of children on the diet have a>90% reduction in seizure frequency, with7% seizure-free at one year. Although the dietis most effective in children, adults have alsoattained good results. It is typically used fortreatment of generalized seizures or multipleseizure types but may also be considered forany patient with refractory seizures or intoler-ance of medications. The diet requires mon-itoring of weight, lipid profiles, electrolytes,urinalyses, urine calcium, and creatinine every3–6 months. The risk of hyperlipidemia, how-ever, is relatively low. More common side ef-fects include weight loss, gastrointestinal up-set, and acidosis.

Unfortunately, the diet also tends to berestrictive and unpalatable. A low-glycemic-index diet, allowing more carbohydrates andless fat, provides a less restrictive alternative.The diet is limited to foods that produce rel-atively little increase in blood glucose lev-els. In a study of 20 patients, 50% of thosetreated with this diet had a >90% reductionin seizure frequency (93). A modified Atkinsdiet offers another less restrictive option. Thisdiet yields seizure reduction rates comparableto that of the ketogenic diet but without thelimitations on calories, fluid, and protein. Atsix months, 35% of 20 patients placed on themodified Atkins diet had a >90% improve-ment in seizure frequency, and particular effi-cacy was noted for absence seizures (94). Somesuggest that this diet may be appropriate forpatients with more recent-onset, less refrac-tory seizures than those treated with the keto-genic diet. Overall, dietary therapies are goodoptions for those resistant to or intolerant ofanticonvulsants, with the goal of discontinu-ing or reducing medications. Our clinical ex-perience with adults, however, suggests thatdiets are difficult to maintain.

OTHER TREATMENT ISSUES

Patients with epilepsy often demonstrate sub-tle or transient cognitive dysfunction in areas


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such as attention, language, and memory, de-spite otherwise normal intelligence. Factorsthat may contribute to cognitive difficultiesinclude seizure type, frequency, severity, andage of onset; side effects of treatment; and,perhaps most important, psychosocialand psychiatric comorbidities (95–97). Pa-tients with seizures have a greater incidenceof anxiety, depression, and bipolar disorder,with suicide rates ten times higher than thatof the general population (3). These cognitiveand emotional symptoms may be the mosttroublesome aspects of epilepsy for patients. Ithas become increasingly clear in recent yearsthat those with epilepsy should be screenedfor concurrent cognitive and psychiatricdisorders.

FUTURE DIRECTIONS

Further advancements in the diagnosis andtreatment of epilepsy may stem from the studyof genetics. It has long been accepted thatmany of the primary generalized epilepsieshave a genetic basis. A recent trend in ge-netic studies of epilepsy has been the find-ing of gene mutations resulting in chan-nelopathies. Mutations in genes encodingsodium channel subunits were found to un-derlie various epileptic syndromes of in-fancy, including generalized epilepsy withfebrile seizures plus (GEFS+), severe my-oclonic epilepsy of infancy, and benign famil-ial neonatal-infantile seizures. The syndromeof benign familial neonatal convulsions hasbeen traced to gene mutations causing aber-rant voltage-dependent potassium channels,and mutations that alter voltage-gated chlo-ride channels have been linked to childhoodabsence epilepsy, juvenile absence epilepsy,juvenile myoclonic epilepsy, and epilepsywith grand-mal seizures on awakening(98).

Recent studies have also revealed a geneticbasis to various focal epilepsies. It is an in-triguing notion that such a diffuse process re-sults in a focal brain abnormality, as seen withnicotinic acetylcholine receptor gene muta-tions in autosomal dominant nocturnal frontallobe epilepsy and LGI-1 mutations in familiallateral temporal lobe epilepsy (99).

The importance of these studies may liein their implications for optimizing futuretreatment. For instance, genetic markers thatpredict anticonvulsant response would be in-valuable. Genetic testing might also identifypatients at risk for seizure recurrence,allowing more rapid initiation of treatment.Many of the genetic tests are now commer-cially available, although interpretation of re-sults may be complicated by possible poly-genetic mechanisms or variable penetrance.Currently such testing does not typically playa role in clinical management. If patients ortheir families desire such testing, referral to agenetic counselor should be considered.

SUMMARY

Recent years have brought new tools forthe diagnosis of epilepsy, with advances inMRI techniques, the advent of MEG, in-creased availability of PET and SPECT, anduse of multimodal imaging studies such asEEG/fMRI. Minimally invasive means of in-tracranial EEG monitoring are more com-monly employed, such as epidural pegs andforamen ovale electrodes. A wider rangeof treatment options also exists, includingnew anticonvulsants, dietary therapies, im-plantable devices, and earlier surgical inter-ventions. Great strides have been made in themanagement of epilepsy, as many of today’sstandard diagnostic procedures and first-linetherapies were not available just a few yearsago.

DISCLOSURE STATEMENT

A.J. Cole is a consultant to GlaxoSmithKline, Pfizer, Ortho McNeil, and Abbott Laboratories.B.A. Leeman has received a grant from the UCB Young Investigators Research Program.

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