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Factors influencing tolerabilityThe ability of patients to tolerate initiation of an antiepileptic drug (AED) can be a function of several factors (Box 1), including how rapidly a dose is escalated, the length of time needed to develop tolerance to early toxicity and the rate at which blood levels of a drug increase, as well as complexity of the titration schedule. For some AEDs, initiation with a small dose given at bed-time, followed by slowly increasing the dose, or dividing a total daily dose into multiple small portions taken throughout the day, may allow a patient to develop tolerance but increases the complexity of the regimen. The result may often be missed doses or confusion about the titration schedule. An extended-release formulation may slow absorption and reduce the peak effects that cause transient toxicity.

The AEDs are often grouped into categories such as ‘first-generation’ (i.e., carbamazepine, phenobarbital, phenytoin, primidone, valpro-ate) and ‘second-generation’ (AEDs coming into use thereafter). Although second-generation AEDs offer some improvement over first-gen-eration drugs, each can cause notable adverse effects. Figure 1 shows data from two previous

reports, now updated to include the newest AEDs [1,2]. The figure describes spontaneously-reported adverse effects listed in US product labels for second-generation AEDs tested for approximately 12–16 weeks as adjunctive treat-ment. The incidence of adverse effects reported by at least 5% of patients were aggregated by type (CNS, behavioral and general medical) and summed for patients receiving the recommended dose of active drug and for placebo. Scores for patients in the placebo groups were deducted from the scores for patients receiving active drugs to indicate the excess reporting of that type of adverse effect. The final scores represent the probable impact of the drug (AED minus placebo = final score). This approach captures a picture of the differences among AEDs by type of predominant adverse effect to help guide selection of an AED based on the needs of the individual patient [1,2]. Attempts have been made to provide physicians with a sense of comparative tolerability among AEDs [1,2] (further expanded later in this article to include the newer AEDs). These indirect comparisons use data from comparable clinical trials to reflect the overall adverse-effect burden for each drug, divided into

Joyce A Cramer†1,2, Scott Mintzer3, James Wheless4 and Richard H Mattson1

1Yale University School of Medicine, New Haven, CT, USA 2Epilepsy Therapy Project, Houston, TX, USA 3Thomas Jefferson University, Philadelphia, PA, USA 4University of Tennessee Health Science Center, Memphis, TN, USA †Author for correspondence:49 Briar Hollow Ln, #1804, Houston, TX 77027–9310, USA Tel.: +1 713 552 0289 joyce.cramer@yale.edu

All medications have some adverse effects, ranging from mild to acute and serious or chronic. Antiepileptic drugs (AEDs) differ in the type and severity of adverse effects, mostly during initiation and early treatment. Some concerns are related to pharmacodynamic tolerance often affected by the dose and rate of initiation, while other concerns are idiosyncratic responses to the drug (rare and not predictable). Thus, lack of tolerability is a common reason for changing medication, quantified in studies as treatment retention. Although adverse effects can occur with all AEDs, and CNS effects are most prevalent, selected effects are hallmarks of specific drugs. The failure of an AED regimen may be the result of unacceptable adverse effects (intolerance), inadequate seizure control (inefficacy) or a combination of both. Although some diminution in adverse effects is typical when a drug is used in monotherapy, the potential for most issues remains if they are dose-related or idiosyncratic. This article describes three categories of prevalent adverse effects (CNS, behavioral and general medical issues) comparing profiles of second- and third-generation AEDs.

Keywords: adverse effect • antiepileptic drug • central nervous system • CNS • hypersensitivity • medical • psychiatric • psychological • tolerance

Adverse effects of antiepileptic drugs: a brief overview of important issuesExpert Rev. Neurother. 10(6), 885–891 (2010)

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categories such as CNS, psychiatric and general medical domains. AED selection may be based on these population-based estimates of the likelihood of types of adverse effects. These data also warn patients and physicians to be alert for common adverse effects for early intervention.

There is no clear-cut answer as to what AED is most appropri-ate because of the ways patients differ in their response to, and willingness to accept, adverse effects. For example, a patient may refuse valproate because of weight gain, although it is the AED most likely to control primary generalized seizures, or a female patient of child-bearing age will not be offered valproate because of the teratogenic risk.

When seizures are poorly controlled, AEDs are used in combination, leading to potential pharmacokinetic or phar-macodynamic interactions, causing more adverse effects than might occur when the AED is taken as monotherapy. Recommendations for achieving desirable adverse-effect pro-files are summarized in Box 2. If a patient can tolerate the first 6–12 weeks of therapy without unacceptable adverse effects the efficacy of the drug can also be ascertained. At that point, the benefit of improved seizure control may be compared with the burden of adverse effects to help in planning further dose or drug change. If well tolerated, the dose can be increased and this may improve efficacy. In some instances, increased efficacy is offset by increased toxicity. Hirsch et al. conducted a study to correlate lamotrigine serum concentrations with tolerability in patients with epilepsy [3]. Although efficacy increased as serum levels increased (up to levels of >20 µg/ml), toxicity increased from 7% of patients who were taking 5–10 µg/ml, to 14% of patients taking 10–15 µg/ml, 24% of patients taking 15–20 µg/ml and 34% of patients taking over 20 µg/ml. If the drug is poorly tol-erated but seizure control is good, the dose could be cautiously lowered to determine whether efficacy can be maintained. If seizure control is inadequate or the balance between seizures and adverse effects cannot be achieved, the drug may have to be discontinued, leaving the patient to start again with an alterna-tive AED [4]. Tolerability of early adverse effects is no guarantee that late-appearing adverse effects may not necessitate further dose adjustment or discontinuation [5].

Tolerance to early-appearing adverse effectsThe incidence of dose-related adverse effects associated with AEDs is often a function of the rapidity of dose escalation. When treat-ment is initiated, whether it is monotherapy or add-on therapy,

it is important to discuss the typical adverse effects for the AED with patients and their families, while explaining that some early problems may dissipate if patients can endure this early period while tolerance develops.

Patients will often adapt to a regimen over a period of time. In a Veterans Affairs Epilepsy Cooperative Study, Mattson et al. examined tolerance to beneficial and adverse effects of standard AEDs [6]. They evaluated patients at every clinic visit over a 12-week period. Patients experienced two common side effects: gastrointestinal complaints and dizziness. Although the incidence of complaints decreased over the 3-month period, the blood levels were higher when patients were better able to tolerate the drug. At the end of week 1, nearly 10% of patients had gastro intestinal side effects and dizziness, when levels of carbamazepine and phenytoin were 6.9 and 10.1 µg/ml, respectively; by the end of week 12, the incidence of those side effects had diminished to less than 3% of patients, when levels of carbamazepine and phenytoin were 8.1 and 12.7 µg/ml, respectively [5]. This study, along with others, illustrated that adaptation or functional tolerance can be developed with the majority of AEDs.

Early tolerance is also affected by cyclic peak–trough effects: blood levels rise quickly after a dose is taken (causing transient effects), followed by rapid decline before the next dose (creating potential for seizures), which can be circumvented by dividing the total daily amount into several doses (e.g., three-times daily instead of twice daily), using an AED with a long half-life, admin-istering the medication with food or by providing an extended-release formulation. The latter is often preferable since fewer doses usually result in improved compliance [7]. Miura evaluated once-daily zonisamide (an AED with a long half-life) monotherapy in 72 children with cryptogenic localization-related epilepsies [8]. The drug was initiated at 2 mg/kg and doubled at weekly intervals until a maintenance dosage was achieved. Low-trough plasma lev-els (15 µg/ml) resulted in uncontrolled seizures in 23 out of the 72 patients; high-trough levels (>40 µg/ml) resulted in drowsiness and a short attention span in five patients. When dosages were adjusted during the course of the study, diminishing fluctuations between trough and peak levels, seizure control improved for 57 out of 72 patients. However, the recent development of extended-release formulations has been based on pharmacokinetic half-life, rather than evidence of improved seizure control with stable plasma levels.

Combination therapy can result in additive or sometimes supra-additive adverse effects. During add-on trials involving lamotrig-ine, dizziness was a complaint for almost 38% of patients, and ataxia occurred in 22% of patients (reflected in the product label). By contrast, during lamotrigine monotherapy, dizziness occurred in 8% of patients and ataxia occurred in less than 1% of patients [9]. This divergence may be related to pharmacodynamic interactions of lamotrigine with concomitant AEDs. Gradual initiation of topiramate therapy significantly enhanced patient tolerability without sacrificing therapeutic response. Biton et al. evaluated the tolerability and efficacy of two titration rates for topiramate: initial dosage of 50 mg/day increased in 50-mg/day increments at weekly intervals; and initial dosage of 100 mg/day increased by 100–200 mg/day at weekly intervals [10]. The maximum

Box 1. Factors affecting antiepileptic drug tolerability and safety.

• Dose escalation rate

• Habituation period (early tolerance)

• Blood levels (e.g., rate of increase, peaks)

• Timing of doses

• Pharmacokinetic interactions

• Pharmacodynamic interactions

• Pharmacogenomics

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Adverse effects of antiepileptic drugs

dosage of 400 mg/day was achieved in 8 weeks and 3 weeks, respectively (although the current recommended maximum dose is usually 100–200 mg/day, these are the higher doses used in regulatory clinical tri-als). The lower initial and escalation dose (50 mg) resulted in fewer treatment-emer-gent adverse events than the higher rate. This approach required fewer adjustments to therapy (i.e., dosage reductions, inter-ruptions, or discontinuations) and signifi-cantly reduced treatment interruptions or withdrawals owing to treatment-emergent adverse events.

When initiating an AED, a very low test dose (smaller than the recommended dose), could be tried at bedtime for the first day, or longer, to increase the likelihood of tolerance. Thus, if sedation or lighthead-edness occurs, they may resolve overnight rather than disrupt work or school during the day. If side effects occur, the dose can be reduced to allow the patient to gradu-ally build up tolerance to the adverse effects of the drug [5,11]. When possible, taking AEDs with food may be effective in slowing absorption and decreasing peak blood level effects. When dividing the total daily dose, the largest portion may be taken at bedtime to minimize the presence of adverse effects (particularly sedation) during daily activities.

CNS adverse effectsCognitive effectsHermann et al. provided a conceptual framework for the effects of epilepsy, AEDs and neuroanatomic changes across the lifespan [12]. Although drugs have distinct effects on brain function, many other factors are involved, particularly for people with long-term uncontrolled seizures. Cognitive effects typically include dimin-ished attention, executive function, intelligence, language skills, memory and processing speed. Phenobarbital and topiramate have the greatest potential for these problems, although many AEDs may impair aspects of cognition. Mental slowing has been linked to phenobarbital in studies showing improvement when the drug is discontinued. Children exposed to phenobarbital have lower intelligence scores than those taking valproate [13]. In a placebo-controlled study, mean IQ was 7 points lower among children taking phenobarbital than in the placebo group [14]. Phenobarbital is also linked to hyperactivity in preschool-aged children [15]. Meador also demonstrated that phenobarbital impaired cognition in adults significantly more than phenytoin or valproate, but there was no clinically significant difference between the two [16]. Later studies showed that topirimate may cause mental confusion and word-finding difficulty, particularly at high doses [17–19].

Psychiatric effectsDepression and anxiety are common among people with epi-lepsy [20]. When present before the diagnosis of epilepsy, any worsening with treatment may develop slowly and in a subtle way, making it difficult to recognize. Psychosis is rare. It may be pre-existing, peri-ictal or could be the result of forced normaliza-tion of brain activity [21]. Behavioral side effects can occur with levetiracetam, as well as with topiramate, zonisamide and phe-nobarbital. Irritability and hostility are the main concerns with levetiracetam, often seen soon after initiation [22]. Hirsch et al. reported on a study of 629 patients who were given levetiracetam to compare its effects on older versus younger adults: 31.7% of younger and 40.7% of older patients reported intolerability to levetiracetam on at least one occasion [23]. In both age groups, psy-chiatric and behavioral side effects (as well as drowsiness, which can be eliminated by slow escalation) were the most common adverse effects associated with levetiracetam. Younger patients tolerated levetiracetam better than older patients; however, 1-year retention was 72% in the older group compared with 54% in the younger group, but the difference was not statistically signifi-cant. Patients are often unaware of cognitive and mood changes. However, family members are often more aware of behavioral changes than the patient.

Figure 1. Major categories of adverse experiences occurring in 5% or more of patients in Phase III clinical trials. The data were derived from US product labeling, using data for the recommended dose. The Cramer et al. study reports on all adverse effects on active treatment minus reports on placebo. Includes adverse events (COSTART terms) reported by more than 5% of patients based on Phase III clinical trial data from US and European labeling [1].ESL: Eslicarbamazepine; GBP: Gabapentin; LCM: Lacosamide; LEV: Levetiracetam; LTG: Lamotrigine; N: Number of patients in the active treatment group and the placebo group; OCBZ: Oxcarbazepine; PGB: Pregabalin; RUF: Rufinamide; TGB: Tiagabine; TPM: Topiramate; ZNS: Zonisamide. Adapted from [1,2].

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Mood disorders, notably anxiety and depression, are common comorbidities in epilepsy that may or may not be associated with AED therapy [24]. Anxiety and depression may be present, with depression more likely to predominate [25]. Patients should be assessed for mood disturbance before and regularly during treat-ment because chronic dysthymia and depression affect reporting of adverse effects and seizure severity, as well as affecting overall quality of life. The association between AEDs and the risk for suicidal ideation and completed suicide was the subject of a recent US FDA warning [101], but it is not at all clear whether this find-ing pertains to all drugs, to specific agents within the class or represents merely a chance finding of no true importance. Rather than an association with AEDs, mood disorders (and suicidal-ity) may be the result of fronto–temporal connections; wherein hippocampal damage from seizures may affect serotonin and other neuromodulators related to depression and anxiety [26]. In contrast to reports of AEDs causing depression, carbamazepine, lamotrigine and valproate have positive psychotropic effects, with lamotrigine having obtained FDA approval for the treatment of bipolar depression. Depression should be evaluated regularly because of the special concern for suicidal behavior related to epilepsy and the use of AEDs.

General medical effectsMany AEDs have limited use because of the risk for rare but serious effects that may result in death. Use of felbamate and vigabatrin are limited because of the risk for aplastic anemia [27] and visual field deficits, respectively [28]. However, phenytoin, the most widely-used AED in the USA [29], may also cause hepatic failure [27]. As is the case for other drugs, AEDs have been impli-cated in some serious systemic adverse effects, although for most of the AEDs such effects are rare.

HypersensitivityHypersensitivity often results in a maculopapular eruption on the chest, inner elbow and knee areas, which indicate that the drug should be stopped immediately. In those cases, careful re-initiation may be successful and worthwhile if seizures are controlled with that AED and alternative AEDs are not effective. Rash has been a leading cause of withdrawal from some AED clinical trials [9]. With experience, physicians have learned that slow titration often reduces the likelihood of rash. This is particularly important for lamotrig-ine. Rash is a serious concern because it may progress to a life-threat-ening hypersensitivity reaction (e.g., Stevens–Johnson syndrome), requiring hospitalization [10,27,30].

Not all AEDs are allergenic, a property most closely associated with older drugs, such as barbiturates, phenytoin, carbamazepine and ethosuximide, as well as some of the newer drugs, including lamotrigine, zonisamide and oxcarbazepine. In a major retro-spective study of 1890 out-patients with epilepsy, researchers assessed the rates of rash associated with 15 AEDs [31]. First assessing non-AED predictors of rash, they compared rash rates for individual AEDs. The highest rash rates occurred with phe-nytoin (5.9%), lamotrigine (4.8%) and carbamazepine (3.7%). The lowest rash rates occurred with felbamate, primidone, topi-ramate (all <1%), levetiracetam (0.6%), gabapentin (0.3%) and valproate (0.7%). A valuable finding was that the risk of AED-linked rash is approximately five-times more likely in patients who have had a previous AED rash (8.8%) than those who did not (1.7%) [31].

Among the causes cited for lamotrigine rash are high starting dose and rapid escalation, as well as young age and concurrent valproate [28]. The drug should be discontinued if the patient develops a rash. If it is unclear whether lamotrigine caused the rash, or no other options exist, the drug may be re-initiated after a month with a very slow escalation and careful monitoring.

Some patients have a genetic susceptibility for developing seri-ous cutaneous reactions when using AEDs. The FDA recently issued a warning regarding the use of carbamazepine in patients of Asian descent. It has been found that the HLA-B*1502 hap-lotype is very common in the Han Chinese population and to some extent in other Asian populations as well. Studies in Hong Kong and Taiwan determined that the HLA-B*1502 haplotype was present in 100% of the patients who had developed carba-mazepine-associated Stevens–Johnson syndrome [32]. Another study, conducted in Hong Kong, matched 48 AED-tolerant con-trols with 24 Han Chinese who had severe cutaneous reactions that were induced by carbamazepine, phenytoin and lamotrigine; the HLA-B*1502 haplotype was found in the patients with the reactions. They concluded that although HLA typing might be considered before prescribing carbamazepine for patients of Asian ancestry, it requires a long turnaround time, is expensive and is only available in specialized centers [33].

Pediatric issues The potential for adverse events in children is greater than in adults because young children have immature detoxifica-tion mechanisms and a greater variability in dosing owing to a wider range of body size and weight [34]. Few data are avail-able defining adverse effects in children because clinical trials for pediatric use of AEDs are generally small and focused on efficacy [35]. Information accumulates over long periods of use, thus we know most about older AEDs [36]. Valproate has been implicated in hepatic toxicity in children, while phenobarbi-tal, phenytoin, carbamazepine, oxcarbazepine and lamotrigine cause higher incidences of rash in children than adults [37,38]. Topiramate and zonisamide have been associated with neph-rolithiasis, oligohydrosis, hyperthermia and metabolic acidosis in children and adults [34–36]. However, significant metabolic acidosis in children can lead to growth retardation [39]. Gingival

Box 2. Acceptable adverse-event profile for an antiepileptic drug.

• No need for routine surveillance or laboratory monitoring (no organ toxicity)

• No lethal side effects

• Adverse effect occurs early in therapy

• Adverse events are obvious to the parent/caretaker

• Adverse events reversible when decreasing or discontinuing drug

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hyperplasia, an adverse event seen in patients of all ages who take phenytoin, occurs much more commonly in developmentally impaired patients and young children [15,40].

Adverse effects, such as diplopia or dizziness, may be difficult in children and nonverbal children and adults who are unable to describe their symptoms to caregivers [15]. Effects such as ataxia and nausea and vomiting are obvious, but slowed motor and cognitive capacity may be difficult to detect. Careful clinical assessment of patients will enable caregivers to detect adverse effects, and routine laboratory testing can reveal some occult problems [15]. Family members should observe the patient for typical adverse effects and report them to the clinician when witnessing even subtle changes.

Late-appearing adverse effectsSome adverse effects are insidious because of the slow, incremental increase in severity or impact over time. When phenobarbital was in common use, patients would describe decreased sexual potency and Dupuytren’s contractures [41], as well as mental slowing after months or years of treatment [14]. The association with the drug was made when the problems diminished after drug discontinu-ation. The main difficulty with late-appearing adverse effects is the lack of reporting by patients because they do not consider the problem to be related to their AED. Thus, physicians should be aware of these subtle problems and ask about them during follow-up assessments or perform surveillance studies (e.g., bone density scan for osteopenia).

There are also some concerns relating to late-appearing pharmaco kinetic effects on metabolism that are beyond the scope of this report [42].

Weight changesWeight gain may occur slowly during AED treatment, particu-larly with the use of selected AEDs. It is most prominent with valproate and pregabalin, but may be seen to a lesser degree with carbamazepine and high-dose gabapentin as well [43]. Children taking valproate appear to be less prone to weight gain than adults [44]. Poorly controlled seizures restrict physical activity for many people, which may make it very difficult to lose weight once gained from drug treatment. In addition to its cosmetic effects, weight gain can accelerate a decline in overall health, leading to increased morbidity and mortality (e.g., hip and knee joint dam-age, sleep apnea and compromised cardiovascular health). At the other end of the spectrum, weight loss occurs with topiramate, felbamate and, less often, with zonisamide [43]. Caregivers should weigh patients regularly and select AEDs after determining each patient’s profile, but should not sacrifice therapeutic efficiency.

ConclusionAll the AEDs now available offer the benefit of control of seizures, but all have the potential to cause adverse effects. While clinicians (and patients and their families) are aware of obvious early adverse effects, late-appearing and subtle adverse effects may not be attrib-uted to the drug. Selection of the AED most appropriate for the individual patient, careful initiation to avoid early intolerance

and continuous monitoring for late-appearing, insidious effects will improve the likelihood of realizing the benefit of the AED selected. Success with the AED initiation reduces the problems and risks involved with (another) treatment change. Taking time to initiate the AED in a low dose, then escalating the dose slowly and monitoring carefully for any adverse events, would help to provide the best chance of tolerability.

Success with the first AED reduces the problems and risks involved with treatment changes that require careful uptitration of the added drug simultaneous with downtitration of the drug to be discontinued. Recommendations for minimizing adverse effects are summarized in Box 2. If a patient can tolerate the first 6–12 weeks of therapy without unacceptable adverse effects, the efficacy of the drug can also be ascertained. At that point, the ben-efit of improved seizure control may be compared with the burden of adverse effects to help in planning further dose or drug change. If the AED is well tolerated, the dose can be increased, with the possibility of improving efficacy. If the drug is poorly tolerated but seizure control is good, the dose could be cautiously lowered to determine whether efficacy can be maintained. Overall, adverse effects are a major reason for AED discontinuation [45]. Every change in dose and drug requires extra visits and telephone calls to the doctor, as well as pharmacy, administrative and drug costs.

Expert commentaryAt their current stage of development, AEDs expose prescribers and patients with epilepsy to the risk of adverse effects with every potential treatment. The lack of trials comparing AEDs results in a series of within-patient (uncontrolled) trials, in which an indi-vidual patient is tested with a drug (often at various doses), fol-lowed by sequential testing until an acceptable regimen is found (or the patient declines further testing). The system of within-patient trials is fraught with complexities, including multiple dose changes, inadequate communication, breakthrough seizures and fear on the part of the patient regarding all of the foregoing. The risks of uncontrolled seizures are equally serious. Primary care physicians wisely refer patients to a neurologist, who in turn refers to an epileptologist when the case becomes complex. The future of epilepsy treatment awaits a ‘clean’ AED that truly does not cause adverse effects in most patients.

Five-year view A variety of novel treatments are in the pipeline that have the potential to alter the trajectory of epilepsy treatment, but it could take more than 5 years for these treatments to achieve regulatory approval. Small molecules, neuropeptides and gene therapies are in development. While efficacy cannot be predicted, it is likely that treatments delivered directly into the brain will produce fewer adverse effects of the type commonly seen with current drugs. Delivering current drugs directly will remove the first-pass effects, as well as systemic toxicities. The ultra-low doses may also avoid hepatotoxicity, hypersensitivity and other serious problems, but evidence will be needed. Of course, direct delivery into the brain is not without other potential complications. As we learn more about devices that will be implanted in the brain, we will

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Key issues

• All antiepileptic drugs can produce adverse effects – most notably, effects related to CNS exposure.

• Adverse effects might be divided into those that appear early, often associated with dose escalation, and those that appear later, which tend to be idiosyncratic.

• Early tolerability is best achieved by slow introduction of the drug, with careful dose titration to achieve the optimum tolerable dose.

• Dose-related effects may be modulated by dose reduction, balanced with efficacy for seizure control.

• Idiosyncratic effects may require drug discontinuation (e.g., because of hypersensitivity).

• Hypersensitivity requires immediate attention to avoid serious complications.

• CNS effects include impaired cognition and, less commonly, psychiatric problems.

• Less information is available describing tolerability in children.

• Late-appearing adverse effects can be modulated by behavioral change (e.g., dieting to avoid weight gain).

• In summary, clinicians balance dose selection between tolerance for adverse effects and seizure control.

ReferencesPapers of special note have been highlighted as:

• of interest

1 Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 40, 590–600 (1999).

2 Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res. 47, 17–25 (2001).

• References[1]and[2]comparedatafromplacebo-controlled,double-blindedtrialsofthenewerantiepilepticdrugs(AEDs).Althoughnotcomparedwithinastudy,theuseofalmostidenticalprotocolsprovidesthebasisforcomparingefficacyandadverse-effectprofiles.

3 Hirsch LJ, Weintraub D, Du Y et al. Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy. Neurology 63(6), 1022–1026 (2004).

4 Mattson RH. Medical management of epilepsy in adults. Neurology 51, S15–S20 (1998).

5 Mattson RH, Cramer JA, Collins JF et al. Early tolerance to anti-epileptic drug side effects: a controlled trial of 247 patients. In: Tolerance to Beneficial and Adverse

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6 Mattson RH, Cramer JA, Collins JF et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic clonic seizures. N. Engl. J. Med. 313, 145–151 (1985).

• Earliestlong-termplacebo-controlled,blindedstudycomparingmultipleAEDs.Theresultsdemonstratedthatsomediscontinuationisoftenrelatedtointolerableadverseeffectsaloneorincombinationwithseizures.AEDswerealsodiscontinuedwhendoseswereincreasedtomaximaltolerancewithoutseizurecontrol.

7 Cramer JA, Mattson RH, Prevey ML, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. J. Am. Med. Assoc. 261, 3273–3277 (1989).

8 Miura H. Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies. Seizure 13, S17–S23 (2004).

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10 Biton V, Edwards KR, Montouris GD et al. Topiramate titration and tolerability. Ann. Pharmacother. 35, 172–179 (2001).

11 Mattson RH. An overview of the new antiepileptic drugs. Neurologist 4, S2–S10 (1998).

12 Hermann B, Meador BJ, Gaillard WD, Cramer JA. Cognition across the lifespan: antiepileptic drugs, epilepsy, or both? Epilepsy Behav. 17, 1–5 (2010).

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determine whether the morbidity of the placement and need for refilling reservoirs will be worth the risks compared with oral administration with its attendant adverse effects.

Financial & competing interests disclosureThe report was derived from a roundtable discussion supported by Epilepsy Therapy Project, a nonprofit organization whose mission is to accelerate new therapies for people with epilepsy. The program was supported by an unrestricted educational grant from Eisai. All authors have received funds from most companies whose products are discussed, as detailed later, but maintain fair balance in this manuscript, without deference to Eisai, or

any other company. Joyce Cramer: Johnson & Johnson, Medtronic, Sepracor, UCB; Scott Mintzer: Eisai, GSK, Johnson & Johnson, Medtronic, Neuropace, Ovation, Sepracor, UCB; James Wheless: Cyberonics, Cydex, Novartis, Eisai, GSK, Lundbeck, Pfizer, UCB, Valeant; and Richard Mattson: GSK, Johnson & Johnson, Sepracor, UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. Robertson Paton provided transcription and editorial support.

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on intelligence and on seizure recurrence. N. Engl. J. Med. 322, 364–369 (1990).

15 Willmore LJ, Wheless JW, Pellock JM. Adverse effects of antiepileptic drugs. In: Pediatric Epilepsy: Diagnosis and Therapy. Pellock JM, Bourgeois BFD, Dodson WE, Nordli DR Jr, Sankar R (Eds). Demos Medical Publishing, LLC, NY, USA 449–559 (2008).

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17 Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia 37, S18–S22 (1996).

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