Innovative Designs of Controlled Clinical Trials in Epilepsy

Summary: Uncontrolled noncomparative clinical observations of investigational antiepileptic drugs (AEDs) often lead to overoptimistic efficacy results and are therefore of very limited value for clinical AED development. The classic add-on trial with placebo as control treatment, in contrast, has provided unequivocal evidence of the efficacy of classic and new AEDs and has also identified less useful AEDs. Drug interactions, carryover effects, difficulty in analyzing individual drug action, and the recognition that monotherapy is by far the more common way of prescribing AEDs have led to the development of classic active control monotherapy trials. A major problem of these trials is a no-difference outcome, which allows no useful interpretation. Recently, two alternative monotherapy designs have been developed to avoid the deadlock of a no-difference outcome. In these designs the active control drug is administered in an attenuated form (low dosage or low concentration) or a placebo control is used when standard treatment is discontinued during presurgical evaluation. Both designs have produced unequivocal evidence of the efficacy of the investigational AED during monotherapy. Ethical concerns are minimized by the introduction of preset escape criteria for patient protection. These designs are valuable new supplements for the clinical development of investigational AEDs for monotherapy in epilepsy. In our opinion, alternative monotherapy designs should be preceded by more than one pivotal add-on, placebo-controlled trial.     

Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double-Blind, Placebo-Controlled Trials

Summary: A pooled analysis of data from five similarly designed double-blind, placebo-controlled trials of topiramate (TPM) as add-on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200-1,000 mg daily and 174 who received placebo. In the intent-to-treat pooled analysis, TPM was significantly ( p ≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly ( p ≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly ( p ≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.     

Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis

Purpose: Because of the lack of head‐to‐head adjunctive‐therapy trials of antiepileptic drugs (AEDs) in refractory partial epilepsy, meta‐analyses of placebo‐controlled randomized controlled trials (RCTs) represent a potentially important source of evidence to guide treatment decisions. However, such indirect comparisons raise various methodologic issues that may hamper their relevance. Methods: All RCTs in adult refractory partial epilepsy were analyzed to assess whether efficacy outcomes are influenced by: characteristics of patients and trials ; use of last observation carried forward (LOCF) analysis; evaluation period (entire period versus maintenance period); and year of publication. A meta‐analysis of these AEDs was then performed taking these factors into consideration. Key Findings: Sixty‐three RCTs evaluating 20 AEDs were included. The following variables influenced efficacy estimates: (1) responder rates correlated positively with duration of the entire treatment period (p = 0.038); (2) response to placebo was significantly greater in the maintenance period than in the entire treatment period (p = 0.005); (3) responder rates increased over the years both for AEDs (p < 0.001) and for placebo (p = 0.001); (4) LOCF analysis overestimated responder rates for AEDs (p < 0.001) and for placebo (p = 0.001) compared with completer‐based analysis, and the overestimation correlated positively with withdrawal rates (p < 0.001). A meta‐analysis of available data showed large differences in efficacy ranking in relation to dose selection and type of analysis, but these were mostly nonsignificant due to statistical power limitations. Significance: Several methodologic issues hamper the relevance of indirect comparisons of AEDs in the adjunctive‐therapy of refractory partial epilepsy. Some of these issues could be overcome by improved standardization in the reporting of efficacy outcomes.     

The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm?

In January 2008, the U.S. Food and Drug Administration (FDA) issued an alert about an increased risk for suicidality in 199 clinical trials of 11 antiepileptic drugs (AEDs) for three different indications, including epilepsy. An advisory panel voted against a black-box warning on AED labels, and the FDA has accepted this recommendation. We discuss three potential problems with the alert. First, adverse event data were used rather than systematically collected data. Second, the 11 drugs grouped together as a single class of AEDs have different mechanisms of action and very different relative risks, many of which were not statistically significant and some of which were smaller than one. These facts suggest that they should not be grouped as a class. Third, the risk of adverse effects from uncontrolled seizures almost certainly outweighs the small risk of suicidality. We place our comments in the context of a review of the literature on suicidality and depression in epilepsy and the sparse literature on AEDs and suicidality. We recommend that all patients with epilepsy be routinely evaluated for depression, anxiety, and suicidality, and that future clinical trials include validated instruments to systematically assess these conditions to determine whether the possible signal observed by the FDA is real.     

Monotherapy trials: prerequisite data.

Is it possible for an antiepileptic drug (AED) to be effective as add-on therapy in refractory epilepsy but ineffective as monotherapy for the same seizure type(s)? If the answer is 'no', why not award a new AED a monotherapy licence once it has been shown to be effective as adjunctive treatment in placebo controlled, dose-ranging studies in patients with difficult-to-control epilepsy? The recent comparative study between carbamazepine and remacemide, however, suggests that subtle pharmacokinetic/pharmacodynamic interactions between established and new AEDs can indicate efficacy in add-on studies that does not necessarily transfer to monotherapy. There is some evidence that an AED whose primary mechanism of action does not involve blockade of voltage-dependent sodium channels may do less well than carbamazepine in terms of efficacy end-points in a double-blind, head-to-head comparison. These observations lead to the conclusion that monotherapy trials are, indeed, required. They should be undertaken after proof of efficacy has been obtained using a single short presurgical AED withdrawal study backed up by a substantive dose-ranging phase III efficacy trial. There is no reason to recommend earlier assessment since the clinical need for new AEDs is in refractory epilepsy. The subsequent monotherapy trial programme should contain elements utilising comparative and withdrawal designs. Sponsors should be able to seek a licence for their drug either as a first choice treatment in newly diagnosed epilepsy or as substitution monotherapy once treatment with at least one other AED has failed.     

Epilepsy surgery,antiepileptic drug trials,and the role of evidence

Objective: We assessed whether recent randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) are informed by evidence about surgical effectiveness. We explored whether RCTs of AEDs consider the patients’ candidacy for surgery in their eligibility criteria, and whether the necessary investigations are requested in participating patients to determine their potential eligibility for surgery. Methods: We systematically analyzed RCTs published in the last 2 years investigating the efficacy of new AEDs in localization‐related epilepsy. Results from a surgical RCT and recommendations from an epilepsy surgery practice parameter were used to assess the degree to which surgical evidence informed the drug study design. Results: Eleven RCTs were analyzed. All were conducted in countries with access to epilepsy surgery. None of the studies required magnetic resonance imaging (MRI) with an epilepsy protocol or explicit statement of the epilepsy syndrome, which could lead to the identification of surgical candidates. Having temporal lobe epilepsy or being a potential surgical candidate were not exclusion criteria in any of the trials. The primary efficacy end point was the reduction in seizure frequency or responder rate. Seizure freedom was never the primary outcome, and it was reported in only seven studies. The pooled data analysis of these trials revealed that 1.9% of patients became seizure‐free on placebo and 4.4% on the study drug (p < 0.01). Conclusions: Important aspects of patient selection for new AED trials are not informed by the evidence about surgical effectiveness. Investigations that could lead to identification of patients for presurgical evaluation were not required in any of the studies.     

Efficacy of New Antiepileptic Drugs

Regarding efficacy of new antiepileptic drugs (AEDs) for seizure control, there are three important clinical questions. How effective are new AEDs when corrected for the efficacy of placebo? And even more important: How do new AEDs fare in terms of seizure remission compared with established agents? And finally: Have patients seizure-free on new AEDs a better chance for lasting remission after withdrawal versus those withdrawing from older agents? The answers raise concerns. Although add-on therapy with marketed new AEDs is more effective than placebo, as expected, the treatment difference for becoming seizure-free is disappointingly small (6%; 95% CI: 4–8%; z = 6.47; p < 0.001). Although many, but not all, new AEDs have comparable efficacy to old standard drugs in well-controlled trials, none of the new AEDs is superior to old drugs in terms of seizure remission. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course. The sobering results suggest the need for novel experimental and clinical strategies for the development of more effective new AEDs that interrupt ictogenesis more effectively and prevent or abort epileptogenesis. Ideally, we need new drugs that block both ictogenesis and epileptogenesis, resulting in complete cure of epilepsy.Although a large number of new antiepileptic drugs (AEDs) that suppress or prevent seizures are now available, about 30 to 40 percent of the patients, children as well as adults, remain resistant to drug treatment (1). The situation is even worse for a range of severe epilepsy syndromes of infancy and adolescence. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course (2). The introduction of each new AED into the market raises valid expectations in patients and physicians for more effective treatment of epilepsy. Although safety, tolerability, and lack of interactions are important, better efficacy is a crucial feature for a new AED. This brief review is limited to a discussion of the efficacy of new versus old AEDs. In that respect, three questions are of particular clinical interest: How effective are new AEDs when corrected for the efficacy of placebo? And even more relevant: Are new AEDs more often leading to seizure remission compared with established agents? And finally: Can more patients maintain seizure remission after withdrawal of new AEDs compared with withdrawal of older agents? The following brief overview, which is not a comprehensive literature review, outlines the available evidence on the efficacy of modern AEDs based on randomized controlled trials of marketed modern AEDs.     

Mortality in antiepileptic drug development programs

BACKGROUND: Pooled data from New Drug Applications (NDAs) submitted to the U.S. Food and Drug Administration (FDA) provide an opportunity to study the incidence of and risk factors for rare events. OBJECTIVE: To examine the incidence and causes of mortality in patients with epilepsy participating in clinical trials of antiepileptic drugs (AEDs); and to examine the incidence of and risk factors for sudden unexplained death in such patients. METHODS: Exposure data and death narratives were obtained from the NDAs of five recently reviewed AEDs. Deaths were classified as sudden unexplained, accidental, or other cause using the 1993 Burroughs-Wellcome expert panel criteria, and mortality rates were calculated for each category. Add-on trials were analyzed separately from monotherapy initiation trials. RESULTS: Among 9,144 patients in the add-on trial database, the all-cause and sudden unexplained mortality rates were 9.1 and 3.8 deaths per 1,000 person-years (124 and 52 deaths in 13,617.1 person-years of drug exposure). Sixty-five percent of all deaths were related to the underlying epilepsy. Of the examined risk factors, only age was associated with the incidence of sudden unexplained death. Among 1,293 patients in the monotherapy initiation trials, the all-cause and sudden unexplained mortality rates were 7.1 and 0 deaths per 1,000 person-years (7 and 0 deaths in 982.5 person-years of drug exposure). CONCLUSIONS: A large proportion of the deaths in the add-on cohort was attributable to epilepsy-related causes. Mortality due to sudden death in the add-on cohort falls into the high end of the reported range for patients with epilepsy. The difference in mortality due to sudden death between the add-on and monotherapy initiation cohorts suggests that disease severity is the primary determining factor for risk of sudden unexplained death.     

Measuring the efficacy of antiepileptic drugs.

Clinical trials of new antiepileptic drugs (AEDs) include regulatory studies aimed at demonstrating efficacy and reasonable safety, post-marketing open-open label studies and longer term outcome studies. Regulatory trials involve a carefully selected population of patients and are conducted under rigorously standardised conditions. Data from such studies cannot often be translated into clinical practice. Pragmatic post-marketing studies using flexible dosing schedules allow clinicians to better judge the utility of the new drug in a wider population of patients with epilepsy and decide the most appropriate dosing schedules. This paper discusses some of the issues surrounding the measurement of efficacy of new AEDs in both pre- and post-marketing phases of their development. All of the newer AEDs are initially used in patients with refractory partial seizures as adjunctive treatment. These trials are generally parallel-group studies although cross-over designs have been employed. The use of placebo-control is uncontroversial in this type of study. Efficacy endpoints are generally manipulations of seizure frequency on study drug compared to control. Global outcome measures and health related quality of life scores can also be used to measure efficacy. As the standard AEDs are associated with a high rate of seizure remission in patients who receive them as monotherapy, demonstration of superior efficacy of a new agent in a comparative trial will require large numbers of patients in a design that takes into account the natural history of treated epilepsy. Comparing investigational agents to a standard AED in an 'active-control' study with demonstration of equivalent efficacy would seem to be an acceptable way of assessing efficacy of new AEDs in this population. Some regulators, however, do not accept equivalence as proof of efficacy and insist on demonstration of superiority compared to a control. The use of placebo alone in the control group is ethically dubious. Several innovative study designs have, therefore, been used to satisfy regulatory requirements, while maintaining patient safety including withdrawal to monotherapy using high versus low dose comparators. Observational outcome studies provide the best opportunity of exploring the long-term utility of individual AEDs. Such studies largely follow standard clinical practice and need considerable time and resources. They can, however, yield valuable information about the effectiveness of AEDs in everyday clinical practice. Data from regulatory trials should be complemented by postmarketing studies and longer term studies of outcome to help clinicians decide the best way of utilising new AEDs and establishing their role in the therapeutic armamentarium.     

Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed-effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.51-4.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.29-0.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings.     

Randomized, Double-Blind, Placebo-Controlled, Clinical Trial of D-α-Tocopherol (Vitamin E) as Add-on Therapy in Uncontrolled Epilepsy

Summary: In a double-blind, cross-over trial, vitamin E, and placebo were compared as add-on therapy in 43 patients with uncontrolled epilepsy. The study consisted of a 3-month baseline period followed by two treatment phases of vitamin E or placebo with cross-over to the second phase after 3 months. No significant side effects were noted during the study. Mean seizure frequency in the baseline period was 15.9 ± 10.5 as compared with 11.8 ± 10.9 during the placebo phase and 13.7 ± 11.1 during the vitamin E phase. No significant change in seizure frequency was observed with vitamin E as compared with placebo (p > 0.1). Similar observation was noted in subgroups with generalized seizures (n = 25), partial with secondarily generalized seizures (n = 11), or complex partial seizures (CPS) (n = 7). This study did not corroborate the earlier claims of therapeutic efficacy of vitamin E as add-on therapy in refractory epilepsy in adults.     

Clinical Science

Dieter Schmidt and Wolfgang Löscher
Drug-resistant epilepsy, with uncontrolled severe seizures despite the best available drug treatment, continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or disappear in the course of epilepsy or its treatment, in most patients so-called de novo drug resistance seems to exist already when treatment starts. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients. However, add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few percent become seizure-free during the trial. It is not known why and how epilepsy becomes drug-resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several possible mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiological theories have been put forward: a) removal of AEDs out of the epileptogenic tissue (where AEDs exert their effect) through excessive activity of multidrug transporters and, b) reduced efficacy through lower target sensitivity to drugs in brain tissue involved in epilepsy. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to-date supporting the drug-transport and the drug-target hypotheses and provide directions for future research to more clearly define the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy. Epilepsia 2005;46(6).

     

Monotherapy in epilepsy: role of the newer antiepileptic drugs

BACKGROUND: Monotherapy is the goal for pharmacological treatment of epilepsy. Well-controlled trials have established the efficacy of some of the newer antiepileptic drugs (AEDs) as monotherapy. OBJECTIVE: To review clinical data and expert opinions pertinent to the evaluation of most of the newer AEDs as monotherapy for epilepsy. DATA SOURCES: The MEDLINE database was searched for clinical trials using newer AEDs. Reference sections of review articles were manually searched to identify relevant studies not retrieved in MEDLINE. STUDY SELECTION: The resulting list of references was manually reviewed to identify monotherapy studies. RESULTS: Lamotrigine and oxcarbazepine demonstrated efficacy in randomized active-control trials in patients with newly diagnosed epilepsy and in substitution trials in patients refractory to conventional AEDs. CONCLUSION: Lamotrigine and oxcarbazepine are as effective as conventional AEDs at controlling partial seizures and are better tolerated.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

International Experience with Tiagabine Add-On Therapy

Summary: Tiagabine (TGB) hydrochloride is a novel antiepileptic drug (AED) that is a potent and specific inhibitor of γ-aminobutyric acid (GABA) uptake into glial and neuronal elements. In accordance with medical and regulatory standards, the clinical development program for TGB as an AED has assessed the value of TGB in add-on treatment, focusing mainly on partial seizures, including secondarily generalized seizures. Five add-on, placebo-controlled trials and six non-comparative, open-label, long-term multicenter trials have been or are being conducted in Australia, Europe, and the U.S.A. The results of these trials, involving 2,261 patients, indicate that TGB has efficacy as add-on therapy in patients with epilepsy difficult to control with existing AEDs. Efficacy of TGB is also sustained with long-term treatment. A clear dose-response has been demonstrated, and the minimal effective dose level is 30 mg. TGB is also tolerated, and with long-term therapy no new or more severe types of adverse events develop. These studies have included a wide age range of patients, including adolescents and the elderly.     

Long-Term Experience with Topiramate as Adjunctive Therapy and as Monotherapy in Patients with Partial Onset Seizures: Retrospective Survey of Open-Label Treatment

Summary: Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset epilepsy.     

Psychogenic nonepileptic seizures and suicidal behavior on a video/EEG telemetry unit: The need for psychiatric assessment and screening for suicide risk

Patients with epilepsy and psychogenic nonepileptic seizures (PNES) have an increased prevalence of psychiatric illness and risk for suicidal ideation/suicidal behavior/suicide compared with the general population. Recent literature suggests that antiepileptic drugs (AEDs) used to treat epilepsy, pain, and psychiatric disorders increase the risk of suicide and that this increased risk may be AED selective. This case analyzes a suicide attempt on a video/EEG telemetry unit. Specific risk factors associated with increased risk of suicidal behaviors pertinent to this case are reviewed: epilepsy, multiple psychiatric diagnoses including affective disorder, AEDs, PNES, prior medically serious suicide attempt, and suicide attempt within the past month. Specific psychometric rating scales to screen for both psychiatric illness and suicide risk and psychiatric assessment should be integral components of the evaluation and treatment of patients on video/EEG telemetry units.     

Psychogenic nonepileptic seizures and suicidal behavior on a video/EEG telemetry unit: the need for psychiatric assessment and screening for suicide risk

Patients with epilepsy and psychogenic nonepileptic seizures (PNES) have an increased prevalence of psychiatric illness and risk for suicidal ideation/suicidal behavior/suicide compared with the general population. Recent literature suggests that antiepileptic drugs (AEDs) used to treat epilepsy, pain, and psychiatric disorders increase the risk of suicide and that this increased risk may be AED selective. This case analyzes a suicide attempt on a video/EEG telemetry unit. Specific risk factors associated with increased risk of suicidal behaviors pertinent to this case are reviewed: epilepsy, multiple psychiatric diagnoses including affective disorder, AEDs, PNES, prior medically serious suicide attempt, and suicide attempt within the past month. Specific psychometric rating scales to screen for both psychiatric illness and suicide risk and psychiatric assessment should be integral components of the evaluation and treatment of patients on video/EEG telemetry units.     

Antikonvulsive Pharmakotherapie Jugendlicher und Erwachsener

In spite of the introduction and improvement especially of epilepsy surgery and also of other treatment options, such as ketogenic diet or neurostimulation, anticonvulsant chronic drug treatment has clearly remained the standard for the vast majority of epilepsy patients. Since 1992 when the first antiepileptic drug (AED) of the newer generation was introduced, a marked increase of seizure freedom among epilepsy patients, which is still the primary goal of treatment, has, however, not been reached. However, some of the new AEDs potentially allow better tolerable long-term treatment due to superior pharmacological characteristics. This might help to address the aspect of chronic AED treatment or comorbidities more efficiently. Hence, tolerability reasons led to a ranking according to the guidelines of the German Neurological Society that recommend lamotrigine and levetiracetam as first-line AEDs in cases of focal epileptogenesis. Special individual needs and considerations may allow and justify other AEDs in certain patients who are labelled for monotherapy. In cases of generalized epileptogenesis in adults valproic acid remains the first-line AED but lamotrigine may be preferred in special circumstances which include aspects such as teratogenicity. Ethosuximide is a first-line AED together with valproic acid followed by lamotrigine. If bilateral convulsive seizures occur primidone and phenobarbital may be considered as third-line AEDs. Several experts prefer levetiracetam although it is labelled only for off-label treatment in juvenile myoclonic epilepsy and not as monotherapy. The latter, however, should remain state of the art, as it more practicable and the easiest to assess concerning effectiveness. If treatment fails in spite of a correct diagnosis and classification an alternative monotherapy should be considered although a variety of publications have indicated that in the era of new AEDs combinations may be necessary to achieve sustained freedom of seizures. Thus the necessity to obtain alternative monotherapies should probably be expressed less dogmatically than currently published in the guidelines. Combinations should be as simple as possible and be comprehensible concerning the individual impact of the combination partners. High efficacy, lack of interactions and good tolerability have made levetiracetam to the most important add-on drug beyond the well-established and supra-additive combination of valproic acid and lamotrigine. Further investigations must be carried out on whether the latest new AEDs lacosamide, retigabine and perampanel all offer new modes of action with benefits for patients and opening the door to a more rational polytherapy in epilepsy treatment. Currently similar efficacy suggests that the risk of clinically relevant interactions and tolerability is the most important factor when choosing the appropriate add-on drug. Discontinuation may be considered only after freedom of seizures for many years and the prognosis is most favorable when the major causative factor no longer exists or has been eliminated.     

Antiepileptic Drugs in Pediatric Practice

Summary: Several factors characterize the current medical treatment of epilepsy during childhood. Children do not present the same types of seizures or epilepsies as adults, and certain epilepsy syndromes are seen only during childhood. Accordingly, the choice of antiepileptic drugs (AEDs) may differ in children. In addition, certain medical therapies, such as ACTH or pyridoxine, are used only in children. It is also common practice to prescribe AEDs in children for indications that are "off-label," such as the treatment of partial-onset seizures with car-bamazepine before the age of 6 years. The natural history of epilepsy and the risk for seizure recurrence may be different in the pediatric age range, and this may influence the decision to institute chronic prophylactic therapy in children. Similar considerations may apply to the decision to discontinue AED therapy. The pharmacokinetics of several AEDs are age-dependent, and dosages are more variable among patients. The adverse effects of AEDs may be age-dependent, and the pattern of exacerbation of certain seizures by AEDs may be different in children. In addition, several new AEDs are now available, or are about to be released, and the preferential sequence of AEDs of choice in children with epilepsy will need to be reassessed as experience grows and as the results of comparative studies become available.