Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.

Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
Epilepsia (Impact Factor: 4.58). 01/2013; DOI: 10.1111/epi.12074
Source: PubMed

ABSTRACT The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.

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    ABSTRACT: Background The evidence base for management of childhood epilepsy is poor, especially for the most common specific syndromes such as rolandic epilepsy (RE) and Panayiotopoulos syndrome (PS). Considerable international variation in management and controversy about non-treatment indicate the need for high quality randomised controlled trials (RCT). The aim of this study is, therefore, to describe current UK practice and explore the feasibility of different RCT designs for RE and PS. Methods We conducted an online survey of 590 UK paediatricians who treat epilepsy. Thirty-two questions covered annual caseload, investigation and management practice, factors influencing treatment, antiepileptic drug preferences and hypothetical trial design preferences. Results 132 responded (22%): 81% were paediatricians and 95% at consultant seniority. We estimated, annually, 751 new RE cases and 233 PS cases. Electroencephalography (EEG) is requested at least half the time in approximately 70% of cases; MRI brain at least half the time in 40%-65% cases and neuropsychological evaluation in 7%-8%. Clinicians reported non-treatment in 40%: main reasons were low frequency of seizures and parent/child preferences. Carbamazepine is the preferred older, and levetiracetam the preferred newer, RCT arm. Approximately one-half considered active and placebo designs acceptable, choosing seizures as primary and cognitive/behavioural measures as secondary outcomes. Conclusions Management among respondents is broadly in line with national guidance, although with possible overuse of brain imaging and underuse of EEG and neuropsychological assessments. A large proportion of patients in the UK remains untreated, and clinicians seem amenable to a range of RCT designs, with carbamazepine and levetiracetam the preferred active drugs.
    Archives of Disease in Childhood 09/2014; 100(1). DOI:10.1136/archdischild-2013-304211 · 2.91 Impact Factor
  • 11/2014; 5(Suppl 1):S5-6. DOI:10.4103/0976-3147.145192
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    ABSTRACT: Introduction: Zonisamide (ZNS) is an antiepileptic drug with a broad spectrum of action mechanisms. Although ZNS is usually indicated for the adjunctive treatment of partial seizures in Western countries, it has long been used for partial and generalized seizures as monotherapy or adjunctive treatment in South Korea and Japan. The present study was to evaluate the long-term retention rate of ZNS in clinical practice. Methods: This was a retrospective, single-center, long-term observational study. A total of 148 patients (82 men, 66 women; 14-85 years) who were treated with ZNS as monotherapy or adjunctive treatment were included. Zonisamide was administrated with a starting dose of 100 mg/d, and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed during a 6-year follow-up. Results: The overall retention rate was 66.1% at 1-year and 55.1% at 6-year follow-up. Patients with monotherapy (70.8% vs 44.1%) and generalized seizures (71.6% vs 48.2%) were more likely to continue ZNS at 6-year follow-up compared with those with adjunctive therapy and partial seizures. The most common cause of discontinuation was adverse events such as somnolence, rash, and gastrointestinal problems. Conclusions: Our study shows the high retention rate of ZNS in the treatment of patients with epilepsy. The retention rate of ZNS was comparable with those of other antiepileptic drugs including lamotrigine, topiramate, and levetiracetam, and it can be suggested that ZNS can be considered for monotherapy and for the patients with generalized seizures.
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