Elinor Ben-Menachem

ILAE Treatment Guidelines: Evidence‐based Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes

Summary:  Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long‐term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy.

Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial‐Onset Seizures

Summary:  Purpose: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial‐onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions.

Efficacy and Tolerability of Levetiracetam 3000 mg/d in Patients with Refractory Partial Seizures: A Multicenter, Double-Blind, Responder-Selected Study Evaluating Monotherapy

Purpose: To evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in selected patients with refractory partial seizures.

Pregabalin pharmacology and its relevance to clinical practice.

Summary:  Pregabalin is a potent ligand for the alpha‐2‐delta subunit of voltage‐gated calcium channels in the central nervous system that exhibits potent anticonvulsant, analgesic, and anxiolytic activity in a range of animal models. In addition, pregabalin has been shown to be a highly effective adjunctive therapy for partial seizures in clinical trials. Potent binding to the alpha‐2‐delta site reduces depolarization‐induced calcium influx with a consequential modulation in excitatory neurotransmitter release. Pregabalin has no demonstrated effects on GABAergic mechanisms. Pregabalin demonstrates highly predictable and linear pharmacokinetics, a profile that makes it easy to use in clinical practice. Absorption is extensive, rapid, and proportional to dose. Time to maximal plasma concentration is ∼1 h and steady state is achieved within 24–48 h. These characteristics reflect the observed onset of efficacy as early as day two in clinical trials. High bioavailability, a mean elimination half life (t1/2) of 6.3 h, and dose‐proportional maximal plasma concentrations and total exposures predict a dose–response relationship in clinical practice and allow an effective starting dose of 150 mg/day in clinical practice without need for titration. Administration with food has no clinically relevant effect on the amount of pregabalin absorbed, providing for a dosing regimen uncomplicated by meals. Pregabalin does not bind to plasma proteins and is excreted virtually unchanged (<2% metabolism) by the kidneys. It is not subject to hepatic metabolism and does not induce or inhibit liver enzymes such as the cytochrome P450 system. Therefore, pregabalin is unlikely to cause, or be subject to, pharmacokinetic drug–drug interactions—an expectation that has been confirmed in clinical pharmacokinetic studies. However, dose adjustment may be necessary in patients with renal insufficiency. Thus, the pharmacological and pharmacokinetic profiles of pregabalin provide a predictable basis for its use in clinical practice.

Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy

Objective: We report the results of a prospective study of the efficacy and tolerability of levetiracetam, a new antiepileptic drug with a unique mechanism of action, in comparison with controlled-release carbamazepine as first treatment in newly diagnosed epilepsy. Methods: Adults with ≥2 partial or generalized tonic–clonic seizures in the previous year were randomly assigned to levetiracetam (500 mg twice daily, n = 288) or controlled-release carbamazepine (200 mg twice daily, n = 291) in a multicenter, double-blind, noninferiority, parallel-group trial. If a seizure occurred within 26 weeks of stabilization, dosage was increased incrementally to a maximum of levetiracetam 1,500 mg twice daily or carbamazepine 600 mg twice daily. Patients achieving the primary endpoint (6-month seizure freedom) continued on treatment for a further 6-month maintenance period. Results: At per-protocol analysis, 73.0% (56.6%) of patients randomized to levetiracetam and 72.8% (58.5%) receiving controlled-release carbamazepine were seizure free at the last evaluated dose (adjusted absolute difference 0.2%, 95% CI −7.8% to 8.2%) for ≥6 months (1 year). Of all patients achieving 6-month (1-year) remission, 80.1% (86.0%) in the levetiracetam group and 85.4% (89.3%) in the carbamazepine group did so at the lowest dose level. Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. Conclusions: Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage.

Vagus-nerve stimulation for the treatment of epilepsy.

Vagus-nerve stimulation (VNS) is now an accepted treatment for patients with refractory epilepsy. There have been many studies suggesting that VNS affects the brain in such areas as the thalamus and other limbic structures. In addition, there is some evidence that norepinephrine is important in the prophylactic antiseizure effects of VNS. The efficacy of VNS has been established for partial seizure types, even in refractory patients who did not respond to surgical treatment for epilepsy. There are also data, from open-label studies, that suggest efficacy in other seizure types. Therefore, VNS seems to be a broad-spectrum treatment for epilepsy. Improvement is not immediate but increases over 18-24 months of treatment. Most studies report subjective improvements in various quality-of-life measurements during treatment with VNS--objective trials have confirmed this observation. Side-effects are mainly stimulation related and reversible and they tend to decrease over time. They are generally mild to moderate and seldom necessitate the removal of the device. No idiosyncratic side-effects have been reported in 12 years of experience, and VNS does not interact with antiepileptic drugs. Most adverse events are predictable and related to the specific stimulation regimen. VNS does not have cognitive and systemic side-effects and can, therefore, be a valuable treatment approach even for patients who have poor tolerance of antiepileptic drugs.

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

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 patients AED, all relevant variables and not just efficacy and effectiveness should be considered.

Double-Blind, Placebo-Controlled Trial of Topiramate as Add-On Therapy in Patients with Refractory Partial Seizures

Summary: In a double‐blind, randomized, parallel‐group trial, we compared topiramate (TPM) with placebo as addon therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b. i. d.)] or to the maximal tolerated dose if lower. Twenty‐eight (28) patients were randomized to each treatment group. In the intent‐to‐treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo‐treated patients and 43% of the patients treated with TPM experienced 250% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75–100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentation, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM‐treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefithisk ratio of TPM in resistant partial epilepsy.

Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years

Article abstract We assessed the long-term efficacy of vagus nerve stimulation (VNS) in 64 refractory epilepsy patients. After implantation, intermittent stimulation was delivered and seizure frequency and severity were counted. Average treatment time was 20 months. Nineteen of 47 patients with partial seizures, five of nine patients with idiopathic generalized seizures, and five of eight patients with Lennox–Gastaut syndrome had >50% seizure reduction. Side effects were mild. VNS is a safe and effective treatment for refractory epilepsy.

New antiepileptic drugs : Comparison of key clinical trials

Summary: Purpose: Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self‐reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated.