Faculty Bibliography

PURPOSE: The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. METHODS: Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. RESULTS: In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). CONCLUSIONS: By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available

PURPOSE: Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS: Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS: Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION: This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted

The incidence of refractory epilepsy remains high despite the influx of many new antiepileptic drugs (AEDs) over the past 10 years. Epidemiological data indicate that 20-40% of the patients with newly diagnosed epilepsy will become refractory to treatment. Factors that may be used to predict whether or not a patient will respond favorably to AED therapy include the type of epilepsy, underlying syndrome, etiology, and the patient's history of seizure frequency, density, and clustering. Environmental factors, such as trauma and prior drug exposure, and genetic factors that predetermine the rate of absorption, metabolism, and uptake of a drug by target tissue may also uniquely impact an individual and influence their response to AED therapy. Treatment resistance is, therefore, a multifaceted phenomenon. Since individuals with refractory epilepsy do not share a common reason for their treatment resistance, the use of targeted drug therapies may be our best option for improving treatment outcomes in this patient population. Pharmacogeneticists are currently attempting to understand the genetic basis of refractory epilepsy so that they can identify subgroups of patients who share a common genetic background and then target drug therapies to meet their specific needs