Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: subgroup analysis of the randomized, unblinded KOMET study.

BACKGROUND: Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. METHODS: This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged ≥ 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. RESULTS: Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2-89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28-0.67); LEV vs. VPA-ER: 0.46 (0.16-1.33); LEV vs. CBZ-CR: 0.45 (0.28-0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63-1.35), LEV and VPA-ER (0.77, 0.38-1.56), and LEV and CBZ-CR (1.02, 0.64-1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively. CONCLUSIONS: Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV may be a suitable option for initial monotherapy for patients aged ≥ 60 years with newly diagnosed epilepsy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00175903 ; September 9, 2005.

Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions.

This study, supported by the Rwandan Ministry of Health and the World Health Organization, was conducted in 2005 to determine the prevalence of epilepsy and its sociocultural perception in Rwanda, as well as epilepsy-related knowledge and practices of health-care professionals (HCPs). A cross-sectional, nationally representative survey was conducted throughout Rwanda by trained investigators. Participants were recruited by random cluster sampling based on the organization of administrative units in the country. Overall, 1137 individuals (62% from rural areas) were interviewed. The prevalence of epilepsy was estimated to be 49 per 1000 people or 41 per 1000 for active epilepsy. Onset of epilepsy before the age of 2years was reported in 32% of the cases. Family history of epilepsy, head trauma, and premature delivery were reported in 53%, 50%, and 68% of the cases, respectively. Most (68%) patients did not receive any medical treatment for epilepsy; 21.5% had received some form of traditional treatment. According to responses from the general population, people with epilepsy should not be entitled to schooling (according to 66%), to work (according to 72%), to the use of public places (according to 69%), or to marriage (according to 66%). Furthermore, 50% believed that epilepsy was untreatable, and 40% thought that it was transmissible. Of the 29 HCPs interviewed, the majority knew the definition of epilepsy and status epilepticus, as well as basic treatment options and side effects. However, 90% believed that treatment was only necessary in the first week after a seizure. Living with epilepsy was associated heavily with stigma, and a significant treatment gap (68%) was identified. Following this study, numerous actions have been taken by the Rwandan government, the Rwandan League Against Epilepsy, and several nongovernmental organizations to increase awareness about epilepsy and to close the treatment gap. An overview of these activities is provided.

Measures for improving treatment outcomes for patients with epilepsy--results from a large multinational patient-physician survey.

In this large-scale, multinational, descriptive survey, we sought to identify measures for improving treatment outcomes for individuals with epilepsy. As a framework, questions relating specifically to each of the five steps of the 'patient-physician journey', namely, patient identification (omitted in this survey), diagnosis, choice of drug, disease and drug information, and patient monitoring were asked. Overall, 337 physicians and 1150 patients across France, Germany, and the United States returned questionnaires. Results indicated that 16% of the patients were initially misdiagnosed. Treatment choice was driven by efficacy, safety, experience with a drug (physician only), and convenience (patient only). Physicians were identified as the primary source of information for patients, and, as expected, better informed patients were found to adhere better to their therapy than those who were less well informed. Approximately 50% of the patients had not seen their specialist in the last year, which indicates poor follow-up; furthermore, important topics such as seizures, treatment, and its side effects were not discussed at every visit. Specialists, but not primary care practitioners (PCPs), consistently reported discussing all topics more frequently than their patients, suggesting that specialists may overestimate the clarity of their questions. There was also substantial disparity in the reasons cited for nonadherence - patients overwhelmingly cited forgetfulness, while both PCPs and specialists cited complacency, forgetfulness, and tolerability. We also noted a disparity between physicians and their patients, as well as between PCPs and specialists, in their views on the impact of epilepsy on patients' lives. Our results indicate multiple opportunities to intervene at all stages of the patient-physician journey to improve treatment outcomes. We provide practical suggestions to achieve the most from these opportunities.

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Current understanding of the mechanism of action of the antiepileptic drug lacosamide.

The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation.