Bassel Abou-Khalil

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

Levetiracetam for partial seizures Results of a double-blind, randomized clinical trial

Objective: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. Methods: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. Results: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p ≤ 0.001 for both groups). More patients responded (defined as minimum 50% reduction in partial seizure frequency) to levetiracetam than placebo, with rates of 33.0% in the 1000 mg/day and 39.8% in the 3000 mg/day group, compared to 10.8% in the placebo group (p < 0.001). Of 199 patients receiving levetiracetam, 11 became seizure free; no patient became seizure free in the placebo group. Treatment-emergent adverse events (≥10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. Conclusion: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.

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.

EEG and ECG in Sudden Unexplained Death in Epilepsy

Summary:  Purpose: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality for patients with epilepsy. Cardiac factors may be involved and were evaluated in this study.

Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation

Background: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel α-subunit (SCN1A) and β1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types. Methods: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives. Results: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A→C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T). Conclusions: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.

Temporal Lobe Epilepsy After Prolonged Febrile Convulsions: Excellent Outcome After Surgical Treatment

We studied 47 consecutive patients who underwent temporal resection for seizure control. Nineteen (40%) had febrile convulsions preceding onset of their habitual seizures. In 17 of 18 patients whose disease duration was known, the febrile convulsions were prolonged (mean 4 h). As compared with patients without preceding febrile convulsions, patients with antecedent febrile convulsions had a significantly higher prevalence of positive family history of febrile convulsions, an increased incidence of retrospectively identified gestational or perinatal complications, and no foreign tissue lesions. Pathologic studies showed gliosis and cell loss in mesiotemporal structures, usually moderate, in addition to usually mild gliosis in lateral temporal cortex. These patients had an excellent outcome after temporal resection: 84% were seizure‐free, had residual auras only, or occasional convulsions with medication discontinuation. One patient (5%) had >90% improvement. Two patients (11%) in whom the hippocampus was totally spared continued to have complex partial seizures: in both, seizures stopped after reoperation and hippocampal resection. Thus, 95% of these patients had an excellent result. Only 16% required invasive preoperative studies to confirm lateralization. These results were significantly better than those of the group without preceding febrile convulsions (p= 0.0013).

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Adjunctive therapy with oxcarbazepine in children with partial seizures

Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). Background: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. Design: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30–46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. Methods: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. Results: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a ≥50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported ≥1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. Conclusion: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy

Objective: To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZG[RTG]) 1,200 mg/day as adjunctive treatment in adults with drug-resistant epilepsy with partial-onset seizures with or without secondary generalization. Methods: RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZG[RTG] 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase. Results: In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZG[RTG], 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZG[RTG]) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo. Conclusions: This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. Classification of evidence: This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.

Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial.

Brivaracetam (BRV) is a novel high‐affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial‐onset (focal) seizures.