Long-term safety and efficacy of adjunctive brivaracetam in pediatric patients with epilepsy: An open-label, follow-up trial.

OBJECTIVE: This study was undertaken to evaluate the long-term safety, tolerability, and efficacy of adjunctive brivaracetam (BRV) treatment in pediatric patients with epilepsy. METHODS: A phase 3, open-label, multicenter, long-term follow-up trial (N01266; NCT01364597) was conducted on patients (aged 1 month to <17 years at core trial entry; direct enrollers aged 4 to <17 years) treated with BRV. Outcomes included treatment-emergent adverse events (TEAEs), behavior assessments (Achenbach Child Behavior Checklist [CBCL], Behavior Rating Inventory of Executive Function [BRIEF]/BRIEF-Preschool version [BRIEF-P]), and efficacy outcomes (percent change in focal seizure frequency, 50% responder rate for all seizure types for patient subgroups <2 years and ≥2 years of age using daily record card data). RESULTS: Of 257 patients with ≥1 dose of BRV (141 [54.9%] male; mean age = 8.0 years [SD = 4.5]), 36 patients were <2 years of age, and 72.0% of patients had a history of focal seizures. Mean BRV exposure was 3.2 patient-years. At least one TEAE occurred in 93.4% patients, and 32.3% had serious TEAEs. Seven patients died during the trial; no deaths were considered treatment-related. Patients ≥2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 62.9%, and 50.9% had a ≥50% response in all seizures. Patients <2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 96.9%, and 68.2% had a ≥50% response in all seizures. Kaplan-Meier estimated treatment retention was 72.7%, 64.5%, 57.8%, 53.3%, 50.1%, and 44.8% at 1, 2, 3, 4, 5, and 6 years, respectively. Mean changes (baseline to last evaluation) for all Achenbach CBCL and BRIEF-P/BRIEF subscale scores were negative, reflecting stability/slight improvement. SIGNIFICANCE: Long-term adjunctive BRV treatment was generally well tolerated and efficacious in reducing seizure frequency, and had high retention rates, with generally stable cognitive/behavioral scores in pediatric patients with epilepsy.

Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial.

OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15-min intravenous (IV) infusion and bolus (≤2-min injection). METHODS: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open-label trial in patients ≥1 month to <16 years of age with epilepsy. Patients received up to 5 mg/kg/day BRV (not exceeding 200 mg/day). Enrollment was sequential by descending age, depending on safety review. Outcomes included BRV plasma concentrations before and after IV administration, treatment-emergent adverse events (TEAEs), and discontinuations due to TEAEs. RESULTS: Fifty patients were enrolled, received BRV, and completed the trial. Twenty-six patients (52.0%) received 15-min infusions and 24 (48.0%) received bolus injections. Most patients (80.0%) received one IV dose. In the 15-min infusion group, geometric mean (GeoMean) BRV concentrations 15 (±2) min (n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15-min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug-related TEAEs (15-min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred. SIGNIFICANCE: IV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15-min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15-min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

Rectal diazepam gel in the home management of seizures in children.

This study assessed the utility of rectal diazepam gel in the home management of prolonged or repetitive seizures in children. Thirty-eight children being prescribed rectal diazepam gel by their clinician were prospectively recruited. Seizures, rectal diazepam use, emergency department visits, and quality of life data before and after study entry were recorded. The 38 children included 14 (37%) with complex febrile seizures, and 24 with epilepsy (n = 22) or a single seizure (n = 2). There were 23 (61%) children with prolonged seizures and 15 (39%) with repetitive seizures. During the 6-month follow-up period, 12 children experienced 26 seizures which met the criteria for rectal diazepam administration. Rectal diazepam gel was administered to 8 children on 19 occasions. In 16 (84%) of these episodes, seizures stopped and no emergency department visit was required. Parental stress was decreased between baseline and 6 months in both the overall group and in all the subgroups. Home use of rectal diazepam gel is effective in aborting seizure activity, often avoiding an emergency department visit. Its use reduces morbidity and costs associated with hospital visits and provides parents a treatment option for home management of prolonged or repetitive seizures.

Surgical management of medically refractory epilepsy due to early childhood stroke.

UNLABELLED: OBJECT.: The risk of developing epilepsy after perinatal stroke, hypoxic/ischemic injury, and intracerebral hemorrhage is significant, and seizures may become medically refractory in approximately 25% of these patients. Surgical management can be difficult due to multilobar or bilateral cortical injury, nonfocal or poorly lateralizing video electroencephalography (EEG) findings, and limited functional reserve. In this study the authors describe the surgical approaches, seizure outcomes, and complications in patients with epilepsy due to vascular etiologies in the perinatal period and early infancy. METHODS: The records were analyzed of 19 consecutive children and adults with medically refractory epilepsy and evidence of perinatal arterial branch occlusions, hypoxic/ischemic insult, or hemorrhagic strokes, who underwent surgery at the Comprehensive Epilepsy Center of Beth Israel Medical Center and St. Luke's-Roosevelt Hospital Center. Preoperative findings including MRI, video EEG, functional MRI, and neuropsychological testing were analyzed. The majority of patients underwent staged operations with invasive mapping, and all patients had either extra- or intraoperative functional mapping. RESULTS: In 7 patients with large porencephalic cysts due to major arterial branch occlusions, periinsular functional hemispherotomy was performed in 4 children, and in 3 patients, multilobar resections/disconnections were performed, with 1 patient undergoing additional resections 3 years after initial surgery due to recurrence of seizures. All of these patients have been seizure free (Engel Class IA) after a mean 4.5-year follow-up (range 15-77 months). Another 8 patients had intervascular border-zone ischemic infarcts and encephalomalacia, and in this cohort 2 hemispherotomies, 5 multilobar resections/disconnections, and 1 focal cortical resection were performed. Seven of these patients remain seizure free (Engel Class IA) after a mean 4.5-year follow-up (range 9-94 months), and 1 patient suffered a single seizure after 2.5 years of seizure freedom (Engel Class IB, 33-month follow-up). In the final 4 patients with vascular malformation-associated hemorrhagic or ischemic infarction in the perinatal period, a hemispherotomy was performed in 1 case, multilobar resections in 2 cases, and in 1 patient a partial temporal lobectomy was performed, followed 6 months later by a complete temporal and occipital lobectomy due to ongoing seizures. All of these patients have had seizure freedom (Engel Class IA) with a mean follow-up of 4.5 years (range 10-80 months). Complications included transient monoparesis or hemiparesis in 3 patients, transient mutism in 1 patient, infection in 1 patient, and a single case of permanent distal lower-extremity weakness. Transient mood disorders (depression and anxiety) were observed in 2 patients and required medical/therapeutic intervention. CONCLUSIONS: Epilepsy surgery is effective in controlling medically intractable seizures after perinatal vascular insults. Seizure foci tend to be widespread and rarely limited to the area of injury identified through neuroimaging, with invasive monitoring directing multilobar resections in many cases. Long-term functional outcomes have been good in these patients, with significant improvements in independence, quality of life, cognitive development, and motor skills, despite transient postoperative monoparesis or hemiparesis and occasional mood disorders.

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.