OBJECTIVE: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.

METHODS: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential.

RESULTS: Of the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to lamotrigine, and significantly more attention problems than levetiracetam-exposed children. Lamotrigine-exposed children had significantly more attention deficit, but significantly less anxious behavior when compared to levetiracetam-exposed children.

SIGNIFICANCE: Compared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common antiepileptic drugs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all antiepileptic drug exposure groups. It is important that prenatally antiepileptic drug-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalised tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks.

Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo.

The safety profile was similar to that observed in other studies.

The trial was conducted as a post-marketing requirement by the FDA.

Pfizer is investigating the drug as part of its wider Lyrica Pediatric Epilepsy Program, which is composed of six studies in patients with epilepsy evaluating Lyrica as adjunctive therapy, five of which have been completed.

Another phase 3 trial in May 2018 was successful, showing that in paediatric patients with epilepsy a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo – however no statistically significant reduction was observed with a 7 mg dose.

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).

METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age 12 years or older on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout.

RESULTS: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced 1 or greater TEAE.

SIGNIFICANCE: MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing a seizure cluster in the outpatient setting and was associated with a favorable safety profile.

Introduction: Epilepsy treatment in older people requires specific consideration owing to more physical co-morbidities, the risk of drug-to-drug interactions through polypharmacy, and differences in pharmacodynamics and pharmacokinetics. There are many ‘newer’ antiepileptic drugs (AEDs) widely used for various seizure types and seizure disorders. However, there is limited specific evidence for the efficacy, safety, and tolerability of these treatments in the elderly population.

Areas covered: This review summarizes the current and most robust evidence available for the use of the newer AEDs belonging to generation two and three in elderly people with epilepsy. The article provides practical evidenced based clinical information to help prescribers choose the most appropriate AED from the drugs discussed.

Expert opinion: Diagnosing new onset epilepsy in the elderly population requires specialist assessment. Treatment plans need to be tailored to accommodate an individual’s co-morbidities, concurrent medications, and general health status. To date, few clinical investigations consider the elderly population specifically despite the increased risk factors. There is a need for large quality trial data to assess the impact of the newest AEDs on seizure control and quality of life in this population with complex needs.

The off-label pervasive use of a type of anticonvulsant originally marketed to treat epilepsy – called gabapentinoids – could place some patients at risk, according to a new study led by a team at the McGill University Health Centre (MUHC) and published on May 10th in the Journal of Hospital Medicine. These findings could have important clinical implications, as gabapentinoids, initially intended to treat epilepsy, are now commonly prescribed as a pain killer to the general population, including to elderly patients with multiple conditions. The study found that one in eight adults admitted to a hospital in Quebec had been prescribed the drug as part of their usual home medications.

“In certain cases, some patients may derive benefit from the off-label use of gabapentinoids, but the public also needs to know about their possible harms. This class of medications is becoming increasingly common, despite very little evidence that it helps with pain, and despite evidence that the medications increase the risk of falls, fractures and memory impairment,” says senior author Dr. Emily G. McDonald, a physician in General Internal Medicine at the MUHC and an assistant professor of Medicine at McGill University, as well as a scientist at the Research Institute of the McGill University Health Centre (RI-MUHC).

PURPOSE: The rate of brivaracetam-related behavioral adverse events is a current focus of discussion. This study aims to assess the effect of brivaracetam on anger levels in patients with epilepsy, adjusted by mood symptoms, history of psychiatric disorders, and seizure response.

METHOD: Prospective analysis of 37 patients assessed for anger levels (STAXI-2), depression-anxiety (HADS) and quality of life (QOLIE-10) before adjunctive brivaracetam treatment and reassessed 3-6 months later. A control group following the same protocol of assessment was used for 1:1 comparison. A high percentage of mood stabilizers were included in this control group.

RESULTS: Brivaracetam was indicated for patients including focal onset (79%) and generalized epilepsy (21%). Nearly 60% of responders and no psychiatric adverse events were found. This was similar to controls. The overall results revealed that brivaracetam was associated with better in anger levels, mood scores and quality of life at baseline. Prior use of levetiracetam or the presence of a psychiatric background did not influence the results. However, improvements in anger levels were seen in the brivaracetam responders.

CONCLUSION: This study shows that brivaracetam is not associated with an increased level of anger in patients with either focal or generalized epilepsy in the absence of psychiatric comorbidity. However, an improvement in anger levels is possibly influenced by a good seizure response.