Faculty Bibliography

High-quality placebo-controlled drug trials for focal-onset seizures in infants and children younger than 4 years have become increasingly difficult to perform because of eligibility constraints and onerous study designs. Traditional designs used in these populations require a high baseline seizure frequency, two hospitalizations for video-electroencephalography (video-EEG) monitoring, and willingness to accept potential exposure to placebo when the drugs to be tested are usually already available for off-label prescription. To address these constraints, the International League Against Epilepsy (ILAE) regulatory taskforce and the ILAE pediatric commission, in collaboration with the Pediatric Epilepsy Research Consortium (PERC), propose a novel trial design which involves seizure counting by caregivers based on previous video-EEG/video validation of specific seizure semiologies. We present a novel randomized placebo-controlled trial design intended to be used for studying new antiseizure medications (ASMs) for focal-onset seizures (FOS) in children aged one month to four years. This design uses "time to Nth seizure" as the primary outcome and incorporates a new element of variable baseline duration. This approach permits enrollment of infants with lower seizure burden, who might not have video-EEG-recorded seizures within 2-3 days of monitoring. Repeated hospitalizations for video-EEG recordings are avoided, and duration of baseline and exposure to placebo or ineffective treatment(s) are minimized. By broadening eligibility criteria, reducing risks from prolonged placebo exposure, and relying on validated recording of seizure counting by caregivers, clinical trials will be likely to be completed more efficiently than in the recent past.

There have been few studies of agreement between seizure descriptions obtained from patients and observers. We investigated 220 patients and observers who completed structured questionnaires about patients' semiological seizure features at the initial clinical visit. Inter-rater reliability was assessed using Cohen's kappa and indices of positive and negative agreement. Patients and observers had excellent agreement on the presence of memory impairment and generalized shaking and stiffness during seizures. In addition, patients under-reported seizure descriptions more easily observed externally, whereas observers under-reported change in patient location at seizure end. These findings may guide interpretation of clinical histories obtain in epilepsy care.

OBJECTIVE:To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy. METHODS:In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed. RESULTS:Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 μg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence. CONCLUSIONS:This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT00616148. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.

OBJECTIVE:Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS:Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS:Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE/CONCLUSIONS:This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

BACKGROUND:Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS:This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS:About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION/CONCLUSIONS:In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.