Faculty Bibliography

OBJECTIVE/UNASSIGNED:Little is known about psychiatric symptoms among patients with migraine and newly diagnosed focal epilepsy. The investigators compared symptoms of depression, anxiety, and suicidality among people with newly diagnosed focal epilepsy with migraine versus without migraine. METHODS/UNASSIGNED:The Human Epilepsy Project is a prospective multicenter study of patients with newly diagnosed focal epilepsy. Depression (measured with the Center for Epidemiologic Studies Depression Scale), anxiety (measured with the 7-item Generalized Anxiety Disorder scale), and suicidality scores (measured with the Columbia-Suicide Severity Rating Scale [C-SSRS]) were compared between participants with versus without migraine. Data analysis was performed with the Kolmogorov-Smirnov test for normality assessment, the Mann-Whitney U test, chi-square test, and linear regression. RESULTS/UNASSIGNED:Of 349 patients with new-onset focal epilepsy, 74 (21.2%) had migraine. There were no differences between the patients without migraine versus those with migraine in terms of age, race, and level of education. There were more women in the group with migraine than in the group without migraine (75.7% vs. 55.6%, p=0.0018). The patients with epilepsy and comorbid migraine had more depressive symptoms than the patients with epilepsy without migraine (35.2% vs. 22.7%, p=0.031). Patients with epilepsy with comorbid migraine had more anxiety symptoms than patients with epilepsy without migraine, but this relation was mediated by age in logistic regression, with younger age being associated with anxiety. Comorbid migraine was not associated with C-SSRS ideation or behavior. CONCLUSIONS/UNASSIGNED:Among a sample of patients with newly diagnosed focal epilepsy, 21.2% had migraine. Migraine comorbidity was associated with higher incidence of depressive symptoms. Future studies should be performed to better assess these relationships and possible treatment implications.

OBJECTIVE:To update a 1996 American Academy of Neurology practice parameter. METHODS:The authors systematically reviewed literature published from January 1991 to March 2020. RESULTS:The long-term (24-60 months) risk of seizure recurrence is possibly higher among adults who have been seizure-free for 2 years and taper antiseizure medications (ASMs) vs those who do not taper ASMs (15% vs 7% per the 1 Class I article addressing this issue). In pediatric patients, there is probably no significant difference in seizure recurrence between those who begin tapering ASMs after 2 years vs 4 years of seizure freedom, and there is insufficient evidence of significant difference in risk of seizure recurrence between those who taper ASMs after 18 months of seizure freedom and those tapering after 24 months. There is insufficient evidence that the rate of seizure recurrence with ASM withdrawal following epilepsy surgery after 1 year of seizure freedom vs after 4 years is not significantly different than maintaining patients on ASMs. An epileptiform EEG in pediatric patients increases the risk of seizure recurrence. ASM withdrawal possibly does not increase the risk of status epilepticus in adults. In seizure-free adults, ASM weaning possibly does not change quality of life. Withdrawal of ASMs at 25% every 10 days to 2 weeks is probably not significantly different from withdrawal at 25% every 2 months in children who are seizure-free in more than 4 years of follow-up. RECOMMENDATIONS/CONCLUSIONS:Fourteen recommendations were developed.

OBJECTIVE:Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017). METHODS:After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire. RESULTS:Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study. SIGNIFICANCE/CONCLUSIONS:The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

BACKGROUND AND OBJECTIVES/OBJECTIVE:To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy. METHODS:Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed. RESULTS:= 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo. DISCUSSION/CONCLUSIONS:Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted. TRIAL REGISTRATION INFORMATION/UNASSIGNED:The ClinicalTrials.gov registration number is NCT03283371. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.

Importance/UNASSIGNED:The literature on neural autoantibody positivity in epilepsy has expanded over the last decade, with an increased interest among clinicians in identifying potentially treatable causes of otherwise refractory seizures. Observations/UNASSIGNED:Prior studies have reported a wide range of neural autoantibody positivity rates among various epilepsy populations, with the highest frequency reported in individuals with focal epilepsy of unknown cause and new-onset seizures. The antibodies in some cases are of uncertain significance, and their presence can cause conundrums regarding therapy. Conclusions and Relevance/UNASSIGNED:There is likely some role for neural autoantibody assessment in patients with unexplained epilepsy who lack clear evidence of autoimmune encephalitis, but the clinical implications of such testing remain unclear owing to limitations in previous published studies. A framework for study design to bridge the current gaps in knowledge on autoimmune-associated epilepsy is proposed.

From August 27-28, 2020 the Epilepsy Foundation hosted the Pipeline Conference, exploring emerging issues related to antiepileptic drug and device development. The conference featured epilepsy therapeutic companies and academic laboratories developing drugs for focal epilepsies, innovations for rare and ultra-rare diseases, and devices both in clinical trials and approved for use. In this paper, we outline the virtual presentations by the authors, including novel data from their development pipeline.

The COVID-19 pandemic has had an unprecedented impact on people and healthcare services. The disruption to chronic illnesses, such as epilepsy, may relate to several factors ranging from direct infection to secondary effects from healthcare reorganization and social distancing measures.

Importance/UNASSIGNED:Most antiseizure medications (ASMs) carry a US Food and Drug Administration-mandated class label warning of increased suicidality risk, based on a meta-analysis comparing suicidality between individuals treated with medications vs placebo in randomized clinical trials done before 2008. ASMs approved since then carry this warning although they were not similarly studied. Objective/UNASSIGNED:To review all placebo-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to evaluate the risk of suicidality of these drugs compared with placebo. Data Sources/UNASSIGNED:Primary publications and secondary safety analyses in PubMed of all phase 2 and 3 randomized placebo-controlled epilepsy trials of ASMs approved since 2008, using keywords epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation, and the names of individual drugs. Study Selection/UNASSIGNED:All phase 2 and 3 randomized clinical trials of adjunctive treatment of drug-resistant epilepsy and their secondary safety analyses. Data Extraction and Synthesis/UNASSIGNED:Articles were reviewed for frequency of suicidality (ideation, attempts, and completed suicides). Mode of suicidality ascertainment included treatment-emergent adverse event reports, Standardized Medical Dictionary for Regulatory Activities queries for events in prespecified categories including suicidal ideation and behavior, prospective collection of suicidality data as a prespecified safety outcome using the Columbia-Suicide Severity Rating Scale, and retrospective evaluation by blinded review using the Columbia-Classification Algorithm of Suicide Assessment. A meta-analysis compared risk for drugs vs placebo of each outcome for all drugs overall and by individual drugs and trials. Main Outcomes and Measures/UNASSIGNED:Suicidality (total and by ideation), attempts, and completed suicides. Results/UNASSIGNED:Excluding studies that did not evaluate suicidality (everolimus and fenfluramine) or did not evaluate it prospectively (lacosamide, ezogabine, and clobazam), 5 drugs were analyzed: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Suicidality was evaluated in 17 randomized clinical trials of these drugs, involving 5996 patients, of whom 4000 patients were treated with ASMs and 1996 with placebo. There was no evidence of increased risk of suicidal ideation (drugs vs placebo overall risk ratio, 0.75; 95% CI, 0.35-1.60) or attempt (risk ratio, 0.75; 95% CI, 0.30-1.87) overall or for any individual drug. Suicidal ideation occurred in 12 of 4000 patients treated with ASMs (0.30%) vs 7 of 1996 patients treated with placebo (0.35%) (P = .74). Three patients treated with ASMs and no patients treated with placebo attempted suicide (P = .22). There were no completed suicides. Conclusions and Relevance/UNASSIGNED:There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.

OBJECTIVE:This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS:Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS:One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE/CONCLUSIONS:Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.