Faculty Bibliography

OBJECTIVE:Seizures can impact cognition both acutely and chronically. However, among those without significant comorbidities and broadly average cognition at epilepsy onset, the relationship between cognitive function at the time of diagnosis and long-term seizure control has been relatively unexplored. This analysis investigated associations between participant characteristics including specific aspects of cognitive performance at the time of focal epilepsy diagnosis and antiseizure medication (ASM) treatment resistance. METHODS:This was a secondary analysis of Human Epilepsy Project (HEP) data, which enrolled people with newly diagnosed focal epilepsy and broadly average cognition (estimated IQ ≥ 70) from June 29, 2012, to September 1, 2019. Participants analyzed in this study were between 18 and 60 years old, and scored within an acceptable range (i.e., Standard Score of ≥80) on measures estimating premorbid cognitive ability were offered the Cogstate Brief Battery (CBB). Participant characteristics were analyzed, including the presence of any anxiety disorders or depression, and summary CBB scores. HEP participants who were classified by the study as treatment resistant if they had experienced failure to achieve seizure freedom after two adequate trials of ASMs. Treatment resistance was modeled using multiple logistic regression to assess for independent associations between attention and working memory after correcting for the presence of the other potentially explanatory variables. RESULTS:200 HEP participants had comprehensive enrollment records including CBB results and complete seizure outcome data for analysis in this study. After correcting for potentially confounding variables, there were no independent associations between cognitive measures on the CBB at the time of enrollment and subsequent development of ASM treatment resistance. Specifically, z-scores for reaction time on the CBB (an average of the CBB Identification and Detection tests) were not associated with treatment resistance (p = 0.51) and z-scores for memory performance (an average of the CBB One Card Learning test and One Back tests) were not associated with treatment resistance (p = 0.24). There were no significant independent associations between age or the presence of depression or anxiety disorders at the time of CBB testing and treatment resistance. However, there was an independent association between employment status and treatment resistance, with those who were employed or students (>18 years old) at the time of enrollment and CBB testing having 0.35 times lower odds of treatment resistance (95 %CI 0.15-0.81, p = 0.01). SIGNIFICANCE/CONCLUSIONS:The findings from this study suggest that in otherwise healthy people with new onset focal epilepsy who have broadly average intelligence, attention and working memory as measured by the CBB at the time of diagnosis is not associated with treatment resistance. Although performance on cognitive testing at epilepsy onset may not be predictive of risk of treatment resistance in this population, other individual characteristics such as employment status at the time of diagnosis may be indirect markers of long-term seizure outcomes and require further investigation.

OBJECTIVE:Randomized controlled trials (RCTs) are necessary to evaluate the efficacy of novel treatments for epilepsy. However, there have been concerning increases in the placebo responder rate over time. To understand these trends, we evaluated features associated with increased placebo responder rate. METHODS:Using individual-level data from 20 focal-onset seizure trials provided by seven pharmaceutical companies, we evaluated associations with change in seizure frequency in participants randomized to placebo. We used multivariable logistic regression to evaluate participant and study factors associated with differing rates of 50% reduction in seizure frequency during blinded placebo treatment, as compared to pre-randomization baseline seizure frequency. In addition, we focused on the association of placebo responder rate with pre-randomization baseline seizure frequency and country of recruitment. RESULTS:). In addition, there was a significantly higher 50RR in participants with a baseline seizure frequency of six or fewer seizures per 28 days (29% vs 21%, p = .00018). SIGNIFICANCE/CONCLUSIONS:These results can assist future RCTs in estimating the expected placebo responder rate, which may lead to more reliable power estimates. Higher placebo responder rate was associated with markers of less-refractory epilepsy. There were concerning significant differences in placebo responder rate by country and geographic region as well as an elevated placebo responder rate in participants with baseline seizure frequency close to the minimum eligibility criteria.

IMPORTANCE/UNASSIGNED:Antiseizure medications (ASMs) are potential teratogens commonly prescribed for multiple indications. ASM fetal exposure can impair neurodevelopment. Folate improves pregnancy outcomes, but higher doses may pose risks. OBJECTIVES/UNASSIGNED:To compare the outcomes of 6-year-old children of women with epilepsy (WWE) vs those of healthy women (HW), and assess the association of outcomes to third-trimester ASM exposures. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:After informed consent, pregnant WWE and HW were enrolled from 2012 through 2016 in this prospective, multicenter, nonrandomized clinical trial. Children were assessed at 6 years of age (2019-2022). Participants were recruited from 20 US epilepsy centers. Study data were analyzed from August 2023 to August 2024. EXPOSURES/UNASSIGNED:Fetal ASM exposures. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The a priori main neurodevelopmental outcome was the blindly assessed Verbal Index Score in 6-year-old children. The Verbal Index Score is calculated as the mean of the scores from the Word Definitions and Verbal Similarities subtests from the Differential Ability Scales, Expressive One-Word Picture Vocabulary Test, Phonological Processing, Comprehension of Instructions, and Sentence Repetition subtests from the Neuropsychological Assessment and Peabody Picture Vocabulary Test. The 2 primary analyses (1) compared children of WWE and HW using linear regression and (2) examined the outcomes of fetal exposure via ASM blood concentrations. Analyses were adjusted for multiple potential confounding factors. Other outcomes and folate exposure-related outcomes were assessed. RESULTS/UNASSIGNED:A total of 1123 pregnant women were screened, and 456 were enrolled (426 did not meet criteria, and 241 chose not to participate). A total of 298 children of WWE (mean [SD] age, 6.4 [4.2] years; 158 female [53.0%]; 140 male [47.0%]) vs 89 children of HW (mean [SD] age, 6.4 [4.2] years; 41 female [46.1%]; 48 male [53.9%]) did not differ on Verbal Index Score (parameter estimate, -0.6; 95% CI, -3.2 to 1.9; P = .64). Exposure-dependent outcomes differed across ASMs. Assessment of other ASMs was limited because 232 of 298 WWE (78%) were taking lamotrigine or levetiracetam alone or in combination. Folate supplementation during the first 12 weeks of pregnancy had positive associations with cognition and behavior with no signal for risks at higher folate doses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this prospective nonrandomized clinical trial suggest that verbal abilities in children of WWE vs HW did not differ. Exposure-dependent outcomes of ASMs highlight the importance of dosing high enough to protect the mother and fetus from seizures but low enough to protect the fetus. Folate supplementation early in pregnancy including higher doses was associated with improved cognitive and behavioral outcomes. Additional research is needed for ASMs with inadequate information on fetal exposure risks. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01730170.

Epilepsy care generates multiple sources of high-dimensional data, including clinical, imaging, electroencephalographic, genomic, and neuropsychological information, that are collected routinely to establish the diagnosis and guide management. Thanks to high-performance computing, sophisticated graphics processing units, and advanced analytics, we are now on the cusp of being able to use these data to significantly improve individualized care for people with epilepsy. Despite this, many clinicians, health care providers, and people with epilepsy are apprehensive about implementing Big Data and accompanying technologies such as artificial intelligence (AI). Practical, ethical, privacy, and climate issues represent real and enduring concerns that have yet to be completely resolved. Similarly, Big Data and AI-related biases have the potential to exacerbate local and global disparities. These are highly germane concerns to the field of epilepsy, given its high burden in developing nations and areas of socioeconomic deprivation. This educational paper from the International League Against Epilepsy's (ILAE) Big Data Commission aims to help clinicians caring for people with epilepsy become familiar with how Big Data is collected and processed, how they are applied to studies using AI, and outline the immense potential positive impact Big Data can have on diagnosis and management.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy. METHODS:The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always"). RESULTS:= 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%). DISCUSSION/CONCLUSIONS:Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

OBJECTIVE:To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS:Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS:Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE/CONCLUSIONS:While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

OBJECTIVE:The Human Epilepsy Project (HEP) is a large multinational cohort study of people with newly diagnosed and treated focal epilepsy. HEP utilized the Cogstate Brief Battery (CBB) as a self-directed online assessment to examine cognitive outcomes in study participants. The CBB has previously been validated in healthy individuals and people with various brain disorders, but its use in adults participating in HEP has not been assessed. In this study, we describe how the CBB was used in the HEP cohort and assess factors associated with test completion among study participants. METHODS:Enrollment data for HEP included 408 participants with comprehensive enrollment records, of whom 249 completed CBB assessments. HEP enrolled cognitively normal-range participants between the ages of 12 and 60 from June 29, 2012, to November 7, 2017, with newly diagnosed focal epilepsy and within 4 months of initial treatment. Baseline participant characteristics were analyzed, including demographics, pre-treatment seizure histories, MRI abnormalities, and the presence of any learning difficulties while in school, including formal learning disability diagnoses, repeated grades, and remediation. HEP participant characteristics for those who completed CBB testing were compared to those who did not using multiple logistic regression. RESULTS:The analysis of HEP participants who completed CBB testing showed that, after controlling for other factors, male participants were more likely to engage in testing (OR 2.14, 95 % CI 1.29 to 3.5, p < 0.01), Black subjects were less likely (OR 0.45, 95 % CI 0.22 to 0.9, p = 0.02), primary English speakers were more likely (OR 3.1, 95 % CI 1.21 to 7.96, p = 0.02), and those with a history of learning challenges were less likely (OR 0.69, 95 % CI 0.49 to 0.97, p = 0.03). There were no significant associations between completing CBB testing and age, employment (employed or student vs not), education (higher education vs not), diagnostic delay, pre-diagnostic seizure burden, or initial seizure semiology (motor vs non-motor). SIGNIFICANCE/CONCLUSIONS:The findings from this study highlight factors associated with the application of remote and unsupervised assessments of cognition in a prospective cohort of adults with focal epilepsy. These factors can be considered when interpreting performance on the CBB in HEP, as well as assisting the design of future studies that use similar approaches.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS:A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS:The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION/CONCLUSIONS:These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

OBJECTIVE:Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. METHODS:We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. RESULTS:Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). SIGNIFICANCE/CONCLUSIONS:Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months. METHODS:This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records. RESULTS:A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10). DISCUSSION/CONCLUSIONS:The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.