Faculty Bibliography

Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes. It is therefore now possible to consider precision medicine and novel therapeutic approaches for these devastating diseases with trials of repurposed and new drugs, including gene therapies. Trials are being designed to target either DEE diseases more broadly, specific DEE syndromes, or specific genetic DEEs. To serve this purpose, a clear operational definition of DEEs is needed to ensure that appropriate patients are selected for trials with precisely defined, targeted outcome measures. Herein we propose the operational definition of DEEs to set the stage for the development of DEE therapies.

The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day - 1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20 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. In addition, pharmacokinetics and safety were assessed. Of 27 evaluable patients, 9 reentered to receive a 2nd dosing 1-6 months later, providing a total of 36 individual exposures. At all doses administered - even the lowest -, several subjects reached a complete abolishment of PPR, with a rapid onset of effect. Overall, complete abolishment of PPR was obtained in 40-71 % of the patients; the effect increasing with the dose. In terms of effective doses to suppress PPR, SEL was at least 1,500 times more potent than levetiracetam and 10-20 times more potent than brivaracetam. Adverse events of SEL, including dizziness and somnolence, were mild to moderate. Pharmacokinetics of SEL demonstrated rapid absorption and a linear dose:plasma level relationship. This proof-of-principle study demonstrates that - based on our own experience - SEL is the most potent compound ever tested in the photosensitivity model.

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.

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.

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.

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.

Epilepsy diagnosis is often delayed or inaccurate, exposing people to ongoing seizures and their substantial consequences until effective treatment is initiated. Important factors contributing to this problem include delayed recognition of seizure symptoms by patients and eyewitnesses; cultural, geographical, and financial barriers to seeking health care; and missed or delayed diagnosis by health-care providers. Epilepsy diagnosis involves several steps. The first step is recognition of epileptic seizures; next is classification of epilepsy type and whether an epilepsy syndrome is present; finally, the underlying epilepsy-associated comorbidities and potential causes must be identified, which differ across the lifespan. Clinical history, elicited from patients and eyewitnesses, is a fundamental component of the diagnostic pathway. Recent technological advances, including smartphone videography and genetic testing, are increasingly used in routine practice. Innovations in technology, such as artificial intelligence, could provide new possibilities for directly and indirectly detecting epilepsy and might make valuable contributions to diagnostic algorithms in the future.

INTRODUCTION/BACKGROUND:This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice. METHODS AND ANALYSIS/METHODS:Adults with epileptologist-confirmed epilepsy from two Australian Epilepsy Centres are being recruited. People with functional seizures, or who are unable to self-complete English-language validated instruments are excluded. Participants providing informed consent are invited to complete questionnaires at baseline, 3 and 6 months later. SERIAS includes five questions that ask about the number of days per month that seizures or treatment-related adverse effects partially or fully impact work/home/school and family/social/non-work activities, as well as a visual analogue scale regarding epilepsy-related disability. SERIAS is completed alongside seven internationally validated instruments measuring treatment-related adverse effects, mood disorders and quality of life. Target recruitment is n=100, ensuring>50 people complete all questionnaires at all timepoints. Comprehensive psychometric analysis will be performed. Convergent validity will be investigated using bivariate correlations with relevant measures. Reliability will be investigated using Cronbach's alpha, McDonald's omega and test-retest correlation coefficients. SERIAS will be a novel PROM for epilepsy clinical trials and practice. ETHICS AND DISSEMINATION/BACKGROUND:Multisite ethics approval was granted by the Alfred Health Ethics Committee (HREC 17/23). Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER/BACKGROUND:ACTRN12623000599673.

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.

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.