Faculty Bibliography

IMPORTANCE/UNASSIGNED:Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses. OBJECTIVE/UNASSIGNED:To determine whether seizure frequency in FTRE improves over time. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample. EXPOSURES/UNASSIGNED:Participants were treated with multiple interventions at their physicians' discretion. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes. RESULTS/UNASSIGNED:Of 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Findings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretation of open-label studies positing disease-modifying effects and further research into FTRE treatment response.

OBJECTIVE:People with focal epilepsy experience one or more seizures prior to diagnosis. The Human Epilepsy Project (HEP) was a prospective study enrolling people with newly diagnosed focal epilepsy. It collected information including cognitive testing at the time of enrollment. This was completed utilizing a computerized test battery called the Cogstate Brief Battery (CBB). A prior analysis found that enrollment CBB test scores were below that of age matched controls and that performance on testing was not independently associated with the longer-term development of treatment resistance over the course of the HEP study. The present study assesses the impact of pretreatment seizures on cognition at time of diagnosis, considering time-to-treatment initiation in relation to seizure onset, pre-treatment seizure frequency, and pretreatment seizure classification. METHODS:Participants with newly diagnosed focal epilepsy and no other major medical comorbidities or intellectual disability (estimated IQ > 70) were enrolled between June 29, 2012, and September 1, 2019. A subset of the 448 enrolled participants (N = 183) were over 18 years old, had complete HEP enrollment data that included pre-treatment seizure histories, and complete enrollment CBB testing for analysis in this study. Performance on enrollment CBB testing was modeled using multiple linear regression with pre-treatment seizure characteristics including seizure type and duration between seizure onset and treatment initiation, controlling for other key baseline participant characteristics. RESULTS:There were no independent associations between cognitive measures on the CBB at the time of enrollment and pre-treatment seizures after correcting for potentially confounding variables. Z-scores for the attention composite on CBB (an average of Identification and Detection tests) were not associated with a global pre-treatment seizure score that quantified time with seizures (days) and seizure count by seizure type (motor, non-motor, bilateral tonic clonic) (p = 0.29). Similarly, z-scores for the memory composite (an average of the One Card Learning test and One Back tests) were not associated with the pre-treatment seizure score (p = 0.1). No additional independent associations were found to be significant between z-scores for attention or memory composites and other potential explanatory variables. SIGNIFICANCE/CONCLUSIONS:This study highlights an important finding for people who develop focal epilepsy and otherwise are in good health: pre-treatment time-limited seizures do not have an independent impact on cognition early on, as measured by a brief validated cognitive screening test. This suggests that that cognition at the time of epilepsy diagnosis may be more strongly related to underlying etiology, chronic disease, and comorbidities.

IMPORTANCE/UNASSIGNED:Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. OBJECTIVE/UNASSIGNED:To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. EXPOSURE/UNASSIGNED:ASM (variable). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). RESULTS/UNASSIGNED:Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21-44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33-3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7-16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8-3.2) than those who did (median, 7.4 months; 95% CI, 4.0-10.7). Those with infrequent pretreatment seizures were 0.41-fold more likely to be treatment resistant than those with very frequent seizures (relative risk [RR], 0.41; 95% CI, 0.18-0.89; P = .03; HB-corrected P = .02). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (RR, 1.78; 95% CI, 1.26-2.52; P = .001). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02126774.

OBJECTIVE:Central to the development of novel antiseizure medications (ASMs) is testing of antiseizure activity in preclinical models. Although various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS). METHODS:The Praxis Analysis of Concordance (PAC) framework was implemented to assess the translational concordance between preclinical and clinical ASM response for 32 US Food and Drug Administration-approved ASMs. Preclinical ASM responses in historically used seizure models were collected. Protective indices based on reported median tolerability and median efficacy values were calculated for each ASM in each preclinical model. A weighted scale representing relative antiseizure effect was used to grade preclinical ASM response for each seizure model. Data depth was further scored based on the number of evaluated ASMs with publicly available data. Established reports of clinical ASM use in patients with FOS were similarly evaluated, and a weighted scale representing prescribing patterns and perceived efficacy was used to grade clinical ASM response. To assess the predictive validity of preclinical models, a unified translational scoring matrix was developed to assign a concordance score spanning the spectrum from complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were summed and normalized to generate a global translational concordance score. RESULTS:The preclinical models with the highest translational concordance and greatest data depth for FOS were rodent maximal electroshock seizure (MES), mouse audiogenic seizure, mouse 6 Hz (32 mA), and rat amygdala kindling. SIGNIFICANCE/CONCLUSIONS:The PAC-FOS framework highlights mouse MES, mouse audiogenic, and mouse 6 Hz (32 mA) as three acute seizure models consistently demonstrating high predictive validity for FOS. We provide a pragmatic decision tree approach to support efficient resource utilization for novel ASM discovery for FOS.

OBJECTIVE:Evaluate real-world effectiveness, patient-reported outcomes (PROs), and safety/tolerability of brivaracetam in patients (≥16 years) with focal-onset seizures currently receiving ≥ 1 antiseizure medication (ASM), and with historical or current use of levetiracetam, lamotrigine, oxcarbazepine, and/or carbamazepine. METHODS:EP0088 was a 12-month, prospective, observational study of brivaracetam in a clinical practice setting in the US. Primary study outcome was brivaracetam retention at 12 months after brivaracetam initiation. Effect of brivaracetam on patients' perceptions of their health was assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) short forms and Seizure-Related Disability Assessment Scale (SERDAS). Safety outcomes included incidence of treatment-emergent adverse events (TEAEs). RESULTS:254 patients (mean age: 44.3 years; median duration of epilepsy: 17.3 years) received ≥ 1 brivaracetam dose (Safety Set; SS). Patients had a median of 3.0 historical and 2.0 concomitant ASMs (SS). For all patients (SS), including those who dropped out with unknown brivaracetam treatment status, 12-month brivaracetam retention was 57.1 % (n = 145/254); in patients with known brivaracetam treatment status (post hoc analysis), 12-month brivaracetam retention was 72.1 % (n = 145/201). Slight improvements in mean PROMIS T-scores, and improvements in mean SERDAS scores, were seen by month 1.5, and generally maintained up to 12 months (Full Analysis Set). 49.6 % of patients reported ≥ 1 TEAE, 38.2 % had drug-related TEAEs, and 16.1 % discontinued due to TEAEs (SS). CONCLUSIONS:Brivaracetam was effective in patients with difficult-to-control focal-onset seizures; as shown by brivaracetam retention at 12 months. Improvements in PROs were seen early. Brivaracetam was well-tolerated and no new safety signals were observed.

OBJECTIVE:In traditionally designed randomized clinical trials of antiseizure medications, participants take a blinded treatment for a prespecified number of weeks, irrespective of continued seizures. The alternative design time to prerandomization monthly seizure count (T-PSC) allows participants to end the blinded treatment after an individually prespecified number of seizures, which shortens exposure to placebo and ineffective treatment. Previous reanalyses have shown that T-PSC replicated the efficacy conclusions of trials; therefore, we evaluated whether T-PSC also could replicate tolerability and safety conclusions. METHODS:We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from three blinded, placebo-controlled trials of perampanel for focal onset seizures (NCT00699972, NCT00699582, NCT00700310). We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs that prompted medication adjustment compared to those observed during the full-length trial. RESULTS:Of the 1480 participants in the three trials, 1093 experienced any TEAE, of whom 1006 (92%) had onset prior to T-PSC. When evaluating the differences in each type of TEAE for each dose of perampanel from placebo within each trial, there was no consistent pattern of under- or overestimation. Across the three studies, 23 of 79 (29%) serious TEAEs, most requiring hospitalization, occurred after T-PSC. SIGNIFICANCE/CONCLUSIONS:Almost all TEAEs occurred before T-PSC. Similar conclusions regarding the tolerability and safety of perampanel would have been reached if the T-PSC design had been used. This suggests that the T-PSC design may potentially benefit participants by allowing earlier change from an ineffective treatment to an alternate treatment, which could reduce the risk of serious consequences of ineffective treatment, such as hospitalization.

OBJECTIVE:To report interim data from an ongoing, open-label extension (OLE) of a Phase 2b study (X-TOLE) of azetukalner in adults with focal onset seizures (FOS) receiving 1-3 antiseizure medications. METHODS:Eligible participants enrolled in the 7-year OLE at 20 mg azetukalner once daily with food. Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of ≥50%, ≥75%, ≥90%, and 100% seizure reductions. RESULTS:285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the 24-month interim analysis (September 5, 2023), 182 participants had been treated for ≥12 months and 165 for ≥24 months; 152 (55.3%) continued in the study. The median (range) treatment duration in the OLE was 26.3 (0.1-46.6) months. MPC reduction was 83.2% at 24 months in the OLE vs. DBP baseline. For all participants who entered the OLE, 56.4% (155/275) and 44.4% (122/275) achieved a ≥50% seizure reduction, 28.4% (78/275) and 19.6% (54/275) achieved a ≥90% seizure reduction, and 22.2% (61/275) and 14.9% (41/275) achieved seizure freedom (100% seizure reduction) for any consecutive ≥6- and ≥12-month period, respectively. For those who reached ≥24 months in the OLE, seizure freedom was achieved by 34.5% (57/165) and 23.6% (39/165) for any consecutive ≥6- and ≥12-month period, respectively. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Serious AEs were reported in 35 (12.7%) participants. SIGNIFICANCE/CONCLUSIONS:The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis. Azetukalner was generally well tolerated, with no new safety signals compared to the DBP. These data suggest sustained long-term efficacy and safety of azetukalner in a difficult-to-treat population. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:This long-term study assessed the safety and efficacy of azetukalner to treat focal seizures. Patients taking azetukalner daily with food for about 2 years had far fewer focal seizures with azetukalner than before taking the medication. For those who had been treated for 24 months, about a third were seizure-free for a consecutive 6-month period, and about a quarter were seizure-free for a consecutive 12-month period. Most side effects were mild or moderate, and these included dizziness, headache, and somnolence (sleepiness).

OBJECTIVE:This study was undertaken to investigate diagnostic delay in adolescent onset focal epilepsy, including reasons for longer delays and associated morbidities. METHODS:Secondary analysis was done using enrollment data from the Human Epilepsy Project, a multi-institutional cohort including 34 sites in the USA, Canada, Finland, Austria, and Australia (2012-2017). Participants were aged 11-64 years at enrollment and within 4 months of treatment initiation for newly diagnosed focal epilepsy. Participants with seizure onset at age ≤ 21 years were evaluated. Data included seizure diaries documenting onset, frequency, and characteristics of seizures, reasons for diagnostic delays, and prediagnosis morbidities, including injuries, suicidal ideation, and self-injurious behaviors. RESULTS: = 7.04, p = .008). SIGNIFICANCE/CONCLUSIONS:This study highlights significant delays in diagnosing adolescent onset focal epilepsy, especially in cases with nonmotor seizures. These delays, often due to lack of recognition by patients and health care providers, are linked to more frequent seizures, higher injury rates, and increased suicidal ideation and self-injury. Early recognition and diagnosis may mitigate adverse outcomes and improve quality of life for adolescents with epilepsy.

The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic-clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource-limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

Presence of focal to bilateral tonic-clonic seizures (FBTCS) in focal epilepsy is associated with increased morbidity and mortality. Risk factors for FBTCS are poorly understood, and little is known regarding FBTCS recurrence after treatment initiation. This study aimed to investigate factors related to FBTCS in newly diagnosed focal epilepsy and their recurrence after starting antiseizure medications (ASMs) in the Human Epilepsy Project (HEP) cohort. HEP was an international, prospective cohort study that enrolled people with newly diagnosed focal epilepsy within 4 months of treatment initiation and followed them for up to 6 years. Baseline characteristics, treatment choices, and seizure outcomes were collected. Descriptive and inferential statistical analysis was conducted to assess the differences between study participants who had FBTCS and those who never experienced FBTCS. A total of 443 participants were included in this analysis; 77% (n = 342) had FBTCS at some point prior to or within the study period. In participants with FBTCS, regardless of initial seizure type, diagnosis was mostly made after FBTCS (335/342, 98%). After treatment initiation, FBTCS did not recur in 57% (n = 194/342) of cases. A higher number of total pretreatment seizures (median = 16 vs. 11, p = .048, Mann-Whitney U-test), predominantly focal aware seizures (FAS) or focal impaired awareness seizures (FIAS; median = 15 vs. 10, p = .049, Mann Whitney U-test), was associated with no recurrence in FBTCS after treatment initiation. Of 108 participants without FBTCS prior to treatment, only seven (6%) developed FBTCS after treatment initiation. There was no significant difference in choice of initial ASM class (levetiracetam vs. sodium channel blockers) between participants who experienced FBTCS and those who did not. This study highlights the significance of FBTCS among individuals with newly diagnosed focal epilepsy. The majority of participants who experienced FBTCS were diagnosed with epilepsy after experiencing their first FBTCS despite preceding FAS/FIAS. The more frequent FAS/FIAS in participants whose FBTCS resolved may be a characteristic of their epilepsy.