Response: Lenses protecting against photosensitivity violate international driving regulations

Epilepsia · 2026-03-03 · 1 citations

Drs. Bender, Lagrèze, Hirsch, and Schulze-Bonhage raise excellent points about the danger of driving with blue glasses, particularly the Zeiss Z1 lenses. We did advise to “avoid lenses that make it hard to proceed with orange traffic lights.” The letter correctly indicates that any spectacles that darken the field of view or potentially affect perceiving taillights or traffic signals can present a driving danger. Rather than just stating a caution, we might better have said that driving with dark glasses should be prohibited and that doing so is contrary to traffic regulations in several jurisdictions. For those interested in more detail about this issue, regulation ISO 12312-1:2022, the current international standard for sunglasses, categorized commercial sunglasses into five groups (0–4), depending on visible light transmission (VLT). Standards vary among countries, but the following table indicates a common European standard: The Z1 lens transmits 20% of luminance (Capovilla et al., Epilepsia 2006;47:529–533),1 making it unsuitable in general for nighttime driving. Japanese industrial standards determined appropriate VLT of lenses as ≥8% in daytime use and ≥75% in night and twilight use for driving. Train conductors in Japan are permitted to use polarized sunglasses, but not colored sunglasses that can interfere with recognition of traffic signals. Although driving automobiles with dense tinted lenses is not illegal in Japan, it is dangerous, and more public education is needed. Various special glasses can inhibit the photoparoxysmal response while maintaining varying degrees of visible light transmission (Takahashi et al., Neurology 2001;57:1767–1773).2 However, protective lenses with VLT better than 75% have not yet been developed and tested. In conclusion, Zeiss Z1 lenses should not be used by drivers given the risk of missing orange traffic lights, such as taillights. Driving with dark sunglasses is contrary to traffic regulations in many jurisdictions and is unsafe at night. Dark, polarized, or blue lenses may be useful when viewing media, visually provocative stimuli, or as a passenger in a moving vehicle, but not when driving. RF received support from the Maslah Saul MD Chair, National Institutes of Health (NINDS; 1RO1NS137650), NaviFUS, the James and Carrie Anderson, the Steve Chen, and the Pilliod Funds for epilepsy research. FMB received research funding from NINDS K23NS116110, the Doris Duke Charitable Foundation, the Rita Allen Foundation, the Wu Tsai Neuroscience Institute, and the O'Farrel-Principe family. JS received funding from the National Institutes of Health, National Science Foundation, Department of Defense, Shor Foundation for Epilepsy Research, UCB Biosciences, NeuroPace Inc., SAGE Therapeutics Inc., Serina Therapeutics Inc., LivaNova Inc., Greenwich Biosciences Inc., Biogen Inc., Eisai Inc., and the State of Alabama. KNT acknowledges support from the European Union for a Marie Curie Excellence Chair position in Sapienza University, Rome, Italy (MEXC-CT-2005-24224: Visual Sensitivity) and for continued working with the Roman and Italian (child)-neurologists on this subject. R.F. has no disclosures relevant to this paper but has stock options in Avails Medical, Eysz, Irody/CareTuner, Smart Monitor, and Zeto. L.L.T. is on the editorial board for Neurology and is a consultant for the Epilepsy Study Consortium, serving as a consultant for Anavex Life Sciences Corp, Eisai, GW Pharmaceuticals, the LouLou Foundation, Marinus Pharmaceuticals, Ovid Therapeutics, SK Biopharmaceuticals, Stoke Therapeutics, Takeda Pharmaceuticals, and Zogenix. J.F. receives salary support from the Epilepsy Foundation and the Epilepsy Study Consortium for consulting work and/or attending scientific advisory boards for Acadia Pharmaceuticals, Access Industries, Acuta Capital Partners, AFASCI, Agrithera, Alterity Therapeutics Limited, Angelini Pharma, Autifony Therapeutics Limited, Axonis Therapeutics, Bain Capital, Beacon Biosignals, Biogen, Biohaven Pharmaceuticals, Bloom Science, Bright Minds Biosciences, Capsida Biotherapeutics, Cerebral Therapeutics, Cerecin, Cerevel, Ceribell, Cognizance Biomarkers, Cowen and Company, Crossject, EcoR1 Capital, EG 427, Eisai, Encoded Therapeutics, Engrail, EpiMinder, Epitel, GRIN Therapeutics, Harmony/Epygenix, Ionis Pharmaceuticals, iQure Pharma, IQVIA RDS, Janssen Pharmaceutica, Jazz Pharmaceuticals, Leal Therapeutics, LivaNova, London Research & Pharmaceuticals, Longboard Pharmaceuticals, Maplight Therapeutics, Marinus, Medscape/WebMD, Modulight.bio, Mosaica Therapeutics, Neumirna Therapeutics, Neurelis, Neurocrine, Neurona Therapeutics, NeuroPace, NeuroPro Therapeutics, Neuroventis, Neurvati, Noema Pharma, Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics, Praxis, PureTech, Rapport Therapeutics, Receptor Holdings, Rivervest Venture Partners, Sage Therapeutics, SK Life Sciences, Stoke, Stream Neuroscience, Supernus, Takeda, Taysha Gene Therapies, UCB, uniQure, Ventus Therapeutics, Vida Ventures Management, and Xenon. J.F. has also received research support from the Epilepsy Study Consortium (funded by Eisai and UCB), Epilepsy Study Consortium/Epilepsy Foundation (funded by UCB), GW/FACES/One8Foundation, NINDS, and Praxis. She is on the editorial board of Lancet Neurology and Neurology Today. She is Medical Director for the Epilepsy Foundation. She is the President and on the board of directors for the Epilepsy Study Consortium. She has received travel/meal reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Biohaven Pharmaceuticals, Cerebral Therapeutics, Ceribell, Cowen and Company, Harmony Biosciences, LivaNova, Longboard, Maplight Therapeutics, Neumirna Therapeutics, Neurocrine, NeuroPace, Neurvati, Praxis, Rapport, Supernus, Takeda, Ventus, and Xenon. J.S. has worked as a consultant and/or served on advisory boards for PureTech Health, Biopharmaceutical Research Company, LivaNova, UCB Pharma, AdCel Pharma, and iFovea; and is Editor-in-Chief of Epilepsy & Behavior Reports (paid). B.T.'s institution receives research funding from the C.G. Swebilius Foundation. D.K.-N.T. reports no disclosures relevant to this paper but has served as a consultant in the past 3 years for Jazz Pharmaceuticals, Praxis Precision Medicines, NeuroPro Therapeutics, and Axonis Therapeutics. She receives royalties from Wolters Kluwer Publishers (UptoDate). None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. This article is linked to paper by Fisher et al. To view this article, visit https://doi.org/10.1111/epi.18702.

<scp>PAC</scp> ‐ <scp>FOS:</scp> A novel translational concordance framework identifies preclinical seizure models with highest predictive validity for clinical focal onset seizures

Epilepsia · 2025-08-06 · 1 citations

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: 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.

Bexicaserin for the treatment of seizures in developmental and epileptic encephalopathies: A phase 1b/2a trial ( <scp>PACIFIC</scp> )

Epilepsia · 2025-10-24 · 3 citations

OBJECTIVE: This randomized, double-blind, phase 1b/2a clinical trial was designed to evaluate the safety, tolerability, and efficacy of oral bexicaserin versus placebo for the treatment of seizures in adolescents and adults with developmental and epileptic encephalopathies (DEEs). METHODS: Eligible participants had a DEE diagnosis, were aged 12-65 years, and were taking 1-4 concomitant antiseizure medications. Randomization to treatment groups (4:1 bexicaserin:placebo) was stratified by type of DEE (Dravet syndrome [DS], Lennox-Gastaut syndrome [LGS], or DEE Other). Following a 28-day baseline period, the treatment period consisted of a 15-day flexible uptitration period (6, 9, or 12 mg three times daily, 5 days each) and a 60-day maintenance period on the highest tolerated dose. Primary end points were safety (adverse events) and change from baseline in countable motor seizure frequency. RESULTS: Forty-three and nine participants were assigned to bexicaserin treatment and placebo, respectively, and received ≥1 dose (safety set); 35 bexicaserin and nine placebo participants completed titration, entered the maintenance period, and had ≥1 seizure measurement during the maintenance period (full analysis set). Twenty-eight of 43 bexicaserin-treated participants (65.1%) and three of nine (33.3%) in the placebo group reported drug-related treatment-emergent adverse events (TEAEs); seven of 43 participants (16.3%) discontinued bexicaserin due to a TEAE during titration and two of 43 (4.7%) during maintenance, most frequently due to somnolence. Median reductions in countable motor seizure frequencies were -59.8% with bexicaserin and -17.4% with placebo; reductions with bexicaserin were observed across DEEs (DS, -74.6%; LGS, -50.8%; DEE Other, -65.5%). The proportion of participants achieving ≥50% reductions during the treatment period (responder analysis) was 60.0% with bexicaserin versus 33.3% with placebo. SIGNIFICANCE: Bexicaserin was well tolerated and associated with clinically relevant reductions in countable motor seizure frequencies in participants with a variety of DEEs. This novel trial design may expand treatment access to patients previously excluded from clinical trials.

Knowledge Tree Driven Contextualized Instruction Tuning of Foundation Models for Epilepsy Drug Recommendation

Lecture notes in computer science · 2025-09-18 · 1 citations

A randomized, double‐blind, placebo‐controlled, time‐to‐event study of the efficacy and safety of <scp>JNJ</scp> ‐40411813 in combination with levetiracetam or brivaracetam in patients with focal onset seizures

Epilepsia · 2025-11-01 · 2 citations

OBJECTIVE: Up to 30% of people with epilepsy are refractory to current antiseizure medications (ASMs). JNJ-40411813 is a positive allosteric modulator of metabotropic glutamate 2 receptor, a presynaptic glutamate release inhibitor, and was hypothesized to reduce glutamate-mediated neuronal toxicity through inhibition of excessive glutamate release during seizures. METHODS: This 12-week, double-blinded, placebo-controlled phase 2a study, which employed a rational polypharmacy approach using a novel time-to-event endpoint for epilepsy clinical trials, evaluated JNJ-40411813 (Cohort 1: 50/100 mg; Cohort 2: 100/200 mg) as adjunctive treatment for focal seizures in participants aged 18-64 years receiving levetiracetam or brivaracetam and ≤3 other ASMs. Participants were stratified as induced or noninduced based on treatment or no treatment with a cytochrome P450 3A4 enzyme-inducing ASM. The primary endpoint was time-to-baseline monthly seizure count. RESULTS: Cohorts 1 and 2 randomized 60 and 50 patients, respectively. No significant clinical benefits were observed in the median time (95% confidence interval [CI]) to reach the baseline monthly seizure count in Cohort 1 (JNJ-40411813: 34 days [27-48], placebo 32 days [28-37], hazard ratio [HR] = .75 [.41-1.38], p = .36) or Cohort 2 (JNJ-40411813: 38 days [28-48], placebo: 29 days [22-69], HR = .83 [.40-1.75], p = .63). Similarly, no clinical benefits of JNJ-40411813 were observed for any of the secondary endpoints. JNJ-40411813 displayed an acceptable safety profile; treatment-emergent adverse events were mild to moderate in severity and not treatment limiting. SIGNIFICANCE: JNJ-40411813 adjunctive to levetiracetam or brivaracetam showed no significant clinical benefit over placebo in reducing time-to-baseline monthly seizure count or improvement in other key measures in patients with focal onset seizures. The time-to-event study design was successful at reducing participant exposure to ineffective treatment. Despite an acceptable safety profile, the overall efficacy and benefit-risk assessment of JNJ-40411813 does not support its use for patients with focal seizures.

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of focal seizures

Epilepsia · 2025-05-15

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: 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.

Validation of the Seizure-Related Impact Assessment Scale

Neurology · 2025-07-16 · 2 citations

BACKGROUND AND OBJECTIVES: There is a clear need in epilepsy clinical trials and practice for a measure that captures the trade-off between seizure and treatment-related adverse effects, which is reliable over time and across different treatment regimens. We aimed to create and validate the Seizure-Related Impact Assessment Scale (SERIAS) to fill this need. METHODS: This was a prospective longitudinal study of adults with epilepsy recruited from an Australian comprehensive epilepsy center. Participants completed SERIAS at baseline and 3 and 6 months later. SERIAS has 6 self-report items. Five items record the number of days per month that seizures or treatment-related adverse effects partially or fully affect work/home/school and family/social/nonwork activities. The final item is an epilepsy disability visual analog scale. SERIAS is scored by adding the days per month of disability, with scores ranging from 0 to 150 (higher scores indicate more disability). SERIAS was completed alongside 7 validated instruments measuring seizure-related and treatment-related adverse effects (Work and Social Adjustment Scale [WSAS], Liverpool Adverse Events Profile [LAEP]), mood disorders (Neurological Disorders Depression Inventory for Epilepsy [NDDI-E], Generalized Anxiety Disorder [GAD-7]), somatic symptoms (Somatic Symptom Scale [SSS-8]), and quality of life (Quality of Life in Epilepsy Inventory [QOLIE]-31, EuroQol 5 Dimensions [EQ-5D]). General linear mixed models were used to investigate the relationship between the SERIAS and other relevant clinical and psychometric data. Standardized model coefficients β are presented with 95% confidence intervals. RESULTS: A total of 90 patients (64.4% female, mean age 43.1 years) completed baseline SERIAS. Most patients reported at least 1 day of disability (62%, median SERIAS score = 3, interquartile range = 18.3). Greater disability was negatively correlated with QOLIE-31 total score (β = -0.17, 95% CI -0.27 to -0.07) and positively correlated with scores on 5-level EQ-5D (β = 0.15, 95% CI 0.04-0.25), NDDI-E (β = 0.22, 95% CI 0.13-0.31), GAD-7 (β = 0.21, 95% CI 0.09-0.32), SSS8 (β = 0.29, 95% CI 0.17-0.41), LAEP (β = 0.29, 95% CI 0.20-0.39), WSAS seizure-related adverse events (β = 0.23, 95% CI 0.14-0.33), and WSAS treatment-related adverse events (β = 0.36, 95% CI 0.26-0.46). Higher seizure frequency was associated with higher SERIAS score (β = 0.07, 95% CI 0.03-0.11). Psychometric reliability for the SERIAS was acceptable (all coefficients >0.70) as was test-retest reliability (n = 35 patients, intraclass correlation coefficient = 0.72, 95% CI 0.51-0.85). DISCUSSION: SERIAS shows good psychometric reliability and strong test-retest stability. These findings suggest that SERIAS is a valid scale to measure epilepsy-related disability.

PAC – A novel translational concordance framework identifies preclinical seizure models with highest predictive validity for clinical focal onset seizures

bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-08

ABSTRACT/SUMMARY Objective Central to the development of novel antiseizure medications (ASMs) is testing of anticonvulsant activity in preclinical models. While 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 FDA-approved ASMs. Preclinical ASM responses in historically used seizure models were collected. Protective indices based on reported TD 50 and ED 50 values were calculated for each ASM in each preclinical model. A weighted scale representing relative anticonvulsant 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 used to grade clinical ASM response for each indication. To assess the predictive validity of preclinical models, a unified translational scoring matrix was developed to assign a concordance score spanning the spectrum of 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 (32mA) and rat amygdala kindling. Significance The PAC-FOS framework highlights mouse MES, mouse audiogenic and mouse 6 Hz (32mA) 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. KEY POINT BOX Using a newly developed translational scoring matrix, we provide novel insights into the clinical validity of common preclinical seizure models for FOS. The PAC-FOS Framework identifies mouse MES, audiogenic and 6-Hz 32 mA as three acute models with greatest predictive validity and versatility for FOS drug discovery. We present a pragmatic approach and decision tree to support efficient use of drug discovery resources and in consideration of the 3Rs of animal ethics. The work presented would allow for faster and more effective screening of ASMs, while potentially reducing future patient exposures to likely ineffective drugs.

Revidierte Klassifikation epileptischer Anfälle: Positionspapier der Internationalen Liga gegen Epilepsie

Clinical Epileptology · 2025-10-10

Zusammenfassung Die Internationale Liga gegen Epilepsie (ILAE) hat die operationale Klassifikation epileptischer Anfälle 2017 auf der Grundlage der damals entwickelten Rahmenbedingungen aktualisiert. In diese Überarbeitung wurden die publizierten Erfahrungen mit der Umsetzung der 2017er-Klassifikation einbezogen. Eine 37 Personen zählende Arbeitsgruppe wurde vom ILAE-Exekutivausschuss eingesetzt. Die internationalen Expertinnen und Experten aus allen ILAE-Regionen wandten ein modifiziertes Delphi-Verfahren an, bei dem für jeden Vorschlag ein Konsens von mehr als zwei Dritteln erforderlich war. Nach Veröffentlichung auf der ILAE-Homepage mit dem Ersuchen, Kommentare zu dem Entwurf einzugeben, ernannte der Exekutivausschuss 7 zusätzliche Sachverständige für die Arbeitsgruppe zur Überarbeitung des Positionspapieres, um die eingegangenen Kommentare zu diskutieren und gegebenenfalls einzubeziehen. Die aktualisierte Klassifikation behält die Hauptklassen von Anfällen bei: fokal, generalisiert, unbekannt (ob fokal oder generalisiert) und nicht klassifiziert. Taxonomische Regeln unterscheiden zwischen Klassifikatoren , die biologische Klassen widerspiegeln und sich direkt auf die klinische Behandlung auswirken, und Deskriptoren , die andere wichtige Anfallsmerkmale angeben. Fokale Anfälle und Anfälle unbekannten Ursprungs werden darüber hinaus nach dem Bewusstseinszustand des Patienten während des Anfalls klassifiziert, je nachdem ob eine Bewusstseinsstörung vorliegt oder nicht. Die Bewertung, ob eine Bewusstseinsstörung vorliegt, wird durch Gewahrsein (engl. „awareness“) und Reaktionsfähigkeit (engl. „responsiveness“) während eines Anfalls und erhaltene Erinnerung (engl. „recall“) nach einem Anfall klinisch operationalisiert. Wenn der Bewusstseinszustand nicht bestimmbar ist, wird der Anfall unter dem übergeordneten Begriff, d. h. der Hauptanfallsklasse (fokaler Anfall oder Anfall unbekannten Ursprungs) klassifiziert. Generalisierte Anfälle werden in Absencen, generalisierte tonisch-klonische Anfälle und andere generalisierte Anfälle eingeteilt, wobei jetzt auch der negative Myoklonus als Anfallstyp beschrieben wird. Anfälle werden in der Grundversion als solche mit oder ohne beobachtbare Manifestationen beschrieben, während eine erweiterte Version die chronologische Abfolge der Anfallssemiologie verwendet. Diese aktualisierte Klassifikation umfasst 4 Hauptklassen und nur noch 21 Anfallstypen (und nicht mehr 63 wie in der 2017 Klassifikation; Anm. d. Übersetzer). Besonderer Wert wurde auf die Übersetzbarkeit in andere Sprachen jenseits von Englisch gelegt. Ziel ist es, eine gemeinsame Sprache für alle im Bereich Epilepsie tätigen Gesundheitsfachkräfte zu schaffen – von ressourcenarmen Gebieten bis hin zu hoch spezialisierten Zentren – und leicht zugängliche Begriffe für Patientinnen und Patienten sowie Betreuungspersonen bereitzustellen.

Pre-treatment seizures and cognition at the time of focal epilepsy diagnosis

Epilepsy & Behavior · 2025-10-04