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A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group., (© 2021 International League Against Epilepsy.)

Attention-deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large-population prospective studies., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered., (© 2018 National Association of Medical Examiners. This paper has been simultaneously published in Epilepsia. Volume 59, #3 and Academic Forensic Pathology: The Official Publication of the National Association of Medical Examiners, Volume 8, #1.)

The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed., Method: A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012., Results: In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p < .05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p = .92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p = .23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p = .27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients had a lower rate of epilepsy remission. Lennox-Gastaut syndrome was seen in 7%. Febrile/illness-related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment-refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures., Significance: This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

This White Paper builds on the publication of the International League Against Epilepsy (ILAE) and International Bureau for Epilepsy (IBE) report "Listening for a change-medical and social needs of people with intellectual disability who have epilepsy" (Listening for a change the medical and social needs of people with epilepsy and intellectual disability, ILAE, 2013). The Paper presents an overview of the recommendations of the report, which aim to improve the health and social care of this important population of people with epilepsy worldwide. Actions in four domains are indicated: (1) the development of standards and initiatives that would enhance diagnosis, pathways to investigation, and treatment; (2) the development of guidelines for treatment, specifically best practice in the management of antiepileptic drugs including rescue medication; (3) the development of standards for primary care, multidisciplinary teamwork, and clinical consultations, with emphasis on the need to enhance communication and improve access to information; and (4) the enhancement of links among different stakeholders including medical services, educational establishments, employment services, organizations providing opportunities for social engagement, and family members. The breadth of needs of this population is a challenge to the epilepsy world, spanning all the professional groupings, care providers, and the research modalities in epilepsy., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Up to 35% of individuals diagnosed with epilepsy continue to have seizures despite treatment, commonly referred to as drug-resistant epilepsy. Uncontrolled seizures can directly, or indirectly, negatively impact an individual's quality of life. To inform clinical management and life decisions, it is important to be able to predict the likelihood of seizure control. Those likely to achieve seizure control will be able to return sooner to their usual work and leisure activities and require less follow-up, whereas those with a poor prognosis will need more frequent clinical attendance and earlier consideration of epilepsy surgery. This is a systematic review aimed at identifying demographic, clinical, physiological (e.g., electroencephalographic), and imaging (e.g., magnetic resonance imaging) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). MEDLINE and Embase were searched for prediction models of treatment outcomes in patients with NDE. Study characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST (Prediction Model Risk of Bias Assessment Tool) tool. Baseline variables associated with treatment outcomes are reported as prognostic factors. After screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally scored high for susceptibility to bias. Outcomes reported fit broadly into four categories: drug resistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics/types, epilepsy history, and age at onset. Antiseizure medication response was often included as a baseline variable, potentially obscuring other factor relationships at baseline. Currently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) practices. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence-based approach for tailoring individualized antiepileptic treatment in this specific population., Methods: In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens., Results: The pharmacokinetic profile of PER was adequately described by a one-compartment model with first-order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were .016 ± .009 L/h/kg and 1.47 ± .78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215-862 μg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis., Significance: In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real-world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population., (© 2024 International League Against Epilepsy.)

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy., Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician., Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants., Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG., (© 2023 International League Against Epilepsy.)

As part of the 2009 International League Against Epilepsy (ILAE) Centenary Celebration, a special symposium was dedicated to Epilepsia (100 Years of Epilepsia: Landmark Papers and Their Influence). The Associate Editors were asked to identify a particularly salient and meaningful paper in their areas of expertise. From the content areas of neuropsychology and neuropsychiatry two very interesting papers were identified using quite different ascertainment techniques. One paper addressed the problem of psychosis in temporal lobe epilepsy, whereas the other represents the first paper to appear in Epilepsia presenting quantitative assessment of cognitive status in epilepsy. These two papers are reviewed in detail and placed in historical context.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

Objective: This study was undertaken to analyze whether the rate of breakthrough seizures in patients taking antiseizure medication (ASM) who have been seizure-free for at least 12 months varies among different types and etiologies of epilepsy. Given the relative ease of achieving seizure freedom with ASM in patients with post-ischemic stroke epilepsy, we hypothesized that this etiology is associated with a reduced risk of breakthrough seizures., Methods: We defined a breakthrough seizure as an unprovoked seizure occurring while the patient was taking ASM after a period of at least 12 months without seizures. Data were analyzed retrospectively from a tertiary epilepsy outpatient clinic. Patients were eligible for inclusion if they either had a breakthrough seizure at any time or a seizure-free interval of at least 2 years. Our primary endpoint was rate of breakthrough seizures. We conducted univariable and multivariable analyses to identify variables associated with breakthrough seizures., Results: Of 521 patients (53% females, median age = 49 years) included, 29% had a breakthrough seizure, which occurred after a median seizure-free interval of 34 months (quartiles = 22, 62). When controlling for clinically relevant covariates, breakthrough seizures were associated with post-ischemic stroke epilepsy (odds ratio [OR] = .267, 95% confidence interval [CI] = .075-.946), genetic generalized epilepsy (OR = .559; 95% CI = .319-.978), intellectual disability (OR = 2.768, 95% CI = 1.271-6.031), and the number of ASMs previously and currently tried (OR = 1.203, 95% CI = 1.056-1.371). Of the 151 patients with breakthrough seizures, 34.3% did not reachieve terminal 12-month seizure freedom at the last visit., Significance: This is the first study to show an association between type and etiology of epilepsy and risk of breakthrough seizures. Our data suggest that epilepsies in which seizure freedom can be obtained more easily also exhibit a lower risk of breakthrough seizures. These findings may help to better counsel seizure-free patients on their further seizure prognosis., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature., Methods: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains., Results: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum., Significance: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy., (© 2024 International League Against Epilepsy.)

Objectives: To assess the occurrence rate, characteristics, and impact of eating disorders (EDs) in adolescents with epilepsy., Methods: In this observational study, adolescents with epilepsy seen in a single center between 2013 and 2022 who had comorbid EDs were compared to two control groups of adolescents with only epilepsy and only EDs. Patients with intellectual disability or autism spectrum disorder were excluded. Data retrieved included demographic and anthropometric details and clinical variables relating to seizure types, EDs, and psychiatric disorders and behaviors., Results: A total of 376 subjects were included in the study: 84 adolescents with both epilepsy and eating disorders, 135 with only epilepsy, and 157 with only EDs. The rate of EDs in adolescents with epilepsy was 7.0% (95% confidence interval [CI] 5.6%-8.5%) overall, 11.3% (95% CI 8.8%-14.3%) in females, and 3.1% (95% CI 1.9%-4.8%) in males. The median (interquartile range [IQR]) time difference between the onset of epilepsy to an ED was 1.6 (.5-3.6) years. Among adolescents with epilepsy, those with an ED were more likely to be female (p = .001) and have a lower body mass index z-score (zBMI) percentile (p < .001). Epilepsy type, seizure frequency, or seizure duration were not specific for having or not having EDs. Among adolescents with EDs, those with epilepsy had a younger onset of their EDs (p < .001), included relatively more males (p = .007), and consisted of more cases of anorexia-nervosa-restrictive type (p < .001), and fewer cases of bulimia nervosa (p = .04) and binge eating disorder (p = .003). Adolescents with epilepsy and a comorbid ED were more likely to have psychiatric comorbidities such as depression, anxiety, and suicidality than adolescents with only epilepsy or EDs., Significance: EDs should be suspected and screened for in intellectually intact female and male adolescents with epilepsy, irrespective of their epilepsy type. If disturbed eating behaviors or EDs are identified, further evaluation should be directed at detecting other psychopathologies, including suicidality., (© 2023 International League Against Epilepsy.)

Objective: This study was undertaken to describe extracerebral biosignal characteristics of overall and various seizure types as compared with baseline physical activities using multimodal devices (Empatica E4); develop predictive models for overall and each seizure type; and assess diagnostic performance of each model., Methods: We prospectively recruited patients with focal epilepsy who were admitted to the epilepsy monitoring unit for presurgical evaluation during January to December 2020. All study participants were simultaneously applied gold standard long-term video-electroencephalographic (EEG) monitoring and an index test, E4. Two certified epileptologists independently determined whether captured events were seizures and then indicated ictal semiology and EEG information. Both were blind to multimodal biosignal findings detected by E4. Biosignals during 5-min epochs of both seizure events and baseline were collected and compared. Predictive models for occurrence overall and of each seizure type were developed using a generalized estimating equation. Diagnostic performance of each model was then assessed., Results: Thirty patients had events recorded and were recruited for analysis. One hundred eight seizure events and 120 baseline epochs were collected. Heart rate (HR), acceleration (ACC), and electrodermal activity (EDA) but not temperature were significantly elevated during seizures. Cluster analysis showed trends of greatest elevation of HR and ACC in bilateral tonic-clonic seizures (BTCs), as compared with non-BTCs and isolated auras. HR and ACC were independent predictors for overall seizure types, BTCs, and non-BTCs, whereas only HR was a predictor for isolated aura. Diagnostic performance including sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve of the predictive model for overall seizures were 77.78%, 60%, and .696 (95% confidence interval = .628-.764), respectively., Significance: Multimodal extracerebral biosignals (HR, ACC, EDA) detected by a wrist-worn smartwatch can help differentiate between epileptic seizures and normal physical activities. It would be worthwhile to implement our predictive algorithms in commercial seizure detection devices. However, larger studies to externally validate our predictive models are required., (© 2023 International League Against Epilepsy.)

Objective: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2 Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV + neurons occur in the hippocampus of MeCP2 Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility., Methods: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2 Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2 Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2 Tg1 :PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV + neurons for structural analysis., Results: Epilepsy susceptibility was increased in MeCP2 Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2 Tg1 mice. The dendritic complexity in MeCP2 Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2 Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2 Tg1 mice., Significance: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy., (© 2024 International League Against Epilepsy.)

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Due to the high clinical heterogeneity of epilepsy, there is a critical need for novel metrics aimed at capturing its biological and phenotypic complexity. Frailty is increasingly recognized in various medical disciplines as a useful construct to understand differences in susceptibility to adverse outcomes. Here, we develop a frailty index (FI) for patients with epilepsy (PwE) and explore its association with demographic and clinical features., Methods: In this cross-sectional study, we consecutively enrolled 153 PwE from an outpatient epilepsy clinic. Participants were assessed for various health deficits to calculate the FI. Associations between FI and demographic/clinical features, antiseizure medications (ASMs), and patient-reported outcomes were analyzed using general linear models and Spearman correlation., Results: The median age at the time of study visit was 47 years (interquartile range = 33-60), and 89 (58.2%) patients were females. Multiple linear regression revealed that the developed 33-item FI showed an independent association with age, female sex, higher body mass index, family history of epilepsy, intellectual disability, and the number of ASMs used. A robust analysis of covariance showed higher FI levels in patients using cytochrome P450 3A4-inducer ASMs. We found a moderate positive correlation between FI and psychological distress, lower quality of life, and physical frailty, measured by the Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy Inventory-10, and handgrip strength, respectively. Finally, a weak association was observed between higher FI scores and an increased number of epileptic falls., Significance: This study highlights the significance of frailty as a comprehensive health measure in epilepsy. It suggests that frailty in this specific population is not only a manifestation of aging but is inherently linked to epilepsy and treatment-related factors. Future research is warranted to validate and refine the FI in diverse epilepsy populations and investigate its impact on specific adverse outcomes in longitudinal studies., (© 2024 International League Against Epilepsy.)

Objective: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria., Methods: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data., Results: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy., Significance: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study aims to determine the contribution of comorbidities to excess psychogenic nonepileptic seizures (PNES) mortality., Methods: A retrospective cohort study was conducted of tertiary epilepsy outpatients from St. Vincent's Hospital Melbourne, Australia with an 8:1 comparison cohort, matched by age, sex, and socioeconomic status (SES) to national administrative databases between 2007 and 2017. Privacy-preserving data linkage was undertaken with the national prescription, National Death Index, and National Coronial Information System. Forty-five comorbid disease classes were derived by applying the Australian validated RxRisk-V to all dispensed prescriptions. We fitted Cox proportional hazard models controlling for age, sex, SES, comorbidity, disease duration, and number of concomitant antiseizure medications, as a marker of disease severity. We also performed a parallel forward-selection change in estimate strategy to explore which specific comorbidities contributed to the largest changes in the hazard ratio., Results: A total of 13 488 participants were followed for a median 3.2 years (interquartile range = 2.4-4.0 years), including 1628 tertiary epilepsy outpatients, 1384 patients with epilepsy, 176 with PNES, and 59 with both. Eighty-two percent of epileptic seizures and 92% of typical PNES events were captured in an epilepsy monitoring unit. The age-/sex-/SES-adjusted hazard ratio was elevated for epilepsy (4.74, 95% confidence interval [CI] = 3.36-6.68) and PNES (3.46, 95% CI = 1.38-8.68) and remained elevated for epilepsy (3.21, 95% CI = 2.22-4.63) but not PNES (2.15, 95% CI = .77-6.04) after comorbidity adjustment. PNES had more pre-existing comorbidities (p = .0007), with a three times greater median weighted Rx-RiskV score. Psychotic illness, opioid analgesia, malignancies, and nonopioid analgesia had the greatest influence on PNES comorbid risk., Significance: Higher comorbidity appears to explain the excess PNES mortality and may represent either a wider underrecognized somatoform disorder or a psychological response to physical illness. Better understanding and management of the bidirectional relationship of these wider somatic treatments in PNES could potentially reduce the risk of death., (© 2023 International League Against Epilepsy.)

Objective: Medication adherence is considered an important risk factor for sudden unexpected death in epilepsy (SUDEP), although measurement accuracy is difficult. Using prescription dispensations, this study aims to estimate antiseizure medication (ASM) adherence and identify adherence patterns that influence epilepsy mortality., Methods: This is a retrospective cohort study of tertiary epilepsy outpatients seen at St Vincent's Hospital Melbourne, Victoria, Australia, from January 1, 2012 until December 31, 2017. Privacy-preserving data linkage with the Australian national prescription, death, and coroner's databases was performed. We fitted a four-cluster longitudinal group-based trajectory model for ASM adherence from recurring 90-day windows of prescription dispensations during a 3-year "landmark period" from January 1, 2012 to December 31, 2014, using the AdhereR package. We estimated the risk of SUDEP and all-cause death for each adherence pattern during an "observation period" from January 1, 2015 to December 31, 2017. The Cox proportional hazards and logistic regression models were adjusted for age, sex, socioeconomic status, epilepsy duration, comorbidity, drug resistance, and inadequate seizure control., Results: One thousand one hundred eighty-seven participants were observed for a median of 3.2 years (interquartile range = 2.4-4.0 years). We observed 66 deaths with 10 SUDEP cases during the observation period. We identified four patterns of ASM adherence: good, 51%; declining, 24%; poor, 16%; and very poor, 9%. Declining adherence was associated with an increased risk for SUDEP, with hazard ratio (HR) = 8.43 (95% confidence interval [CI] = 1.10-64.45) at 1 year and HR = 9.17 (95% CI = 1.16-72.21) at 3 years. Compared to no ASM therapeutic change, the addition of a second to fourth ASM offered increased protection against SUDEP in patients with continuing drug-resistant epilepsy., Significance: ASM nonadherence was observed in half of outpatients with epilepsy. A declining pattern of adherence, observed in a quarter of patients, was associated with more than eight times increased risk of SUDEP. Any ongoing medication interventions must include strategies to maintain and improve ASM adherence if we are to reduce the risk of SUDEP., (© 2023 International League Against Epilepsy.)

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women., Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance., Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester., Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period., (© 2024 International League Against Epilepsy.)

Objective: To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry., Methods: We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein., Results: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif., Significance: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases., (© 2024 International League Against Epilepsy.)

The current pace of development and applications of large language models (LLMs) is unprecedented and will impact future medical care significantly. In this critical review, we provide the background to better understand these novel artificial intelligence (AI) models and how LLMs can be of future use in the daily care of people with epilepsy. Considering the importance of clinical history taking in diagnosing and monitoring epilepsy-combined with the established use of electronic health records-a great potential exists to integrate LLMs in epilepsy care. We present the current available LLM studies in epilepsy. Furthermore, we highlight and compare the most commonly used LLMs and elaborate on how these models can be applied in epilepsy. We further discuss important drawbacks and risks of LLMs, and we provide recommendations for overcoming these limitations., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Refractory epilepsy may have an underlying autoimmune etiology. Our aim was to assess the prevalence of neural autoantibodies in a multicenter national prospective cohort of patients with drug-resistant epilepsy undergoing epilepsy surgery utilizing comprehensive clinical, serologic, and histopathological analyses., Methods: We prospectively recruited patients undergoing epilepsy surgery for refractory focal epilepsy not caused by a brain tumor from epilepsy surgery centers in the Czech Republic. Perioperatively, we collected cerebrospinal fluid (CSF) and/or serum samples and performed comprehensive commercial and in-house assays for neural autoantibodies. Clinical data were obtained from the patients' medical records, and histopathological analysis of resected brain tissue was performed., Results: Seventy-six patients were included, mostly magnetic resonance imaging (MRI)-lesional cases (74%). Mean time from diagnosis to surgery was 21 ± 13 years. Only one patient (1.3%) had antibodies in the CSF and serum (antibodies against glutamic acid decarboxylase 65) in relevant titers; histology revealed focal cortical dysplasia (FCD) III (FCD associated with hippocampal sclerosis [HS]). Five patients' samples displayed CSF-restricted oligoclonal bands (OCBs; 6.6%): three cases with FCD (one with FCD II and two with FCD I), one with HS, and one with negative histology. Importantly, eight patients (one of them with CSF-restricted OCBs) had findings on antibody testing in individual serum and/or CSF tests that could not be confirmed by complementary tests and were thus classified as nonspecific, yet could have been considered specific without confirmatory testing. Of these, two had FCD, two gliosis, and four HS. No inflammatory changes or lymphocyte cuffing was observed histopathologically in any of the 76 patients., Significance: Neural autoantibodies are a rare finding in perioperatively collected serum and CSF of our cohort of mostly MRI-lesional epilepsy surgery patients. Confirmatory testing is essential to avoid overinterpretation of autoantibody-positive findings., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments., Methods: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration., Results: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p = .243; PER, p = .113) or responder status (BRV, p = .118; LCM, p = .478; PER, p = .069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%)., Significance: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The ketogenic diet (KD) is a widely used therapeutic option for individuals with medically refractory epilepsy. As the diet's name implies, ketosis is a historically important component of the diet, but it is not well understood how important ketosis is for seizure control. The ketogenic ratio is defined as the ratio of fat to carbohydrate plus protein by weight in the diet (grams). Traditionally, the classic KD contains a 4:1 ratio, and a very high proportion of fat in the diet. The classic KD, with its high proportion of fat and limited carbohydrate intake can be restrictive for patients with epilepsy. Recently, there is experience with use of lower ketogenic ratios and less-restrictive diets such as the modified Atkins diet and the low glycemic index treatment. In this narrative review, we examine the role of ketosis and ketogenic ratios in determining the efficacy of the KD in children with epilepsy., (© 2022 International League Against Epilepsy.)

Objective: This study was undertaken to characterize somatic symptoms and related disorders (SSD) in epilepsy., Methods: Adults with epilepsy under active follow-up at a tertiary epilepsy center were consecutively enrolled. The diagnosis of SSD was performed by an experienced psychologist based on the structured clinical interview for Statistical Manual of Mental Disorders, 5th edition. Detailed social/demographic data, epilepsy features, psychiatric features, life quality, disability, and economic burden were collected and compared between people with SSD and those without. Bodily distress syndrome checklist, Somatic Symptom Disorder-B Criteria Scale, Patient Health Questionnaire-9, and Generalized Anxiety Disorder seven-item scale (GAD-7) were used to evaluate SSD individuals' somatic symptoms, symptom-related psychological distress, and depressive and anxious symptoms. Quality of life and disability were assessed by Quality of Life in Epilepsy Inventory 31 (QOLIE-31) and World Health Organization Disability Assessment Schedule V.2.0 (WHO DAS 2.0). A risk prediction nomogram was generated using least absolute shrinkage and selection operator (LASSO) analysis and validated., Results: One hundred fifty of 631 participants (24%) were diagnosed with SSD. In people with SSD, the top three most common somatic symptoms were memory impairment, headache, and dizziness (85%, 80%, and 78%, respectively), and multiple systems were involved in most (82%) people with SSD. Compared with people without SSD, those with SSD had lower QOLIE-31 total scores, and higher WHO DAS 2.0 scores and disease economic burdens. LASSO analysis suggested that a history of severe traumatic brain injury, hippocampal sclerosis, low seizure worry and medication effects scores on QOLIE-31, multiple systems affected by somatic symptoms, and a high GAD-7 score were risk factors of SSD. The nomogram was validated for good accuracy in the training and testing cohorts., Significance: SSD are likely to be a common comorbidity in epilepsy and harm epilepsy prognosis. Our risk prediction nomogram was successfully developed but needs further validation in larger cohorts., (© 2022 International League Against Epilepsy.)

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes., (© 2022 International League Against Epilepsy.)

Objective: Because resources are limited in modern health care systems, the decision on the allocation of expensive drugs can be supported by a public consent. This study examines how various factors influence subjectively perceived "fair" pricing of antiseizure medication (ASM) among four groups including physicians, persons with epilepsy (PWEs), their relatives, and a control group., Methods: We conducted a factorial survey. Vignettes featured a fictional PWE receiving a fictional ASM. The characteristics of the fictional PWE, ASM, and epilepsy varied. Participants were asked to assess the subjectively appropriate annual cost of ASM treatment per year for each scenario., Results: Fifty-seven PWEs (mean age (SD) 37.7 ± 12.3, 45.6% female), 44 relatives (age 48.4 ± 15.7, 51.1% female), 46 neurologists (age 37.1 ± 9.6, 65.2% female), and 47 persons in the control group (age 31.2 ± 11.2, 68.1% female) completed the questionnaire. The amount of money that respondents were willing to spend for ASM treatment was higher than currently needed in Germany and increased with disease severity among all groups. All groups except for PWEs accepted higher costs of a drug with better seizure control. Physicians and the control group, but not PWEs and their relatives, tended to do so also for minor or no side effects. Physicians reduced the costs for unemployed patients and the control group spent less money for older patients., Significance: ASM effectiveness appears to justify higher costs. However, the control group attributed less money to older PWEs and physicians allocated fewer drug costs to unemployed PWEs., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives., Methods: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models., Results: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM., Significance: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The International League Against Epilepsy (ILAE) introduced a classification for seizure types in 2017 and updated the classification for epilepsy syndromes in 2022. These classifications aim to improve communication among healthcare professionals and help patients better describe their condition. So far, regulatory agencies have used different terminology. This paper stresses the crucial need for consistently adopting ILAE terminology in both regulatory processes and clinical practice. It highlights how language plays a significant role in healthcare communication and how standardized terminology can enhance patient comprehension. The ongoing review of guidelines by regulatory bodies offers a timely opportunity. Aligning regulatory terminologies holds the potential to facilitate discussions on future drug development and harmonize practices across diverse regions, ultimately fostering improved care and research outcomes in epilepsy treatment., (© 2023 International League Against Epilepsy.)

In addition to the primary aim of seizure freedom, a key secondary aim of pediatric epilepsy surgery is to stabilize and, potentially, optimize cognitive development. Although the efficacy of surgical treatment for seizure control has been established, the long-term intellectual and developmental trajectories are yet to be delineated. We conducted a systematic review and meta-analysis of studies reporting pre- and postsurgical intelligence or developmental quotients (IQ/DQ) of children with focal lesional epilepsy aged ≤18 years at epilepsy surgery and assessed at >2 years after surgery. We determined the IQ/DQ change and conducted a random-effects meta-analysis and meta-regression to assess its determinants. We included 15 studies reporting on 341 patients. The weighted mean age at surgery was 7.1 years (range = .3-13.8). The weighted mean postsurgical follow-up duration was 5.6 years (range = 2.7-12.8). The overall estimate of the mean presurgical IQ/DQ was 60 (95% confidence interval [CI] = 47-73), the postsurgical IQ/DQ was 61 (95% CI = 48-73), and the change was +.94 IQ/DQ (95% CI = -1.70 to 3.58, p = .486). Children with presurgical IQ/DQ ≥ 70 showed a tendency for higher gains than those with presurgical IQ/DQ < 70 (p = .059). Higher gains were determined by cessation of antiseizure medication (ASM; p = .041), not just seizure freedom. Our findings indicate, on average, stabilization of intellectual and developmental functioning at long-term follow-up after epilepsy surgery. Once seizure freedom has been achieved, ASM cessation enables the optimization of intellectual and developmental trajectories in affected children., (© 2023 International League Against Epilepsy.)

Objective: In Australia, 30% of newly diagnosed epilepsy patients were not immediately treated at diagnosis. We explored health outcomes between patients receiving immediate, deferred, or no treatment, and compared them to the general population., Methods: Adults with newly diagnosed epilepsy in Western Australia between 1999 and 2016 were linked with statewide health care data collections. Health care utilization, comorbidity, and mortality at up to 10 years postdiagnosis were compared between patients receiving immediate, deferred, and no treatment, as well as with age- and sex-matched population controls., Results: Of 603 epilepsy patients (61% male, median age = 40 years) were included, 422 (70%) were treated immediately at diagnosis, 110 (18%) received deferred treatment, and 71 (12%) were untreated at the end of follow-up (median = 6.8 years). Immediately treated patients had a higher 10-year rate of all-cause admissions or emergency department presentations than the untreated (incidence rate ratio [IRR] = 2.0, 95% confidence interval [CI] = 1.4-2.9) and deferred treatment groups (IRR = 1.7, 95% CI = 1.0-2.8). They had similar 10-year risks of mortality and developing new physical and psychiatric comorbidities compared with the deferred and untreated groups. Compared to population controls, epilepsy patients had higher 10-year mortality (hazard ratio = 2.6, 95% CI = 2.1-3.3), hospital admissions (IRR = 2.3, 95% CI = 1.6-3.3), and psychiatric outpatient visits (IRR = 3.2, 95% CI = 1.6-6.3). Patients with epilepsy were also 2.5 (95% CI = 2.1-3.1) and 3.9 (95% CI = 2.6-5.8) times more likely to develop a new physical and psychiatric comorbidity, respectively., Significance: Newly diagnosed epilepsy patients with deferred or no treatment did not have worse outcomes than those immediately treated. Instead, immediately treated patients had greater health care utilization, likely reflecting more severe underlying epilepsy etiology. Our findings emphasize the importance of individualizing epilepsy treatment and recognition and management of the significant comorbidities, particularly psychiatric, that ensue following a diagnosis of epilepsy., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The management of patients after a first unprovoked seizure (FUS) can benefit from stratification of the average 50% risk for further seizures. We characterized subjects with FUSs, out of a large generally healthy homogenous population of soldiers recruited by law to the Israeli Defense Forces, to investigate the role of the type of service, as a trigger burden surrogate, in the risk for additional seizures., Methods: Soldiers recruited between 2005 and 2014, who experienced an FUS during their service, were identified from military records. Subjects with a history of epilepsy or lack of documentation of FUS characteristics were excluded from the study. Data on demographics and military service and medical details were extracted for the eligible soldiers., Results: Of 816 252 newly recruited soldiers, representing 2 138 000 person-years, 346 had an FUS, indicating an incidence rate of 16.2 per 100 000 person-years. The FUS incidence rate was higher in combat versus noncombat male and female soldiers (p < .0001). Most subjects (75.7%) were prescribed antiseizure medications (ASMs), and 29.2% had additional seizures after the FUS. Service in combat units, abnormal magnetic resonance imaging, and being prescribed ASMs were correlated with a lower risk of having multiple seizures (95% confidence interval [CI] = .48-.97, .09-.86, .15-.28, respectively). On multivariate analysis, service in combat units (odds ratio [OR] = .48 for seizure recurrence, 95% CI = .26-.88) and taking medications (OR = .46, 95% CI = .24-.9) independently predicted not having additional seizures., Significance: FUS incidence rate was higher in combat soldiers, but they had a twofold lower risk of additional seizures than noncombat soldiers, emphasizing the value of strenuous triggers as negative predictors for developing epilepsy. This suggests a shift in the perception of epilepsy from a "yes or no" condition to a continuous trend of predisposition to seizures, warranting changes in the ways etiologies of epilepsy are weighted and treatments are delivered., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of sudden and unexpected death in epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of preclinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation. Preclinical models of SUDEP are heterogeneous and include rodent and nonrodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such as models where seizures are elicited by electrical stimulation, pharmacological intervention, or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of nongenetic epilepsy etiology or from genetically based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis, whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardiorespiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of periseizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models., (© 2023 International League Against Epilepsy.)

Objective: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS., Methods: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks., Results: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality., Significance: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Wrist- or ankle-worn devices are less intrusive than the widely used electroencephalographic (EEG) systems for monitoring epileptic seizures. Using custom-developed deep-learning seizure detection models, we demonstrate the detection of a broad range of seizure types by wearable signals., Methods: Patients admitted to the epilepsy monitoring unit were enrolled and asked to wear wearable sensors on either wrists or ankles. We collected patients' electrodermal activity, accelerometry (ACC), and photoplethysmography, from which blood volume pulse (BVP) is derived. Board-certified epileptologists determined seizure onset, offset, and types using video and EEG recordings per the International League Against Epilepsy 2017 classification. We applied three neural network models-a convolutional neural network (CNN) and a CNN-long short-term memory (LSTM)-based generalized detection model and an autoencoder-based personalized detection model-to the raw time-series sensor data to detect seizures and utilized performance measures, including sensitivity, false positive rate (the number of false alarms divided by the total number of nonseizure segments), number of false alarms per day, and detection delay. We applied a 10-fold patientwise cross-validation scheme to the multisignal biosensor data and evaluated model performance on 28 seizure types., Results: We analyzed 166 patients (47.6% female, median age = 10.0 years) and 900 seizures (13 254 h of sensor data) for 28 seizure types. With a CNN-LSTM-based seizure detection model, ACC, BVP, and their fusion performed better than chance; ACC and BVP data fusion reached the best detection performance of 83.9% sensitivity and 35.3% false positive rate. Nineteen of 28 seizure types could be detected by at least one data modality with area under receiver operating characteristic curve > .8 performance., Significance: Results from this in-hospital study contribute to a paradigm shift in epilepsy care that entails noninvasive seizure detection, provides time-sensitive and accurate data on additional clinical seizure types, and proposes a novel combination of an out-of-the-box monitoring algorithm with an individualized person-oriented seizure detection approach., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Seizures beget seizures is a longstanding theory that proposed that seizure activity can impact the structural and functional properties of the brain circuits in ways that contribute to epilepsy progression and the future occurrence of seizures. Originally proposed by Gowers, this theory continues to be quoted in the pathophysiology of epilepsy. We critically review the existing data and observations on the consequences of recurrent seizures on brain networks and highlight a range of factors that speak for and against the theory. The existing literature demonstrates clearly that ictal activity, especially if recurrent, induces molecular, structural, and functional changes including cell loss, connectivity reorganization, changes in neuronal behavior, and metabolic alterations. These changes have the potential to modify the seizure threshold, contribute to disease progression, and recruit wider areas of the epileptic network into epileptic activity. Repeated seizure activity may, thus, act as a pathological positive-feedback mechanism that increases seizure likelihood. On the other hand, the time course of self-limited epilepsies and the presence of seizure remission in two thirds of epilepsy cases and various chronic epilepsy models oppose the theory. Experimental work showed that seizures could induce neural changes that increase the seizure threshold and decrease the risk of a subsequent seizure. Due to the complex nature of epilepsies, it is wrong to consider only seizures as the key factor responsible for disease progression. Epilepsy worsening can be attributed to the various forms of interictal epileptiform activity or underlying disease mechanisms. Although seizure activity can negatively impact brain structure and function, the "seizures beget seizures" theory should not be used dogmatically but with extreme caution., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The coronavirus disease 2019 (COVID-19) pandemic had widespread impact on health care systems globally-particularly services arranged around elective admission and attendance such as epilepsy monitoring units and home video-EEG telemetry (HVET). Here, we review the ongoing impacts of the pandemic on HVET services among several different providers who used different initial models of HVET. We discuss the features of HVET that led to success in providing continued diagnostic services to patients with epilepsy and related disorders and through retrospective audit of our services demonstrate the high diagnostic yield of HVET. We reflect on this unforeseen future and its implications for other diagnostic techniques and approaches., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)