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Abstract: Cenobamate is a novel antiseizure medication (ASM) commercially available in Europe and in the U.S. for the treatment of focal seizures in adults. The mechanisms responsible for its antiseizure activity include enhancement of the inactivated state of voltage-gated sodium channels with blockade of the persistent sodium current and positive allosteric modulation of GABAA receptors at a non-benzodiazepine binding site. Cenobamate has a high oral bioavailability that is not influenced by food intake. The terminal half-life is 50-60 hours, allowing for once-daily dosing. Cenobamate is a CYP2C19 inhibitor and an inducer of CYP3A4 and CYP2B6, and consequently, it can cause a number of drug-drug interactions. Efficacy and safety have been evaluated in two randomized, double-blind, placebo-controlled adjunctive therapy trials in adults with focal seizures. In both trials, cenobamate decreased significantly the frequency of focal seizures, with relatively high seizure freedom rates. Adverse events most commonly reported in double-blind trials included dizziness, somnolence, headache, fatigue, and diplopia. The occurrence of three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) during early clinical development led to the conduction of a Phase 3 open-label long-term safety study in a total of 1339 patients. In this study, no serious idiosyncratic adverse reactions were observed using a start-low and go-slow approach. Further studies are required to determine whether the clinical activity profile of cenobamate extends to protection against other seizure types and to evaluate its efficacy and safety profile in special patient groups such as infants, children, the elderly, and patients with comorbid conditions.

Cenobamate is a new antiseizure medication (ASM) recently introduced in the USA for the treatment of adults with focal-onset seizures. In March 2021, the European Commission authorized its use for the adjunctive treatment of focal-onset seizures with or without secondary generalization (focal seizures with or without progression to bilateral tonic-clonic seizures, according to current ILAE terminology) in adults with epilepsy not adequately controlled despite the treatment with at least two ASMs. This review summarizes the mechanism of action, efficacy, and safety of Cenobamate. The authors provide their expert opinions on the use of this drug. The aim of this paper is to report on the Italian preliminary experience with the use of cenobamate, focusing on treatment goals, optimal dosing and titration schedules, strategies to minimize adverse effects, and identification of suitable candidates for treatment. There was agreement that slow titration may improve tolerability, and that clinically significant benefit can be achieved in many patients at relatively low doses. A favorable response to relatively low doses of cenobamate could be an early predictor of ultimate responsiveness. Overall, cenobamate is a welcome new treatment for adults with focal seizures resistant to conventional ASMs.

Major disruption in the delivery of healthcare services can occur in exceptional situations such as natural disasters, conflicts, periods of severe economic hardship, and epidemics. These disruptions typically affect to the greatest extent the most vulnerable segments of the population, including people with epilepsy. Inability to access healthcare services can lead to failure to undergo necessary diagnostic investigations, or to receive needed therapeutic interventions, including epilepsy surgery. Stress and other factors associated with the nature or the cause of the disruption can adversely affect seizure control status, or precipitate the occurrence of psychiatric disorders and other comorbid conditions. Failure to access antiseizure medications is a common occurrence in these situations and can result in loss of seizure control, withdrawal seizures, and status epilepticus. In this article, we provide examples of recent disruptions in healthcare and their implications for people with epilepsy. We discuss the consequences of natural disasters, conflicts, economic sanctions, and focus in greater detail on lessons learnt during the COVID-19 pandemic. We also discuss possible mitigation procedures, focusing in particular on the application of telemedicine to epilepsy care. Finally, we underline the need for governments, healthcare authorities, and international organizations to improve their preparedness to deal with exceptional situations that may arise in the future.

Lorcaserin, a selective serotonin 5-HT

The 2017 International League Against Epilepsy classification has defined a three‐tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self‐limited focal epilepsies, comprising four syndromes: self‐limited epilepsy with centrotemporal spikes, self‐limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic–atonic seizures, Lennox–Gastaut syndrome, developmental and/or epileptic encephalopathy with spike‐and‐wave activation in sleep, hemiconvulsion–hemiplegia–epilepsy syndrome, and febrile infection‐related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.

The coronavirus disease 2019 (COVID‐19) pandemic has affected the care of all patients around the world. The International League Against Epilepsy (ILAE) COVID‐19 and Telemedicine Task Forces examined, through surveys to people with epilepsy (PWE), caregivers, and health care professionals, how the pandemic has affected the well‐being, care, and services for PWE. The ILAE included a link on their website whereby PWE and/or their caregivers could fill out a survey (in 11 languages) about the impact of the COVID‐19 pandemic, including access to health services and impact on mental health, including the 6‐item Kessler Psychological Distress Scale. An anonymous link was also provided whereby health care providers could report cases of new‐onset seizures or an exacerbation of seizures in the context of COVID‐19. Finally, a separate questionnaire aimed at exploring the utilization of telehealth by health care professionals since the pandemic began was available on the ILAE website and also disseminated to its members. Seventeen case reports were received; data were limited and therefore no firm conclusions could be drawn. Of 590 respondents to the well‐being survey (422 PWE, 166 caregivers), 22.8% PWE and 27.5% caregivers reported an increase in seizure frequency, with difficulty in accessing medication and health care professionals reported as barriers to care. Of all respondents, 57.1% PWE and 21.5% caregivers had severe psychological distress (k score >13), which was significantly higher among PWE than caregivers (p

The COVID‐19 pandemic has changed the face of many practices throughout the world. Through necessity to minimize spread and provide clinical care to those with severe disease, focus has been on limiting face‐to‐face contact. Research in many areas has been put on hold. We sought to determine the impact of the COVID‐19 pandemic on epilepsy research from international basic science and clinical researchers. Responses to five questions were solicited through a convenience sample by direct email and through postings on the ILAE social media accounts and an ILAE online platform (utilizing Slack). Information was collected from 15 respondents in 11 countries by email or via Zoom interviews between May 19, 2020, and June 4, 2020. Several themes emerged including a move to virtual working, project delays with laboratory work halted and clinical work reduced, funding concerns, a worry about false data with regard to COVID research and concern about research time lost. However, a number of positive outcomes were highlighted, not least the efficiency of online working and other adaptations that could be sustained in the future.

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.

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 representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older.

Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of progressing to severe COVID-19 disease. Nirmatrelvir is the active component against the SARS-CoV-2 virus, whereas ritonavir, a potent CYP3A inhibitor, is intended to boost the activity of nirmatrelvir by increasing its concentration in plasma to ensure persistence of antiviral concentrations during the 12-hour dosing interval. RBN is involved in many clinically important drug-drug interactions both as perpetrator and as victim, which can complicate its use in patients treated with antiseizure medications (ASMs). Interactions between RBN and ASMs are bidirectional. As perpetrator, RBN may increase the plasma concentration of a number of ASMs that are CYP3A4 substrates, possibly leading to toxicity. As victims, both nirmatrelvir and ritonavir are subject to metabolic induction by concomitant treatment with potent enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital and primidone). According to US and European prescribing information, treatment with these ASMs is a contraindication to the use of RBN. Although remdesivir is a valuable alternative to RBN, it may not be readily accessible in some settings due to cost and/or need for intravenous administration. If remdesivir is not an appropriate option, either bebtelovimab or molnupiravir may be considered. However, evidence about the clinical efficacy of bebtelovimab is still limited, and molnupiravir, the only orally active alternative, is deemed to have appreciably lower efficacy than RBN and remdesivir.

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.

OBJECTIVE: Optimal choice of antiseizure medication (ASM) depends on seizure type, syndrome, age, gender, comorbidities and co-medications. There are no fixed rules on how to weigh these factors; choices are subjective and experience-driven. We investigated agreement among experts in selecting ASM as monotherapy and used their prevailing choices to validate a web-based decision-support application.METHODS: Twenty-four international experts, blinded to the app, selected the optimal ASM for 25 individual patient-cases covering a wide variation of seizure types and other factors influencing ASM selection. The app ranked ASMs in order of likely appropriateness for each case. In a second step, experts rated anonymously the choices of the app.RESULTS: Of the 25 patient-cases (age 13-74 years), 13 were female, 18 (72%) had comorbidities, six (24%) were on contraceptives, and 13 (52%) had other co-medications. The median number of experts who selected the same ASM for a given case was 15 (62.5%) and interquartile range (IQR) 13-18 (54%-75%). Gwet's agreement coefficient among experts was 0.38 (95% confidence interval [CI] 0.32-0.44), corresponding to a "fair" agreement. Agreement between the app and the prevailing expert choice for each case was 0.48 (95% CI 0.29-0.67), corresponding to a "moderate" beyond chance agreement. The percent agreement between the highest ranked selections of the app and the expert selections was 73% (95% CI 64%-82%). Ninety-five percent of the experts considered that no incorrect or potentially harmful ASMs were ranked highest by the app, and most experts strongly agreed with the app's selections.SIGNIFICANCE: This app, now validated by experts, provides an objective, reproducible method for selecting ASM that accounts for relevant clinical features. It is freely available at: https://epipick.org.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the “genetic generalized epilepsies” (GGEs), which contained the “idiopathic generalized epilepsies” (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE’s Task Force on Nosology and Definitions (2017–2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic‐clonic and myoclonic‐tonic‐clonic seizures, with 2.5–5.5 Hz generalized spike‐wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as “a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious).” The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age‐dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.

This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the available data suggest that the absolute bioavailability of CBD after oral dosing under fasting conditions is approximately 6%, and increases fourfold when the medication is co-administered with a high-fat meal. Based on measurements of CBD plasma exposure after oral dosing and a 6% absolute oral bioavailability estimate, the actual clearance of CBD in adults can be inferred to be in the order of 67 L/h, which is similar to the value of 74 ± 14 L/h (mean ± standard deviation) determined after intravenous injection of a 20-mg dose of deuterium-labeled CBD in five healthy subjects. Assuming that the CBD blood-to-plasma ratio is about 1, as in the case of tetrahydrocannabinol (THC), and that CBD metabolism takes place virtually entirely in the liver, it can be estimated that about 70 to 75% of an orally absorbed dose of CBD can be removed by hepatic metabolism before reaching the systemic circulation, and additionally CBD gastrointestinal absorption is incomplete. A formulation with improved biopharmaceutical properties could increase the extent of CBD absorption about fourfold (i.e., to the level achieved with the currently available formulations co-administered with a high-fat meal) and minimize the influence of food effects on CBD bioavailability. There is also potential for favoring the absorption of CBD through the enteric lymphatic system, thereby reducing the extent of presystemic hepatic elimination. Evidence that CBD can behave as a high hepatic clearance compound also has implications when predicting the magnitude of drug-drug interactions affecting CBD metabolism. These considerations have important clinical relevance, particularly with respect to the objective of minimizing pharmacokinetic variability and consequent intra- and interindividual differences in therapeutic response and susceptibility to adverse effects.

Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.

Medicines currently used in the management of epilepsy have been developed to suppress seizures, and they have no known impact on the underlying disease. Using the term “antiepileptic” to describe these compounds is misleading because it suggests an action on the epilepsy itself. Pharmacological agents that have a merely symptomatic effect should be referred to as antiseizure medicines. Using appropriate terminology is especially important at a time innovative treatments targeting the development of epilepsy and its comorbidities are being actively pursued.

This article was prepared to outline the article collection submitted on behalf of Lega Italiana Contro l'Epilepsia, or LICE, for the 50th anniversary of the founding of the ILAE Italian Chapter, and provides a brief summary of the history, with its landmark achievements and challenges. LICE is a multidisciplinary, inclusive, educational, informative and multifaceted organization. Initially in 1955 and then formally in 1972, LICE was born in Milano, with the mission to devote itself to people suffering with epilepsy and by promoting appropriate treatment and care, integration into society, to promote and pursue all kinds of activities designed to achieve those aims. The LICE is currently composed of more than 1000 members including neurologists, pediatric neurologists, neurosurgeons, neurophysiologists, and neuropsychologists who function throughout Italy dealing mainly or exclusively with the diagnosis and treatment of people with epilepsy.

Background and purposeAntiseizure medications (ASMs) should be tailored to individual characteristics, including seizure type, age, sex, comorbidities, comedications, drug allergies, and childbearing potential. We previously developed a web-based algorithm for patient-tailored ASM selection to assist health care professionals in prescribing medication using a decision support application (https://epipick.org). In this validation study, we used an independent dataset to assess whether ASMs recommended by the algorithm are associated with better outcomes than ASMs considered less desirable by the algorithm.MethodsFour hundred twenty-five consecutive patients with newly diagnosed epilepsy were followed for at least 1 year after starting an ASM chosen by their physician. Patient characteristics were fed into the algorithm, blinded to the physician's ASM choices and outcome. The algorithm recommended ASMs, ranked in hierarchical groups, with Group 1 ASMs labeled as the best option for that patient. We evaluated retention rates, seizure freedom rates, and adverse effects leading to treatment discontinuation. Survival analysis contrasted outcomes between patients who received favored drugs and those who received lower ranked drugs. Propensity score matching corrected for possible imbalances between the groups.ResultsAntiseizure medications classified by the algorithm as best options had a higher retention rate (79.4% vs. 67.2%, p = 0.005), higher seizure freedom rate (76.0% vs. 61.6%, p = 0.002), and lower rate of discontinuation due to adverse effects (12.0% vs. 29.2%, p < 0.001) than ASMs ranked as less desirable by the algorithm.ConclusionsUse of the freely available decision support system is associated with improved outcomes. This drug selection application can provide valuable assistance to health care professionals prescribing medication for individuals with epilepsy.

The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development.A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues.Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting.Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts.

Objective: To develop and validate a pragmatic algorithm that classifies seizure types, to facilitate therapeutic decision-making. Methods: Using a modified Delphi method, five experts developed a pragmatic classification of nine types of epileptic seizures or combinations of seizures that influence choice of medication, and constructed a simple algorithm, freely available on the internet. The algorithm consists of seven questions applicable to patients with seizure onset at the age of 10 years or older. Questions to screen for nonepileptic attacks were added. Junior physicians, nurses, and physician assistants applied the algorithm to consecutive patients in a multicenter prospective validation study (ClinicalTrials.gov identifier: NCT03796520). The reference standard was the seizure classification by expert epileptologists, based on all available data, including electroencephalogram (EEG), video-EEG monitoring, and neuroimaging. In addition, physicians working in underserved areas assessed the feasibility of using the web-based algorithm in their clinical setting. Results: A total of 262 patients were assessed, of whom 157 had focal, 51 had generalized, and 10 had unknown onset epileptic seizures, and 44 had nonepileptic paroxysmal events. Agreement between the algorithm and the expert classification was 83.2% (95% confidence interval = 78.6%–87.8%), with an agreement coefficient (AC1) of.82 (95% confidence interval =.77–.87), indicating almost perfect agreement. Thirty-two health care professionals from 14 countries evaluated the feasibility of the web-based algorithm in their clinical setting, and found it applicable and useful for their practice (median = 6.5 on 7-point Likert scale). Significance: The web-based algorithm provides an accurate classification of seizure types, which can be used for selecting antiseizure medications in adolescents and adults.

High‐quality placebo‐controlled drug trials for focal‐onset seizures in infants and children younger than 4 years have become increasingly difficult to perform because of eligibility constraints and onerous study designs. Traditional designs used in these populations require a high baseline seizure frequency, two hospitalizations for video‐electroencephalography (video‐EEG) monitoring, and willingness to accept potential exposure to placebo when the drugs to be tested are usually already available for off‐label prescription. To address these constraints, the International League Against Epilepsy (ILAE) regulatory taskforce and the ILAE pediatric commission, in collaboration with the Pediatric Epilepsy Research Consortium (PERC), propose a novel trial design which involves seizure counting by caregivers based on previous video‐EEG/video validation of specific seizure semiologies. We present a novel randomized placebo‐controlled trial design intended to be used for studying new antiseizure medications (ASMs) for focal‐onset seizures (FOS) in children aged one month to four years. This design uses “time to Nth seizure” as the primary outcome and incorporates a new element of variable baseline duration. This approach permits enrollment of infants with lower seizure burden, who might not have video‐EEG‐recorded seizures within 2‐3 days of monitoring. Repeated hospitalizations for video‐EEG recordings are avoided, and duration of baseline and exposure to placebo or ineffective treatment(s) are minimized. By broadening eligibility criteria, reducing risks from prolonged placebo exposure, and relying on validated recording of seizure counting by caregivers, clinical trials will be likely to be completed more efficiently than in the recent past.

Introduction\ud The unpredictability of epileptic seizures is considered an important threat to the quality of life of a person with epilepsy. Currently, however, there are no tools for seizure prediction that can be applied to the domestic setting. Although the information about seizure-alert dogs – dogs that display changes in behavior before a seizure that are interpreted by the owner as an alert – is mostly anecdotal; living with an alerting dog (AD) has been reported to improve quality of life of the owner by reducing the stress originating from the unpredictability of epileptic seizures and, sometimes, diminishing the seizure frequency.\ud \ud Aim of the study\ud The aim of the study was to investigate, at an international level, the behaviors displayed by trained and untrained dogs that are able to anticipate seizures and to identify patient- and dog-related factors associated with the presence or absence of alerting behavior.\ud \ud Methodology\ud An online questionnaire for dog owners with seizures was designed. Information about the participants (demographics, seizure type, presence of preictal symptoms) and their dogs (demographics, behavior around the time of seizures) was collected. In addition, two validated scales were included to measure the human–dog relationship (Monash Dog–Owner Relationship scale (MDORS)) and five different traits of the dogs' personality (Monash Canine Personality Questionnaire refined (MCPQ-R)).\ud \ud Results\ud Two hundred and twenty-seven responses of people experiencing seizures were received from six participant countries: 132 from people with dogs that had started alerting spontaneously, 10 from owners of trained AD, and the rest from owners of dogs that did not display any alerting behavior (nonalerting dog (NAD)). Individuals' gender, age, or seizure type did not predict the presence of alerting behavior in their dogs. People who indicated that they experience preictal symptoms were more likely to have a spontaneously AD. The owner–dog bond was significantly higher with ADs compared with NADs, and ADs scored significantly higher than NADs in the personality traits “Amicability”, “Motivation”, and “Training focus”.\ud \ud Conclusion\ud This study collected a large group of dog owners with seizures reporting behavioral changes in their dogs before their seizures occurred. This was associated with the presence of preictal symptoms. The seizure-alerting behavior of the dog may have a positive influence on the bond between the owner and the dog.

We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure.Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation.The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

We thank Dr. Bruzzone for her interest in our article.1 We agree that participation in the study per se could have impacted outcomes. In particular, as pointed out in our Discussion, patients in the control group were also administered the questionnaire, and therefore, they might have been sensitized to report adverse effects that otherwise could have been neglected. We also agree that screening for adverse effects should be part of the routine management of people with epilepsy. Ideally, this should be supplemented by other measures aimed at raising awareness about the impact of adverse effects on quality of life, and about the strategies that can be applied to optimize drug treatment according to individual needs.

Despite the availability of 28 antiseizure medications (ASMs), one-third of people with epilepsy fail to achieve sustained freedom from seizures. Clinical outcome is even poorer for children with developmental and epileptic encephalopathies (DEEs), many of which are due to single-gene mutations. Discovery of causative genes, however, has paved the way to understanding the molecular mechanism underlying these epilepsies, and to the rational application, or development, of precision treatments aimed at correcting the specific functional defects or their consequences. This article provides an overview of current progress toward precision medicine (PM) in the management of monogenic pediatric epilepsies, by focusing on four different scenarios, namely (a) rational selection of ASMs targeting specifically the underlying pathogenetic mechanisms; (b) development of targeted therapies based on novel molecules; (c) use of dietary treatments or food constituents aimed at correcting specific metabolic defects; and (d) repurposing of medications originally approved for other indications. This article is part of the Special Issue "Severe Infantile Epilepsies".

The International League Against Epilepsy (ILAE) / American Epilepsy Society (AES) Task Force on the cardiac effects of lamotrigine was convened in response to a recent addition to the lamotrigine label by the US Food and Drug Administration (FDA). 1 Lamotrigine is the nonproprietary name for a medicine that is sold under its generic name and several brand names including Lamictal™. The present advisory is based on an assessment of currently available evidence. It is not intended to replace regulatory requirements, nor is it intended to be an exhaustive review. Its purpose is to advise healthcare professionals worldwide on how to minimize cardiac safety risks associated with lamotrigine use.

Introduction Spontaneous reports of adverse drug reactions (ADRs) are a valuable supplement to clinical studies in informing about the safety of medications. This is especially relevant for pediatric populations, which are not often included in large-scale clinical trials. Objectives To evaluate patterns of pediatric ADRs to antiseizure medications (ASMs) reported to the Italian Spontaneous Reporting System (SRS) database during the period November 1, 2001─May 31, 2019. Methods Suspected ADRs ascribed to medications listed under ATC code N03, plus clobazam (code N05BA09), and affecting individuals below age 18 years were sourced from the Italian SRS database, categorized based on a modification of the MedDRA® high-level term, and analyzed using descriptive statistics. Results A total of 956 reports listing a total of 1806 ADRs ascribed to one or more ASMs were received for individuals in pediatric age. The most commonly reported ADRs were skin rashes (24.0% of all reports), epileptic seizures (12.6%), gastrointestinal disturbances (11.8%), and somnolence (10.6%). A more detailed analysis was conducted on 675 reports listing a single ASM as suspected drug and occurring in patients with a specified or presumed diagnosis of epilepsy. Adverse drug reaction patterns differed widely across ASMs. Skin rashes were the most commonly reported ADR for lamotrigine (62.3%), carbamazepine (50.3%), phenobarbital (42.3%), and oxcarbazepine (33.0%). Other most commonly reported ADRs were gastrointestinal symptoms for ethosuximide (44%), irritability/aggression for levetiracetam (25.0%), epileptic seizures for valproic acid (16.1%), fever (often associated with hypohidrosis) for topiramate (17.9%), and utilization error (mostly accidental drug administration) for clonazepam (34.6%). Conclusions Patterns of spontaneous ADR reports are indicative of major differences in safety profile among individual ASMs. Most, but not all, frequently reported ADRs were in line with findings from clinical trials and observational studies.

Introduction When monotherapy used alone or sequentially fails to achieve seizure control, a trial of combination therapy may be considered. Objective To define optimal criteria to guide choice of an antiseizure medication (ASM) for use as first add-on. Methods A standardized Delphi procedure was applied to produce a list of consensus statements. First, an Expert Board consisting of 5 epileptologists agreed on a set of 46 statements relevant to the objective. The statements were then finalized through an iterative process by a Delphi Panel of 84 Italian pediatric and adult neurologists with expertise in the management of epilepsy. Panel members provided anonymous ratings of their level of agreement with each statement on a 9-point Likert scale. Results Consensus, defined as agreement by at least 80% of Panel members, was reached for 36 statements. Medication-related factors considered to be important for drug selection included efficacy, tolerability and safety, interaction potential, mechanism of action, and ease of use. The need to optimize adherence and to tailor drug selection to individual characteristics was emphasized. Conclusions Choice of an ASM for first add-on requires consideration of many factors, many of which also apply to choose initial treatment. Factors more specifically relevant to add-on use include drug interaction potential and the preference for an ASM with a different mechanism of action.