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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.

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.

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.

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 laborato

Epilepsy syndromes during the early years of life may be attributed to an acquired insult, such as hypoxic-ischemic injury, infection, status epilepticus, or brain trauma. These conditions are frequently modeled in experimental rodents to delineate mechanisms of epileptogenesis and investigate novel therapeutic strategies. However, heterogeneity and subsequent lack of reproducibility of such models across laboratories is an ongoing challenge to maintain scientific rigor and knowledge advancement. To address this, as part of the TASK3-WG1B Working Group of the International League Against Epilepsy/American Epilepsy Society Joint Translational Task Force, we have developed a series of case report forms (CRFs) to describe common data elements for pediatric acquired epilepsy models in rodents. The "Rodent Models of Pediatric Acquired Epilepsy" Core CRF was designed to capture cohort-general information; while two Specific CRFs encompass physical induction models and chemical induction models, respectively. This companion manuscript describes the key elements of these models and why they are important to be considered and reported consistently. Together, these CRFs provide investigators with the tools to systematically record critical information regarding their chosen model of acquired epilepsy during early life, for improved standardization and transparency across laboratories. These outcomes will support the ultimate goal of such research; that is, to understand the childhood onset-specific biology of epileptogenesis after acquired insults, and translate this knowledge into therapeutics to improve pediatric patient outcomes and minimize the lifetime burden of epilepsy.

OBJECTIVE: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). METHODS: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52. RESULTS: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. SIGNIFICANCE: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.

Rodent models of epilepsy remain the cornerstone of research into the mechanisms underlying genetic epilepsy. Reproducibility of experiments using these rodent models, occurring across a diversity of laboratories and commercial vendors, remains an issue impacting the cost-effectiveness and scientific rigor of the studies performed. Here, we present two case report forms (CRFs) describing common data elements (CDE) for genetic rodent models, developed by the TASK3-WG1B Working Group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Joint Translational Task Force. The first CRF relates to genetic rodent models that have been engineered based on variants described in epilepsy patients. The second CRF encompasses both spontaneous and inbred rodent models. This companion piece describes the elements and discusses the important factors to consider before documenting each required element. These CRFs provide tools that allow investigators to more uniformly describe core experimental data on different genetic models across laboratories, with the aim of improving experimental reproducibility and thus translational impact of such studies.

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Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Im

AIM To give evidence-based recommendations on the application of ketogenic diet parenteral nutrition (KD-PN) in emergency situations. METHOD An international group of experts (n=14) researched the literature and distributed a survey among 150 expert centers. International accepted guidelines (European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition and the American Society for Parenteral and Enteral Nutrition) and handbooks for parenteral nutrition were considered general standards of care. RESULTS In the literature, we identified 35 reports of patients treated by KD-PN. International guidelines and handbooks provided some conflicting information. Twenty-four expert teams from nine countries responded to the survey, reflecting the limited clinical experience. INTERPRETATION This paper highlights 23 consensus-based recommendations for safe and effective KD-PN (e.g. diet initiation, calculation, application, monitoring, and evaluation) based on the best evidence available and expert opinions.

AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

OBJECTIVE: To examine the genotype to phenotype connection in glucose transporter type 1 (GLUT1) deficiency and whether a simple functional assay can predict disease outcome from genetic sequence alone. METHODS: GLUT1 deficiency, due to mutations in SLC2A1, causes a wide range of epilepsies. One possible mechanism for this is variable impact of mutations on GLUT1 function. To test this, we measured glucose transport by GLUT1 variants identified in population controls and patients with mild to severe epilepsies. Controls were reference sequence from the NCBI and 4 population missense variants chosen from public reference control databases. Nine variants associated with epilepsies or movement disorders, with normal intellect in all individuals, formed the mild group. The severe group included 5 missense variants associated with classical GLUT1 encephalopathy. GLUT1 variants were expressed in Xenopus laevis oocytes, and glucose uptake was measured to determine kinetics (Vmax) and affinity (Km). RESULTS: Disease severity inversely correlated with rate of glucose transport between control (Vmax = 28 ± 5), mild (Vmax = 16 ± 3), and severe (Vmax = 3 ± 1) groups, respectively. Affinities of glucose binding in control (Km = 55 ± 18) and mild (Km = 43 ± 10) groups were not significantly different, whereas affinity was indeterminate in the severe group because of low transport rates. Simplified analysis of glucose transport at high concentration (100 mM) was equally effective at separating the groups. CONCLUSIONS: Disease severity can be partly explained by the extent of GLUT1 dysfunction. This simple Xenopus oocyte assay complements genetic and clinical assessments. In prenatal diagnosis, this simple oocyte glucose uptake assay could be useful because standard clinical assessments are not available.

Item does not contain fulltext, Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme