INTRODUCTION:This study aimed to assess the availability of national transition guidelines in paediatric neurology across Europe and to provide a review of the existing literature. METHODS:A mixed-methods descriptive study was conducted, combining a survey of national representatives of the European Paediatric Neurology Society and a scoping literature review. The survey, performed in 2021 with an update in 2026, assessed the existence of national or officially endorsed transition guidelines. The literature review (2002-2025) followed the Arksey and O'Malley framework and PRISMA-ScR recommendations. RESULTS:Thirty-six of 42 representatives responded to the 2021 survey; 66.7% reported no national transition guidelines in paediatric neurology, while 16.7% reported officially endorsed guidance. The literature search identified 23372 records, of which 132 publications were included in the final analysis. Most described centre-based transition models or general recommendations, while formal guidelines were rare. Drawing on the gaps identified through literature review and survey findings, this paper proposes a series of targeted recommendations to enhance the transition process in paediatric neurology. CONCLUSIONS:Transition guidance in paediatric neurology remains limited and heterogeneous across Europe. Specific recommendations are needed to provide guidance and enhance the effectiveness of this process. An EPNS-EAN Transition Task Force is currently developing a transition framework.

Background: Autoimmune encephalitis (AE) is an increasingly well recognized disorder in the past decade both in adults and in children, yet pediatric data are still limited. A full peripheral blood cell count is a routine examination that provides valuable information regarding the immune system. Thus, there are peripheral blood cell count (PBCC)-derived ratios that reflect systemic inflammatory activity and they have been associated with disease severity in adults: the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune–inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). Methods: This study is a retrospective chart review of children under 18 years diagnosed with definite or probable AE and treated in our institution from 1 January 2018 until 1 December 2025. Only patients with available PBCC results at the time of the first hospital admission after neurological/psychiatric symptom onset were included. An age-matched control group was created by selecting the results of PBCC of patients presenting for routine pediatric follow-ups with normal inflammatory and hematologic parameters. The group means were compared using an independent-samples t-test or the Mann–Whitney U test for non-normally distributed data. Analysis of the receiver operating characteristics curve (ROC curve) was conducted, followed by the area under the curve ROC curve (AUC). Results: A total of 45 children with AE and 150 controls were included in the study. Of these, 22 patients (49%) had probable AE and 23 patients (51%) had definite AE. The NLR, PLR, SII, SIRI and AISI values were significantly higher in AE patients compared with the controls, but the AUC values (~0.58–0.66) indicate poor-to-fair discriminative ability. Youden’s index-based cut-off values were associated with high specificity and modest sensitivity. The likelihood ratios in the range of 2–3 (LR+) and 0.6–0.7 (LR−) suggest weak rule-in capacity and limited rule-out utility. Conclusions: Our results suggest that at the time of the initial hospitalization, children with AE already show altered peripheral immune cell profiles compared to their age-matched peers. The high specificity and the low sensitivity of the inflammatory indices make them more suitable for supporting the AE diagnosis in suggestive clinical circumstances, but not for screening. These results represent a foundation for further investigation of the roles that these indices have both as diagnostic and prognostic factors for these children.

Genetic neurodevelopmental disorders (NDDs) encompass a heterogeneous group of conditions characterized by impaired cognitive, behavioral, and neurological development resulting from pathogenic variants affecting brain development and synaptic function. Advances in molecular genetics and next-generation sequencing have significantly expanded the understanding of the genetic architecture underlying disorders such as Rett syndrome (RTT), Fragile X syndrome (FXS), Angelman syndrome (AS), and autism spectrum disorders. Beyond these classical neurodevelopmental disorders, spinal muscular atrophy (SMA) is included as a paradigmatic example of successful RNA-based therapeutic translation. Concurrently, RNA-based therapeutics have emerged as promising precision medicine strategies capable of modulating gene expression at the transcriptional and post-transcriptional levels. These approaches include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNA (mRNA) therapies, RNA editing technologies, and splice-modulating agents. Recent clinical successes, particularly in spinal muscular atrophy, have demonstrated the transformative potential of RNA therapeutics in neurological disease. However, substantial challenges remain, including BBB penetration, long-term safety, immune activation, and genotype-specific variability in therapeutic response. This review summarizes current advances in RNA-based therapeutics for genetic NDDs, highlighting molecular mechanisms, disease-specific therapeutic strategies, translational progress, delivery challenges, and future directions. Overall, continued progress will depend on the integration of disease biology, rational RNA therapeutic design, and effective CNS-targeted delivery, supporting the broader implementation of precision RNA medicine for genetic neurodevelopmental disorders.

An epilepsy syndrome is defined by a characteristic combination of clinical features, including seizure type(s), ictal and interictal EEG patterns, age at onset, clinical history, and neurological findings, often supported by specific structural, genetic, metabolic, immune, or infectious etiologies. This article describes the most common seizure types in early childhood epilepsy syndromes and how they differ from one another. In addition, the most common and relevant epilepsy syndromes in early childhood are discussed in terms of their electroclinical characteristics. The diagnosis of an epilepsy syndrome in this age group frequently carries prognostic and treatment implications. Therefore, knowledge of the electroclinical phenotype and its differentiation from other types is important.

BACKGROUND:Duchenne/Becker muscular dystrophy (DMD/BMD) is associated with a wide spectrum of brain-related comorbidities. METHODS:This retrospective study assesses the neuropsychiatric profile of DMD/BMD patients and the hypothesis of a functional-versus-structural approach of dystrophin gene variants/impaired isoforms in relation to brain comorbidities. Patients with documented mutation in the DMD gene and neuropsychiatric assessments were included. Seven comorbidities were analyzed based on variant location and dystrophin brain isoform disruption. The clustering of comorbidities and genotype-phenotype correlations were studied. RESULTS:264 DMD/BMD patients met inclusion criteria. 22 variants have never been described before. A high prevalence of neuropsychiatric comorbidities was identified in the cohort with higher values in patients with distal mutations. The number of comorbidities increased with the number of brain dystrophin isoforms predicted to be lost. Functional-versus-structural comparison revealed that Dp140 5'UTR variants might not affect protein expression. Epilepsy and intellectual disability (ID) showed significant association in this cohort. Neuropsychiatric phenotype varied greatly in patients with identical variants, even between siblings. CONCLUSIONS:This is one of the largest European cohorts for which all these comorbidities were studied in association with DMD gene mutation site and the first study of this kind performed on the Eastern European DMD/BMD population. Our group analyzed, for the first time, Dp140 5'UTR variants in relation to all neuropsychiatric phenotypes and showed that epilepsy and ID are strongly associated in DMD/DMB patients.

This article examines the complex relationship between seizures, epilepsy, and multiple sclerosis (MS) in pediatric patients, based on detailed findings from a single-center study. Background: Although multiple sclerosis is primarily recognized as an adult-onset disease, its occurrence in children presents distinctive challenges, especially related to seizure disorders. Methods: We reviewed 120 pediatric MS patients evaluated over 7 years; six of these (5%) experienced seizures (including one case of acute status epilepticus), and five were diagnosed with epilepsy according to the latest International League Against Epilepsy (ILAE) classification. This study aimed to evaluate the occurrence rates and types of seizures while investigating their management strategies in this specific group. Results: Through a detailed case analysis and patient follow-up, we identified key factors contributing to seizure onset and explored implications for treatment and care. In our cohort, children with MS and seizures showed a higher risk for disease progression and greater cumulative disability, evidenced by a significantly higher last Expanded Disability Status Scale (EDSS) score (after a minimum 2-year follow-up) in the seizure group (p < 0.006). The analysis recognized early MS onset and highly active disease types as further risk factors that led to worse health outcomes. Conclusions: Genetic causes of epilepsy in children are common and may interact with MS-related inflammation in the same patient; our observations underscore the need to investigate how these two conditions interact. This work contributes to the broader understanding of epilepsy comorbid with MS among pediatric patients, seeking to facilitate the creation of improved interdisciplinary clinical practices in pediatric neurology.

Pediatric-onset multiple sclerosis (POMS) is a rare but increasingly recognized autoimmune condition affecting children under 18 years. The disease course is more aggressive than in adults, with frequent relapses, rapid accumulation of lesions, and early onset of motor and cognitive impairments. Due to limited approved disease-modifying therapies (DMTs) for children, first-line treatment often relies on injectable agents with moderate efficacy. Fingolimod, a high-efficacy therapy (HET), was recently approved for pediatric use, yet its uptake remains variable across regions. This retrospective, observational, monocentric study included 115 children diagnosed with POMS between 2018 and 2024 in a tertiary center in Romania. Patients were divided into three groups: 79 treated with interferon beta (IFNβ), 14 treated with fingolimod (FTY), and 22 untreated. We compared clinical outcomes, including annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and brain MRI lesion burden over 1 to 3 years of follow-up. Adverse events and treatment delays were also analyzed. All fingolimod-treated patients remained relapse-free during follow-up, while 42% of those on IFNβ experienced between 1 and 8 relapses. Fingolimod patients had significantly fewer new MRI lesions after 2 and 3 years of treatment (p < 0.01). EDSS scores remained stable or improved in both treated groups, with better outcomes in the FTY group. Adverse events included flu-like symptoms in all IFNβ-treated children and lymphopenia (mild to severe) in all FTY cases, managed by dose adjustment. Treatment initiation was delayed in the FTY group due to vaccination status and age-related barriers. Fingolimod demonstrated superior efficacy and comparable safety to IFNβ in pediatric MS. Our findings support early initiation of HETs in POMS and highlight real-world barriers to their implementation in Eastern Europe, including vaccination requirements and caregiver hesitancy.

Background/Objectives: Very early pediatric onset multiple sclerosis (POMS) is rare; clinical studies using disease modifying treatments (DMTs) have not been performed. Clinicians rely on studies performed at older age. This review resulted due to difficulties faced by clinicians and off label use of DMTs at this age. Methods: A literature review be-tween 1980 – 2025 of very early POMS with onset before age 5 has been performed searching for outcome without or with DMTs. The curated database of the selected patients was analyzed using computed descriptive and integrated cohort-level estimates. The clinical, paraclinical, treatment and outcome characteristics were analyzed. Statistical analysis used JASP, with GenAI-assisted verification. Treatment outcome of a 16 year old patient with very early POMS starting at 2 years 4 months that consecutively received interferon, immunoglobulins and natalizumab is presented. Results: 101 patients with very early POMS presented at onset ataxic syndrome (57.4%), pyramidal syndrome (41.4%), ophthalmoplegia (10.3%) and optic neuritis (6.9%). In evolution 22.7% had seizures. Half of the patients were not treated. Among those treated, acute steroid therapy was administered; 11 received DMTs: interferon, glatiramer acetate, dimethyl fumarate, azathioprine (three) and only two – high-efficacy therapies (natalizumab, rituximab). Our patient had partial remission under interferon, relapses when stopped and replaced by immunoglobulins and 9 years relapse-free interval when natalizumab was introduced. Conclusions: Early treatment with high efficiency DMTs should be considered in very early POMS; association with known increased neuroplasticity at this age may improve prognosis, allowing good recovery of acquired disability.

This article examines the complex relationship between seizures, epilepsy, and multiple sclerosis (MS) in pediatric patients, based on detailed findings from a single-center study. Background : Although multiple sclerosis is primarily recognized as an adult-onset disease, its occurrence in children presents distinctive challenges, especially related to seizure disorders. Methods : We reviewed 120 pediatric MS patients evaluated over 7 years; 6 of these (5%) experienced seizures (including one case of acute status epilepticus), and 5 were diagnosed with epilepsy according to the latest ILAE classification. This study aims to evaluate the occurrence rates and types of seizures while investigating their management strategies in this specific group. Results: Through detailed case analysis and patient follow-up, we identified key factors contributing to seizure onset and explored implications for treatment and care. In our cohort, children with MS and seizures showed a higher risk for disease progression and greater cumulative disability, evidenced by a significantly higher last Expanded Disability Status Scale (EDSS) score (after a minimum 2-year follow-up) in the seizure group (p < 0.006). The analysis recognized early MS onset and highly active disease types as further risk factors that led to worse health outcomes. Conclusions: Genetic causes of epilepsy in children are common and may interplay with MS-related inflammation in the same patient; our observations underscore the need to investigate how these two conditions interact. This work contributes to the broader understanding of epilepsy comorbidity with MS among pediatric patients, to facilitate the creation of improved interdisciplinary clinical practices in pediatric neurology.

In 2005, the Epilepsy Foundation published an expert consensus ( Epilepsia 2005; 46:1423–1425) on actions to minimize risks of visually‐provoked (photosensitive) seizures (VPS). Since then, technology, scientific information, and experience have greatly expanded. An international expert panel convened by the Epilepsy Foundation collated literature, information, and opinions regarding VPS. Consensus guidelines are divided into advice for: patients and families, clinicians, designers of video games, architects, and regulatory agencies. No attempt was made to develop a formal systematic review. Patients are advised about symptoms and epilepsy syndromes that relate to VPS. Commonly used medications and useful behavioral modifications are reviewed. Clinicians are advised on an approach to events that are concerning for VPS, including how to use history and electroencephalography (EEG) to assess whether an event was a seizure (vs another neurologic symptom) and what visual stimuli (light or patterns) provoked it. The utility of magnetic resonance imaging (MRI) to assess for an epileptogenic lesion, routine blood tests, and genetic studies is discussed. Media designers of video games, movies, TV productions, web videos, and artificial or virtual reality images are advised to avoid bright flashing patterns in the 10–20 Hz range, repetitive color flashes, and oscillating or static stripes of ~1–8 cycles per visual degree. Signal analysis or trained human inspectors can identify provocative visual patterns. Architects and designers of public spaces should be aware that some striped patterns can provoke seizures. Government and regulatory agencies require screening of potentially provocative media in some nations. VPS are both an individual and public health problem. The Epilepsy Foundation encourages further research and efforts to minimize risks of seizures provoked by visual stimuli.

Duchenne muscular dystrophy (DMD) is a rare fatal genetic disorder with a tight correlation between the genotype and the phenotype of the patients. However, the relationship between genotype and phenotype is yet incompletely understood, with some cases manifesting a different phenotype than predicted from their genotype. Since the genetic diagnosis is often targeted to specific gene sections, and the genotype-phenotype correlations guide early treatment decisions, accumulating clinical and epidemiological data for these rare disorders is required to refine local management strategies. This article describes the genotype and phenotype landscape of 239 patients treated in the Pediatric Neurology Clinic of the Clinic Psychiatry Hospital "Prof. Dr. Alexandru Obregia" in Bucharest, using randomly collected data from a ten-year interval (2012-2022). It revealed a significant improvement in the quality of care, highlighted by a notable reduction in the average age at diagnosis in recent years, although considerable variability remains across counties. The study identified three mutations that were not previously described in the Edystrophin or TREAT-NMD DMD Global Database. The accuracy of the Reading-Frame rule was 88.4 % for deletions. For exceptions from the rule, the involvement of different isoforms, binding domains, structural domains, and the disturbance of the three-dimensional structure of the rod domain were not reliable indicators of the phenotype. 12.9 % of all patients had nonsense mutations with a DMD phenotype that could benefit from Ataluren treatment within the National Treatment Program, and 15 % were eligible for exon-skipping therapies, with exon 51 having the broadest applicability (7.1 %).

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for ‘actionable’ genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

Background: Pediatric-onset multiple sclerosis (POMS) is a rare and heterogeneous condition, with clinical features, progression, and therapeutic response varying significantly according to age at onset. Early-onset MS (<10 years) presents particular diagnostic and management challenges due to atypical presentations and more active inflammatory profiles. Objectives: To identify age-related clinical, radiological, and therapeutic characteristics of pediatric MS, with a specific focus on early-onset cases, and to compare them with intermediate (10–12 years) and late-onset (>12 years) forms. Methods: We conducted a retrospective analysis of medical records from 120 pediatric patients diagnosed with MS at a tertiary neurology center between 2018 and 2024. Patients were grouped by age at onset and assessed for clinical presentation, number and timing of relapses, EDSS scores, imaging findings, and treatment patterns. Results: Early-onset MS was associated with atypical symptoms, delayed diagnosis, more frequent relapses, and multifocal brainstem and cerebellar involvement. The diagnosis was significantly delayed in younger children compared to adolescents. EDSS scores tended to remain stable in the first 2–3 years, but early-onset patients showed a notable decline after the fourth year. While most patients received disease-modifying therapies, high-efficacy agents were underused due to age-related restrictions. Intermediate-onset patients presented overlapping features of both early and late-onset MS and had the highest proportion of fully preserved motor function (EDSS 0) at the end of follow-up. MRI findings revealed more extensive and confluent lesions in younger patients, particularly in the first two years after onset. Conclusions: Age at disease onset is a key determinant of clinical course and treatment response in pediatric MS. Early recognition and timely initiation of appropriate therapy—especially high-efficacy agents—may improve outcomes and reduce long-term disability. Further multicenter studies with standardized imaging and cognitive assessment protocols are needed to optimize care for this vulnerable population.

Background/Objectives: Very early pediatric-onset multiple sclerosis (POMS) is rare; clinical studies using disease-modifying treatments (DMTs) have not been performed. Clinicians rely on studies performed at older ages. This review resulted from difficulties faced by clinicians and the off-label use of DMTs at this age. Methods: A literature review of studies dated between 1982 and 2025 on very early POMS, specifically with onset before age 5, has been performed, searching for outcomes without or with DMTs. The curated database of the selected patients was analyzed using computed descriptive and integrated cohort-level estimates. The clinical, paraclinical, treatment, and outcome characteristics were analyzed. Statistical analysis used JASP, with GenAI-assisted verification. The treatment outcome of a 16-year-old patient with very early POMS starting at 2 years 4 months that consecutively received interferon, immunoglobulin, and Natalizumab is presented. Results: A total of 101 patients with very early POMS presented, at onset, with ataxic syndrome (57.4%), pyramidal syndrome (41.4%), ophthalmoplegia (10.3%), and optic neuritis (6.9%). In evolution, 22.7% had seizures. Half of the patients were not treated. Among those treated, acute steroid therapy was administered; 11 received the DMTs interferon, Glatiramer acetate, Dimethyl fumarate, and Azathioprine (three), with only two high-efficacy therapies (Natalizumab and Rituximab). Our patient had partial remission under interferon, relapses when stopped and replaced by immunoglobulin and 9 years relapse-free interval when Natalizumab was introduced. Conclusions: Early treatment with high-efficiency DMTs should be considered in very early POMS; association with known increased neuroplasticity at this age may improve prognosis, allowing good recovery of acquired disability.

OBJECTIVE:Transition planning in epilepsy is crucial to ensure continuity of care, particularly for adolescents with complex needs, yet global practices remain undefined. The International League Against Epilepsy Transition Task Force (ILAE TTF) aimed to evaluate worldwide practices, barriers, and provider perspectives on transitioning patients with epilepsy from pediatric to adult healthcare systems. METHODS:A cross-sectional, web-based survey was conducted between August 2021 and March 2024. The 50-item survey, adapted from validated instruments, was distributed in eight languages through ILAE chapters to health care professionals involved in the care of individuals with epilepsy. This study sought to evaluate the availability of structured transition programs, educational and systemic barriers, and recommendations to improve transition. Descriptive statistics, Fisher's exact tests, and multivariate logistic regression analyses were used to compare responses between adult and child neurologists, as well as by country region and income level. RESULTS:A total of 316 neurologists from 58 countries completed the survey. Only 9% reported structured transition programs both locally and nationally, whereas 59% reported none or were unaware of any. Respondents from the Global South were significantly less likely to report transition programs (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.94-0.27; p < .001). Half of the participants believed pediatric teams should continue follow-up after transfer. Major barriers included a lack of financial support, limited transition-specific training, and adult neurologists unfamiliar with childhood-onset epilepsies. Reported patient-educational gaps included vocational guidance (73%), reproductive health (60%), and driving (57%). Recommendations to improve transition included integrating transition training into neurology curricula (87%), creating dedicated clinical structures and care networks (87%), establishing joint consultations between pediatric and adult neurologists (86%), and implementing national guidelines (89%). SIGNIFICANCE:This study demonstrates that epilepsy transition practices remain fragmented and underdeveloped worldwide, especially in low-resource settings. Enhanced training, improved clinical infrastructure, and better policy coordination are crucial to facilitate effective and equitable transitions.

Background: Baló’s concentric sclerosis stands out as a rare form of multiple sclerosis that features large tumor-like demyelinating lesions, which resemble brain tumors and create significant diagnostic and therapeutic obstacles for pediatric patients. Case Presentations: We present two case studies of pediatric patients, aged 11 and 15, diagnosed with extensive cerebral tumefactive inflammatory lesions indicative of Balo’s type multiple sclerosis (MS). Both cases highlight the unique challenges faced in the diagnosis and treatment of this rare form of MS, characterized by the presence of large, tumor-like lesions that can mimic primary brain tumors. We will explore the diagnostic complexities, including the need for advanced imaging techniques, MR (Magnetic Resonance) spectroscopy, along with the time needed for differential diagnoses, which might delay the start of proper treatment. Current therapies, such as corticosteroids and immunomodulators, require customization to individual patients, carefully monitoring of clinical outcomes and possible side effects. This paper emphasizes that handling these cases requires a multidisciplinary approach, addressing not only the medical treatment but also the psychosocial needs of affected children and their families. By sharing these experiences, we aim to increase awareness about Balo’s type MS in pediatric populations and provide clinical insights into effective management strategies for similar cases in clinical practice. Conclusions: Timely detection of atypical demyelinating lesions together with immediate treatment intervention plays a crucial role in pediatric Baló-type MS. These cases demonstrate the essential role of advanced imaging and immunological testing in precise diagnosis while showcasing successful treatment approaches through corticosteroids and second-line immunotherapies, which improve patient outcomes in this atypical MS variant.

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

This paper provides a practical guide to applying the updated seizure classification in clinical settings. The updated classification, published by the International League Against Epilepsy in 2025, builds on the operational classification introduced in 2017. It aims to enhance clarity, clinical relevance, and consistency in seizure terminology across various healthcare settings. The classification system distinguishes between four main seizure classes: focal, generalized, unknown whether focal or generalized, and unclassified. The basic version allows for application even in resource-limited or primary care environments, while the expanded version offers detailed semiological descriptors and supports advanced diagnostic and surgical decision-making. Consciousness, defined through awareness (recall) and responsiveness, is now considered a classifier. The paper also highlights the importance of distinguishing observable from non-observable features and integrates semiology into the expanded classification with attention to temporal sequence and somatotopic detail. Generalized seizures are categorized into seizure types having a direct impact on syndrome diagnosis and treatment decisions. Epileptic spasms are given special attention because of their unique presentation and the urgency of early intervention, particularly in infants. To support clinical implementation, this paper includes a comprehensive table of semiological descriptors, definitions of generalized seizure types, and a series of real-world case vignettes illustrating the application of the updated seizure classification. Supplementary figures and videos further support the educational aims of the paper. This practical guide is intended for healthcare professionals managing patients with epilepsy, providing a clear, structured approach to seizure classification that is adaptable to varying levels of clinical expertise and diagnostic resources.

BACKGROUND AND OBJECTIVES:Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants.METHODS:Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology.RESULTS:We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function.DISCUSSION:In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.