OBJECTIVE:Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Task Force study provides an updated overview of current trends and regional differences. METHODS:Group-level data were collected from 61 epilepsy surgery programs (49 pediatric-only) across 29 countries and six continents, identified through ILAE networks, and included all children and adolescents treated in 2023 who underwent presurgical evaluation/epilepsy surgery. RESULTS:Group-level data were available for 2427 patients. Mean age at surgery was 9.1 ± 4.9 years; mean epilepsy duration was 5.3. At surgery, 3.2% were <1 year old (highest in Oceania: 5.1%), and 6.1% were nonpharmacoresistant (highest in Europe: 15.0%). Prior neurosurgery was reported in 14.2% (highest in North America: 28.8%), including 8.0% resections (6.1% for epilepsy, 1.5% for tumors; highest in Oceania: 16.5%), 2.3% disconnections (1.3% corpus callosotomy; highest in South America: 4.7%), and 4.2% neuromodulation (3.7% vagal nerve stimulation, .2% responsive neurostimulation, one deep brain stimulation; highest in North America: 12.2%). Developmental and epileptic encephalopathies (DEEs) at surgery included Lennox-Gastaut syndrome (7.4%), infantile epileptic spasms syndrome (5.1%), and DEE with spike-wave activation in sleep (1.5%). Presurgical investigations included fluorodeoxyglucose positron emission tomography (52.6%; highest in Oceania: 79.7%), genetic testing (46.8%; highest in Asia: 54.3%), magnetic resonance imaging (MRI) postprocessing (32.4%; highest in South America: 53.0%), functional MRI (fMRI; 15.2%; highest in North America: 40.3%), magnetoencephalography (11.9%; highest in North America: 39.3%), single photon emission computed tomography (9.6%; highest in North America: 22.2%), high-density electroencephalography (EEG; 1.9%; highest in Europe: 4.7%), source localization (1.6%; highest in Oceania: 7.6%), Wada test (1.2%; highest in North America: 3.5%), and EEG-fMRI (.5%; highest in Europe: 1.1%). SIGNIFICANCE:Despite some early surgeries, including in infancy and before pharmacoresistance, mean epilepsy duration before surgery remains >5 years. Reoperations are common, with resection more frequent than neuromodulation. Genetic testing in nearly half of patients reflects its growing relevance, and the high rate of DEEs underscores the complexity of surgical candidates.

PURPOSE:The course of epilepsy in patients with tuberous sclerosis complex (TSC) is highly variable. Consistency of the epileptogenic zone is considered important in presurgical evaluation. The authors aimed to (1) assess consistency of ictal epileptogenic foci over time in patients with TSC, (2) evaluate concordance between interictal epileptiform abnormalities and ictal epileptogenic foci, and (3) identify determinants of ictal consistency. METHODS:This single-center retrospective, observational study included children with definite TSC and epilepsy with ≥2 ictal presurgical EEGs with an interval ≥1 year. In all EEGs, the regional localization of interictal and ictal epileptiform abnormalities was scored based on the EEG reports. All ictal epileptogenic foci were classified with an "ictal focus consistency score," according to one of the following subcategories: "single focus, consistent," "from unclear localization/diffuse or generalized to unifocal," "≥2 or more foci, each consistent," "≥2 foci of which at least one is consistent," "starting multifocal but at last EEG unifocal," and "multifocal changing otherwise." The primary end point was unifocal or multifocal consistency of ictal foci. The secondary end point was concordance between ictal epileptogenic foci and localization of interictal epileptiform abnormalities. The third end point involved an exploratory assessment of potential determinants of ictal consistency, including TSC variant, age at epilepsy onset, epileptic spasms, multiple seizure types, interictal multifocality, and tuber load. RESULTS:The authors included 45 patients with TSC with a median of 3 (interquartile range 2-4) ictal and 8 (interquartile range 5-10) interictal EEGs per patient. Median time between first and last ictal EEG was 28.4 months (19.0-60.3). Ictal foci were consistent over time in 11 patients (24.4%), of whom 9 had 1 consistent ictal focus. Nine other patients had a single consistent ictal focus on the first EEGs, but developed a second focus at the median age of 67.7 months. Of the 13 patients who later underwent surgery, 3 had a single focus, and only 2 of 13 had consistent ictal EEGs. The same three patients with a single focus over time were part of the seven postoperative seizure-free patients. All six nonseizure-free children had ictal multifocality. Interictal and ictal epileptogenic foci were discordant in 42 of 45 patients (93.3%). Exploratory analyses of potential determinants of ictal consistency suggested a negative association with interictal multifocality (risk ratio 0.32, 95% confidence interval 0.06-0.97, p = 0.04), which was not significant after adjustment for monitoring duration. CONCLUSIONS:Ictal epileptogenic foci are consistent in only 25% of the patients with TSC. Interictal epileptogenic foci are often discordant with ictal foci. This instability in the ictal epileptogenic focus might be explained by the presence of larger epileptogenic networks in TSC that undergo evolution over time. SIGNIFICANCE:The findings in this study could have important implications for presurgical evaluation in patients with TSC and might help to understand the cause of (late) surgical failure.

Objective N-of-1 trials aim to determine the therapeutic effect for a single individual. This individualized approach necessitates collecting multiple data points over time through repeated alternating periods of active treatment and a comparator or control condition. The extended duration of the treatment periods may increase patient burden, prolong placebo exposure, and increase the likelihood of study discontinuation. In theory, treatment responders (or non-responders) can be identified early during the trial if the therapeutic effect is strong (or completely lacking). There are no theoretical constraints to evaluate treatment efficacy more regularly-instead of only after a predetermined number of treatment periods. Regularly updating estimates on treatment effects allows clinicians to accelerate clinical decision-making regarding N-of-1 study termination. This study examined the value of continuous treatment effect estimation using Bayesian hypothesis testing in N-of-1 trials to accelerate and nuance clinical decision-making.Methods An N-of-1 trial with severe epilepsy was simulated and three N-of-1 trials in neurological conditions were (re-)analyzed continuously with consecutive data points using Bayesian hypothesis testing and/or a minimally clinically important threshold (30% seizure frequency reduction). Trial duration based on Bayesian testing with strong evidence for treatment effects was compared to original trial duration.Results Original trial duration could be reduced between 9.5% and 35% of the trial length by using continuous outcome estimation in two of the analyzed trial examples. The moment that strong evidence supporting beneficial treatment effects using Bayesian hypothesis testing and a significant probability of minimally clinically important differences are achieved during the trial may differ. Obtaining additional data points and alternating interventions over time improve certainty of the estimates of treatment effects.Significance Treatment efficacy decisions can be expedited when outcome estimation is performed continuously rather than delayed until the end of the trial. Clinical significance of N-of-1 trial outcome can be improved combining both Bayesian hypothesis testing and a minimally clinically important threshold.

OBJECTIVE:To define and articulate research priorities in epilepsy identified by the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE), addressing key unmet needs across the spectrum of rare and complex epilepsies. METHODS:This position paper was developed through a structured collaborative process involving patient associations and experts from EpiCARE Working Groups, the EpiCARE Executive Committee, and its Research Council. Contributions were integrated and harmonized to establish a shared set of research priorities reflecting clinical, translational, and methodological perspectives. RESULTS:Six priority areas were identified and examined: prevention of epileptogenesis and disease-modifying challenges; genetics and targeted therapies; improved surgical decision-making; innovative trial designs and outcome measures; artificial intelligence for diagnosis and prediction; understanding and preventing comorbidities and mortality. For each priority, the paper discusses the current state of research, identifies challenges, and proposes strategic directions for future investigations. SIGNIFICANCE:This position paper provides a strategic framework to guide future research efforts, inform prioritization by funders and policymakers, and foster coordinated collaboration across stakeholders. By advancing these priorities, the epilepsy research community aims to improve patient care, reduce health disparities, and develop innovative solutions to address the complexities of epilepsy. PLAIN LANGUAGE SUMMARY:This position paper, developed by the European Reference Network for Rare and Complex Epilepsies (EpiCARE) in collaboration with its Patient Advocacy Group, defines six areas of research priorities in epilepsy. Each section describes key challenges, current knowledge, and areas for improvement. They focus on preventing epilepsy, developing targeted therapies, improving surgery and clinical trials, using artificial intelligence to support diagnosis, and addressing comorbidities such as cognition, sleep, and overall health. Each provides a roadmap for clinicians and researchers to guide their research projects within their areas of expertise. Collectively, these priorities converge on actions for improving diagnosis, treatment, and patient outcomes through European collaboration and sustainable research efforts.

OBJECTIVES:Timely referral and efficient presurgical evaluation are important to optimize postoperative seizure and developmental outcomes in epilepsy surgery patients. We aimed to identify determinants of time intervals from epilepsy diagnosis to referral to specialized centers and epilepsy surgery in children with malformations of cortical development (MCDs) and low-grade epilepsy-associated tumors (LEATs). METHODS:We performed a retrospective cohort study in 3 European centers, including children with MCD or LEAT who underwent epilepsy surgery between 2010 and 2020. Primary endpoints were (1) time interval between epilepsy diagnosis and referral for presurgical evaluation, (2) duration of presurgical evaluation trajectory, and (3) time from diagnosis to surgery. The secondary endpoint was postoperative seizure outcome. In our primary analysis, we performed a multivariable Cox proportional hazards analysis and used histopathological diagnosis, age at first seizure, presence of developmental delay, 1st seizure classification, initial EEG and MRI findings, duration until drug resistance, and family history as covariates. RESULTS:Of the 507 children included, 259 (51%) had an MCD and 248 (49%) had a LEAT. Earlier drug resistance and the presence of an MR-visible epileptogenic lesion were associated with shorter times from diagnosis to referral and surgery, and later onset of seizures was associated with a shorter time to surgery. LEAT was associated with a shorter presurgical evaluation and shorter time to surgery. An older age at surgery, shorter time from diagnosis to surgery, and a histopathological diagnosis of FCDII and LEAT were all independently associated with better postoperative seizure outcome. SIGNIFICANCE:Epilepsy surgery was performed earlier in children with MR-visible lesions and early drug resistance, particularly those with LEAT, and a shorter duration to epilepsy surgery was associated with better seizure outcomes. Many patients were initially considered MRI-negative in the referring center, highlighting the importance of early referral, epilepsy-dedicated MRI protocols, and experienced neuroradiologists. Increasing awareness of timely referral and surgery benefits is crucial for improving outcomes. PLAIN LANGUAGE SUMMARY:Children with severe focal structural epilepsy who have not responded to medication often benefit from surgery, especially when they are referred early. This study of 507 children found that certain factors-such as visible brain abnormalities on the first MRI, especially a specific type of brain tumor (LEAT), early signs of drug resistance, and seizures starting later in childhood-were linked to shorter times from diagnosis to surgery and that shorter time to surgery was linked to better seizure outcomes. Many children whose initial MRIs appeared to be normal were later found to have an epileptogenic brain lesion when examined at specialized centers. Early referral, advanced imaging, and expert evaluation are key to improving postsurgical outcomes.

Angiography is critical for visualizing cerebral blood flow in intracranial steno-occlusive diseases. Current 4D magnetic resonance angiography (MRA) techniques primarily focus on macrovascular structures, yet few have quantified hemodynamic timing. This study introduces a novel model to estimate macrovascular arterial transit time (mATT) derived from arterial spin labeling (ASL)-based 4D-MRA. We provide examples of our method that visualize mATT differences throughout the brain of patients with intracranial steno-occlusive disease (moyamoya), as well as changes in mATT resulting from the cerebrovascular reactivity response to an acetazolamide (ACZ) injection. Furthermore, we present a method that projects sparse arterial signals into a 3D native brain-region atlas space and correlates regional mATT with other hemodynamic parameters of interest, such as tissue transit time and cerebrovascular reactivity. This approach offers a non-invasive, quantitative assessment of macrovascular dynamics, with potential to enhance understanding of large-vessel and tissue-level hemodynamics and augment monitoring of treatment outcomes in steno-occlusive disease patients. Furthermore, it sets the stage for more in-depth investigations of the macrovascular contribution to brain hemodynamics.

After epilepsy surgery, it varies when children re-enter school. The aim of this study was to identify determinants for this variation. Parents of 21 school-attending children participated in semi-structured interviews during their child's hospitalization for epilepsy surgery and one year afterward (based on the standard neuropsychological post-surgical follow-up). The mean time to school re-entry was 10.7 weeks (SD = 6.3). One child did not attend school after one year, whilst the fastest child resumed school 2 weeks after surgery. We performed univariable linear regression models with bootstrapped R2 for all variables deemed theoretically or clinically relevant to school re-entry. We found that temporal surgery was significantly related to shorter time to school re-entry; and that longer hospitalization, and presurgical outpatient educational counseling were significantly related to longer time to school re-entry. In multivariable linear regression, these variables together predicted 57% of variance (bootstrapped) in time to school re-entry. In conclusion, our findings indicate that school re-entry varies considerably among children but can partly be explained by surgery related variables and the presence of counseling. Given the importance of school in children's daily lives, we argue that school attendance should be stimulated by increasing professionals' awareness of children's school re-entry process.

Magnetic resonance imaging (MRI) techniques have now widely replaced positron emission tomography (PET) as the modality of choice to assess cerebrovascular reactivity (CVR) and other hemodynamic parameters in intracranial steno-occlusive disease (ISOD), such as moyamoya vasculopathy (MMV). Therefore, radiologists should be aware of the choices in imaging techniques and potential pitfalls in the imaging interpretation. We developed a protocol based on multi-delay arterial spin labeling (ASL), with which, since its implementation in routine clinical practice in 2018, approximately 100 patients have been evaluated for CVR and other parameters. The protocol demonstrates clinical feasibility and utility, allowing detailed cerebral hemodynamic evaluations of individual patients that are useful for clinical decision-making. While multi-delay ASL offers benefits compared to single-delay ASL in patients with arterial transit delays, it is not completely insensitive to transit times, and further methodological improvements could mitigate this issue in the near future. Potential pitfalls in imaging acquisition and interpretation include artefacts due to motion, susceptibility, and misalignment in imaging registration, inadequate labeling, and the effects of anesthesia on CVR. This work serves as a practical guide for clinicians, radiologists, and MRI experts seeking to implement these advanced imaging methods in their institutions. Our MRI protocol, based on multi-delay ASL with a vascular challenge of acetazolamide, can be successfully used for hemodynamic assessments of patients with ISOD in clinical settings.

Objective: Accurate and timely epilepsy diagnosis is crucial to reduce delayed or unnecessary treatment. While language serves as an indispensable source of information for diagnosing epilepsy, its computational analysis remains relatively unexplored. This study assessed and compared the diagnostic value of different language model applications in extracting information and identifying overlooked language patterns from first-visit documentation to improve the early diagnosis of childhood epilepsy. Methods: We analyzed 1,561 patient letters from two independent first seizure clinics. The dataset was divided into training and test sets to evaluate performance and generalizability. We employed two approaches: an established Naive Bayes model as a natural language processing technique, and a sentence-embedding model based on the Bidirectional Encoder Representations from Transformers (BERT)-architecture. Both models analyzed anamnesis data only. Within the training sets we identified predictive features, consisting of keywords indicative of [epilepsy] or [no epilepsy]. Model outputs were compared to the clinician's final diagnosis (gold standard) after follow-up. We computed accuracy, sensitivity, and specificity for both models. Results: The Naive Bayes model achieved an accuracy of 0.73 (95% CI: 0.68-0.78), with a sensitivity of 0.79 (95% CI: 0.74-0.85) and a specificity of 0.62 (95% CI: 0.52-0.72). The sentence-embedding model demonstrated comparable performance with an accuracy of 0.74 (95% CI: 0.68-0.79), sensitivity of 0.74 (95% CI: 0.68-0.80), and specificity of 0.73 (95% CI: 0.61-0.84). Conclusion: Both models demonstrated relatively good performance in diagnosing childhood epilepsy solely based on first-visit patient anamnesis text. Notably, the more advanced sentence-embedding model showed no significant improvement over the computationally simpler Naive Bayes model. This suggests that modeling of anamnesis data does depend on word order for this particular classification task. Further refinement and exploration of language models and computational linguistic approaches are necessary to enhance diagnostic accuracy in clinical practice. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional ethics committee of both University Medical Center Utrecht and Martini Hospital approved the use of anonymized retrospective data for research purposes without informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

OBJECTIVE:Language serves as an indispensable source of information for diagnosing epilepsy, and its computational analysis is increasingly explored. This study assessed - and compared - the diagnostic value of different language model applications in extracting information. The aim is to identify language patterns that may contain useful clinical information that is not overtly considered by the clinician from first-visit documentation to improve the early diagnosis of childhood epilepsy. METHODS:We analyzed 1561 patient letters from the first two seizure clinics. The dataset was divided into training and test sets to evaluate performance and generalizability. We employed an established Naïve Bayes model as a natural language processing technique and a sentence-embedding (large language) model based on the Bidirectional Encoder Representations from Transformers (BERT) architecture. Both models analyzed anamnesis texts as noted by the treating physician only. Within the training sets, we identified predictive features consisting of keywords indicative of 'epilepsy' or 'no epilepsy.' Model outputs were compared to the clinician's final diagnosis (gold standard) after a two-year follow-up period. We computed accuracy, sensitivity, and specificity for both models. RESULTS:The Naïve Bayes model achieved an accuracy of 0.73 (95% CI: 0.68-0.78), with a sensitivity of 0.79 (95% CI: 0.74-0.85) and a specificity of 0.62 (95% CI: 0.52-0.72). The sentence-embedding model demonstrated comparable performance with an accuracy of 0.74 (95% CI: 0.68-0.79), a sensitivity of 0.74 (95% CI: 0.68-0.80), and a specificity of 0.73 (95% CI: 0.61-0.84). SIGNIFICANCE:Both models demonstrated relatively good performance in diagnosing childhood epilepsy solely based on the first-visit patient anamnesis text. Notably, the more advanced sentence-embedding model showed no improvement over the computationally simpler Naïve Bayes model. This suggests that modeling of anamnesis data does depend on word order for this particular classification task. Further refinement and exploration of language models and computational linguistic approaches are necessary to enhance diagnostic accuracy in clinical practice.

Objective The identification of pathogenic variants in developmental epileptic encephalopathy (DEE) genes can be vital for counseling and individualized treatment. Penetrance is usually considered to be high or full, although this has never been studied in population cohorts. Recent evidence shows that common polygenic risk factors (polygenic risk score [PRS]) are increased in DEE cases, suggesting they might modify risk.Methods We calculated the penetrance of autosomal dominant epilepsy variants that have previously been classified as (likely) pathogenic in ClinVar, in two large cohorts (n = 42 863 and n = 386 306) using whole genome sequencing data. Next, we calculated PRS to assess whether common variants could modify epilepsy risk among people carrying pathogenic variants.Results Most people carrying pathogenic DEE variants did not have epilepsy. Penetrance estimates suggested that the probability of epilepsy in pathogenic variant carriers ranges between 4.1% and 9.8%. Among people carrying epilepsy variants, PRS was predictive of an epilepsy diagnosis. A high PRS was associated with increased risk of severe epilepsy, whereas a low PRS seems protective in people carrying a pathogenic variant.Significance Our results suggest that average variant penetrance is lower than expected and modified by PRS. A high PRS combined with a pathogenic variant may be necessary to develop a severe epilepsy phenotype like DEE. Reconsidering penetrance assumptions could improve variant classification and diagnostic yield. Our findings may enhance genetic counseling by refining risk estimates and could extend to other diseases.

OBJECTIVE:This study aimed to identify the determinants of intellectual and developmental outcomes following pediatric hemispherotomy in a large, contemporary multicenter cohort. METHODS:We retrospectively analyzed the intellectual and developmental outcomes of 296 children and adolescents who underwent hemispherotomy between 2000 and 2016 and received a standardized postsurgical evaluation of intelligence or developmental quotient (IQ/DQ). Outcomes at the last follow-up were classified into four categories: normal (IQ/DQ > 85), mildly impaired (IQ/DQ = 70-84), moderately impaired (IQ/DQ = 55-69), or severely impaired (IQ/DQ < 55). Determinants of these outcomes were identified using ordinal regression modeling with imputation for missing data. RESULTS:At a median follow-up of 2.1 years (interquartile range = 1.3-5.3), 84% of the children and adolescents were seizure-free, and 60% had discontinued antiseizure medication (ASM). Intellectual and developmental functioning at the last assessment was normal in 11% of the patients, mildly impaired in 16%, moderately impaired in 22%, and severely impaired in 51%. Higher functioning was less likely in patients with polymicrogyria as the underlying etiology (odds ratio [OR] = .3 [.11-.77], p = .013), those with contralateral magnetic resonance imaging abnormalities (OR = .47 [.22-.99], p = .047), and those who continued ASM after surgery (OR = .51 [.29-.9], p = .021). Conversely, patients with a later age at epilepsy onset were more likely to achieve higher functioning (OR = 1.16 [1.04-1.3], p = .011). SIGNIFICANCE:Age at epilepsy onset, underlying etiology, presence of bilateral structural brain abnormalities, and postsurgical ASM management were key determinants of intellectual and developmental outcomes following hemispherotomy. These findings underscore the importance of timely ASM discontinuation as the only modifiable factor that may optimize intellectual and developmental trajectories. Although direct presurgical comparisons were not possible, the observed associations provide valuable insights into factors influencing cognitive outcomes.

Identification of the epileptogenic lesion is challenging in tuberous sclerosis complex as multiple lesions might represent the seizure onset zone. A combination of dysplastic MRI features has diagnostic value in pre-surgical evaluation. However, these radiological characteristics may be difficult to identify and have not been studied on early unmyelinated brain MRI in tuberous sclerosis complex infants. Our study aimed to assess the diagnostic accuracy of T2-hypointense lesions on unmyelinated MRI in identifying the epileptogenic lesion. We included children with tuberous sclerosis complex who underwent resective or disconnective epilepsy surgery in the Motol University Hospital Prague and the University Medical Center Utrecht with available (i) unmyelinated MRI (before the age of 9 months), (ii) pre- and post-operative brain MRI and (iii) at least 2 years follow-up post-surgery. We identified T2-hypointense lesions and highly dysplastic lesions on unmyelinated or myelinated MRI, assessing their diagnostic accuracy in epileptogenic lesion identification by comparing seizure free to non-seizure free patients. Twenty-seven patients met inclusion criteria. We identified 54 T2-hypointense lesions in 24 patients, 30 were already highly dysplastic on unmyelinated MRI, showing cortical thickening and transmantle sign in most cases, while calcifications appeared later. Diagnostic accuracy of T2-hypointense (70.8%) was superior to the presence of the most dysplastic features (55.6%) in epileptogenic lesion identification. Positive predictive value for complete resection of all T2-hypointense lesions was 63.6%, compared to 50.0% for highly dysplastic lesions. Seizure recurrence was high (negative predictive value 76.9%) when T2-hypointense lesions remained outside the resected area. Assessing T2-hypointense lesions on unmyelinated brain MRI has important diagnostic value in identifying the epileptogenic lesion in pre-surgical work-up in infants with tuberous sclerosis complex and drug-resistant epilepsy. Unmyelinated brain MRI deserves a more important position in pre-surgical evaluation in infants with tuberous sclerosis complex and drug-resistant epilepsy.

AbstractObjectiveNew‐onset seizure‐like events (SLEs) are common in children, but differentiating between epilepsy and its mimics is challenging. This study provides an overview of the clinical characteristics, diagnoses, and corresponding etiologies of children evaluated at a first seizure clinic (FSC), which will be helpful for all physicians involved in the care of children with SLEs.MethodsWe included 1213 children who were referred to the FSC of a Dutch tertiary children's hospital over a 13‐year period and described their clinical characteristics, first routine EEG recording results, and the distribution and specification of their eventual epilepsy and non‐epilepsy diagnoses. The time interval to correct diagnosis and the diagnostic accuracy of the FSC were evaluated.Results“Epilepsy” was eventually diagnosed in 407 children (33.5%), “no epilepsy” in 737 (60.8%), and the diagnosis remained “unclear” in 69 (5.7%). Epileptiform abnormalities were seen in 60.9% of the EEG recordings in the “epilepsy” group, and in 5.7% and 11.6% of the “no epilepsy” and “unclear” group, respectively. Of all children with final “epilepsy” and “no epilepsy” diagnoses, 68.6% already received their diagnosis at FSC consultation, and 2.9% of the children were initially misdiagnosed. The mean time to final diagnosis was 2.0 months, and 91.3% of all children received their final diagnosis within 12 months after the FSC consultation.SignificanceWe describe the largest pediatric FSC cohort to date, which can serve as a clinical frame of reference. The experience and expertise built at FSCs will improve and accelerate diagnosis in children with SLEs.Plain language summaryMany children experience events that resemble but not necessarily are seizures. Distinguishing between seizures and seizure mimics is important but challenging. Specialized first‐seizure clinics can help with this. Here, we report data from 1213 children who were referred to the first seizure clinic of a Dutch children's hospital. One‐third of them were diagnosed with epilepsy. In 68.8% of all children—with and without epilepsy—the diagnosis was made during the first consultation. Less than 3% were misdiagnosed. This study may help physicians in what to expect regarding the diagnoses in children who present with events that resemble seizures.

The majority of people with epilepsy achieves long-term seizure-freedom and may consider withdrawal of their anti-seizure medications (ASMs). Withdrawal of ASMs can yield substantial benefits but may be associated with potential risks. This review critically examines the existing literature on ASM withdrawal, emphasizing evidence-based recommendations, where available. Our focus encompasses deprescribing strategies for individuals who have attained seizure freedom through medical treatment, those who have undergone successful epilepsy surgery, and individuals initiated on ASMs following acute symptomatic seizures. We explore state-of-the-art prognostic models in these scenarios that could guide the decision-making process. The review underscores the importance of a collaborative shared-decision approach between patients, caregivers, and physicians. We describe the subjective and objective factors influencing these decisions and illustrate how trade-offs may be effectively managed in practice.

OBJECTIVE:Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants. METHODS:The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated. RESULTS:Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77). SIGNIFICANCE:VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.

OBJECTIVE:Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy. METHODS:We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations. RESULTS:Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden. SIGNIFICANCE:The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies.

We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations of cortical development (MCD) who underwent surgery between 2015 and 2020 at University Medical Center Utrecht (the Netherlands) and pooled our data with four previously published cohort studies. Tissue analysis yielded a pathogenic variant in 203 of 663 (31%) combined cases. In 126 of 379 (33%) focal cortical dysplasia (FCD) type II cases and 23 of 37 (62%) hemimegalencephaly cases, a pathogenic variant was identified, mostly involving the mTOR signaling pathway. Pathogenic variants in 10 focal epilepsy genes were found in 48 of 178 (27%) FCDI/mild MCD/mMCD with oligodendroglial hyperplasia and epilepsy cases; 36 of these (75%) were SLC35A2 variants. Six of 69 (9%) patients without a histopathological lesion had a pathogenic variant in SLC35A2 (n = 5) or DEPDC5 (n = 1). A germline variant in blood DNA was confirmed in all cases with a pathogenic variant in tissue, with a variant allele frequency (VAF) of ~50%. In seven of 114 patients (6%) with a somatic variant in tissue, mosaicism in blood was detected. More than half of pathogenic somatic variants had a VAF < 5%. Further analysis of the correlation between genetic variants and surgical outcomes will improve patient counseling and may guide postoperative treatment decisions.

BACKGROUND AND OBJECTIVE:Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS:We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS:Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION:This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.