OBJECTIVE:Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)-negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. METHODS:Group-level data were collected from 61 epilepsy surgery programs (49 pediatric-only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. RESULTS:A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG-guided radiofrequency thermocoagulation (RF-TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). SIGNIFICANCE:This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG-guided RF-TC. The high proportion of MRI-negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.

OBJECTIVE:To examine the clinical features of new-onset focal seizures in children and investigate clinical associations and predictors of underlying etiology and drug resistance. METHODS:Data were gathered from The Children's Hospital at Westmead admissions for patients aged 1 month to 18 years who presented with new-onset focal seizures between 2018 and 2022 (n = 140). Seizure characteristics, etiology, clinical comorbidities, investigations, and antiseizure medications were analyzed. Clinical associations between etiologies and comorbidities/treatment outcomes were investigated using nonparametric tests and hierarchical cluster analysis. Multivariable logistic regression was performed to identify predictors of drug resistance. RESULTS:The median age of seizure onset was 4.7 years (IQR 1.9-8.1). The etiologies included unknown (n = 53, 39%) followed by structural (n = 36, 26%), self-limited childhood focal epilepsy (n = 21, 15%), genetic (n = 12, 9%), inflammatory (n = 12, 9%), and metabolic (n = 3, 2%). The explosive seizure-onset seizures (p = 0.04), focal neurological abnormalities (p = 0.04), younger age at seizure onset (p = 0.01), abnormal neuroimaging findings (p < 0.001), and drug resistance (p < 0.001) were associated with known etiology. Regression analysis showed the drug resistance risk increased with the presence of known genetic (OR 6.7; 95% CI 1.6-31.8), structural (OR 6.4; 95% CI 2.3-19.5), and inflammatory (OR 4.6; 95% CI 1.0-21.2) etiologies. SIGNIFICANCE:Our study examines the important associations and predictors of etiology and drug resistance in children with new-onset focal seizures. The significance of known etiologies as risk factors for drug resistance promotes the need for improved monitoring and etiology-driven treatment. PLAIN LANGUAGE SUMMARY:This study looked at children who had focal seizures for the first time. In many cases, the cause was unknown, but a large portion was linked to structural brain changes, childhood epilepsies that usually resolve, or genetic, inflammatory, and metabolic conditions. Children with a known cause, especially genetic, structural, or inflammatory, were more likely to have seizures that did not improve with anti-seizure medications. Identifying the cause early can help doctors choose better treatments and provide closer monitoring for patients.

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.

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remains poorly understood. While numerous genetic aetiologies have been implicated, systematic characterization across diverse populations is lacking. This study aimed to delineate the molecular and clinical landscape of EDS in a large, multinational cohort, focusing on movement disorder phenomenologies, genotype-phenotype correlations, and treatment responses. We conducted a multicentre, cross-sectional study involving 609 patients with childhood-onset movement disorders associated with pathogenic variants in 105 predefined genes. Clinical data were collected from over 30 centres across 25 countries using a standardized survey, capturing movement disorder phenomenologies, seizure types, developmental trajectories, motor function and treatment outcomes. We classified EDS-associated genes into biologically meaningful groups by performing unsupervised clustering, which integrated protein-protein interactions and functional data. Genotype-phenotype correlations were assessed using a one-versus-remainder approach to quantify differential enrichment of clinical manifestations and treatment responses. Pathogenic variants were identified in 74 of the 105 predefined genes, with 12 genes accounting for two-thirds of cases. The most frequently reported genes were MECP2, ATP1A3, and GNAO1. Data-driven gene cluster analysis identified 12 functional groups, mapping EDS to relevant biological pathways and informing genotype-phenotype analyses. Dystonia (34.2%), stereotypies (24.6%) and ataxia (16.2%) were the most prevalent movement disorders, with gene- and pathway-specific movement disorder signatures extending beyond previously known associations. Notably, most patients exhibited mixed movement disorders, highlighting the phenotypic complexity of EDS. Epilepsy was diagnosed in only 66.8% of cases, suggesting that some EDS primarily manifest as movement disorders. Developmental trajectories varied by genetic aetiology. Pharmacological responses demonstrated gene- and pathway-specific treatment effects, confirming established therapeutic associations (e.g. PRRT2 variants responding to carbamazepine) and identifying previously unrecognized effects, such as exacerbation of motor symptoms with levodopa/carbidopa in GNAO1 and MECP2 variants. This study provides a detailed characterization of EDS, identifying distinct genetic, phenotypic and therapeutic patterns. The findings underscore the need for early recognition of movement disorders within epilepsy cohorts, offer immediate insights to improve anticipatory guidance and clinical management of EDS, and advocate for personalized treatment strategies. By laying the groundwork for longitudinal studies to refine genotype-phenotype correlations and establish a natural history, this work paves the way for interventional clinical trials and precision medicine approaches.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

AIM:To evaluate genetic testing practices (exome sequencing, commercial panel, and in-house genetic panels) from a large tertiary hospital for determining gaps, and to identify clinical associations with pathogenic genetic variants. METHOD:This retrospective cohort study included patients (age < 18 years) from a neurology department for whom genetic testing was requested for neurological disorders, epilepsy, and movement disorders (2020-2023). Logistic regression was used to identify clinical features predictive of positive results. The clinical benefits of genetic testing were studied. RESULTS:Three hundred and ninety patients underwent genetic testing by exome sequencing (n = 125), commercial panel (n = 143), in-house epilepsy (n = 78), and movement disorder (n = 44) gene panels. Exome sequencing had the highest pathogenic yield (n = 49, 39%), followed by epilepsy (n = 22, 28%), movement disorder (n = 11, 25%), and commercial (n = 22, 15%) panels. Variants of uncertain significance were highest in commercial (64%) and epilepsy (34%) panels. Among the exome sequencing cohort, the predominant clinical features were developmental delay (89%), intellectual disability (51%), and epilepsy (35%). Pathogenic variants in the exome sequencing cohort were more likely in patients with severe developmental delay (33%, p = 0.03) and hypotonia (39%, p = 0.05). There was significant utility of genetic testing in informing clinical decision making (49% of pathogenic variants in exome sequencing cohort). INTEPRETATION:Exome sequencing outperforms gene panels in confirming genetic diagnoses in paediatric neurological disorders, and highlights the need for building local diagnostic genetic-testing resources.

BACKGROUND:Thrombolysis is infrequently delivered to children with acute ischemic strokes (AIS). We explored potential eligibility for treatment with tPA (tissue-type plasminogen activator) for pediatric AIS. METHODS:This retrospective, multicenter, observational, cohort study reviewed children aged 29 days to 17 years with symptomatic AIS identified via Children's Hospital Westmead, John Hunter Children's Hospital, and Sydney Children's Hospital between January 1, 2010, and December 31, 2019. Medical records were examined to evaluate eligibility for treatment with tPA based on established multinational and the 2026 American Heart Association guidelines, reasons for exclusion beyond delay to diagnosis, and long-term outcomes as pediatric modified Rankin Scale scores. We also explored additional exclusions and outcomes among children with small-vessel AIS and AIS in the context of brain tumors, who are currently excluded from tPA. RESULTS:A total of 135 patients with 139 symptomatic AIS were identified-median age, 6 years; 36% female; 73% presented via emergency departments; mean follow-up, 43 months; 12% deaths. Irrespective of delay to diagnosis, only 26 of 139 (19%) AIS were potentially eligible for treatment with tPA. Among patients potentially eligible for tPA, acute neuroimaging revealed large-vessel occlusions, unilateral focal cerebral arteriopathy, or extracranial dissections. Thirteen of 26 (50%) had nondisabled outcomes without tPA treatment. One hundred thirteen of 139 (81%) AIS were ineligible for treatment with tPA, irrespective of delay to diagnosis. All deaths occurred among patients excluded from tPA, predominantly related to underlying disorders. Fifty-four small-vessel AIS accounted for 39% of AIS. Eighteen (33%) had no additional ineligibilities to thrombolysis, among whom 10 had nondisabled outcomes without tPA. CONCLUSIONS:Based on current recommendations, 19% of symptomatic childhood AIS were potentially eligible for treatment with tPA, irrespective of delay to diagnosis. Selected patients with small-vessel AIS may offer an opportunity to extend the role of tPA. These observations may be relevant for optimizing pediatric stroke management strategies.

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

OBJECTIVE:A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. METHODS:Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review. RESULTS:We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. INTERPRETATION:Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561-572.

BACKGROUND AND OBJECTIVES:Periventricular nodular heterotopia (PVNH) is a common malformation of cortical development. We describe a distinctive imaging phenotype characterized by bilateral small heterotopic nodules of grey matter in the frontal periventricular regions, with an overview of the clinical, imaging, and genetic features. METHODS:Investigators reviewed available brain MRI studies, clinical records and genetic findings of 32 individuals with bilateral frontal PVNH, ascertained from multiple centres between 1996 and 2021. RESULTS:The imaging phenotype consists of multiple, small, bilateral nodules of PVNH maximal along the frontal horns of the lateral ventricles. Frontal PVNH was associated with heterogeneous, often subtle, additional brain malformations in 72 % (23/32) individuals. The clinical phenotype was variable and included mild focal epilepsy in 7/32 and mild-moderate cognitive impairment or developmental delay in 13/32. Microarray was normal in 13/16 and exome or genome sequencing normal in 8/13 where testing was performed. A genetic diagnosis was achieved in seven patients; pathogenic chromosome deletions of 7q11.23 and 7p22.1, pathogenic intragenic variants in KANSL1, STXBP1 and MAP1B (mother-daughter pair), and a combined 13q12.12 deletion (containing SACS) and an intragenic SACS variant. DISCUSSION:Bilateral frontal PVNH has a variable clinical phenotype, but generally milder sequelae than other forms of bilateral PVNH. A genetic diagnosis was made by chromosome microarray alone in 13 % or by exome or genome sequencing in 38 % where access to testing was available, with no recurrent genetic cause being found. Our PVNH cohort data suggest that PVNH could be classified in three main groups: FLNA-associated "classic" bilateral frontocentral PVNH, posterior/infrasylvian PVNH and this third pattern of bilateral frontal PVNH, accounting for ∼10 % of all cases of PVNH.

BACKGROUND AND AIMS:Much of the focus of ketogenic diet (KD) literature has been on the macronutrient profile, as the appropriate distribution of carbohydrate, fat and protein is essential to inducing ketosis. Few studies have evaluated the micronutrient adequacy of the KD in paediatric epilepsy, despite the importance of adequate vitamin and mineral intake in growth and development. Our study evaluated the nutritional adequacy of the Modified Atkins Diet (MAD) and Classical Ketogenic Diet (CKD) in children with epilepsy, relative to baseline diets and Nutrient Reference Values (NRVs). METHODS:Twenty children with epilepsy on the MAD and CKD underwent dietary analysis of 28 key nutrients at baseline and 3 months on diet ( ± multivitamin). Nutrient intake was expressed as % relative to recommended daily intake (RDI), adequate intake (AI), and upper limit as per the Australian NRVs. Nonparametric statistical comparisons were performed with a significance of p < 0.05. RESULTS:Sixty percent of children were KD 'responders,' exhibiting >50 % seizure reduction with median beta-hydroxybutyrate (blood ketone) level of 2.75 mmol/L on MAD and 4.25 mmol/L on CKD. Despite restriction of fruits, vegetables, dairy and wholegrains, children on MAD (without multivitamin) met 100 % of RDI for all nutrients except potassium. Intake of fibre and polyunsaturated fat increased significantly on the MAD compared to baseline. With multivitamin supplementation, some children on MAD were close to meeting upper limits for vitamin A, zinc, and selenium. Dietary recommendations to optimise nutritional adequacy using a 'food-first' ketogenic approach are provided. CONCLUSIONS:Although it is commonly reported that the restrictive nature of the KD induces nutritional deficiencies, our findings indicate that a well-designed MAD can induce positive dietary changes including increased fibre intake, increased mono- and polyunsaturated fat intake, and increased omega-3 essential fatty acid intake in children with epilepsy, whilst producing adequate ketosis.

BACKGROUND:Invasive/ intracranial EEG forms an important component of assessment for epilepsy surgery in many patients with Drug-Resistant Epilepsy (DRE). Intracranial EEG has been poorly utilized though Southeast Asia (SEA) and Oceania. This study aimed to document the development of stereo-EEG (SEEG) across the region and highlight regional barriers to utilization and access. METHODS:A survey was developed by multicenter consensus. The survey captured institutional characteristics, geographic distributions, intracranial EEG utilization, and barriers to SEEG. Respondents were representative epilepsy centers across the region. RESULTS:Four epilepsy centers with established intracranial/ SEEG and two centers from a country without any access to SEEG participated. The responses identified that 1. Access to SEEG remained highly restricted across the region with an estimated one capable epilepsy center per 100 million people; 2. The region includes over half a billion people living in countries with no access to SEEG; 3. Staffing/ financial constraints were universal factors that limited growth of services or development of new services; 4. SEEG numbers have plateaued as a result of these challenges. CONCLUSION:The study puts into real numbers the challenges faced by the region in accessing SEEG. SEEG remains highly underutilized and future approaches should focus on regional training and referral pathways.

AIM:To review the aetiopathogenesis of infantile epileptic spasms syndrome (IESS) and mechanisms of action of adrenocorticotrophin hormone (ACTH)/corticosteroids established in humans. METHOD:MEDLINE, PubMed, and Embase were systematically searched from inception to December 2023 to identify studies related to IESS aetiology and treatment response. Mechanistic themes were identified and through consensus meetings refined and grouped into five overarching hypotheses. RESULTS:Five hypotheses were generated from 17 mechanistic themes: (1) gene and epigenetic regulation altering expression of 'vulnerability' genes; (2) stress and hypothalamic-pituitary-adrenal axis activation; (3) neuroinflammation and altered immune function; (4) altered neuronal transmission and pathways; and (5) dysfunction of metabolic pathways. INTERPRETATION:The evidence that ACTH/corticosteroids alter these processes remains limited. It is plausible that these processes interact with one another, rather than existing independently, and affect maturational and regulatory processes in the central nervous system, consistent with proposals that IESS is a neurodevelopmental disorder. Understanding how ACTH/corticosteroids work in IESS may facilitate disease-modifying treatments and improve neurodevelopmental outcomes.

We report eight children with de novo pathogenic DNA variants in chromatin-related genes: MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1HIE, EP300, and KMT2B. All children experienced infection or vaccine-provoked neuroregression or abrupt-onset neuropsychiatric syndromes. Most had delayed development (n = 6) before the first regression, and four had immune deficiency or autoimmunity (n = 4). At a mean age of 4 years 2 months (range 1-8 years), symptoms included infection-provoked autistic/language regression (n = 6), cognitive decline (n = 3), gait deterioration (n = 3), or abrupt-onset anxiety, obsessive-compulsive disorder, and/or tics (n = 5). Three children had ongoing infection-provoked deteriorations. Six children benefited from intravenous immunoglobulin (n = 3) or antibiotics (n = 4). Ribonucleic acid expression of the eight chromatin genes was similar in neuronal, glial, and peripheral leukocytes, unlike non-chromatin neurodevelopmental genes, which have predominantly neuronal expression. These cases demonstrate the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation.

OBJECTIVE:To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). METHODS:All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. RESULTS:We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. INTERPRETATION:DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932-943.

We present two cases with focal seizures where scalp electroencephalography (EEG) had prominent features of a developmental and epileptic encephalopathy (DEE): Case 1: a 17-year-old male with complex motor seizures whose EEG demonstrated a slow spike-and-wave pattern and generalized paroxysmal fast activity (GPFA). Case 2: a 12-year-old male with startle-induced asymmetric tonic seizures whose EEG also had a slow spike-and-wave pattern. Both patients had intracranial EEG assessment, and focal cortical resections resulted in long-term seizure freedom and resolution of generalized findings. These cases exemplify patients with focal epilepsy with networks that share similarities to generalized epilepsies, and importantly, these features did not preclude curative epilepsy surgery.

Background Thrombolysis is infrequently delivered to children with acute ischemic stroke (AIS). Consideration of eligibility criteria and outcomes after AIS may enhance utility of thrombolysis in pediatric AIS. Methods This retrospective observational study assessed eligibility for acute tissue plasminogen activator (tPA) and outcome in a 10-year population cohort of 151 children with AIS and a first symptomatic AIS cohort of 68 children. Outcomes among children with small vessel AIS, residual brain tumors and intracranial dissection, who are currently excluded from tPA, were explored to assess potential for benefit from tPA in these subgroups. Results Approximately 80% of each cohort were excluded from tPA, irrespective of delay to diagnosis, related to multiple underlying disorders. All deaths occurred among patients excluded from tPA. The minority eligible for tPA had large vessel occlusions, focal cerebral arteriopathy or extracranial dissections. More than half of eligible patients had non-disabled outcomes without tPA. Approximately 40% of both cohorts had small vessel AIS, more than half of whom were excluded from tPA for additional reasons. Among those not additionally excluded, 78-88% of each cohort had non-disabled outcomes without tPA. Among 12 patients excluded from tPA due to residual brain tumors, all had additional exclusions. In contrast, patients with AIS due to intracranial dissection infrequently had additional cause for exclusion and outcomes were relatively poor. Conclusions Only 20% of childhood AISs were eligible for tPA, irrespective of delay to diagnosis, and more than half of these patients manifest non-disabled outcomes without tPA, suggesting relatively restricted potential for benefit with tPA. Relaxation of some exclusions for selected patients may enhance beneficial delivery of tPA. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No external funding was received. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Sydney Children's Hospital Network HREC 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. Not Applicable 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). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable The data that support the findings of this study are available from the corresponding author upon reasonable request.

To (i) determine whether accelerated long-term forgetting (ALF) can be found using standardized verbal memory test materials in children with genetic generalized epilepsy (GGE) and temporal lobe epilepsy (TLE), and (ii) to establish whether ALF is impacted by executive skills and repeat testing over long delays. One hundred and twenty-three children aged 8 to 16, (28 with GGE, 23 with TLE, and 72 typically developing; TD) completed a battery of standardized tests assessing executive functioning and memory for two stories. Stories were recalled immediately and after a 30-min delay. To examine whether repeat testing impacts long-term forgetting, one story was tested via free recall at 1-day and 2-weeks, and the other at 2-weeks only. Recognition was then tested for both stories at 2-weeks. Children with epilepsy recalled fewer story details, both immediately and after 30-min relative to TD children. Compared to TD children, the GGE group, but not the TLE group, showed ALF, having significantly poorer recall of the story tested only at the longest delay. Poor executive skills were significantly correlated with ALF for children with epilepsy. Standard story memory materials can detect ALF in children with epilepsy when administered over long delays. Our findings suggest that (i) ALF is related to poor executive skills in children with epilepsy, and (ii) repeated testing may ameliorate ALF in some children.

The increasing integration of high-throughput genomic strategies, e.g., whole genome sequencing (WGS) has revolutionised diagnostics of rare diseases. There is growing evidence of its clinical utility in acute care, particularly when early therapeutic interventions are facilitated in critically ill paediatric patients.