The number of neurons in the developing brain is greater than typically found in adulthood, and the brain possesses delicate mechanisms to induce the death of excess cells and refine neural circuitry. The correct tuning between the processes of neuronal death and survival generates a mature and functional brain in its complexity and plastic capacity. Epilepsy is a highly prevalent neurological condition worldwide, including among young individuals. However, exposure to the main treatment approaches, the long-term use of Antiseizure Medication (ASM), during the critical period of development can induce a series of changes in this delicate balance. Acting by various mechanisms of action, ASMs may induce an increase in neuronal death, something that translates into deleterious neuropsychiatric effects in adulthood. Several investigations conducted in recent years have brought to light new aspects related to this dynamic, yet many questions, such as the cellular mechanisms of death and the pathophysiology of late effects, still have unresolved elements. In this review, we aimed to explore the mechanisms of action of the most widely used ASMs in the treatment of neonatal epilepsy, the broad aspects of neuronal death in the developing brain and the repercussions of this death and other effects in adulthood. We review the evidence indicating a relationship between exposure to ASMs and the manifestation of associated psychiatric comorbidities in adulthood and discuss some possible mechanisms underlying the induction of this process by morphological and physiological changes in the related behaviors.

The neurodevelopmental outcome of infants with early-onset epilepsies varies widely, ranging from typical development to global developmental delay. Visual skills, which emerge during infancy, are crucial for the development of cognitive functions. The aim of this observational cohort study was to explore gaze behavior in infants with early-onset epilepsy and evaluate if eye tracking could support prognostication of their neurodevelopment.

Fifty-one infants (22 females, mean seizure onset-age 5, SD ± 2, months) from a prospective epilepsy cohort underwent repeated eye tracking and Hammersmith Infantile/Neonatal Neurological examination (HINE/HNNE). Neurodevelopment at age two was categorized as typical development (mean Bayley [BSID-III] cognitive and language or Griffiths [GMDS-III] scales score ≥ 85) and developmental delay. At initial (age 3-10 months) and 12-month visit, we compared reliability of fixation, probability of gaze shifts and saccadic reaction times (SRTs) in a non-competitive SRT-task between developmental groups. Gaze behavior was also compared across etiologies, syndrome groups and between those with optimal versus suboptimal first HINE/HNNE.

Infants with typical developmental outcome (n = 23) had higher reliability of fixation (p = 0.007) and higher probability of gaze shifts (p = 0.012) at initial eye tracking than those with delay (n = 28). SRTs became faster during the follow-up but did not differ significantly between the developmental groups. Gaze behavior associated with epilepsy syndrome, etiology, and initial HINE/HNNE result.

Ability to fixate reliably and shift gaze soon after the epilepsy diagnosis is associated with developmental outcome in infants with early-onset epilepsy, suggesting that eye tracking could be useful as an additional prognostic tool.

This study explored the potential of miRNA-134-3p and miRNA-155-5p as biomarkers for assessing seizure severity in children.

Healthy children and children with epilepsy from Fujian Provincial Hospital (Sept 2022 to July 2023) were grouped into the control group (n = 20), the well-controlled group (n = 22), and the poorly-controlled group (n = 18). Clinical data and serum samples were analyzed using quantitative real-time polymerase chain reaction to detect miRNA levels. Receiver operating characteristic curve analysis evaluated diagnostic potential.

The poorly-controlled group showed increased seizure frequency (P < 0.001), medication dosage (P < 0.001), and intellectual disabilities (P = 0.041). MiRNA-134-3p and miRNA-155-5p levels were higher in epilepsy patients, especially in the poorly-controlled group (P < 0.001). When the critical value of miRNA-134-3p for diagnosing seizure control was 4.336, the specificity was 90.9 % and the sensitivity was 88.9 %. When the diagnostic threshold of miRNA-155-5p was 2.870, the specificity was 63.6 % and the sensitivity was 100 %. The sensitivity, specificity, and accuracy of the combined diagnosis of serum miRNA-134-3p and miRNA-155-5p for seizure control were 88.9 %, 100 %, and 94.45 %, respectively.

The expressions of miRNA-134-3p and miRNA-155-5p were elevated in the serum of children with epilepsy, and were positively correlated with the severity of seizures. The serum miRNA-134-3p has high specificity in diagnosing the degree of seizure control in children, while miRNA-155-5p has high sensitivity. Their combination of the two can improve the specificity of predicting the degree of seizure control in children.

Epilepsy is a chronic neurological disorder marked by a persistent tendency to generate seizures, leading to substantial cognitive, behavioral, and psychosocial consequences. This study investigated psychiatric disorder-related adverse events (AEs) associated with antiseizure medications (ASMs) in children using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

This study conducted a comprehensive analysis of FAERS data from 2004 to 2024, focusing on psychiatric AEs in children with epilepsy or seizures treated with ASMs. Signal values were computed using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).

A total of 2539 preferred terms (PTs) were included, involving 25 system organ classifications (SOCs). Nervous system, skin and subcutaneous tissue, and psychiatric disorders are the three most common SOCs for ASMs in children. There were 24 ASMs, whose AEs involved psychiatric disorders, totaling 110 PTs and 214 drug-PT relationships. Psychotic symptoms (notably lorazepam and topiramate, n = 116 and 109), substance dependence and abuse (notably pregabalin and clonazepam, n = 291 and 110), and the other neuropsychiatric symptoms (notably levetiracetam and valproic acid, n = 70 and 62) were the common types of psychiatric disorder-related AEs of ASMs in children. A total of nine ASMs (brivaracetam, clonazepam, diazepam, eslicarbazepine, gabapentin, lamotrigine, lorazepam, perampanel, and tiagabine) were associated with suicidal and self-injurious behavior in children.

This study highlights psychiatric AEs of ASMs in children, offering critical insights to improve clinical medication practices and enhance treatment safety. Further research with broader clinical data is needed to promote safe and rational medication use.

Neurological disorder can cause functional network changes in white matter (WM). However, changes in the WM functional network in children with drug-resistant temporal lobe epilepsy (DRTLE) require further clarification. Therefore, we combine graph theory with resting-state functional magnetic resonance imaging (rs-fMRI) and T1-weighted imaging (T1WI) to investigate the topological features of the WM network in children with DRTLE, discover potential biomarkers, and understand the underlying neurological mechanisms. We included 91 children (43 with DRTLE and 48 healthy controls), acquiring structural and functional MRI data to construct WM functional networks. Graph theory was applied to evaluate topological differences and their correlation with onset age, disease duration and cognitive measures. A Support Vector Machine model classified individuals with DRTLE based on WM connectivity, with accuracy validated through leave-one-out cross-validation. The global topological properties of the WM network in children with DRTLE were altered, manifesting as an imbalance between global integration and segregation Local nodal efficiency changes in the association fibers exhibited reduced information transfer and centrality at several nodes. Conversely, commissural and projection fibers displayed increased network properties. Cognitive metrics correlated with nodal disturbances. The classification model achieved 73.6% accuracy and an area under the curve (AUC) of 0.744. This indicates that the WM functional network in DRTLE presents with anomalies in the topological attributes, which are associated with cognitive impairments. The WM functional connectivity may serve as valuable indicators for clinical classification of the condition. The insights provided have augmented our understanding of the complex neurological mechanisms involved in epilepsy.

A single instance of early-life status epilepticus (SE) in neonatal mice results in cognitive and behavioral impairments. The present study investigated the effects of SE on postnatal day (PD) 7 to determine the impact on auditory communication behavior. We used kainic acid to induce SE on PD7 and recorded isolation-induced ultrasonic vocalizations (USV) on PD8 and 9. We found SE did not alter the total number, total duration, average call duration, peak frequency, or low frequency in male and female mice on PD8 or PD9. However, there were sex-specific differences in call types. Female SE mice had an increase in chevron, complex, and upward calls, and a decrease in frequency steps, short, and two-component calls compared to female saline controls on PD8. Females with SE recorded on PD9 had an increase in composite, downward, and flat calls and a decrease in chevron, complex, upward, and frequency steps compared to female saline controls, p < 0.05. Male SE mice that had their USVs recorded on PD8 had an increase in chevron, frequency steps, and two-component calls, and had a decrease in downward, upward, and flat calls compared to male saline controls. In contrast, SE males that had their USVs recorded on PD9 had an increase in downward and short calls, and a decrease in chevron, composite, frequency steps, and two-component calls compared to male saline controls, p < 0.05. This study contributes to a systematic examination of the influence of early-life seizures on communication in mice and the sensitivity of call types in determining deficits.

Brivaracetam is a novel third-generation antiseizure medication and an analog of levetiracetam with selective affinity for synaptic vesicle protein 2A (SV2A). By binding SV2A, brivaracetam decreases pre-synaptic neurotransmitter release.

We aimed to assess the safety and efficacy of brivaracetam in pediatric epilepsy.

We searched PubMed, Scopus, and Web of Science (WOS) for relevant clinical and observational studies from inception until February 2024. We carried out statistical analysis using Open Meta-Analyst. Dichotomous data were pooled as proportions with a 95% confidence interval (CI).

Eleven studies with a total of 805 patients were identified. The analysis of four studies revealed the more than 50% responder rate in a cohort of 252 focal epilepsy patients to be 51.5% (95% CI: [32.6%, 70.5%]). The analysis of three studies involving a cohort of 266 patients found a 20.7% incidence (95% CI: [15.8%, 25.6%]) of complete seizure freedom. The analysis of nine studies involving a cohort of 737 epilepsy patients revealed a retention rate of 66% (95% CI: [40%, 92%]).

This study highlights the efficacy, tolerability, and safety of brivaracetam as adjunctive therapy in pediatric patients with epilepsy. The findings support its consideration as a valuable treatment option for children and adolescents, particularly those with drug-resistant epilepsy. Further trials with longer follow-up durations are needed to study the optimal doses and explore factors affecting drug response.

Juvenile myoclonic epilepsy (JME) is a prevalent genetic generalized epilepsy with linked abnormalities in cognition, behavior, and brain structure. Well recognized is the potential for advancing understanding of the epigenetic contributions to the neurobehavioral complications of JME, but to date there has been no examination of the role of socioeconomic disadvantage in regard to the cognitive and brain health of JME, which is the focus of this investigation.

Seventy-seven patients with JME and 44 unrelated controls underwent neuropsychological assessment, structural neuroimaging, and clinical interview to delineate epilepsy history and aspects of family status. The Area Deprivation Index characterized the presence and degree of neighborhood disadvantage, which was examined in relation to cognitive factor scores underlying a comprehensive neuropsychological test battery, academic metrics, integrity of brain structure, and family characteristics.

JME participants resided in neighborhoods associated with significantly more socioeconomic disadvantage, which was associated with significantly poorer performance across all three cognitive factor scores and reading fluency. JME was associated with significant reduction of total subcortical gray matter (GM) but not total cortical gray or white matter volumes. Among controls, participants residing in more advantaged areas exhibited increased volumes of total subcortical GM and diverse subcortical structures as well as areas of increased cortical thickness and volume in frontal/prefrontal regions, findings that were compromised or not evident in JME, raising the possibility of disease-related attenuation of socioeconomic advantage.

Socioeconomic disadvantage in JME is associated with adverse effects on cognitive and academic status, whereas socioeconomic advantage in controls is associated with increased brain volumes and thickness, markers of brain health that were largely attenuated or absent in JME. The associations detected here argue for the need to better integrate the social determinants of health with genetic and epigenetic factors in advancing understanding of cognitive and brain health in JME.

To report the prevalence of visual acuity, visual field, and ocular motility problems in children with epilepsy referred to the Children's Epilepsy Surgery Service (CESS) for surgery.

This was a retrospective observational study of all children referred to the CESS in Bristol between 2015 and 2020. Data extraction included age, age at epilepsy diagnosis, epilepsy etiology (as determined by seizure semiology, neuroimaging, and electroencephalography), anti-seizure drugs, visual acuity, visual field, ocular motility, and fundus imaging.

A total of 221 children with epilepsy were seen during the study period: 60% (132/221) had structural etiologies, 8% (18/221) were genetic, and in 28% (62/221) the etiology was unknown. Overall, 53% (117/221) were found to have abnormalities, particularly strabismus (16%, 36/221), visual field defects (14%, 27/198), and reduced visual acuity (12%, 26/219). Notably, 54% (63/117) of children with ophthalmic abnormalities were new diagnoses in the CESS clinic. Younger children and those with neurodevelopmental disorders were less likely to complete all vision tests.

Ophthalmic abnormalities were prevalent among children referred for epilepsy surgery in Bristol and more than half were previously undiag-nosed. The data support the adoption of an orthopticled vision screening service for children with medically refractory epilepsy, structural etiologies, and focal seizures, to better support their needs in the community. [J Pediatr Ophthalmol Strabismus. 2025;62(3):211-219.].

Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy that places a substantial burden on both affected individuals and their informal caregivers. The aim of this review is to examine the multifaceted impact of DS on informal caregivers, focusing on key factors that contribute to their challenges and overall burden.

The PRISMA guidelines were followed and a comprehensive search of electronic databases (PubMed, Science Direct, Taylor & Francis) was conducted to identify original research articles from January 2015 till the end of December 2024 in English language. Two reviewers independently carried out the screening. The quality of studies was assessed using the AXIS Critical Appraisal Tool for Cross-Sectional Studies. Relevant data was extracted and a narrative synthesis was performed to integrate the findings.

The review included ten studies involving 887 caregivers of patients with DS. Most studies reported a higher proportion of female caregivers. Additionally, all studies were conducted in Europe and the USA. Patient-related characteristics, caregiver characteristics, psychological and physical strain, family functioning, access to support system, financial burden, and difficulties in balancing caregiving responsibilities and personal needs were found to influence caregivers' experiences and overall well-being. Women, especially mothers, were found to face greater psychological and physical burden, along with productivity loss and difficulties in managing caregiving and personal responsibilities.

Caregivers of individuals with DS face significant challenges. More research is needed to understand the full impact of DS on caregivers. Targeted interventions and improved resources are essential to reduce strain and improve care for both caregivers and individuals with DS.

This study aims to improve genetic diagnosis in childhood onset epilepsy with neurodevelopmental problems by utilizing RNA sequencing of fibroblasts to identify pathogenic variants that may be missed by exome sequencing and copy number variation analysis.

We enrolled 41 individuals with childhood onset epilepsy and neurodevelopmental problems who previously had inconclusive genetic testing. Fibroblast samples were cultured and analyzed using RNA sequencing to detect aberrant expression, aberrant splicing, and monoallelic expression using the Detection of RNA Outlier Pipeline (DROP) pipeline. Detected events were correlated with phenotypes, and long-read genome sequencing was performed on individuals with strong candidate events to identify the causal genomic variant. A systematic literature review on RNA sequencing in rare disorders was conducted to contextualize our findings.

RNA sequencing identified five strong candidate events in four individuals, affecting the genes QRICH1, TSC1, SMARCA1, GNAI1, and PTEN. (Likely) pathogenic genomic variants affecting expression of QRICH1, TSC1, and SMARCA1 were detected, resulting in a diagnostic yield of 7% (3/41). Two variants were not covered in the initial exome sequencing data but were revealed through long-read sequencing. The identification of a pathogenic TSC1 variant led to a previously unrecognized diagnosis of tuberous sclerosis complex. This prompted guideline-based screening, which revealed tuberous sclerosis lesions in the brain and lung, directly impacting clinical care. Notably, two of the three pathogenic events would not have been detected using whole blood due to the lack of expression of the involved genes. The lower yield of this study compared to studies in other rare disorders reflects the genetic heterogeneity of epilepsy and neurodevelopmental disorders, and the inaccessibility of affected tissue.

This research underscores RNA sequencing of cultured fibroblasts as a valuable tool in genetic diagnostics for childhood onset epilepsy, particularly when conventional methods fail. Expanding the control dataset with age-matched samples and incorporating RNA sequencing with nonsense-mediated decay inhibition could further enhance diagnostic yield.

Infantile epileptic spasm syndrome (IESS), a rare age-specific epileptic encephalopathy, exhibits limited therapeutic efficacy, with approximately 50% of patients showing resistance to adrenocorticotropic hormone (ACTH) monotherapy. Herein, we investigated the association between serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3), their ratio, and short-term ACTH therapeutic response in IESS, alongside their correlation with video-electroencephalogram (VEEG) characteristics.

This retrospective study included IESS patients who received ACTH treatment at Shanghai Children's Medical Center from July 2021 to November 2024. Clinical data, including serum IGF-1, IGFBP-3 levels, VEEG findings, and short-term treatment responses, were collected. Before ACTH therapy, we classified patients into hypsarrhythmia and non-hypsarrhythmia groups based on VEEG findings. The hypsarrhythmia cohort was further subdivided into ACTH responders and non-responders. Statistical analyses employed independent t-tests, Mann-Whitney U tests, chi-square tests, and Spearman's rank correlation.

A total of 21 patients (14 hypsarrhythmia, 7 non-hypsarrhythmia) were enrolled. The hypsarrhythmia population exhibited significantly lower serum IGF-1 levels and IGF-1/IGFBP-3 ratios (p < 0.05) compared to the non-hypsarrhythmia population. Within the hypsarrhythmia population, responders (n = 9) showed higher IGF-1, IGFBP-3 levels, and IGF-1/IGFBP-3 ratios than non-responders (n = 5) before ACTH treatment (p < 0.05). Post-ACTH treatment, serum IGF-1 and IGFBP-3 levels increased in all patients, with greater elevation observed in responders.

Our findings demonstrate that serum IGF-1, IGFBP-3 levels, and their ratio correlate with both hypsarrhythmia severity and short-term ACTH response in IESS patients. These biomarkers may help guide personalized treatment decisions.

A ketogenic diet is used in children with drug-resistant epilepsy but predictors for efficacy are largely lacking. Our aim was to evaluate if causative genetic variants could predict seizure response to the ketogenic diet. A cohort study of 226 children with refractory epilepsy and classic ketogenic diet treatment for at least 3 months (76.9% of the 294 who started) was performed. The median age at diet start was 5.1 years (range 0.1-17.8), 118 were girls and 108 boys. They had previous trials of a median of 6.0 anti-seizure medications (range 0-12) and intellectual disability was found in 87%. Seizure response (≥50% reduction) was found in 138/226 patients (61.1%) at 3 months, 121 (53.5%) at 6 months, 107 (47.3%) at 1 year and in 80 (37.0%) at 2 years follow-up of ketogenic diet. Age of epilepsy onset was lower and combined epilepsy type less common in responders compared to non-responders but no differences were found for specific seizure types, ketogenic ratio or beta-hydroxybutyric acid blood levels. A causative pathogenic/likely pathogenic variant was detected in 107/153 = 69.9% in 48 different genes. Next generation sequencing was used in 91/226 (40%) cases with a diagnostic yield of 58.2% (53/91). In comparison with cases without a revealed genetic aetiology, patients with a causative genetic variant had less atonic seizures and epileptic spasms and a better seizure response with 17.3% seizure free and 25% with >90% seizure reduction at 2-year follow-up. Causative variants in SLC2A1, SCN1A, STXBP1 and PAFAH1B1 showed significant diet response (P < 0.05) and good efficacy was also associated with DEPDC5, GLDC, KCNT1, PDHA1, SLC25A12 and TSC1. Causative variants in COL4A1 and DYNC1H1 were among genes linked to a lack of response. To our knowledge not described previously, we report a good ketogenic diet response related to causative variants in CSNK2A1, FARS2, GABRB3, GRIN1, KCNA2, KCTD3, STX1B and SLC16A2 but a lack of response for causative variants in CLN5, GLI3, MACF1, MAGEL2, NANS, NEMO/IKBKG, RORB, SLC17A5 and UFSP2. After grouping of genes into functional groups, causative variants in transporter genes had the best response (P = 0.009) and variants in other membrane-related proteins (ion channels and neurotransmitter receptors) also showed good efficacy. However, the gene group related to cell structural integrity and/or homeostasis had the worst diet response (P = 0.00006). In conclusion, our results support that causative genetic variants may be used as prognostic markers of ketogenic diet response, constituting an example in the expanding area of precision medicine.

The purpose of the study is to evaluate the prevalence of epilepsy in children with surgically treated obstructive sleep apnea (OSA) and examine the associated healthcare utilization. This cross-sectional study included children aged 1-18 years diagnosed with moderate to severe OSA who were treated with adenoidectomy or adenotonsillectomy. A matched control group (1:3 ratio) without OSA was used for comparison. Data were obtained from Clalit Health Services, Israel's largest healthcare provider. The study analyzed the prevalence of epilepsy, hospital admissions for seizures, use of anti-seizure medications (ASMs), and outpatient visits to pediatric neurologists. Among 55,164 children (13,791 in the OSA group and 41,373 in the control group), the prevalence of epilepsy was higher in the OSA group (0.9% vs. 0.4%; odds ratio (OR) = 2.22, p < 0.001). The OSA group also exhibited higher rates of ASM use (1.1% vs. 0.5%; OR = 2.24, p < 0.001), emergency department visits (OR = 15.66, p < 0.001), hospital admissions (OR = 3.18, p < 0.001), and visits to pediatric neurologists (14% vs. 8.1%; OR = 1.85, p < 0.001). The usage of ASMs was significantly higher in the OSA group, particularly for levetiracetam (OR = 3.73, p < 0.001).

Children with surgically treated OSA had higher rates of epilepsy and greater healthcare utilization compared to their peers. These findings underscore the necessity for integrated care, including neurological assessments, for children with OSA. Further research is needed to examine the impact of OSA treatment on epilepsy outcomes.

• Obstructive sleep apnea (OSA) and epilepsy are prevalent neurological conditions in children, with evidence suggesting a bidirectional relationship between sleep disorders and epilepsy in adults. • OSA prevalence is notably higher in children with refractory epilepsy or those prescribed multiple anti-seizure medications (ASMs).

• This study demonstrates a twofold increase in epilepsy prevalence among children with surgically treated moderate-to-severe OSA compared to matched controls. • Pediatric patients with OSA exhibit significantly higher rates of epilepsy-related healthcare utilization, including hospital admissions, emergency visits, and consultations with pediatric neurologists.

Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes. It is therefore now possible to consider precision medicine and novel therapeutic approaches for these devastating diseases with trials of repurposed and new drugs, including gene therapies. Trials are being designed to target either DEE diseases more broadly, specific DEE syndromes, or specific genetic DEEs. To serve this purpose, a clear operational definition of DEEs is needed to ensure that appropriate patients are selected for trials with precisely defined, targeted outcome measures. Herein we propose the operational definition of DEEs to set the stage for the development of DEE therapies.

Neuropsychiatric comorbidities are prevalent in children with epilepsy and often pose greater concerns than the seizures themselves. Identifying children at risk for these conditions is crucial for developing effective therapies. In prepubescent rodents, sex significantly influences cognitive dysfunction related to seizures, with prepubescent male rats exhibiting more severe adverse effects than females. However, it remains unclear whether sex plays a similar role in cognitive and behavioral outcomes in children. This review aims to assess the literature on whether sex is a biological factor affecting behavioral and cognitive outcomes in pediatric epilepsy.

We conducted a literature review to explore the impact of sex on cognitive and behavioral outcomes in children (up to age 18 years) with epilepsy of all types. Studies were categorized into observational and interventional types. We analyzed population studies involving children with epilepsy, as well as those addressing genetic factors, surgical interventions, status epilepticus, infantile spasms, pharmacological treatments, and the ketogenic diet.

Few adequately powered studies have examined sex as a biological variable in relation to cognitive and behavioral impairments in children with epilepsy. In addition, many studies failed to examine sex-related differences in behavior and cognition in children without epilepsy. Generally, the sex-related differences in cognitive and behavioral impairments in children with epilepsy match those seen in children without epilepsy. One exception is that in several studies girls with epilepsy had a similar risk for attention deficit hyperactive disorder (ADHD) as boys, whereas in children without epilepsy ADHD is more common in boys than girls. Although there is a modest trend indicating worse cognitive outcomes for boys with epilepsy compared to girls, consistency across studies is lacking.

Sex is not yet a well-explored prognostic factor for outcomes following childhood epilepsy, though some small differences were identified for specific outcomes. More rigorously designed studies are necessary to report outcomes by sex while controlling for potential confounders. The variability in methods for assessing neurodevelopmental outcomes underscores the need for standardized and comprehensive evaluations of cognitive and behavior in children with epilepsy.

The aim of this study was to evaluate the long-term follow-up data of Chinese children with self-limited focal epilepsy with neonatal/infantile onset (SeLFE) and to investigate the clinical features, genetic background and treatment outcomes of this type of epileptic syndrome.

We conducted a retrospective cohort study of twenty-six children with SeLFE admitted to or followed by the Department of Pediatrics, Second Affiliated Hospital of Xi'an Jiaotong University from October 2011 to October 2021. Treatment decisions were based on the children's seizure semiology, frequency, economy, medication accessibility, allergies and other factors, and initial medications including levetiracetam, phenobarbital and oxcarbazepine. All children were followed up regularly in the outpatient clinic.

The 26 children, 13 male and 13 female, were followed for a mean of 54.0 (49.0, 58.5) months. Trio whole-exome sequencing (WES) revealed no pathogenic genetic abnormalities in 16 children, and known pathological genes including PRRT2, SCN2A and KCNQ2 were detected in 10 children. Thirteen children (50.0%) achieved complete seizure control after first-line monotherapy. Among the 12 patients who failed to respond to the first monotherapy, 9 patients achieved a seizure free status with oxcarbazepine, which was used as the second-line monotherapy or as add-on therapy. One patient recovered spontaneously without treatment.

Although SeLFE is often self-limited, this study showed that complete seizure control is not always achieved with initial medication therapy. Oxcarbazepine may be an effective option for the treatment of SeLFE.

The incidence of epilepsy is highest at the extremes of age. Drug resistance is present in approximately one-third of people with epilepsy but occurs at higher than average rates in children with seizure onset before age 3 years, owing to a variety of etiologies unique to this age group. Epilepsy surgery is an effective therapeutic option for drug-resistant epilepsy but is vastly underutilized. Epilepsy surgery in children under age 3 comes with distinct clinical challenges related to brain anatomy, evolving developmental maturation, and limitations of evaluation and surgical strategies. However, epilepsy surgery can lead to seizure freedom or significant seizure reduction in this age group. Early seizure control may have a significant positive impact on long-term cognitive development, making urgency of surgical referral of immense importance. This review highlights available evidence on the safety and efficacy of epilepsy surgery in early-life epilepsy, identifying barriers to surgical therapy, describing utilization of available evaluation and surgical strategies, and examining risks and benefits of earlier surgical consideration in this vulnerable population.

Developmental and epileptic encephalopathies (DEEs) are a group of rare, severe, early-onset epilepsies characterized by pharmacoresistance, marked electroencephalographic abnormalities, and delayed or regressive psychomotor development. DEEs are associated with poor long-term outcomes and increased mortality; however, early recognition and targeted treatment can impact neurodevelopmental outcomes and overall quality of life. Treatment with antiseizure medication is often challenging given drug resistance, chronic polypharmacy, and medication interactions. With advances in genetic testing and increased understanding of the neurobiological mechanisms of DEEs, the treatment approach is evolving and includes repurposed antiseizure medications and targeted therapies, as well as early surgical intervention in select patients. In addition to high seizure burden and neurodevelopmental delay, DEEs are associated with comorbidities affecting a range of body systems; these can include intellectual disability, psychiatric disorders, motor dysfunction, and respiratory and gastrointestinal problems. Over time, these comorbidities increase the complexity of management and have important implications on the disease burden and quality of life for both patients and their caregivers. Multidisciplinary care in DEEs is paramount. We summarize the current evidence on the management of specific DEEs, focusing on targeted therapies and optimizing outcomes.

Childhood epilepsy is frequently associated with neurobehavioral comorbidities such as depression, anxiety, cognitive impairments, and social dysfunction, as revealed by both clinical and experimental studies. Despite extensive neurophysiological research, behavioral studies in developing animals remain limited and underreported. Here, we review the behavioral impact of early-life seizures (ELSs) in commonly used rat models in developmental studies. We outline suitable tests and provide guidance on how traditional tests should be adapted and interpreted in this context. Finally, we examine factors influencing behavioral analysis in developmental studies, exploring confounding variables and offering strategies to minimize their impact.

Epilepsy syndromes are distinct electroclinical entities which have been recently defined by the International League Against Epilepsy Nosology and Definitions Task Force. Each syndrome is associated with "a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings". Syndromes often present in an age-dependent manner, carry both prognostic and treatment implications, and are associated with a specific range of comorbidities. Syndromes are most commonly identified in young children and are less frequent in adults. Syndrome identification assists clinicians in selecting the highest yield investigations, the most effective therapies, and allows them to give more accurate prognoses both with regards to seizure control and potential remission as well as expected, associated comorbidities. This review outlines how syndromes are organized and defined, highlighting the characteristic features of the more common entities. PLAIN LANGUAGE SUMMARY: Epilepsy syndromes are identifiable entities that are characterized by specific seizure type(s) and EEG findings. Identification of an epilepsy syndrome often provides a clue to the underlying cause, helps clinicians select the most effective treatments, and provides information on the likely outcome.

Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform (SCN8A) have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of SCN8A (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the I-V curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.

For patients with infantile epileptic spasms syndrome (IESS) who have achieved remission of epileptic spasms (ES), indicators of how well the electroencephalographic (EEG) state should be maintained during follow-up are not available. We hypothesized that the time course of the Burden of Amplitudes and Epileptiform Discharges (BASED) score after ES remission is associated with ES relapse. This study aimed to investigate the association between ES relapse and BASED scores at the time of initial ES remission and during the subsequent follow-up period.

We collected clinical and digital EEG data at four hospitals from patients with IESS who achieved initial ES remission. The BASED score was evaluated using EEGs obtained before remission, during remission, and after remission. The scoring was performed independently by the three reviewers, who were blinded to each other's scores. We analyzed the associations between clinical factors, BASED score, maximum BASED score, and ES relapse.

Data were collected from 44 patients aged 4-8 months at disease onset, which included 33 nonrelapsed and 11 relapsed patients. We assessed the BASED score of 262 EEGs. Structural etiology (p = .002) and the development of seizure other than ES (p = .04) were positively associated with ES relapse. Whereas BASED score before and at remission was not associated with relapse, a maximum BASED score of ≥3 during the postremission period was significantly associated with relapse (p < .001, odds ratio = 100). In multivariate analysis, only maximum BASED score ≥3 during this period remained significantly associated with relapse (p = .001, odds ratio = 76). The interrater reliability of the BASED score was high, with a quadratically weighted kappa coefficient of .93.

A maximum BASED score of ≥3 during postremission indicates a risk for ES relapse in patients with IESS.

This study was undertaken to describe incidence and distribution of seizures, etiologies, and epilepsy syndromes in the general child and youth population, using the current International League Against Epilepsy (ILAE) classifications.

The study platform is the Norwegian Mother, Father, and Child Cohort Study (MoBa). Epilepsy cases were identified through registry linkages facilitated by Norway's universal health care system and mandatory reporting to the Norwegian Patient Registry. A standardized protocol guided medical record review, leading to validation of diagnoses and classification of seizures, epilepsy types, syndromes, and etiologies based on the latest ILAE criteria.

MoBa included 111 365 participants aged 12-21 years by the end of follow-up on December 31, 2020. We identified 1053 children and youth with epilepsy (CYE). A defined epilepsy syndrome and/or identified etiology was found in 76% of CYE in this population-based study. Seizure types exhibited variation by age at onset. Focal epilepsies were predominant, occurring in 61% of CYE, whereas generalized epilepsies were identified in 24% of CYE. Standard clinical assessment identified etiology in 30% of CYE and in 55% with onset age < 2 years. Structural and identified genetic etiologies constituted 21% and 10%, respectively. Including presumed genetic and rare etiologies, 53% exhibited known etiology. A defined ILAE epilepsy syndrome was found in 53% of CYE. The cumulative incidence per 1000 children of the following ILAE epilepsy syndrome groups were as follows: self-limited epilepsies, 2.25; idiopathic generalized epilepsies, 1.75; and developmental and/or epileptic encephalopathies, 2.62.

Using the new ILAE classifications, this population-based childhood study provides incidences of seizures, epilepsies, and epilepsy syndromes. Half of epilepsy cases are classified as an ILAE epilepsy syndrome with its prognostic and therapeutic implications, but a substantial proportion of cases still have unknown etiology.

To investigate the efficacy and safety of perampanel (PER) add-on therapy in children with epilepsy of genetic etiology.

A retrospective analysis was conducted on the clinical data of 53 children who attended the Department of Neurology, Wuhan Children's Hospital, from November 2020 to April 2023. All children received PER add-on therapy and were diagnosed with epilepsy of genetic etiology based on whole-exome sequencing. The primary outcome measure was the proportion of children with a reduction in seizure frequency of ≥50% at month 12 of PER treatment (i.e., response rate), and the secondary outcome measures were response rates at months 3 and 6 of treatment. The influencing factors for the efficacy of PER add-on therapy in the treatment of epilepsy of genetic etiology were analyzed, and adverse events were recorded.

The median follow-up duration was 13.10 months. After 12 months of follow-up, 42 children were included in the analysis, comprising 25 boys (60%) and 17 girls (40%). The median initial dose of PER was 1.5 (1.0, 2.0) mg/d, and the median maintenance dose was 4.0 (3.0, 8.0) mg/d. The response rates to PER at months 3, 6, and 12 of treatment were 61% (30/49), 54% (25/46), and 48% (20/42), respectively. No significant difference in the efficacy of PER was observed between children with mutations in genes encoding different protein functions (P>0.05). The most common adverse event reported was fatigue, observed in 3 children (6%).

PER add-on therapy demonstrates good efficacy and safety in children with epilepsy of genetic etiology. No influencing factors for the efficacy of PER have been identified to date.

Considerable inter-individual variability in the efficacy of valproic acid (VPA) has been reported, with approximately 20-45% of patients failing to achieve satisfactory seizure control after VPA monotherapy. The aim of this study was to investigate the influence of non-genetic and genetic factors on 12-month VPA-response in a cohort of 194 pediatric patients.

Trough concentrations were determined, and a panel of 48 variants located in pharmacokinetic and pharmacodynamic gene were genotyped.

Aetiology was highlighted as a significant factor for the response to VPA. Specifically, patients with idiopathic epilepsy demonstrated poorer 12-month outcomes (p < 0.001). Trough VPA concentrations did not significantly affect outcomes. Marginal association was found between VPA efficacy and the following genetic variants: GABRA1 rs10068980 (p = 0.02), SLC16A1 rs7169 (p = 0.02), ABCC2 rs1885301 (p = 0.092), ACADM rs1251079 (p = 0.061) and GABRA1 rs6883877 (p = 0.085), as indicated by Fisher's exact test. A significant cumulative effect of two genetic factors (GABRA1 rs10068980 and SLC16A1 rs7169) was observed after a multiple logistic analysis, with ORs of 2.828 (1.213, 6.594) and 4.066 (1.148,14.398), respectively.

Our study indicated that GABRA1 rs10068980 and SLC16A1 rs7169 might serve as potential biomarkers for predicting the 12-month VPA treatment outcomes in pediatric patients with epilepsy.

This study evaluates the electroclinical features of infantile epileptic spasms syndrome (IESS) suddenly appearing in previously normal patients, aiming to describe clinical outcomes and independent predictors.

We retrospectively selected a homogeneous group of patients with IESS from two Italian centers. All patients had normal development prior to IESS onset and a follow-up period lasting at least one year. Patients with clinically relevant risk factors, other seizure types, brain structural abnormalities or known genetic diseases were excluded. The BASED score was used to standardize interictal EEG patterns.

Forty-three patients were enrolled, with a median age at IESS onset of 6 months; median follow-up was 43 months. At onset, 65.11 % exhibited mild behavioral changes, including irritability and poor social smile. At firstEEG, epileptic encephalopathy (EE) was prevalent during wakefulness (69.76 %; median BASED score 4) and sleep (81.40 %; median BASED score 5). Within 15 days of treatment, 83.72 % achieved seizure freedom, primarily with ACTH depot (90.70 %). After six months, all patients were seizure- and EE-free. At the last follow-up, 81.40 % had normal cognitive functioning; in the remaining, specific neurodevelopmental disorders, predominantly involving language were reported. No statistically significant differences were found in the electroclinical presentation and neuropsychological outcome.

We describe a subgroup of IESS patients with prompt response to treatment, long-term seizure freedom, and absence of severe neurodevelopmental impact. Our data suggest that within the IESS spectrum, there is a distinctive subgroup with global favorable outcome. Key clinical features predictors of good outcome could include normal development prior to IESS and early response to treatment.

Background: Epilepsy is a neurological disorder defined by the occurrence of epileptic seizures, which can significantly affect children, often leading to learning and cognitive impairments. Microglia, the resident immune cells of the central nervous system, are essential in clearing damaged neurons through phagocytosis. Notably, GABBR-associated microglia have been implicated in regulating phagocytic activity. Since the phagocytic function of microglia is critical in the pathogenesis of epilepsy, this study aims to investigate the role of GABBR-associated microglia in the development of the immature brain following epileptic seizures. Methods: Epilepsy was induced in a mouse model by the intraperitoneal injection of KA. Changes in the expression of the GABBR-related gene, GABBR2, in hippocampal microglia were analyzed using single-nucleus RNA sequencing (snRNA-seq). Cognitive and emotional changes in the mice were assessed through behavioral analyses. The expression of GABBR2 was semi-quantitatively measured using Western blotting, quantitative reverse transcription PCR, and immunofluorescence. Additionally, the spatial relationship between GABBR2 and hippocampal neurons was evaluated using Imaris software. Results: The snRNA-seq analysis revealed that GABBR2 expression was elevated in activated microglia in the hippocampus during chronic epilepsy compared to the early phase of seizures. Behavioral assessments demonstrated heightened anxiety levels and learning and memory impairments in the chronic epilepsy group compared to the control group. GABBR2 expression was upregulated in chronic epilepsy. Three-dimensional reconstruction analyses revealed a significantly increased contact volume between GABBR-associated microglia and neurons in the chronic epilepsy group compared to the control group. Conclusions: GABBR-associated microglia significantly contribute to the progression of immature brain diseases by promoting neuronal phagocytic activity.

Developmental and epileptic encephalopathies constitute a group of severe epilepsies, with seizure onset typically occurring in infancy or childhood, and diverse clinical manifestations, including neurodevelopmental deficits and multimorbidities. Many have genetic aetiologies, identified in up to 50% of individuals. Whilst classically considered paediatric disorders, most are compatible with survival into adulthood, but their adult phenotypes remain inadequately understood. This cross-sectional study presents detailed phenotypes of 129 adults (age range 17-71 years), with genetic developmental and epileptic encephalopathies involving causal variants in 42 genes. We describe diverse disease aspects, and we sought genetic insights from the age-related trends of expression of the genes involved. Most developmental and epileptic encephalopathies (69.7%) are epileptic encephalopathies in adulthood, with the presence of epileptic encephalopathy correlating with worse cognitive phenotypes (P = 0.0007). However, phenotypic variability was observed, ranging from those with epileptic encephalopathy to seizure-free individuals with normal EEG or intermediate clinical and EEG phenotypes. This variability was found across individual genes and age-related gene expression trends, suggesting that other influential factors are likely at play. Mobility, feeding and communication impairments were common, with significant dependence on others for activities of daily living. Neurological and psychiatric comorbidities were most prevalent, along with additional systemic comorbidities observed, particularly musculoskeletal, cardiac and gastrointestinal conditions, highlighting the need for comprehensive and multisystemic monitoring. Despite an average diagnostic delay of 25.2 years, aetiology-based therapeutic interventions were feasible for 54.8% of the cohort, underscoring the critical need for genome-wide genetic testing for adults with these phenotypes. Optimizing seizure control remains necessary, but it may not be sufficient to ensure good outcomes, which may differ significantly from childhood metrics, like cognitive function and independence in daily living. Therapies addressing additional aspects beyond seizures are necessary for improving overall outcomes. Understanding the intricate relationship between molecular pathways and the age-related trends of gene expression is crucial for development of appropriate gene-specific therapies and timely intervention. Whilst prospective data are also needed to define these complexities, such studies of necessity take years to acquire: insights from adults can inform care strategies for both paediatric and adult populations now.

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with epileptic seizures, severe delay or regression of psychomotor development, and cognitive and behavioral deficits. What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic and therapeutic challenges. Intellectual disability is severe and complicates potential treatment. Pathogenic variants are found in 30-50% of patients with DEE. Many genes mutated in DEEs encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up a significant proportion of DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities -synaptopathies. Here, we review recent publications on non-channelopathies in DEE with an emphasis on the mechanisms linking epileptiform activity with intellectual disability. We focus on three major mechanisms of intellectual disability in DEE and describe several recently identified genes involved in the pathogenesis of DEE.

Dravet syndrome is a developmental and epileptic encephalopathy characterized by frequent, prolonged convulsive seizures and status epilepticus. Symptoms usually appear in the first year of life, and in addition to ongoing severe and intractable epilepsy, children with Dravet syndrome experience neurodevelopmental, behavioral, and motor impairments, along with high rates of mortality, especially in the first 12 years of life. Prompt diagnosis and initiation of treatment with broad-spectrum antiseizure medications are recommended to reduce seizure frequency and status epilepticus, and to potentially minimize the comorbidities associated with the epileptic encephalopathy. Stiripentol is an antiseizure medication approved for adjunctive use in Dravet syndrome in patients aged as young as six months. Data from randomized clinical trials and real-world studies demonstrate that stiripentol added to first-line therapy with clobazam and/or valproate is associated with high rates of seizure control, including freedom from status epilepticus, for extended periods of time including into adulthood. Stiripentol has multiple mechanisms of action and also inhibits several metabolic drug-metabolizing enzymes that can enhance the efficacy of coadministered antiseizure medications. Stiripentol is well tolerated, and treatment-emergent adverse events can often be managed by dose adjustments of comedications. This review updates the use of stiripentol in the modern era.

We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.

Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.

We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%).

Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.

Multiple etiologies of West syndrome have been reported; however, there are cases of unknown etiologies. Exposure to volatile organic compounds (VOCs) increases the risk of epilepsy; however, their effects on children remain unknown. This study aimed to investigate the association between maternal occupational usage of VOCs and West syndrome development in children. Using data from a cohort of 88,280 children, we extracted children born to mothers who had used VOCs during pregnancy. Based on an epilepsy diagnosis by the age of 2 years, the frequency of usage of VOCs was comparatively analyzed among the following groups: never diagnosed with epilepsy, West syndrome, and other epileptic syndromes. A total of 15, 154, and 88,111 children were categorized into the West syndrome, other epileptic syndrome, and never diagnosed with epilepsy groups, respectively. The odds ratio (OR) for West syndrome development increased with the frequency of permanent marker usage (one to three times a month: OR = 2.58, 95% confidence interval [CI] 0.75-8.90; one or more times a week: OR = 4.34, 95% CI 1.23-15.26). These results suggested an association between maternal occupational frequent usage of permanent marker and West syndrome development in children.

Epilepsy, a clinical diagnosis characterised by paroxysmal episodes known as seizures, affects 1% of people worldwide. Safe and patient-specific treatment is vital and can be achieved by the development of rapid pre-clinical models of for identified epilepsy genes. Epilepsy can result from either brain injury or gene mutations, and can also be induced chemically. Xenopus laevis tadpoles could be a useful model for confirmation of variants of unknown significance found in epilepsy patients, and for drug re-purposing screens that could eventually lead to benefits for patients. Here, we characterise and quantify seizure-related behaviours in X. laevis tadpoles arrayed in 24-well plates. To provoke acute seizure behaviours, tadpoles were chemically induced with either pentylenetetrazole (PTZ) or 4-aminopyridine (4-AP). To test the capacity to adapt this method for drug testing, we also exposed induced tadpoles to the anti-seizure drug valproate (VPA). Four induced seizure-like behaviours were described and manually quantified, and two of these (darting, circling) could be accurately detected automatically, using the video analysis software TopScan. Additionally, we recorded swimming trajectories and mean swimming velocity. Automatic detection showed that either PTZ or 4-AP induced darting behaviour and increased mean swimming velocity compared to untreated controls. Both parameters were significantly reduced in the presence of VPA. In particular, darting behaviour was a shown to be a sensitive measure of epileptic seizure activity. While we could not automatically detect the full range of seizure behaviours, this method shows promise for future studies since X. laevis is a well-characterised and genetically tractable model organism.

To evaluate the etiology-specific diagnosis of early-onset developmental epileptic encephalopathies (EO-DEEs) in a nationwide Turkish cohort to determine the implications for therapeutic management.

The cohort comprised 1450 patients who underwent EO-DEE. The utility of genetic testing was assessed with respect to the initial phases of next generation sequencing (NGS) (2005-2013) and the current NGS era (2014-2022). A predefined four-stepwise diagnostic model was evaluated using cost-effectiveness analysis. The diagnostic and potential therapeutic yields of the genetic tests were subsequently determined.

Gene-related EO-DEEs were identified in 48.3 % (n = 701) of the cohort: non-structural genetic (62.6 %), metabolic genetic (15.1 %), and structural genetic (14.1 %). The most common nonstructural genetic variants were SCN1A (n = 132, 18.8 %), CDKL5 (n = 30, 4.2 %), STXBP1 (n = 21, 2.9 %), KCNQ2 (n = 21, 2.9 %), and PCDH19 (n = 17, 2.4 %). The rate of ultra-rare variants (< 0.5 %) was higher in the NGS era (52 %) than that in the initial phase (36 %). The potential therapeutic yields with precision therapy and antiseizure drug modification were defined in 34.5 % and 56.2 % in genetic-EO-DEEs, respectively. The diagnostic model provided an etiology-specific diagnosis at a rate of 78.7 %: structural (nongenetic) (31.4 %), genetic (38.5 %), metabolic (6.1 %), and immune-infectious (2.8 %). Based on a cost-effectiveness analysis, the presented diagnostic model indicated the early implementation of whole-exome sequencing for EO-DEEs.

In the present cohort, the higher rate (48.3 %) of gene-related EO-DEE diagnoses in the NGS era provides a potential therapeutic management plan for more patients.

The relationship between maternal prenatal psychological distress and epilepsy development in offspring has not yet been clarified. Herein, we used a dataset obtained from the Japan Environment and Children's Study, a nationwide birth cohort study, to evaluate the association between six-item Kessler Psychological Distress Scale (K6) scores and epilepsy among 1-3 years old. The data of 97,484 children were retrospectively analyzed. The K6 was administered to women twice: during the first half (M-T1) and second half (M-T2) of pregnancy. M-T1 ranged from 12.3-18.9 (median 15.1) weeks, and M-T2 ranged from 25.3-30.1 (median 27.4) weeks. Participants were divided into six groups based on K6 scores of two ranges (≤4 and ≥5) at M-T1 and M-T2. The numbers of children diagnosed with epilepsy at the ages of 1, 2, and 3 years were 89 (0.1%), 129 (0.2%), and 149 (0.2%), respectively. A maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-old children in the univariate analysis. Moreover, multivariate analysis revealed that a maternal K6 score of ≥5 at both M-T1 and M-T2 was associated with epilepsy diagnosis ratios among 1-, 2-, and 3-year-olds. Continuous moderate-level maternal psychological distress from the first to the second half of pregnancy is associated with epilepsy among 1-, 2-, and 3-year-old children. Hence, environmental adjustments to promote relaxation such as mindfulness in pregnant women might be necessary.

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed.