Search Results (149)

Developmental and/or epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS), previously described as continuous spike-wave during slow-wave sleep (CSWS) or electrical status epilepticus in sleep (ESES), is a childhood-onset disorder characterized by cognitive, language, behavioral, and/or motor regression or stagnation associated with marked activation of epileptiform discharges during non-rapid eye movement sleep. Three themes are central to the evolving understanding of D/EE-SWAS. First, it is a network disorder in which thalamocortical dysfunction, impaired sleep-dependent synaptic homeostasis, and potentially neuroinflammatory mechanisms contribute to neurodevelopmental deterioration. Second, increasing recognition of its genetic and structural heterogeneity is reshaping diagnostic evaluation. Monogenic etiologies are identified in up to one-third of cases, with a higher yield in the developmental and epileptic encephalopathy subtype, supporting early genomic testing alongside prolonged sleep EEG, MRI, and serial neuropsychological assessment. Third, treatment remains empiric and constrained by limited comparative evidence. Corticosteroids retain the strongest evidence base for cognitive improvement, although the overall certainty of this evidence remains low to moderate. Benzodiazepines are commonly used alternatives, and epilepsy surgery can provide substantial benefit in appropriately selected patients with focal structural abnormalities. Emerging etiology-directed therapies, including L-serine for selected GRIN loss-of-function variants and primidone for TRPM3-related disease, illustrate a broader transition from syndrome-based to precision management. However, no pharmacological therapy is specifically approved for D/EE-SWAS, long-term neurodevelopmental morbidity remains common, and adequately powered trials using standardized EEG and neurocognitive outcomes are urgently needed. Full article

Background/Objectives: In resource-limited regions, limited access to genetic testing may delay etiological diagnosis in selected patients with epilepsy and complex neurological manifestations, particularly when the phenotype raises suspicion of an underlying genetic etiology. This study aimed to assess the diagnostic value and clinical utility of phenotype-guided WES in selected patients aged ≥17 years with epilepsy and complex neurological manifestations in Southern Kazakhstan and to characterize clinical, therapeutic, and molecular features associated with drug-resistant epilepsy (DRE). Methods: This observational cohort included 78 patients aged ≥17 years with epilepsy and complex neurological manifestations identified through 25 outpatient medical centers. After enrollment, all patients underwent structured HPO-based phenotyping, assessment of antiseizure medication exposure, seizure burden, treatment response, and proband-only WES. Variants were interpreted according to ACMG/AMP guidelines. Exploratory multivariable logistic regression was used to assess factors associated with DRE. Results: P/LP variants were identified in 12/78 patients, corresponding to a diagnostic yield of 15.4%. VUS were detected in 16/78 patients (20.5%). DRE was present in 41 patients (52.6%), all of whom were receiving polytherapy. Carbamazepine was the most frequently used antiseizure medication (52/78, 66.7%), followed by valproic acid (32/78, 41.0%) and levetiracetam (20/78, 25.6%). Patients with DRE had earlier seizure onset, more frequent definite structural MRI abnormalities, and a higher proportion of P/LP variants. In the adjusted model, P/LP variant presence and definite structural MRI abnormality were associated with DRE. Conclusions: Phenotype-guided proband-only WES provided clinically relevant diagnostic information in a real-world epilepsy cohort with complex neurological manifestations in a resource-limited outpatient setting. The observed burden of DRE and polytherapy supports the potential value of integrating therapeutic profiling, neuroimaging, and genomic testing in the etiological evaluation of patients with epilepsy and additional neurological features. Full article

Background: Resource-constrained programs perform epilepsy surgery under limited access to advanced imaging and neuromodulation. We describe presurgical evaluation findings, early seizure outcomes, and safety from a mixed adult-pediatric cohort. Methods: Retrospective single-center series of 22 consecutive patients meeting surgical candidacy. We captured demographics, epilepsy classification/etiology, presurgical investigations (long-term Video-EEG, MRI, selective FDG-PET), procedure type, histopathology when available, and postoperative seizure outcome (ILAE). Complications were recorded using the ILAE adverse-event taxonomy. Results: Mean age at surgery was 21.2 ± 11.2 years; 15 (68%) were male. Epilepsy was focal in 15 (68%); structural etiologies predominated in 15 (68%). MRI was concordant with the presumed epileptogenic zone in 13 (59%). FDG-PET was obtained in 10 (45.5%) and was concordant in 7 (70%). Long-term Video-EEG (≥2 habitual seizures) was completed in 21. Mean delay to surgery was 10 years (IQR [8–15]); presurgical work-up averaged 10 months (IQR [6–15]). Procedures were resective 14 (64%), disconnective 6 (27%), and neuromodulatory 2 (9%). Histopathology was available in 16 cases, most commonly showing hippocampal sclerosis (n = 5) and focal cortical dysplasia (n = 5). At 14 months median follow-up (range 12–34), ILAE outcomes were: I 41% (9), II 14% (3), III 23% (5), IV 23% (5). Outcomes significantly differed by procedure: curative-intent (resection/disconnection) achieved ILAE I 60% (9) versus ILAE III/IV 7 after palliative-intent (corpus callosotomy/neuromodulation). No deaths or permanent deficits occurred; one corpus callosotomy case developed transient aseptic meningitis. Conclusions: In a resource-limited program, structured presurgical evaluation and careful selection yield resection/disconnection outcomes comparable to high-resource benchmarks, while corpus callosotomy/neuromodulation remain largely palliative. Practical, reproducible pathways may help shorten delays and improve access in similar settings. Full article

Background/Objectives: Adult epilepsy is clinically heterogeneous, and individual clinical predictors may not fully capture the multidimensional burden associated with drug-resistant epilepsy (DRE). This study aimed to identify latent clinical phenotypes in adults with epilepsy and examine their cross-sectional associations with DRE and broader disease burden. Methods: This regional observational cohort study used a source database of 1100 patients with epilepsy. After excluding two patients aged <18 years, the adult analytic cohort included 1098 patients. Complete-case latent class analysis (LCA) was performed in 1054 patients using age at onset, disease duration, seizure type, seizure frequency, serial seizures/status, postictal confusion, neurological status, neuroimaging category, and number of antiseizure medications. Model selection was based on statistical fit, class size, and clinical interpretability. Internal clinical validation outcomes included DRE, quality of life, cognitive screening, and stigma scores. Post hoc characterization described the classes by epilepsy etiology, derived epilepsy type, and seizure categories aligned with current terminology. Results: A three-class solution was selected, with class sizes of 314, 465, and 275. DRE prevalence increased stepwise across classes: 5.7%, 14.2%, and 33.1%, respectively (p < 0.001). In adjusted analysis, Class 2 had higher odds of DRE than Class 1 (odds ratio 2.70, 95% confidence interval 1.56–4.67), while Class 3 showed the strongest association (odds ratio 8.19, 95% confidence interval 4.15–16.16; both p < 0.001). Higher-burden classes showed lower quality-of-life and cognitive scores and higher stigma scores. Conclusions: LCA identified three clinically interpretable, burden-enriched phenotypic profiles associated with a stepwise gradient in DRE and broader multidimensional disease burden. These cross-sectional profiles may provide a useful framework for describing clinical heterogeneity in adult epilepsy and generating hypotheses for future validation studies. Full article

Objective: Hemispherotomy is an effective treatment for select forms of drug-resistant hemispheric epilepsy, including perinatal stroke, Rasmussen’s encephalitis, and Sturge–Weber syndrome. Post-traumatic epilepsy (PTE) has been reported to occur in ~10% of children following traumatic brain injury (TBI). TBI has not been extensively evaluated as an indication for hemispherotomy, as its effects are rarely unilateral. Here, we report the results from five pediatric cases of hemispherotomy for drug-resistant hemispheric PTE. Methods: A retrospective review was performed of all pediatric patients with drug-resistant PTE secondary to TBI who underwent hemispherotomy between 2018 and 2022 at the Children’s Hospital of Philadelphia (n = 5). All patients initially underwent craniectomy and subsequent cranioplasty due to TBI; criteria for hemispherotomy were met in the following years, leading to a recommendation for hemispherotomy at the epilepsy surgery conference. Clinical characteristics, seizure and functional outcomes, and postoperative complications were reviewed. Seizure outcomes were classified according to the Engel criteria. Results: Five children (median age: 8.3 years, range: 5.0–10.3 years) with drug-resistant PTE underwent lateral trans-sylvian hemispherotomy. TBI etiology included non-accidental trauma (n = 3) and motor vehicle accidents (n = 2). All patients exhibited Engel Class Ia seizure outcomes (median follow-up: 15 months, range: 5–39 months), with a reduction in anti-seizure medications from a median of five preoperatively to one postoperatively. No patient experienced re-operation. Neuropsychological outcomes were patient-specific, with most exhibiting a mix of gains and challenges after surgery. Conclusion: We demonstrate the use of hemispherotomy to treat drug-resistant, hemispheric PTE in five children, with excellent reduction in seizure frequency and mixed or improved neuropsychological outcomes. Full article

Neurodegenerative disorders and epilepsy remain major clinical challenges, due to complex etiologies involving protein misfolding, excitotoxicity, metabolic dysregulation, and impaired cellular resilience. These unmet medical needs have stimulated interest in small-molecule modulators capable of targeting multiple pathogenic pathways. Cyclitols, a diverse family of inositol stereoisomers, play essential roles in cellular signaling and brain metabolism; among them, scyllo-inositol (SCI) has gained attention due to its distinct stereochemistry, capacity to cross the blood–brain barrier, and emerging neuroactive properties. Current pharmacokinetic data indicate that SCI exhibits dose-dependent systemic exposure, and good penetration into the central nervous system. Moreover, its supplementation seems to be well-tolerated. In experimental studies both on animals and humans, SCI has been shown to modulate amyloid-β aggregation, stabilize neuronal homeostatic pathways, and reduce network hyperexcitability, suggesting relevance for both neurodegenerative and epileptic phenotypes. Despite promising results, there is still a need for further analyses to define dosing, transporter involvement, and brain exposure thresholds. Collectively, the available data position SCI as a compelling candidate for translational development, warranting further investigation into its therapeutic window and disease-modifying potential across neurological disorders. Full article

Epilepsy is increasingly conceptualized as a disorder of dynamic network instability rather than a static imbalance between excitation and inhibition. However, substantial variability in seizure occurrence, clinical expression, and treatment response remains insufficiently explained by existing models. This narrative review examines how neurotransmitter systems contribute to seizure dynamics within a state-dependent framework, in which factors such as sleep–wake cycles, stress, inflammation, and metabolic conditions modulate network excitability. The review identified four key findings: neurotransmitter function in epilepsy is state-dependent rather than fixed; multiple physiological state modifiers shape seizure susceptibility; seizure termination is an active state-sensitive process; and biomarker performance depends on the prevailing brain state. Evidence from experimental and clinical studies indicates that neurotransmitter function is context-sensitive and interacts with molecular pathways, including ion channel function, synaptic plasticity, and neuromodulatory signaling. These interactions influence key stages of seizure dynamics, including initiation, propagation, and termination, and may differ across etiological categories of epilepsy. This perspective also helps explain the limited performance of static biomarkers, as they do not capture temporal variability in network states. Instead, state-sensitive markers and context-aware interpretations of electrophysiological and clinical data may provide more informative insights. Overall, integrating neurotransmitter mechanisms with dynamic brain states offers a more precise perspective on seizure variability and may support the development of individualized, state-aware approaches to epilepsy management. Full article

Background: Viral meningoencephalitis is a frequent cause of acute central nervous system infection in children, particularly in neonates and young infants. Although etiological diagnosis has improved through molecular testing, management remains largely supportive, and intravenous immunoglobulins (IVIGs) are occasionally used in clinical practice despite limited supporting evidence. Methods: We performed a single-center retrospective observational study including pediatric patients aged 0–10 years admitted between 2016 and 2025 with molecularly confirmed viral meningoencephalitis. Demographic, clinical, microbiological, therapeutic, and follow-up data were collected. Neurological outcomes and length of hospital stay were compared between patients treated with IVIG and those who were not. Results: Twenty-nine patients were included. Enterovirus was the most frequently identified pathogen (50.0%), followed by human herpesvirus (35.7%) and human parechovirus (14.3%). IVIG was administered to 28% of patients, all with enterovirus infection. IVIG-treated patients were significantly younger at presentation and more frequently presented with apnea (42.9% vs. 0%, p = 0.014). Most patients had a favorable neurological outcome (85.7%). Unfavorable outcomes, including neurodevelopmental delay and/or epilepsy, occurred in a minority of cases (14.3%) and exclusively in enterovirus-infected patients. No significant association was found between IVIG administration and neurological outcome. Conclusions: In this real-world pediatric cohort, IVIG use was associated with more severe clinical features rather than improved neurological outcomes, underscoring the need for careful consideration and further investigation in this setting, particularly in the subgroup of infants with enterovirus encephalitis. Full article

Background/Objectives: As a global chromatin organizer, SATB1 is increasingly implicated in neurodevelopmental disorders (NDDs). This study aims to delineate the clinical and molecular characteristics of a novel de novo SATB1 variant in a patient presenting with epilepsy-dominant NDDs phenotypes. Methods: Triggered by the onset of seizures, trio-based whole-exome sequencing (Trio-WES) was performed to identify the genetic etiology. Subsequent sleep electroencephalogram (EEG) and magnetic resonance imaging (MRI) were then conducted to further characterize the patient’s clinical phenotypes. Pathogenicity was assessed through structural modeling and functional characterization. Nonsense-mediated mRNA decay (NMD) status, protein expression profiles, and subcellular localization were determined by reverse-transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence staining. The transcriptional regulatory impacts of the variant were quantified using dual-luciferase reporter system targeting known downstream regulatory elements. Clinical responses to antiepileptic intervention was also monitored. Results: We identified a novel de novo heterozygous pathogenic frameshift variant in SATB1 (NM_002971.5: c.1718_1719insCA; p.Val574Argfs*134) in a patient presenting with early-onset epilepsy, mild intellectual developmental disorder (IDD), speech delay, and dental anomalies. Functional assays demonstrated that the variant-derived transcript escaping NMD, yielding a truncated protein that forms irregular punctate aggregates within nuclei. Dual-luciferase assays revealed significantly increased transcriptional activity, indicating a loss of the protein’s innate transcriptional regulatory capacity. Clinically, treatment with sodium valproate (VPA) successfully stabilized seizures of the patient, markedly reducing both frequency and intensity. Conclusions: The study reports a novel SATB1 frameshift variant that exerts pathogenicity significant functional impairment by disrupting protein localization and transcriptional regulation. These findings expand the genetic spectrum of SATB1-related NDDs and underscore the efficacy of targeted antiepileptic management in genetic diseases. Full article

Background/Objectives: Early-onset epilepsy is associated with a high risk of developing drug-resistant epilepsy (DRE), often manifesting as developmental and epileptic encephalopathies (DEEs). This study aimed to characterize the incidence, syndromes, comorbidities, and etiology of early-onset DRE in Estonia. Methods: This study is a continuation of our earlier nationwide, population-based investigation and included all children with early-onset epilepsy (seizure onset before two years) who developed drug resistance in Estonia between 2013 and 2017 (n = 37). Cases were identified at the country’s only two pediatric neurology departments, ensuring nationwide coverage. Clinical data, electroencephalography, neuroimaging, genetic investigations (chromosomal microarray, single-gene tests, gene panels, exome/genome sequencing), and etiology were analyzed overall and by epilepsy type or syndrome. Results: A total of 37 children with early-onset DRE were included. The incidence of early-onset DRE was 26.5 per 100,000 person-years, peaking in the first year of life (36.1). Drug resistance developed in 43% within six months and 65% within one year. DEEs accounted for 76% of cases, most commonly infantile epileptic spasms syndrome (IESS/West syndrome, 35%). Structural abnormalities were observed in 49% of cases (50% of DEEs), most commonly congenital brain malformations (22%). Pathogenic genetic findings were identified in 41% overall (43% of DEEs). The etiology was established in 78% of children with DRE. Among DEEs, it was found in all Dravet syndrome patients (100%) and 62% of those with IESS/West syndrome. Global developmental delay/intellectual disability occurred in 86%, and motor impairment in 46%. Conclusions: Early-onset DRE, often presenting as DEE, has high incidence, progresses rapidly to drug resistance, and causes substantial comorbidities. Full article

Background/Objectives: Severe neurodevelopmental disorders caused by homozygous ASTN1 variants have recently been reported. The aim of this study is to present the expanded phenotype and prognostic findings through a longitudinal follow-up of a patient with a homozygous ASTN1 variant. Methods: We conducted a 15-year clinical evaluation of a girl who initially presented at 10 years of age. The genetic etiology was investigated using exome sequencing. Results: The patient had a profound intellectual disability, severe expressive language delay, and infantile-onset epilepsy. She also had microcephaly, achieved independent walking at age 7 and had speech limited to only two words at admission. A novel homozygous frameshift variant, c.2096del (p.Cys699Serfs*22), in ASTN1 was identified. Over the follow-up period, her postnatal microcephaly became more pronounced, and she experienced a late relapse into generalized tonic–clonic seizures after a decade-long remission. She remains entirely dependent on caregivers for basic self-care at age 25. Conclusions: ASTN1-related phenotype is associated with a severe neurodevelopmental disease, and the late relapse of seizures after prolonged remission highlights the need for lifelong neurological monitoring and multidisciplinary care. Full article

Mesial temporal lobe epilepsy (TLE) is the most common and severe form of focal epilepsy. This review examines the diverse mechanisms by which the GABAergic system contributes both to seizure generation and to protective processes that limit epileptogenesis and seizure progression in TLE. We focus on findings from established animal models of TLE as well as studies of surgically resected tissue from patients who had undergone therapeutic intervention. Experimental models include sustained electrical stimulation of the perforant path, as well as the kainic acid (KA) and Li-pilocarpine models. Although these paradigms induce status epilepticus (SE) through distinct mechanisms, they ultimately converge on prolonged excitation of hippocampal CA3 pyramidal neurons and interconnected regions of the hippocampus and broader limbic network. In response to epileptic seizures, GABA synthesis is enhanced, as evidenced by the marked upregulation of the GABA-synthesizing enzymes GAD65 and GAD67, along with their ectopic expression in glutamatergic mossy fibers of the hippocampus. Shortly after acute seizures, a transient expression of the embryonic GAD67 splice variant, GAD25, is observed, although its functional significance remains unclear. At the receptor level, animal models of TLE show upregulation of GABA_A receptor subunits α2, α4, β3, and γ2, accompanied by downregulation of α5 and δ subunits, suggesting reduced tonic inhibition. In contrast, hippocampal tissue from patients with TLE exhibits pronounced upregulation of α5 and δ subunits, indicative of enhanced extrasynaptic tonic inhibition. Similarly, whereas GABA_A receptor subunits are mildly downregulated in animal models, they are consistently upregulated across hippocampal subfields in human TLE, pointing toward strengthened GABAergic inhibition. Conversely, genetic variants of GABA_A receptor subunits and autoantibodies targeting these receptors can contribute to the etiology of epilepsy, often with onset in childhood. Moreover, degeneration or functional silencing of specific GABAergic interneuron populations—such as parvalbumin-positive neurons in the subiculum—can induce epilepsy in rodent models and is likewise associated with TLE in humans. Full article

Objective: This study aimed to characterize the population exposure, efficacy, and safety profiles of oxcarbazepine (OXC) in Chinese children with epilepsy using real-world data, define its optimal therapeutic range, and inform individualized therapy. Methods: This single-center retrospective cohort study included pediatric patients (<18 years) who received OXC therapy between September 2021 and August 2024, with follow-up continuing until February 2025. The concentration of the active metabolite 10,11-dihydro-10-hydroxycarbamazepine (MHD) in plasma was monitored. A mixed-effects model identified factors influencing MHD exposure. Logistic regression and Cox proportional hazards models were used to analyze the concentration–efficacy relationship, while Kaplan–Meier and time-to-onset analyses were performed to characterize adverse events. Results: Among 824 included patients (1976 concentration samples), body weight, age, treatment duration, and epilepsy type significantly influenced MHD’s exposure levels. The 12-month overall response rate was higher in monotherapy than add-on therapy (82.9% vs. 60.4%). A plasma MHD concentration ≥ 10 μg/mL was identified as a critical “risk transition point” for treatment failure (PSM-adjusted OR = 2.42, p < 0.001). Multivariate logistic analysis confirmed higher concentrations, specific etiologies, and polytherapy as risk factors for inefficacy. Cox regression further revealed that concentrations ≥ 10 μg/mL and specific etiologies were predictors of reduced long-term treatment persistence. Adverse events occurred in 30.5% of patients; for most, the risk did not change over time. Conclusions: This study tentatively proposed a therapeutic reference range (3.0–20.0 µg/mL) of MHD for Chinese children with epilepsy and identified a concentration ≥ 10 μg/mL as a “risk transition point”. The findings provide practical, evidence-based insights for tailoring OXC therapy and managing potential risks. Full article

Pediatric neurological disorders comprise a highly heterogeneous group of conditions that together represent a substantial global public health burden. Many have a strong genetic basis and are associated with significant morbidity, premature mortality, and long-term disability, with far-reaching consequences for affected children, their families, and healthcare systems worldwide. Clinical heterogeneity is a hallmark of these disorders, as pathogenic variants in the same gene can give rise to diverse phenotypes with variable severity, age at onset, and disease course. In children, ongoing brain development and somatic growth further complicate diagnosis, often leading to nonspecific or atypical presentations that differ from classical adult neurological phenotypes. Advances in genetics and genomics have fundamentally transformed the understanding, diagnosis, and classification of pediatric neurological diseases. The widespread use of high-throughput sequencing, genome-wide association studies, and integrative bioinformatics approaches has enabled the rapid and precise identification of disease-associated genes, even in sporadic and complex conditions, facilitating earlier and more accurate diagnoses and highlighting the role of genetic background and gene–environment interactions in disease pathogenesis. Here we provide an overview of the genetic and genomic landscape of key pediatric neurological disorders with well-characterized molecular etiologies, including neuromuscular disorders, epilepsies, neurodevelopmental disorders, neurodegenerative diseases, and movement disorders. Current knowledge is synthesized with emphasis on clinical presentation, genetic architecture, and genotype–phenotype correlations. Gene-specific management strategies and emerging precision therapies are discussed for selected conditions, underscoring the central role of genetic diagnosis in guiding clinical decision-making and improving outcomes in affected children. Full article

Background/Objectives: Primary metabolic diseases including mitochondrial encephalomyopathies (ME), glycolytic enzymopathies, and disorders of lipid and amino acid metabolism can manifest with severe neurological and neuromuscular symptoms. Conversely, it is increasingly appreciated that primary neurodegenerative diseases can have metabolic etiology and pathophysiology. Pharmacological treatments have limited benefit for these classes of diseases, but dietary therapy is increasingly recognized as a tool for bolstering metabolic processes that can ameliorate neurological symptoms. The ketogenic diet is the best-established example, having long been used as a therapy for epilepsy. Replenishing metabolic intermediates (anaplerosis) especially substrates of the citric acid cycle (CAC) is currently being explored, with ongoing clinical trials of simple metabolic intermediates such as oxaloacetate or NAD+ to treat neurodegenerative diseases. We have shown ketogenic and anaplerotic therapies to be effective in a Drosophila model of ME; however, the full therapeutic potential and role of the CAC in neuronal health is still not well understood. Methods: Here, we have used genetic, behavioral, and dietary approaches to elucidate critical links between the CAC and neurological function. Results: We have found that stimulating the CAC can improve and sustain neurological health in the face of severe metabolic disease, and that its functions include a previously unrecognized role in maintaining normal circadian rhythms, whose disruption is often an early indicator or complicating factor in neurological and neurodegenerative disease. We investigated the hypothesis that the production of GTP by the CAC may be an important mechanistic contributor to the role of the CAC in neurological health and disease, and may underlie its therapeutic potential. Conclusions: Overall, our findings expand our understanding of the role of the CAC in neurological health and disease, support its development as a therapeutic target, and provide a foundation for further studies investigating the intersection between neurological disease and metabolic function. Full article