Aug 2026· Epileptic disorders· 0 citations· 38 references
Medicine
TL;DR
It is suggested that ACTH may be associated with sustained electroclinical improvement in selected genetically defined DEEs, and the identified network-level interactions between ion channel-related genes and intracellular signaling pathways provide a potential molecular framework for understanding variability in treatment response.
Abstract
Objective
Adrenocorticotropic hormone (ACTH) is an effective treatment for infantile epileptic spasms syndrome (IESS); however, its mechanism of action remains incompletely understood. This study aimed to evaluate ACTH treatment response at the level of protein-protein interactions (PPIs) in patients with confirmed and presumed monogenic developmental and epileptic encephalopathies (DEEs).
Methods
Medical records of patients with DEEs followed at our center between 2017 and 2025 were retrospectively reviewed. Patients receiving ACTH therapy who harbored pathogenic, likely pathogenic, or variants of uncertain significance (VUS) were included in the study, whereas those with chromosomal abnormalities and insufficient clinical or follow-up data were excluded. Clinical and electroencephalographic (EEG) responses to ACTH therapy were evaluated at the 2-week (day 14) and 3-month follow-up visits. Maintenance of a ≥50% reduction in seizure frequency at 3-month follow-up defined responders. Gene Ontology and PPI network analyses were performed to investigate relationships between genotype and treatment response.
Results
Among the 245 patients with DEEs, 69 had a confirmed genetic etiology, of whom 10 met the inclusion criteria. At 2-week follow-up, 5 of 10 patients (SCN2A, ELOVL4, CACNA1E, TRRAP) achieved seizure freedom, while 3 (PIGT, SCN1A, ZNF526) showed ≥50% reduction. At month 3, 66.6% (6/9) of patients were classified as responders. At 1 year, patients with SCN2A and PIGT variants showed sustained ≥50% seizure reduction, normalization of background EEG activity, and resolution of epileptiform discharges. PPI analysis revealed network interactions between CALM-SCN2A/CACNA1E and PRKAC-SCN1A, whereas the TRRAP-ATF2 interaction showed low confidence, and no reliable interaction was identified for PIGT.
Significance
These findings suggest that ACTH may be associated with sustained electroclinical improvement in selected genetically defined DEEs. The identified network-level interactions between ion channel-related genes and intracellular signaling pathways provide a potential molecular framework for understanding variability in treatment response.
OBJECTIVE
This study aimed to compare the efficacy of adrenocorticotropic hormone (ACTH) and oral prednisolone therapies in children with infantile epileptic spasms syndrome (IESS), utilizing the Burden of Amplitudes and Epileptiform Discharges (BASED) score to assess electrographic severity and the Early Childhood Epilepsy Severity Scale (E-Chess) to evaluate clinical outcomes.
METHODS
This retrospective cross-sectional study included 40 children aged 1 to 16 months with IESS. Children received either ACTH (n = 23) or high-dose oral prednisolone (n = 17). Electroencephalographic severity was assessed before treatment and on day 28 post-treatment using the BASED score. Clinical epilepsy severity was evaluated at one year post-treatment using the E-Chess score.
RESULTS
Both treatment groups showed significant reductions in BASED scores (overall cohort p < 0.001; ACTH group p < 0.001; prednisolone group p = 0.007). However, there was no statistically significant difference between the ACTH and prednisolone groups regarding post-treatment BASED or E-Chess scores. While clinical factors such as gender, age, and etiology were not associated with favorable outcomes, a lower post-treatment BASED score was significantly associated with a better clinical prognosis (p = 0.007). Notably, a higher number of pretreatment anti-seizure medications (ASMs) was a strong predictor of poor clinical outcome (OR: 5.474, 95% CI: 1.849-16.207; p = 0.002).
CONCLUSION
High-dose oral prednisolone and ACTH therapies demonstrated comparable efficacy in reducing electrographic and clinical seizure burden in children with IESS. Improvement in epileptiform activity, as reflected by reductions in the BASED score, is strongly associated with better clinical outcomes. Additionally, a high pretreatment medication burden may serve as an early indicator of a refractory clinical course.
İrem Şahan Şeref, Z. Öztürk, C. Özbaş et al.· Brain & development (Tokyo....· 0 citations
The relationship between electroclinical features and etiology, as well as the genotype-phenotype characterizations and prognosis with genetically determined DEEs, are defined and several novel variants in disease-associated genes are described.
Burcu Yaman, F. Kurekci, Sinan Akbaş et al.· Epileptic disorders· 0 citations
Background and Objectives Enzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unrecognized central nervous system (CNS) involvement. In this international study, involving patients from the Netherlands, Italy, Argentina, Germany, the United Kingdom, and Taiwan, we investigated whether epilepsy should be considered part of the CNS phenotype. Methods We included patients with classic infantile Pompe disease, defined by the presence of hypertrophic cardiomyopathy, symptom onset < 6 months of age, complete acid α-glucosidase (GAA) deficiency, and/or 2 severe variants in the GAA gene, who developed epilepsy. Data on epilepsy characteristics, electroencephalogram (EEG), cognitive testing, serum neurofilament light chain (NfL), and brain magnetic resonance imaging (MRI) were retrospectively collected. Results Seventeen patients from 10 centers were identified. The median follow-up duration was 13.7 years (range 3.3–19). Seven patients had deceased at the time of analysis. The median age at first seizure was 11.5 years (range 2.5–17.5). Seizure semiology was variable: six patients experienced generalized tonic-clonic seizures and 3 focal seizures with impaired consciousness only; 6 had multiple seizure types, and 7 experienced seizures during fever or infection. Seizure frequency varied considerably (in 9 occasionally, 5 monthly, 2 weekly, 1 daily). The most common EEG findings were a slowed background activity and focal epileptiform discharges, not substantially activated by sleep. Levetiracetam was most frequently used as antiseizure medication. Overall, 70% of patients became seizure-free. Serum NfL was elevated in all 6 patients in whom it was measured, and 8 of 10 patients had an intelligence quotient ≤66 at onset of epilepsy. Although brain MRI was not always performed at the age of first seizure, 14 of 15 patients showed white matter abnormalities, which were extensive in 11 of 14 (score ≥7/12). Brain atrophy was present in 9 cases and calcifications in 4. Discussion Our findings suggest a potential increased frequency of seizures in classic infantile Pompe disease in comparison with unaffected children, occurring predominantly after the age of 7, and that epilepsy is part of the CNS phenotype. The risk of seizures should be evaluated during follow-up in long-term survivors with classic infantile Pompe disease.
M. C. Faraguna, Alexander Broomfield, S. Gasperini et al.· Neurology: Genetics· 0 citations
OBJECTIVE
This study was undertaken to assess cenobamate (CNB) effectiveness, tolerability, and dosing in pediatric developmental and epileptic encephalopathies (DEEs), testing prespecified hypotheses on response by syndrome, etiology, electroencephalographic pattern, seizure type, CNB dose (mg/kg/day), and concomitant medication.
METHODS
A retrospective multicenter cohort of children (≤18 years old) with DEEs were treated with CNB at 17 Spanish hospitals. Primary outcomes were retention, response (≥50% reduction), and seizure freedom at 3, 6, and 12 months. Mixed-effects logistic and ordinal models were adjusted for age, syndrome, etiology, seizure type, and concomitant medication.
RESULTS
Among 152 children (median age = 12 years), 27.6% had Lennox-Gastaut syndrome (LGS) and 58.6% unspecified DEE, with a median of 9 prior antiseizure medications. Retention was 88%, 90%, and 93% and responder rates 64%, 73%, and 79% at 3, 6, and 12 months; seizure freedom was 8%, 12%, and 18% (evaluable n = 152, 105, and 57 at 3, 6, and 12 months, respectively). LGS and other DEEs reached identical 12-month responder rates (both 79%), whereas Dravet syndrome showed limited sustained benefit. By etiology, structural cases had the highest 12-month responder rate (93% vs. 68% in nonstructural, p = .04), but no etiology was independently associated with response. By seizure type, responder rates were highest for tonic (81%) and bilateral tonic-clonic (76%) and lowest for absences (54%, adjusted odds ratio [OR] = .43, p = .032). Treatment-emergent seizure worsening occurred in 10.5%. Sodium channel blockers were the main risk factor for adverse events (OR = 2.10); 10.5% discontinued CNB due to adverse events.
SIGNIFICANCE
CNB was associated with sustained effectiveness and acceptable tolerability across pediatric DEEs. Slow weight-based titration and proactive simplification of sodium channel blockers and clobazam may optimize benefit-risk.
Ángel Aledo-Serrano, Adrián Valls-Carbó, E. González-Alguacil et al.· Epilepsia· 0 citations
PURPOSE
To evaluate the effectiveness of sodium channel blockers (SCBs) in infants with early-onset genetic epilepsies presenting with seizures with a predominant tonic component, excluding KCNQ2/3-related epilepsies.
METHODS
We conducted a retrospective multicenter study including infants with genetically confirmed epilepsy, seizure onset before 12 months, and treatment with SCBs. Electroclinical features, genetic data, treatment response, and outcomes were analyzed. Treatment response was defined as seizure freedom, ≥50% reduction, <50% reduction, or worsening.
RESULTS
Thirty-six patients were included, of whom 25 (69%) had self-limited epilepsies and 11 (31%) developmental and epileptic encephalopathies (DEE). SCBs were effective in 23/25 (92%) patients with self-limited epilepsy, all achieving seizure freedom, and partially effective in the remaining two. In DEE, all patients showed partial, but meaningful response. Overall, 23/36 (64%) achieved seizure freedom and 13/36 (36%) had a ≥ 50% reduction in seizure frequency. No seizure worsening or treatment-related adverse events were observed. In contrast, other anti-seizure medications, including valproic acid and levetiracetam, showed limited efficacy and no seizure freedom.
CONCLUSION
SCBs are safe and highly effective in early-onset genetic epilepsies with tonic seizures, particularly in self-limited phenotypes. Recognition of tonic seizure semiology may guide early, phenotype-driven treatment decisions while awaiting genetic results.
E. Carapancea, B. Semal, Nathalie Mercier et al.· Seizure· 0 citations
PURPOSE
Research on pharmacoresistant epilepsy including developmental and epileptic encephalopathies (DEE) predominantly focuses on seizure control and health-related quality of life (HRQoL), while explicit parental goals concerning treatment outcomes as well as perceived resources and support needs remain somewhat underrepresented. We aimed to systematically assess parental priorities, perceived resources, and support needs in families of children with therapy-resistant epilepsies.
METHODS
We conducted an online survey (September-October 2025). Parents ranked 14 symptom domains according to personal relevance, rated opportunities to address these topics in different healthcare settings and evaluated support needs across medical and psychosocial domains. Descriptive and non-parametric statistical analyses were performed, including subgroup comparisons by age and Dravet/SCN1A status.
RESULTS
A total of 224 questionnaires were analyzed (mean child age 12.0 ± 6.3 years; 34 different genetic etiologies, including 40 Dravet/SCN1A patients). Seizures were the top concern when it came to what most affects families' daily lives. However, cognitive development, sleep, and externalizing behavioral problems consistently followed, indicating a multidimensional goal structure beyond seizure control. Subgroup analyses revealed largely similar priorities. Parents reported sufficient time to address medical issues in specialized settings but expressed substantial unmet needs in psychological support for the child, themselves, and the family. Free-text responses highlighted deficits in access to therapies, educational inclusion, care coordination and psychosocial support.
CONCLUSIONS
While seizures remain a central concern, families prioritize developmental, behavioral, sleep-related, and psychosocial domains nearly as strongly. Current care models and literature emphasize HRQoL measurement but rarely capture explicit parental goals. Systematic goal elicitation and genuine interdisciplinary, family-centered care are needed to alleviate the burden on families through appropriate treatment planning.
P. Borusiak, H. Philippi, T. Bast et al.· Epilepsy & Behavior· 0 citations
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