Pyridoxine-dependent and other pyridoxine-responsive epilepsies—insights into phenotype overlapping and the long-term outcome in a cohort of 21 children
Ettiologic heterogeneity and phenotype overlapping between PDE and PRE, atypical presentations, and good initial response to pyridoxine regardless of genetic and neuroimaging findings suggest the introduction of pyridoxine in all infants when two ASMs have failed.
Abstract
Aim Evaluation of etiology, phenotype, and long-term outcome, and defining the predictors of outcome in children with pyridoxine-responsive seizures. Methods The study included all children with pyridoxine-responsive seizures treated in our hospital from 2006 to 2025. Serial video electroencephalography, brain MRI, metabolic, genetic analyses, and psychological assessment were done in all cases. All patients were divided into two groups: patients with pyridoxine-dependent epilepsy (PDE) associated with pathogenic variants in ALDH7A1, PNPO, and PLPBP (I group) and patients with pyridoxine-responsive epilepsy (PRE) due to other etiologies (II group). The early-onset seizures were initially treated by antiseizure medication (ASM), and if at least two of the ASMs failed to stop the seizures, pyridoxine was given (100 mg/day, iv). Analyzed parameters were age of seizure onset, period from seizure onset to pyridoxine introduction, brain MRI, type of seizures, etiology, ASM, and predictors for outcome. The outcome included seizure control and neurological development. Mann–Whitney test, Fisher’s exact test, and Firth penalized logistic regression were used to test for statistical significance. Results Twenty-one patients were included: 10 in group I and 11 in group II with various etiologies. Median age at seizure onset in both cohorts was 2 (range 1–11) days. Mann–Whitney U test demonstrated no significant difference between the two groups (p = 0.79). The median time from seizure onset to pyridoxine treatment was 12 days in PDE (range 1–61 days) and 10 days (range 1–98) in PRE, and the difference was not statistically significant (p = 0.65). Developmental delay was present in 6/10 (60%) PDE patients and 5/11 (45.5%) PRE patients. Seizure freedom was attained in 8/10 (80%) PDE and 8/11 (72.7%) PRE patients. MRI abnormalities were seen in 8/10 (80%) PDE and 7/11 (63.6%) PRE patients. The difference in these parameters between the two groups was significant. Discussion Etiologic heterogeneity and phenotype overlapping between PDE and PRE, atypical presentations, and good initial response to pyridoxine regardless of genetic and neuroimaging findings suggest the introduction of pyridoxine in all infants when two ASMs have failed. Despite appropriate pyridoxine treatment, more than half of patients with PDE had developmental delay and resistant seizures, suggesting the complexity of the underlying mechanisms.
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
Pathogenic SV2A gene variants have been reported as causes of epilepsy and are often associated with drug resistance and susceptibility to fever-related seizures. No highly effective treatments have been established for this condition. We report a female patient with a family history of epilepsy who developed generalized seizures associated with fever and bathing from 6 months of age. Despite intensive treatment with multiple anti-seizure medications, the seizures remained refractory. Given the severe drug-resistant epilepsy characterized by fever sensitivity, seizure clustering, and multiple seizure types suggestive of Dravet syndrome, fenfluramine (FFA) was initiated at 2 years and 2 months of age. FFA at 0.2 mg/kg/day resulted in immediate and sustained seizure freedom. Subsequent whole-exome sequencing identified a pathogenic SV2A variant (p.Gly660Arg). This is the first report demonstrating the clinical efficacy of FFA for epilepsy associated with an SV2A variant. We propose that FFA's effectiveness stems from its ability to address two core pathologies of SV2A deficiency: correction of the excitatory/inhibitory imbalance by restoring inhibitory tone through its serotonergic mechanism, and mitigation of neuroinflammation, thereby stabilizing the neuronal network. FFA may represent a promising therapeutic option for patients with SV2A variant-associated epilepsy, particularly those with a fever-sensitive, drug-refractory phenotype; however, further studies with larger case series are needed to confirm its efficacy.
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.
Çisem Duman Kayar, Sinan Akbaş, Fulya Kürekçi et al.· Epileptic disorders· 0 citations
Background and Objectives KCNT1-related epilepsy is an ultra-rare pediatric-onset developmental and epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including sleep-related seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by this disorder. Methods The primary aim of this study was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits). Results Thirty-five participants (n = 20 male, 15 female) were enrolled in this study. The average age at the baseline visit was 76.0 months (s.d. = 75.5). This article presents the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population. Discussion Future work will apply the lessons from this study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies.
Heather R. Adams, Viet Nguyen, L. Seltzer et al.· Neurology: Genetics· 0 citations
A comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders is offered and the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records is highlighted.
Mathilde Gras, Gaëlle Quentin-Romand, N. Chemaly et al.· Brain Communications· 0 citations
BACKGROUND
Convulsive status epilepticus (CSE) is a time-sensitive neurological emergency in which delayed treatment may contribute to pharmacoresistance and poor outcomes. Evidence comparing third-line antiseizure medications in children remains limited. Objective To compare intravenous lacosamide and phenytoin in pediatric refractory CSE and to determine whether treatment timing predicts seizure cessation. Methods This prospective observational cohort study included 100 children aged 1 month-16 years with refractory CSE treated with intravenous lacosamide (n = 46) or phenytoin (n = 54) after failure of benzodiazepines and levetiracetam. The primary objective was to evaluate the effect of treatment delay on seizure cessation. Secondary outcomes included treatment response, electroencephalographic findings, cardiac safety, and predictors of treatment failure. Results Seizure cessation was achieved in 56% of patients and did not differ significantly between lacosamide and phenytoin (60.9% vs. 51.9%, p = 0.365). Treatment delay was the strongest independent predictor of failure; each additional hour from seizure onset to treatment initiation increased the odds of failure by 11% (adjusted OR 1.11, 95% CI 1.03-1.19; p = 0.005). Greater baseline antiseizure medication burden was also independently associated with treatment failure (adjusted OR 2.10, 95% CI 1.05-4.17; p = 0.035). Persistent epileptiform activity on 24-hour EEG was significantly associated with poor outcome (p < 0.001). Both medications were well tolerated. Conclusions Lacosamide and phenytoin demonstrated comparable efficacy and safety. Treatment timing, rather than drug selection, was the principal determinant of seizure cessation, emphasizing the importance of rapid escalation of therapy in pediatric refractory CSE.
Michael Nabil Halim, Rasha Hussein Aly Hussein, O. El-Rashidy et al.· Epilepsy & Behavior· 0 citations