Efficacy and safety of fenfluramine in Dravet syndrome; A monocentric, observational study focused on initial dose, blood concentration, and reduction of concomitant medications.

Beyond seizure control: Functional and caregiver-reported outcomes of long-term fenfluramine treatment in Dravet syndrome.

Developmental and epileptic encephalopathies (DEEs) are severe, drug-resistant epilepsies associated with major developmental, cognitive, and behavioral burden. Although pharmaceutical-grade cannabidiol (CBD) has shown efficacy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), evidence across the broader DEE spectrum remains fragmented. The aim of this systematic review was to quantify seizure and safety outcomes with pharmaceutical-grade CBD in DEE and explore whether effectiveness differs by syndrome type, age band, dose, clobazam co-medication, or follow-up duration. We conducted a systematic review and meta-analysis of PubMed, Embase, and CENTRAL from inception to 12 October 2025. Eligible studies enrolled individuals of any age with DEE treated with pharmaceutical-grade CBD, as add-on therapy or monotherapy. Mixed-etiology reports were eligible when DEE-specific data could be isolated or obtained from authors. Main outcomes were proportions achieving ≥50% or ≥75% seizure reduction, and seizure freedom; key safety outcomes were also collected. Random-effects generalized linear mixed models were used; small-study effects were explored with funnel plots and Egger's test. Prespecified subgroup analyses were performed by age (pediatric, adult, mixed) and syndrome (DS, LGS, Doose syndrome, CDKL5-related DEE, unspecified DEE, and other defined DEEs); post-hoc exploratory subgroup analyses examined CBD dose, concomitant clobazam use, and follow-up duration. Effect modification was tested using interaction p-values and interpreted with guidance from the Cochrane Handbook and the Instrument to assess the Credibility of Effect Modification in Analyses (ICEMAN). Forty-six studies (5 randomized controlled trials [RCTs] and 41 non-randomized studies; 2592 patients) met the inclusion criteria. The pooled ≥50% responder rate was 49.9% (95%CI 44.9-55.0); ≥75% responders comprised 26.7% (95%CI 22.0-32.0), and seizure freedom was achieved in 5.7% (95%CI 4.0-8.0). Age, syndrome type, dose, concomitant clobazam use, and follow-up duration did not demonstrate a robust or consistent pattern of effect modification across efficacy outcomes. Although some subgroup analyses reached statistical significance, these findings were often imprecise, based on small subgroups with wide confidence intervals, and did not meet ICEMAN credibility criteria. Adverse-event profiles were consistent across studies: somnolence, decreased appetite, diarrhea, fatigue, and behavioral changes predominated, mostly mild to moderate and manageable with dose adjustment. Transaminase elevations occurred mainly with valproate co-therapy and were reversible upon dose reduction or discontinuation. Serious adverse events were uncommon, and withdrawals due to adverse events were infrequent. Pharmaceutical-grade CBD is associated with clinically meaningful seizure reduction in roughly half of patients with DEE, mirroring pivotal RCT results in DS and LGS. Nevertheless, substantial between-study heterogeneity and low-credibility subgroup signals preclude confident attribution of superior efficacy to any specific subgroup. These findings should be interpreted cautiously given the imprecision and heterogeneity of the available evidence. Future research should prioritize well-powered, prospectively phenotyped, and syndromically defined cohorts with standardized outcome measures and individual participant data sharing to elucidate true effect modifiers and optimize patient selection. CRD420251186064.

Responsive Neurostimulation for Treatment of SCN1A-Associated Developmental and Epileptic Encephalopathies.

Psychiatric disorders are more common in people with epilepsy and vice versa psychiatric patients have an increased risk of epilepsy. Psychosocial factors, medication effects, peri-ictal or interictal symptoms play arole as do shared genetic mechanisms, particularly in rare monogenic epilepsy syndromes. This review article exemplary discusses GRIN2A-associated disorders, development-related and epileptic encephalopathies including Dravet syndrome and tuberous sclerosis complex. Neuropsychiatric manifestations, pathophysiological foundations and targeted treatment are summarized. Emphasis is placed on the systematic assessment of psychiatric symptoms and detailed clinical phenotyping to evaluate disease-modifying effects of emerging therapies beyond seizure control. The article highlights the clinical implications, gaps in care and to present open questions and to promote interdisciplinary neurological psychiatric management.

Developmental and epileptic encephalopathies (DEEs) are characterized by drug-resistant seizures and developmental slowing/regression. We examined the efficacy and tolerability of fenfluramine (FFA) in pediatric and adult patients with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and other DEEs. In this multicenter, retrospective, real-world study, FFA treatment was initiated ≥12 months before database closure. Data from patients' charts at 3, 6 and 12 months were recorded in the Spanish Epilepsy Society's DEEs registry. Effectiveness endpoints included seizure reductions of 100%, ≥75%, and ≥50% (responder), median percent seizure reduction, and seizure worsening. Safety endpoints included adverse event (AE) rates. The study included 166 patients (LGS, n = 84; DS, n = 42; other DEE, n = 40; mean age 16.6 ± 12.1 years [111 pediatric, median 10.1 years; 55 adult, median 26.5 years]). Patients had a median of 3 prior failed anti-seizure medications (ASMs). At 12 months, the median FFA dose was 0.49 mg/kg/day, with 77.1% treatment retention. There was a 68.8% median reduction in seizure frequency between baseline and 12 months (p < .001), with significant reductions across all diagnostic groups (LGS, p < .001; DS, p < .001; other DEE, p = .004). The 12-month ≥50% responder rate was 61%, with no statistically significant differences according to age. At 12 months, there were significant reductions in the mean number of concomitant ASMs (p = .004) and the proportion of patients requiring rescue medication (p < .001). Meaningful improvements in Clinical Global Impression scores for cognition (59.3% of patients), behavior (40.9%), sleep (24.3%), and caregiver (44.8%) domains were observed. At 12 months, AEs were reported in 68.1% of patients (mostly mild-to-moderate) and AEs leading to discontinuation in 12%, with no significant differences according to age. FFA was effective, with predictable tolerability, in patients with different DEEs and seizure types, supporting its use as an effective treatment option in pediatric and adult patients with DEEs.

Developmental and epileptic encephalopathies (DEEs) are severe early-onset disorders featuring refractory seizures, abnormal EEGs, and developmental delays. Clinically and etiologically heterogeneous, they include subtypes such as Dravet syndrome and EIMFS. An increasing number are recognized as etiology-specific, with distinct genetic causes corresponding to characteristic phenotypes, highlighting the need for thorough diagnostic evaluation. This study utilized a multidisciplinary diagnostic approach to investigate DEE. In this descriptive case series, the reported novel variants include a PLPBP duplication (c.596dup), an SCN1A insertion (c.3879dup), and an SLC6A1 in-frame deletion (c.943_945del). Bioinformatics and segregation analysis supported their pathogenicity, with each variant linked to a distinct clinical phenotype. The reported novel variants broaden the phenotypic and genotypic spectrum of these disorders and inform clinical management and genetic counseling.

Healthcare resource utilization and persistence in children and adults with Dravet syndrome receiving fenfluramine: a retrospective analysis using United States claims data.

Lost in Sleep Transition: Tangled Sleep and Thermoregulation in Dravet Syndrome.

Heterozygous loss-of-function variants in the gene SCN1A, which encodes the voltage-gated sodium channel (VGSC) pore-forming (α) subunit NaV1.1, lead to a spectrum of neurological disease, including Dravet syndrome. NaV1.1 is prominently expressed at the proximal portion of the axon initial segment (AIS) of fast-spiking γ-aminobutyric acidergic parvalbumin-expressing inhibitory interneurons (PV+INs). In Dravet syndrome (Scn1a+/- haploinsufficient) mice, action potential firing is impaired in PV+INs during postnatal development; however, in mature animals, PV+IN fast-firing frequency has recovered. We used detailed immunohistochemistry and microscopy to probe the mechanism of this functional recovery, investigating potential upregulation of other brain-expressed VGSC subunits at the PV+IN AIS. We found a specific upregulation of NaV1.6 immunofluorescence at the AIS of PV+INs in adult (but not developing) Scn1a+/- mice compared to wild type, with no upregulation of other brain-expressed subunits NaV1.2 or NaV1.3. These results demonstrate one mechanism through which epilepsy-related gene variants reorganize the developing brain and enact endogenous changes that may be at least partially compensatory.

Temporal lobe epilepsy (TLE) is the most common focal epilepsy, yet the genetic mechanisms underlying its development remain incompletely understood. The sodium channel gene SCN1A, known to be involved in several epilepsy syndromes including Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+), has recently been investigated for its potential role in TLE. This systematic review aimed to synthesize evidence on the role of SCN1A variants in the pathogenesis, clinical features, and treatment outcomes of TLE. A comprehensive literature search of PubMed, Scopus, Web of Science, and the Cochrane Library was conducted up to September 2024. Twenty-six eligible studies, including clinical, molecular, and preclinical investigations, were analyzed to assess associations between SCN1A mutations or polymorphisms and TLE phenotypes, with particular focus on genetic, electrophysiological, and therapeutic findings. Clinical studies reported both common polymorphisms (rs3812718, rs7587026) and rare familial variants (M145T, K1270T) in patients with mesial TLE with hippocampal sclerosis (MTLE-HS) and drug resistance. Transcriptomic and electrophysiological analyses of resected hippocampal tissue suggested altered SCN1A expression and possible interneuron dysfunction. Experimental models further indicated that SCN1A dysregulation may influence hippocampal excitability and seizure thresholds, while sodium channel modulators such as carbamazepine were reported to normalize aberrant expression patterns and reduce epileptiform activity. Current evidence suggests that SCN1A may act as a genetic modifier contributing to TLE susceptibility, pharmacoresistance, and clinical heterogeneity in certain contexts. Integration of genetic and molecular data may support improved phenotypic characterization and individualized management in selected patients. However, larger and well-designed studies incorporating multi-omics and longitudinal data are required to clarify the mechanistic and clinical relevance of SCN1A in TLE.

Dravet syndrome (DS) places tremendous burden on caregivers owing to the extent of required assistance and impact on daily living, as well as the risk to the individual with DS of premature mortality from sudden unexpected death in epilepsy and morbidity associated with nonseizure manifestations. This systematic literature review provides an up-to-date characterization of the mental health impacts experienced by caregivers of people with DS. Databases (1974 to August 29, 2024 in Embase; 1946 to August 29, 2024 in MEDLINE) were searched for records containing keywords relevant to mental health in caregivers of people with DS. The study population comprised caregivers of people with DS with any or no intervention and/or comparator (and excluding pharmacologic interventions affecting caregiver burden-related outcomes) and with mental health outcomes that included depression, anxiety, fatigue, sleep quality, stress, mood, and quality of life scales. Database searches returned 519 records; 20 published articles were included. Most common were cross-sectional studies, with populations from Asia, Australia, Central/South America, Europe, and North America. Study sample sizes ranged from seven to 256 caregivers of people with DS; most caregivers were female. Depression and anxiety were reported in 11 and 10 articles, respectively; the prevalence of depression and anxiety among caregivers ranged 5%-66% and 5.2%-80%, respectively. Some studies used instruments to assess mental health outcomes; Beck Depression Inventory-II for depressive symptoms and the Hospital Anxiety and Depression Scale for symptoms of anxiety and depression were reported in three and two articles, respectively. Factors potentially associated with mental health including sleep quality, fatigue, and stress were commonly reported, with poor sleep quality and fatigue often linked to nighttime monitoring of people with DS. Physicians should routinely assess the mental health of caregivers of people with DS; future studies should focus on identifying interventions that ease burden on caregivers.

To review the pharmacology, usage, efficacy, and safety of fenfluramine in treating seizures in pediatric patients with Lennox-Gastaut syndrome or Dravet syndrome. The PubMed database was searched for studies using the search terms "Lennox-Gastaut Syndrome," "Dravet Syndrome," "fenfluramine," and "Fintepla©." Articles were selected based on the following criteria: published in English, published between January 1950 and September 2025, and included clinical relevancy for pharmacology, efficacy, and adverse events. In a phase 3 trial, patients with Lennox-Gastaut syndrome experienced a median 26.5% decrease in frequency of drop seizures when taking the 0.7 mg/kg/d dose. In a 2-part phase 2 trial, 54% of patients with Dravet syndrome concurrently taking stiripentol experienced a >50% decrease in monthly seizures at a dosage of 0.4 mg/kg/d; 72.9% of patients with Dravet syndrome not concurrently taking stiripentol experienced a >50% decrease in monthly seizures at a dosage of 0.7 mg/kg/d. Most common adverse effects in both trials included lethargy, decreased weight, and decreased appetite. Fenfluramine's dual mechanism of action makes it uniquely suited to reduce seizure activity after previous failures in treatment. Some providers are hesitant to prescribe fenfluramine due to its historical association with severe cardiovascular risks. However, proper dosage and titration, as well as adherence to the Risk Evaluation and Mitigation Strategy program can sufficiently mitigate risk for the outcome of seizure reduction and increased quality of life. As seen through the results of multiple clinical trials, fenfluramine can provide significant seizure reduction for Lennox-Gastaut and Dravet patients with treatment-resistant seizures. Risks can be mitigated through adherence to proper programs and schedules, and can provide enough benefits to outweigh risks in patients with particularly resistant epilepsies.

This study evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in children and young adults with Dravet syndrome (DS). SKYLINE (NCT04940624) was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that enrolled patients with DS aged 2-21 years with uncontrolled convulsive seizures (≥4/month despite adequate treatment). Participants received oral soticlestat 300 mg (weight adjusted) or matching placebo twice daily. The total study duration was 16 weeks, comprising 4-week dose titration and 12-week maintenance treatment periods. The primary endpoint was a comparison of monthly convulsive seizure frequency between baseline and the titration/maintenance periods. Key secondary endpoints included several modified Caregiver and Clinical Global Impression of Improvement (GI-I) scales for DS. One hundred forty-four participants were randomized (71 placebo, 73 soticlestat) with a mean (SD) age of 10.3 (5.0) years; 72 (50%) were male, and 117 (81.3%) were receiving ≥3 antiseizure medications. Median change from baseline in convulsive seizure frequency over the full treatment period was -8.64% with placebo (n = 71) and -22.16% with soticlestat (n = 73), a difference of -15.64% (p = .061); in the maintenance treatment period, these changes were -11.99% with placebo and -23.29% with soticlestat, a difference of -14.29% (p = .089). The proportion of participants with ≥50% reduction in convulsive seizures was 9.9% with placebo and 27.4% with soticlestat (nominal p = .008). Soticlestat showed clinically meaningful results in the Caregiver and Clinical GI-I, and Clinical GI-I Seizure Intensity and Duration scales over the 16-week treatment period (all nominal p-values ≤ .004). The most commonly reported treatment-emergent adverse events related to study drug were somnolence, change in seizure presentation, decreased appetite, and insomnia. Although statistical significance was narrowly missed, soticlestat showed a numerical benefit over placebo for convulsive seizure decrease. Clinically meaningful benefits across multiple secondary endpoints were observed. No new safety concerns emerged.

Developmental and epileptic encephalopathies (DEEs) are a group of pediatric seizure syndromes, accompanied by developmental delay or regression and cognitive, psychiatric, and/or behavioral impairment. Seizures can be frequent and are typically refractory to treatment with antiseizure medications. In addition to the high burden of disease endured by patients, DEEs are also associated with negative psychosocial impacts and reduced quality of life for parents and caregivers. Stiripentol is an antiseizure medication approved for the treatment of seizures associated with Dravet syndrome in children 6 months of age and older currently taking clobazam. Early studies in children with drug-resistant seizures provided preliminary evidence of the efficacy and safety of adjunctive stiripentol in seizure syndromes other than Dravet syndrome. These studies have since been followed by additional studies in cohorts of children with different DEEs, as well as studies in children with a specific non-Dravet DEE diagnosis, which have demonstrated association of add-on stiripentol treatment with improvements in seizure control, increased rates of seizure freedom, reductions in rates of status epilepticus, and, in a few studies, improvements in cognitive outcomes. Given stiripentol's favorable safety and tolerability profile, these results suggest a potential role of stiripentol in the treatment of refractory patients with DEE. The purpose of this paper is to review the available evidence of the efficacy and safety of stiripentol in children with non-Dravet DEEs. Practical considerations regarding the use of stiripentol in clinical practice to treat pediatric patients with DEE will also be discussed.

Dravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by mutations in the SCN1A gene, leading to loss of function of the voltage-gated sodium channel Naᵥ1.1. The latter causes early onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. Using a heterozygous Scn1a knockout (Scn1a+/-) mouse model that recapitulates the DS-human phenotype, we examined astrocyte remodeling at landmark disease stages, as defined by video-electroencephalography and behavioral readouts. From initial disease aggravation (postnatal day [PN] 20-35) to long-term stabilization (up to PN90), Scn1a+/- mice showed increased hippocampal and cortical glial fibrillary acidic protein (GFAP) transcript and protein levels compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a+/- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices, was increased but not sustained long-term. Importantly, these disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a+/- mice long-term, along with increased connexin (Cx30 and Cx43) protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a+/- mice. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented posttetanic synaptic potentiation. In DS, astrocytes undergo long-term remodeling independent of tissue damage. We discuss the association between astrocyte network changes and seizures, as well as synaptic and cognitive deficits.

Seizures in children with Dravet syndrome in extreme heat: A qualitative study of parental perspectives.

Early neurovisual development in Dravet syndrome.

To evaluate the efficacy and safety of adjunctive perampanel (PER) in young children with drug-resistant epilepsy (DRE) aged 7-46 months, and to identify predictors of treatment response in real-world clinical practice. We conducted a nonrandomized, open-label, single-arm, self-controlled real-world study at the Children's Hospital of Chongqing Medical University between December 2020 and August 2024. Eighty-seven children with DRE received PER as adjunctive therapy to existing antiseizure medications (ASMs). The primary endpoint was the responder rate (≥ 50% reduction in seizure frequency) at 3, 6, 9, and 12 months. Secondary endpoints included seizure freedom, treatment retention, and treatment-emergent adverse events (TEAEs). Responder rates were 39.5%, 46.9%, 43.2%, and 44.4% at 3, 6, 9, and 12 months, respectively. Responder rates were 50.0% in Dravet syndrome, 50.0% in Lennox-Gastaut syndrome, and 34.8% in infantile epileptic spasms syndrome. Children with genetic etiologies had a 51.7% responder rate, including 60.0% in those with SCN1A variants. Multivariable logistic regression identified perinatal brain injury as an independent predictor of favorable response, while concomitant use of three ASMs predicted poorer outcomes. Treatment retention rates were 87.4%, 69.0%, 59.8%, and 55.2% at 3, 6, 9, and 12 months. TEAEs occurred in 23.0% of patients, most commonly somnolence (11.5%) and irritability/aggressive behavior (9.2%); 4.6% discontinued due to TEAEs. Adjunctive PER demonstrated clinically meaningful efficacy and a favorable safety profile in young children with DRE, supporting its potential role as a broad-spectrum ASM in this age group.

Does genetic diagnosis influence long-term seizure and developmental outcomes in childhood developmental and epileptic encephalopathies? A longitudinal audit.