2026-08-06 | Beyond seizures in Dravet and Lennox-Gastaut syndromes - An Italian Expert Consensus on Non-Seizure issues and the role of fenfluramine.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies (DEEs) in which disability and family burden are driven by seizures and non-seizure issues (NSIs), including cognition, behavior, sleep, communication, motor function, and adaptive abilities. To develop practical consensus statements on NSIs in DS and LGS, integrating NSI evaluation within a DEE framework and appraising the perceived role of fenfluramine (FFA). An Italian panel of 12 epilepsy specialists spanning pediatric and adult practice developed statements using an Estimate-Talk-Estimate process. Consensus was predefined as ≥ 70% agreement (agree/strongly agree). Eleven final statements were clustered into three macro-areas, with the first two explored in greater depth: (1) the cross-cutting, lifespan impact of NSIs in DS and LGS; (2) the potential for FFA to provide clinically meaningful benefits across selected NSI domains in DS and, more variably, in LGS, with effects not always fully captured by seizure metrics; and (3) the role of other interventions on NSIs and the need for structured assessment tools. Incorporating NSI priorities into shared goal-setting and longitudinal monitoring may improve the clinical relevance of care in DS and LGS. The panel supported an NSI-informed, net-benefit approach to treatment optimization and identified FFA as a relevant option, while recognizing that evidence on NSI outcomes remains heterogeneous and should be strengthened through syndrome-specific, longitudinal assessment.
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2026-08-03 | Changes in effectiveness and safety in patients with Lennox-Gastaut syndrome transitioning from the fenfluramine randomized controlled trial to open-label extension study.
In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine in Lennox-Gastaut syndrome (LGS), patients in fenfluramine treatment groups (0.2 mg/kg/day, 0.7 mg/kg/day) experienced greater reduction from baseline in frequency of seizures associated with a fall versus placebo, which was sustained in the open-label extension (OLE) study (NCT03355209). In this post hoc analysis, trajectories of fenfluramine effectiveness and safety, along with dose changes over time, are described for patients with LGS randomized to placebo in RCT who switched to fenfluramine in OLE (PBO-FFA) and those who received fenfluramine in both RCT/OLE (FFA-FFA). Among patients who completed 12 months in OLE (N = 151), numerical improvements in effectiveness outcomes were seen in the PBO-FFA group (n = 59) after initiating fenfluramine and were similar to those in the FFA-FFA group (n = 92). Regression to the mean was not observed in the PBO-FFA group, suggesting that changes were due to fenfluramine. Incidence of the most commonly reported treatment-emergent adverse events increased in the PBO-FFA group after fenfluramine initiation but decreased in the FFA-FFA group in OLE. These data demonstrate rapid improvement in seizure frequency and global functioning in both groups with continued clinical improvement as the mean fenfluramine dose was increased. These results confirm that sustained fenfluramine treatment is effective and tolerable. PLAIN LANGUAGE SUMMARY: This study assessed the change over time in the number of seizures, overall improvement, and side effects in patients with LGS receiving placebo (no active medicine) or fenfluramine in a 14-week study; all patients later received fenfluramine in the extension study. Overall, the number of seizures (associated with a fall) decreased once patients initially receiving placebo changed to fenfluramine (optimal effect around Month 4 while receiving a higher dose), but as expected, common side effects were reported more frequently once patients began fenfluramine treatment. Patients, parents, and doctors should be aware of this time course to allow fenfluramine enough time to work.
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2026-07-15 | Memantine as Adjunctive Therapy in Lennox–Gastaut Syndrome With Neuropsychiatric Comorbidity: A Case Report
Introduction Lennox–Gastaut Syndrome (LGS) is a severe childhood-onset epileptic encephalopathy characterised by multiple daily seizures of varying semiology, intellectual disability, and a characteristic electroencephalographic pattern. Neuropsychiatric comorbidities - including attention-deficit/hyperactivity disorder (ADHD), autistic spectrum manifestations, and learning difficulties - are well documented in this population. Management is challenging owing to poor seizure response to conventional antiepileptic medications and the complexity introduced by co-occurring psychiatric disorders. Case Presentation We report the case of a patient with LGS severely resistant to antiepileptic therapy and complicated by worsening ADHD symptoms. Following years of trialling multiple antiseizure medications with limited benefit, memantine was initiated alongside other medications and was associated with meaningful improvement in seizure frequency, cognition, and behavioural manifestations. ADHD medications were subsequently reintroduced, were well tolerated, and further improved the patient’s attention and behaviour. Conclusion This case highlights a novel application of memantine - an agent most commonly used in the management of Alzheimer’s disease - and suggests its potential utility as adjunctive therapy for improving both seizure control and neuropsychiatric symptoms in patients with LGS. Further research is warranted to evaluate this therapeutic approach systematically.
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2026-07-11 | Carisbamate treatment of adult and pediatric patients with Lennox-Gastaut syndrome: A phase 1 pharmacokinetic, safety, and tolerability study.
To characterize the single- and multiple-dose pharmacokinetics, safety, and tolerability of carisbamate oral suspension in adult and pediatric patients with Lennox-Gastaut syndrome (LGS). This phase 1, open-label study (NCT03731715) enrolled patients into four age cohorts: Cohort I (C-I), ≥ 18 years; Cohort II (C-II), 12 to < 18 years; Cohort III (C-III), 6 to < 12 years; Cohort IV (C-IV), 2 to < 6 years (C-IV withdrawn due to inability to enroll patients). On Day 1, patients received a single dose of carisbamate: 200 mg (C-I), 140 mg (C-II), 60 mg (C-III), followed by twice-daily multiple-dosing Days 3-17: 100 mg (C-I), 70 mg (C-II), 30 mg (C-III). Pharmacokinetic parameters were determined using noncompartmental analysis. Safety was also assessed. Eighteen patients (C-I: n = 8; C-II: n = 3; C-III: n = 7) were included; 16 (89%) completed the study. Following single doses, carisbamate was rapidly absorbed (tmax, 1-2 h post-dose), with a mean t1/2 of ∼12 h in C-I and C-II and ∼8 h in C-III. After single- and multiple-doses, mean Cmax, AUC0-last, and AUC0-inf increased dose-proportionally. Total carisbamate exposures were comparable across cohorts after dose normalization. Mean (SD) accumulation ratios following multiple dosing were 1.66 (0.15; C-I) and 1.69 (0.06; C-II). Treatment-emergent adverse events (TEAEs) occurred in 66.7% of patients, most commonly nervous system TEAEs (22.2%). One severe TEAE (affective disorder) occurred, and one patient discontinued due to an AE (sedation). No serious TEAEs or deaths occurred. In this small phase 1 PK/safety study, carisbamate appeared to exhibit linear, dose-proportional pharmacokinetic parameters in pediatric and adult LGS patients at doses of 60-200 mg/day and was generally well tolerated during short-term treatment.
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2026-07-05 | Prolonged fenfluramine use in open-label studies of Dravet or Lennox-Gastaut syndromes: Long-term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness.
Long-term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) treated with fenfluramine in an open-label extension (OLE) study after participating in a previous open-label feeder study. Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open-label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day [26 mg/day] without stiripentol or .4 mg/kg/day [17 mg/day] with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long-term safety/tolerability. Global functioning using caregiver- and investigator-reported Clinical Global Impression of Improvement (CGI-I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc. A total of 412 patients enrolled (DS: 265 [64.3%], LGS: 147 [35.7%]); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8-1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171-2800). In this OLE, ≥1 treatment-emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine-related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as "improved or no change" on CGI-I versus this study baseline; subdomain ratings of "improved or no change" were largely consistent with global assessment. In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long-term fenfluramine use in pediatric and adult patients with DS or LGS.
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