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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2026-07-30 | cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.
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2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
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2026-07-14 | PV interneuron-targeted CRISPRa rescue of SCN1A haploinsufficiency in Dravet syndrome
Dravet syndrome is a severe epileptic encephalopathy caused by SCN1A haploinsufficiency, which leads to reduced Na V 1.1 expression in parvalbumin (PV)-expressing interneurons and disrupted excitatory-inhibitory balance in the brain. We developed an AAV-based CRISPR activation system (AAV9-E2-dCas9-VP64) to selectively upregulate SCN1A from its endogenous locus in PV interneurons. An in vitro saturating guide RNA (gRNA) screen across the human SCN1A promoter identified a lead guide with robust and highly specific engagement of the SCN1A locus. This lead gRNA was validated in human Dravet syndrome model GABAergic neurons, where dose-dependent and specific SCN1A upregulation was observed. Intracerebroventricular (ICV) administration in a mouse model of Dravet syndrome produced dose-dependent improvement in survival as well as reduced susceptibility to hyperthermia-induced seizures and increased Na V 1.1 protein expression, with maintained PV interneuron selectivity and minimal off-target expression. In a study in juvenile cynomolgus macaques, MRI-guided ICV administration of the vector was well tolerated, achieved broad cortical biodistribution, and maintained strong detargeting of peripheral tissues, with substantially lower peripheral dCas9 expression relative to the brain. These results support PV interneuron-selective SCN1A gene modulation via CRISPR activation as a promising therapeutic strategy for Dravet syndrome. AAV9-E2-dCas9-VP64 (RT101) is currently in preclinical development and is being advanced toward evaluation in the clinic.
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2026-07-06 | Perampanel in Chinese patients with Dravet syndrome: Efficacy and tolerability assessed via a multicenter, prospective, real-world observational study.
As a third-generation antiseizure medication, the efficacy of perampanel in treating Dravet syndrome (DS) remains incompletely characterized. This multicenter, prospective, real-world observational study aimed to evaluate the efficacy and long-term tolerability of perampanel as adjunctive therapy in Chinese patients with DS. Patients with unresolved DS were enrolled from four participating hospitals in China between January 2019 and December 2023. All patients received perampanel as add-on therapy. Efficacy and retention rate were evaluated at 3, 6, and 12 months of perampanel treatment. Genetic screening for SCN1A mutations was performed in all enrolled patients. Fifty-six patients were enrolled, of whom 48 (85.71%) harbored SCN1A mutations. The mean treatment duration of perampanel was 25.00 ± 7.65 months, with a mean maximum daily perampanel dose of 3.94 ± 1.19 mg. The retention rates at 6 and 12 months were 69.64% and 64.29%, respectively. After 6 and 12 months of treatment, the ≥50% responder rates were 66.07% and 60.71%, while seizure-freedom rates were 21.43% and 12.50%, respectively. Seizure exacerbation occurred in three patients (5.36%). Adverse events occurred in six patients during treatment (three discontinued treatment), with no new safety concerns identified. Among 30 patients with ≥50% seizure frequency reduction throughout 12-month treatment who carried SCN1A mutations, 33.33% had truncating mutations, 46.67% had missense mutations, 13.33% had splice site mutations, 3.33% had in-frame mutations, and 3.33% had large chromosomal deletions encompassing SCN1A. No significant difference in the ≥50% seizure frequency reduction rate was observed between patients with SCN1A truncating mutations and those with missense mutations. Additionally, treatment response to perampanel did not differ significantly according to the specific mutation regions within the Nav1.1 sodium channel. Perampanel demonstrated favorable efficacy and acceptable long-term tolerability as adjunctive therapy in Chinese patients with DS. The efficacy of perampanel remained consistent regardless of the specific genotype or location of SCN1A mutations.
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