結節性硬化症

This article summarizes data for 13 investigational treatments for which at least preliminary seizure outcome data in patients with epilepsy were reported at the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices held in Madrid, Spain, on May 3-6, 2026. The treatments reviewed include bexicaserin, a selective 5-hydroxytryptamine (5-HT, serotonin) type 2C (5-HT2C) receptor superagonist investigated as a treatment for developmental and epileptic encephalopathies (DEEs); BMB-101, a selective 5-HT2C receptor agonist investigated for the treatment of absence seizures and DEEs; elsunersen, an antisense oligonucleotide designed for the treatment of early-onset SCN2A-DEE; EPX-100 (clemizole hydrochloride), an antihistamine endowed with agonist activity at 5-HT2A and 5-HT2B receptors, repurposed as a treatment for DEEs; ES-481, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors containing the transmembrane AMPA receptor regulatory protein γ8 (TARP-γ8), under investigation for the treatment of drug-resistant epilepsy; ETX-101, a gene therapy in development for the treatment of SCN1A-positive Dravet syndrome; PrevEp-006 (intranasal seletracetam), a synaptic vesicle glycoprotein 2A (SV2A) ligand under investigation as an acute seizure rescue therapy; radiprodil, a negative allosteric modulator that binds to the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor, in development for the treatment of seizures and other symptoms associated with GRIN-related neurodevelopmental disorder, tuberous sclerosis complex, and focal cortical dysplasia type II; RAP-219, a selective negative allosteric modulator of TARP-γ8, in development for drug-resistant focal epilepsy; relutrigine, a selective disease-state sodium channel modulator investigated as a treatment for SCN2A- and SCN8A-DEE; Staccato Alprazolam, a breath-actuated device that delivers alprazolam to the lungs for rapid seizure termination; vormatrigine, a functionally selective sodium channel modulator in development for the treatment of focal seizures; and zorevunersen, an antisense oligonucleotide engineered to restore endogenous Nav1.1 protein expression, investigated for the treatment of Dravet syndrome. Overall, the evidence reviewed justifies expectations for improved health outcomes for the millions of children and adults with epilepsy who do not fully benefit from existing therapies.

Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3-6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex-related epilepsy; SN-2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease-modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.

BACKGROUND: To identify factors associated with persistent seizures and disability in adults with tuberous sclerosis complex (TSC)-related epilepsy. METHODS: Retrospective single-center cohort study of adults with TSC followed in Paris (2005-2021). Patients without a seizure history were excluded. Clinical, neuroimaging, and genetic data were collected. Seizure freedom was defined as ≥ 12 months without seizures before last follow-up; disability as modified Rankin Scale (mRS) > 2. Univariable and multivariable logistic regression were used; outcomes were compared between TSC1 and TSC2. Adult-onset epilepsy and mosaic cases were described. RESULTS: Of 180 adults with TSC, 148 were included. At last follow-up, 41.2% were seizure-free and 34.5% had mRS > 2. Persistent seizures were associated in univariable analysis with childhood drug-resistant epilepsy (DRE) (OR 4.98; 95% CI 2.43-10.7), status epilepticus (OR 5.25; 95% CI 1.89-18.7), and severe intellectual disability; only childhood DRE remained significant after adjustment. Disability was associated in univariable analysis with onset before 1 year, spasms at onset, status epilepticus, and childhood DRE. In multivariable analysis, spasms at onset (OR 4.78; 95% CI 1.76-13.7) and childhood DRE (OR 4.65; 95% CI 1.66-13.7) remained significant. Adult-onset epilepsy was rare (5.4%) and generally mild. TSC2 mutations were associated with more severe cognitive and organ involvement but did not influence adult seizure persistence. SIGNIFICANCE: Childhood drug-resistant epilepsy was the strongest predictor of persistent adult seizures and disability. TSC2 mutations were linked to a more severe phenotype but does not predict the course of epilepsy in adulthood. These results support early, optimized seizure management.

Retinoid-related orphan receptor gamma (RORγ) is a lineage-defining transcription factor for T helper 17 (Th17) cells and has long been considered selectively expressed within the immune system. However, accumulating evidence has implicated Th17 cells and other RORγ-expressing immune populations in embryonic brain development and central nervous system (CNS) function. Notably, RORγ-Cre-mediated deletion of the tuberous sclerosis complex (TSC) has been reported to cause spontaneous seizures and premature lethality, leading to the conclusion that RORγ-expressing immune cells directly regulate CNS physiology. Using multiple RORγ-based reporter mouse lines, we identified unexpected and widespread neuronal labeling throughout the forebrain and cerebellum. RORγ-Cre: GFPf/- mice exhibited robust GFP expression in neurons. Neuronal recombination was evident prenatally and independently validated using the mT/mG reporter line, indicating transient RORγ expression in embryonic neurons. In contrast, a RORγ-GFP reporter showed no detectable RORγ expression in the postnatal brain, either at baseline or following pilocarpine-induced status epilepticus. These findings demonstrate that RORγ expression is not restricted to the immune lineage and reveal previously unrecognized developmental expression in the embryonic brain. Consequently, seizures observed following RORγ-Cre-mediated deletion of TSC1 are likely to arise from direct neuronal loss of TSC1. Our results call for careful reinterpretation of prior studies attributing CNS phenotypes to RORγ-expressing immune cells based on RORγ-Cre-driven genetic models. This work identifies transient neuronal RORγ expression as a critical confounder in immune-targeted genetic studies and reveals a previously unrecognized embryonic expression of RORγ in neurons that may contribute to neurodevelopment. Our findings further raise the possibility that embryonic neurons represent unintended off-targets when deploying therapeutic strategies involving RORγ ligands.

Objective: To characterize neurodevelopmental disorders in children and adolescents with Tuberous Sclerosis Complex (TSC) and explore associations with epilepsy onset and cortical tuber burden. Methods: This exploratory cross-sectional study included 18 children and adolescents with TSC followed at a tertiary pediatric neurology center in Brazil. Standardized neuropsychological, behavioral, and neuroimaging assessments were performed. Participants were stratified according to epilepsy onset and cortical tuber burden. Results: Epilepsy was present in 94.4% of participants, and pharmacoresistance in 52.9%. Neurodevelopmental disorders were highly prevalent, particularly autism spectrum disorder and attention-deficit/hyperactivity disorder, frequently occurring as comorbidities. Children with earlier epilepsy onset demonstrated exploratory trends toward poorer cognitive outcomes, whereas greater cortical tuber burden showed exploratory trends toward greater behavioral and emotional dysregulation, although these differences did not reach statistical significance. Conclusions: Neurodevelopmental disorders are highly prevalent in pediatric TSC. Exploratory findings suggest that epilepsy characteristics and lesion burden may be related to cognitive and behavioral outcomes. These exploratory findings support systematic multidisciplinary neurodevelopmental monitoring in children with TSC.