限局性皮質異形成

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.

Focal cortical dysplasias (FCDs) are a major cause of drug-resistant epilepsy, yet their molecular and pathological complexity has limited the development of effective antiseizure medications. Here, we performed single-nucleus RNA sequencing on 49 human neocortical specimens spanning FCDI-III. We identified prominent transcriptional alterations in non-neuronal populations, particularly astrocytes and vascular cells, with signatures suggestive of endothelial and smooth muscle cell dysfunction. In contrast, neuronal populations exhibited additional subtype-specific heterogeneity. Notably, vascular-associated signatures were consistently observed across FCD subtypes, suggesting a convergent feature of diseased cortex. To systematically explore candidate interventions, we integrated cell-type-resolved transcriptional signatures with the Connectivity Map to prioritize compounds from ~40,000 perturbagens. This analysis yielded 20 candidates, among which four compounds (Betamethasone, Lodamin, Valproxam, and Licochalcone A) reduced seizure-like activity in vivo, as assessed by behavioral assays and local field potential recordings. These effects were further evaluated in an mTOR-driven FCD model. Collectively, our findings establish a transcriptome-guided framework for linking multicellular disease signatures to candidate therapeutic strategies in refractory epilepsy.

OBJECTIVE: Epileptic spasms (ES) in children carry a high risk of neurodevelopmental delay, yet predictors of long-term surgical outcome remain incompletely defined. This study aimed to evaluate seizure outcomes following epilepsy surgery and to identify independent prognostic factors for postoperative recurrence. METHODS: This retrospective cohort study included 73 patients (47 males, 64%; median age at surgery: 37 months, IQR: 20-55.5) with drug-resistant ES who underwent resective or ablative surgery at Guangdong Sanjiu Brain Hospital in China between January 2015 and September 2024, with regular follow-up at least 12 months after epilepsy surgery. Independent predictors of recurrence were identified using multivariate Cox proportional hazards regression, and Kaplan-Meier analysis was performed to compare seizure-free survival stratified by seizure duration (SD) and residual lesion status. RESULTS: Seizure-free rates were 75.3% at 1 year and 55.1% at last follow-up. Mean follow-up was 61.36 ± 26.10 months (range: 12-132). Among malformation of cortical development (MCD) subtypes, focal cortical dysplasia (FCD) type II demonstrated the highest 5-year seizure-free rate (100%), whereas mild MCD (m-MCD) showed the lowest (33.3%; p = 0.039). On multivariate Cox analysis, residual lesion on postoperative MRI was the strongest independent predictor of recurrence (HR = 5.13; 95% CI: 2.28-11.51; p < 0.001), followed by SD exceeding 36 months (HR = 2.49; 95% CI: 1.17-5.29; p = 0.018). Kaplan-Meier analysis confirmed a twofold difference in 5-year seizure-free survival between patients with duration ≤36 versus >36 months (73% vs. 36%; log-rank p = 0.00069), and significantly better seizure-free survival in patients without residual lesions (log-rank p < 0.0001). SIGNIFICANCE: Complete lesion resection and early surgical intervention (SD ≤36 months) are independently associated with favorable long-term seizure outcomes in children with drug-resistant ES. Pathological subtype, particularly FCD type II, further refines prognostic stratification. These findings support prompt surgical referral and underscore the importance of achieving complete lesion removal to optimize postoperative seizure control. PLAIN LANGUAGE SUMMARY: Some children develop a severe form of epilepsy called epileptic spasms that cannot be controlled with medication. In this study of 73 children who had brain surgery for this condition, more than half remained seizure-free after 5 years. Children who had surgery earlier-before seizures had continued for 3 years-and those in whom the entire abnormal brain tissue was removed did significantly better in the long run. These findings suggest that referring children for surgery sooner rather than later can meaningfully improve their chances of living seizure-free.

OBJECTIVES: Hypothalamic hamartomas (HHs) are rare, non-neoplastic malformations associated with gelastic seizures and, less frequently, precocius puberty. Recent classifications have linked HH subtypes with clinical features, and emerging evidence suggests that HH may co-occur with other brain abnormalities. This study investigates the imaging characteristics of HH, the prevalence of concurrent structural abnormalities, and metabolic alterations using magnetic resonance spectroscopy (MRS). METHODS: We retrospectively analyzed MRI and MRS findings in 18 patients with HH (mean age, 9.24 ± 8 years). Lesions were classified per Li et al, assessing morphology, signal characteristics, associated abnormalities, and MRS-derived choline-to-N-acetylaspartate (Cho/NAA) ratios. RESULTS: Fourteen patients (77.8%) had gelastic seizures, while 4 had non-seizure-related HH, including precocious puberty (n = 1) and NF1 (n = 3). HH lesions were isointense on T1-weighted MRI; 88.9% were isointense and 11.1% hyperintense on T2. Concurrent brain abnormalities were found in 50%, including focal cortical dysplasia, amygdala enlargement, and corpus callosum hypoplasia. MRS in 3 cases showed elevated Cho/NAA ratios. CONCLUSION: Hypothalamic hamartoma is frequently associated with structural abnormalities and metabolic alterations, particularly in seizure-related cases. These findings support the broader spectrum of HH-related brain abnormalities and highlight the need for further research. ADVANCES IN KNOWLEDGE: This study provides new insights into the imaging and metabolic characteristics of HH, highlighting the significant association between HH subtypes, brain abnormalities, and metabolic alterations. Additionally, it introduces the elevated choline-to-N-acetylaspartate (Cho/NAA) ratio as a potential biomarker, contributing to a deeper understanding of the underlying pathophysiology and diagnostic approach for HH.