Cerulli Irelli Emanuele, Mazzeo Adolfo, Caraballo Roberto H, Perulli Marco, Moloney Patrick B, Peña-Ceballos Javier, Rubino Marica, Mieszczanek Katarzyna M, Santangelo Andrea, Licchetta Laura, De Giorgis Valentina, Reyes Valenzuela Gabriela, Casellato Susanna, Cesaroni Elisabetta, Operto Francesca F, Domínguez-Carral Jana, Ramírez-Camacho Alia, Ferretti Alessandro, Santangelo Giuseppe, Aledo-Serrano Angel, Rüegger Andrea, Mancardi Maria M, Prato Giulia, Riva Antonella, Bergonzini Luca, Cordelli Duccio M, Bonanni Paolo, Bisulli Francesca, Di Gennaro Giancarlo, Matricardi Sara, Striano Pasquale, Delanty Norman, Marini Carla, Battaglia Domenica, Di Bonaventura Carlo, Ramantani Georgia, Gardella Elena, Orsini Alessandro, Coppola Antonietta
Department of Human Neurosciences, Sapienza University, Rome, Italy.
Department of Neurology, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan", Buenos Aires, Argentina.
Epilepsia. 2025 Jul;66(7):2253-2267. doi: 10.1111/epi.18378. Epub 2025 Mar 24.
This real-world, retrospective, multicenter study aims to investigate the effectiveness of highly purified cannabidiol (CBD) in a large cohort of patients with epilepsy of genetic etiology due to an identified monogenic cause. Additionally, we examine the potential relationship between specific genetic subgroups and treatment response.
This study was conducted across 27 epilepsy centers and included patients with monogenic epileptic disorders (pathogenic or likely pathogenic variants) who were treated with highly purified CBD for at least 3 months.
A total of 266 patients (135 females, 50.8%) with monogenic epilepsies were included with a median age at CBD initiation of 12 years (interquartile range [IQR] = 7-19) and a median follow-up duration of 17 months (IQR = 12-24). Overall, 77 different monogenic epilepsies have been included, with the most common genes being SCN1A (32.3%), TSC2 (13.5%), CDKL5, and MECP2 (4.5% each). The mean seizure reduction at the last follow-up was 38.6%, with 47.5% of patients achieving ≥50% seizure reduction and 7.4% achieving seizure freedom. The Clinical Global Impression scale indicated improvement in 65.8% of patients. The general linear mixed model revealed that a shorter maximum duration of seizure freedom before CBD initiation and a higher degree of intellectual disability were independently associated with lower CBD effectiveness. Conversely, no significant differences in seizure outcome were observed across different epilepsy syndromes (Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex epilepsy, and other developmental and epileptic encephalopathy), between approved indications and off-label use, or between concomitant clobazam use or not.
This study supports CBD as a potential treatment for monogenic epilepsies beyond its licensed indications, demonstrating comparable effectiveness between approved and off-label use and suggesting genetic subgroups with promising treatment responses.
本项真实世界、回顾性、多中心研究旨在调查高纯度大麻二酚（CBD）在一大群因明确单基因病因导致的遗传性癫痫患者中的有效性。此外，我们还研究特定基因亚组与治疗反应之间的潜在关系。
本研究在27个癫痫中心开展，纳入了接受高纯度CBD治疗至少3个月的单基因癫痫障碍患者（致病或可能致病的变异）。
共纳入266例单基因癫痫患者（135例女性，占50.8%），开始使用CBD时的中位年龄为12岁（四分位间距[IQR]=7 - 19岁），中位随访时间为17个月（IQR = 12 - 24个月）。总体而言，纳入了77种不同的单基因癫痫，最常见的基因是SCN1A（32.3%）、TSC2（13.5%）、CDKL5和MECP2（各占4.5%）。最后一次随访时癫痫发作减少的均值为38.6%，47.5%的患者癫痫发作减少≥50%，7.4%的患者实现无癫痫发作。临床总体印象量表显示65.8%的患者有改善。一般线性混合模型显示，开始使用CBD前癫痫发作自由的最长持续时间较短和智力残疾程度较高与CBD疗效较低独立相关。相反，在不同癫痫综合征（伦诺克斯 - 加斯东综合征、德雷维特综合征、结节性硬化症复杂癫痫以及其他发育性和癫痫性脑病）之间、批准适应症与超说明书用药之间、或同时使用氯巴占与否之间，癫痫发作结局均未观察到显著差异。
本研究支持将CBD作为单基因癫痫超出其许可适应症的潜在治疗方法，证明了批准用药与超说明书用药之间具有可比的有效性，并提示了具有良好治疗反应的基因亚组。
