目标:Perampanel,一种具有AMPA受体拮抗剂特性的抗癫痫药物,可能在具有压倒性谷氨酸受体激活的遗传性癫痫中具有靶向作用。特殊兴趣持有癫痫与GABA抑制丧失(例如SCN1A),过度活跃的兴奋性神经元(例如SCN2A,SCN8A),和谷氨酸受体的变体(例如GRIN2A)。我们的目的是收集大量罕见的遗传性癫痫患者的数据,检测可能具有高功效的亚组。
方法:基于NETRE(罕见癫痫治疗网络)框架的多中心项目,治疗罕见癫痫的儿科神经科医师网。收集了接受perampanel治疗的遗传性癫痫患者的回顾性数据。结果指标是应答率(癫痫发作减少50%),治疗3个月后癫痫发作减少的百分比。确定了具有高疗效的病因亚组。
结果:137名患者,有79种不同的病因,纳入年龄为2个月-61岁(平均15.48±9.9).平均剂量为6.45±2.47mg,治疗期为2.0±1.78年(1.5个月-8年)。62例患者(44.9%)治疗时间>2年。98名患者(71%)是响应者,93人(67.4%)选择继续治疗.癫痫发作频率平均降低56.61±34.36%。60名患者(43.5%)癫痫发作频率持续减少75%以上,包括38例(27.5%),癫痫发作频率减少>90%。以下基因显示出高治疗效果:SCN1A,GNAO1,PIGA,PCDH19、SYNGAP1、POLG1、POLG2、NEU1。11/17(64.7%)的SCN1A患者,其中35.3%的癫痫发作减少了90%以上。癫痫发作减少90%以上的其他病因是GNAO1和PIGA。14例患者具有CSWSEEG模式,在6例受试者中,perampanel降低了癫痫样活动。
结论:Perampanel在罕见遗传性癫痫患者中表现出高安全性和有效性,尤其是在SCN1A中,GNAO1,PIGA,PCDH19,SYNGAP1,CDKL5,NEU1和POLG,提示与谷氨酸传递相关的靶向效应。
Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.
This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.
A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.
Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.