佩南滨作为精准疗法治疗罕见遗传性癫痫。

Perampanel as precision therapy in rare genetic epilepsies.

机构信息

Pediatric Neurology Unit, Wolfson Medical Center, Holon and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Epilepsy Center for Children and Adolescents, Schön Clinic Vogtareuth, Vogtareuth, Germany.

出版信息

Epilepsia. 2023 Apr;64(4):866-874. doi: 10.1111/epi.17530. Epub 2023 Feb 20.

DOI:10.1111/epi.17530

PMID:36734057

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

SIGNIFICANCE

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.

摘要

目的

仑帕奈是一种抗癫痫药物，具有 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂特性，可能对谷氨酸受体过度激活的遗传性癫痫具有靶向作用。丧失γ-氨基丁酸抑制（例如 SCN1A）、过度活跃的兴奋性神经元（例如 SCN2A、SCN8A）和谷氨酸受体变异（例如 GRIN2A）的癫痫具有特殊的研究意义。我们旨在从接受仑帕奈治疗的大型罕见遗传性癫痫队列中收集数据，以检测可能具有高疗效的亚组。

方法

本多中心项目基于 NETRE（罕见性癫痫治疗网络）的框架，该网络由治疗罕见性癫痫的儿科神经科医生组成。收集了接受仑帕奈治疗的遗传性癫痫患者的回顾性数据。疗效评估指标为应答率（减少 50%的发作）和治疗 3 个月后的发作减少百分比。确定了具有高疗效的病因亚组。

结果

共纳入 79 种病因的 137 例患者，年龄 2 个月至 61 岁（平均 15.48±9.9 岁）。平均剂量为 6.45±2.47mg，治疗期为 2.0±1.78 年（1.5 个月至 8 年）。62 例患者（44.9%）接受治疗时间超过 2 年。98 例（71%）患者为应答者，93 例（67.4%）选择继续治疗。发作频率的平均减少率为 56.61%±34.36%。60 例（43.5%）患者的发作频率减少超过 75%，其中 38 例（27.5%）发作频率减少超过 90%。以下基因显示出较高的治疗效果：SCN1A、GNAO1、PIGA、PCDH19、SYNGAP1、POLG1、POLG2 和 NEU1。17 例因 SCN1A 致病性变异导致的 Dravet 综合征患者中有 11 例（64.7%）对仑帕奈治疗有反应；其中 35.3%的患者发作减少超过 90%。其他病因中发作减少超过 90%的是 GNAO1 和 PIGA。14 例患者有睡眠中持续棘慢波脑电图模式，6 例患者的仑帕奈降低了癫痫样活动。