Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Epilepsia. 2024 Jun;65(6):1644-1657. doi: 10.1111/epi.17947. Epub 2024 Mar 15.
Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity.
Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset.
Median age at seizure onset was 5.4 (interquartile range = 2-7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort.
Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.
局灶性、病变性癫痫患者的癫痫发作具有可变的年龄特征。在混合性皮质发育不良（FCD）队列中，较大的病灶大小和与感觉运动或默认模式网络（DMN）的重叠与癫痫发作年龄较小有关。在此，我们研究了底沟发育不良（BOSD）患者癫痫发作年龄的决定因素，BOSD 是一种具有高度局灶性致痫性的离散性 FCD 类型。
对 84 例 BOSD 患者（77%手术）进行了研究。记录了人口统计学、组织病理学和遗传学发现。确定了 BOSD 体积以及解剖学、原发性与继发性、颅尾和功能网络位置。使用健康儿童静息状态功能磁共振成像数据中的每个 BOSD 作为感兴趣区进行正常功能连接分析。将变量与癫痫发作年龄进行相关性分析。
癫痫发作的中位年龄为 5.4 岁（四分位间距=2-7.9 岁）。在 50 名接受测试的患者中，22 名患者存在体细胞致病性哺乳动物雷帕霉素靶蛋白（mTOR）途径变异，9 名患者存在种系致病性 mTOR 途径变异。癫痫发作年龄较小与 BOSD 体积较大（p=0.002）、种系致病性变异存在（p=0.04）、DMN 重叠（p=0.04）和与 DMN 的功能连接增加（p<0.05，经假发现率校正）有关。在我们相对较小但同质的队列中，位于感觉运动皮层内和网络内的位置与癫痫发作年龄较小无关。
更大的病灶大小、致病性 mTOR 途径种系变异和 DMN 连接与 FCD 癫痫发作年龄较小有关。我们的研究结果加强了 DMN 连接在 FCD 相关局灶性癫痫发作中的作用，并揭示了遗传病因的新贡献。
