SCN8A早发癫痫共患神经发育障碍的影响因素分析:21例随访研究

Factors influencing neurodevelopmental disorders in children with SCN8A-related early-onset epilepsy: a follow-up study of 21 cases

目的分析SCN8A早发癫痫的临床特点,随访患儿的神经发育状况,探讨SCN8A早发癫痫共患神经发育障碍的影响因素。方法回顾性分析2017年1月至2021年2月广州市妇女儿童医疗中心及昆明市儿童医院诊治的SCN8A早发癫痫患儿21例(男13例,女8例;年龄4个月~8岁,平均31.6个月),所有病例经二代测序、Sanger一代验证,根据美国医学遗传学与基因组学学会分类指南评为可能致病或致病。收集所有患儿的起病年龄、发作形式、发作频率、神经发育结局、脑电图、头颅磁共振成像(MRI)资料,随访患儿起病后的药物治疗情况、发作演变或改善、脑电图演变、神经发育状况并分组。采用Fisher′s精确检验分析各因素对患儿神经发育过程及结局的影响,并计算相关系数。结果21例患儿平均起病年龄0~9个月,随访时间4个月~8年,3例死亡。早发婴儿癫痫性脑病16例(76.2%);非脑病的癫痫患儿5例(23.8%),其中1例婴儿良性癫痫。14例(66.7%)为药物难治性癫痫(DRE)。发育正常者仅1例;发育迟滞,但有进步11例;全面发育倒退或停滞9例。起病年龄小(Fisher=9.517,P=0.020,r=0.571)、发作频率高(Fisher=10.512,P=0.003,r=0.572)、脑电图背景(Fisher=10.512,P=0.003,r=0.572)、脑电图放电(Fisher=8.288,P=0.008,r=0.542)、治疗前后脑电图变化(Fisher=10.437,P=0.009,r=0.586)影响癫痫发病后的神经发育过程。神经发育结局仅1例正常,1例轻度发育迟滞,7例中度发育迟滞,3例重度发育迟滞,9例极重度发育迟滞。临床表型(Fisher=10.059,P=0.004,r=0.739)、药物难治(Fisher=13.706,P=0.001,r=0.640)与神经发育结局密切相关。而发作形式、起病时的脑电图表现、突变位置与神经发育障碍的关系不大。结论SCN8A早发癫痫常伴有不同程度的神经发育障碍,癫痫性脑病及药物治疗反应差将导致严重的神经发育障碍。

Objective To explore the influence factors of neurodevelopmental disorders in children with SCN8A-related early-onset epilepsy through analyzing their clinical characteristics and following up their neurodeve-lopmental status.Methods A retrospective analysis was carried out on 21 children(13 males and 8 females,the age ranged from 4 months to 8 years,average 31.6 months)with SCN8A-related early-onset epilepsy treated in Guangzhou Women and Children′s Medical Center and Kunming Children′s Hospital between January 2017 and February 2021.All patients underwent whole-exome sequencing and Sanger sequencing.The pathogenicity was estimated according to the American College of Medical Genetics and Genomics guidelines.The clinical data of all patients were also collected,including the age of onset of the disease,forms of seizures,seizure frequency,neurological development at onset,electroencephalogram(EEG)and brain magnetic resonance imaging(MRI).Besides,the patients were followed up to acquire the effect of sodium channel blockers after the onset of seizures,the process or improvement of neurodeve-lopment,EEG evaluation and neurodevelopmental outcomes.Patients were grouped based on data analysis results.The Fisher′s exact test was conducted to measure the effect of various factors on the neurodevelopmental process and outcome,and corresponding coe-fficients were calculated.Results The average onset age of 21 patients was 0-9 months.The follow-up duration was 4 months-8 years.Three cases died.Sixteen cases(76.2%)had early infantile epileptic encephalopathy(EIEE),5 cases(23.8%)had epilepsy without encephalopathy,and 1 case had benign infantile epilepsy.Fourteen cases(66.7%)belonged to drug resistant epilepsy.Only one child showed normal neurodevelopment.Eleven children showed delayed neurodevelopment,but improvement was observed.Nine children were retrogressed and stagnated in terms of neurodevelopment.Small age at onset(Fisher=9.517,P=0.020,r=0.571),high seizure frequency(Fisher=10.512,P=0.003,r=0.572),EEG background(Fisher=10.512,P=0.003,r=0.572),epileptic discharges(Fisher=8.288,P=0.008,r=0.542),and EEG changes before and after treatment(Fisher=10.437,P=0.009,r=0.586)were important factors affecting the neurodevelopmental process.Neurodevelopmental outcome was normal in only 1 case,1 child belonged to mild mental retardation(MR),7 children belonged to moderate MR,3 children belonged to severe MR,and 9 children belonged to profound MR.Statistical analysis indicated that the clinical phenotype(Fisher=10.059,P=0.004,r=0.739)and drug resistance(Fisher=13.706,P=0.001,r=0.640)were significantly correlated with neurodevelopmental outcomes.However,the forms of seizures,EEG findings at onset and mutation sites were not related to neurodevelopmental disorders.Conclusions Most children with SCN8A-related early-onset epilepsy are accompanied with neurodevelopmental retardation of varying degrees.Epileptic encephalopathy and poor response to drug treatment will lead to severe neurodevelopmental disorders.