抗癫痫发作药物应用对自身免疫性脑炎后慢性癫痫形成的影响

Effect of application of anti-seizure medications on the development of chronic epilepsy after autoimmune encephalitis

目的探讨并分析自身免疫性脑炎(AE)后慢性癫痫患者抗癫痫发作药物(ASMs)的使用及疗程,以及使用ASMs对此类型癫痫形成的影响,为AE急性癫痫发作期及慢性癫痫期患者ASMs的选择提供相关依据。方法对2013年12月1日至2022年10月31日在南京医科大学附属脑科医院诊断为AE(含抗体阴性的自身免疫性边缘叶脑炎)的患者进行随访,记录其首次癫痫发作日期及免疫治疗1年后慢性癫痫形成情况,分别收集其急性症状性癫痫发作(ASS)期ASMs的启动时间、选用类型及数量与慢性癫痫期ASMs的维持时间、种类及数量(是否联合ASMs等),并通过Logistic回归模型分析AE后慢性癫痫形成的影响因素。结果共入组332例患者,其中32.5%(108/332)为抗体阴性自身免疫性边缘叶脑炎患者;54.8%(182/332)为男性,发病年龄(40.7±19.7)岁;81.0%(269/332)出现ASS,截至最后1次随访57.2%(190/332)形成慢性癫痫。伴有ASS的AE患者均接受了ASMs治疗,其中48.0%(129/269)为单药治疗,52.0%(140/269)为联合治疗;70.3%(189/269)早期给药(癫痫发作24 h内),29.7%(80/269)延迟给药;81.0%(218/269)维持给药(>6个月),19.0%(51/269)非维持给药。在慢性癫痫期,79.5%(151/190)的患者继续使用ASMs,其中37.1%(56/151)接受单药治疗,62.9%(95/151)接受联合治疗;慢性癫痫均来源于AE中发生ASS的患者,其中延迟ASMs治疗组慢性癫痫发生率为81.3%(65/80),显著高于早期给药组的66.1%(125/189),差异有统计学意义(χ2=6.189,P=0.013);而ASMs的种类、是否联合治疗等在慢性癫痫形成组和非慢性癫痫形成组之间差异均无统计学意义。Logistic回归分析结果进一步显示ASMs启动延迟(OR=2.306,95%CI 1.032~6.387,P=0.018)、抗神经元胞内抗体阳性(OR=2.626,95%CI 1.536~9.531,P=0.004,与抗神经元细胞膜抗体相比)、头颅磁共振成像异常(OR=9.883,95%CI 3.608~27.071,P<0.001)、脑脊液蛋白升高(OR=2.874,95%CI 1.115~7.409,P=0.029)、脑电图异常(OR=9.287,95%CI 3.767~22.896,P<0.001)是AE后慢性癫痫形成的独立危险因素。结论AE后慢性癫痫形成与ASS的发生以及ASMs使用延迟有关,而ASMs的种类、是否联合治疗可能与AE后慢性癫痫发生无关。早期ASMs对症治疗,可以减少慢性癫痫的发生;对于经早期规范治疗的伴有ASS的AE患者,可能无需长时程、联合ASMs治疗。

Objective To investigate and analyze the use and duration of anti-seizure medications(ASMs)in patients with chronic epilepsy after autoimmune encephalitis(AE),as well as the effect of ASMs use on the formation of this epilepsy to provide relevant evidence for the choice of ASMs in patients with acute seizure or chronic epilepsy after AE.Methods A retrospective follow-up study was performed on AE patients(including patients with antibody-negative autoimmune limbic encephalitis)diagnosed in the Affiliated Brain Hospital of Nanjing Medical University from December 1,2013 to October 31,2022.The dates of the first seizure onset and the chronic epilepsy formation(defined as 1 year after immunotherapy)were recorded.The initial time,types and numbers of ASMs used in acute symptomatic seizure(ASS)and the maintenance time,types and numbers of ASMs in chronic epilepsy period(the continuation or the combined therapy of ASMs)were collected,respectively.A Logistic regression model was used to analyze multi-influencing factors on the formation of chronic epilepsy after AE.Results A total of 332 patients were enrolled in this study,of whom 32.5%(108/332)with antibody-negative autoimmune limbic encephalitis.In total,54.8%(182/332)of patients were males,and the age of onset was(40.7±19.7)years.Finally,81.0%(269/332)of participants manifested ASS,and 57.2%(190/332)developed chronic epilepsy up to the last follow-up.The follow-up time was 1-8 years,with a median of 2 years.All patients received ASMs treatment during ASS period.Among the ASS patients,48.0%(129/269)were prescribed monotherapy of ASMs,and 52.0%(140/269)were given the combined therapy of ASMs.Of all the patients with ASMs,70.3%(189/269)were given early ASMs treatment(within 24 hours of the seizure onset),and 29.7%(80/269)were given delayed ASMs treatment.Subsequently,81.0%(218/269)of the ASS patients continued the ASMs treatment(>6 months),and 19.0%(51/269)stopped use of ASMs.In the chronic epilepsy stage,79.5%(151/190)of thee epilepsy patients continued ASMs,of whom 37.1%(56/151)were treated with monotherapy,and 62.9%(95/151)were treated with combined therapy.The incidence of chronic epilepsy was 81.3%(65/80)in the delayed ASMs treatment group,higher than the 66.1%(125/189)in the early ASMs treatment group,with statistically significant difference(χ2=6.189,P=0.013).There were no statistically significant differences in the ASMs types and whether combined therapy of ASMs was used between chronic epilepsy group and non-chronic epilepsy group.The Logistic regression model showed that delayed ASMs treatment(OR=2.306,95%CI 1.032-6.387,P=0.018),positive anti-neuronal intracellular antibodies(OR=2.626,95%CI 1.536-9.531,P=0.004,compared with anti-neuronal surface antibodies),abnormal brain magnetic resonance imaging(OR=9.883,95%CI 3.608-27.071,P<0.001),elevated cerebrospinal fluid protein(OR=2.874,95%CI 1.115-7.409,P=0.029),and abnormal electroencephalogram(OR=9.287,95%CI 3.767-22.896,P<0.001)were independent risk factors for chronic epilepsy after AE.Conclusions The development of chronic epilepsy after AE is associated with the occurrence of ASS and the delayed use of ASMs,but the type of ASMs or whether the combined ASMs therapy is used is not associated with the formation of chronic epilepsy after AE.It is concluded that early ASMs treatment for the AE patients with ASS may reduce the incidence of chronic epilepsy.For AE patients with ASS who have undergone early standardized treatment,long-term,combined ASMs treatment may not be necessary.