儿童抗N-甲基-D-天门冬氨酸受体脑炎71例临床分析

Clinical analysis of 71 cases of anti-N-methyl-D-aspartate receptor encephalitis in children

目的探讨儿童抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的临床特点、治疗方案及预后特点。方法收集2014年3月至2017年10月中南大学湘雅医院儿科抗NMDAR脑炎患儿临床资料,回顾性总结分析其临床表现、辅助检查、治疗及预后等特点。共入组71例患儿,其中男33例、女38例,起病年龄为(9±4)岁,最小起病年龄为4月龄。抗NMDAR脑炎的一线免疫治疗方案为短疗程激素(急性期大剂量冲击加口服序贯维持,疗程1个月)和(或)丙种球蛋白方案,一线免疫治疗2周后进行评估,若症状无明显改善,改良Rankin量表(mRS)评分≥3分,给予二线免疫治疗,包括利妥昔单抗和(或)环磷酰胺。所有患儿均进行了随访和预后评估。对抗NMDAR脑炎预后良好组和预后不良组,一线免疫治疗组和一线联合二线免疫治疗组进行组间比较,统计学方法采用t检验、非参数检验(Mann-WhitneyU检验)及χ2检验或Fisher精确概率法。结果抗NMDAR脑炎常见的临床表现依次为精神症状(61例,86%),运动障碍(55例,77%)和惊厥(51例,72%);2例(3%)合并肿瘤;脑电图异常83%(59/71);脑脊液异常39%(27/69);头颅磁共振成像(MRI)检查异常38%(27/71)。71例患儿均接受一线免疫治疗,治疗14 d后40例(56%)患儿症状改善,1例(1%)患儿死亡;30例(42%)患儿接受二线免疫治疗,71例患儿随访时长5.0~41.8个月,中位随访期为19.3个月,预后分析提示49例(69%)患儿完全康复,15例(21%)存在轻度残疾,6例有严重残疾(8%),1例死亡(1%),3例复发(4%)。预后良好组和预后不良组在是否入住儿科重症监护病房(PICU)和意识障碍方面差异均有统计学意义(10/64比5/7,39/64比7/7,P=0.047、0.004);一线免疫治疗组与一线联合二线免疫治疗组在是否入住PICU、意识障碍、睡眠障碍以及初始mRS评分方面差异均有统计学意义[12%(5/41)比33%(10/30),44%(18/41)比93%(28/30),56%(23/41)比90%(27/30),3(1~5)比4(3~5);χ^2=4.645、18.555、9.560,Z=-5.184,P=0.031、<0.01、0.002、<0.01]。结论抗NMDAR脑炎可发生于儿童各年龄段,常见的临床表现依次为精神症状、运动障碍和惊厥;与成人相比,合并肿瘤非常少见;免疫治疗有效,一线免疫治疗失败后14 d如果mRS评分≥3分应给予二线免疫治疗。

Objective To investigate the clinical features,treatment strategies and long term outcomes of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods The data of clinical features,auxiliary examinations,treatments and prognosis in children with anti-NMDAR encephalitis in Xiangya Hospital of Central South University from March 2014 to October 2017 were collected and retrospectively analyzed.A total of 71 patients were enrolled,including 33 males and 38 females.The youngest age of onset was 4 months old,and the age of onset was (9±4) years.The first-line immunotherapy treatment for anti-NMDAR encephalitis was short course corticosteroid (high-dose impulse therapy and oral maintenance therapy for 1 month in acute period) and (or) immunoglobulin.The clinical evaluation was performed 2 weeks after first-line immunotherapy treatment.The second-line immunotherapy treatment,including rituximab and (or) cyclophosphamide,would be started if the symptoms did not improve significantly and the modified Rankin scale (mRS) score ≥3.All patients were followed up and evaluated for prognosis.T-test,Mann-Whitney U,Chi square test and Fisher′s exact probability method were used for comparison between good outcome group and poor outcome group,first-line immunotherapy group and first-line immunotherapy combined with second-line immunotherapy group. Results The more common clinical manifestations were psychiatric symptoms (n=61,86%),dyskinesia (n=55,77%) and convulsions (n=51,72%).Two cases (3%) had tumors.Electroencephalogram (EEG),cerebro-spinal fluid (CSF) and brain magnetic resonance imaging (MRI) studies were abnormal in 83% (59/71),39% (27/69) and 38% (27/71) patients,respectively.For the treatment regimens,all the 71 patients underwent first-line immunotherapy,resulting in improvement within 14 days in 40 cases (56%),and 1 case (1%) died.The rest 30 cases (42%) received second-line immunotherapy.The patients were followed up for 5.0-41.8 months,with a median of 19.3 months.At the last follow-up,49 cases (69%) recovered completely,15 cases (21%) had mild disability,6 cases (8%) had severe disability,1 case (1%) died and 3 cases (4%) had relapse.There were significant differences between the groups with good prognosis and poor prognosis on admission to pediatric intensive care unit (PICU) and consciousness disorder (10/64 vs.5/7,39/64 vs.7/7,P=0.047,0.004).There were significant differences between first-line immunotherapy group and the first-line combined second-line immunotherapy group on admission to PICU,consciousness disorder,sleep disorder and first mRS score (12% (5/41) vs.33% (10/30),44% (18/41) vs.93% (28/30),56% (23/41) vs.90% (27/30),3 (1-5) vs.4 (3-5),respectively;χ^2=4.645,18.555,9.560,Z=5.184,P=0.031,<0.01,0.002,<0.01,respectively). Conclusions Anti-NMDAR encephalitis can occur in all ages of children.The most common clinical manifestations are psychotic symptoms,dyskinesia and convulsions.Paraneoplastic cases are less common in children.Immunotherapy is effective.The second-line immunotherapy should be given after the failure of first-line therapy (mRS score≥3).