急性症状性发作对抗NMDA受体脑炎患者预后的影响.pdf

论463脑与神经疾病杂志2 0 2 3年第31卷第8 期急性症状性发作对抗NMDA受体脑炎患者预后的影响王雪刘霄王群【摘要】目的探讨急性症状性发作（ASS）是否为抗N-甲基-D-天冬氨酸（NMDA）受体脑炎功能预后不良的危险因素。方法选择2 0 13年2 月至2 0 2 0 年8 月在首都医科大学附属北京天坛医院神经内科就诊的6 8 例抗NMDA受体脑炎患者进行研究。根据改良Rankin量表（mRS）将患者预后分为两组：预后良好组（mRS2）和预后不良组（mRS2）。采用单因素和多因素Logistic回归分析评估ASS与抗NMDA受体脑炎功能预后的相关性。结果与预后良好组相比，预后不良组ASS（P=0.0 33）、精神行为异常（P=0.0 0 7）、脑脊液寡克隆区带阳性（P=0.032）比例均较高，男性（P=0.045）比例较低，年龄（P=0.010）较大，发病至首次免疫治疗时间（P=0.009）较长。多因素Logistic回归分析显示：经校正年龄、性别、发病至首次免疫治疗时间、精神行为异常、脑脊液寡克隆区带阳性后，ASS比例增加是抗NMDA受体脑炎患者预后不良的独立危险因素（OR=18.023，9 5%CI：1.59 4 2 0 3.7 7 1，P=0.0 19）。结论ASS是抗NMDA受体脑炎的主要表现，对免疫治疗疗效明确，也是脑炎功能预后不良的独立危险因素，临床工作中应注意该症状的早期诊断和治疗，对提高患者的预后有重要意义。【关键词】抗NMDA受体脑炎；癫痫；预后；Logistic模型中图分类号：R512.3文献标识码：A文章编号：10 0 6-351X（2 0 2 3）0 8-0 46 3-0 5Seizures on outcome in patients with anti-NMDA receptor encephalitisWang Xue,Liu Xiao,Wang QunDepartment of Neurology,Beijing Renhe Hospital,Beijing 102600,ChinaCorresponding author:Wang Qun,Email:AbstractJ Objective To investigate whether acute symptomatic seizure(ASS)is a risk factor for poorprognosis of anti-N-methyl-D-aspartic acid(NMDA)receptor encephalitis.Methods 68 patients with anti-NMDAreceptor encephalitis admitted to the Department of Neurology in Beijing Tiantan hospital affiliated to Capital MedicalUniversity from February 2013 to August 2020 were selected.According to the modified Rankin Scale(mRS),thepatients prognosis was divided into two groups:the good prognosis group(mRS 2)and the poor prognosis group(mRS 2).Univariate and multivariate Logistic regression analysis were used to evaluate the correlation between ASSand functional prognosis of anti-NMDA receptor encephalitis.Results Compared with the good prognosis group,thepoor prognosis group had higher proportions of ASS(P=0.033),psychosis and abnormal behavior(P=0.007)andpositive oligoclonal bands in cerebrospinal fluid(P=0.032),lower proportion of male(P=0.045),and older age(P=0.010).The time from onset to first immunotherapy(P=0.009)was longer.Multivariate Logistic regression analysisshowed that increased ASS ratio was an independent risk factor for poor prognosis in patients with anti-NMDA receptorencephalitis after adjusting for age,sex,time from onset to first immunotherapy,psychosis and abnormal behavior,andpositive oligoclonal bands in cerebrospinal fluid(OR=18.023,95%CI:1.594-203.771,P=0.019).Conclusion ASSis the main manifestation of anti-NMDA receptor encephalitis,which has clear effect on immunotherapy,and is also基金项目：“十四五”科技部国家重点研发计划（2 0 2 2 YFC2503800）；首都卫生发展科研专项（首发2 0 2 0-1-2 0 13）；北京市自然科学基金（Z200024、7 2 32 0 45）作者单位：10 2 6 0 0 北京，北京市仁和医院神经内科（王雪）；首都医科大学附属北京天坛医院神经内科（刘霄、王群）通信作者：王群，Email：w a n g q c c mu.e d u.c n464脑与神经疾病杂志2 0 2 3年第31卷第8 期an independent risk factor for poor functional prognosis of encephalitis.Attention should be paid to early diagnosis andtreatment of this symptom for clinicians,which is of great significance for improving the prognosis of patients.Key wordsAnti-NMDA receptor encephalitis;Epilepsy;Prognosis;Logistic models近年来，抗N-甲基-D-天冬氨酸（N-methyl-D-aspartic acid，NM D A）受体脑炎备受关注，是自身免疫性脑炎（autoimmune encephalitis，A E）的最常见类型-4。抗NMDA受体脑炎可发生于任何年龄段，以青年女性多见，临床上以癫痫发作、精神行为异常、记忆力下降为主要表现，多合并卵巢畸胎瘤，且大多数患者（约8 0%）经早期免疫治疗后预后良好5-7 。既往研究表明抗NMDA受体脑炎的预后可能与年龄、运动障碍、免疫治疗时机、疾病严重程度等有关8-13。急性症状性发作（acute symptomaticseizure，A SS）是发生于抗NMDA受体脑炎急性期的痫性发作，且常作为首发症状代14-16。一项研究表明8 1%的抗NMDA受体脑炎患者在活动期可表现为ASS，经长期随访后仍有部分患者表现为ASS，可能与其预后不良相关17 。因此，本研究收集抗NMDA受体脑炎患者的临床资料，并对入组患者进行随访和预后分析，评估早期ASS是否为抗NMDA受体脑炎功能预后不良的影响因素，对提高患者生活质量和预后具有重要意义。资料和方法1.研究对象本研究纳人2 0 13年2 月至2 0 2 0 年8 月在首都医科大学附属北京天坛医院神经内科就诊的6 8 例抗NMDA受体脑炎患者，其中男性35例，女性33例；年龄范围为6 7 8 岁，中位年龄为2 8（四分位间距，2237)岁。纳人标准：抗NMDA受体脑炎的诊断符合2016年Graus与Dalmau标准18 ，确诊需要符合以下三个条件：（a）6 项主要症状中的1项或者多项：精神行为异常或认知功能障碍、言语障碍、癫痫发作、运动障碍/不自主运动、意识水平下降、自主神经功能障碍或者中枢性低通气；（b）抗NMDA受体抗体阳性，以血和脑脊液CBA法抗体阳性为准19 ；（c）合理排除其它病因；继发于抗NMDA受体脑炎的ASS定义8 ：指发生于抗NMDA受体脑炎活动期或急性期背景下的癫痫发作，这种发作是急性症状性或诱发性的，可以在数周或数月内好转，患者在免疫治疗后可实现完全无癫痫发作，抗癫痫发作药物（a n t i-s e i z u r e me d i c a t i o n s，A SM s）最终可以停止使用；具体评估如下：（a）发病时间3个月；（b）由2位神经内科副主任医师同时评估，临床表现和脑电图符合癫痫发作的定义，即临床表现多样，包括感觉障碍、运动障碍、自主神经功能障碍和意识障碍等，同时具有突发突止、短暂性、自限性特点；脑电图提示异常过度同步化放电（尖波、棘波）即癫痫样放电。所有人组患者均已签署知情同意书。排除标准：癫痫发作病史 3个月；存在抗体重叠情况；无法配合完成随访或失访。2.临床资料收集记录患者性别、年龄、吸烟史、饮酒史、发病至首次免疫治疗时间、前驱症状、临床症状、合并肿瘤、脑脊液NMDA受体抗体滴度、脑脊液白细胞计数、脑脊液蛋白浓度、脑脊液寡克隆区带、脑电图、头颅MRI、治疗情况等资料。3.随访及预后评估本研究终末随访时间为2 0 2 1年10 月1日，所有人组患者均完成门诊随访。随访内容包括临床症状的转归情况及后遗症,采用改良Rankin量表（mRS）评估患者的功能预后（预后良好：mRS2，预后不良:mRS 2)8。4.统计学方法采用SPSS24.0统计软件对数据进行分析。对于计量资料，符合正态分布的数据采用（元s）表示，组间比较应用两独立样本t检验，不符合正态分布的数据采用中位数和四分位间距（IQRP25,Ps）表示，两组间比较应用非参数检验Mann-WhitneyU检验。分类变量采用率或百分比描述，组间比较采用x检验或Fisher确切概率法。应用单因素和多因素Logistic回归分析（人=0.0 5，出=0.10）评估ASS是否为抗NMDA受体脑炎功能预后不良的独立危险因素。以P 330(63.83)13(61.90)0.0230.879n(%)前驱症状n（%)18(38.30)11(52.38)1.1770.278ASS n(%)28(59.57)18(85.71)4.5320.033精神行为异常n（%）】2 4（51.0 6）18(85.71)7.3790.007认知功能障碍n（%)】11（2 3.40）7(33.33)0.735 0.391睡眠障碍n（%)12(25.53)7(33.33)0.4390.508运动障碍n（%)14(29.79)6(28.57)0.0100.919意识障碍n（%)11(23.40)3(14.29)0.2860.593言语障碍n（%)9(19.15)2(9.52)0.4090.523自主神经功能障碍6(12.77)4(19.05)0.0930.760n（%)合并畸胎瘤n（%)4(8.51)3(14.29)NA0.668脑脊液NMDA受体抗38(80.85)18(85.71)0.020 0.887体1:32 n(%)脑脊液白细胞计数增38(80.85)18(85.71)0.020 0.887多n（%)脑脊液蛋白定量升高14(29.79)5(23.81)0.2580.612n（%)脑脊液寡克隆区带阳16(34.04)13(61.90)4.6070.032性n(%)脑电图n(%)NA0.599区慢波26(55.32)13(61.90)区痫样放电14(29.79)7(33.33)两者同时存在7(14.89)1(4.76)头颅MRIn（%)NA0.277正常或非特异性改变34(72.34)17(80.95)皮质病变9(19.15)1(4.76)皮质下病变4(8.51)3(14.29)免疫治疗n（%)NA0.492单纯激素冲击13(27.66)3(14.29)单纯丙球4(8.51)2(9.52)激素冲击联合丙球30(63.83)16(76.19)ASMs 治疗n（%)3.9930.136未接受ASMs治疗18(38.30)3(14.29)单药治疗15(31.91)10(47.62)多药治疗14(29.79)8(38.10)注：NA，采用Fisher确切概率法。与预后良好组相比，预后不良组年龄较大，男性比例较低，ASS、精神行为异常、脑脊液寡克隆区带阳性比例均较高，发病至首次免疫治疗时间较长，差异有统计学意义(P3前驱症状0.5720.5301.1660.2801.7720.6275.008ASS1.4040.6914.1300.042 4.071 1.05115.768精神行为异常1.7490.6896.4550.0115.7501.49122.168认知功能障碍0.4920.5770.7280.3931.6360.5285.071睡眠障碍0.3770.5710.4360.509 1.4580.4764.467运动障碍0.059 0.5790.0100.9190.9430.3032.932意识障碍-0.606 0.7120.7240.395 0.5450.1352.204言语障碍-0.811 0.8310.9530.329 0.4440.0872.264自主神经功能障碍0.4750.7070.4510.502 1.6080.4026.428合并畸胎瘤0.5830.8140.5140.4741.7920.3648.829脑脊液NMDA受体0.3510.725 0.2350.6281.4210.3435.890抗体1:32脑脊液白细胞计数0.3510.725 0.2350.6281.4210.3435.890增多脑脊液蛋白定量-0.306 0.6040.2570.612 0.7370.2262.404升高脑脊液寡克隆区带1.1470.5454.4340.0353.1481.0839.157阳性区慢波0.0000.5740.0001.0001.0000.3253.081区痫样放电和慢-1.253 1.1651.1560.2820.2860.0292.803波同时存在皮质病变0.4050.8190.2450.621 1.5000.3017.476皮质下病变-1.504 1.0951.8860.170 0.2220.0261.901单纯丙球0.7731.0770.5150.4732.167 0.26217.892激素冲击联合丙球0.8380.7111.3870.239 2.3110.5739.319单药治疗1.3860.7453.4590.063 4.000 0.92817.239多药治疗1.2320.7652.5940.1073.4290.76515.358注：单因素Logistic回归分析显示，男性、高龄、发病至首次免疫治疗时间、ASS、精神行为异常、脑脊液寡克隆区带阳性是抗NMDA受体脑炎患者预后不良的影响因素（P 45岁的抗NMDA受体脑炎患者研究发现，高龄与患者预后不良密切相关，主要原因与该年龄段通常免疫治疗不及时、容易合并肺癌等肿瘤相关。然而，本研究为单中心、回顾性研究，样本量有限，尚需扩大样本量进一步验证研究结果。综上所述，ASS是抗NMDA受体脑炎的主要表现，对免疫治疗疗效明确，也是脑炎功能预后不良的独立危险因素，临床工作中应注意该症状的早期诊断和治疗，对提高患者的预后有重要意义。然而，未来尚需更多样本、多中心、前瞻性设计及长期随访的研究来验证ASS与抗NMDA受体脑炎功能预后的相关性，旨在提高患者的诊疗和预后利益冲突所有作者均声明不存在利益冲突作者贡献声明王雪：负责数据收集、查阅资料、文章撰写工作；刘霄：负责数据统计工作；王群：负责研究设计、文章审阅及修改工作参考文献1Seery N,Butzkueven H,OBrien TJ,et al.Contemporary advances inanti-NMDAR antibody(Ab)-mediated encephalitisJ.AutoimmunRev,2022,21(4):103057.2Dalmau J,T u z u n E,Wu HY,et al.Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratomaJ.Ann Neurol,2007,61(1):25-36.3Guasp M,Rosa-Justicia M,Munoz-Lopetegi A,et al.Clinicalcharacterisation of patients in the post-acute stage of anti-NMDAreceptor encephalitis:a prospective cohort study and comparison withpatients with schizophrenia spectrum disordersJ.Lancet Neurol,2022,21(10):899-910.4中华医学会神经病学分会神经感染性疾病与脑脊液细胞学学组.中国自身免疫性脑炎诊治专家共识（2 0 2 2 年版）.中华神经科杂志，2 0 2 2,55(9):9 31-9 49.5 Raja P,Shamick B,Nitish LK,et al.Clinical characteristics,treatment and long-term prognosis in patients with anti-NMDAR467脑与神经疾病杂志2023年第31卷第8 期encephalitisJ.Neurol Sci,2021,42(11):4683-4696.6Vill ga F,Pr iu ss H,van Elst LT,et al.Cognitive and psychiatricfeatures of anti-NMDA receptor encephalitisJ.Lancet Neurol,2022,21(10):861-862.7Gong X,Luo R,Liu J,et al.Efficacy and tolerability of intravenousimmunoglobulin versus intravenous methylprednisolone treatment inanti-N-methyl-d-aspartate receptor encephalitisJ.Eur J Neurol,2022,29(4):1117-1127.8Titulaer MJ,McCracken L,Gabilondo I,et al.Treatment andprognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis:an observational cohort studyJ.LancetNeurol,2013,12(2):157-165.9Feng J,Yang M,Cui D,et al.Recurrence of anti-N-Methyl-D-aspartate receptor encephalitis:a cohort study in central ChinaJ.Front Neurol,2022,13:832634.10 Yeshokumar A,Gordon-Lipkin E,Arenivas A,et al.Younger ageat onset is associated with worse long-term behavioral outcomesin anti-NMDA receptor encephalitisJ.Neurol NeuroimmunolNeuroinflamm,2022,9(5):e200013.11 Sun Y,Ren G,Ren J,et al.The prognosis of late-onset anti-N-methyl-D-aspartate receptor encephalitis in ChinaJJ.Acta NeurolScand,2022,145(4):449-455.12 Wu Q,Xie Q,Liu L,et al.Factors influencing prognosis and relapsein patients with anti-N-methyl-D-aspartate receptor encephalitisJ.Mult Scler Relat Disord,2023,74:104697.13 Zeng W,Cao L,Zheng J,et al.Clinical characteristics and long-term prognosis of relapsing anti-N-methyl-D-aspartate receptorencephalitis:a retrospective,multicenter,self-controlled studyJ.Neurol Sci,2021,42(1):199-207.14Steriade C,Britton J,Dale RC,et al.Acute symptomatic seizuressecondary to autoimmune encephalitis and autoimmune-associatedepilepsy:Conceptual definitionsJJ.Epilepsia,2020,61(7):1341-1351.15Chen B,Lopez Chiriboga AS,Sirven JI,et al.Autoimmuneencephalitis-related seizures and epilepsy:diagnostic andtherapeutic approachesJJ.Mayo Clin Proc,2021,96(8):2029-2039.16Woo H,Shim Y,Chae JH,et al.Seizure evolution and outcome inpediatric autoimmune encephalitisJ.Pediatr Neurol,2023,139:35-42.17Liu X,Yan B,Wang R,et al.Seizure outcomes in patients withanti-NMDAR encephalitis:A follow-up studyJ.Epilepsia,2017,58(12):2104-2111.18 Graus F,Titulaer MJ,Balu R,et al.A clinical approach to diagnosisof autoimmune encephalitisJJ.Lancet Neurol,2016,15(4):391-404.19中华医学会神经病学分会神经免疫学组。中枢神经系统自身免疫性疾病相关抗体检测专家共识2 0 2 2 J.中华神经科杂志，2023,56(3):257268.20Scheffer IE,Berkovic S,Capovilla G,et al.ILAE classification of theepilepsies:position paper of the ILAE commission for classificationand terminologyJ.Epilepsia,2017,58(4):512-521.21Fisher RS,Cross JH,French JA,et al.Operational classification ofseizure types by the international league aagainst epilepsy:positionpaper of the ILAE commission for classification and terminologyJ.Epilepsia,2017,58(4):522-530.22 Goi LDS,Altenhofen S,Nabinger DD,et al.Decreased convulsivethreshold and memory loss after anti-NMDAR positive CSF injectionin zebrafishJ.J Neuroimmunol,2021,359:577689.23Moscato EH,Peng X,Jain A,et al.Acute mechanisms underlyingantibody effects in anti-N-methyl-D-aspartate receptorencephalitisJJ.Ann Neurol,2014,76(1):108-119.24Gurrera RJ.Frequency and temporal sequence of clinical featuresin adults with anti-NMDA receptor encephalitis presenting withpsychiatric symptomsJJ.Psychol Med,2019,49(16):2709-2716.25 Liu X,Zhang L,Chen C,et al.Long-term cognitive andneuropsychiatric outcomes in patients with anti-NMDARencephalitisJJ.Acta Neurol Scand,2019,140(6):414-421.26Titulaer MJ,McCracken L,Gabilondo I,et al.Late-onset anti-NMDA receptor encephalitisJJ.Neurology,2013,81(12):1058-1063.（收稿日期：2 0 2 3-0 4-2 7）学习园地杂志社版权页声明：论文授权意见：我们（包括所有作者）同意将本文的使用授权予脑与神经疾病杂志社，并对贵刊以电子期刊（包括网络版光盘版)方式使用本文无异议。未经你刊同意，本文的任何部分不得以任何形式转载使用。本刊已许可中国学术期刊（光盘版）电子杂志社在中国知网及其系列数据库产品中以数字化方式复制、汇编、发行、信息网络传播本刊全文。该社著作权使用费与本刊稿酬一并支付。作者向本刊提交文章发表的行为即视为同意我社上述声明。本刊邮箱投稿：脑与神经疾病杂志社