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抗NMDA受体脑炎误诊分析并文献复习

2017-03-06李晨霞马康平李云林

临床误诊误治 2017年7期
关键词:畸胎瘤脑炎脑脊液

李晨霞,马康平,梁 乐,倪 俊,章 颖,付 静,李云林

抗NMDA受体脑炎误诊分析并文献复习

李晨霞,马康平,梁 乐,倪 俊,章 颖,付 静,李云林

目的 探讨抗N-甲基-D-天冬氨酸(N-methyl-D-asparate, NMDA)受体脑炎的临床特点,提高该病诊治水平。方法 对我院诊治的抗NMDA受体脑炎1例误诊资料进行回顾性分析,并复习相关文献。结果 患者为青年女性,因发作性意识丧失伴肢体抽动6 d入院。外院按癫痫发作处理效果不佳,转我院后视频脑电图检查示间隙期双额颞区慢波,头颅MRI检查未见明显异常,初步诊断癫痫?予左乙拉西坦口服。病程中出现发热、精神行为异常、性格改变,伴幻觉及口面部不自主运动。盆腔影像学检查提示卵巢畸胎瘤,高度怀疑抗NMDA受体脑炎,行血液及脑脊液抗NMDA受体抗体检测阳性,明确诊断抗NMDA受体脑炎。在免疫治疗的基础上行手术切除畸胎瘤后,患者神经精神症状消失,痊愈出院。结论 当年轻卵巢畸胎瘤患者出现不明原因的精神症状伴意识和运动障碍时,应高度怀疑抗NMDA受体脑炎,行血液及脑脊液抗NMDA受体抗体检测可确诊。

抗N-甲基-D-门天冬氨酸受体脑炎;误诊;癫痫;畸胎瘤

抗N-甲基-D-天冬氨酸(N-methyl-D-asparate, NMDA)受体脑炎是近年来新发现的一类副肿瘤性大脑边缘叶脑炎,卵巢畸胎瘤是目前唯一与其发生明确相关的肿瘤[1]。因抗NMDA受体脑炎以神经精神症状为主,临床表现差异性大,易误诊误治[2]。现将我院诊治的1例误诊病例资料结合相关文献报告如下。

1 临床资料

女,21岁。因发作性意识丧失伴肢体抽动6 d入院。6 d前患者于劳累后出现发作性意识不清,首先表现为突发舌头麻木、言语不清、口唇向右歪斜、头向右偏,随即意识丧失、四肢强直抽动,伴面色青紫及口吐白沫,20余分钟后意识转清,此后每日发作1或2次。2 d前就诊于外院,诊断为癫痫发作(具体检查不详),予苯巴比妥肌内注射后仍有发作。为进一步诊治转我院功能神经科。患者姑姑有癫痫病史。查体:体温36.5℃,脉搏80/min,呼吸18/min,血压100/60 mmHg。心肺及腹部查体未见异常。意识清楚,言语流利,四肢肌力正常,肌张力正常,腱反射对称,病理征未引出。视频脑电图检查示:间隙期双额颞区慢波,未捕捉到癫痫发作波形。头颅MRI检查未见明显异常。初步诊断:发作性疾病,癫痫可能性大。予左乙拉西坦500 mg每日2次口服,症状未再出现。入院第5日患者出现性格情绪改变,言语增多,夜间哭闹、紧张、畏光,每次发作持续数十分钟,给予苯巴比妥和地西泮等药物治疗效果不佳。第6日出现发热。查体:体温38.7℃,反应迟钝,言语缓慢,近期记忆力减退,余未见明显异常。上级医师查房认为癫痫诊断较为明确,需进一步明确癫痫病因。需鉴别诊断:①病毒性脑炎:患者劳累后急性发病,发热,癫痫发作并性格改变,行腰椎穿刺(腰穿)脑脊液检查,同时予抗病毒与糖皮质激素治疗。②副肿瘤导致的边缘性脑炎:患者为青年女性,急性起病,表现为癫痫发作和性格改变,近期记忆力减退,脑电图提示额颞叶为主的高波幅慢波,提示病变累及边缘叶,应行腹部及妇科B超,复查头颅MRI,查肿瘤标志物。

入院第8日患者精神症状加重,表现为恐惧感、哭闹、谵语、刻板重复语言、幻觉及答非所问,加用劳拉西泮0.5 mg每晚1次、奥氮平5 mg每日1次口服,精神症状却持续加重,出现明显幻觉、妄想及口面部不自主运动,间断给予咪达唑仑静脉泵入后处于镇静状态。行腰穿脑脊液检查示:压力正常,白细胞3×106/L,总细胞3×106/L,葡萄糖3.94 mmol/L,蛋白171 mmol/L,氯125 mmol/L;脑脊液涂片查新型隐球菌、抗酸杆菌、脑膜炎双球菌均阴性;脑脊液培养无细菌生长。妇科B超检查示:右卵巢内见1.7 cm×1.8 cm×1.2 cm不均匀回声团,内未见明显血流信号;左卵巢回声未见异常。提示右卵巢畸胎瘤可能。

2 结果

根据上述检查结果临床考虑卵巢畸胎瘤合并抗NMDA受体脑炎,予地塞米松及人免疫球蛋白治疗,同时查肿瘤标志物:癌胚抗原4.16 μg/L(正常参考值<3.4 μg/L),甲胎蛋白0.746 U/ml(正常参考值<5.8 U/ml),鳞状细胞相关抗原0.8 μg/L(正常参考值<1.5 μg/L),癌抗原(CA)199<0.6 U/ml,CA125 17.24 U/ml,细胞角蛋白19片段21-1 1.54 μg/L(正常参考值<3.3 μg/L),神经元特异性烯醇化酶10.72 μg/L (正常参考值<13.6 μg/L);脑脊液抗NMDA受体抗体阳性,血液抗NMDA受体抗体阳性。入院第15日明确诊断为抗NMDA受体脑炎、卵巢畸胎瘤,经妇产科会诊,在全麻下行腹腔镜探查术。术中见双侧卵巢外观基本正常,切开右卵巢表面正常组织,顺利找到瘤体,完整剥除右卵巢肿物,直径约2.2 cm。术后病理诊断:右侧卵巢成熟性囊性畸胎瘤。术后患者症状缓解,继续予地塞米松和人免疫球蛋白治疗2个疗程,患者精神症状明显改善,3周后精神症状消失,复查脑电图示双侧额颞区少量低中波幅、散发或连续性慢波,脑脊液抗NMDA受体抗体弱阳性,血液抗NMDA受体抗体阴性。术后1个月患者痊愈出院,随访1年患者症状及脑电图均未见明显异常。

3 讨论

3.1 发病机制 抗NMDA受体脑炎是近几年发现的一种中枢神经系统自身免疫性疾病,人群发病率尚无统计数据,目前资料多为个案或小规模病例报道。随着对本病病因研究的深入,发现肿瘤尤其是卵巢畸胎瘤是成年女性抗NMDA受体脑炎患者的主要病因,但儿童患者肿瘤检出率远低于成年患者,12岁以下女性患者仅6%合并肿瘤(其中94%为卵巢畸胎瘤),未发现18岁以下男性患者合并肿瘤[1]。而性别、基因、种族等遗传因素在抗NMDA受体脑炎发病中所起的作用不容忽视[3-4]。另外,在儿童患者中病毒感染是更常见的诱发因素,尤其是单纯疱疹病毒感染。上述因素诱发抗NMDA受体抗体的产生,及由此引发的抗原、抗体反应是抗NMDA受体脑炎的病理基础[5],这种免疫反应造成中枢神经可逆性功能减低,从而出现精神行为异常、自主神经功能紊乱等表现。

3.2 临床特点 抗NMDA受体脑炎典型病程分为5期[3,6],即前驱期、神经精神症状期、无反应期、运动障碍期和恢复期,但各期间无严格分界[7]。国际最大的多中心随访研究表明,典型的抗NMDA受体脑炎常呈综合征样表现[8-9],总体可归为认知障碍、精神行为异常、记忆缺陷、语言障碍、意识障碍、运动障碍(运动减少与不自主运动)、癫痫发作及其他症状,其中以认知障碍、精神行为异常、运动障碍、癫痫发作最为常见[10]。本例发病初期劳累后很快出现意识障碍、癫痫发作,并伴有幻觉及口面部不自主运动,发热、近期记忆力下降及精神行为异常,这与抗NMDA受体脑炎的临床特点一致。

3.3 诊断方法 抗NMDA受体脑炎尚无统一的诊断标准,目前多数学者倾向采用以下诊断标准:对于年轻女性患者,当出现不明原因的精神症状伴癫痫发作、记忆丧失、意识和运动障碍甚至出现中枢性通气障碍,特别是伴有卵巢畸胎瘤者,脑脊液和(或)血液抗NMDA受体抗体阳性,即可明确诊断[11-13]。有助于本病诊断的医技检查方法有:①脑脊液抗NMDA受体抗体检测:此为确诊依据,阳性率可达100%[14-15]。②血液学检查:85%的患者血清抗NMDA受体抗体可为阳性[14-15]。③头颅影像学检查:可完全正常,亦可随病情发展在大脑皮质、边缘系统、基底核区、小脑、脑干等处出现异常改变[16]。④脑电图检查:可无异常,亦可出现广泛棘波、尖波、棘慢波等。Schmitt等[17]认为,视异常“δ刷”为本病特征性脑电图表现,但出现原因不清。⑤胸腹部超声和CT检查:可用于查找肿瘤,以女性卵巢畸胎瘤最常见。本例头颅MRI表现无特异性改变,脑电图可见额颞区慢波,但无特异性,发病早期脑脊液中蛋白和白细胞轻度升高,最终经超声检查发现右侧卵巢畸胎瘤,提示抗NMDA受体脑炎可能,进一步行血液及脑脊液抗NMDA受体抗体检测而明确诊断。

3.4 误诊原因分析 ①临床表现无特异性:本例起病急,有抽搐、发热、精神行为异常等表现,故早期误诊为癫痫,这也是本病最常见的误诊疾病[18]。②对本病缺乏认识:本病早期表现的非特异性和多样性特点,常使鉴别诊断困难。有学者报道北京协和医院诊断的30例抗NMDA受体脑炎,首诊均未考虑本病,29例反复辗转于各级医院,主要误诊原因是对本病缺乏认识[18]。③早期未行特异性检查:目前大多医院尚未开展脑脊液或血液抗NMDA受体抗体检测,且神经受体脑炎系列抗体检查亦非脑脊液常规检查项目,故大多数患者未能在病程早期行抗NMDA受体脑炎特异性检查,导致误诊。

3.5 治疗及预后 抗NMDA受体脑炎治疗方法包括肿瘤切除和免疫治疗[8,14,19]。一线免疫治疗包括糖皮质激素、丙种球蛋白及血浆置换;二线免疫治疗主要为环磷酰胺、利妥昔单抗等免疫抑制剂药物治疗。Titulae等[8]研究显示,472例患者经一线免疫治疗或肿瘤切除,其中251例4周内症状改善,一线治疗未改善的221例接受二线免疫治疗后症状亦有所改善。故在明确诊断后,一线免疫治疗后症状无明显改善者,可行二线免疫治疗[14,20]。此病及时确诊,预后大多较好[21]。本例入院15 d明确诊断后,行肿瘤切除术,共接受3个疗程丙种球蛋白冲击治疗,预后良好。

总之,抗NMDA受体脑炎好发于青年女性,主要表现为癫痫、精神症状、意识障碍、口-面-舌部异常活动等,易误诊,确诊需行脑脊液及血液抗NMDA受体抗体检测。本病一旦确诊,应立即使用足量、足疗程的免疫球蛋白和糖皮质激素治疗,对于发现肿瘤者宜及早行肿瘤切除术,以改善预后。

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Misdiagnosis Analysis of a Patient with Anti-N-methyl-D-Aspartate Receptor Encephalitis and Literature Review

LI Chen-xia1a, MA Kang-ping2, LIANG Le1b, NI Jun1a, ZHANG Ying1a, FU Jing1b, LI Yun-lin2

(a. Department of Gynaecology and Obstetrics, b. Department of Pathology, 1. Haidian Hospital of Beijing, Beijing 100080, China; 2. Department of Neurosurgery, Children Hospital Affiliated to Capital Institute of Pediatrics, Beijing 100203, China)

Objective To investigate clinical features of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis in order to improve the diagnosis and treatment. Methods Clinical data one of a patient with NMDA receptor encephalitis was retrospectively analyzed, and related literature was also reviewed. Results This young female was admitted for intermittent loss of consciousness associated by limb vellicating for 6 days, and the effect for epileptic seizure was poor in other hospital. After transferring to our hospital, electroencephalography (EEG) examination showed that bilateral foreheads temporal intermittent slow waveform, and no obvious abnormalities was found by brain magnetic resonance imaging (MRI) examination, so the primary diagnosis was epilepsy. Levetiracetam was given orally. During the course of treatment, she had fever, abnormally mental behavior, personality change, hallucinations and orofacial involuntary movement. Pelvic imaging examination suggested ovarian teratoma, and NMDA receptor encephalitis was highly suspected, and then the result of anti-NMDA receptor antibody examination for serum and cerebrospinal fluid was positive. NMDA receptor encephalitis was confirmed. The teratoma was exsected by surgery on the basis of immunotherapy, and the patient's neural and mental symptoms were disappeared, and the patient recovered completely and was discharged. Conclusion Young females with ovarian embryoma have unknown causes of mental symptom and movement disorders, the anti-NMDA receptor encephalitis should be highly considered, and anti-NMDA receptor antibody examination for serum and cerebrospinal fluid can confirmed the diagnosis.

Anti-N-methyl-D-aspartate receptor encephalitis; Misdiagnosis; Epilepsy; Teratoma

100080 北京,北京市海淀医院妇产科(李晨霞、倪俊、章颖),病理科(梁乐、付静);100203 北京,首都儿科研究所附属儿童医院神经外科(马康平、李云林)

R512.3

A

1002-3429(2017)07-0010-04

10.3969/j.issn.1002-3429.2017.07.003

2016-11-23 修回时间:2017-04-22)

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