多重抗神经元抗体阳性的自身免疫性脑炎临床分析

Clinical analysis of autoimmune encephalitis with co-existence of multiple anti-neuronal antibodies

目的探讨自身免疫性脑炎患者出现多重抗神经元抗体阳性的临床意义。方法对2013年5月至2014年12月送检北京协和医院神经科实验室的不明病因脑炎患者的血清和脑脊液采用间接免疫荧光法进行脑炎多项抗体检测，包括N-甲基-D-天冬氨酸受体（NMDAR）抗体、抗接触蛋白相关蛋白2（CASPR2）抗体、抗α-氨基-3-羟基-5-甲基-4-异嚼唑丙酸受体（AMPAR）抗体、抗富亮氨酸胶质瘤失活1蛋白（LGI1）抗体、抗γ-氨基丁酸B型受体（GABA_BR）抗体；对阳性样本同时采用免疫印迹法进行副肿瘤相关抗体（抗Hu、Yo、Ri抗体等）检测，采用间接免疫荧光法进行水通道蛋白4（AQP4）抗体的检测。结果在531例脑炎相关抗体阳性患者中合并其他抗体阳性的患者仅有10例，包括：5例抗GABA_BR抗体阳性患者中同时合并抗Hu抗体阳性，其中1例抗NMDAR抗体亦呈阳性；1例抗NMDAR阳性自身免疫性脑炎患者多次复发后出现AQP4抗体阳性；1例抗LGll抗体合并抗CASPR2抗体阳性；1例抗LGI1抗体合并抗Yo抗体阳性；2例抗AMPAR抗体分别合并抗CV2抗体、抗Hu抗体阳性。全部病例的临床表现均符合脑炎或者边缘性脑炎，其中3例合并脑干受累，1例合并感觉性周嗣神经病，1例合并肌肉疼痛与束颤，7例对免疫治疗有效，7例合并肿瘤（经病理或影像检查确定），包括肺癌5例、可疑胸腺瘤1例、未明病因纵隔占位1例。结论多重自身抗体的存在，可影响患者的临床表现，导致临床综合征的变异与叠加。合并副肿瘤相关抗体阳性对潜在的恶性肿瘤具有提示意义。

Objective To explore the clinical significance of expressing multiple autoantibodies in patients with autoimmune encephalitis. Methods Cerebrospinal fluid and serum were tested in patients with undefined encephalitis admitted to Peking Union Medical College Hospital from May 2013 to December 2014. Indirect immunofluorescence test was firstly used to identify the antibodies to neuronal cell-surface or synaptic receptors （including N-methyl-D-aspartate receptor （NMDAR）, contactin-associated protein-like 2 （ CASPR2 ）, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor （ AMPAR ）, leucine-rich glioma inactivated protein 1 （LGI1）, and gamma-aminobutyric acid beta receptor （GABABR） ）. In those patients with positive antibodies, antibodies against intracellular neuronal antigens associated with paraneoplastic neurological symptoms were tested. Anfi-aquaporin protein-4 （AQP4） antibody was tested depending on patients＇ clinical manifestations. Results Ten patients were detected combined with additional autoantibodies in 531 patients with positive antibodies related to autoimmune encephalitis. Anti- Hu antibody was positive in 5 patients with anti-GABA^R encephalitis, in 1 of whom anti-NMDAR antibody was also identified; anti-AQP4 antibody was positive in 1 patient with relapsing anti-NMDAR encephalitis; anti-CASPR2 and anti-Yo antibodies were respectively positive in 2 patients with anti-LGI1 encephalitis; anti-CV2 and anti-Hu antibodies were respectively positive in 2 patients with anti-AMPAR encephalitis. Clinical presentation of all cases was consistent with typical encephalitis or limbic encephalitis. Brain stemwas involved in 3 patients. Peripheral sensory neuropathy was present in 1 patient, while myalgia and fasciculation were present in 1 patient. Seven patients responded well to the immunotherapy. Tumors were pathologically or radiologically confirmed in 7 cases, including lung cancer in 5 cases, suspected thymoma in 1 case and highly suspected mediastinal tumor without pathological identification in 1 case. Conclusions Due to the pathological mechanism, co-existence of multiple autoantibodies affects clinical manifestations of patients and results in variation and overlap of them. The additional positivity of onconeuronal antibodies directs the search for occult tumor.