抗amphiphysin抗体相关副肿瘤神经综合征临床研究

Paraneoplastic neurological syndromes associated with anti-amphiphysin antibodies

目的 探讨抗amphiphysin抗体相关的副肿瘤神经综合征的临床特征。方法对北京协和医院2012-2015年急性或亚急性临床表现怀疑副肿瘤神经综合征患者的血清及脑脊液标本采用蛋白免疫印迹法进行抗amphiphysin抗体检测，对其中抗amphiphysin抗体阳性患者进行临床观察及随访。结果在15000例患者中检测出抗amphiphysin抗体阳性患者13例，其中男性6例，女性7例；平均年龄54岁。神经系统表现包括：边缘系统脑炎4例，周围神经病3例，僵人综合征2例，亚急性小脑变性、脑干脑炎合并斜视性眼阵挛、自主神经障碍、肌阵挛各1例，4例合并抗利尿激素异常分泌综合征。发现恶性肿瘤6例（6／13）：5例小细胞肺癌，1例乳腺癌。6例（6／13）合并其他抗体阳性。所有患者神经系统症状均在肿瘤诊断之前出现，自神经系统症状出现到检出肿瘤时间平均13．83周，没有检测到恶性肿瘤的5例患者平均随访时间32．2个月。7例接受免疫治疗，5例神经系统症状改善，1例治疗前后无变化，1例复发进展。结论抗amphiphysin抗体相关的神经综合征有一个相对广泛的临床疾病谱，最常见的神经系统表现是非僵人综合征，部分患者与肿瘤相关，免疫治疗可能使患者获益。

Objective To investigate the clinical features of paraneoplastic neurological syndromes associated with anti-amphiphysin antibody in Peking Union Medical College Hospital （PUMCH）. Methods Patients with an acute or subacute neurological presentation that was suspected to be paraneoplastic in PUMCH from 2012 to 2015 were screened for anti-amphiphysin antibody. Samples of serum or cerebrospinal fluid were tested by the immunoblotting. Clinical features of patients with anti-amphiphysin antibody were analyzed. Results Anti-amphiphysin antibody was identified in the serum of 13 among 15 000 patients, 6 of which were male and 7 were female, the mean age being 54 years. Neurological manifestations included limbic encephalitis （ n = 4） , peripheral neuropathy （ n = 3 ; 1 sensory, 1 neuropathy and paraproteinaemia, 1 multiple mononeuropathy ） , stiff-person syndrome （ SPS, n = 2 ） , paraneoplastic cerebellar degeneration （ n = 1 ）, brainstem encephalitis and paraneoplastic opsoelonus-myoclnia （ n = 1 ） , dysautonomia （ n = 1 ）, myoclonus （ n = 1 ）. Four of the 13 patients had additional syndrome of inappropriate antidiuretic hormone secretion. Cancer was detected in 6 patients （6/13）, including small-cell lung cancer （n = 5 ）, and breast cancer （n = 1 ）. Coexisting autoantibodies were identified in 6 patients （6/13）. All the patients with cancer developed neurological symptoms before the diagnosis of cancer. The mean interval from neurological symptom onset to cancer detection overall was 13.83 weeks. The mean follow-up for the 5 patients in whom a malignant neoplasm was not detected was 32. 2 months. Seven patients were treated with immunotherapy, including intravenous immunoglobulin （IVIG） and methylprednisolone. Five of these patients had favorable responses, 1 patient did not improve after immunotherapy, 1 patient＇s symptoms were aggravated after shortterm remission. Conclusions The results suggest that anti-amphiphysin antibody is a rare autoantibody. Despite emphasis on its association with paraneoplastic SPS, its associated spectrum of neurological disorders is much broader. Many patients with anti-amphiphysin antibody developed neurological symptoms instead of SPS and are only partially associated with cancer. Immunotherapy, including IVIG or steroid, would be beneficial.