摘要：

目的: 分析抗神经元抗体阳性免疫检查点抑制剂相关副肿瘤神经综合征（ICI-PNS）的临床特征。方法与结果: 纳入2012年1月至2024年3月中国医学科学院北京协和医院诊断与治疗的5例抗神经元抗体阳性ICI-PNS患者，肿瘤类型包括小细胞肺癌（2例）、恶性黑色素瘤（1例）、霍奇金淋巴瘤（1例）、宫颈癌（1例），免疫检查点抑制剂包括程序性死亡蛋白-1抑制剂（3例）、程序性死亡蛋白配体-1抑制剂（1例）、程序性死亡蛋白-1/细胞毒性T细胞相关抗原4双抑制剂（1例）。5例患者均出现副肿瘤神经综合征的高风险表型，其中4例表现为边缘性脑炎，1例表现为快速进展的小脑综合征。血清和（或）脑脊液中检出的抗神经元抗体包括抗Hu、γ-氨基丁酸B型受体、Y染色体性别决定区相关高迁移率组盒蛋白1、代谢型谷氨酸受体5型、Yo抗体。4例神经系统症状出现在应用免疫检查点抑制剂2周内。4例病情达峰时改良Rankin量表评分为3分，1例为5分。5例患者常见不良事件评价标准分级（CTCAE）均为3级。治疗方面，停用免疫检查点抑制剂，给予糖皮质激素联合静脉注射免疫球蛋白治疗，神经系统症状均有改善。结论: 中高风险抗神经元抗体是ICI-PNS的诊断标志物，可依据ICI-PNS临床表型及CTCAE分级等综合制定免疫治疗方案，停用免疫检查点抑制剂，应用糖皮质激素、静脉注射免疫球蛋白可以改善患者预后。

关键词: 副肿瘤综合征，神经系统, 免疫检查点抑制剂（非MeSH词）, 神经元, 自身抗体, 药物相关性副作用和不良反应

Abstract:

Objective: To analyze the clinical characteristics of anti-neuronal antibody positive paraneoplastic neurological syndrome related to immune checkpoint inhibitors (ICI-PNS). Methods and Results: A total of 5 patients with anti-neuronal antibody positive ICI-PNS in Peking Union Medical College Hospital from January 2012 to March 2024 were included. Tumor types included small cell lung cancer (2 cases), malignant melanoma (one case), Hodgkin lymphoma (one case) and cervical cancer (one case). Immune checkpoint inhibitors (ICIs) included programmed death 1 (PD-1) inhibitors (3 cases), programmed cell death ligand 1 (PD-L1) inhibitors (one case) and bispecific PD-1/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors (one case). All 5 patients presented with high-risk neurologic phenotypes of paraneoplastic neurological syndrome (PNS), of which 4 presented with limbic encephalitis and one presented with rapidly progressive cerebellar syndrome. Anti-neuronal antibodies detected in serum and/or cerebrospinal fluid of patients included anti-Hu, γ-aminobutyric acid receptor type B (GABA_BR), sex-determining region of Y chromosome-related high mobility group box 1 (SOX1), metabotropic glutamate receptor 5 (mGluR5) and Yo antibodies. Neurological syndromes occurred within 2 weeks after receiving ICIs in 4 patients. The modified Rankin Score (mRS) of 4 patients was 3 at peak of illness, and one patient was 5 at peak of illness. The Common Terminology Criteria for Adverse Events (CTCAE) was grade 3 in all 5 patients. After withdrawal of ICIs and treatment with glucocorticoids and intravenous immunoglobulin (IVIg), the neurological symptoms of the patients were improved. Conclusions: High/intermediate-risk anti-neuronal antibodies are diagnostic markers of ICI-PNS. Evaluation of ICI-PNS clinical phenotypes and CTCAE grading are important for immunotherapy. Discontinuation of ICIs, administration of glucocorticoids and IVIg can improve the prognosis of patients.

Key words: Paraneoplastic syndromes, nervous system, Immune checkpoint inhibitors (not in MeSH), Neurons, Autoantibodies, Drug-related side effects and adverse reactions