肿瘤免疫检查点抑制剂的神经系统相关不良反应及管理策略

Nervous System Related Adverse Reactions and Management Strategies of Tumor Immune Checkpoint Inhibitors

摘要: 免疫检查点抑制剂(Immune checkpoint inhibitors, ICIs)是为阻断人体免疫系统中抑制性免疫调节位点、增强人体抗肿瘤作用而开发的一类蛋白类分子。目前已被食品药品监督管理局(Food and Drug Administration, FDA)批准用于治疗晚期恶性肿瘤的一类新型药物，其显著提高了癌症患者的生存期，尽管疗效显著，但治疗所产生的免疫相关不良事件(immune-related adverse events, irAEs)发生率及死亡率亦不断升高。常见的irAEs包括皮肤、胃肠道、肝脏和内分泌事件等，神经系统不良反应比较少见，目前已有报道的包括吉兰–巴雷综合征、重症肌无力、无菌性脑膜炎、多发性硬化和肌炎等。对于诊断免疫介导的神经系统不良反应，需要结合患者、症状体征及影像学、脑脊液细胞学、脑电图或肌电图等检查，除外感染或恶性肿瘤后获得诊断。治疗中，大部分患者运用糖皮质激素或丙种球蛋白治疗和对症支持治疗症状能得到显著改善。本文的目的是总结了神经系统的irAEs发生率、临床表现和诊断、发生机制及管理策略进行阐述，旨在为临床医师应用ICIs提供参考。

Abstract: Immune checkpoint inhibitors (ICIs) are a class of protein molecules developed to block inhibitory immune regulatory sites in the human Immune system and enhance the anti-tumor effect of human body. A new class of drugs approved by the Food and Drug Administration to treat advanced malig-nancies significantly improves survival in cancer patients; at the same time, a wide range of im-mune-related adverse events (irAEs) will also occur. The common irAEs include cutaneous, gastro-intestinal, liver and endocrine events, while neurological adverse reactions are relatively rare. Cur-rently, there have been reports of Guillan-Barre syndrome, myasthenia gravis, aseptic meningitis, multiple sclerosis and myitis. For the diagnosis of immune-mediated neurologic adverse reactions, it is necessary to combine with patients, symptoms and signs, imaging, cerebrospinal fluid cytology, electroencephalogram or electromyography to exclude after infections or malignancies to obtain the diagnosis. The purpose of this review is to summarize the incidence, clinical manifestations, di-agnosis, pathogenesis and management strategies of irAEs in the nervous system, so as to provide reference for clinicians to apply ICIs.