免疫检查点抑制剂致免疫相关性脑炎临床案例分析
收稿日期: 2024-11-14
修回日期: 2025-08-26
录用日期: 2025-12-03
网络出版日期: 2025-12-17
基金资助
河北省卫生厅科研基金项目（20232177）
Analysis of Clinical Case Reports on Immune-Related Encephalitis Caused by Immune Checkpoint Inhibitors
Received date: 2024-11-14
Revised date: 2025-08-26
Accepted date: 2025-12-03
Online published: 2025-12-17
目的：通过对免疫相关性脑炎患者的基线特征、脑炎发生时间、临床症状、实验室检查结果及治疗转归等进行汇总分析，为医务人员临床工作中对免疫相关性脑炎的鉴别和治疗提供参考。方法：检索中国知网、万方和维普等中文数据库及PubMed、Embase、ScienceDirect 等英文数据库，收集数据库中有关免疫检查点抑制剂（包括细胞毒性T淋巴细胞相关抗原-4抑制剂、程序性死亡受体-1抑制剂及程序性死亡配体-1抑制剂）所致免疫相关性脑炎的文献报道，对所得数据进行汇总分析。结果：本研究共收集到免疫相关性脑炎个案报道72例，分析结果显示，65岁以上及联合使用两种免疫检查点抑制剂的患者免疫相关性脑炎发病率较高。免疫相关性脑炎中位发生时间为87 d，实验室检查提示脑脊液中白细胞数及蛋白质数量增高，影像学特征主要表现为异常强化，脑电图多表现为弥漫性慢波。其中50例患者经积极治疗后症状好转，18例患者死亡。结论：免疫相关性脑炎是一种罕见的神经系统不良反应，临床表现不同，且死亡率高，发病时间长短不一，可能难以及时进行识别。若考虑为免疫相关性脑炎，应及早应用糖皮质激素甚至免疫抑制剂，密切关注患者神经系统症状的转归，积极调整治疗方案。
李曼
,
石庆芳
,
高军
,
杨俊娥
.
免疫检查点抑制剂致免疫相关性脑炎临床案例分析
Objective： By summarizing and analyzing the baseline characteristics， occurrence time， clinical symptoms， laboratory test results and treatment outcomes of patients with immune-related encephalitis， to provide reference for the identification and treatment of immune-related encephalitis in clinical work.Methods： Search Chinese literature databases such as CNKI， Wanfang and VIP， as well as English literature databases such as PubMed， Embase and ScienceDirect， collect the literature reports on immune-related encephalitis caused by immune checkpoint inhibitors （including cytotoxic T-lymphocyte-associated antigen-4 inhibitors， programmed death receptor-1 inhibitors and programmed death ligand 1 inhibitors ） from the databases and analyzed the obtained data.Results： A total of 72 cases of immune-related encephalitis were collected. The analysis results show that the incidence of immune-related encephalitis is higher in patients over 65 years old and those who use two kinds of immune checkpoint inhibitors. The median occurrence time was 87 days. Laboratory tests indicated an increase in the number of leukocytes and protein numbers in the cerebrospinal fluid， the imaging features were mainly abnormal enhancement， and the electroencephalogram features were mainly diffuse slow wave. 50 patients had improved symptoms after active treatment， and 18 patients died.Conclusion： Immune-related encephalitis is a rare neurological adverse reaction， with inconsistent clinical manifestations and high mortality. Immune-related encephalitis has different onset times， making it difficult to be identified in time. If considered to be immune-related encephalitis， glucocorticoids or immunosuppressants should be used as early as possible. It is necessary to pay close attention to the outcome of neurological symptoms of the patients， and actively adjust the treatment plan.
［1］ Topalian SL， Hodi FS， Brahmer JR， et al. Safety， activity and immune correlates of anti-PD-1 antibody in cancer［J］.N Engl J Med，2012，366（26）：2443-2454.
［2］ Brahmer JR， Tykodi SS， Chow LQ， et al. Safety and activity of anti-PDL-1 antibody in patients with advanced cancer［J］.N Engl J Med，2012，366（26）：2455-2465.
［3］ Abdel-Rahman O， Elhalawani H， Fouad M. Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors： a meta-analysis［J］.Expert Opin Drug Saf，2015，14（10）：1507-1518.
［4］ Abdel-Rahman O， Elhalawani H， Fouad M. Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors： a meta-analysis［J］.Immunotherapy，2015，7（11）：1213-1227.
［5］ Abdel-Rahman O， Elhalawani H， Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors： a meta-analysis［J］.Future Oncol，2015，11（17）：2471-2484.
［6］ Abdel-Rahman O， Fouad M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors： a meta-analysis［J］.Ther Adv Respir Dis，2016，10（3）：183-193.
［7］ Abdel-Rahman O， Fouad M. A network meta-analysis of the risk of immune-related renal toxicity in cancer patients treated with immune checkpoint inhibitors［J］.Immunotherapy，2016，8（5）：665-674.
［8］ Abdel-Rahman O， Helbling D， Schmidt J， et al. Treatment-associated fatigue in cancer patients treated with immune checkpoint inhibitors： a systematic review and meta-analysis［J］.Clin Oncol，2016，28（10）：e127-e138.
［9］ 周炜，蒋俊杰，王法财，等.替雷利珠单抗致免疫相关性脑炎一例［J］.临床药物治疗杂志，2023，21（8）：90-92.
［10］ Bossart S， Thurneysen S， Rushing E， et al. Case report： encephalitis， with brainstem involvement， following checkpoint inhibitor therapy in metastatic melanoma［J］.Oncologist，2017，22（6）：749-753.
［11］ Markus L， Varosanec MV， Slaven P， et al. Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer：case report and review of the literature［J］.Front Immunol，2018，9：108.
［12］ Sakam S， Lavin T， Turan A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma［J］.BMJ Case Rep，2016，2016：bcr2016215012.
［13］ Popat S， Ardizzoni A， Ciuleanu T. Nivolumab in previously treated patients with metastatic squamous NSCLC： results of a European single-arm， phase 2 trial （CheckMate 171） including patients aged ≥70 years and with poor performance status［J］.Ann Oncol，2017，28（suppl 5）：v460-v496.
［14］ Chen C， Wu B， Zhang C， et al. Immune-related adverse events associated with immune checkpoint inhibitors： an updated comprehensive disproportionality analysis of the FDA adverse event reporting system［J］.Int Immunopharmacol，2021，95：107498.
［15］ 韩琳，谢刚，王燎，等.纳武利尤单抗联合伊匹木单抗治疗胸膜间皮瘤导致免疫相关性脑炎一例报道及文献复习［J］.中国肿瘤生物治疗杂志，2022，29（11）：1017-1020.
［16］ Elkayam N， Sharma S. Dual checkpoint inhibitor induced autoimmune encephalitis［J］.Arch Oncol，2019，25（2）：22-24.
［17］ Larkin J， Hodi FS， Wolchok JD. Comibined nivolumab and ipilimumab or monotherapy in untreated melanoma［J］.N Engl J Med，2015，373（13）：1270-1271.
［18］ 庞军，董娅.PD-1抑制剂联合放疗治疗非小细胞肺癌脑转移致免疫相关性脑炎1例［J］.临床肿瘤学杂志，2024，29（2）：206-208.
［19］ Spain L， Walls G， Julve M， et al. Neurotoxicity from immune checkpoint inhibition in the treatment of melanoma： a single centre experience and review of the literature［J］.Ann Oncol，2017，28（2）：377-385.
［20］ Zimmer L， Goldinger SM， Hofmann L， et al. Neurological，respiratory，musculoskeletal，cardiac and ocular side-effects of anti-PD-1 therapy［J］.Eur J Cancer，2016，60：210-225.
［21］ Johnson DB， Manouchehri A， Haugh AM， et al. Neurologic toxicity associated with immune checkpoint inhibitors： a pharmacovigilance study［J］.J Unnunother Cancer，2019，7（1）：134.
［22］ Fan SY， Ren HT， Zhao L， et al. Neurological immune-related adverse events associated with immune checkpoint inhibitors： a review of the literature［J］.Asia Pac J Clin Oncol，2020，16（6）：291-298.
［23］ Kao JC， Liao B， Markovic SN， et al. Neurological complications associated with anti-programmed death 1（PD-1） antibodis［J］.JAMA Neurol，2017，74（10）：1216-1222.
［24］ Haugh AM， Probasco JC， Johnson DB. Neurologic complications of immune checkpoint inhibitor［J］.Expert Opin Drug Saf，2020，19（4）：479-488.
［25］ 吴汀溪，续畅，张杨，等.基于美国不良反应自发性呈报系统数据库对免疫检查点抑制剂致免疫相关性脑炎的分析［J］.中国医药导报，2023，20（13）：156-160.
［26］ 史佳宇，牛婧雯，沈东超，等.免疫检查点抑制剂相关神经系统不良反应的临床诊治建议［J］. 中国肺癌杂志，2019，22（10）：633-638.
［27］ Nersesjan V， Mcwiliam O， Krarup LH， et al. Autoimmune encephalitis related to cancer treatment with immune checkpoint inhibitors： systematic review［J］.Neurology，2021，97（2）：e191-e202.
［28］ Velasco R， Villagran M. Jove M，et al. Encephalitis induced by immune checkpoint inhibitors： a systematic review［J］.JAMA Neurol，2021，78（7）：864-873.
［29］ Sanchis-Borja M， Ricordel C， Chiappa AM， et al. Encephalitis related to immunotherapy for lung cancer： analysis of a multicenter cohort［J］.Lung Cancer，2020，143：36-39.
［30］ 中华医学会神经病学分会.中国自身免疫性脑炎诊治专家共识［J］.中华神经科杂志，2017，50（2）：91-98.
［31］ Martinor M， Ahle G， Petrosyan L， et al. Progressive multifocal leukoencephalopathy after treatment with Nivolumab［J］.Emerg Infect Dis，2018，24（8）：1594-1596.
［32］ Arbour KC， Mezquita L， Long N， et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small lung cancer［J］.J Clin Oncol，2018，36（28）：2872-2878.
［33］ Hendriks LEL， Henon C， Auclin E， et al. Outcome of patients with non-small lung cancer and brain metastases treated with checkpoint inhibitors［J］.J Thorac Oncol，2019，14（7）：1244-1254.
［34］ Riccuti B， Dhlberg SE， Adeni A， et al. Immune checkpoint inhibitor outcomes for patients with non-small lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications［J］.J Clin Oncol，2019，37（22）：1927-1934.
［35］ Shafqat H， Gourdin L， Sion A. Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy［J］.Semin Oncol，2018，45（3）：156-163.
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