抗N-甲基-D-天冬氨酸受体脑炎免疫治疗的研究进展

李宇航; 蒋莉

doi:10.7499/j.issn.1008-8830.2204021

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中国当代儿科杂志 ›› 2022, Vol. 24 ›› Issue (8) : 948-953. DOI: 10.7499/j.issn.1008-8830.2204021

综述

抗N-甲基-D-天冬氨酸受体脑炎免疫治疗的研究进展

李宇航, 蒋莉

作者信息 +

Recent research on immunotherapy for anti-N-methyl-D-aspartate receptor encephalitis

LI Yu-Hang, JIANG Li

Author information +

文章历史 +

摘要

抗N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor，NMDAR）脑炎是一种以神经及精神症状为主要表现的中枢神经系统疾病。免疫治疗是基础治疗，包括急性期的一线治疗和二线治疗，以及慢性期的长程治疗。抗NMDAR脑炎总体预后良好，但仍有部分患者对当前免疫治疗方案反应欠佳，遗留神经系统功能障碍。此外，药物的不良反应及经济负担也是临床工作中常遇到的现实问题。为解决上述问题，近年来免疫治疗方案在药物的剂量、使用途径、疗程方面不断改进，同时涌现出一些新免疫治疗药物。因此，该文就抗NMDAR脑炎免疫治疗的研究进展进行综述。

Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a central nervous system disease characterized by neurological and psychiatric symptoms. Immunotherapy is the basic treatment for this disease, including first- and second-line therapies for the acute stage and the long-course therapy for the chronic stage. Anti-NMDAR encephalitis often has a good prognosis, but some patients may still have neurological dysfunction due to poor response to current immunotherapy. In addition, the adverse reactions and economic burden of drugs are practical problems in clinical practice. To solve the above problems, continuous improvements have been made in immunotherapy regimens in terms of dose, route of administration, and course of treatment, and some new immunotherapy drugs have emerged. This article reviews the recent research on immunotherapy for anti-NMDAR encephalitis.

导出引用

李宇航, 蒋莉. 抗N-甲基-D-天冬氨酸受体脑炎免疫治疗的研究进展[J]. 中国当代儿科杂志. 2022, 24(8): 948-953 https://doi.org/10.7499/j.issn.1008-8830.2204021

LI Yu-Hang, JIANG Li. Recent research on immunotherapy for anti-N-methyl-D-aspartate receptor encephalitis[J]. Chinese Journal of Contemporary Pediatrics. 2022, 24(8): 948-953 https://doi.org/10.7499/j.issn.1008-8830.2204021

参考文献

1 Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma[J]. Ann Neurol, 2007, 61(1): 25-36. PMID: 17262855. PMCID: PMC2430743. DOI: 10.1002/ana.21050.
2 Ren H, Fan S, Zhao Y, et al. The changing spectrum of antibody-mediated encephalitis in China[J]. J Neuroimmunol, 2021, 361: 577753. PMID: 34739913. DOI: 10.1016/j.jneuroim.2021.577753.
3 Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models[J]. Lancet Neurol, 2019, 18(11): 1045-1057. PMID: 31326280. DOI: 10.1016/S1474-4422(19)30244-3.
4 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. DOI: 10.3760/cma.j.issn.1006-7876.2017.02.004.
5 Zuliani L, Nosadini M, Gastaldi M, et al. Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations[J]. Neurol Sci, 2019, 40(10): 2017-2030. PMID: 31161339. DOI: 10.1007/s10072-019-03930-3.
6 Nosadini M, Thomas T, Eyre M, et al. International consensus recommendations for the treatment of pediatric NMDAR antibody encephalitis[J]. Neurol Neuroimmunol Neuroinflamm, 2021, 8(5): e1052. PMID: 34301820. PMCID: PMC8299516. DOI: 10.1212/NXI.0000000000001052.
7 Li X, Hou C, Wu WL, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis in southern China: analysis of 111 cases[J]. J Neuroimmunol, 2021, 352: 577479. PMID: 33486307. DOI: 10.1016/j.jneuroim.2021.577479.
8 Seifert-Held T, Eberhard K, Lechner C, et al. Functional recovery in autoimmune encephalitis: a prospective observational study[J]. Front Immunol, 2021, 12: 641106. PMID: 34093529. PMCID: PMC8175889. DOI: 10.3389/fimmu.2021.641106.
9 Zhang Y, Liu G, Jiang M, et al. Efficacy of therapeutic plasma exchange in patients with severe refractory anti-NMDA receptor encephalitis[J]. Neurotherapeutics, 2019, 16(3): 828-837. PMID: 30868469. PMCID: PMC6694354. DOI: 10.1007/s13311-019-00725-4.
10 Guang S, Ma J, Ren X, et al. Immunotherapies for anti-N-M-methyl-D-aspartate receptor encephalitis: multicenter retrospective pediatric cohort study in China[J]. Front Pediatr, 2021, 9: 691599. PMID: 34268281. PMCID: PMC8276978. DOI: 10.3389/fped.2021.691599.
11 Buttgereit F. Glucocorticoids: surprising new findings on their mechanisms of actions[J]. Ann Rheum Dis, 2021, 80(2): 137-139. PMID: 33162396. DOI: 10.1136/annrheumdis-2020-218798.
12 王国丽, 尹飞, 王颖, 等. 儿童抗N-甲基-D-天门冬氨酸受体脑炎71例临床分析[J]. 中华儿科杂志, 2019, 57(2): 125-130. PMID: 30695887. DOI: 10.3760/cma.j.issn.0578-1310.2019.02.012.
13 Zhang Y, Huang HJ, Chen WB, et al. Clinical efficacy of plasma exchange in patients with autoimmune encephalitis[J]. Ann Clin Transl Neurol, 2021, 8(4): 763-773. PMID: 33609012. PMCID: PMC8045938. DOI: 10.1002/acn3.51313.
14 Jamshidian A, Abd-Nikfarjam B, Khademi Z, et al. Therapeutic plasma exchange may adjust IL-6 and TGF-β signals in relapsed MS patients peripheral blood[J]. J Clin Apher, 2020, 35(2): 72-78. PMID: 31899560. DOI: 10.1002/jca.21755.
15 Zanatta E, Cozzi M, Marson P, et al. The role of plasma exchange in the management of autoimmune disorders[J]. Br J Haematol, 2019, 186(2): 207-219. PMID: 30924130. DOI: 10.1111/bjh.15903.
16 Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue[J]. J Clin Apher, 2019, 34(3): 171-354. PMID: 31180581. DOI: 10.1002/jca.21705.
17 Chen Y, Wang C, Xu F, et al. Efficacy and tolerability of intravenous immunoglobulin and subcutaneous immunoglobulin in neurologic diseases[J]. Clin Ther, 2019, 41(10): 2112-2136. PMID: 31445679. DOI: 10.1016/j.clinthera.2019.07.009.
18 Yang S, Yang L, Liao H, et al. Clinical characteristics and prognostic factors of children with anti-N-methyl-D-aspartate receptor encephalitis[J]. Front Pediatr, 2021, 9: 605042. PMID: 33968840. PMCID: PMC8100243. DOI: 10.3389/fped.2021.605042.
19 Raja P, Shamick B, Nitish LK, et al. Clinical characteristics, treatment and long-term prognosis in patients with anti-NMDAR encephalitis[J]. Neurol Sci, 2021, 42(11): 4683-4696. PMID: 33728548. DOI: 10.1007/s10072-021-05174-6.
20 Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study[J]. Lancet Neurol, 2013, 12(2): 157-165. PMID: 23290630. PMCID: PMC3563251. DOI: 10.1016/S1474-4422(12)70310-1.
21 Wang K, Chen Z, Wu D, et al. Early second-line therapy is associated with improved episodic memory in anti-NMDA receptor encephalitis[J]. Ann Clin Transl Neurol, 2019, 6(7): 1202-1213. PMID: 31353868. PMCID: PMC6649545. DOI: 10.1002/acn3.50798.
22 Xu X, Lu Q, Huang Y, et al. Anti-NMDAR encephalitis: a single-center, longitudinal study in China[J]. Neurol Neuroimmunol Neuroinflamm, 2020, 7(1): e633. PMID: 31619447. PMCID: PMC6857906. DOI: 10.1212/NXI.0000000000000633.
23 Shim Y, Kim SY, Kim H, et al. Clinical outcomes of pediatric anti-NMDA receptor encephalitis[J]. Eur J Paediatr Neurol, 2020, 29: 87-91. PMID: 33046392. DOI: 10.1016/j.ejpn.2020.10.001.
24 Zhang XT, Wang CJ, Wang BJ, et al. The short-term efficacy of combined treatments targeting B cell and plasma cell in severe and refractory anti-N-methyl-D-aspartate receptor encephalitis: two case reports[J]. CNS Neurosci Ther, 2019, 25(1): 151-153. PMID: 30345626. PMCID: PMC6436585. DOI: 10.1111/cns.13078.
25 Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management[J]. J Neurol Neurosurg Psychiatry, 2021, 92(7): 757-768. PMID: 33649022. PMCID: PMC8223680. DOI: 10.1136/jnnp-2020-325300.
26 Mooneyham GC, Ferrafiat V, Stolte E, et al. Developing consensus in the assessment and treatment pathways for autoimmune encephalitis in child and adolescent psychiatry[J]. Front Psychiatry, 2021, 12: 638901. PMID: 33854451. PMCID: PMC8039450. DOI: 10.3389/fpsyt.2021.638901.
27 Dou X, Li D, Wu Y, et al. Efficacy and safety of rituximab in Chinese children with refractory anti-NMDAR encephalitis[J]. Front Neurol, 2020, 11: 606923. PMID: 33381080. PMCID: PMC7767921. DOI: 10.3389/fneur.2020.606923.
28 Bartolini L, Muscal E. Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey[J]. J Neurol, 2017, 264(4): 647-653. PMID: 28154970. DOI: 10.1007/s00415-017-8407-1.
29 Cao XS, Kessi M, Ji TY, et al. A survey on pediatric anti-N-methyl-D-aspartate-receptor encephalitis treatment strategies in China[J]. Chin Med J (Engl), 2020, 134(12): 1498-1499. PMID: 33323814. PMCID: PMC8213264. DOI: 10.1097/CM9.0000000000001308.
30 Nepal G, Shing YK, Yadav JK, et al. Efficacy and safety of rituximab in autoimmune encephalitis: a meta-analysis[J]. Acta Neurol Scand, 2020, 142(5): 449-459. PMID: 32484900. DOI: 10.1111/ane.13291.
31 Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort[J]. Neurology, 2016, 86(18): 1683-1691. PMID: 27037228. DOI: 10.1212/WNL.0000000000002635.
32 Deng B, Yu H, Liu X, et al. Reduced dosage rituximab in the treatment of anti-N-methyl-D-aspartate receptor encephalitis: an observation study in Chinese patients[J]. J Neuroimmunol, 2019, 330: 81-86. PMID: 30851542. DOI: 10.1016/j.jneuroim.2019.02.008.
33 Wang BJ, Wang CJ, Zeng ZL, et al. Lower dosages of rituximab used successfully in the treatment of anti-NMDA receptor encephalitis without tumour[J]. J Neurol Sci, 2017, 377: 127-132. PMID: 28477682. DOI: 10.1016/j.jns.2017.04.007.
34 Zou X, Zhao W, Kong M, et al. Low-dose rituximab in the treatment of anti-N-methyl-D-aspartate receptor encephalitis with antibody superposition syndrome: a case report[J]. Acta Neurol Belg, 2022, 22(3): 797-799. PMID: 33689111. DOI: 10.1007/s13760-021-01636-y.
35 Dhawan SR, Sankhyan N. Low-dose rituximab in children with anti-NMDAR encephalitis[J]. Pediatr Neurol, 2018, 87: 82. PMID: 30501890. DOI: 10.1016/j.pediatrneurol.2018.07.006.
36 Ahlmann M, Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy[J]. Cancer Chemother Pharmacol, 2016, 78(4): 661-671. PMID: 27646791. DOI: 10.1007/s00280-016-3152-1.
37 Gastaldi M, Thouin A, Vincent A. Antibody-mediated autoimmune encephalopathies and immunotherapies[J]. Neurotherapeutics, 2016, 13(1): 147-162. PMID: 26692392. PMCID: PMC4720680. DOI: 10.1007/s13311-015-0410-6.
38 林希, 陈丽婷, 曾甲斌, 等. 环磷酰胺对一线免疫治疗失败的儿童抗N-甲基-D-天冬氨酸受体脑炎疗效分析[J]. 中国神经精神疾病杂志, 2020, 46(2): 98-102. DOI: 10.3969/j.issn.1002-0152.2020.02.008.
39 Casares M, Skinner HJ, Gireesh ED, et al. Successful intrathecal rituximab administration in refractory nonteratoma anti-N-methyl-D-aspartate receptor encephalitis: a case report[J]. J Neurosci Nurs, 2019, 51(4): 194-197. PMID: 31180943. DOI: 10.1097/JNN.0000000000000450.
40 Santiago JA, Babico M, Stitt G, et al. Low-dose intrathecal rituximab is a safe and potentially effective treatment for pediatric neuroimmunologic disorders[J]. J Neuroimmunol, 2021, 359: 577687. PMID: 34364103. DOI: 10.1016/j.jneuroim.2021.577687.
41 Yang XZ, Zhu HD, Ren HT, et al. Utility and safety of intrathecal methotrexate treatment in severe anti-N-methyl-D-aspartate receptor encephalitis: a pilot study[J]. Chin Med J (Engl), 2018, 131(2): 156-160. PMID: 29336363. PMCID: PMC5776845. DOI: 10.4103/0366-6999.222327.
42 Eaton JE, Kleinholz-Owens P, Sriram S, et al. Intrathecal methotrexate—another tool for the treatment of refractory autoimmune encephalitis—single institution cohort and literature review[J]. J Neurol Sci, 2021, 431: 120042. PMID: 34740019. DOI: 10.1016/j.jns.2021.120042.
43 Wang T, Wang B, Zeng Z, et al. Efficacy and safety of bortezomib in rituximab-resistant anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis as well as the clinical characteristics: an observational study[J]. J Neuroimmunol, 2021, 354: 577527. PMID: 33652303. DOI: 10.1016/j.jneuroim.2021.577527.
44 Dinoto A, Cheli M, Bratina A, et al. Bortezomib in anti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis: a systematic review[J]. J Neuroimmunol, 2021, 356: 577586. PMID: 33975246. DOI: 10.1016/j.jneuroim.2021.577586.
45 Lim JA, Lee ST, Moon J, et al. New feasible treatment for refractory autoimmune encephalitis: low-dose interleukin-2[J]. J Neuroimmunol, 2016, 299: 107-111. PMID: 27725107. DOI: 10.1016/j.jneuroim.2016.09.001.
46 Govil-Dalela T, Datta I, Williams M. Refractory NMDA-receptor encephalitis in a teenager: a novel use of Bortezomib[J]. J Neuroimmunol, 2021, 355: 577565. PMID: 33813318. DOI: 10.1016/j.jneuroim.2021.577565.
47 Cordani R, Micalizzi C, Giacomini T, et al. Bortezomib-responsive refractory anti-N-methyl-D-aspartate receptor encephalitis[J]. Pediatr Neurol, 2020, 103: 61-64. PMID: 31759783. DOI: 10.1016/j.pediatrneurol.2019.09.004.
48 Shin YW, Lee ST, Kim TJ, et al. Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis[J]. Ann Clin Transl Neurol, 2018, 5(5): 598-605. PMID: 29761122. PMCID: PMC5945964. DOI: 10.1002/acn3.557.
49 Wickel J, Chung HY, Platzer S, et al. Generate-boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis[J]. Trials, 2020, 21(1): 625. PMID: 32641101. PMCID: PMC7346383. DOI: 10.1186/s13063-020-04516-7.
50 Mihara M, Kasutani K, Okazaki M, et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family[J]. Int Immunopharmacol, 2005, 5(12): 1731-1740. PMID: 16102523. DOI: 10.1016/j.intimp.2005.05.010.
51 Lee WJ, Lee ST, Moon J, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study[J]. Neurotherapeutics, 2016, 13(4): 824-832. PMID: 27215218. PMCID: PMC5081109. DOI: 10.1007/s13311-016-0442-6.
52 Ratuszny D, Skripuletz T, Wegner F, et al. Case report: daratumumab in a patient with severe refractory anti-NMDA receptor encephalitis[J]. Front Neurol, 2020, 11: 602102. PMID: 33414761. PMCID: PMC7782967. DOI: 10.3389/fneur.2020.602102.
53 Lazzarin SM, Vabanesi M, Cecchetti G, et al. Refractory anti-NMDAR encephalitis successfully treated with bortezomib and associated movements disorders controlled with tramadol: a case report with literature review[J]. J Neurol, 2020, 267(8): 2462-2468. PMID: 32535682. DOI: 10.1007/s00415-020-09988-w.
54 Yang J, Liu X. Immunotherapy for refractory autoimmune encephalitis[J]. Front Immunol, 2021, 12: 790962. PMID: 34975890. PMCID: PMC8716621. DOI: 10.3389/fimmu.2021.790962.
55 Nosadini M, Mohammad SS, Toldo I, et al. Mycophenolate mofetil, azathioprine and methotrexate usage in paediatric anti-NMDAR encephalitis: a systematic literature review[J]. Eur J Paediatr Neurol, 2019, 23(1): 7-18. PMID: 30318435. DOI: 10.1016/j.ejpn.2018.09.008.
56 Downing HJ, Pirmohamed M, Beresford MW, et al. Paediatric use of mycophenolate mofetil[J]. Br J Clin Pharmacol, 2013, 75(1): 45-59. PMID: 22519685. PMCID: PMC3555046. DOI: 10.1111/j.1365-2125.2012.04305.x.