Anti-N-METHYL-D-aspartate receptor encephalitis, recurrent course

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR-encephalitis) was first described as an immune-mediated disorder of behavior and cognitive functions in patients with ovarian teratoma. Subsequently, it was recognized as a separate type of autoimmune encephalitis with a characteristic clinical picture and the possibility of development in the absence of data on tumor formations. The course can have both monophase and recurrent variants with periods of improvement or stabilization of the condition and subsequent progression of the disease. The article presents a clinical observation of a patient with a relapse of the disease 2 years later. The diagnosis of anti-NMDAR-encephalitis was established based on the presence of antibodies to NMDA receptor epitopes in the patient's cerebrospinal fluid, both at the onset of the disease and during the relapse. According to foreign literature, the incidence of recurrent anti-NMDAR-encephalitis varies from 12% to 24%, depending on the study, which requires additional monitoring of patients with this diagnosis.

1. Dalmau J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology. 2016 Dec 6;87(23):2471–2482. doi: 10.1212/WNL.0000000000003414.

2. Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008 Dec;7(12):1091–8. doi: 10.1016/S1474-4422(08)70224-2.

3. Belova AN, Grygorieva VN, Rasteryaeva MV, Ruina EA, Belova EM, Solovieva VS, Boyko AN. Anti-NMDAR encephalitis associated with relapsing optic neuritis. S.S. Korsakov Journal of Neurology and Psychiatry = Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2020;120(6):105–113. (In Russ.). https://doi.org/10.17116/jnevro2020120061105

4. Dalmau J, Armangué T, Planagumà J Radosevic, M., Mannara, F., Leypoldt, F., Geis, C., Lancaster, E., Titulaer, M. J., Rosenfeld, M. R., & Graus, F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019 Nov;18(11):1045–1057. doi: 10.1016/S1474-4422(19)30244-3.

5. Surovtseva A.V., Skripchenko N.V., Ivanova G.P., Pulman N.F., Konev A.I. Anti-NMDA receptor encephalitis. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2014;59(6):103–105. (In Russ.) https://doi.org/10.21508/1027-4065-2014-59-6-120-124

6. Pashkovsky V.I., Makarov S.A., Kalbus A.I., Andreychenko D.I., Zhogaleva O.V., Grishin V.I., Enotova N.V. Anti-NMDA-receptor Encephalitis: Current Literature Data, Analysis of Clinical Cases. Neurology and Neurosurgery. Eastern Europe. 2021;11(2):234– 244. http://doi.org/10.34883/PI.2021.11.2.038

7. Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M. R., BaliceGordon, R., Graus, F., & Dalmau, J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157–65. doi: 10.1016/S1474-4422(12)70310-1.

8. Liu CY, Zhu J, Zheng XY, Ma C, Wang X. Anti-N-MethylD-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis. Mediators Infl amm. 2017;2017:6361479. doi: 10.1155/2017/6361479.

9. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, VargasCañas S, Fricchione GL, Bayliss L, Martinez-Juarez IE, Hernandez-Vanegas LE, Martinez-Hernandez R, Bautista-Gomez P, Solis-Vivanco R, Perez-Esparza R, Bustamante-Gomez PA, Restrepo-Martinez M, Ramirez-Bermudez J. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019 Sep;73(9):574–580. doi: 10.1111/pcn.12867.

10. Lynch DR, Rattelle A, Dong YN, Roslin K, Gleichman AJ, Panzer JA. Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms. Adv Pharmacol. 2018;82:235–260. doi: 10.1016/bs.apha.2017.08.005.

11. Wang H. Effi cacies of treatments for anti-NMDA receptor encephalitis. Front Biosci (Landmark Ed). 2016 Jan 1;21(3):651– 63. doi: 10.2741/4412.

12. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391–404. doi: 10.1016/S1474-4422(15)00401-9.

13. Polonsky Е.L., Skulyabin D.I., Lapin S.V., Krasakov I.V., Tikhomirova O.V., Nazarov V.D., Моshnikova А.N., Litvinenko I.V., Slashcheva I.M., Маmatova N.T., Zakharova N.I., Sokolova N.A., Маzing А.V., Lyamina А.V., Belozerova I.B. [Polymorphism of autoimmune encephalitis]. Annals of Clinical and Experimental Neurology. 2019;13(2):79–91. (In Russ.) DOI: 10.25692/ACEN.2019.2.9

14. Murashko A.A., Ipatova S.L., Falkovich S.P. Pavlov K.A., Pavlova O.V., Gurina O.I., Shmukler A.B. Difficulties in Differential Diagnosis: A Case of Anti-NMDA Receptor Encephalitis. Social and Clinical Psychiatry. 2021;31(4):57–61. https://cyberleninka.ru/article/n/slozhnosti-differentsialnoy-diagnostiki-sluchay-anti-nmda-retseptornogo-entsefalita

15. Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391–419. doi: 10.1586/14737175.2015.1115720.

16. Gabilondo I, Saiz A, Galán L, González V, Jadraque R, Sabater L, Sans A, Sempere A, Vela A, Villalobos F, Viñals M, Villoslada P, Graus F. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011 Sep 6;77(10):996–9. doi: 10.1212/WNL.0b013e31822cfc6b.

17. Zhong R, Chen Q, Zhang X, Zhang H, Lin W. Relapses of Anti-NMDAR, Anti-GABABR and Anti-LGI1 Encephalitis: A Retrospective Cohort Study. Front Immunol. 2022 Jun 9;13:918396. doi: 10.3389/fimmu.2022.918396.

18. Gong X, Chen C, Liu X, Lin J, Li A, Guo K, Zhou D, Hong Z. Long-term Functional Outcomes and Relapse of Anti-NMDA Receptor Encephalitis: A Cohort Study in Western China. Neurol Neuroimmunol Neuroinfl amm. 2021 Feb 15;8(2):e958. doi: 10.1212/NXI.0000000000000958.

19. Feng J, Yang M, Cui D, Huang Z, Ji T, Lian Y. Recurrence of Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Cohort Study in Central China. Front Neurol. 2022 Mar 7;13:832634. doi: 10.3389/fneur.2022.832634.

20. Zeng W, Cao L, Zheng J, Yu L. Clinical characteristics and long-term prognosis of relapsing anti-N-methyl-D-aspartate receptor encephalitis: a retrospective, multicenter, self-controlled study. Neurol Sci. 2021 Jan;42(1):199–207. doi: 10.1007/s10072-02004482-7.

21. Nosadini M, Granata T, Matricardi S, Freri E, Ragona F, Papetti L, Suppiej A, Valeriani M, Sartori S. Italian Working Group on Paediatric Anti-N-methyl-D-aspartate Receptor Encephalitis. Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2019 Sep;61(9):1101–1107. doi: 10.1111/dmcn.14267.

22. AlShimemeri S, Alsaeed M, Lai J, Uy C, Javidan M. Delayed Nmethyl-D-aspartate Receptor Encephalitis Relapse. Can J Neurol Sci. 2020 Mar;47(2):264–266. doi: 10.1017/cjn.2019.332.

23. Kayal AK, Das M, Bhowmick S, Synmon B. Relapsing Anti-NMDAR Encephalitis after a gap of eight years in a girl from North-East India. Ann Indian Acad Neurol. 2014 Jul;17(3):349– 51. doi: 10.4103/0972-2327.138526.

24. Caravias G., Steffl bauer M., Vosko M.R., Janko O., Guger M., Ransmayr G., Gruber F. (2013). Immunoadsorption and cyclophosphamide in a relapse of an anti-NMDA-receptor-encephalitis. Journal of the Neurological Sciences. (2013). Immunoadsorption and cyclophosphamide in a relapse of an anti-NMDA-receptor-encephalitis. Journal of the Neurological Sciences. 333, e52. doi: 10.1016/j.jns.2013.07.186

25. Nakajima H, Unoda K, Hara M. Severe relapse of anti-NMDA receptor encephalitis 5 years after initial symptom onset. eNeurological Sci. 2019 Jul 19;16:100199. doi: 10.1016/j.ensci.2019.100199.

26. Nosadini M, Eyre M, Molteni E, Thomas T, Irani SR, Dalmau J, Dale RC, Lim M. International NMDAR Antibody Encephalitis Consensus Group; Anlar B, Armangue T, Benseler S, Cellucci T, Deiva K, Gallentine W, Gombolay G, Gorman MP, Hacohen Y, Jiang Y, Lim BC, Muscal E, Ndondo A, Neuteboom R, Rostásy K, Sakuma H, Sartori S, Sharma S, Tenembaum SN, Van Mater HA, Wells E, Wickstrom R, Yeshokumar AK. Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis. JAMA Neurol. 2021 Nov 1;78(11):1333–1344. doi: 10.1001/jamaneurol.2021.3188.

27. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011 Jan;10(1):63–74. doi: 10.1016/S1474-4422(10)70253-2.

28. Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R, Rosenfeld MR, Lynch D, Graus F, Dalmau J. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014 Feb;13(2):167–77. doi: 10.1016/S1474-4422(13)70282-5.

29. Hongzhi G, Weize K, Bin P, Yan H, Qiang L, Yuan J, Qing L, Hang S, Haitao R, Yicheng Z, Dawei S, Liying C. Clinical analysis of relapsing anti-N-methyl-D-aspartate receptor encephalitis. Zhonghua Yi Xue Za Zhi. 2015 Apr 7;95(13):996–1001. Chinese. PMID: 26506710.

30. Xu X, Lu Q, Huang Y, Fan S, Zhou L, Yuan J, Yang X, Ren H, Sun D, Dai Y, Zhu H, Jiang Y, Zhu Y, Peng B, Cui L, Guan H. Anti-NMDAR encephalitis: A single-center, longitudinal study in China. Neurol Neuroimmunol Neuroinfl amm. 2019 Oct 16;7(1):e633. doi: 10.1212/NXI.0000000000000633.

31. Yuan J, Peng B, Guan HZ, Huang Y, Lu Q, Ren HT, Yang XZ, Jiang N, Zhu YC, Cui LY. Immunotherapy strategy for 35 cases of severe anti-N-methyl-D-aspartate receptor encephalitis. Zhonghua Yi Xue Za Zhi. 2016 Apr 5;96(13):1035–9. Chinese. doi: 10.3760/cma.j.issn.0376-2491.2016.13.011.

32. Li Y, Zhang M, Liu D, Wei M, Sheng J, Wang Z, Xue S, Yu T, Xue W, Zhu B and He J (2018) The report of 7 cases of recurrence in autoimmune encephalitis and literature review. J Apoplexy Nerv Dis. 35:220–225

33. Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese MA, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010 Jun;133(Pt 6):1655–67. doi: 10.1093/brain/awq113.

34. Dale RC, Brilot F, Duff y LV, Twilt M, Waldman AT, Narula S, Muscal E, Deiva K, Andersen E, Eyre MR, Eleftheriou D, Brogan PA, Kneen R, Alper G, Anlar B, Wassmer E, Heineman K, Hemingway C, Riney CJ, Kornberg A, Tardieu M, Stocco A, Banwell B, Gorman MP, Benseler SM, Lim M. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014 Jul 8;83(2):142–50. doi: 10.1212/WNL.0000000000000570. Epub 2014 Jun 11.

35. Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin JP, Pike M, Pullaperuma S, Siddiqui A, Wassmer E, Waters P, Irani SR, Buckley C, Vincent A, Lim M. NMDA receptor antibodies associated with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm. 2014 Apr 24;1(1):e2. doi: 10.1212/NXI.0000000000000002.

36. Chiang S, Garg T, Hu A, Amin H, Davalos-Balderas A, Alfradique-Dunham I, Goldsmith CE. Pearls & Oy-sters: Relapse of anti-NMDA receptor encephalitis after prior first- and secondline immunotherapy. Neurology. 2018 May 15;90(20):936–939. doi: 10.1212/WNL.0000000000005517.