Volume 11, Issue 2 (2025)                   IEM 2025, 11(2): 189-203 | Back to browse issues page


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Jachman-Kapułka J, Rorat M. Anti-NMDA Receptor Encephalitis Associated with SARS-CoV-2 Infection in the COVID-19 Pandemic: A Systematic Review. IEM 2025; 11 (2) :189-203
URL: http://iem.modares.ac.ir/article-4-75413-en.html
1- Department of Internal Medicine and Rheumathology, J. Gromkowski Specialist Regional Hospital, Wroclaw, Poland , justyna.jachman@gmail.com
2- Department of Social Sciences and Infectious Diseases, Medical Faculty, Wroclaw University of Science and Technology, Poland
Abstract:   (196 Views)
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with neurological complications, like various autoimmune encephalitis (AE) types. This study aimed to identify and analyze COVID-19 cases diagnosed with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (anti-NMDARE).
Materials & Methods: This research summarized all post-pandemic reports. The review was conducted based on PRISMA (preferred reporting items for systematic reviews and meta-analyses) 2020 guidelines. Electronic databases were search using search terms to find anti-NMDARE cases associated with COVID-19.
Findings: After analyzing 649 records, 16 patients (ten women and six men) with a median age of 19.5 years were identified. All AE cases were confirmed by the presence of anti-NMDAR IgG, dominant behaviour and mental status changes, psychiatric symptoms, epileptic seizures, movement disorders, and sleep and speech problems. Abnormalities were more common in electroencephalography (EEG) and cerebrospinal fluid (CSF) than in brain MRI scans. All patients received first-line guideline-based therapy (intravenous methylprednisolone, intravenous immunoglobulin, plasma exchange), and five patients received second-line immunotherapy (rituximab, azathioprine, cyclophosphamide). Nine out of 16 patients had complete recovery or significant improvement.
Conclusion: Considering the magnitude of the pandemic and the few anti-NMDAR encephalitis cases temporally diagnosed with COVID-19, this association was relatively rare. The appearance of characteristic features of encephalitis during SARS-CoV-2 infection necessitates further diagnostic tests, especially detection of auto-antibodies and possible neoplasm, since earlier diagnosis and treatment provide a better prognosis. This review highlights the need for further investigation into the co-occurrence of anti-NMDARE with COVID-19, long-term clinical outcomes, and possible relapses.
Full-Text [PDF 668 kb]   (61 Downloads)    
Article Type: Systematic Review | Subject: Virology
Received: 2024/06/1 | Accepted: 2024/08/21 | Published: 2025/06/22

References
1. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90. [DOI:10.1001/jamaneurol.2020.1127] [PMID] []
2. Studart-Neto A, Guedes BF, Tuma RL, Camelo Filho AE, Kubota GT, Iepsen BD, et al. Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital. Arq Neuropsiquiatr. 2020;78(8):494-500. [DOI:10.1590/0004-282x20200089] [PMID]
3. Misra S, Kolappa K, Prasad M, Radhakrishnan D, Thakur KT, Solomon T, et al. Frequency of neurologic manifestations in COVID-19: A systematic review and meta-analysis. Neurology. 2021;97(23):e2269-81. [DOI:10.1212/WNL.0000000000012930] [PMID] []
4. Brola W, Wilski M. Neurological consequences of COVID-19. Pharmacol Rep. 2022;74(6):1208-22. [DOI:10.1007/s43440-022-00424-6] [PMID] []
5. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-83. [DOI:10.1016/S1474-4422(20)30221-0] [PMID]
6. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yan L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020;87:18-22. https://doi.org/10.1016/j.bbi.2020.04.043 [DOI:10.1016/j.bbi.2020.03.031]
7. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995-8. [DOI:10.1021/acschemneuro.0c00122] [PMID]
8. Yassin A, Nawaiseh M, Shaban A, Alsherbini K, El-Salem K, Soudah O, et al. Neurological manifestations and complications of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. BMC Neurol. 2021;21:1-7. [DOI:10.1186/s12883-021-02161-4] [PMID] []
9. Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol. 2021;268(9):3059-71. [DOI:10.1007/s00415-021-10406-y] [PMID] []
10. Nabizadeh F, Balabandian M, Sodeifian F, Rezaei N, Rostami MR, Moghadasi AN. Autoimmune encephalitis associated with COVID-19: A systematic review. Mult Scler Relat Dis. 2022;62:103795. [DOI:10.1016/j.msard.2022.103795] [PMID] []
11. Guedes BF. NeuroCOVID-19: A critical review. Arq Neuro Psiquiatr. 2022;80(5 Suppl 1):281-9. [DOI:10.1590/0004-282x-anp-2022-s136] [PMID] []
12. Pinzona RT, Wijayaa VO, Jodya AA, Nunsioa PN, Buana RB. Persistent neurological manifestations in long COVID-19 syndrome: A systematic review and meta-analysis. J Infect Public Health. 2022;15(8):856-69. [DOI:10.1016/j.jiph.2022.06.013] [PMID] []
13. Xue H, Zeng L, He X, Xu D, Ren K. Autoimmune encephalitis in COVID-19 patients: A systematic review of case reports and case series. Front Neurol. 2023;14:1207883. [DOI:10.3389/fneur.2023.1207883] [PMID] []
14. Stoian A, Stoian M, Bajko Z, Maier S, Andone S, Cioflinc RA, et al. Autoimmune encephalitis in COVID-19 infection: Our experience and systematic review of the literature. Biomedicines. 2022;10(4):774. [DOI:10.3390/biomedicines10040774] [PMID] []
15. Islam MA, Cavestro C, Alam SS, Kundu S, Kamal MA, Reza F. Encephalitis in patients with COVID-19: A systematic evidence-based analysis. Cells. 2022;11(16):2575. [DOI:10.3390/cells11162575] [PMID] []
16. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-51. [DOI:10.1056/NEJMra1708712] [PMID]
17. Kayser MS, Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res. 2016;176(1):36-40. [DOI:10.1016/j.schres.2014.10.007] [PMID] []
18. Miya K, Takahashi Y, Mori H. Anti-NMDAR autoimmune encephalitis. Brain Dev. 2014;36(8):645-52. [DOI:10.1016/j.braindev.2013.10.005] [PMID]
19. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A cohort study. Lancet Neurol. 2013;12(2):157-65. [DOI:10.1016/S1474-4422(12)70310-1] [PMID]
20. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: Mechanisms and models. Lancet Neurol. 2019;18(11):1045-57. [DOI:10.1016/S1474-4422(19)30244-3] [PMID]
21. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. [DOI:10.1016/S1474-4422(15)00401-9] [PMID]
22. Wang H. Anti-NMDA receptor encephalitis and vaccination. Int J Mol Sci. 2017;18(1):193. [DOI:10.3390/ijms18010193] [PMID] []
23. Schabitz WR, Rogalewski A, Hagemisteir C, Bien CG. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83(24):2309-11. [DOI:10.1212/WNL.0000000000001072] [PMID]
24. Vasilevska V, Guest PC, Bernstein HG, Schroeter ML, Geis C, Steiner J. Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases. J Neuroinflammation. 2021;18(1):1-8. [DOI:10.1186/s12974-021-02293-x] [PMID] []
25. McHattie AW, Coebergh J, Khan F, Morgante F. Palilalia as a prominent feature of anti-NMDA receptor encephalitis in a woman with COVID-19. J Neurol. 2021;268(11):3995-7. [DOI:10.1007/s00415-021-10542-5] [PMID] []
26. Mukherjee J, Goyal S, Arshad F, Nashi S, Srijithesh PR, Kulkarni GB, et al. Co-occurrence of anti-N-methyl-D-aspartate receptor encephalitis and COVID-19 infection: Case series of two patients with a brief review of literature. Asian J Med Sci. 2022;13(8):245-9. [DOI:10.3126/ajms.v13i8.44089]
27. Lee H, Jeon JH, Choi H, Koh SH, Lee KY, Lee YJ, et al. Anti-N-methyl-D-aspartate receptor encephalitis after coronavirus disease 2019. A case report and literature review. Medicine. 2022;101(35):e30464. [DOI:10.1097/MD.0000000000030464] [PMID] []
28. Allahyari F, Hosseinzadeh R, Nejad JH, Heiat M, Ranjbar R. A case report of simultaneous autoimmune and COVID-19 encephalitis. J Neurovirol. 2021;27(3):504-6. [DOI:10.1007/s13365-021-00978-w] [PMID] []
29. Alvarez Bravo G, Ramio IT. Anti-NMDA receptor encephalitis secondary to SARS-CoV-2 infection. Neurologia. 2020;35(9):699-700. [DOI:10.1016/j.nrl.2020.07.013] []
30. Alvi JR, Sultan MH, Sultan T. Post COVID anti-NMDAR encephalitis in an adolescent girl. Pak J Neurol Sci. 2022;17(1):16-20. [DOI:10.56310/pjns.v17i01.167]
31. Burr T, Barton C, Doll E, Lakhotia A, Sweeney M. N-methyl-d-aspartate receptor encephalitis associated with COVID-19 infection in a toddler. Pediatr Neurol. 2021;114:75-6. [DOI:10.1016/j.pediatrneurol.2020.10.002] [PMID] []
32. Derakhshani F, Ghazavi M, Hosseini N. Autoimmune encephalitis due to COVID-19 in a young patient. Iran J Child Neurol. 2023;17(2):135-42.
33. Kaur P, MV V, Madarkar BS. Infantile anti-N-methyl-D-aspartate receptor encephalitis post-SARS-CoV-2 infection. Indian Pediatr, 2022;59(4):343-4. [DOI:10.1007/s13312-022-2506-5] [PMID] []
34. Monti G, Giovannini G, Marudi A, Bedin R, Melegari A, Simone AM, et al. Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure. 2020;81:18-20. [DOI:10.1016/j.seizure.2020.07.006] [PMID] []
35. Panariello A, Bassetti R, Radice A, Rossotti R, Puoti M, Corradin M, et al. Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report. Brain Behav Immun. 2020;87:179-81. [DOI:10.1016/j.bbi.2020.05.054] [PMID] []
36. Saini L, Krishna D, Tiwari S, Goyal JP, Kumar P, Khera D, et al. Post-COVID-19 immune-mediated neurological complications in children: An ambispective study. Pediatr Neurol. 2022;136:20-7. [DOI:10.1016/j.pediatrneurol.2022.06.010] [PMID] []
37. Sanchez-Larsen A, Rojas-Bartolomé L, Fernández-Valiente M, Sopelana D. Anti-NMDA-R encephalitis post-COVID-19: Case report and proposed physiopathologic mechanism. Neurologia. 2023;38(7):513-6. [DOI:10.1016/j.nrl.2022.08.002] []
38. Sanchez-Morales AE, Urrutia-Osorio M, Camacho-Mendoza E, RosalesPedraza G, Davila-Maldonado L, Gonzalez-Duarte A, et al. Neurological manifestations temporally associated with SARS-CoV-2 infection in pediatric patients in Mexico. Childs Nerv Syst. 2021;37(7):2305-12. [DOI:10.1007/s00381-021-05104-z] [PMID] []
39. Sarigecili E, Arslan I, Ucar HK, Celik U. Pediatric anti-NMDA receptor encephalitis associated with COVID-19. Childs Nerv Syst. 2021;37(12):3919-22. [DOI:10.1007/s00381-021-05155-2] [PMID] []
40. Valadez-Calderon J, Navarro AO, Rodriguez-Chavez E, Vera-Lastra O. Co-expression of anti-NMDAR and anti-GAD65 antibodies. A case of autoimmune encephalitis in a post-COVID-19 patient. Neurologia. 2022;37(6):503-4. [DOI:10.1016/j.nrl.2021.09.003]
41. Joubert B, Dalmau J. The role of infections in autoimmune encephalitides. Rev Neurol. 2019;175(7-8):420-6. [DOI:10.1016/j.neurol.2019.07.004] [PMID]
42. Swayne A, Warren N, Prain K, Gillis D, Wong R, Blum S. Analysing triggers for anti-NMDA-receptor encephalitis including herpes simplex virus encephalitis and ovarian teratoma: Results from the Queensland Autoimmune Encephalitis cohort. Intern Med J. 2021;52(11):1943-9. [DOI:10.1111/imj.15472] [PMID]
43. Armangue T, Leypoldt F, Málaga I, Raspall‐Chaure M, Marti I, Nichter C, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317-23. [DOI:10.1002/ana.24083] [PMID] []
44. Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: A prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-72. [DOI:10.1016/S1474-4422(18)30244-8] [PMID]
45. Mohammad SS, Sinclair K, Pillai S, Merheb V, Aumann TD, Gill D, et al. Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-d-aspartate receptor or dopamine-2 receptor. Mov Disord. 2014;29(1):117-22. [DOI:10.1002/mds.25623] [PMID]
46. Leypoldt F, Titulaer MJ, Aguilar E, Walther J, Bönstrup M, Havemeister S, et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: Case report. Neurology. 2013;81(18):1637-9. [DOI:10.1212/WNL.0b013e3182a9f531] [PMID] []
47. Salovin A, Glanzman J, Roslin K, Armangue T, Lynch DR, Panzer JA. Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e458. [DOI:10.1212/NXI.0000000000000458] [PMID] []
48. Schäbitz WR, Rogalewski A, Hagemeister C, Bien C. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83(24):2309-11. [DOI:10.1212/WNL.0000000000001072] [PMID]
49. Ma J, Zhang T, Jiang L. Japanese encephalitis can trigger anti-N-methyl-D-aspartate receptor encephalitis. J Neurol. 2017;264:1127-31. [DOI:10.1007/s00415-017-8501-4] [PMID]
50. Xu CL, Liu L, Zhao WQ, Li JM, Wang RJ, Wang SH, et al. Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: A case report and one year follow-up. BMC Neurol. 2011;11:1-7. [DOI:10.1186/1471-2377-11-149] [PMID] []
51. Ioannidis P, Papadopoulos G, Koufou E, Parissis D, Karacostas D. Anti-NMDA receptor encephalitis possibly triggered by measles virus. Neurol Belg. 2015;115:801-2. [DOI:10.1007/s13760-015-0468-2] [PMID]
52. Moloney PB, Hutchinson S, Heskin J, Mulcahy F, Langan Y, Conlon NP, et al. Possible N-methyl-D-aspartate receptor antibody-mediated encephalitis in the setting of HIV cerebrospinal fluid escape. J Neurol. 2020;267(5):1348-52. [DOI:10.1007/s00415-019-09693-3] [PMID]
53. Pacheco-Herrero M, Soto-Rojas LO, Harrington CR, Flores-Martinez YM, Villegas-Rojas MM, León-Aguilar AM, et al. Elucidating the neuropathologic mechanisms of SARS-CoV-2 infection. Front Neurol. 2021;12:660087. [DOI:10.3389/fneur.2021.660087] [PMID] []
54. Wang H. COVID−19, anti-NMDA receptor encephalitis, and microRNA. Front Immunol. 2022;13:825103. [DOI:10.3389/fimmu.2022.825103] [PMID] []
55. Muñoz-Lopetegi A, de Bruijn MA , Boukhrissi S, Bastiaansen AE, Nagtzaam MM. Neurologic syndromes related to anti-GAD65. Clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm 2020;7(3):e696. [DOI:10.1212/NXI.0000000000000696] [PMID] []
56. Emekli AS, Parlak A, Göcen NY, Kürtüncü M. Anti-GAD associated post-infectious cerebellitis after COVID-19 infection. Neurol Sci. 2021;42:3995-4002. [DOI:10.1007/s10072-021-05506-6] [PMID] []
57. Salari M, Harofteh ZB, Etemadifar M. Autoimmune meningoencephalitis associated with anti‐glutamic acid decarboxylase antibody following COVID‐19 infection: A case report. Clin Case Rep. 2022;10(12):e6597. [DOI:10.1002/ccr3.6597] [PMID] []
58. Martin S, Azzouz B, Morel A, Trenque T. Anti-NMDA receptor encephalitis and vaccination: A disproportionality analysis. Front Pharmacol. 2022;13:940780. [DOI:10.3389/fphar.2022.940780] [PMID] []
59. Flannery P, Yang I, Keyvani M, Sakoulas G. Acute psychosis due to anti-N-methyl D-aspartate receptor encephalitis following COVID-19 vaccination: A case report. Front Neurol. 2021;12:764197. [DOI:10.3389/fneur.2021.764197] [PMID] []
60. Abdelhady M, Husain MA, Hawas Y, Elazb MA, Mansour LS, Mohamed M, et al. Encephalitis following COVID-19 vaccination: A systematic review. Vaccines. 2023;11(3):576. [DOI:10.3390/vaccines11030576] [PMID] []
61. Martin S, Azzouz B, Morel A, Tralongo F, Dorguin G, Trenque T. Anti-NMDA receptor encephalitis and COVID-19 vaccination? Fundam Clin Pharmacol. 2022;36 :99. [DOI:10.3389/fphar.2022.940780] [PMID] []

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