Neurological Consequences of COVID-19: A Literature Review of Pathophysiology, Clinical Manifestations, and Therapeutic Strategies
DOI:
https://doi.org/10.12775/QS.2025.41.60372Keywords
SARS-CoV-2, COVID-19, neurological disorders, nervous system, neuroinflammation, cognitive functions, neuropsychological rehabilitation, pathophysiology of the central nervous systemAbstract
The COVID-19 pandemic, caused by SARS-CoV-2, has become a major global health crisis with widespread effects on healthcare, society, and economies. Initially seen as a respiratory illness, it is now recognized as a multisystem disease, with growing evidence of its impact on the nervous system.
Neurological complications - such as cognitive impairment ("brain fog"), strokes, Guillain-Barré syndrome, and mood disorders - have been reported in both severe and mild COVID-19 cases, highlighting the unpredictable nature of post-COVID sequelae. These symptoms can persist long after the acute phase of infection.
The mechanisms behind these effects are complex and not yet fully understood. They include direct viral invasion of the central nervous system, immune dysregulation (e.g., cytokine storm, autoimmunity), and blood–brain barrier disruption, all of which may lead to neuroinflammation and neurodegeneration.
The long-term neurological consequences pose significant clinical and societal challenges, requiring multidisciplinary care and tailored rehabilitation strategies. This review summarizes current knowledge on the neurological manifestations of COVID-19, underlying mechanisms, and therapeutic approaches, aiming to inform evidence-based post-COVID care.
References
[1] WHO Director-General’s opening remarks at the media briefing on COVID-19–11 March 2020. Available at: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
[2] Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein [published correction appears in Cell. 2020 Dec 10;183(6):1735. doi: 10.1016/j.cell.2020.11.032.]. Cell. 2020;181(2):281-292.e6. https://doi.org/10.1016/j.cell.2020.02.058
[3] Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003;348(20):1953-1966. https://doi.org/10.1056/NEJMOA030781
[4] Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia [published correction appears in N Engl J Med. 2013 Jul 25;369(4):394]. N Engl J Med. 2012;367(19):1814-1820. https://doi.org/10.1056/NEJMoa1211721
[5] Bala A, Sengupta A, Matsabisa MG, Chabalala HP. Covid-19: Pathophysiology; Mechanism of Transmission and Possible Molecular Drug Target for Management. Curr Pharm Biotechnol. 2020. https://doi.org/10.2174/1874467213999200831104324
[6] Huang X, Wei F, Hu L, Wen L, Chen K. Epidemiology and Clinical Characteristics of COVID-19. Arch Iran Med. 2020;23(4):268-271. Published 2020 Apr 1. https://doi.org/10.34172/aim.2020.09
[7] Desai AD, Lavelle M, Boursiquot BC, Wan EY. Long-term complications of COVID-19. Am J Physiol Cell Physiol. 2022;322(1):C1-C11. https://doi.org/10.1152/ajpcell.00375.2021
[8] Koralnik IJ, Tyler KL. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020;88(1):1-11. https://doi.org/10.1002/ana.25807
[9] Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004;203(2):622-630. https://doi.org/10.1002/path.1560
[10] Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S2008.Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2. J Virol82:.https://doi.org/10.1128/jvi.00737-08
[11] Duong L, Xu P, Liu A. Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020. Brain Behav Immun. 2020;87:33. https://doi.org/10.1016/j.bbi.2020.04.024
[12] Huang YH, Jiang D, Huang JT. SARS-CoV-2 Detected in Cerebrospinal Fluid by PCR in a Case of COVID-19 Encephalitis. Brain Behav Immun. 2020;87:149. https://doi.org/10.1016/j.bbi.2020.05.012
[13] Dunai C, Collie C, Michael BD. Immune-Mediated Mechanisms of COVID-19 Neuropathology. Front Neurol. 2022;13:882905. https://doi.org/10.3389/fneur.2022.882905
[14] Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. https://doi.org/10.1016/S0140-6736(20)30628-0
[15] Pilotto A, Masciocchi S, Volonghi I, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Encephalitis Is a Cytokine Release Syndrome: Evidences From Cerebrospinal Fluid Analyses. Clin Infect Dis. 2021;73(9):e3019-e3026. https://doi.org/10.1093/cid/ciaa1933
[16] Domingues RB, Leite FBV, Senne C. Cerebrospinal fluid analysis in patients with COVID-19-associated central nervous system manifestations: a systematic review. Arq Neuropsiquiatr. 2022;80(5):430-439. https://doi.org/10.1590/0004-282X-ANP-2021-0117
[17] Michael BD, Bricio-Moreno L, Sorensen EW, et al. Astrocyte- and neuron-derived CXCL1 drives neutrophil transmigration and blood-brain barrier permeability in viral encephalitis. Cell Rep. 2020;32(6):108150. https://doi.org/10.1016/j.celrep.2020.108150
[18] Maiese A, Manetti AC, Bosetti C, et al. SARS-CoV-2 and the brain: a review of the current knowledge on neuropathology in COVID-19. Brain Pathol. 2021;31(6):e13013. https://doi.org/10.1111/bpa.13013
[19] Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393–e400. https://doi.org/10.1016/S2665-9913(20)30164-8
[20] Afzali B, Noris M, Lambrecht BN, Kemper C. The state of complement in COVID-19. Nat Rev Immunol. 2022;22(2):77–84. https://doi.org/10.1038/s41577-021-00665-1
[21] The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704. https://doi.org/10.1056/NEJMoa2021436
[22] Dotan A, Muller S, Kanduc D, et al. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun Rev. 2021;20(4):102792. https://doi.org/10.1016/j.autrev.2021.102792
[23] Kreye J, Reincke SM, Prüss H. Do cross-reactive antibodies cause neuropathology in COVID-19? Nat Rev Immunol. 2020;20(11):645–646. https://doi.org/10.1038/s41577-020-00458-y
[24] Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13. https://doi.org/10.1016/j.trsl.2020.04.007
[25] Gupta M, Weaver DF. COVID-19 as a trigger of brain autoimmunity. ACS Chem Neurosci. 2021;12(14):2558–2561. https://doi.org/10.1021/acschemneuro.1c00403
[26] Vanderheiden A, Klein RS. Neuroinflammation and COVID-19. Curr Opin Neurobiol. 2022;76:102608. https://doi.org/10.1016/j.conb.2022.102608
[27] Alquisiras-Burgos I, Peralta-Arrieta I, Alonso-Palomares LA, et al. Neurological complications associated with the blood-brain barrier damage induced by the inflammatory response during SARS-CoV-2 infection. Mol Neurobiol. 2021;58(9):3842–3855. https://doi.org/10.1007/s12035-020-02134-7
[28] Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683–690. https://doi.org/10.1001/jamaneurol.2020.1127
[29] Virhammar J, Kumlien E, Fallmar D, et al. Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid. Neurology. 2020;95(10):445–449. https://doi.org/10.1212/WNL.0000000000010250
[30] Anzalone N, Castellano A, Scotti R, et al. Multifocal laminar cortical brain lesions: a consistent MRI finding in neuro–COVID–19 patients. J Neurol. 2020;267(10):2806–2809. https://doi.org/10.1007/s00415-020-09966-2
[31] Espinosa PS, Rizvi Z, Sharma P, et al. Neurological complications of coronavirus disease (COVID-19): encephalopathy, MRI brain and cerebrospinal fluid findings: case 2. Cureus. 2020;12(5):e7930. https://doi.org/10.7759/cureus.7930
[32] Fischer D, Threlkeld ZD, Bodien YG, et al. Intact brain network function in an unresponsive patient with COVID-19. Ann Neurol. 2020;88(4):851–854. https://doi.org/10.1002/ana.25838
[33] Parsons T, Banks S, Bae C, et al. COVID–19–associated acute disseminated encephalomyelitis (ADEM). J Neurol. 2020;267(10):2799–2802. https://doi.org/10.1007/s00415-020-09951-9
[34] Nordvig AS, Mangala R, Lau JD, et al. Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions. Front Neurol. 2023;14:1150096. https://doi.org/10.3389/fneur.2023.1150096
[35] Junco B, Samano Martin Del Campo D, Karakeshishyan V, et al. Long-term brain fog and cognitive impairment in previously hospitalized COVID-19 patients. PLoS One. 2023;18(6):e0309102. https://doi.org/10.1371/journal.pone.0309102
[36] Lanz-Luces JR, Aceituno H, Quiroz-Bravo F, et al. Long-lasting brain fog is related with severity clusters of symptoms in COVID-19 patients. Rev Med Chil. 2022;150(11):1484. https://doi.org/10.4067/s0034-98872022001101484
[37] Cabett Cipolli G, Alonso V, Yasuda CL, et al. Cognitive impairment in post-acute COVID-19 syndrome: a scoping review. J Neurol Surg A Cent Eur Neurosurg. 2023;84(1):1–10. https://doi.org/10.1055/s-0043-1777115
[38] Khieukhajee J, Rojana-Udomsart A, Srisarakorn P, Wongsurit T, Aungsumart S. Cognitive impairment and risk factors in post-COVID-19 hospitalized patients. Eur Neurol. 2023;86(2):1–6. https://doi.org/10.1159/000531743
[39] Asadi-Pooya AA, Akbari A, Emami A, et al. Long COVID syndrome-associated brain fog. J Med Virol. 2023;95(1):e27404. https://doi.org/10.1002/jmv.27404
[40] Siow I, Lee KS, Zhang JJYZ, Saffari SE, Ng A, Young B. Stroke as a neurological complication of COVID-19: a systematic review and meta-analysis of incidence, outcomes and predictors. J Stroke Cerebrovasc Dis. 2021;30(3):105549. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105549
[41] Syzdoł B, Rzewuska AM, Sielwanowska W, et al. Ischemic stroke in the course of COVID-19 in a 16-year-old boy. J Clin Med. 2023;12(22):6963. https://doi.org/10.3390/jcm12226963
[42] Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19. Am J Emerg Med. 2020;38(7):1504–1507. https://doi.org/10.1016/j.ajem.2020.04.048
[43] Pimentel V, Wallau Luchsinger V, Leal Carvalho G, et al. Guillain-Barré syndrome associated with COVID-19: a systematic review. Brain Behav Immun Health. 2022;22:100578. https://doi.org/10.1016/j.bbih.2022.100578
[44] Mahmoud H, Alhathla A, El-Fiky A, et al. Incidence of Guillain-Barré syndrome post COVID-19: a systematic review of case reports and case series. Eur Rev Med Pharmacol Sci. 2023;27(5):2102–2114. https://doi.org/10.26355/eurrev_202303_31588
[45] Chmiela T, Rzepka M, Krzystanek E, Gorzkowska A. A 50-year-old patient with Guillain-Barré syndrome after COVID-19: a case report. Medicina (Kaunas). 2021;57(8):775. https://doi.org/10.3390/medicina57080775
[46] Filosto M, Cotti Piccinelli S, Gazzina S, et al. Guillain-Barré syndrome and COVID-19: a 1-year observational multicenter study. Eur J Neurol. 2022;29(9):2506–2514. https://doi.org/10.1111/ene.15497
[47] Masuccio FG, Tipa V, Invernizzi M, Solaro C. Guillain-Barré syndrome related and unrelated to COVID-19: clinical follow-up in the COVID-19 era. Phys Ther. 2022;102(5):pzac049. https://doi.org/10.1093/ptj/pzac049
[48] García-Molina A, García-Carmona S, Espiña-Bou M, et al. Neuropsychological rehabilitation for post–COVID-19 syndrome: results of a clinical programme and six-month follow up. Neurología (Engl Ed). 2022;37(9):729–737. https://doi.org/10.1016/j.nrleng.2022.06.007
[49] García-Molina A, Espiña-Bou M, Rodríguez-Rajo P, et al. Neuropsychological rehabilitation program for patients with post-COVID-19 syndrome: a clinical experience. Neurología (Engl Ed). 2021;36(8):567–572. https://doi.org/10.1016/j.nrleng.2021.03.003
[50] Mathern R, Senthil P, Vu N, Thiyagarajan T. Neurocognitive rehabilitation in COVID-19 patients: a clinical review. South Med J. 2022;115(3):174–179. https://doi.org/10.14423/SMJ.0000000000001371
[51] Sobrino-Relaño S, Balboa-Bandeira Y, Peña J, et al. Neuropsychological deficits in patients with persistent COVID-19 symptoms: a systematic review and meta-analysis. Sci Rep. 2023;13:12633. https://doi.org/10.1038/s41598-023-37420-6
[52] Łojek E, Egbert AR, Gambin M, et al. Neuropsychological disorders after COVID-19. Urgent need for research and clinical practice. Psychiatr Pol. 2021;55(6):1231–1244. https://doi.org/10.5114/ppn.2021.108474
[53] Frontera JA, Guekht A, Allegri RF, et al. Evaluation and treatment approaches for neurological post-acute sequelae of COVID-19: a consensus statement and scoping review from the global COVID-19 neuro research coalition. J Neurol Sci. 2023;452:120827. https://doi.org/10.1016/j.jns.2023.120827
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Copyright (c) 2025 Paulina Łobaza, Martyna Kudła, Gabriela Zając, Mikołaj Antkiewicz, Aleksandra Arczyńska, Julia Kociuba, Dorota Kołkowicz, Zuzanna Kruczek, Agata Krawczyk, Natalia Pawełczak
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