COVID-19: infection and neurological complications

Authors

DOI:

https://doi.org/10.25305/unj.243599

Keywords:

COVID-19, SARS-CoV-2 virus , neurotoxicity, neurological complications

Abstract

The issues of neurological complications after coronavirus disease 2019 (COVID-19) are highlighted, since coronaviruses affect not only the respiratory system but also other organs and systems of the body, notably they can cause neurological disorders and diseases. There is little evidence for a direct mechanism of SARS-CoV-2 virus neuroinvasiveness and neurotoxicity. Various mechanisms of coronavirus invasion into the brain are discussed - anterograde and retrograde, neuronal spread, transcriptional and hematogenous pathways. Retrograde / anterograde transport and transsynaptic transmission of the virus have been confirmed by in vitro studies, notably SARS-CoV-2 can enter the central nervous system through olfactory nerve receptor cells. Once in the olfactory bulb, the coronavirus can spread to the cortex and other brain structures, in particular the hippocampus and spinal cord. Invasion of the virus into the central nervous system is also possible by spreading along peripheral nerves, such as along the vagus nerve, which innervates the lungs and intestines. The virus invasion into the central nervous system through the blood-brain barrier is considered to be one of the most frequent routes. There are several possible mechanisms for the spread of SARS-CoV-2 across the blood-brain barrier (circulation of viral particles in the bloodstream, viral transcytosis through vascular and capillary endothelial cells, infection of leukocytes with viruses and their transmission of viruses across the blood-brain barrier ("Trojan horse")). However, there is no robust evidence of CNS infection with SARS-CoV-2. Hypoxia induced by the cytokine storm and respiratory distress lead to the impairment of brain metabolism and neurological complications development. There is an ongoing debate as to whether neurological disorders are primary neurological symptoms or secondary consequences of acute respiratory distress syndrome and inflammation.

Among the large number of disorders of the nervous system, there are five main types with long-term neurological complications associated with COVID-19: 1) encephalopathy with delirium / psychosis, 2) inflammatory syndromes of the central nervous system, including encephalitis, myelitis, acute disseminated encephalomyelitis, 3) ischemic strokes (half of them with pulmonary embolism), 4) peripheral neuropathies, Guillain-Barré syndrome and brachial plexopathies, 5) other disorders of the central nervous system.

Incompleteness or inconsistency of statistical data on neurological complications after infection was noted. Further study is required of all early and long-term manifestations of neurological disorders and diseases in mild and asymptomatic manifestations of infection, acute and long COVID-19 and after vaccination.

Author Biographies

Mykola I. Lisianiy, Romodanov Neurosurgery Institute, Kyiv

Department of Neuroimmunology

Eugene G. Pedachenko, Romodanov Neurosurgery Institute, Kyiv

Director

References

Zhou Z, Kang H, Li S, Zhao X. Understanding the neurotropic characteristics of SARS-CoV-2: from neurological manifestations of COVID-19 to potential neurotropic mechanisms. J Neurol. 2020 Aug;267(8):2179-2184. doi: 10.1007/s00415-020-09929-7.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565-574. doi: 10.1016/S0140-6736(20)30251-8.

Lukiw WJ, Pogue A, Hill JM. SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell Mol Neurobiol (2020) 1–8. doi:10.1007/s10571-020-00947-7

Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020 Jul;92(7):699-702. doi: 10.1002/jmv.25915.

Millet JK, Whittaker GR. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology. 2018 Apr;517:3-8. doi: 10.1016/j.virol.2017.12.015.

Matías-Guiu J, Gomez-Pinedo U, Montero-Escribano P, Gomez-Iglesias P, Porta-Etessam J, Matias-Guiu JA. Should we expect neurological symptoms in the SARS-CoV-2 epidemic? Neurologia (Engl Ed). 2020 Apr;35(3):170-175. English, Spanish. doi: 10.1016/j.nrl.2020.03.001.

Yang N, Shen HM. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19. Int J Biol Sci. 2020 Mar 15;16(10):1724-1731. doi: 10.7150/ijbs.45498.

Sanclemente-Alaman I, Moreno-Jiménez L, Benito-Martín MS, Canales-Aguirre A, Matías-Guiu JA, Matías-Guiu J, Gómez-Pinedo U. Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2. Front Immunol. 2020 Aug 28;11:2163. doi: 10.3389/fimmu.2020.02163.

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 Apr 1;11(7):995-998. doi: 10.1021/acschemneuro.0c00122.

Amin M, Sorour MK, Kasry A. Comparing the Binding Interactions in the Receptor Binding Domains of SARS-CoV-2 and SARS-CoV. J Phys Chem Lett. 2020 Jun 18;11(12):4897-4900. doi: 10.1021/acs.jpclett.0c01064.

Hassanzadeh K, Perez Pena H, Dragotto J, Buccarello L, Iorio F, Pieraccini S, Sancini G, Feligioni M. Considerations around the SARS-CoV-2 Spike Protein with Particular Attention to COVID-19 Brain Infection and Neurological Symptoms. ACS Chem Neurosci. 2020 Aug 5;11(15):2361-2369. doi: 10.1021/acschemneuro.0c00373.

Gussow AB, Auslander N, Faure G, Wolf YI, Zhang F, Koonin EV. Genomic determinants of pathogenicity in SARS-CoV-2 and other human coronaviruses. Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15193-15199. doi: 10.1073/pnas.2008176117.

Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-1448. doi: 10.1126/science.abb2762.

Wang L, Shen Y, Li M, Chuang H, Ye Y, Zhao H, Wang H. Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis. J Neurol. 2020 Oct;267(10):2777-2789. doi: 10.1007/s00415-020-09974-2.

Acharya A, Kevadiya BD, Gendelman HE, Byrareddy SN. SARS-CoV-2 Infection Leads to Neurological Dysfunction. J Neuroimmune Pharmacol. 2020 Jun;15(2):167-173. doi: 10.1007/s11481-020-09924-9.

Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020 May;109:102433. doi: 10.1016/j.jaut.2020.102433.

Chen X, Laurent S, Onur OA, Kleineberg NN, Fink GR, Schweitzer F, Warnke C. A systematic review of neurological symptoms and complications of COVID-19. J Neurol. 2021 Feb;268(2):392-402. doi: 10.1007/s00415-020-10067-3.

Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, Anheim M, Meziani F. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020 Jun 4;382(23):2268-2270. doi: 10.1056/NEJMc2008597.

Zhang BZ, Chu H, Han S, Shuai H, Deng J, Hu YF, Gong HR, Lee AC, Zou Z, Yau T, Wu W, Hung IF, Chan JF, Yuen KY, Huang JD. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 2020 Oct;30(10):928-931. doi: 10.1038/s41422-020-0390-x.

Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Jun;92(6):552-555. doi: 10.1002/jmv.25728.

Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol. 2004 Sep 15;173(6):4030-9. doi: 10.4049/jimmunol.173.6.4030.

Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr. Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4. J Infect Dis. 2016 Mar 1;213(5):712-22. doi: 10.1093/infdis/jiv499.

Talbot PJ, Ekandé S, Cashman NR, Mounir S, Stewart JN. Neurotropism of human coronavirus 229E. Adv Exp Med Biol. 1993;342:339-46. doi: 10.1007/978-1-4615-2996-5_52.

Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M, Talbot PJ. Axonal Transport Enables Neuron-to-Neuron Propagation of Human Coronavirus OC43. J Virol. 2018 Aug 16;92(17):e00404-18. doi: 10.1128/JVI.00404-18.

Li YC, Bai WZ, Hirano N, Hayashida T, Taniguchi T, Sugita Y, Tohyama K, Hashikawa T. Neurotropic virus tracing suggests a membranous-coating-mediated mechanism for transsynaptic communication. J Comp Neurol. 2013 Jan 1;521(1):203-12. doi: 10.1002/cne.23171.

Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, Chance R, Macaulay IC, Chou HJ, Fletcher RB, Das D, Street K, de Bezieux HR, Choi YG, Risso D, Dudoit S, Purdom E, Mill J, Hachem RA, Matsunami H, Logan DW, Goldstein BJ, Grubb MS, Ngai J, Datta SR. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020 Jul 31;6(31):eabc5801. doi: 10.1126/sciadv.abc5801.

Bullen CK, Hogberg HT, Bahadirli-Talbott A, Bishai WR, Hartung T, Keuthan C, Looney MM, Pekosz A, Romero JC, Sillé FCM, Um P, Smirnova L. Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2. ALTEX. 2020;37(4):665-671. doi: 10.14573/altex.2006111.

Yavarpour-Bali H, Ghasemi-Kasman M. Update on neurological manifestations of COVID-19. Life Sci. 2020 Sep 15;257:118063. doi: 10.1016/j.lfs.2020.118063.

Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol. 2020 Aug 1;77(8):1018-1027. doi: 10.1001/jamaneurol.2020.2065.

Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the Nervous System. Cell. 2020 Oct 1;183(1):16-27.e1. doi: 10.1016/j.cell.2020.08.028.

Kim WK, Corey S, Alvarez X, Williams K. Monocyte/macrophage traffic in HIV and SIV encephalitis. J Leukoc Biol. 2003 Nov;74(5):650-6. doi: 10.1189/jlb.0503207.

Dey J, Alam MT, Chandra S, Gupta J, Ray U, Srivastava AK, Tripathi PP. Neuroinvasion of SARS-CoV-2 may play a role in the breakdown of the respiratory center of the brain. J Med Virol. 2021 Mar;93(3):1296-1303. doi: 10.1002/jmv.26521.

Li Z, Liu T, Yang N, Han D, Mi X, Li Y, Liu K, Vuylsteke A, Xiang H, Guo X. Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. Front Med. 2020 Oct;14(5):533-541. doi: 10.1007/s11684-020-0786-5.

Al-Obaidi MMJ, Bahadoran A, Wang SM, Manikam R, Raju CS, Sekaran SD. Disruption of the blood brain barrier is vital property of neurotropic viral infection of the central nervous system. Acta Virol. 2018;62(1):16-27. doi: 10.4149/av_2018_102.

Miner JJ, Diamond MS. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. Curr Opin Immunol. 2016 Feb;38:18-23. doi: 10.1016/j.coi.2015.10.008.

Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, Zhuang H, Wu B, Zhong H, Shao H, Fang W, Gao D, Pei F, Li X, He Z, Xu D, Shi X, Anderson VM, Leong AS. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005 Aug 1;202(3):415-24. doi: 10.1084/jem.20050828.

Desforges M, Miletti TC, Gagnon M, Talbot PJ. Activation of human monocytes after infection by human coronavirus 229E. Virus Res. 2007 Dec;130(1-2):228-40. doi: 10.1016/j.virusres.2007.06.016.

Barrantes FJ. Central Nervous System Targets and Routes for SARS-CoV-2: Current Views and New Hypotheses. ACS Chem Neurosci. 2020 Sep 16;11(18):2793-2803. doi: 10.1021/acschemneuro.0c00434.

Yachou Y, El Idrissi A, Belapasov V, Ait Benali S. Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients. Neurol Sci. 2020 Oct;41(10):2657-2669. doi: 10.1007/s10072-020-04575-3.

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-690. doi: 10.1001/jamaneurol.2020.1127.

Almeria M, Cejudo JC, Sotoca J, Deus J, Krupinski J. Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment. Brain Behav Immun Health. 2020 Dec;9:100163. doi: 10.1016/j.bbih.2020.100163.

Jacomy H, Fragoso G, Almazan G, Mushynski WE, Talbot PJ. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology. 2006 Jun 5;349(2):335-46. doi: 10.1016/j.virol.2006.01.049.

Matthews AE, Weiss SR, Paterson Y. Murine hepatitis virus--a model for virus-induced CNS demyelination. J Neurovirol. 2002 Apr;8(2):76-85. doi: 10.1080/13550280290049534.

Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, Kneen R, Defres S, Sejvar J, Solomon T. Neurological associations of COVID-19. Lancet Neurol. 2020 Sep;19(9):767-783. doi: 10.1016/S1474-4422(20)30221-0.

Groiss SJ, Balloff C, Elben S, Brandenburger T, Müttel T, Kindgen-Milles D, Vollmer C, Feldt T, Kunstein A, Ole Jensen BE, Hartung HP, Schnitzler A, Albrecht P. Prolonged Neuropsychological Deficits, Central Nervous System Involvement, and Brain Stem Affection After COVID-19-A Case Series. Front Neurol. 2020 Nov 5;11:574004. doi: 10.3389/fneur.2020.574004.

Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, Zandi MS, Lewis G, David AS. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020 Jul;7(7):611-627. doi: 10.1016/S2215-0366(20)30203-0.

Bougakov D, Podell K, Goldberg E. Multiple Neuroinvasive Pathways in COVID-19. Mol Neurobiol. 2021 Feb;58(2):564-575. doi: 10.1007/s12035-020-02152-5.

Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL, Sultan M, Easton A, Breen G, Zandi M, Coles JP, Manji H, Al-Shahi Salman R, Menon DK, Nicholson TR, Benjamin LA, Carson A, Smith C, Turner MR, Solomon T, Kneen R, Pett SL, Galea I, Thomas RH, Michael BD; CoroNerve Study Group. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020 Oct;7(10):875-882. doi: 10.1016/S2215-0366(20)30287-X.

Yassin A, Nawaiseh M, Shaban A, Alsherbini K, El-Salem K, Soudah O, Abu-Rub M. Neurological manifestations and complications of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. BMC Neurol. 2021 Mar 30;21(1):138. doi: 10.1186/s12883-021-02161-4.

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. doi: 10.1002/path.1570.

Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB, Yoshida M, Barnes JL; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020 May;26(5):681-687. doi: 10.1038/s41591-020-0868-6.

Sedaghat AR, Gengler I, Speth MM. Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 With Public Health Significance. Otolaryngol Head Neck Surg. 2020 Jul;163(1):12-15. doi: 10.1177/0194599820926464.

Cabello-Verrugio C, Morales MG, Rivera JC, Cabrera D, Simon F. Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med Res Rev. 2015 May;35(3):437-63. doi: 10.1002/med.21343.

Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, Wang H, Shen H, Qiu L, Li Z, Geng J, Cai J, Han H, Li X, Kang W, Weng D, Liang P, Jiang S. 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 Jun;203(2):622-30. doi: 10.1002/path.1560.

Disser NP, De Micheli AJ, Schonk MM, Konnaris MA, Piacentini AN, Edon DL, Toresdahl BG, Rodeo SA, Casey EK, Mendias CL. Musculoskeletal Consequences of COVID-19. J Bone Joint Surg Am. 2020 Jul 15;102(14):1197-1204. doi: 10.2106/JBJS.20.00847.

Zakeri A, Jadhav AP, Sullenger BA, Nimjee SM. Ischemic stroke in COVID-19-positive patients: an overview of SARS-CoV-2 and thrombotic mechanisms for the neurointerventionalist. J Neurointerv Surg. 2021 Mar;13(3):202-206. doi: 10.1136/neurintsurg-2020-016794.

Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: A relevant observation? J Thromb Haemost. 2020 Sep;18(9):2191-2201. doi: 10.1111/jth.14994.

Mankad K, Perry MD, Mirsky DM, Rossi A. COVID-19: A primer for Neuroradiologists. Neuroradiology. 2020 Jun;62(6):647-648. doi: 10.1007/s00234-020-02437-5.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0.

Akhmerov A, Marbán E. COVID-19 and the Heart. Circ Res. 2020 May 8;126(10):1443-1455. doi: 10.1161/CIRCRESAHA.120.317055. Epub 2020 Apr 7. PMID: 32252591.

Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg. 2020 Jul;194:105921. doi: 10.1016/j.clineuro.2020.105921.

Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, Vivekanandam V, Khoo A, Geraldes R, Chinthapalli K, Boyd E, Tuzlali H, Price G, Christofi G, Morrow J, McNamara P, McLoughlin B, Lim ST, Mehta PR, Levee V, Keddie S, Yong W, Trip SA, Foulkes AJM, Hotton G, Miller TD, Everitt AD, Carswell C, Davies NWS, Yoong M, Attwell D, Sreedharan J, Silber E, Schott JM, Chandratheva A, Perry RJ, Simister R, Checkley A, Longley N, Farmer SF, Carletti F, Houlihan C, Thom M, Lunn MP, Spillane J, Howard R, Vincent A, Werring DJ, Hoskote C, Jäger HR, Manji H, Zandi MS. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020 Oct 1;143(10):3104-3120. doi: 10.1093/brain/awaa240.

Chen X, Laurent S, Onur OA, Kleineberg NN, Fink GR, Schweitzer F, Warnke C. A systematic review of neurological symptoms and complications of COVID-19. J Neurol. 2021 Feb;268(2):392-402. doi: 10.1007/s00415-020-10067-3.

Yao XH, He ZC, Li TY, Zhang HR, Wang Y, Mou H, Guo Q, Yu SC, Ding Y, Liu X, Ping YF, Bian XW. Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient. Cell Res. 2020 Jun;30(6):541-543. doi: 10.1038/s41422-020-0318-5.

Published

2022-03-27

How to Cite

Lisianiy, M. I. ., & Pedachenko, E. G. . (2022). COVID-19: infection and neurological complications. Ukrainian Neurosurgical Journal, 28(1), 3–9. https://doi.org/10.25305/unj.243599

Issue

Section

Review articles