Preview

Clinical Medicine (Russian Journal)

Advanced search
Open Access Open Access  Restricted Access Subscription Access

Pathogenesis of nervous system lesions and clinical syndromes of the new coronavirus infection COVID-19

https://doi.org/10.30629/0023-2149-2024-102-9-10-707-713

Abstract

Based on the analysis of literature data, the issues of neurological complications after the new coronavirus infection COVID-19 are highlighted. There is little evidence for a direct mechanism for the neuroinvasiveness and neurotoxicity of the SARS-CoV-2 virus. Various mechanisms of coronavirus penetration into the brain are discussed - anterograde and retrograde, neuronal spread, transcriptional and hematogenous pathways. Retrograde/anterograde transport and transsynaptic transfer of the virus have been confi rmed by in vitro studies. Penetration of the virus into the central nervous system is also possible by spreading through peripheral nerves, for example, along the vagus nerve, which innervates the lungs and intestines. 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 endothelial cells of blood vessels and capillaries, infection of leukocytes by viruses and transfer of viruses through the blood-brain barrier. Hypoxia caused by cytokine storm and respiratory distress lead to disruption of brain metabolism and the development of neurological complications.

Aim. Analysis of literature data on the study of early and long-term manifestations of neurological disorders and diseases during a new coronavirus infection, postCovid syndrome (long COVID-19), as well as after vaccination.

Results. Among the large number of nervous system disorders, 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; 3) ischemic strokes; 4) peripheral neuropathies, in particular Guillain–Barre syndrome and brachial plexopathies; 5) other disorders of the central nervous system.

About the Authors

M. B. Patsenko
Military Medical Academy named after S.M. Kirov (Branch, Moscow) of the Ministry of Defense of the Russia
Russian Federation

Mikhail B. Patsenko — Doctor of Medical Sciences, Associate Professor, Chief Therapist of the Ministry of Defense of the Russian Federation, Head of the Department of Emergency Medicine 

Moscow



V. L. Glotko
Military Medical Academy named after S.M. Kirov (Branch, Moscow) of the Ministry of Defense of the Russia
Russian Federation

Vladimir L. Glotko — Doctor of Medical Sciences, Associate Professor of the Department of Emergency Medicine 

Moscow



E. A. Shirokov
Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russia
Russian Federation

Evgeniy A. Shirokov — Doctor of Medical Sciences, Professor of the Department of Cardiology

Moscow



I. N. Gaivoronskii
Military Medical Academy named after S.M. Kirov (Branch, Moscow) of the Ministry of Defense of the Russia
Russian Federation

Ivan N. Gaivoronskii — Candidate of Medical Sciences, Associate Professor of the Department of Emergency Medicine 

Moscow



References

1. 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;267(8):2179–2184. PMID: 32458193; PMCID: PMC7249973. DOI: 10.1007/s00415-020-09929-7

2. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565574. PMID: 32007145; PMCID: PMC7159086. DOI: 10.1016/ S0140- 6736(20)30251-8

3. Lukiw W.J., Pogue A., Hill J.M. SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell. Mol. Neurobiol. 2020:1–8. DOI: 10.1007/s10571-020-00947-7

4. Paniz-Mondolfi A., Bryce C., Grimes Z., Gordon R.E., Reidy J., Lednicky J., Sordillo E.M., Fowkes M. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARSCoV-2). J. Med. Virol. 2020;92(7):699–702. PMID: 32314810; PM-CID: PMC7264598. DOI: 10.1002/jmv.25915

5. Millet J.K., Whittaker G.R.. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology. 2018;517:3–8. PMID: 29275820; PMCID: PMC7112017. DOI: 10.1016/j. virol.2017.12.015

6. Matías-Guiu J., Gomez-Pinedo U., Montero-Escribano P., Gomez-Iglesias P., Porta-Etessam J., Matias-Guiu J.A. Should we expect neurological symptoms in the SARS-CoV-2 epidemic? Neurologia (Engl Ed). 2020;35(3):170–175. English, Spanish. PMID: 32299636; PMCID: PMC7136883. DOI: 10.1016/j.nrl.2020.03.001

7. Yang N., Shen H.M. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19. Int. J. Biol. Sci. 2020;16(10):1724–1731. PMID: 32226290; PMCID: PMC7098027. DOI: 10.7150/ijbs.45498

8. Sanclemente-Alaman I., Moreno-Jiménez L., Benito-Martín M.S., Canales-Aguirre A., Matías-Guiu J.A., Matías-Guiu J., Gómez-Pinedo U. Experimental models for the study of central nervous system infection by SARS-CoV-2. Front. Immunol. 2020;11:2163. PMID: 32983181; PMCID: PMC7485091. DOI: 10.3389/fimmu.2020.02163

9. Baig A.M., Khaleeq A., Ali U., Syeda H. Evidence of the COVID19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 2020;11(7):995–998. Epub 2020 Mar 13. PMID: 32167747; PMCID: PMC7094171. DOI: 10.1021/acschemneuro.0c00122

10. Amin M., Sorour M.K., Kasry A. Comparing the binding interactions in the receptor binding domains of SARS CoV-2 and SARS-CoV. J. Phys. Chem. Lett. 2020;11(12):4897–4900. PMID: 32478523; PMCID: PMC7294866. DOI: 10.1021/acs.jpclett.0c01064

11. 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;11(15):2361–2369. PMID: 32627524; PMCID: PMC7374936. DOI: 10.1021/acschemneuro.0c00373

12. Gussow A.B., Auslander N., Faure G., Wolf Y.I., Zhang F., Koonin E.V. Genomic determinants of pathogenicity in SARS CoV-2 and other human coronaviruses. Proc. Natl. Acad. Sci. USA. 2020;117(26):15193–15199. PMID: 32522874; PMCID: PMC7334499. DOI: 10.1073/pnas.2008176117

13. 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;367(6485):1444–1448. PMID: 32132184; PMCID: PMC7164635. DOI: 10.1126/science.abb2762

14. 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 metaanalysis. J. Neurol. 2020;267(10):2777–2789. PMID: 32529575; PMCID: PMC7288253. DOI: 10.1007/s00415-020-09974-2

15. Acharya A., Kevadiya B.D., Gendelman H.E., Byrareddy S.N. SARS-CoV-2 Infection Leads to Neurological Dysfunction. J. Neuroimmune Pharmacol. 2020;15(2):167–173. PMID: 32447746; PMCID: PMC7244399. DOI: 10.1007/s11481-020-09924-9

16. Rothan H.A., Byrareddy S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J. Autoimmun. 2020;109:102433. PMID: 32113704; PMCID: PMC7127067. DOI: 10.1016/j.jaut.2020.102433

17. Helms J., Kremer S., Merdji H., Clere-Jehl R., Schenck M., Kummerlen C.et al. Neurologic features in severe SARS-CoV-2 infection. N. Engl. J. Med. 2020;382(23):2268–2270. PMID: 32294339; PMCID: PMC7179967. DOI: 10.1056/NEJMc2008597

18. Chen X., Laurent S., Onur O.A., Kleineberg N.N., Fink G.R., Schweitzer F., Warnke C. A systematic review of neurological symptoms and complications of COVID-19. J. Neurol. 2021;268(2):392–402. PMID: 32691236; PMCID: PMC7370630. DOI: 10.1007/s00415-020-10067-3

19. Li Y.C., Bai W.Z., Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J. Med. Virol. 2020;92(6):552–555. PMID: 32104915; PMCID: PMC7228394. DOI: 10.1002/jmv.25728

20. Glass W.G., Subbarao K., Murphy B., Murphy P.M. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 2004;173(6):4030–9. PMID: 15356152. DOI: 10.4049/jimmunol.173.6.4030

21. Li K., Wohlford-Lenane C., Perlman S., Zhao J., Jewell A.K., Reznikov L.R.et al. Middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J. Infect. Dis. 2016;213(5):712–22. PMID: 26486634; PMCID: PMC4747621. DOI: 10.1093/infdis/jiv499

22. Talbot P.J., Ekandé S., Cashman N.R., Mounir S., Stewart J.N. Neuro tropism of human coronavirus 229E. Adv. Exp. Med. Biol. 1993;342:339–46. PMID: 8209751. DOI: 10.1007/978-1-4615-2996-5_52

23. Dubé M., Le Coupanec A., Wong A.H.M., Rini J.M., Desforges M., Talbot P.J. Axonal Transport Enables Neuron-to-Neuron Propagation of Human Coronavirus OC43. J. Virol. 2018;92(17):e00404– 18. PMID: 29925652; PMCID: PMC6096804. DOI: 10.1128/JVI.00404-18

24. Zhang B.Z., Chu H., Han S., Shuai H., Deng J. Hu Y.F. et al. SARSCoV-2 infects human neural progenitor cells and brain organoids. Cell. Res. 2020;30(10):928–931. PMID: 32753756; PMCID: PMC7399356. DOI: 10.1038/s41422-020-0390-x

25. Brann D.H., Tsukahara T., Weinreb C., Lipovsek M., Van den Berge K., Gong B.et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci. Adv. 2020;6(31):eabc5801. PMID: 32937591. DOI: 10.1126/sciadv.abc5801

26. Bullen C.K., Hogberg H.T., Bahadirli-Talbott A., Bishai W.R., Hartung T., Keuthan C.et al. Infectability of human Brain-Sphere neurons suggests neurotropism of SARSCoV-2. ALTEX. 2020;37(4):665–671. PMID: 32591839. DOI: 10.14573/ altex.2006111

27. Yavarpour-Bali H., Ghasemi-Kasman M. Update on neurological manifestations of COVID-19. Life Sci. 2020;257:118063. PMID: 32652139; PMCID: PMC7346808. DOI: 10.1016/j.lfs.2020.118063

28. Zubair A.S., McAlpine L.S., Gardin T., Farhadian S., Kuruvilla D.E., Spudich S. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol. 2020;77(8):1018–1027. PMID: 32469387; PMCID: PMC7484225. DOI: 10.1001/jamaneurol.2020.2065

29. Li Y.C, Bai W.Z., 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;521(1):203–12. PMID: 22700307; PMCID: PMC7162419. DOI: 10.1002/cne.23171

30. Kim W.K., Corey S., Alvarez X., Williams K. Monocyte/ macrophage traffic in HIV and SIV encephalitis. J. Leukoc. Biol. 2003;74(5):650–6. PMID: 12960230. DOI: 10.1189/jlb.0503207

31. Dey J., Alam M.T., Chandra S., Gupta J., Ray U., Srivastava A.K., Tripathi P.P. Neuroinvasion of SARS-CoV-2 may play a role in the breakdown of the respiratory center of the brain. J. Med. Virol. 2021;93(3):1296–1303. PMID: 32964419. DOI: 10.1002/jmv.26521

32. Iadecola C., Anrather J., Kamel H. Eff ects of COVID-19 on the Nervous System. Cell. 2020;183(1):16–27.e1. PMID: 32882182; PMCID: PMC7437501. DOI: 10.1016/j.cell.2020.08.028

33. Li Z., Liu T., Yang N., Han D., Mi X., Li Y.et al. Neurological manifestations of patients with COVID-19: potential routes of SARSCoV-2 neuroinvasion from the periphery to the brain. Front. Med. 2020;14(5):533–541. PMID: 32367431; PMCID: PMC7197033. DOI: 10.1007/s11684-020-0786-5

34. Al-Obaidi M.M.J., Bahadoran A., Wang S.M., Manikam R., Raju C.S., Sekaran S.D. 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. PMID: 29521099. DOI: 10.4149/av_2018_102

35. Miner J.J., Diamond M.S. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. Curr. Opin. Immunol. 2016;38:18– 23. PMID: 26590675; PMCID: PMC4715944. DOI: 10.1016/j. coi.2015.10.008

36. Gu J., Gong E., Zhang B., Zheng J., Gao Z., Zhong Y.et al. Multiple organ infection and the pathogenesis of SARS. J. Exp. Med. 2005;202(3):415–24. PMID: 16043521; PMCID: PMC2213088. DOI: 10.1084/jem.20050828

37. Desforges M., Miletti T.C., Gagnon M., Talbot P.J. Activation of human monocytes after infection by human coronavirus 229E. Virus Res. 2007;130(1–2):228–40. virusres.2007.06.016. PMID: 17669539; PMCID: PMC7114174. DOI: 10.1016/j

38. Barrantes F.J. Central nervous system targets and routes for SARSCoV-2: current views and new hypotheses. ACS Chem. Neurosci. 2020;11(18):2793–2803. PMID: 32845609; PMCID: PMC7460807. DOI: 10.1021/acschemneuro.0c00434

39. Yachou Y., 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;41(10):2657–2669. PMID: 32725449; PMCID: PMC7385206. DOI: 10.1007/s10072-020-04575-3

40. 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):683–690. PMID: 32275288; PMCID: PMC7149362. DOI: 10.1001/jamaneurol.2020.1127

41. Almeria M., Cejudo J.C., Sotoca J., Deus J., Krupinski J. Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment. Brain Behav. Immun. Health. 2020;9:100163. PMID: 33111132; PMCID: PMC7581383. DOI: 10.1016/j.bbih.2020.100163

42. Jacomy H., Fragoso G., Almazan G., Mushynski W.E., Talbot P.J. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology. 2006;349(2):335–46. PMID: 16527322; PMCID: PMC7111850. DOI: 10.1016/j.virol.2006.01.049

43. Matthews A.E., Weiss S.R., Paterson Y. Murine hepatitis virus-— a model for virus-induced CNS demyelination. J. Neurovirol. 2002;8(2):76–85. PMID: 11935460; PMCID: PMC7095071. DOI: 10.1080/13550280290049534

44. Ellul M.A., Benjamin L., Singh B., Lant S., Michael B.D., Easton A. et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767–783. PMID: 32622375; PMCID: PMC7332267. DOI: 10.1016/S1474-4422(20)30221-0

45. Groiss S.J., Balloff C., Elben S., Brandenburger T.., Müttel T., Kindgen-Milles D. et al. Prolonged neuropsychological deficits, central nervous system involvement, and brain stem affection after COVID-19-A case series. Front. Neurol. 2020;11:574004. PMID: 33224088; PMCID: PMC7674620. DOI: 10.3389/fneur.2020.574004

46. Rogers J.P., Chesney E., Oliver D., Pollak T.A., McGuire P., FusarPoli P.et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and metaanalysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7(7):611–627. PMID: 32437679; PMCID: PMC7234781. DOI: 10.1016/S2215-0366(20)30203-0

47. Bougakov D., Podell K., Goldberg E. Multiple Neuroinvasive Pathways in COVID-19. Mol. Neurobiol. 2021;58(2):564–575. PMID: 32990925; PMCID: PMC7523266. DOI: 10.1007/s12035-020-02152-5

48. Varatharaj A., Thomas N., Ellul M.A., Davies N.W.S., Pollak T.A., Tenorio E.L. et al., CoroNerve Study Group. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020;7(10):875–882. Erratum in: Lancet Psychiatry. 2020 Jul 14; PMID: 32593341; PMCID: PMC7316461. DOI: 10.1016/S2215-0366(20)30287-X

49. 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;21(1):138. PMID: 33784985; PMCID: PMC8007661. DOI: 10.1186/s12883-021-02161-4

50. Hamming I., Timens W., Bulthuis M.L., Lely A.T., 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. 2004Jun;203(2):631–7. PMID: 15141377; PMCID: PMC7167720. DOI: 10.1002/path.1570

51. Sungnak W., Huang N., Bécavin C., Berg M., Queen R., Litvinukova M. et al., HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 2020;26(5):681–687. PMID: 32327758; PMCID: PMC8637938. DOI: 10.1038/s41591-020-0868-6

52. Sedaghat A.R., Gengler I., Speth M.M. Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 With Public Health Significance. Otolaryngol. Head Neck Surg. 2020;163(1):12–15. PMID: 32366160. DOI: 10.1177/0194599820926464

53. Cabello-Verrugio C., Morales M.G., Rivera J.C., Cabrera D., Simon F. Renin-angiotensin system: an old player with novel functions in skeletal muscle. Med. Res. Rev. 2015;35(3):437–63. Epub 2015 Mar 11. PMID: 25764065. DOI: 10.1002/med.21343

54. Ding Y., He L., Zhang Q., Huang Z., Che X., Hou J.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):622–30. PMID: 15141376; PMCID: PMC7167761. DOI: 10.1002/path.1560

55. Disser N.P., De Micheli A.J., Schonk M.M., Konnaris M.A., Piacentini A.N., Edon D.L.et al. Musculoskeletal consequences of COVID19. J. Bone Joint Surg. Am. 2020;102(14):1197–1204. PMID: 32675661; PMCID: PMC7508274. DOI: 10.2106/JBJS.20.00847

56. Zakeri A., Jadhav A.P., Sullenger B.A., Nimjee S.M. Ischemic stroke in COVID-19-positive patients: an overview of SARS-CoV-2 and thrombotic mechanisms for the neurointer ventionalis. J. Neurointer. v Surg. 2021;13(3):202–206. PMID: 33298508. DOI: 10.1136/neurintsurg-2020-016794

57. Devreese K.M.J., Linskens E.A., Benoit D., Peperstraete H. Antiphospholipid antibodies in patients with COVID19: A relevant observation? J. Thromb. Haemost. 2020;18(9):2191–2201. PMID: 32619328; PMCID: PMC7361253. DOI: 10.1111/jth.14994

58. Mankad K., Perry M.D., Mirsky D.M., Rossi A. COVID-19: A primer for Neuroradiologists. Neuroradiology. 2020;62(6):647–648. PMID: 32342126; PMCID: PMC7186113. DOI: 10.1007/s00234-020-02437-5

59. Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J.; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. PMID: 32192578; PMCID: PMC7270045. DOI: 10.1016/S0140-6736(20)30628-0

60. Akhmerov A., Marbán E. COVID-19 and the Heart. Circ. Res. 2020;126(10):1443–1455. PMID: 32252591. DOI: 10.1161/CIRCRESAHA.120.317055

61. 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;194:105921. PMID: 32422545; PMCID: PMC7227498. DOI: 10.1016/j.clineuro.2020.105921

62. Paterson R.W., Brown R.L., Benjamin L., Nortley R., Wiethoff S., Bharucha T.et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020;143(10):3104–3120. PMID: 32637987; PMCID: PMC7454352. DOI: 10.1093/brain/awaa240

63. Chen X., Laurent S., Onur O.A., Kleineberg N.N., Fink G.R., Schweitzer F., Warnke C. A systematic review of neurological symptoms and complications of COVID-19. J. Neurol. 2021;268(2):392–402. PMID: 32691236; PMCID: PMC7370630. DOI: 10.1007/s00415-020-10067-3

64. Yao X.H., He Z.C., Li T.Y., Zhang H.R., Wang Y., Mou H., Guo Q., Yu S.C., Ding Y., Liu X., Ping Y.F., Bian X.W. Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient. Cell. Res. 2020;30(6):541–543. PMID: 32346074; PMCID: PMC7186763. DOI: 10.1038/s41422-020-0318-5


Review

For citations:


Patsenko M.B., Glotko V.L., Shirokov E.A., Gaivoronskii I.N. Pathogenesis of nervous system lesions and clinical syndromes of the new coronavirus infection COVID-19. Clinical Medicine (Russian Journal). 2024;102(9-10):707–713. (In Russ.) https://doi.org/10.30629/0023-2149-2024-102-9-10-707-713

Views: 247


ISSN 0023-2149 (Print)
ISSN 2412-1339 (Online)