Pathogenetic mechanisms of neurologycal post COVID syndrome and the basis of its pathogenetic treatment and prevention (literature review) 

Tat'yana I. Vlasova, Doctor of medical sciences, associate professor, professor of the sub-department of normal and pathological physiology, Medical Institute, Ogarev Mordovia State University (68 Bolshevistskaya street, Saransk, Russia), E-mail: v.t.i@bk.ru
Mariya A. Spirina, Candidate of medical scinences, associate professor of the sub-department of normal and pathological physiology, Medical Institute, Ogarev Mordovia State University (68 Bolshevistskaya street, Saransk, Russia), E-mail: v.t.i@bk.ru
Ekaterina V. Arsent'eva, Candidate of medical scinences, associate professor, associate professor of the sub-department of normal and pathological physiology, Medical Institute, Ogarev Mordovia State University (68 Bolshevistskaya street, Saransk, Russia), E-mail: ev.arsenteva@yandex.ru
Elena A. Shamrova, Candidate of medical scinences, associate professor, associate professor of the sub-department of normal and pathological physiology, Medical Institute, Ogarev Mordovia State University (68 Bolshevistskaya street, Saransk, Russia), E-mail: v.t.i@bk.ru
Anastasiya V. Sitdikova, Postgraduate student, Medical Institute, Ogarev Mordovia State University (68 Bolshevistskaya street, Saransk, Russia), E-mail: v.t.i@bk.ru 

616-092.18 

10.21685/2072-3032-2021-4-11 

The neurological manifestations in the post COVID period are identified about 34 % of surviving patients. Currently, the term “neurological post COVID syndrome” is proposed, which includes the functional or organic brain disorders after the survived COVID infection. The presence of neurological complications after COVID gave the beginning of research on studying the impact of this viral infection on neurons. However, the total pathophysiological mechanism of nerve cells disorders remains understandable only partially and requires additional research and clarification. In the article such the probable factors of the neurological post-person syndrome pathogenesis, as chronic hypoxia, the pathological immune response, the direct damaging action of the virus and the neurotropism of immune complexes, the endothelial dysfunction of the brain vessels, the state of the intestinal microbiota and the complication of therapy used for the treatment of acute SARSCOV-2 are discussed. In accordance with these mechanisms, recommendations on the pathogenetic treatment and prevention of neurological post COVID syndrome are given. 

neurological post COVID syndrome, COVID-19, neurotropism, endothelial dysfunction, pathological immune response, microbiota 

1. Harapan B.N.,Yoo H.J. Neurological Symptoms, Manifestations, and Complications Associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 19 (COVID-19). Journal of Neurology. 2021;268:3059–3071. Available at: https://doi.org/10.1007/s00415-021-10406-y
2. Wijeratne T., Crewther S. COVID-19 and Long-Term Neurological Problems: Challenges Ahead with Post-COVID-19 Neurological Syndrome. Australian Journal of General Practice. 2021;50. Available at: https://doi.org/10.31128/AJGP-COVID-43
3. Taquet M., Geddes J.R., Husain M. [et al.]. 6-Month Neurological and Psychiatric Outcomes in 236 379 Survivors of COVID-19: A Retrospective Cohort Study Using Electronic Health Records. The Lancet Psychiatry. 2021;8(5):416–427. Available at: https://doi.org/10.1016/S2215-0366(21)00084-5
4. Huang C., Huang L., Wang Y. [et al.]. 6-Month Consequences of COVID-19 in Patients Discharged from Hospital: A Cohort Study. The Lancet. 2021;397(10 270):220–232. Available at: https://doi.org/10.1016/S0140-6736(20)32656-8
5. Shepeleva I.I., Chernysheva A.A., Kir'yanova E.M. [et al.]. COVID-19: damage to the nervous system and psychological and psychiatric complications. Cotsial'naya i klinicheskaya psikhiatriya = Social and clinical psychiatry. 2020;30(4):76–82. (In Russ.)
6. Morgul E., Bener A., Atak M. [et al.]. COVID-19 Pandemic and Psychological Fatigue in Turkey. Int. J. Soc. Psychiatry. 2021;67(2):128–135. Available at: https://doi.org/ 10.1177/0020764020941889
7. Nordvig A.S., Fong K.T., Willey J.Z. [et al.]. Potential Neurologic Manifestations of COVID-19. Neurol. Clin. Pract. 2021;11(2):e135–e146. Available at: https://doi.org/ 10.1212/cpj.0000000000000897
8. Ostroumova T.M., Chernousov P.A., Kuznetsov I.V. Cognitive impairments in patients after COVID-19. Nevrologiya, neyropsikhiatriya, psikhosomatika = Neurology, neuropsychiatry, psychosomatics. 2021;13(1):126–130. (In Russ.). doi:10.14412/2074-2711-2021-1-126-130
9. Iadecola C., Anrather J., Kamel H. Effects of COVID-19 on the Nervous System. Cell. 2020;183(1):16–27. Available at: https://doi.org/10.1016/j.cell.2020.08.028
10. Nuzzo D., Vasto S., Scalisi L. [et al.]. Post-Acute COVID-19 Neurological Syndrome: A New Medical Challenge. J. Clin. Med. 2021;10(9):1947. Available at: https://doi.org/10.3390/jcm10091947
11. Wang Z., Yang Y., Liang X. COVID-19 Associated Ischemic Stroke and Hemorrhagic Stroke: Incidence, Potential Pathological Mechanism, and Management. Front. Neurol. 2020;11. Available at: https://doi.org/10.3389/fneur.2020.571996
12. Liotta E.M., Batra A., Clark J.R. [et al.]. Frequent Neurologic Manifestations and Encephalopathy-Associated Morbidity in Covid-19 Patients. Ann. Clin. Transl. Neurol. 2020;7(11):2221–2230. Available at: https://doi.org/10.1002/acn3.51210
13. Needham E., Newcombe V., Michell A. [et al.]. Mononeuritis Multiplex: An Unexpectedly Frequent Feature of Severe COVID-19. Journal of Neurology. 2021;268:2685–2689. Available at: https://doi.org/10.1007/s00415-020-10321-8
14. Wijeratne T., Crewther S. Post-COVID 19 Neurological Syndrome (PCNS); a Novel Syndrome with Challenges for the Global Neurology Community. J. Neurol. Sci. 2020;419:117179. Available at: https://doi.org/10.1016/j.jns.2020.117179
15. Belopasov V.V., Zhuravleva E.N., Nugmanova N.P. [et al.]. Postcovid neurological syndromes. Klinicheskaya praktika = Clinical practice. 2021;12(2):69–82. (In Russ.). doi:10.17816/clinpract71137
16. Ambardar S.R., Hightower S.L., Huprikar N.A. [et al.]. Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic. J. Clin. Med. 2021;10:2452.
17. Khoury M.K., Gupta K., Franco S.R. [et al.]. Necroptosis in the Pathophysiology of Disease. Am. J. Pathol. 2020;190:272–285.
18. Archer S.L., Sharp W.W., Weir E.K. Differentiating COVID-19 Pneumonia from Acute Respiratory Distress Syndrome (ARDS) and High Altitude Pulmonary Edema (HAPE): Therapeutic Implications. Circulation. 2020;142(2):101–104. Available at: https://doi.org/10.1161/circulationaha.120.047915
19. Donina Zh.A., Baranova E.V., Aleksandrova N.P. Influence of inhibition of cyclooxygenase pathways on resistance to progressive hypoxia in rats with elevated levels of interleukin-1 beta. Rossiyskiy fiziologicheskiy zhurnal imeni I. M. Sechenova = Russian Physiological journal named after I. M. Sechenov. 2020;106(11):1400–1411. (In Russ.). doi:10.31857/S0869813920110047
20. Boyko A.N., Sivertseva S.A., Spirin N.N. Nervous system damage in COVID-19 infection with a focus on the management of patients with multiple sclerosis. Nevrologiya, neyropsikhiatriya, psikhosomatika = Neurology, neuropsychiatry, psychosomatics. 2020;12(1C):44–47. (In Russ.). doi:10.14412/2074-2711-2020-1S-44-47
21. Serrano-Castro P.J., Estivill-Torrus G., Cabezudo-Garcia P. [et al.]. Impact of SARSCoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic? Neurologia. 2020;35(4):245–251. doi:10.7759/cureus.8192
22. Kempuraj D., Selvakumar G. P., Ahmed M. E. [et al.]. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. The Neuroscientist. 2020;26(5–6):402–414. doi:10.1177/1073858420941476
23. Monroy-Gómez J., Torres-Fernández O. Effects of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) on the Nervous System. What Can We Expect from SARS-CoV-2? Biomedica. 2020;40(2):173–179. Available at: https://doi.org/10.7705/BIOMEDICA. 5682
24. Ellul M.A., Benjamin L., Singh B. [et al.]. Neurological Associations of COVID-19. The Lancet. Neurology. 2020;19(9):767–783. Available at: https://doi.org/10.1016/ S1474-4422(20)30221-0
25. Strumentova E.S., Lobzin V.Yu., Lobzin S.V. Sense of smell impairment, damage to the central nervous system and the risk of developing neurodegenerative diseases in COVID-19. Opinion Leader. 2020;(8):28–34. (In Russ.)
26. Bostancıklıoğlu M. Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2. Inflammatory bowel diseases. 2020;26(8):e89–e91. Available at: https://doi.org/10.1093/ibd/izaa131
27. Cantuti-Castelvetri L., Ojha R., Pedro L.D. [et al.]. Neuropilin-1 Facilitates SARSCoV-2 Cell Entry and Infectivity. Science. 2020;370(6518):856–860. Available at: https://doi.org/10.1126/science.abd2985
28. Baig A.M., Khaleeq A., Ali U. Evidence of the COVID-19 Virus Targeting the CNS: Tis-sue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem. Neurosci. 2020;11(7):995–998. Available at: https://doi.org/10.1021/ acschemneuro.0c00122
29. Webb S., Wallace V.C.J., Martin-Lopez D. [et al.]. Guillain-Barré Syndrome Following COVID-19: A Newly Emerging Post-Infectious Complication. BMJ Case Rep. 2020;13(6). Available at: https://doi.org/10.1136/bcr-2020-236182
30. Wijeratne T., Wijeratne C. Clinical Utility of Serial Systemic Immune Inflammation Indices (SSIIi) in the Context of Post Covid-19 Neurological Syndrome (PCNS). J. Neurol. Sci. 2021;423:117356. Available at: https://doi.org/10.1016/j.jns.2021.117356
31. Azkur A.K., Akdis M., Azkur D. [et al.]. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020;75(7):doi:10.1111/ all.14364
32. Coperchini F., Chiovato L., Croce L. [et al.]. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020;53:25–32. Available at: https://doi.org/10.1016/j.cytogfr. 2020.05.003
33. Nuzzo D., Picone P. Potential Neurological Effects of Severe COVID-19 Infection. Neurosci. Res. 2020;158:1–5. Available at: https://doi.org/10.1016/j.neures. 2020.06.009
34. Heneka M.T., Golenbock D., Latz E. [et al.]. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alz. Res. Therapy. 2020;12(69). Available at: https://doi.org/10.1186/s13195-020-00640-3
35. Espíndola O.M., Brandão C.O., Gomes Y.C.P. [et al.]. Cerebrospinal Fluid Findings in Neurological Diseases Associated with COVID-19 and Insights into Mechanisms of Disease Development. Int. J. Infect. Dis. 2021;102:155–162. Available at: https://doi.org/10.1016/j.ijid.2020.10.044
36. Novikova L.B., Akopyan A.P., Sharapova K.M. [et al.]. Neurological and mental disorders associated with COVID-19. Arterial'naya gipertenziya = Arterial hypertension. 2020;26(3):317–326. (In Russ.). doi:10.18705/1607-419X-2020-26-3-317-326
37. Wichmann D., Sperhake J.P., Lütgehetmann M. [et al.]. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann. Intern. Med. 2020;173(4):268–277. doi:10.7326/M20-2003
38. Keragala C.B., Draxler D.F., McQuilten Z.K. [et al.]. Haemostasis and innate immunity – a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. Br. J. Haematol. 2018;180(6):782–798. doi:10.1111/bjh.15062
39. Khoury M.K., Gupta K., Franco S.R. [et al.]. Necroptosis in the Pathophysiology of Disease. Am. J. Pathol. 2020;190:272–285. doi:10.1016/j.ajpath.2019.10.012
40. Xu K., Wei Y., Giunta S. [et al.]. Do inflammaging and coagulaging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people? Exp. Gerontol. 2021;151:111423. doi:10.1016/j.exger.2021.111423
41. Bikdeli B., Madhavan M.V., Jimenez D. [et al.]. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow- Up. J. Am. Coll. Cardiol. 2020;75:2950–2973. doi:10.1016/j.jacc.2020.04.031
42. Kurushina O.V., Barulin A.E. Damage to the central nervous system in COVID-19. Zhurnal nevrologii i psikhiatrii imeni S. S. Korsakova = Journal of neurology and psychiatry named after S. S. Korsakov. 2021;121(1):92–97. (In Russ.)
43. Sousa L.P., Pinho V., Teixeira M.M. Harnessing Inflammation Resolving-Based Therapeutic Agents to Treat Pulmonary Viral Infections: What Can the Future Offer to COVID-19? British Journal of Pharmacology. 2020;177(17):3898–3904. Available at: https://doi.org/10.1111/bph.15164
44. Michaelsen V.S., Ribeiro R.V.P., Brambate E. [et al.]. A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide. PLoS One. 2021;16(10):e0258368. doi:10.1371/journal.pone.0258368
45. Ferreto L.E.D., Bortoloti D.S., Fortes P.C.N. [et al.]. Dexamethasone for treating SARS-CoV-2 infection: a systematic review and meta-analysis. Sao Paulo Med J. 2021;139(6):657–661. doi:10.1590/1516-3180.2021.0120.R1.30062021
46. Gavriatopoulou M., Ntanasis-Stathopoulos I., Korompoki E. [et al.]. Emerging treatment strategies for COVID-19 infection. Clin. Exp. Med. 2021;21(2):167–179. doi:10.1007/s10238-020-00671-y
47. Zhang R., Wang X., Ni L. [et al.]. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;250:117583. doi:10.1016/j.lfs.2020.117583
48. Kempuraj D., Thangavel R., Kempuraj D.D. [et al.]. Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma. Biofactors. 2021;47(2):190–197. doi:10.1002/biof.1687
49. Xu Y., Baylink D.J., Chen C.S. [et al.]. The importance of vitamin D metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19. J Transl Med. 2020;18(1):322. doi:10.1186/s12967-020-02488-5
50. Xiong Y., Zhu G.H., Wang H.N. [et al.]. Discovery of naturally occurring inhibitors against SARS-CoV-2 3CLpro from Ginkgo biloba leaves via large-scale screening. Fitoterapia. 2021;152:104909. doi:10.1016/j.fitote.2021.104909
51. Kharlamenkova N.E., Bykhovets Yu.V., Dan M.V. [et al.]. Experiencing uncertainty, anxiety, anxiety in the context of COVID-19. Psikhologicheskiy zhurnal = Journal of psychology. 2020. (In Russ.). Available at: http://ipras.ru/cntnt/rus/institut_p/covid- 19/kommentarii-eksp/har-1.html
52. Dorozhenok I.Yu. Depression during the COVID-19 pandemic (analysis of clinical cases). Nevrologiya, neyropsikhiatriya, psikhosomatika = Neurology, neuropsychiatry, psychosomatics. 2021;13(1):81–86. (In Russ.). doi:10.14412/2074-2711-2021-1- 81-86