The incidence and pathophysiology of neurological symptoms in COVID-19

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Abstract

The central nervous system seems to be quite vulnerable to SARS-CoV-2, leading to a variety of alteration pathways, high incidence and variability of the neurological symptoms of COVID-19. The COVID-19 symptoms, possibly associated with alteration to the central nervous system, include hyperthermia, shortness of breath, fatigue, headache, dizziness, dysphonia, dysphagia, hyposmia and anosmia, hypogeusia and ageusia, impairment of consciousness. The impairment of olfaction and gustation are the most common symptoms of the nervous system alteration (98% and 70%, respectively), which is most likely a consequence of the alteration of the receptors. Presumably the pathogenesis of dysphonia and dysphagia may involve neurodegenerative mechanisms or may be associated with a predominantly demyelinating alteration of the caudal cranial nerves. Pathomorphological findings in the brain of the COVID-19 patients include diffuse hypoxic and focal ischemic injuries of various sizes up to ischemic infarctions (in thrombosis of large arteries); microangiopathy; vasculitis; diapedetic and confluent hemorrhages with possible progression to hemorrhagic infarctions and rarely intracerebral hematomas. Acute cerebrovascular accident worsens the course of COVID-19 and can worsen the clinical outcome, taking into account the mechanisms of the central nervous system alteration in highly contagious coronavirus infections (SARS-CoV, MERS, SARS-CoV-2), including embolism, hypoxia, neurodegeneration, systemic inflammatory response and immune-mediated alteartion to the nervous tissue. A fairly rare complication of coronavirus infection, however, acute myelitis requires attention due to the severity of neurological disorders. The literature data show high incidence and polymorphism of the symptoms of the central nervous system alteration, as well as the important role of the cerebrovascular and neurodegenerative pathogenesis of brain alteration in COVID-19, which is taken into account in examining and treating the patients with new coronavirus infection. (1 figure, bibliography: 61 refs)

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About the authors

Igor V. Litvinenko

S.M. Kirov Military Medical Academy

Email: litvinenkoiv@rambler.ru
ORCID iD: 0000-0001-8988-3011
SPIN-code: 6112-2792
ResearcherId: F-9120-2013

D.Sc. (Medicine), Professor

Russian Federation, Saint Petersburg

Miroslav M. Odinak

S.M. Kirov Military Medical Academy

Email: odinak@rambler.ru
ORCID iD: 0000-0002-7314-7711
SPIN-code: 1155-9732
Scopus Author ID: 7003327776
ResearcherId: I-6024-2016

Corresponding Member of the Russian
Academy of Sciences, D.Sc. (Medicine), Professor

Russian Federation, Saint Petersburg

Nikolay V. Tsygan

S.M. Kirov Military Medical Academy

Email: 77tn77@gmail.com
ORCID iD: 0000-0002-5881-2242
SPIN-code: 1006-2845
Scopus Author ID: 37066611200
ResearcherId: H-9132-2016

D.Sc. (Medicine), Associate Professor

Russian Federation, Saint Petersburg

Aleksander V. Ryabtsev

S.M. Kirov Military Medical Academy

Author for correspondence.
Email: ryabtsev_av@pnpi.nrcki.ru
ORCID iD: 0000-0002-3832-2780
SPIN-code: 9915-4960
ResearcherId: AAD-3948-2019
Russian Federation, Saint Petersburg

References

  1. Chen X, Laurent S, Onur OA, et al. A systematic review of neurological symptoms and complications of COVID-19. J Neurol. 2021;268(2):392–402. doi: 10.1007/s00415-020-10067-3
  2. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospita lized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683–690. doi: 10.1001/jamaneurol.2020.1127
  3. Yan CH, Faraji F, Prajapati DP, et al. Self-reported olfactory loss associates with outpatient clinical course in COVID-19. International Forum of Allergy & Rhinology. 2020;10(7):821–831. doi: 10.1002/alr.22592
  4. Yan CH, Faraji F, Prajapati DP, et al. Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms. International Forum of Allergy & Rhinology. 2020;10(7):806–813. doi: 10.1002/alr.22579
  5. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;277(8):2251–2261. doi: 10.1007/s00405-020-05965-1
  6. Santos REA, da Silva MG, do Monte Silva MCB, et al. Onset and duration of symptoms of loss of smell/taste in patients with COVID-19: A systematic review. Am J Otolaryngol. 2021;42(2):102889. doi: 10.1016/j.amjoto.2020.102889
  7. Beltrán-Corbellini Á, Chico-García JL, Martínez-Poles J, et al. Acute-onset smell and taste disorders in the context of COVID-19: a pilot multicentre polymerase chain reaction based case–control study. European Journal of Neurology. 2020;27(9):1738–1741. doi: 10.1111/ene.14273
  8. Lechien JR, Chiesa-Estomba CM, Place S, et al. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. Journal of Internal Medicine. 2020;288(3):335–344. doi: 10.1111/joim.13089
  9. Collantes MEV, Espiritu AI, Sy MCC, Anlacan VMM, Jamora RDG. Neurological Manifestations in COVID-19 Infection: A Systematic Review and Meta-Analysis. Can J Neurol Sci. 2021;48(1):66–76. doi: 10.1017/cjn.2020.146
  10. Cagnazzo F, Arquizan C, Derraz I, et al. Neurological manifestations of patients infected with the SARS-CoV-2: a systematic review of the literature. J Neurol. 2021;268(8):2656–2665. doi: 10.1007/s00415-020-10285-9
  11. Kim GU, Kim MJ, Ra SH, et al. Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19. Clin Microbiol Infect. 2020;26(7):948.e1–948.e3. doi: 10.1016/j.cmi.2020.04.040
  12. Soltani S, Tabibzadeh A, Zakeri A, et al. COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis. Rev Neurosci. 2021;32(3):351–361. doi: 10.1515/revneuro-2020-0108
  13. Garg S. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 – COVID-NET, 14 States, March 1–30, 2020. Weekly. 2020;69(15):458–464. doi: 10.15585/mmwr.mm6915e3
  14. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110–118. doi: 10.1016/j.jaci.2020.04.006
  15. Godaert L, Proye E, Demoustier-Tampere D, et al. Clinical characteristics of older patients: The experience of a geriatric short-stay unit dedicated to patients with COVID-19 in France. J Infect. 2020;81(1): e93–e94. doi: 10.1016/j.jinf.2020.04.009
  16. Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV-2 Infection. New England Journal of Medicine. 2020;382(23):2268–2270. doi: 10.1056/NEJMc2008597
  17. Li K, Wohlford-Lenane C, Perlman S, 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):712–722. doi: 10.1093/infdis/jiv499
  18. Netland J, Meyerholz DK, Moore S, et al. Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2. Journal of Virology. 2008;82(15):7264–7275. doi: 10.1128/JVI.00737-08
  19. Fazzini E, Fleming J, Fahn S. Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson’s disease. Mov Disord. 1992;7(2):153–158. doi: 10.1002/mds.870070210
  20. Dessau RB, Lisby G, Frederiksen JL. Coronaviruses in brain tissue from patients with multiple sclerosis. Acta Neuropathol. 2001;101(6):601–604. doi: 10.1007/s004010000331
  21. Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Pro vince. Chinese Medical Journal. 2020;133(9):1025–1031. doi: 10.1097/CM9.0000000000000744
  22. Xu XW, Wu X, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:606. doi: 10.1136/bmj.m606
  23. Liu M, He P, Liu HG, et al. Clinical characteristics of 30 medical workers infected with new coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0): E016. doi: 10.3760/cma.j.issn.1001-0939.2020.0016
  24. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513. doi: 10.1016/S0140-6736(20)30211-7
  25. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5
  26. Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020;69(6):1002–1009. doi: 10.1136/gutjnl-2020-320926
  27. Zhang X, Cai H, Hu J, et al. Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings. International Journal of Infectious Diseases. 2020;94:81–87. doi: 10.1016/j.ijid.2020.03.040
  28. Duanmu Y, Brown IP, Gibb WR, et al. Characteristics of Emergency Department Patients With COVID-19 at a Single Site in Northern California: Clinical Observations and Public Health Implications. Acad Emerg Med. 2020;27(6):505–509. doi: 10.1111/acem.14003
  29. Meng Y, Wu P, Lu W, et al. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients. PLoS Pathog. 2020;16(4): e1008520. doi: 10.1371/journal.ppat.1008520
  30. Chen Q, Zheng Z, Zhang C, et al. Clinical characteristics of 145 patients with corona virus disease 2019 (COVID-19) in Taizhou, Zhejiang, China. Infection. 2020;48(4):543–551. doi: 10.1007/s15010-020-01432-5
  31. Kujawski SA, Wong KK, Collins JP, et al. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nature Medicine. 2020;26(6): 861–868. doi: 10.1038/s41591-020-0877-5
  32. Zheng S, Fan J, Yu F, et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020;369:1443. doi: 10.1136/bmj.m1443
  33. Zhou Y, Han T, Chen J, et al. Clinical and Autoimmune Characteristics of Severe and Critical Cases of COVID-19. Clin Transl Sci. 2020;13(6):1077–1086. doi: 10.1111/cts.12805
  34. Jie B, Liu X, Suo H, et al. Clinical and Dynamic Computed Tomography Features of 24 Patients with Coronavirus Disease 2019. Can Assoc Radiol J. 2021;72(2):279–284. doi: 10.1177/0846537120918834
  35. Chen R, Liang W, Jiang M, et al. Risk Factors of Fatal Outcome in Hospitalized Subjects with Coronavirus Disease 2019 From a Nationwide Analysis in China. Chest. 2020;158(1):97–105. doi: 10.1016/j.chest.2020.04.010
  36. Wang X, Liu W, Zhao J, et al. Clinical characteristics of 80 hospitalized frontline medical workers infected with COVID-19 in Wuhan, China. J Hosp Infect. 2020;105(3):399–403. doi: 10.1016/j.jhin.2020.04.019
  37. Du W, Yu J, Wang H, et al. Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China. Infection. 2020;48(3):445–452. doi: 10.1007/s15010-020-01427-2
  38. Ma J, Yin J, Qian Y, Wu Y. Clinical characteristics and prognosis in cancer patients with COVID-19: A single center’s retrospective study. J Infect. 2020;81(2):318–356. doi: 10.1016/j.jinf.2020.04.006
  39. Chen T, Dai Z, Mo P, et al. Clinical Characteristics and Outcomes of Older Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: A Single-Centered, Retrospective Study. J Gerontol A Biol Sci Med Sci. 2020;75(9):1788–1795. doi: 10.1093/gerona/glaa089
  40. Zheng F, Tang W, Li H, et al. Clinical characteristics of 161 cases of corona virus disease 2019 (COVID-19) in Changsha. Eur Rev Med Pharmacol Sci. 2020;24(6):3404–3410. doi: 10.26355/eurrev_202003_20711
  41. Wang L, He W, Yu X, et al. Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up. J Infect. 2020;80(6):639–645. doi: 10.1016/j.jinf.2020.03.019
  42. Wang X, Fang J, Zhu Y, et al. Clinical characteristics of non-critically ill patients with novel coronavirus infection (COVID-19) in a Fangcang Hospital. Clin Microbiol Infect. 2020;26(8):1063–1068. doi: 10.1016/j.cmi.2020.03.032
  43. Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol. 2020;92(7):797–806. DOI:1 0.1002/jmv.25783
  44. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069. doi: 10.1001/jama.2020.1585
  45. Yu X, Sun X, Cui P, et al. Epidemiological and clinical characteristics of 333 confirmed cases with coronavirus disease 2019 in Shanghai, China. Transboundary and Emerging Diseases. 2020;67(4):1697–1707. doi: 10.1111/tbed.13604
  46. Alberici F, Delbarba E, Manenti C, et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int. 2020;97(6):1083–1088. doi: 10.1016/j.kint.2020.04.002
  47. Yan J, Guo J, Fan C, et al. Coronavirus disease 2019 in pregnant women: a report based on 116 cases. Am J Obstet Gynecol. 2020;223(1):111.e1–111.e14. doi: 10.1016/j.ajog.2020.04.014
  48. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020;20(7):1800–1808. doi: 10.1111/ajt.15941
  49. Han C, Duan C, Zhang S, et al. Digestive Symptoms in COVID-19 Patients with Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes. Am J Gastroenterol. 2020;115(6):916–923. doi: 10.14309/ajg.0000000000000664
  50. Feng Y, Ling Y, Bai T, et al. COVID-19 with Different Severities: A Multicenter Study of Clinical Features. Am J Respir Crit Care Med. 2020;201(11):1380–1388. doi: 10.1164/rccm.202002-0445OC
  51. Cao J, Tu WJ, Cheng W, et al. Clinical Features and Short-term Outcomes of 102 Patients with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71(15):748–755. doi: 10.1093/cid/ciaa243
  52. Toljan K. Letter to the Editor Regarding the Viewpoint “Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanism”. ACS Chem Neurosci. 2020;11(8):1192–1194. doi: 10.1021/acschemneuro.0c00174
  53. Li Y, Bai W, 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. doi: 10.1002/jmv.25728
  54. Kryukov EV, Shulenin KS, Cherkashin DV, et al. Pathogenesis and clinical manifestations lesions of the cardiovascular system in patients with new coronavirus infection (COVID-19). Saint Petersburg: Veda Print Publisher; 2021. (In Russ.)
  55. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22. doi: 10.1016/j.bbi.2020.03.031
  56. Gusev EI, Martynov MYu, Boyko AN, et al. Novel coronavirus infection (COVID-19) and nervous system involvement: pathogenesis, clinical manifestations, organization of neurological care. Neuroscience and Behavioral Physiology. 2020;120(6):7–16. doi: 10.17116/jnevro20201200617. (In Russ.)
  57. Zairatyants O, Samsonova M, Mikhaleva L, et al. Pathological anatomy of COVID-19: Atlas. Moscow: GBU NIIOZMM DZM Publishing House; 2020. (In Russ.)
  58. Gulko E, Oleksk ML, Gomes W, et al. MRI Brain Findings in 126 Patients with COVID-19: Initial Observations from a Descriptive Literature Review. American Journal of Neuroradiology. 2020;41(12):2199–2203. doi: 10.3174/ajnr.A6805
  59. Politi LS, Salsano E, Grimaldi M. Magnetic Resonance Imaging Alteration of the Brain in a Patient with Coronavirus Disease 2019 (COVID-19) and Anosmia. JAMA Neurol. 2020;77(8):1028–1029. doi: 10.1001/jamaneurol.2020.2125
  60. Román GC, Gracia F, Torres A, et al. Acute Transverse Myelitis (ATM): Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222). Front Immunol. 2021;12:653–786. doi: 10.3389/fimmu.2021.653786
  61. Zaytsev AA, Chernov SA, Stets VV, et al. Algorithms of the management of patients with a new coronavirus infection COVID-19 in the hospital: guidelines. Consilium Medicum. 2020;22(11):91–97. (In Russ.) doi: 10.26442/20751753.2020.11.200520

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2. Figure. Mechanisms of the effect of highly contagious coronaviruses on the central nervous system (adapted from [55]). BBB - blood-brain barrier; ACE-2 - angiotensin converting enzyme-2

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