COVID-19: neurological sequelae

View or download the full article: 
PDF icon health-risk-analysis-2021-2-16.pdf
UDC: 
614.1
DOI: 
10.21668/health.risk/2021.2.16.eng
Authors: 

P.S. Spencer1, G. Román2, A. Buguet3, A. Guekht4, J. Reis5

Organization: 

1Oregon Health & Science University, Portland, Oregon, 97201, USA
2Houston Methodist Hospital, 6560 Fannin Street, Houston, TX 77030, USA
3University Claude-Bernard Lyon-1, 43 Boulevard du 11 Novembre 1918, 69622, Villeurbanne, France
4Scientific and Practical Psychoneurological Center named after Z.P. Solovyov, 43 Donskaya Str., 115419, Moscow, Russian Federation
5Université de Strasbourg, 67000 Strasbourg, France and Association RISE, 67205 Oberhausbergen, France

Abstract: 

COVID-19, the human primarily respiratory disease caused by the coronavirus SARS-CoV-2, commonly involves the nervous system, the effects of which may persist for many months. Post-acute sequelae of COVID-19 include relapsing and remitting neurological and neuropsychiatric symptoms that can affect children and adults, including those who had mild acute illness. Since longer-term adverse effects on the central and peripheral nervous system of COVID-19 cannot be excluded, patient and societal health trends should be monitored going forward. Urgent present needs include not only global immunization against SARS-CoV-2 but also the reestablishment of lapsed mass vaccination programs to prevent resurgence of other viral diseases (e.g., measles, polio) that can impact the nervous system.

Keywords: 
SARS-CoV-2, PASC: post-acute sequelae of SARS-CoV-2 (Long Covid), vaccines
Spencer P.S., Román G., Buguet A., Guekht A., Reis J. COVID-19: neurological sequelae. Health Risk Analysis, 2021, no. 2, pp. 168–176. DOI: 10.21668/health.risk/2021.2.16.eng
References: 
  1. Andersen K.G., Rambaut A., Lipkin W.I., Holmes E.C., Garry R.F. The proximal origin of SARS-CoV-2. Nat Med, 2020, vol. 26, no. 4, pp. 450–452. DOI: 10.1038/s41591-020-0820-9
  2. Lawrence S.V. COVID-19 and China: A Chronology of Events (December 2019-January 2020). USA, Congressional Research Service Publ., 2020, 47 p.
  3. Lu D. The hunt to find the coronavirus pandemic's patient zero. New Sci, 2020, vol. 4, no. 245, pp. 9. DOI: 10.1016/S0262-4079(20)30660-6
  4. Pekar J., Worobey M., Moshiri N., Scheffler K., Wertheim J.O. Timing the SARS-CoV-2 index case in Hubei Province. Science, 2021, no. 372, pp. 412–417. DOI: 10.1126/science.abf8003
  5. Platto S., Wang Y., Zhou J., Carafoli E. History of the COVID-19 pandemic: Origin, explosion, worldwide spreading. Biochem Biophys Res Commun, 2021, no. 538, pp. 14–23. DOI: 10.1016/j.bbrc.2020.10.087
  6. Platto S., Xue T., Carafoli E. COVID19: an announced pandemic. Cell Death Dis, 2020, no. 11, pp. 799. DOI: 10.1038/s41419-020-02995-9
  7. Zaheer A. The first 50 days of COVID-19: A detailed chronological timeline and extensive review of literature documenting the pandemic. Surveying the COVID-19 Pandemic and its implications, 2020, pp. 1–7. DOI: 10.1016/B978-0-12-824313-8.00001-2
  8. Fan Y., Zhao K., Shi Z.L., Zhou P. Bat coronaviruses in China. Viruses, 2019, vol. 11, no. 3, pp. 210. DOI: 10.3390/v1103021
  9. Chen R., Wang K., Yu J., Howard D., French L., Chen Z., Wen C., Xu Z. The spatial and cell-type distribution of SARS-CoV-2 Receptor ACE2 in the human and mouse brains. Front Neurol, 2021, vol. 20, no. 11, pp. 573095. DOI: 10.3389/fneur.2020.573095
  10. Fenrich M., Mrdenovic S., Balog M., Tomic S., Zjalic M., Roncevic A., Mandic D., Debeljak Z., Heffer M. SARS-CoV-2 dissemination through peripheral nerves explains multiple organ injury. Front Cell Neurosci, 2020, vol. 5, no. 14, pp. 229. DOI: 10.3389/fncel.2020.00229
  11. Holappa M., Vapaatalo H., Vaajanen A. Many faces of renin-angiotensin system – focus on eye. Open Ophthalmol J, 2017, no. 11, pp. 122–142. DOI: 10.2174/1874364101711010122
  12. Higaki A., Mogi M., Iwanami J., Min L.‐J., Bai H.‐Y., Shan B.‐S., Kukida M., Yamauchi T. [et al.]. Beneficial Effect of Mas Receptor Deficiency on Vascular Cognitive Impairment in the Presence of Angiotensin II Type 2 Receptor. J Am Heart Assoc, 2018, vol. 7, no. 3, pp. e008121. DOI: 10.1161/JAHA.117.008121
  13. Salamanna F., Maglio M., Landini M.P., Fini M. Body localization of ACE-2: On the trail of the keyhole of SARS-CoV-2. Front Med (Lausanne), 2020, vol. 3, no. 7, pp. 594495. DOI: 10.3389/fmed.2020.594495
  14. Wang X.L., Iwanami J., Min L.J., Tsukuda K., Nakaoka H., Bai H.-Y., Shan B.-S., Kan-No H. [et al.]. Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function. NPJ Aging Mech Dis, 2016, vol. 20, no. 2, pp. 16024. DOI: 10.1038/npjamd.2016.24
  15. Kirillov Y., Timofeev S., Avdalyan A., Nikolenko V.N., Gridin L., Sinelnikov M.Y. Analysis of risk actors in COVID-19 adult mortality in Russia. J Prim Care Community Health, 2021, vol. 12, pp. 21501327211008050. DOI: 10.1177/21501327211008050
  16. Sanyaolu A., Okorie C., Marinkovic A., Patidar R., Younis K., Desai P., Hosein Z., Padda I. [et al.]. Comorbidity and its impact on patients with COVID-19. SN Compr Clin Med, 2020, vol. 25, pp. 1–8. DOI: 10.1007/s42399-020-00363-4
  17. Verdecchia P., Cavallini C., Spanevello A., Fabio A. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med, 2020, vol. 76, pp. 14–20. DOI: 10.1016/j.ejim.2020.04.037
  18. Erickson M.A., Rhea E.M., Knopp R.C., Banks W.A. Interactions of SARS-CoV-2 with the blood-brain barrier. Int J Mol Sci, 2021, vol. 6, no. 22 (5), pp. 2681. DOI: 10.3390/ijms22052681
  19. Alomari S., Abou-Mrad Z., Bydon A. COVID-19 and the central nervous system. Clin Neurol Neurosurg, 2020, vol. 198, pp. 106116. DOI: 10.1016/j.clineuro.2020.106116
  20. Ellul M.A., Benjamin L., Singh B., Lant S., Michael B.D., Easton A., Kneen R., Defres S. [et al.]. Neurological associations of COVID-19. Lancet Neurol, 2020, vol. 19, no. 9, pp. 767–783. DOI: 10.1016/S1474-4422(20)30221-0
  21. El-Sayed A., Aleya L., Kamel M. COVID-19: a new emerging respiratory disease from the neurological perspective. Environ Sci Pollut Res Int, 2021, vol. 15, pp. 1–15. DOI: 10.1007/s11356-021-12969-9
  22. Liotta E.M., Batra A., Clark J.R., Shlobin N.A., Hoffman S.C., Orban Z.S., Koralnik I.J. [et al.]. Frequent neurologic manifestations and encephalopathy-associated morbidity in COVID-19 patients. Ann Clin Transl Neurol, 2020, vol. 7, no. 11, pp. 2221–2230. DOI: 10.1002/acn3.51210
  23. Nazari S., Azari Jafari A., Mirmoeeni S., Sadeghian S., Eghbal Heidari M., Sadeghian S., Assarzadegan F., Mahmoud Puormand S. [et al.]. Central nervous system manifestations in COVID-19 patients: A systematic review and meta-analysis. Brain Behav, 2021, pp. e02025. DOI: 10.1002/brb3.2025
  24. Perez D.L., Edwards M.J., Nielsen G., Kozlowska K., Hallett M., Curt LaFrance Jr. W. Decade of progress in motor functional neurological disorder: continuing the momentum. J Neurol Neurosurg Psychiatry, 2021, vol. 92, no. 6, pp. 668–667. DOI: 10.1136/jnnp-2020-323953
  25. Qi R., Chen W., Liu S., Thompson P.M., Zhang L.J., Xia F., Cheng F., Hong A. [et al.]. Psychological morbidities and fatigue in patients with confirmed COVID-19 during disease outbreak: prevalence and associated biopsychosocial risk factors. medRxiv, 2020, no. 11, pp. 1–21. DOI: 10.1101/2020.05.08.20031666
  26. Román G.C., Spencer P.S., Reis J., Buguet A., El Alaoui Faris M., Katrak S.M., Láinez M., Tulio Medina M. [et al.]. The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries. J Neurol Sci, 2020, vol. 15, no. 414, pp. 116884. DOI: 10.1016/j.jns.2020.116884
  27. Tan B.H., Liu J.M., Gui Y., Wu S., Suo J.-L., Li Y.-C. Neurological involvement in the respiratory manifestations of COVID-19 patients. Aging (Albany NY), 2021, vol. 14, no. 13 (3), pp. 4713–4730. DOI: 10.18632/aging.202665
  28. Wildwing T., Holt N. The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services. Ther Adv Chronic Dis, 2021, vol. 12, pp. 2040622320976979. DOI: 10.1177/2040622320976979
  29. Cabona C., Deleo F., Marinelli L., Audenino D., Arnaldi D., Rossi F., Di Giacomo R., Buffoni C. [et al.]. Epilepsy course during COVID-19 pandemic in three Italian epilepsy centers. Epilepsy Behav, 2020, vol. 112, pp. 107375. DOI: 10.1016/j.yebeh.2020.107375
  30. Rider F.K., Lebedeva A.V., Mkrtchyan V.R., Gekht A.B. Epilepsy and COVID-19: patient management and optimization of antiepileptic therapy during pandemic. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova, 2020, vol. 120, № 10, pp. 100–107 (in Russian).
  31. Singh B., Lant S., Cividini S., Cattrall J.W.S., Goodwin L., Benjamin L., Michael B., Khawaja A. [et al.]. Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: A systematic review and individual patient data meta-analysis. Lancet, 2021, vol. 27, pp. 95. DOI: 10.21.2139/ssrn.3834310
  32. Azghandi M., Kerachian M.A. Detection of novel coronavirus (SARS-CoV-2) RNA in peripheral blood specimens. J Transl Med, 2020, no. 18, pp. 412. DOI: 10.1186/s12967-020-02589-1
  33. Lou J.J., Movassaghi M., Gordy D., Olson M.G., Zhang T., Khurana M.S., Chen Z., Perez-Rosendahl M. [et al.]. Neuropathology of COVID-19 (neuro-COVID): clinicopathological update. Free Neuropathol, 2021, vol. 2, no. 2. DOI: 10.17879/freeneuropathology-2021-2993
  34. Neumann B., Schmidbauer M.L., Dimitriadis K., Otto S., Knier B., Niesen W.-D., Hosp J.A., Günther A. [et al.]. Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms. J Neurol Sci, 2020, vol. 15, no. 418, pp. 117090. DOI: 10.1016/j.jns.2020.117090
  35. Wang W., Xu Y., Gao R., Lu R., Han K., Wu G., Tan W. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA, 2020, vol. 12, no. 323 (18), pp. 1843–1844. DOI: 10.1001/jama.2020.3786
  36. Lee M.H., Perl D.P., Nair G., Li W., Maric D., Murray H., Dodd S.J., Koretsky A.P. [et al.]. Microvascular injury in the brains of patients with COVID-19. N Engl J Med, 2021, vol. 4, no. 384 (5), pp. 481–483. DOI: 10.1056/NEJMc2033369
  37. Matschke J., Lütgehetmann M., Hagel C., Sperhake J.P., Schröder A.S., Edler C., Mushumba H., Fitzek A. [et al.]. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol, 2020, vol. 19, no. 11, pp. 919–929. DOI: 10.1016/S1474-4422(20)30308-2
  38. Brundin P., Nath A., Beckham J.D. Is COVID-19 a perfect storm for Parkinson's Disease? Trends Neurosci, 2020, no. 43, pp. 931–933. DOI: 10.1016/j.tins.2020.10.009
  39. Al-Aly Z., Xie Y., Bowe B. High-dimensional characterization of post-acute sequalae of COVID-19. Nature, 2021, vol. 594, no. 7862, pp. 259–264. DOI: 10.1038/s41586-021-03553-9
  40. Carfì A., Bernabei R., Landi F. for the Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA, 2020, vol. 11, no. 324 (6), pp. 603–605. DOI: 10.1001/jama.2020.12603
  41. Miners S., Kehoe P.G., Love S. Cognitive impact of COVID-19: looking beyond the short term. Alzheimers Res Ther, 2020, no. 12, pp. 170. DOI: 10.1186/s13195-020-00744-w
  42. Román G.C., Gracia F., Torres A., Palacios A., Gracia K., Harris D. [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, vol. 26, no. 12, pp. 653786. DOI: 103389/fimmu.2021.653786
  43. Simon Junior H., Sakano T.M.S., Rodrigues R.M., Eisencraft A.P., Lemos de Carvalho V.E., Schvartsman C., da Costa Reis A.G.A. Multisystem inflammatory syndrome associated with COVID-19 from the pediatric emergency physician's point of view. J Pediatr (Rio J), 2021, vol. 97, no. 2, pp. 140–159. DOI: 10.1016/j.jped.2020.08.004
  44. Taquet M., Geddes J.R., Husain M., Luciano S., Harrison P.J. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiat, 2021, no. 8, pp. 416–427. DOI: 10.1016/s2215-0366(21)00084-5
  45. Munblit D., Bobkov P., Spiridonova E., Shikhaleva A., Gamirova A., Blyuss O., Nekliudov N., Bugaev P. [et al.]. Risk factors for long-term consequences of COVID-19 in hospitalized adults in Moscow using the ISARIC Global follow-up protocol: Stop COVID cohort study. medRxiv, 2021, no. 19, pp. 26. DOI: 10.1101/2021.02.17.21251895
  46. Torjeson I. Covid-19: Middle aged women face greater risk of debilitating long term symptoms. BMJ, 2021, no. 372, pp. n829. DOI: 10.1136/bmj.n829
  47. Baig A.M. Chronic COVID syndrome: Need for an appropriate medical terminology for long-COVID and COVID long-haulers. J Med Virol, 2021, no. 93, pp. 2555–2556. DOI: 10.1002/jmv.26624
  48. Fernández-de-Las-Peñas C., Palacios-Ceña D., Gómez-Mayordomo V., Cuadrado M.L., Florencio L.L. Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An integrative classification. Int J Environ Res Public Health, 2021, no. 18, pp. 2621. DOI: 10.3390/ijerph18052621
  49. Moldofsky H., Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol, 2011, vol. 24, no. 11, pp. 37. DOI: 10.1186/1471-2377-11-37
  50. Dani M., Dirksen A., Taraborrelli P., Torocastro M., Panagopoulos D., Sutton R., Lim P.B. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin Med J, 2021, no. 21, pp. e63–e67. DOI: 10.7861/clinmed.2020-089
  51. Wijeratne T., Crewther S. Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. J Neurol Sci, 2020, no. 419, pp. 117179. DOI: 10.1016/j.jns.2020.117179
  52. Zhou L., Zhang M., Wang J., Gao J. Sars-Cov-2: Underestimated damage to nervous system. Travel Med Infect Dis, 2020, no. 36, pp. 101642. DOI: 10.1016/j.tmaid.2020.101642
  53. Hawkes C. Olfaction in neurodegenerative disorder. Adv Otorhinolaryngol, 2006, no. 63, pp. 133–151. DOI: 10.1159/000093759
  54. Kuo C.L., Pilling L.C., Atkins J.L., Masoli J.A.H., Delgado J., Kuchel G.A., Melzer D. APOE e4 Genotype predicts severe COVID-19 in the UK Biobank Community Cohort. J Gerontol A Biol Sci Med Sci, 2020, vol. 15, no. 75 (11), pp. 2231–2232. DOI: 10.1093/gerona/glaa131
  55. Wang C., Zhang M., Garcia Jr G., Tian E., Cui Q., Chen X., Sun G., Wang J. [et al.]. ApoE-isoform-dependent SARS-CoV-2 neurotropism and cellular response. Cell Stem Cell, 2021, no. 28, pp. 331–342.e5. DOI: 10.1016/j.stem.2020.12.018
  56. Gear J.S., Cassel G.A., Gear A.J., Trappler B., Clausen L., Meyers A.M., Kew M.C., Bothwell T.H. [et al.]. Outbreak of Marburg virus disease in Johannesburg. Br Med J, 1975, vol. 29, no. 4, pp. 489–493. DOI: 10.1136/bmj.4.5995.489
  57. Van Gelder R.N., Margolis T.P. Ebola and the ophthalmologist. Ophthalmology, 2015, no. 122, pp. 2152–2154. DOI: 10.1016/j.ophtha.2015.08.027
  58. Varkey J.B., Shantha J.G., Crozier I., Kraft C.S., Lyon G.M., Mehta A.K., Kumar G., Smith J.R. [et al.]. Persistence of Ebola Virus in ocular fluid during convalescence. N Engl J Med, 2015, no. 372, pp. 2423–2427. DOI: 10.1056/NEJMoa1500306
  59. Durrheim D.N., Andrus J.K., Tabassum S., Bashour H., Githanga D., Pfaff G. [et al.]. A dangerous measles future looms beyond the COVID-19 pandemic. Nat Med, 2021, vol. 27, no. 3, pp. 360–361. DOI: 10.1038/s41591-021-01237-5
  60. Fading measles immunity over time. Center for Infectious Disease Research and Policy. CIDRAP. Available at: https://www.cidrap.umn.edu/news-perspective/2020/09/news-scan-sep-02-2020 (03.04.2021).
  61. Harris R.C., Chen Y., Côte P., Ardillon A., Nievera M.C., Ong-Lim A., Aiyamperumal S., Chong C.P. [et al.]. Impact of COVID-19 on routine immunisation in South-East Asia and Western Pacific: Disruptions and solutions. Lancet Reg Health West Pac, 2021, no. 10, pp. 100140. DOI: 10.1016/j.lanwpc.2021.100140
  62. Ibrahim S.H., Amjad N., Saleem A.F., Chand P., Rafique A., Nuzhat K. Humayun The upsurge of SSPE--a reflection of national measles immunization status in Pakistan. J Trop Pediatr, 2014, vol. 60, no. 6, pp. 449–453. DOI: 10.1093/tropej/fmu050
  63. Desforges M., Le Coupanec A., Dubeau P., Bourgouin A., Lajoie L., Dubé M., Talbot P.J. Human coronaviruses and other respiratory viruses: Underestimated opportunistic pathogens of the central nervous system? Viruses, 2019, vol. 20, no. 12 (1), pp. 14. DOI: 10.3390/v12010014
  64. 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, vol. 16, no. 92 (17), pp. e00404-18. DOI: 10.1128/JVI.00404-18
Received: 
26.05.2021
Accepted: 
15.06.2021
Published: 
30.06.2021

You are here

Home