COVID-19 in the nervous system: physiopathology and neurological manifestations

Abstract

Background Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although respiratory manifestations have received greater visibility during the pandemic caused by this virus, numerous neurological complaints related to coronavirus 2 infection have been documented in several countries. These records suggest that this pathogen presents neurotropism, and it can cause different neurological conditions of varying intensity.

Objective To investigate the ability of coronavirus 2 to invade the central nervous system (CNS) and its neurological clinical outcomes.

Methods The present study consists in a comprehensive literature review of the records available in the PubMed, SciELO, and Google Scholar databases. The descriptors COVID-19, brain and physiopathology, associated with the Boolean operator AND, were used in the search. Regarding the inclusion and exclusion criteria, we selected the papers published since 2020 with the highest number of citations.

Results We selected 41 articles, most of them in English. The main clinical manifestation associated with COVID-19 patients was headache, but cases of anosmia, hyposmia, Guillain-Barré syndrome, and encephalopathies were also described with considerable frequency.

Conclusion Coronavirus-2 presents neurotropism, and it can reach the CNS by hematogenous dissemination and by direct infection of the nerve endings. It causes brain injuries through several mechanisms, such as cytokine storm, microglial activation, and an increase in thrombotic factors.

Resumo

Antecedentes A doença do coronavírus 2019 (coronavirus disease 2019, Covid-19, em inglês) é uma infecção viral provocada pelo coronavírus 2 da síndrome respiratória aguda grave (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês). Embora as manifestações respiratórias tenham recebido maior visibilidade ao longo da pandemia provocada por esse vírus, inúmeras queixas neurológicas relacionadas à infecção pelo coronavírus 2 foram documentadas em diversos países. Tais registros sugerem que esse patógeno apresenta neurotropismo, e é capaz de provocar quadros neurológicos diversos e de intensidade variáveis.

Objetivo Investigar a capacidade de invasão do sistema nervoso central (SNC) pelo coronavírus 2 e seus principais desfechos clínicos neurológicos.

Métodos O presente estudo consiste em uma ampla revisão de literatura a partir dos registros das bases de dados PubMed, SciELO e Google Acadêmico. Nesse contexto, os descritores COVID-19, cérebro e fisiopatologia, associados com o operador booleano AND, foram utilizados na busca. Quanto aos critérios de inclusão e exclusão, selecionou-se os trabalhos publicados a partir de 2020 com o maior número de citações.

Resultados Foram selecionados 41 artigos, a maioria na língua inglesa. A principal manifestação clínica associada a pacientes acometidos pela COVID-19 foi a cefaleia, mas casos de anosmia, hiposmia, síndrome de Guillain-Barré e encefalopatias também foram descritos com frequência considerável.

Conclusão O coronavírus 2 apresenta neurotropismo, e é capaz de alcançar o SNC por disseminação hematogênica e por infecção direta das terminações nervosas. Ele provoca injúria cerebral por meio de variados mecanismos, como tempestade de citocinas, ativação da micróglia e aumento dos fatores trombóticos.

Keywords

COVID-19 - Neurological Manifestations - Viral Tropism - Cytokine Release Syndrome

Palavras-chave

Covid-19 - Manifestações Neurológicas - Tropismo Viral - Síndrome da Liberação de Citocina

Authors' Contributions

VCMMF (main author): conceptualization, data curation, formal analysis, investigation, methodology, project administration, writing of the original draft, and writing – review and editing; AGO: conceptualization, formal analysis, project administration, and writing – review and editing; IFVCM: data curation, project administration, and visualization; ACMF, BGB, LBZ: resources, validation; and FHMA: conceptualization, data curation, project administration, supervision, validation, visualization, and writing of the original draft.

Publikationsverlauf

Eingereicht: 29. August 2022

Angenommen: 24. Januar 2023

Artikel online veröffentlicht:
04. Juli 2023

• References

• 1 Petersen E, Koopmans M, Go U. et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis 2020; 20 (09) e238-e244
• 2 Generoso JS, Barichello de Quevedo JL, Cattani M. et al. Neurobiology of COVID-19: how can the virus affect the brain?. Br J Psychiatry 2021; 43 (06) 650-664
• 3 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
• 4 Abboud H, Abboud FZ, Kharbouch H, Arkha Y, El Abbadi N, El Ouahabi A. COVID-19 and SARS-Cov-2 Infection: Pathophysiology and Clinical Effects on the Nervous System. World Neurosurg 2020; 140: 49-53
• 5 Asadi-Pooya AA, Simani L. Central nervous system manifestations of COVID-19: A systematic review. J Neurol Sci 2020; 413: 116832
• 6 Vieira GDD, Sousa CMde. Aspectos celulares e fisiológicos da Barreira Hematoencefálica. Journal of Health & Biological Sciences 2013; 1 (04) 166 https://doi.org/10.12662/2317-3076jhbs.v1i4.38.p166.2013
• 7 Xia H, Lazartigues E. Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochem 2008; 107 (06) 1482-1494
• 8 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; 41 (10) 2657-2669
• 9 Hassett CE, Gedansky A, Migdady I, Bhimraj A, Uchino K, Cho S-M. Neurologic complications of COVID-19. Cleve Clin J Med 2020; 87 (12) 729-734
• 10 Achar A, Ghosh C. COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Relevance. Cells 2020; 9 (11) 2360
• 11 Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol 2020; 16 (11) 636-644 [Internet]
• 12 Mahalakshmi AM, Ray B, Tuladhar S. et al. Does COVID-19 contribute to development of neurological disease?. Immun Inflamm Dis 2021; 9 (01) 48-58
• 13 Rochfort KD, Collins LE, Murphy RP, Cummins PM. Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS One 2014; 9 (07) e101815
• 14 Boldrini M, Canoll PD, Klein RS. How COVID-19 Affects the Brain. JAMA Psychiatry 2021; 78 (06) 682-683
• 15 Mao L, Jin H, Wang M. et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol 2020; 77 (06) 683-690
• 16 Kempuraj D, Selvakumar GP, Ahmed ME. et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neurosci a Rev J bringing Neurobiol Neurol psychiatry 2020; 26 (5–6): 402-414
• 17 Mukerji SS, Solomon IH. What can we learn from brain autopsies in COVID-19?. Neurosci Lett 2021; 742: 135528
• 18 Ellul MA, Benjamin L, Singh B. et al. Neurological associations of COVID-19. Lancet Neurol 2020; 19 (09) 767-783
• 19 Nepal G, Rehrig JH, Shrestha GS. et al. Neurological manifestations of COVID-19: a systematic review. Crit Care 2020; 24 (01) 421 [Internet]
• 20 Munhoz RP, Pedroso JL, Nascimento FA. et al. Neurological complications in patients with SARS-CoV-2 infection: a systematic review. Arq Neuropsiquiatr 2020; 78 (05) 290-300
• 21 Zhang T, Hirsh E, Zandieh S, Rodricks MB. COVID-19-Associated Acute Multi-infarct Encephalopathy in an Asymptomatic CADASIL Patient. Neurocrit Care 2021; 34 (03) 1099-1102
• 22 Zhao K, Huang J, Dai D, Feng Y, Liu L, Nie S. Acute myelitis after SARS-CoV-2 infection: a case report. medRxiv [Internet]. 2020; 3 (16) 20035105
• 23 Finsterer J, Scorza FA, Scorza C, Fiorini A. COVID-19 associated cranial nerve neuropathy: A systematic review. Bosn J Basic Med Sci 2022; 22 (01) 39-45
• 24 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 (08) 2251-2261
• 25 Vaira LA, Deiana G, Fois AG. et al. Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck 2020; 42 (06) 1252-1258
• 26 Taga A, Lauria G. COVID-19 and the peripheral nervous system. A 2-year review from the pandemic to the vaccine era. J Peripher Nerv Syst 2022; 27 (01) 4-30
• 27 Canetta C, Accordino S, Buscarini E. et al. Syncope at SARS-CoV-2 onset. Auton Neurosci 2020; 229: 102734
• 28 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; 77 (08) 1018-1027
• 29 Jarius S, Pache F, Körtvelyessy P. et al; in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry. Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients. J Neuroinflammation 2022; 19 (01) 19
• 30 Kilic O, Kalcioglu MT, Cag Y. et al. Could sudden sensorineural hearing loss be the sole manifestation of COVID-19? An investigation into SARS-COV-2 in the etiology of sudden sensorineural hearing loss. Int J Infect Dis 2020; 97: 208-211
• 31 Costa Martins D, Branco Ribeiro S, Jesus Pereira I, Mestre S, Rios J. Unilateral Hypoglossal Nerve Palsy as a COVID-19 Sequel. Am J Phys Med Rehabil 2020; 99 (12) 1096-1098
• 32 Toscano G, Palmerini F, Ravaglia S. et al. Guillain-Barré Syndrome Associated with SARS-CoV-2. N Engl J Med 2020; 382 (26) 2574-2576
• 33 D V, Sharma A, Kumar A, Flora SJS. Neurological Manifestations in COVID-19 Patients: A Meta-Analysis. ACS Chem Neurosci 2021; 12 (15) 2776-2797
• 34 Finsterer J, Scorza FA, Scorza CA, Fiorini AC. Peripheral neuropathy in COVID-19 is due to immune-mechanisms, pre-existing risk factors, anti-viral drugs, or bedding in the Intensive Care Unit. Arq Neuropsiquiatr 2021; 79 (10) 924-928 [online]
• 35 Canineu RFB, Cabral MM, Guimarães HP, Lopes RD, Saes LS, Lopes AC. Polineuropatia no paciente crítico: um diagnóstico comum em medicina intensiva?. Rev Bras Ter Intensiva 2006; 18 (03) 307-310 [Internet]
• 36 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
• 37 Chen T, Wu D, Chen H. et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020; 368: m1091
• 38 Giacomelli A, Pezzati L, Conti F. et al. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study. Clin Infect Dis 2020; 71 (15) 889-890
• 39 Hopkins C, Surda P, Whitehead E, Kumar BN. Early recovery following new onset anosmia during the COVID-19 pandemic - an observational cohort study. J Otolaryngol Head Neck Surg 2020; 49 (01) 26
• 40 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
• 41 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
• 42 Li Y, Li M, Wang M. et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc Neurol 2020; 5 (03) 279-284
• 43 Lodigiani C, Iapichino G, Carenzo L. et al; Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9-14
• 44 Wan S, Xiang Y, Fang W. et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol 2020; 92 (07) 797-806
• 45 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
• 46 Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 Cases With Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis 2020; 71 (15) 769-777
• 47 Yang X, Yu Y, Xu J. et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8 (05) 475-481
• 48 Rifino N, Censori B, Agazzi E. et al. Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy. J Neurol 2021; 268 (07) 2331-2338 [Internet]
• 49 Premraj L, Kannapadi NV, Briggs J. et al. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci 2022; 434: 120162
• 50 Sriuoginys S, Margareta S, Jon Hersir E. De Novo Presentation of Idiopathic Intracranial Hypertension (IIH) Associated With COVID-19 Infection. Neurohospitalist 2022; 12 (04) 691-692
• 51 Sundholm A, Burkill S, Waldenlind E, Bahmanyar S, Nilsson Remahl AIM. Infectious and inflammatory disorders might increase the risk of developing idiopathic intracranial hypertension - a national case-control study. Cephalalgia 2020; 40 (10) 1084-1094
• 52 Silva MTT, Lima MA, Torezani G. et al. Isolated intracranial hypertension associated with COVID-19. Cephalalgia 2020; 40 (13) 1452-1458
• 53 de Sousa Moreira JL, Barbosa SMB, Vieira JG. et al. The psychiatric and neuropsychiatric repercussions associated with severe infections of COVID-19 and other coronaviruses. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106: 110159
• 54 Sher L. Post-COVID syndrome and suicide risk. QJM 2021; 114 (02) 95-98