COVID-19 neurological manifestations: a narrative review on the mechanisms, pathogenesis, and clinical management
DOI:
https://doi.org/10.33448/rsd-v9i12.10724Keywords:
Central nervous system viral diseases; Encephalitis; SARS virus; Viral tropism.Abstract
Coronaviruses are a large viral family, whose infections are recognized since 1960, varying from the common cold to more critical respiratory conditions. Regarding coronavirus 2019 (COVID-19), a wide spectrum of neurological manifestations among infected patients were reported, raising concerns whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had tropism for the central nervous system. To clarify these questions, this bibliographic review was carried out by searching for articles based on national and international data during the period from December 2019 to June 2020. Thus, this review summarizes the current evidence on the transmission routes, focusing on the olfactory bulb and the hematogenic pathways, as well as the direct and indirect pathological mechanisms through which SARS-CoV-2 causes neurological damage. Moreover, clinical, laboratorial, and therapeutic aspects to manage patients with COVID-19 related neurological symptoms are outlined. Finally, development of treatments tackling specific structures and pathways related to viral entry and cardiovascular regulation on the brain are expected, in addition to monitoring of patients affected by the COVID-19 to assess long-term consequences on the nervous system.
References
Aggarwal, G., Lippi, G., & Michael Henry, B. (2020). Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature. International Journal of Stroke, 15(4), 385–389. https://doi.org/10.1177/1747493020921664
Alenina, N., & Bader, M. (2019). ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models. Neurochemical Research, 44(6), 1323–1329. https://doi.org/10.1007/s11064-018-2679-4
Atallah, B., Mallah, S. I., & AlMahmeed, W. (2020). Anticoagulation in COVID-19. European Heart Journal. Cardiovascular Pharmacotherapy, 1–2. https://doi.org/10.1093/ehjcvp/pvaa036
Biancardi, V. C., Stranahan, A. M., Krause, E. G., de Kloet, A. D., & Stern, J. E. (2016). Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. American Journal of Physiology. Heart and Circulatory Physiology, 310(3), H404–H415. https://doi.org/10.1152/ajpheart.00247.2015
Bohmwald, K., Gálvez, N. M. S., Ríos, M., & Kalergis, A. M. (2018). Neurologic alterations due to respiratory virus infections. Frontiers in Cellular Neuroscience, 12(October), 1–15. https://doi.org/10.3389/fncel.2018.00386
Das, G., Mukherjee, N., & Ghosh, S. (2020). Neurological Insights of COVID-19 Pandemic. ACS Chemical Neuroscience, 11(9), 1206–1209. https://doi.org/10.1021/acschemneuro.0c00201
De Felice, F. G., Tovar-Moll, F., Moll, J., Munoz, D. P., & Ferreira, S. T. (2020). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System. Trends in Neurosciences, 43(6), 355–357. https://doi.org/10.1016/j.tins.2020.04.004
Ding, Y., He, L., Zhang, Q., Huang, Z., Che, X., Hou, J., Wang, H., Shen, H., Qiu, L., Li, Z., Geng, J., Cai, J., Han, H., Li, X., Kang, W., Weng, D., Liang, P., & Jiang, S. (2004). Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis virus transmission pathways. Journal of Pathology, 203(2), 622–630. https://doi.org/10.1002/path.1560
Dolhnikoff, M., Duarte-Neto, A. N., de Almeida Monteiro, R. A., da Silva, L. F. F., de Oliveira, E. P., Saldiva, P. H. N., Mauad, T., & Negri, E. M. (2020). Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. Journal of Thrombosis and Haemostasis, 18(6), 1517–1519. https://doi.org/10.1111/jth.14844
Doobay, M. F., Talman, L. S., Obr, T. D., Tian, X., Davisson, R. L., & Lazartigues, E. (2007). Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 292(1). https://doi.org/10.1152/ajpregu.00292.2006
Gandhi, S., Srivastava, A. K., Ray, U., & Tripathi, P. P. (2020). Is the Collapse of the Respiratory Center in the Brain Responsible for Respiratory Breakdown in COVID-19 Patients? ACS Chemical Neuroscience, 11(10), 1379–1381. https://doi.org/10.1021/acschemneuro.0c00217
Gheblawi, M., Wang, K., Viveiros, A., Nguyen, Q., Zhong, J. C., Turner, A. J., Raizada, M. K., Grant, M. B., & Oudit, G. Y. (2020). Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circulation Research, 1456–1474. https://doi.org/10.1161/CIRCRESAHA.120.317015
Gooz, M. (2010). ADAM-17: the enzyme that does it all. Critical Reviews in Biochemistry and Molecular Biology, 45(2), 146–169. https://doi.org/10.3109/10409231003628015
Graham, R. L., Donaldson, E. F., & Baric, R. S. (2013). A decade after SARS: Strategies for controlling emerging coronaviruses. Nature Reviews Microbiology, 11(12), 836–848. https://doi.org/10.1038/nrmicro3143
Gu, J., Gong, E., Zhang, B., Zheng, J., Gao, Z., Zhong, Y., Zou, W., Zhan, J., Wang, S., Xie, Z., Zhuang, H., Wu, B., Zhong, H., Shao, H., Fang, W., Gao, D., Pei, F., Li, X., He, Z., … Leong, A. S. Y. (2005). Multiple organ infection and the pathogenesis of SARS. Journal of Experimental Medicine, 202(3), 415–424. https://doi.org/10.1084/jem.20050828
Guan, W. J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., Liu, L., Shan, H., Lei, C. L., Hui, D. S. C., Du, B., Li, L. J., Zeng, G., Yuen, K. Y., Chen, R. C., Tang, C. L., Wang, T., Chen, P. Y., Xiang, J., … Zhong, N. S. (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. The New England Journal of Medicine, 1–13. https://doi.org/10.1056/NEJMoa2002032
Harmer, D., Gilbert, M., Borman, R., & Clark, K. L. (2002). Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Letters, 532(1–2), 107–110. https://doi.org/10.1016/S0014-5793(02)03640-2
Haspula, D., & Clark, M. A. (2018). Molecular basis of the brain renin angiotensin system in cardiovascular and neurologic disorders: Uncovering a key role for the astroglial angiotensin type 1 receptor AT1R. Journal of Pharmacology and Experimental Therapeutics, 366(2), 251–264. https://doi.org/10.1124/jpet.118.248831
Helms, J., Kremer, S., Merdji, H., Clere-Jehl, R., Schenck, M., Kummerlen, C., Collange, O., Boulay, C., Fafi-Kremer, S., Ohana, M., Anheim, M., & Meziani, F. (2020). Neurologic Features in Severe SARS-CoV-2 Infection. The New England Journal of Medicine, 382(23), 2268–2270. https://doi.org/10.1056/NEJMc2008597
Hoch, D. H., Akiyama, S., Suyama, K., & Takano, T. (2020). Guillain–Barré Syndrome Associated with SARS-CoV-2. In New England Journal of Medicine. https://doi.org/10.56/NEJMc1509759
Kim, J. M., Chung, Y. S., Jo, H. J., Lee, N. J., Kim, M. S., Woo, S. H., Park, S., Kim, J. W., Kim, H. M., & Han, M. G. (2020). Identification of coronavirus isolated from a patient in Korea with covid-19. Osong Public Health and Research Perspectives, 11(1), 3–7. https://doi.org/10.24171/j.phrp.2020.11.1.02
Kreuziger, L. B., Lee, A., Garcia, D., Cuker, A., Cushman, M., DeSancho, M., & Connors, J. M. (2020). COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. American Society of Hematology. https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation
Law, H. K. W., Cheung, C. Y., Ng, H. Y., Sia, S. F., Chan, Y. O., Luk, W., Nicholls, J. M., Peiris, J. S. M., & Lau, Y. L. (2005). Chemokine up-regulation in SARS-coronavirus – infected , monocyte-derived human dendritic cells. Blood, 106(7), 2366–2374. https://doi.org/https://doi.org/10.1182/blood-2004-10-4166
Li, X., Geng, M., Peng, Y., Meng, L., & Lu, S. (2020). Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis, 10(2), 102–108. https://doi.org/10.1016/j.jpha.2020.03.001
Li, Y. C., Bai, W. Z., & Hashikawa, T. (2020). The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. Journal of Medical Virology, 92(6), 552–555. https://doi.org/10.1002/jmv.25728
Li, Y. C., Bai, W. Z., Hirano, N., Hayashida, T., & Hashikawa, T. (2012). Coronavirus infection of rat dorsal root ganglia: Ultrastructural characterization of viral replication, transfer, and the early response of satellite cells. Virus Research, 163(2), 628–635. https://doi.org/10.1016/j.virusres.2011.12.021
Lippi, A., Domingues, R., Setz, C., Outeiro, T. F., & Krisko, A. (2020). SARS-CoV-2: At the Crossroad Between Aging and Neurodegeneration. Movement Disorders, 35(5), 716–720. https://doi.org/10.1002/mds.28084
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., … Tan, W. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 395(10224), 565–574.
Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Miao, X., Li, Y., & Hu, B. (2020). Neurologic Manifestations of Hospitalized Patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology, 1–8. https://doi.org/10.1001/jamaneurol.2020.1127
Matsuda, K., Park, C. H., Sunden, Y., Kimura, T., Ochiai, K., Kida, H., & Umemura, T. (2004). The vagus nerve is one route of transneural invasion for intranasally inoculated influenza A virus in mice. Veterinary Pathology, 41(2), 101–107. https://doi.org/10.1354/vp.41-2-101
Mattos, R. De, Rafael, R., Ii, M. N., Maria, M., Carvalho, B. De, Maria, H., Leal, S., Iv, D., V, S. A., Guimarães, M., & Faria, D. A. (2020). Epidemiology, public policies and Covid-19 pandemics in Brazil: what can we expect ? Rev Enfrem UERJ, Rio de Janeiro, 28, e49570. https://doi.org/10.12957/reuerj.2020.49570
McCray, P. B., Pewe, L., Wohlford-Lenane, C., Hickey, M., Manzel, L., Shi, L., Netland, J., Jia, H. P., Halabi, C., Sigmund, C. D., Meyerholz, D. K., Kirby, P., Look, D. C., & Perlman, S. (2007). Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus. Journal of Virology, 81(2), 813–821. https://doi.org/10.1128/jvi.02012-06
Moriguchi, T., Harii, N., Goto, J., Harada, D., Sugawara, H., Takamino, J., Ueno, M., Sakata, H., Kondo, K., Myose, N., Nakao, A., Takeda, M., Haro, H., Inoue, O., Suzuki-Inoue, K., Kubokawa, K., Ogihara, S., Sasaki, T., Kinouchi, H., … Shimada, S. (2020). A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases, 94(May), 55–58. https://doi.org/10.1016/j.ijid.2020.03.062
Nadeem, M. S., Zamzami, M. A., Choudhry, H., Murtaza, B. N., Kazmi, I., Ahmad, H., & Shakoori, A. R. (2020). Origin, Potential Therapeutic Targets and Treatment for Coronavirus Disease (COVID-19). Pathogens 2020, Vol. 9, Page 307, 9(4), 307. https://doi.org/10.3390/PATHOGENS9040307
Nakagawa, P., & Sigmund, C. D. (2017). How Is the Brain Renin-Angiotensin System Regulated? Hypertension, 70(1), 10–18. https://doi.org/10.1161/HYPERTENSIONAHA.117.08550
Natoli, S., Oliveira, V., Calabresi, P., Maia, L. F., & Pisani, A. (2020). Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models. European Journal of Neurology, 0–2. https://doi.org/10.1111/ene.14277
Ogier, M., Andéol, G., Sagui, E., & Bo, G. D. (2020). How To Detect and Track Chronic Neurologic Sequelae of Covid-19? Use of Auditory Brainstem Responses and Neuroimaging for Long-Term Patient Follow-Up. Brain, Behavior, & Immunity - Health, 100081. https://doi.org/10.1016/j.bbih.2020.100081
Patel, V. B., Clarke, N., Wang, Z., Fan, D., Parajuli, N., Basu, R., Putko, B., Kassiri, Z., Turner, A. J., & Oudit, G. Y. (2014). Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: A positive feedback mechanism in the RAS. Journal of Molecular and Cellular Cardiology, 66, 167–176. https://doi.org/10.1016/j.yjmcc.2013.11.017
Romero-Sánchez, C. M., Díaz-Maroto, I., Fernández-Díaz, E., Sánchez-Larsen, Á., Layos-Romero, A., García-García, J., González, E., Redondo-Peñas, I., Perona-Moratalla, A. B., Del Valle-Pérez, J. A., Gracia-Gil, J., Rojas-Bartolomé, L., Feria-Vilar, I., Monteagudo, M., Palao, M., Palazón-García, E., Alcahut-Rodríguez, C., Sopelana-Garay, D., Moreno, Y., … Segura, T. (2020). Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry. Neurology, 10.1212/WNL.0000000000009937. https://doi.org/10.1212/wnl.0000000000009937
Rother, E. T. (2007). Systematic literature review X narrative review. ACTA Paulista de Enfermagem, 20(2), 7–8. https://doi.org/10.1590/s0103-21002007000200001
Ruan, Q., Yang, K., Wang, W., Jiang, L., & Song, J. (2020). Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine, 46(5), 846–848. https://doi.org/10.1007/s00134-020-05991-x
Shanmugaraj, B., Malla, A., & Phoolcharoen, W. (2020). Emergence of novel coronavirus 2019-nCoV: Need for rapid vaccine and biologics development. Pathogens, 9(2), 1–10. https://doi.org/10.3390/pathogens9020148
Školoudík, D., Bar, M., Šaňák, D., Bardoň, P., Roubec, M., Langová, K., Herzig, R., & Kaňovský, P. (2010). D-dimers increase in acute ischemic stroke patients with the large artery occlusion, but do not depend on the time of artery recanalization. Journal of Thrombosis and Thrombolysis, 29(4), 477–482. https://doi.org/10.1007/s11239-009-0372-9
Spiegel, M., Schneider, K., Weber, F., Weidmann, M., & Hufert, F. T. (2006). Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells. Journal of General Virology, 87(7), 1953–1960. https://doi.org/10.1099/vir.0.81624-0
Steardo, L., Steardo, L., Zorec, R., & Verkhratsky, A. (2020). Neuroinfection may potentially contribute to pathophysiology and clinical manifestations of COVID-19. Acta Physiologica (Oxford, England), March, e13473. https://doi.org/10.1111/apha.13473
Tang, N., Bai, H., Chen, X., Gong, J., Li, D., & Sun, Z. (2020). Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. Journal of Thrombosis and Haemostasis, March, 1094–1099. https://doi.org/10.1111/jth.14817
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020). The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology, 1–12. https://doi.org/10.1038/s41577-020-0311-8
The WHO MERS-CoV Research Group. (2013). State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Humans. PLoS Currents, 5(October), 1–31. https://doi.org/10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8
Tortoric, M. A., & Veesler, D. (2020). Structural insights into coronavirus entry. Advances in Virus Research, 105(January), 93–116. https://doi.org/https://doi.org/10.1016/bs.aivir.2019.08.002 #
Vaira, L. A., Deiana, G., Fois, A. G., Pirina, P., Madeddu, G., De Vito, A., Babudieri, S., Petrocelli, M., Serra, A., Bussu, F., Ligas, E., Salzano, G., & De Riu, G. (2020). Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head and Neck, 42(6), 1252–1258. https://doi.org/10.1002/hed.26204
Williams, E., Bevers, M., & Feske, S. (2020). Stroke. BRIGHAM AND WOMEN’S HOSPITAL COVID-19 CLINICAL GUIDELINES. https://covidprotocols.org/protocols/neurology/#stroke
Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., & Yang, L. (2020). Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity, March. https://doi.org/https://doi.org/10.1016/j.bbi.2020.03.031
Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., Yang, L., Liu, C., & Yang, C. (2020). Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity, 87(March), 18–22. https://doi.org/10.1016/j.bbi.2020.03.031
Xu, J., Zhong, S., Liu, J., Li, L., Li, Y., Wu, X., Li, Z., Deng, P., Zhang, J., Zhong, N., Ding, Y., & Jiang, Y. (2005). Detection of Severe Acute Respiratory Syndrome Coronavirus in the Brain: Potential Role of the Chemokine Mig in Pathogenesis. Clinical Infectious Diseases, 41(8), 1089–1096. https://doi.org/10.1086/444461
Xu, Jiaxi, Sriramula, S., & Lazartigues, E. (2018). Excessive Glutamate Stimulation Impairs ACE2 Activity Through ADAM17-Mediated Shedding in Cultured Cortical Neurons. Cellular and Molecular Neurobiology, 38(6), 1235–1243. https://doi.org/10.1007/s10571-018-0591-8
Yamashita, M., Yamate, M., Li, G. M., & Ikuta, K. (2005). Susceptibility of human and rat neural cell lines to infection by SARS-coronavirus. Biochemical and Biophysical Research Communications, 334(1), 79–85. https://doi.org/10.1016/j.bbrc.2005.06.061
Yan, Y., Shin, W. I., Pang, Y. X., Meng, Y., Lai, J., You, C., Zhao, H., Lester, E., Wu, T., & Pang, C. H. (2020). The first 75 days of novel coronavirus (SARS-CoV-2) outbreak: Recent advances, prevention, and treatment. International Journal of Environmental Research and Public Health, 17(7). https://doi.org/10.3390/ijerph17072323
Ye, Z. W., Yuan, S., Yuen, K. S., Fung, S. Y., Chan, C. P., & Jin, D. Y. (2020). Zoonotic origins of human coronaviruses. International Journal of Biological Sciences, 16(10), 1686–1697. https://doi.org/10.7150/ijbs.45472
Zhang, H., Penninger, J. M., Li, Y., Zhong, N., & Slutsky, A. S. (2020). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine, 46(4), 586–590. https://doi.org/10.1007/s00134-020-05985-9
Zhao, H., Shen, D., Zhou, H., Liu, J., & Chen, S. (2020). Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? The Lancet Neurology, 19(5), 383–384. https://doi.org/10.1016/S1474-4422(20)30109-5
Zhou, Y., Li, W., Wang, D., Mao, L., Jin, H., Li, Y., Hong, C., Chen, S., Chang, J., He, Q., Wang, M., & Hu, B. (2020). Clinical time course of COVID-19, its neurological manifestation and some thoughts on its management. Stroke and Vascular Neurology, svn-2020-000398. https://doi.org/10.1136/svn-2020-000398
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2020 Letícia Nunes Campos; Ana Clara Santos Costa; Débora Dantas Nucci Cerqueira; Gabriele Rodrigues Rangel; Isabela Cristina de Farias Andrade; Stella Costa Batista de Souza; Julio Cesar Dias de Melo Silva; Brayan Marques da Costa; Sura Wanessa Santos Rocha
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.