Neurological Effects of Covid-19

The World Health Organization reported as of December 29, 2021, that more than 281.8 million cases and 5.4 million deaths of COVID-19 have been confirmed globally. The pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is incredibly pathogenic and has a startlingly rapid transmission rate, causing flu-like symptoms such as fever, cough, shortness of breath, and respiratory failure. Further progression of COVID-19 points to neurological effects in some patients, for example, anosmia, ageusia, seizures, stroke, and paralysis at varying incidence rates [1]. ICU patients admitted due to neurological symptoms have a higher mortality rate; those who are discharged remain at higher risk of developing conditions like depression, OCD, psychosis, Parkinson’s Disease, and Alzheimer’s Disease [2]. 

SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2), a step believed to be the source of clinical manifestations of the infection. In healthy individuals, ACE2 regulates blood pressure and converts angiotensin II (AT2) to angiotensin (1-7), processes inhibited by the binding of SARS-CoV-2 to the enzyme protein. Higher levels of AT2 are associated with pro-inflammatory markers, vasoconstriction, renal failure, heart disease, and oxidative processes accelerating brain degeneration [3]. Once bound to ACE2, SARS-CoV-2 is believed to drive up levels of interleukin-1, interleukin-6, and tumor necrosis factor. These cytokines contribute to complications such as edema, vascular permeability, and widespread inflammation, as well as stimulating hypercoagulation cascades and blood clots [4]. Formation of blood clots in the brain can result in cerebral thrombosis, and high cytokine levels may damage neurons and glia in the surrounding cerebral tissue.

In olfactory epithelial cells, nasopharynx and oral mucosa, high densities of ACE2 are blocked by SARS-CoV-2, effectively inhibiting sensory receptors critical in olfaction and gustation. The virus is believed to be passed from specialized glia cells such as high ACE2-expressing olfactory ensheathing cells (OECs) to low ACE2-expressing olfactory receptor neurons (ORNs) [5]. The infection of OEC support cells could negatively affect function of higher-order olfactory neurons, leading to anosmia 3-4 weeks after clinical onset [5-6]. Similarly, the damage caused by viral cells to neurons in the nucleus solitarius of the medulla may explain the ageusia often reported by COVID-19 patients [3].

Major risk factors for cerebrovascular disease alongside COVID-19 infection, which are more commonly observed in Asian populations, include hypertension, diabetes, and obesity [7-9]. Hypercoagulation in cerebral arteries and veins can lead to ischemic stroke, which may occur simultaneously with deep vein thrombosis [8]. Although most reported strokes in COVID-19 patients have been a result of ischemic events, cases with intracranial hemorrhage have also been described. The prominent hypothesis posits that as SARS-CoV-2 binds and suppresses ACE2, AT2 levels are upregulated; this higher concentration is associated with vasoconstriction, which could potentially lead to rupture of blood vessels in the brain [3].

The peripheral neuropathy Guillain-Barre Syndrome (GBS) is a rare complication of COVID-19 infection that further suggests neurological effects due to SARS-CoV-2. GBS is thought to operate via molecular mimicry, where pathogens camouflage themselves to look like natural immunoglobins [3, 10]. A case report of the first COVID-19 patient diagnosed with GBS posted the question of whether the neuroinflammatory effects of SARS-CoV-2 may be the cause of direct invasion to peripheral nerves [11].

Neurological manifestations of COVID-19 symptoms can be due to damage to the central and peripheral nervous systems of the body, through suppression of the enzyme ACE2, hypercoagulation, molecular mimicry, and more. To fine-tune global understanding on the full neurological effects behind COVID-19, further work, including standardized neuroimaging studies, should be conducted.

References

1. Li, Z., Liu, T., Yang, N. et al. (2020). Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. Front. Med. 14, 533–541. https://doi.org/10.1007/s11684-020-0786-5
2. Troyer, E. A., Kohn, J. N., Hong, S. (2020). Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain. Behav. Immun., https://doi.org/10.1016/j.bbi.2020.04.027
3. Fotuhi, M., Mian, A., Meysami, S., & Raji, C. A. (2020). Neurobiology of COVID-19. Journal of Alzheimer’s Disease, 76(1), 3–19. https://doi.org/10.3233/JAD-200581
4. Xiong, M., Liang, X., & Wei, Y. (2020). Changes in blood coagulation in patients with severe coronavirus disease 2019 (COVID‐19): A meta‐analysis. British Journal of Haematology, 189(6), 1050–1052. https://doi.org/10.1111/bjh.16725
5. Butowt, R., & Bilinska, K. (2020). SARS-CoV-2: Olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chemical Neuroscience, 11(9), 1200–1203. https://doi.org/10.1021/acschemneuro.0c00172
6. Vaira, L. A., Hopkins, C., Salzano, G., Petrocelli, M., Melis, A., Cucurullo, M., Ferrari, M., Gagliardini, L., Pipolo, C., Deiana, G., Fiore, V., De Vito, A., Turra, N., Canu, S., Maglio, A., Serra, A., Bussu, F., Madeddu, G., Babudieri, S., … De Riu, G. (2020). Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study. Head & Neck, 42(7), 1560–1569. https://doi.org/10.1002/hed.26269
7. Fang, L., Karakiulakis, G., & Roth, M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory Medicine, 8(4), e21. https://doi.org/10.1016/S2213-2600(20)30116-8
8. Zhou, B., She, J., Wang, Y., & Ma, X. (2020). A case of coronavirus disease 2019 with concomitant acute cerebral infarction and deep vein thrombosis. Frontiers in Neurology, 11, 296. https://doi.org/10.3389/fneur.2020.00296
9. Carter, S. J., Baranauskas, M. N., & Fly, A. D. (2020). Considerations for obesity, vitamin D, and physical activity amid the Covid-19 pandemic. Obesity, 28(7), 1176–1177. https://doi.org/10.1002/oby.22838
10. Wim Ang, C., Jacobs, B. C., & Laman, J. D. (2004). The Guillain–Barré syndrome: A true case of molecular mimicry. Trends in Immunology, 25(2), 61–66. https://doi.org/10.1016/j.it.2003.12.004
11. Sedaghat, Z., & Karimi, N. (2020). Guillain Barre syndrome associated with COVID-19 infection: A case report. Journal of Clinical Neuroscience, 76, 233–235. https://doi.org/10.1016/j.jocn.2020.04.062