A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the recent pandemic of coronavirus disease 19 (COVID-19). As the infection spreads, there is increasing evidence of neurological and psychiatric involvement in COVID-19. Headache, impaired consciousness, and olfactory and gustatory dysfunctions are common neurological manifestations described in the literature. Studies demonstrating more specific and more severe neurological involvement such as cerebrovascular insults, encephalitis and Guillain-Barre syndrome are also emerging. Respiratory failure, a significant condition that leads to mortality in COVID-19, is hypothesized to be partly due to brainstem impairment. Notably, some of these neurological complications seem to persist long after infection. This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.

Figure 1. Viral journey to the central nervous system (CNS)

A. Axonal transport. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown in the olfactory epithelium, where they can disseminate along the olfactory nerve, ascending from the cribriform plate into the olfactory bulb, then disseminate throughout the CNS via interconnected neurons. SARS-CoV-2 is also presented in the lungs and the gastrointestinal tract, where they can spread along the vagus nerve to reach the CNS, including the brainstem. B. Hematogenesis dissemination. SARS-CoV-2 first invades peripheral epithelial cells, which express ACE2 and TMPRSS2. Once inside the bloodstream, the virus penetrates through the impaired BBB and invades the CNS. (Created with BioRender.com).

Figure 2. Neuroinflammation in the CNS

A. Hypoxia. Inadequate oxygen supply to the brain leads to ATP crisis and exacerbated inflammatory state. B. Demyelination. A leaky BBB allows the entrance of virus and peripheral lymphocytes into the CNS, resulting in activation of microglia. Reactivated microglia release inflammatory cytokines (TNF-α and IL-6), contributing to demyelination and neuron death. C. Oligodendrocyte apoptosis. Infiltrating neutrophils adversely impact neuronal function by inducing oligodendrocyte apoptosis. (Created with BioRender.com).