Debate on the Significance of Neurological Symptoms of COVID-19

May 4, 2020 by Sam Bazzi

During the past week, while I was surveying the literature for any new neurological reports in COVID-19, I found a paper that casted doubt on the connections between neurological disease and COVID-19, which led me down a rabbit hole of dissenting papers. A few weeks ago, I wrote a blog post that briefly outlined the possibility that SARS-CoV-2 may perhaps invade the CNS and infect neurons in the brainstem that affect respiration and that this may play in part in respiratory failure. (Li, Bai, and Hashikawa, 2020) This week, in the Journal of Medical Virology, Lance Turtle dissents with this conclusion, suggesting   that respiratory failure alone is not sufficient  to suggest the involvement of the CNS because the type of respiratory failure that occurs typically from neurological failure (ventilatory failure, Type 2) is distinct from the type of respiratory failure seen in COVID-19 patients (hypoxic, Type 1). The author also claims that while some connection between human coronaviruses (HCoVs) and CNS cells has been explored in vitro, HCoVs have never been definitively linked with directly causing CNS disease. (Turtle, 2020) To the author’s  point, many of the neurological symptoms seen in patients with COVID-19 so far have been relatively “nonspecific” (except for stroke) and may be secondary results of the inflammatory cytokine storm. While multiple mechanisms have been proposed such as ACE-2-mediated entry into neurons and glia, there is currently no evidence to support these hypotheses. However, SARS-CoV-2 has proven to be a different beast than the previous SARS outbreak and there also has not been evidence that contradicts the idea that SARS-CoV-2 can directly invade the CNS. Additionally, there have been reported cases of acute neurological symptoms such as stroke and acute necrotizing encephalopathy.(Poyiadji, et al., 2020)

In a response to Turtle, Li, et al. describe how at least four human coronaviruses have been shown to invade the nervous system, which opens up many questions regarding neurological symptoms not only during the normal course of the respiratory illness, but also well after the acute disease has subsided. (Li, Bai, and Hashikawa, 2020) These viruses are HCoV-229E, HCoV-OC43, SARS-CoV, and MERS-CoV. (Arbour, et al., 2000, Gu, et al., 2005, Xu, et al., 2005, Li, et al., 2016) Of these studies, one found that in post-mortem human brain tissue, patients with multiple sclerosis had significantly higher levels of HCoV-OC43 RNA than in healthy controls. (Arbour, et al., 2000) This finding raises interesting questions about potential long-term effects of coronavirus infection on neurological disease beyond just the normal course of respiratory illness. It may be the case that the neurological symptoms seen with COVID-19 may be secondary to the inflammation due to the cytokine storm, but there does seem to be some link between viral infections and chronic autoimmune disease. The same phenomenon has been observed with Guillaine-Barré Syndrome (GBS), where two-thirds of patients with this autoimmune disorder reported symptoms of respiratory or gastrointestinal infection within 4 weeks preceding the onset of the syndrome. (Willison, et al., 2016) As the number of cases of COVID-19 begin to fall, it will be important to track the long-term health outcomes of those who have been infected. More work needs to be done to identify the role of infection in autoimmunity, and the mechanism by which viruses enter the CNS.

Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
5/4/2020