COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Relevance

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). The virus invades human cells through the angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway, primarily targeting the human respiratory tract. However, emerging reports of neurological manifestations demonstrate the neuroinvasive potential of SARS-CoV-2. This review highlights the possible routes by which SARS-CoV-2 may invade the central nervous system (CNS) and provides insight into recent case reports of COVID-19-associated neurological disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, and inflammatory-mediated neurological disorders. We hypothesize that SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may be implicated in the development of the observed disorders; however, further research is critical to understand the detailed mechanisms and pathway of infectivity behind CNS pathogenesis.

Keywords: CNS; COVID-19; SARS-CoV-2; blood-brain barrier; cerebrovascular; neurological disorders.

Figure 1

Potential routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the central nervous system (CNS) and preliminary activation of the immune system. (a) Once SARS-CoV-2 is inhaled into the nasal cavity, the virus may travel to the CNS by retrograde axonal transport along sensory and olfactory nerves via the cribriform plate, a bone structure located nearby the olfactory bulb. In this pathway, SARS-CoV-2 would bypass the blood-brain barrier (BBB). (b) Following a respiratory tract infection characteristic of the virus, SARS-CoV-2 may disseminate into the systemic circulatory system. Upon reaching the BBB, SARS-CoV-2 may invade host endothelial cells by interaction with the angiotensin-converting enzyme 2 (ACE2) receptor, altering tight junction proteins formed by BBB endothelial cells, or phagocytosis by immune cells. These three mechanisms are termed transcellular migration, paracellular migration, and the Trojan horse strategy, respectively. (c) In both pathways, cells infected with SARS-CoV-2 release type I interferons, which alert neighboring and immune cells to the presence of pathogen. Under normal conditions, infected cells are eliminated by host immune cells to prevent further replication and the spread of SARS-CoV-2.