The Neurological Implications of COVID-19: A Comprehensive Narrative Review

Abstract

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 revealed a huge number of problems as well as discoveries in medicine, notably, regarding the effects of the virus on the central nervous system (CNS) and peripheral nervous system (PNS). This paper is a narrative review that takes a deep dive into the complex interactions between COVID-19 and the NS. Therefore, this paper explains the broad range of neurological manifestations and neurodegenerative diseases caused by the virus. It carefully considers the routes through which SARS-CoV-2 reaches the NS, including the olfactory system and of course, the hematogenous route, which are also covered when discussing the virus's direct and indirect mechanisms of neuropathogenesis. Besides neurological pathologies such as stroke, encephalitis, Guillain-Barré syndrome, Parkinson's disease, and multiple sclerosis, the focus area is also given to the challenges of making diagnosis, treatment, and management of these conditions during the pandemic. The review also examines the strategic and interventional approaches utilized to prevent these disorders, as well as the ACE2 receptors implicated in the mediation of neurological effects caused by COVID-19. This detailed overview, which combines research outputs with case data, is directed at tackling this pandemic challenge, with a view toward better patient care and outcomes in the future.

Keywords: covid-19; encephalitis; guillain-barre syndrome; neuroimmunology; neuroinvasion; neurological complications; neuropathogenesis; parkinson's disease; sars-cov-2; treatment strategies.

Figure 1. Routes of Coronavirus Infection into the CNS

(1) Olfactory pathway: The virus enters via the mouth, binding to olfactory nerve receptors, and transmitting through the nerve to the brain. (2) receptor binding: The virus binds host cell receptors with TMPRSS2 aid, entering via endocytosis or fusing with cell membranes for nucleic acid release. (3) Trojan Horse mechanism: The virus activates pro-inflammatory pathways via ACE2 and NF-κB, inducing a cytokine storm and immune cell recruitment, potentially damaging the blood-brain barrier and activating neurotoxic responses. (4) Neurons retrograde: The virus spreads retro-transsynaptically after infecting peripheral neurons, reaching central or other peripheral neurons. CNS: central nervous system; TMPRSS2: transmembrane protease serine 2; ACE2: angiotensin-converting enzyme 2; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B Cells Reproduced under the terms and conditions of the Creative Commons Attribution License (CC-BY) from Ref [47]. Copyright © 2023 Sha and Chen. Published by Frontiers in Neuroscience.

Figure 2. Main Effects of the COVID-19 Infection on Multiple Sclerosis

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; CNS: central nervous system Reproduced under the terms and conditions of the Creative Commons Attribution (CC-BY) license from Ref. [88]. Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland.

Figure 3. (A) Transmission and structural proteins of SARS-CoV-2. (B) Infection mechanisms and inflammatory response in the lungs, featuring key components

ACE2: angiotensin-converting enzyme 2; Ang: angiotensin; ARDS: acute respiratory distress syndrome; AT1R: angiotensin II type I receptor; CASP1: caspase 1; E protein: envelope small membrane protein; HE: hemagglutinin esterase; IL1β: interleukin 1 beta; IRAKs: interleukin-1 receptor-associated kinases; M protein: membrane protein; MyD88: myeloid differentiation primary response 88; N protein: nucleoprotein; N: neutrophils; NF-κB: nuclear factor kappa B; NK: natural killer cells; NLRP3: nucleotide-binding domain; leucine-rich repeat-containing receptor; pyrin domain-containing 3; RNA: ribonucleic acid; S protein: spike protein; TMPRSS2: transmembrane serine protease 2; TRAF6: tumor necrosis factor receptor-associated factor 6 Reproduced under the terms and conditions of the Creative Commons Attribution (CC-BY) license from Ref. [96]. Copyright © 2021 Pacheco-Herrero, Soto-Rojas, Harrington, et al. Published by Frontiers in Neurology.