Emerging COVID-19 Neurological Manifestations: Present Outlook and Potential Neurological Challenges in COVID-19 Pandemic

Abstract

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.

Keywords: CNS; COVID-19; COVID-19 pandemic; Neuroinvasion; Neurological complications; PNS; SARS-CoV-2.

Fig. 1

Different neurologic manifestations in COVID-19 patients

Fig. 2

SARS-CoV-2 infection routes and mechanism of CNS invasion in COVID-19. ACE2, angiotensin-converting enzyme 2; CNS, the central nervous system; IFN-γ, interferon-gamma; IL, interleukin; TNF-α, tumor necrosis factor-alpha

Fig. 3

Proposed mechanism by which SARS-CoV-2 intercedes neurologic manifestations in COVID-19. 3HK, 3-hydroxykynurenine; 5HT, 5-hydroxytryptamine; ACE2, angiotensin-converting enzyme 2; ACE-Ang II-AT1, angiotensin-converting enzyme-angiotensin II-angiotensin II subtype I; CCL2, C–C motif chemokine ligand 2; G-CSF, granulocyte colony-stimulating factor; IFN-γ, interferon-gamma; IL, interleukin; MIP-2, macrophage inflammatory protein 2; NK, natural killer; TNF-α, tumor necrosis factor-alpha, indicates downstream pathway; ↑ indicates upregulation; ↓ indicates downregulation

Fig. 4

Proposed mechanism by which SARS-CoV-2 infection in COVID-19 worsens AD and PD. IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha