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Review
. 2024 May 22;12(6):1147.
doi: 10.3390/biomedicines12061147.

COVID-19: Unveiling the Neuropsychiatric Maze-From Acute to Long-Term Manifestations

Daniela Ariza  1 , Lily Castellar-Visbal  2 , Maria Marquina  1 , Diego Rivera-Porras  3 , Nestor Galbán  1 , Raquel Santeliz  1 , Melissa Gutiérrez-Rey  2 , Heliana Parra  1 , José Vargas-Manotas  2 , Wheeler Torres  1 , Laura Quintana-Espinosa  2 , Alexander Manzano  1 , Lorena Cudris-Torres  4 , Valmore Bermúdez  2   5
Affiliations
Review

COVID-19: Unveiling the Neuropsychiatric Maze-From Acute to Long-Term Manifestations

Daniela Ariza et al. Biomedicines. .

Abstract

The SARS-CoV-2 virus has spread rapidly despite implementing strategies to reduce its transmission. The disease caused by this virus has been associated with a diverse range of symptoms, including common neurological manifestations such as dysgeusia, anosmia, and myalgias. Additionally, numerous cases of severe neurological complications associated with this disease have been reported, including encephalitis, stroke, seizures, and Guillain-Barré syndrome, among others. Given the high prevalence of neurological manifestations in this disease, the objective of this review is to analyze the mechanisms by which this virus can affect the nervous system, from its direct invasion to aberrant activation of the immune system and other mechanisms involved in the symptoms, including neuropsychiatric manifestations, to gain a better understanding of the disease and thus facilitate the search for effective therapeutic strategies.

Keywords: COVID-19; Guillain–Barré syndrome; SARS-CoV-2; encephalitis; neuroinflammation; stroke.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The SARS-CoV-2 structure.
Figure 2
Figure 2
Mechanism of SARS-CoV-2 infection. (1) The interaction of the receptor-binding domain (RBD) of the S protein with the angiotensin-converting enzyme 2 (ACE2), as well as the action of proteases like trans-membrane serine protease 2 (TMPRSS2), which, together, allow (2) the entry of the virus into the type II alveolar cell. Subsequently, (3) the viral RNA enters the cell nucleus for (4) replication and (5) protein biosynthesis, (6) both products are included in new viral particles that will be released. This results in (7) the activation of inflammasome 3 (NLRP3), (8) undergoing cell apoptosis and pyroptosis through gasdermin-D pores, and (9) cytosolic content release, including some damage-associated molecular patterns (DAMPs) that are detected by alveolar macrophages, triggering (10) an inflammatory response mediated by pro-inflammatory cytokines that (11) attract monocytes and T lymphocytes. The latter (12) releases granulocyte–macrophage colony-stimulating factor (GM-CSF), which (13) activates CD14+ and CD16+, resulting in a pro-inflammatory feedback loop that ultimately (14) leads to severe lung damage through the direct action of the virus, proteases, and reactive oxygen species.
Figure 3
Figure 3
Potential neuroinvasive pathways of SARS-CoV-2. (1) It has been speculated that SARS-CoV-2 can invade the brain through olfactory pathways. (2) Hematogenous spread is another possible form of neuroinvasion; some similar viruses have been able to cross the blood–brain barrier. (3) The virus can invade tissues, utilizing TMPRSS2 and ACE2 receptors. Abbreviations: TMPRSS2, transmembrane protease, serine 2; ACE2, angiotensin converting enzyme 2.
Figure 4
Figure 4
Cytokine storm in SARS-CoV-2 infection. Patients infected with SARS-CoV-2 present immune dysregulation, characterized by hyperinflammatory events. First of all, there is an increased activity of a wide variety of immune cells, such as dendritic cells, macrophages, T cells and natural killer cells, leading to a significant elevation in plasma concentrations of interleukin-1β (IL-1β), interleukin-7 (IL-7), interleukin-10 (IL-10), interferon-gamma (IFNγ), tumor necrosis factor α (TNFα), and vascular endothelial growth factor (VEGF), ending in dysregulation of the immune system leading to acute systematic inflammation, secondary organ dysfunction, multi-organ failure and finally death in many cases [61].
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Internal funds for research strengthening were sourced from the Universidad Simón Bolívar, Vicerrectoría de Investigación, Extensión e Innovación, Barranquilla, Colombia.

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