Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms

Abstract

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.

Meta-analysis of EEG findings in patients with COVID-19

“…Symptoms such as fever, hypoxia, and sedation may cause encephalopathy. Furthermore, encephalopathy associated with COVID-19 might be caused by any of the three pathways as follows: (1) indirect immune-mediated responses such as a cytokine storm, (2) direct central nervous system invasion by the virus, and (3) damage to the neural cells through angiotensin-converting enzyme 2 (ACE2) receptors [27] . In addition, we found discontinuous/burst suppression/background suppression and GPDs in 5.33% and 16.5% of the patients, respectively.…”

Pathophysiological Clues to How the Emergent SARS-CoV-2 Can Potentially Increase the Susceptibility to Neurodegeneration

“…-Increased IL-1β in AD patients compared to controls, and higher IL-6 in PD patients compared to controls, as well as increased TNF-α has been detected [33,34]. Microglial activation -SARS-CoV-2 open reading frame 3a (ORF-3a) protein stimulates NLRP3 inflammasomes, thereby accelerates the microglial activation [35,36].…”

“…Consistently, high levels of cytokines such as Intelukin-6 (IL-6), IL-8, IL-10, and Tumor Necrosis Factor alpha (TNF-α) as well as positive anti-S1 IgM have been detected in three cases of COVID-19 meningoencephalitis [93]. Indeed, high levels of peripheral cytokines can pass BBB directly and initiate neuroinflammatory reactions or compromise BBB integrity allowing permeation of virus-infected peripheral white blood cells and especially monocytes leading to uncontrolled production of cytokines, microglial activation and neuroinflammation [33,94]. Immune response dysregulation, on the other hand, is recognized as a main mechanism involved in pathophysiology of neurodegenerative diseases and increment in levels of proinflammatory cytokines such as IL-1β and IL-6 is observable in these patients [34,95].…”

SARS-CoV-2 journey to the brain with a focus on potential role of docosahexaenoic acid bioactive lipid mediators

“…Researchers reported that SARS-CoV-2 neuroinvasion happens following three main phases [ 34 ]. The viral invasion into the CNS is the first phase.…”

“…This response, known as a cytokine storm ‘CS’ is generated by the stimulation of numerous white blood cells (B cells, T cells, NK cells, macrophages, dendritic cells, neutrophils, monocytes) and tissue cells (epithelial and endothelial cells) [ 49 ]. In the brain, CS can be considered as a crucial factor to cause BBB disruption [ 34 , 50 ]. Monocytes and lymphocytes penetrate into the vessel walls and cause neuroinflammation, neurodegeneration and demyelination [ 50 ].…”