Neurological complications caused by SARS-CoV-2

Abstract

SUMMARYSARS-CoV-2 can not only cause respiratory symptoms but also lead to neurological complications. Research has shown that more than 30% of SARS-CoV-2 patients present neurologic symptoms during COVID-19 (A. Pezzini and A. Padovani, Nat Rev Neurol 16:636-644, 2020, https://doi.org/10.1038/s41582-020-0398-3). Increasing evidence suggests that SARS-CoV-2 can invade both the central nervous system (CNS) (M.S. Xydakis, M.W. Albers, E.H. Holbrook, et al. Lancet Neurol 20: 753-761, 2021 https://doi.org/10.1016/S1474-4422(21)00182-4 ) and the peripheral nervous system (PNS) (M.N. Soares, M. Eggelbusch, E. Naddaf, et al. J Cachexia Sarcopenia Muscle 13:11-22, 2022, https://doi.org/10.1002/jcsm.12896), resulting in a variety of neurological disorders. This review summarized the CNS complications caused by SARS-CoV-2 infection, including encephalopathy, neurodegenerative diseases, and delirium. Additionally, some PNS disorders such as skeletal muscle damage and inflammation, anosmia, smell or taste impairment, myasthenia gravis, Guillain-Barré syndrome, ICU-acquired weakness, and post-acute sequelae of COVID-19 were described. Furthermore, the mechanisms underlying SARS-CoV-2-induced neurological disorders were also discussed, including entering the brain through retrograde neuronal or hematogenous routes, disrupting the normal function of the CNS through cytokine storms, inducing cerebral ischemia or hypoxia, thus leading to neurological complications. Moreover, an overview of long-COVID-19 symptoms is provided, along with some recommendations for care and therapeutic approaches of COVID-19 patients experiencing neurological complications.

Keywords: COVID-19; SARS-CoV-2; central nervous system; long-COVID-19; neurological disorders; peripheral nervous system.

Fig 1

The mechanisms of SARS-CoV-2 initiate coagulation cascades. SARS-CoV-2 can induce a cytokine storm, among them, IL-6 with the IL-6 receptor complexes, and IL-1β can bind to platelets and over-activate platelets. SARS-CoV-2 can increase heparanase activity. Also, heparanase can cleave the heparan sulfate proteoglycan, thus releasing the coagulation factor. Heparanase induces the expression of tissue factors which initiates blood coagulation.

Fig 2

SARS-CoV-2 invades the brain via the retrograde neuronal pathway. (A) SARS-CoV-2 infects the brain by infecting the olfactory bulb through the olfactory nerve passing through the cribriform plate. At the same time, it can trigger a significant release of inflammatory signals to promote neuroinflammation and brain cell death. (B) After SARS-CoV-2 infects the gastrointestinal tract, the virus can gain access to the central nervous system through the vagus nerve. Concurrently, the gut microbiota can impact the central nervous system by the synthesis of metabolites that affect neurotransmitter levels.

Fig 3

SARS-CoV-2 enters the brain via the hematogenous route. (A) After SARS-CoV-2 infects blood cells, these cells can traverse the BBB utilizing a Trojan horse mechanism. Additionally, high-density lipoprotein (HDL) can bind to the SARS-CoV-2 spike protein and cross the BBB through blood circulation. Exosomes also have the potential to act as Trojan horses to facilitate the entry of SARS-CoV-2 into the BBB. (B) Increased expression of ACE2 on various components of BBB cells, including endothelial cells, pericytes, and astrocytes, suggests that SARS-CoV-2 can infect brain endothelial cells, ultimately resulting in dysfunction and damage to the brain endothelium. Blood flow promotes the interaction between SARS-CoV-2 and ACE2, which helps the entry of virus into the brain. BBB, blood-brain barrier; HDL, high-density lipoprotein.

Fig 4

Cytokine storm induced by SARS-CoV-2 infection. (A) SARS-CoV-2 infection induces the cytokine storm, resulting in endothelial cell damage, astrocyte activation, and exacerbation of blood-brain barrier dysfunction. (B) Viral replication can trigger cell pyroptosis, resulting in the release of pro-inflammatory factors. In addition, SARS-CoV-2 infection downregulates ACE2 expression, increases AngII levels, and activates of NF- κB signaling pathways. This cascade induces the expression of the TNF-α and IL-6 receptor alpha, the production of various pro-inflammatory cytokines and chemokines.

Fig 5

Other mechanisms of SARS-CoV-2 cause neurological complications. (A) SARS-CoV-2 infects pericytes located on brain capillaries, causing capillary constriction and ultimately reducing blood flow to the brain, thereby impacting cerebral blood supply and impairing neuronal function. (B) Patients diagnosed with COVID-19 exhibit reduced blood oxygen levels, leading to cerebral hypoxia. This hypoxia will trigger mitochondrial anaerobic metabolism in neuronal cells, heighten lactate production, reduce intracellular pH, and lead to cerebral vasodilation, eventually destroying the integrity of the blood-brain barrier. (C) SARS-CoV-2 infection can induce fusion between neuronal cells or between neuronal cells and glial cells, leading to neuronal damage.