Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation

Abstract

ObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators.MethodsIn this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2–specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/− sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS).ResultsWe detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10).ConclusionsOur results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms

“… 10 , 11 Although increased CSF concentrations of IL-6 and TNF-α have also been described previously, 11 , 12 , 33 results are less consistent across studies. 13 , 34 Although other CNS infections and inflammatory conditions can generate significantly higher inflammatory CSF biomarker concentrations, 13 , 35 the CSF inflammatory biomarker profile seen in patients with COVID-19 in our study remains a consistent finding and adds to previous reports 11 , 29 , 36 , 37 indicating the importance of CNS immune activation in the neuropathogenesis of COVID-19.…”

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

“…This suggested that one potential mechanism could be the activation of neurovascular cells (endothelial cells, pericytes, astrocytes, and ependymal cells) which could lead to barrier disruption due to a combination of peripheral inflammation (PCC) and/or hypoxia. Further, these authors suggested a role for corticosteroid usage as a result of their findings [93].…”

“…Importantly, Bernard-Valnet et al [93] just shared (June 2021) their results from 22 patients with acute COVID-19. They examined the cerebrospinal fluid (CSF) for chemokines and concluded that their results did not indicate an active replication of SARS-CoV-2 in the CSF or massive inflammation in the CSF compartment; however, they did highlight a specific impairment of the neurovascular unit which authors felt were linked to intrathecal production of the chemokine CXCL 8.…”

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

“…Indicative for a compromised blood-brain barrier, fibrinogen leakage into brain parenchyma was seen in more than 50% of the assessed brains in three case series of COVID-19 patients ( Bocci et al, 2021 ; Lee et al, 2021 ; Schwabenland et al, 2021 ). Further, assessment of cerebrospinal fluid from COVID-19 patients presenting with neurological symptoms revealed elevated albumin levels, suggesting that impaired blood-brain barrier or blood-cerebrospinal fluid barrier properties may play a role during the COVID-19 disease course ( Bernard-Valnet et al, 2021 ).…”