Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm

Abstract

Objective To study in cerebrospinal fluid (CSF) of COVID-19 subjects if a “cytokine storm” or neuroinflammation are implicated in pathogenesis of neurological complications. Methods Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity. COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls ( n = 82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. Results CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls. Conclusion The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. The role of CSF SARS-CoV2 IgG antibodies and mechanisms of neuronal damage are still undetermined.

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

“…Using cerebrospinal fluid may have had a higher predictive value [ 57 , 116 , 117 , 118 ]. Elevations in serum NF-L levels were reported inconsistently in studies plagued with small fibers, unadjusted for comorbidities, or limited to the most sick patients [ 12 , 32 , 35 , 94 , 119 , 120 , 121 ]. Gisslen et al reported the normalization of GFAP and NF-L six months after the resolution of COVID-19, but their patients continued to exhibit neurological symptoms and their study was limited to these markers [ 34 ].…”

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

“…Multiple cytokines were found to be elevated in the blood during acute COVID-19, while increased levels of proinflammatory markers were not detected in the cerebrospinal fluid (CSF) [ 41 ]. Serum levels of IL-4, IL-10, IL-6 and IL1β were elevated in COVID-19 patients [ 33 , 42 , 43 ].…”

“…SARS-CoV-2 antibodies were frequently detected in the CSF of COVID-19 patients, although this does not prove intrathecal antibody production [ 41 , 44 , 45 ]. The detection of the virus via PCR from CSF was impossible in most cases [ 41 , 44 , 45 ].…”

“…SARS-CoV-2 antibodies were frequently detected in the CSF of COVID-19 patients, although this does not prove intrathecal antibody production [ 41 , 44 , 45 ]. The detection of the virus via PCR from CSF was impossible in most cases [ 41 , 44 , 45 ]. Only few authors described sporadic positive results in SARS-CoV-2 PCR from CSF in patients with severe cerebral symptoms [ 46 , 47 , 48 ].…”

Neuropathogenesis of severe acute respiratory syndrome coronavirus 2

“…Biomarker analyses of cerebrospinal fluid consistently demonstrates abnormal CSF to plasma albumin ratio in a portion of patients with acute SARS-CoV2 infection suggesting breakdown of the BBB during acute infection, particularly in patients experiencing severe SARS-CoV2 infection. Additionally, neurofilament light chain, a marker of neuronal injury, is found to be elevated in the CSF of patients with acute SARS-CoV2 infection and is higher in individuals with severe SARS-CoV2 infection [ 38 ]. These data suggest that severe, acute SARS-CoV2 infection may result in BBB breakdown and that this process may allow for the extravasation of immune cells or inflammatory cytokines into the CNS space with the potential to cause neuronal injury.…”