Although encephalopathies in patients with severe SARS-CoV-2 infection are not due to major viral infections in the brain or cytokine storm leakage from the periphery into the central nervous system (CNS), there is a strong association between encephalopathies and impairment of the blood brain barrier (BBB), according to study results published in Neurology Neuroimmunology & Neuroinflammation.

While outbreaks of COVID-19 have often been associated with neurologic disorders and a range of neurologic complications, hypotheses firmly explaining these complications are still scarce. The response of encephalitis and encephalopathies to corticosteroids, however, suggests that immune mechanisms may be involved.

To better understand the underlying mechanisms of neurologic symptoms associated with SARS-CoV-2 infection, a team of investigators conducted a cross-sectional study in Switzerland to determine whether neurologic symptoms were caused directly by SARS-CoV-2 infection or by either systemic or local proinflammatory mediators.

Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), study researchers tested 77 patients for SARS-CoV-2 ribonucleic acid (RNA), SARS-CoV-2-specific antibodies, and for 49 cytokines, chemokines, and growth factors in the cerebrospinal fluid (CSF). 22 patients had COVID-19 and 55 patients were included in the control cohort.


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Of the 22 patients with COVID-19, 13 patients were admitted to the intensive care unit (ICU), and 9 patients required mechanical ventilation. 11 of the 13 ICU-admitted patients presented with encephalopathy. Of the 8 patients who underwent nerve conduction studies, 6 patients had confirmed critical illness myopathy or polyneuropathy. No significant magnetic resonance imaging abnormalities were observed. Additionally, 7 of the 8 electroencephalography (EEG) tests revealed abnormalities.

Although all RT-qPCR results were negative for the detection of SARS-CoV-2 in the CSF, antibodies against SARS-CoV-2 were detected in the CSF of 10 of 21 patients with COVID-19. None of the control patients had detectable SARS-CoV-2 antibodies in the CSF (P <.0001).

Additionally, the antibody index was elevated in the majority of patients who had severe COVID-19 (5 of 8 patients; 62.5%); this suggested the intrathecal synthesis of antibodies against SARS-CoV-2 in some patients.

Compared with patients with moderate COVID-19, those with severe COVID-19 had a higher proportion of elevated albumin levels (P =.049). Consequently, the study researchers assessed the relationship between albumin ratio and CSF levels of C-X-C motif chemokine ligand 8 (CXCL8), C-C motif chemokine ligand 2 (CCL2), and vascular endothelial growth factor A (VEGF-A).

Findings indicated that patients with elevated albumin ratios had significantly more CXCL8 in CSF. While, VEGF-A levels were also almost significant in these patients (P =.059), CCL2 levels showed no difference.

The CXCL8 CSF/serum index was elevated in 6 of 9 patients with severe COVID-19 and in 0 of 5 patients with milder forms (P =.0310), suggesting intrathecal synthesis.

“[O]ur study identifies a potential mechanism by which the activation of neurovascular unit cells leads to barrier disruption, as a result of peripheral inflammation and/or hypoxia. The fact that [COVID-19-associated] encephalopathies respond to corticosteroids actually supports this hypothesis,” the study investigators concluded.

Reference

Bernard-Valnet R, Perriot S, Canales M, et al. Encephalopathies associated with severe COVID-19 present neurovascular unit alterations without evidence for strong neuroinflammation. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1029. doi:10.1212/NXI.0000000000001029

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