Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19

Abstract

Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS‐CoV‐2 infection

“…Buzhdygan et al 69 found that SARS-CoV-2 spike protein could trigger a proinflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. In an in vivo study, Perrin et al 70 found that serum levels of the astroglial marker, S100B protein, were increased at the time of cytokine release syndrome in COVID-19 patient, reflecting an increased permeability of the BBB. These findings indicate that SARS-CoV-2 may also invade the CNS by impaired BBB.…”

Neurological issues during COVID-19: An overview

“…A cytokine release syndrome in which patients develop confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism has also been described. These patients respond to corticosteroid therapy [ 6 , 7 ]. Some others may develop wide spread microcerebral hemorrhages [ 8 ].…”

Cellular and Molecular Effects of SARS-CoV-2 Linking Lung Infection to the Brain

“…Next, the whole cascade results in a leaky and impaired BBB. Perrin and colleagues reported COVID-19 cases in which an elevated astroglia marker, S100B level was detected as a sign of increased BBB permeability (95). When an intense systemic inflammatory response occurs, more virus and peripheral cytokines such as IL-1b, IL-6, IL-17 and TNF-a, among others, can enter the brain via the damaged BBB.…”