Cytokine release syndrome‐associated encephalopathy in patients with COVID‐19

Abstract

Background Neurological manifestations in coronavirus disease (COVID)‐2019 may adversely affect clinical outcomes. Severe COVID‐19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. Methods In this longitudinal study, we sought to describe the neurological manifestations of patients with COVID‐19 and gain pathophysiological insights especially with respect to the CRS. Extensive clinical, laboratory, and imaging phenotyping was performed in five patients admitted to our renal unit. Results 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 (CSF). Hyperalbuminorrachia 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. SARS‐CoV2 was undetectable in 88 of the 90 patients with COVID‐19 who underwent RT‐PCR testing of CSF. Conclusions 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.

Neurological manifestations associated with SARS-CoV-2 and other coronaviruses: A narrative review for clinicians

“…Neurological short-term prognosis was available for 26 patients in the case reports ( Table 3 ) or case series [29] , [32] , [33] and 116 patients in cohort studies [4] , [5] , [8] , [9] , [10] . A complete or partial recovery was noted in 109/142 patients (77%) either spontaneously ( n = 68) or with immunotherapy ( n = 41) including high-dose steroid treatment and/or intravenous immunoglobulins (IV Ig).…”

Cerebrospinal fluid in COVID-19: A systematic review of the literature

“…Although the CSF RBC count was only reported for 61/430 (14%) patients [ 22 , 28 , 29 , 31 , 35 , 39 , 40 , 44 , 73 , 74 , 77 , 78 , 81 , 89 , 92 , 102 , 110 , 118 , [120] , [121] , [122] , [123] , 128 , 133 , 134 , [138] , [139] , [140] , 156 , 165 , 166 , [172] , [173] , [174] , [175] , [176] , 180 , 184 , 188 , 191 , 192 , 198 , 202 , 204 , 208 , 215 , 220 , 225 , 227 , 233 , 241 , 242 , 246 ], the CSF white blood cell (WBC) count was provided for 409/430 (95%) patients, 270 (66%) of whom had >0 cells/μL, >1 WBC:1,000 RBC or were noted to have “pleocytosis” ( Fig. 3 ) [ [5] , [6] , [7] , [8] , 10 , 13 , [15] , [16] , [17] , [18] ...…”

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.…”