SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses

Pilotto, Andrea; Masciocchi, Stefano; Volonghi, Irene; De Giuli, Valeria; Caprioli, Francesca; Mariotto, Sara; Ferrari, Sergio; Bozzetti, Silvia; Imarisio, Alberto; Risi, Barbara; Premi, Enrico; Benussi, Alberto; Focà , Emanuele; Castelli, Francesco; Zanusso, Gianluigi; Monaco, Salvatore; Stefanelli, Paola; Gasparotti, Roberto; Zekeridou, Anastasia; McKeon, Andrew; Ashton, Nicholas J; Blennov, Kaj; Zetterberg, Henrik; Padovani, Alessandro

BACKGROUND: Recent findings indicated that SARS-CoV-2 related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune‐mediated mechanisms. Very few studies have fully investigated the CSF correlates of SARS-CoV-2 encephalitis. METHODS: Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin). RESULTS: Thirteen COV-Enc, 21 ENC and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases. CONCLUSIONS: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.