The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
Authors: Pilotto Andrea , Masciocchi Stefano , Volonghi Irene , del Zotto Elisabetta , Magni Eugenio , De Giuli Valeria , Caprioli Francesca , Rifino Nicola , Sessa Maria , Gennuso Michele , Cotelli Maria Sofia , Turla Marinella , Balducci Ubaldo , Mariotto Sara , Ferrari Sergio , Ciccone Alfonso , Fiacco Fabrizio , Imarisio Alberto , Risi Barbara , Benussi Alberto , Premi Enrico , Focà Emanuele , Caccuri Francesca , Leonardi Matilde , Gasparotti Roberto , Castelli Francesco , Zanusso Gianluigi , Pezzini Alessandro , Padovani Alessandro 
Published: June 2020

ABSTRACTImportanceSeveral preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet.Objectiveto describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment.DesignThe ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded.ResultsOut of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis.Conclusions and relevanceWe found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations.Questionwhat are the phenotypes of encephalitis associated to SARS-CoV-2 infection?Findings25 cases of encephalitis in SARS-CoV-2 infection were included in a prospective observational multi-centre study. Encephalitis cases in COVID-19 exhibited a wide heterogeneity in terms of clinical features, CSF, MRI findings, response to treatment and outcomes with 13 cases with normal MRI, 7 with heterogeneous MRI alterations and rarer ADEM/limbic encephalitis cases.Meaningheterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms