The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study

Background: Several 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. Objective: to 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. Design: The 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. Results: Out 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 relevance: We 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.

[1]  William T. Hu,et al.  Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease, Atlanta, Georgia, USA, 2020 , 2020, Emerging infectious diseases.

[2]  K. Blennow,et al.  Steroid‐Responsive Encephalitis in Coronavirus Disease 2019 , 2020, Annals of neurology.

[3]  G. Breen,et al.  UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients , 2020, SSRN Electronic Journal.

[4]  A. Dinçer,et al.  Plasmapheresis treatment in COVID-19–related autoimmune meningoencephalitis: Case series , 2020, Brain, Behavior, and Immunity.

[5]  M. Leonardi,et al.  Clinical features and outcomes of inpatients with neurological disease and COVID-19 , 2020, medRxiv.

[6]  J. McArthur,et al.  Neurological manifestations associated with COVID-19: a review and a call for action , 2020, Journal of Neurology.

[7]  J. Sejvar,et al.  Neurological associations of COVID-19 , 2020, The Lancet Neurology.

[8]  T. Zhang,et al.  COVID-19-Associated Acute Disseminated Encephalomyelitis: A Case Report , 2020, medRxiv.

[9]  R. D. Du Pasquier,et al.  Two patients with acute meningoencephalitis concomitant with SARS‐CoV‐2 infection , 2020, medRxiv.

[10]  Xiaopei Xu,et al.  Neurological manifestations of the coronavirus (SARS-CoV-2) pandemic 2019–2020 , 2020, Journal of Neurology, Neurosurgery, and Psychiatry.

[11]  S. Kremer,et al.  Neurologic Features in Severe SARS-CoV-2 Infection , 2020, The New England journal of medicine.

[12]  N. Latronico,et al.  Clinical presentation and initial management critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brescia, Italy , 2020, Journal of Critical Care.

[13]  L. Mao,et al.  Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. , 2020, JAMA neurology.

[14]  R. Carlier,et al.  Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study , 2020, European Archives of Oto-Rhino-Laryngology.

[15]  N. Enomoto,et al.  A first case of meningitis/encephalitis associated with SARS-Coronavirus-2 , 2020, International Journal of Infectious Diseases.

[16]  Suresh Patel,et al.  COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features , 2020, Radiology.

[17]  P. Mehta,et al.  COVID-19: consider cytokine storm syndromes and immunosuppression , 2020, The Lancet.

[18]  J. Xiang,et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study , 2020, The Lancet.

[19]  L. Mao,et al.  Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study , 2020, medRxiv.

[20]  Alain Le Coupanec,et al.  Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? , 2019, Viruses.

[21]  Benedict Michael,et al.  Faculty Opinions recommendation of Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[22]  M. Juan,et al.  Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis , 2018, The Lancet Neurology.

[23]  L. Deangelis,et al.  Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia. , 2018, Cancer discovery.

[24]  A. Wensing,et al.  Acute influenza virus-associated encephalitis and encephalopathy in adults: a challenging diagnosis , 2016, JMM case reports.

[25]  A. Venkatesan,et al.  A clinical approach to diagnosis of autoimmune encephalitis , 2016, The Lancet Neurology.

[26]  A. Hajeer,et al.  Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV) , 2015, Infection.

[27]  A. Venkatesan,et al.  Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[28]  A. Vincent,et al.  Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. , 2010, The Lancet. Infectious diseases.

[29]  S. Ng,et al.  Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. , 2006, AJNR. American journal of neuroradiology.

[30]  K. Yuen,et al.  Possible Central Nervous System Infection by SARS Coronavirus , 2004, Emerging infectious diseases.

[31]  Timothy W. Cooke,et al.  Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. , 2002, Stroke.

[32]  U. Schulz,et al.  Improving the Assessment of Outcomes in Stroke: Use of a Structured Interview to Assign Grades on the Modified Rankin Scale , 2002, Stroke.