The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study
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Abstract
Importance
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 20 th and May 31 st , 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.
Question
what are the phenotypes of encephalitis associated to SARS-CoV-2 infection?
Findings
25 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.
Meaning
heterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms
Article activity feed
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SciScore for 10.1101/2020.06.19.20133991: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The Institutional Ethical Standards Committee on human experimentation at Brescia University Hospital provided approval for the study (NP 4067, approved May 8th, 2020). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We acknowledge that this study entails several limitations. …
SciScore for 10.1101/2020.06.19.20133991: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The Institutional Ethical Standards Committee on human experimentation at Brescia University Hospital provided approval for the study (NP 4067, approved May 8th, 2020). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We acknowledge that this study entails several limitations. First, due to the absence of autopsy or SARS-CoV-2 evidence in CSF, our cases can be classified as “probably associated” with SARS-CoV-2 infection11 and further studies on CSF using recently-developed intrathecal antibodies are urgently needed. Second, the study might have underestimated the total number of cases, especially severe cases who could not undergo MRI, EEG and CSF assessment, likely due to the prominent respiratory insufficiency with early intubation and/or death. Third, the extensive panel of paraneoplastic/autoimmune encephalitis was not performed in about a third of patients exhibiting transitory symptomatology albeit MRI/CSF was not suggestive for immune disorders. Despite these limitations, this is the first multicentre study including the highest number of SARS-CoV-2 cases fulfilling criteria for encephalitis.13
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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