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BackgroundCoronavirus disease 2019 (COVID-19) leads to peripheral and central disorders, frequently with neurological implications. Blood-brain barrier disruption (BBBd) has been hypothesized as a mechanisms in the acute phase. We tested whether markers of BBBd, brain injury and inflammation could help identify a blood signature for disease severity and neurological complications. MethodsBiomarkers of BBBd (MMP-9, GFAP), neuronal damage (NFL) and inflammation (PPIA, IL-10, TNF) were measured by SIMOA, AlphaLISA and ELISA, in two COVID-19 patient cohorts with high disease severity (ICU Covid; n=79) and neurological complications (NeuroCovid; n=78), and in two control groups with no COVID-19 history: healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). ResultsBiomarkers of BBBd and neuronal damage were high in COVID-19 patients, with levels similar to or higher than in ALS. NeuroCovid patients had lower levels of PPIA but higher levels of MMP-9 than ICU Covid patients. There was evidence of different temporal dynamics in ICU Covid compared to NeuroCovid patients with PPIA and IL-10 levels highest in ICU Covid patients in the acute phase. In contrast, MMP-9 was higher in the acute phase in NeuroCovid patients, with severity-dependency in the long term. We also found clear severity-dependency of NFL and GFAP. ConclusionsThe overall picture points to an increased risk of neurological complications in patients with high levels of biomarkers of BBBd. Our observations may provide hints for therapeutic approaches mitigating BBBd to reduce the neurological damage in the acute phase and potential dysfunction in the long term.
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ImportanceSeveral 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
