Background and Objectives:In patients with severe coronavirus disease 2019 (COVID-19), disorders of consciousness (COVID-DoC) have emerged as a serious complication. The prognosis and pathophysiology of COVID-DoC remain unclear, complicating decisions about continuing life-sustaining treatment. We describe the natural history of COVID-DoC and investigate its associated brain connectivity profile.Methods:In a prospective, longitudinal study, we screened consecutive patients with COVID-19 at our institution. We enrolled critically ill adult patients with a DoC unexplained by sedation or structural brain injury, and who were planned to undergo a brain MRI. We performed resting state functional MRI and diffusion MRI to evaluate functional and structural connectivity, as compared to healthy controls and patients with DoC resulting from severe traumatic brain injury (TBI). We assessed the recovery of consciousness (command-following) and functional outcomes (Glasgow Outcome Scale Extended [GOSE] and the Disability Rating Scale [DRS]) at hospital discharge, three months post-discharge, and six months post-discharge. We also explored whether clinical variables were associated with recovery from COVID-DoC.Results:After screening 1,105 patients with COVID-19, we enrolled twelve with COVID-DoC. The median age was 63.5 years [interquartile range 55-76.3]. Excluding one who died shortly after enrollment, all of the remaining eleven patients recovered consciousness, after 0-25 days (median 7 [5-14.5]) following the cessation of continuous intravenous sedation. At discharge, all surviving patients remained dependent – median GOSE 3 [1-3], median DRS 23 [16-30]. However ultimately, except for two patients with severe polyneuropathy, all returned home with normal cognition and minimal disability – at three months, median GOSE 3 [3-3], median DRS 7 [5-13]; at six months, median GOSE 4 [4-5], median DRS 3 [3-5]. Ten patients with COVID-DoC underwent advanced neuroimaging; functional and structural brain connectivity in COVID-DoC was diminished compared to healthy controls, and structural connectivity was comparable to patients with severe TBI.Discussion:Patients who survived invariably recovered consciousness after COVID-DoC. Though disability was common following hospitalization, functional status improved over the ensuing months. While future research is necessary, these prospective findings inform the prognosis and pathophysiology of COVID-DoC.Trial Registration Information:Clinicaltrials.gov, NCT04476589, submitted 7/2020, first enrolled 7/20/2020, https://clinicaltrials.gov/ct2/show/NCT04476589