Disorders of Consciousness Associated With COVID-19: A Prospective Multimodal Study of Recovery and Brain Connectivity

Abstract

Background and objectives: In patients with severe coronavirus disease 2019 (COVID-19), disorders of consciousness (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 fMRI and diffusion MRI to evaluate functional and structural connectivity 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 and 3 and 6 months after 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 12 with COVID-DoC. The median age was 63.5 years (interquartile range 55-76.3 years). After the exclusion of 1 patient who died shortly after enrollment, all of the remaining 11 patients recovered consciousness 0 to 25 days (median 7 [5-14.5] days) after the cessation of continuous IV sedation. At discharge, all surviving patients remained dependent: median GOSE score 3 (1-3) and median DRS score 23 (16-30). Ultimately, however, except for 2 patients with severe polyneuropathy, all returned home with normal cognition and minimal disability: at 3 months, median GOSE score 3 (3-3) and median DRS score 7 (5-13); at 6 months, median GOSE score 4 (4-5), median DRS score 3 (3-5). Ten patients with COVID-DoC underwent advanced neuroimaging; functional and structural brain connectivity in those with COVID-DoC was diminished compared to healthy controls, and structural connectivity was comparable to that in patients with severe TBI.

Discussion: Patients who survived invariably recovered consciousness after COVID-DoC. Although disability was common after 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 identifier: NCT04476589.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Neuroimaging Features and Recovery of Patients With COVID-DoC

Patients are listed by descending duration of disorders of consciousness in coronavirus disease 2019 (COVID-DoC). The patient who died shortly after enrollment (patient 12) is not depicted. Patients with microhemorrhages or leukoencephalopathy on a structural brain MRI are marked with a black circle; those without findings are marked with a white circle. Intranetwork functional connectivity of the default mode network, measured with resting-state fMRI (rs-fMRI), is represented by colored circles; red represents the average intranetwork default mode network connectivity of healthy controls (z = 0.23), and purple represents absent connectivity (z = 0). White matter integrity, measured as whole-brain fractional anisotropy (FA) with diffusion MRI (d-MRI), is represented by colored circles; red represents the average whole-brain FA of healthy controls (0.59), and purple represents the lowest FA measured among patients (0.45). Recovery of consciousness is depicted relative to the day of intubation. Duration of intubation is depicted in dark blue (terminating with tracheostomy or extubation), and the duration of IV sedation (including propofol, midazolam, hydromorphone, or ketamine) is depicted in light blue. Duration of unresponsiveness, starting with the cessation of IV sedation and ending with the first documentation of command following (represented by a red circle), is depicted in red. Timing of the brain MRI is depicted as gray arrows. Outcomes at hospital discharge are depicted in the right-hand column, including acute hospitalization length of stay (LOS) and disposition. LTAC = long-term acute care; Rehab = rehabilitation facility.

Figure 2. Longer-term Functional Outcomes for Patients With COVID-DoC

Glasgow Outcome Scale Extended (GOSE; A) and Disability Rating Scale (DRS; B) scores for each patient are shown (higher scores on GOSE and lower scores on DRS reflect less disability). Functional outcomes are depicted at hospital discharge and 3 and 6 months after discharge. COVID-DoC = disorders of consciousness in coronavirus disease 2019.

Figure 3. Resting-State Functional Connectivity for Patients With COVID-DoC and Healthy Controls

Connectivity of the default mode network is depicted as group-wise seed-to-voxel maps, generated with seeds at 4 nodes—the medial prefrontal cortex, posterior cingulate cortex, and bilateral inferior parietal lobules—for healthy controls (A) and patients with disorders of consciousness in coronavirus disease 2019 (COVID-DoC; B). Warmer colors represent positive correlations (reflecting intranetwork connectivity); cooler colors represent negative correlations (reflecting internetwork connectivity). Patients with COVID-DoC demonstrated less positive intranetwork connectivity (C) and less negative internetwork connectivity (D) than healthy controls. **p < 0.01. ***p < 0.001.

Figure 4. Diffusion MRI Metrics for Patients With COVID-DoC and Healthy Controls

White matter integrity within a white matter skeleton is depicted as a 3-dimensional group-wise fractional anisotropy (FA) map, with warmer colors representing higher FA and thus higher white matter integrity, for healthy controls (A) and patients with disorders of consciousness in coronavirus disease 2019 (COVID-DoC; B). Whole-brain (C) and brainstem (D) FA values of patients with COVID-DoC were low compared to those of healthy controls but comparable to those of patients with severe traumatic brain injury (TBI). ***p < 0.001. ****p < 1 × 10-8.