Patients With COVID-19-Related Disorders of Consciousness May Invariably Recover Consciousness

Dubbed COVID-DoC, the prospective study is the largest of its kind to date and provides initial data on the prognosis and pathophysiology of the condition in a group of patients at Massachusetts General Hospital.

A study recently published in Neurology concluded that patients who developed a disorder of consciousness (DoC) as a result of severe COVID-19 infection invariably regained consciousness. Investigators reported that disability was common following hospitalization, but functional status also improved over time.1 

A total of 1105 patients with COVID-19 were screened for the study between July 2020 and March 2021 in the intensive care unit at Massachusetts General Hospital, with 12 patients who developed disorders of consciousness with COVID-19 (COVID-DoC) eventually enrolled. Patients had a median age of 63.5 years (interquartile range [IQR], 55-76.3), and 1 patient died shortly after enrollment due to COVID-19 complications, leaving a total of 11 study participants.

Within 0 to 25 days, with a median of 7 days (IQR, 5-14.5), all 11 patients recovered consciousness after discontinuing IV sedation, 10 while still hospitalized and 1 after discharge. While 4 patients died during hospitalization due to medical complications of COVID-19, no deaths were attributed to the withdrawal of life-sustaining treatment based on a poor neurologic prognosis. 

The 8 patients who survived to discharge initially remained dependent, presenting a median Glasgow Outcome Scale Extended (GOSE) score of 3 (IQR, 1-3) and median Disability Rating Scale (DRS) score of 23 (IQR, 16-30). Normal cognition and minimal disability were attained by all patients, excluding 2 with severe polyneuropathy. Median GOSE score was 3 (IQR, 3-3) and median DRS score was 7 (IQR, 5-13) at month 3, and a median GOSE score of 4 (IQR, 4-5) and a median DRS score of 3 (IQR, 3-5) at month 6. 

“In terms of their recovery, what we found is that these patients all invariably recover consciousness if given enough time. For some patients it’s as soon as a few days, for some patients it's as late as 1 or 2 months, but they all regained consciousness. If you follow them for long enough, by about 6 months or so—excluding a couple [patients] who had pretty severe ongoing medical issues—the rest all regained significant neurologic function to the point of being almost independent at home,” lead author David Fischer, MD, neurocritical care fellow at Massachusetts General Hospital and Brigham and Women’s Hospital, told NeurologyLive®

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“We anticipated that some of the patients would not have regained consciousness or neurologic function to quite that extent, and so we were surprised by how good the prognosis was in these disorders of consciousness. We also found, through some of those advanced neuroimaging techniques, that these patients do have pretty severely diminished network conductivity, both functionally and structurally. We don't yet know exactly what causes that diminished network connectivity in these patients, but it does seem like there's some brain abnormalities associated with these disorders of consciousness,” Fischer added.

Ten patients with COVID-DoC underwent advanced neuroimaging, exhibiting significantly reduced intra-network connectivity within the default mode network (DMN), when compared with healthy controls (COVID-DoC: 0.12 [standard deviation (SD), 0.06]; healthy controls: 0.23 [SD, 0.07]; t[22] = 3.88; P <.001). Additionally, those with COVID-DoC had significantly reduced inter-network connectivity between the DMN and the salience network (COVID-DoC, 0.04 [SD, 0.03]; healthy controls: –0.003 [SD, 0.04]; t[22] = 2.86; P <.01). COVID-DoC remained significantly associated with reduced intra-network (b = –0.15; P <.01) and inter-network connectivity (b = 0.06; P <.05), after controlling for age.

Also observed was reduced whole brain fractional anisotropy (FA) in patients with COVID-DoC compared with healthy controls (COVID-DoC: 0.51 [SD, 0.02]; healthy controls: 0.59 [SD, 0.02], t[21] = 9.06; P <1x10-8), and reduced brainstem FA (COVID-DoC: 0.53 [SD, 0.04]; healthy controls = 0.59 [SD, 0.02]; t[21] = 4.27, P <0.001). COVID-DoC remained significantly associated with reduced who brain FA (b = –0.09; P <.05) and brainstem FA (b = 0.06; P <.005) after controlling for age, and both were comparable to patients with severe traumatic brain injury (P >.05)

As there are associated challenges with obtaining advanced neuroimaging for these patients, the study was limited by its small cohort, despite it being among the largest to date and the first prospective study of COVID-DoC. The study may have also been underpowered to detect associations between time to recover consciousness and other clinical variables, as no significant association was identified. Heterogeneity may have also existed in the cohort, and investigators were unable to match the control subjects to patients with COVID-DoC, as they were enrolled in a separate study. Lastly, investigators noted that clinical teams were not blinded to the neuroimaging findings and therefore cannot rule out the potential for subtle influence on patient care. 

Findings have immediate implications for clinical practice, Fischer said, influencing decisions on whether to withdraw life-sustaining treatment. There are, however, areas that require additional research.

“Certainly, there is a lot that we still don't know—we still don't totally understand what causes these disorders of consciousness. It's something that we looked at. We looked at the degree of sedation that they received, the degree of structural brain injury that they had, and things like that, and none of those things reliably predicted which patients had disorders of consciousness and which didn't, and they didn't help predict when those patients would wake up,” Fischer said. “I think in terms of next steps, we need to have a better understanding of what causes these disorders of consciousness, and to try to better identify biomarkers that we can use to try to help predict exactly when these patients will recover.”

REFERENCE
1. Fischer D, Snider SB, Barra ME, et al. Disorders of consciousness associated with COVID-19: A prospective, multimodal study of recovery and brain connectivity. Neurology. Published online December 3, 2021. doi:10.1212/WNL.0000000000013067