COVID-19 Resource Center

COVID-19 Resource Center

Disclosures: Frontera reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.
March 18, 2021
3 min read

Toxic metabolic encephalopathy occurs in 12% of patients with COVID-19 in large study

Disclosures: Frontera reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.
You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

One in eight patients hospitalized with COVID-19 developed toxic metabolic encephalopathy including multiple etiologies in most patients, in a retrospective, multicenter cohort study published in Neurocritical Care.

The presence of toxic metabolic encephalopathy (TME) correlated with a 24% increased risk for in-hospital mortality, according to the study results.

Most frequent etiologies in patients with TME: Septic encephalopathy, 62%; Hypoxic-ischemic encephalopathy, 59%; Uremia, 28%
Data were derived from Frontera JA, et al. Neurocrit Care. 2021;doi:10.1007/s12028-021-01220-5.

“In our first publication on neurological events during hospitalization, we identified TME as the most common neurological complication among patients with COVID-19,” Jennifer A. Frontera, MD, professor in the department of neurology at NYU Grossman School of Medicine and a specialist in vascular neurology and neurocritical care at NYU Langone Hospital-Brooklyn, told Healio Neurology. “We wanted to understand underlying etiologies, which patients are most at risk for developing this complication, and the impact of TME on hospital outcomes, including mortality rates.”

TME occurs as a secondary effect of COVID-19, according to Frontera, and is “very common among the critically ill in general.”

The researchers performed a retrospective, multicenter, observational cohort study of patients with confirmed COVID-19 infection at four New York City hospitals between March 1, 2020, and May 20, 2020. The researchers included diagnoses of TME in patients with altered mental status off sedation or following “an adequate sedation washout,” according to the study results. They excluded patients with structural brain disease, seizures or primary neurological diagnoses.

“What distinguishes our paper from the delirium literature is that we wanted to remove the effect of sedation from the equation,” Frontera said. “This is important because the pathophysiology underlying various causes of TME is difficult to identify and treat without eliminating the confounder of sedation, and the prognosis varies depending on the cause of encephalopathy.”

TME in patients with COVID-19

Rates of TME, as stratified by etiology and in-hospital death among patients with TME vs. patients without TME, served as the coprimary outcomes. The researchers excluded patients who transitioned to comfort care at any point during hospitalization from mortality analyses.

The study included 4,491 patients with COVID-19, 559 of whom (12%) were diagnosed with TME. Most of the patients diagnosed with TME (n = 435; 78%) developed encephalopathy immediately before hospital admission, according to the study results. The most frequent etiologies among the 559 patients who developed TME included septic encephalopathy (n = 247; 62%), hypoxic-ischemic encephalopathy (n = 331; 59%) and uremia (n = 156; 28%). Frontera and colleagues identified multiple etiologies in 78% of these patients (n = 435).

Jennifer Frontera
Jennifer Frontera

“TME occurred in 1 in 8 patients hospitalized with COVID-19. This may even be an underestimation, since many patients could not tolerate a sedation interruption for a neurological exam and some patients died before being assessed by a neurology team,” Frontera said. “Though the main etiologies of TME were sepsis, hypoxia and uremia, multiple etiologies were present in 78% of cases. We previously published data on COVID-19-related hyponatremia, which sometimes can be very severe and cause encephalopathy as well.”

The researchers found that, compared with patients without TME, patients with TME were older (76 vs. 62 years) and more frequently had dementia (27% vs. 3%) or history of psychiatric illness (20% vs. 10%). They also found that patients with TME, compared with those without TME, were more likely to be intubated (37% vs. 20%), have a longer length of hospital stay (7.9 vs. 6 days) and were less likely to be discharged home (25% vs. 66%). All correlations between patients with TME vs. those without TME were statistically significant, according to the study results (P < .001 for all).

“Despite the fact that several types of TME are reversible with supportive care and appropriate correction of blood pressure, electrolyte levels and other factors, TME was still associated with an increased risk for in-hospital death after adjusting for other confounders,” Frontera said.

TME remained associated with a greater risk for in-hospital death when patients who received comfort care (n = 267 of 4,491; 6%) were excluded and confounders were adjusted for, according to the study results: 30% of patients with TME died compared with 16% of patients without TME (adjusted HR, 1.24; 95% CI, 1.02-1.52). Specifically, Frontera and colleagues found that TME due to hypoxemia conferred the greatest risk: 42% of patients with hypoxic-ischemic encephalopathy died compared with 16% of patients without hypoxic-ischemic encephalopathy (aHR, 1.56; 95% CI, 1.21-2).

Next steps

The medical community “did not know” what to expect regarding neurological complications during the first wave of COVID-19, Frontera said.

“Now, a year since the first U.S. outbreak, we can be more vigilant about neurological complications such as TME,” she said. “We would probably be more aggressive with oxygen supplementation earlier on and perhaps would address renal replacement therapy differently. Similarly, we were unable to image patients with CT/MRI for early diagnosis and intervention as much as we would have liked because of concerns about infection containment and also because many patients were too sick for transport.”

The researchers are continuing to investigate the neurological complications associated with COVID-19, she continued.

“We plan to evaluate the MRIs we do have for patients with hypoxic ischemic encephalopathy to see if we can determine imaging biomarkers or other patient factors that may suggest predisposition to this type of injury,” Frontera said. “Separately, we are applying for NIH funding to understand phenotypes and endotypes of neurological injury related to COVID-19.”