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The most common set of neurological symptoms seen with coronavirus disease (COVID-19)—toxic metabolic encephalopathy, or TME—comes with a 24 percent increase in risk of death in patients hospitalized due to infection with the pandemic virus, SARS-CoV-2.

This is the finding of a , which also found TME occurred in 12 percent of hospitalized COVID-19 patients, and in 20 percent of COVID-19 patients in intensive care units. 

Neurological damage is known to accompany severe infections, which generate toxins as the immune system overreacts (sepsis), kidneys fail (uremia), and oxygen delivery to tissues is compromised (hypoxia), researchers say. These processes cause TME, with symptoms ranging from confusion to coma. 
    
“The dramatic effect of common causes of encephalopathy on COVID-19 mortality suggests that we may need more aggressive use of countermeasures—oxygen supplementation, early dialysis in renal failure, and fluids to counter the low blood pressure seen in sepsis,” says first author Jennifer A. Frontera, MD, professor in the at �ٺ���Ƶ Health.

“Some COVID-19 patients do not feel breathless when their oxygen levels are very low,” adds Dr. Frontera, a neurology clinician, “but clinicians may still need to consider earlier oxygen supplementation.” Similarly, patients that come in with signs of uremia may not be immediately referred to dialysis, with the procedure saved for those with the most severe kidney stress.

Common Causes

The current study analyzed data from patients with COVID-19 hospitalized at �ٺ���Ƶ Health hospitals between March and May of 2020. Among 4,491 COVID-19 patients, 12 percent were diagnosed with TME. As both TME (related to COVID-19) and sedation used to make patients comfortable can cause confusion, the study was careful to exclude sedated patients. 

Specifically, the research team found that the most common causes of encephalopathy in COVID-19 patients were sepsis (62 percent), low oxygen levels in the blood or hypoxemia (59 percent), and uremia (28 percent), with three quarters of patients having more than one kind. 

Septic encephalopathy occurs when too high levels of immune signaling proteins interfere with neurochemicals that pass on nerve messages, say the authors. Uremia occurs when toxins build up in the blood as kidneys, known to be injured by COVID-19, stop filtering them out. Hypoxic ischemic encephalopathy (HIE), which occurs when the brain does not receive enough oxygen, was associated by the authors with the highest risk of in-hospital death. 

Past studies had found that up to 31 percent of people with COVID-19 experienced encephalopathy, but arrived at the number using the Confusion Assessment Method (CAM), which cannot differentiate confusion caused by sedation from other etiologies. Studying these patients in the absence of sedation helped the research team to draw better conclusions about the causes of brain dysfunction, and on how to target treatments, Dr. Frontera says.

“Hypoxic encephalopathy may occasionally be a reversible condition,” says senior study author Steven L. Galetta, MD, the Philip K. Moskowitz, MD, Professor and Chair of Neurology at �ٺ���Ƶ Health. “Studies have shown for instance that hikers, exposed to low oxygen at high altitudes briefly, typically recover. By linking TME and HIE with greater COVID-19 mortality and longer hospital stays, however, our results argue that these conditions have permanent consequences, and that this area requires further investigation to determine the best management strategies.”

Along with Dr. Frontera, the authors of the study from the Department of Neurology at �ٺ���Ƶ Health were Kara R. Melmed MD; Taolin Fang, MD; Andre Granger, MD; Jessica Lin, MD; Shadi Yaghi, MD; Ting Zhou, MD; Ariane K. Lewis, MD; David Ethan Kahn, DO; , MD; Aaron S. Lord, MD; Thomas M. Wisniewski, MD; and Laura J. Balcer, MD. , and , from �ٺ���Ƶ’s , and Joshua Huang of Medical Center Information Technology (MCIT) also contributed. Additional authors were Sebastian Kurz of Icahn School of Medicine at Mount Sinai, and Adam de Havenon in the Department of Neurology at University of Utah School of Medicine.

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