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Healio Interviews

Disclosures: Frontera reports no relevant financial disclosures.
June 22, 2021
6 min read

Q&A: 6 months after COVID-19, abnormal functional outcomes persist in most patients


Healio Interviews

Disclosures: Frontera reports no relevant financial disclosures.
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More than 90% of patients in a prospective, observational study of approximately 600 experienced issues related to functional outcomes, activities of daily living, mental health and sleep 6 months after hospitalization for COVID-19.

The study results, which were published in Journal of the Neurological Sciences, demonstrated that patients who experienced neurological complications during COVID-19 infection had “significantly worse” functional outcomes at 6 months compared to those without such complications.

The researchers examined 6-month outcomes among patients who had been hospitalized for COVID-19. Using propensity scoring, they matched patients with new neurological complications during the hospitalization with patients who experienced no neurological complications and were hospitalized during the same time period. Multivariable ordinal analysis of the modified Rankin Scale score that compared patients with and without neurological complications served as the primary outcome. Secondary outcomes included activities of daily living and Montreal Cognitive Assessment and Neuro Quality of Life batteries for anxiety, depression, fatigue and sleep obtained via telephone.

Healio Neurology spoke with lead study author 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, to learn more about the study results and its implications in clinical practice.

Healio Neurology: What prompted this research?

Frontera: This is a follow-up to our prospective study that we started in the first COVID-19 wave in New York. As people were hospitalized, we prospectively screened them for a neurological event during hospitalization associated with COVID-19. We did a 6-month follow-up and now we are into our 1-year follow-up after that.

My research, historically, has been this type of longitudinal, epidemiological work, where I looked at the prevalence of risk factors and outcomes among patients with intracerebral hemorrhage, but in this case it was COVID-19. We had already planned to look at functional and cognitive outcomes in these patients, even before this long-haul COVID-19 syndrome was something we knew about. With the identification of long-haul COVID-19 syndrome, though, it became more important to understand the symptoms that people might have had, such as fatigue, anxiety, depression or brain fog, and to have actual quantitative measures for these factors.

We looked at standardized tools that we use to measure outcomes in neurological patients, such as the modified Rankin scale and Barthel Index for Activities of Daily Living. We also conducted the Montreal Cognitive Assessment, or MoCA, via telephone in a shortened version. This is an objective measure of cognitive function as opposed to subjective measure. We also conducted Neuro Quality of Life batteries for anxiety, depression, fatigue and sleep. Those measures are subjective, but they quantify the degree of severity of symptoms so that we can compare one person to another. For example, we could look at one person’s anxiety level and however they rate it on a general scale and see how that may be different than someone else.

Healio Neurology: What did the study results demonstrate?

Frontera: Overall, we were surprised, because very few people at 6 months were left unscathed by their COVID-19 infection: 90% of patients had a negative outcome according to one of the metrics, something abnormal. It might be something as relatively benign as a sleep disturbance or fatigue, if you consider those benign, but a lot of people do not. It ranged from that to people who could not use the toilet or bathe themselves or who were experiencing severe cognitive dysfunction. Half of the patients had abnormal telephone MoCA scores, even after adjusting for age and excluding patients with pre-existing dementia. It was very high in both groups. We were surprised by that and concerned, because it seems to be one of the top symptoms people report with long-haul COVID-19 syndrome. This study gave us a quantifiable, objective measure to show that these patients were not functioning normally.

Healio Neurology: What specific neurological complications did patients experience?

Frontera: During the index hospitalization, the most common symptom was toxic metabolic encephalopathy. That involves mental status changes. We excluded people who had encephalopathy due to sedation, seizures or a structural brain injury; the most common etiologies included sepsis, Wernicke encephalopathy and hypoxic encephalopathy. We also saw stroke, both ischemic and hemorrhagic, and a few people had new-onset seizures, new-onset movement disorders and new-onset myopathy and neuropathy. That usually occurs in patients with a critical illness who are hospitalized for a long time.

Healio Neurology: How did these neurological complications during the infection impact patients later?

Frontera: The patients with those complications did worse than those who did not have complications in terms of their modified Rankin scores. They also had worse Barthel Index for Activities of Daily Living scores. Strangely enough, cognitive scores were equally bad in both groups. I would have expected patients with neurological complications to be worse across the board, but they were not. The neurological quality of life measures, including anxiety, depression, fatigue and sleep, were also similar in the two groups. It was really the functional measures; in patients who had a stroke, the modified Rankin scale score was not going to be as good and the activities of daily living were going to be impacted for patients who, for example, could not walk. Those results were not too much of a surprise, but the degree of cognitive dysfunction, even among the people who did not have a recognized neurologic event during hospitalization, was robust.

Healio Neurology: What do these results add to our knowledge of the long-term impact of COVID-19?

Frontera: Currently, we are looking at these outcomes 12 months after the hospitalization; we are interested in trajectories of recovery because, in this study, we found that people are still experiencing many issues at 6 months. So far, the research corroborates the story of “long haulers” with COVID-19 that has become clearer, where patients are saying “I'm not okay and it's been months,” but in a more quantitative fashion.

There are some patients who think they are okay, but they do not even recognize that they have a cognitive deficit; it may be some vague feeling that something is different. We interviewed a younger patient who was in his 30s and, after he had not been able to go back to work after 6 months, he had recently started working again. This patient’s MoCA scores were abnormal at 6 months and remained abnormal at 12 months. He did not feel like he had a cognitive problem, but he would say things like, “I'm not as patient as I used to be. I just let things go; I don't really drill down on issues.” He could not really put his finger on what it was. One of our reporters was interviewing him at the end of the day and he said, “I can't really concentrate right now.” He would not have called that a cognitive problem, but it is a cognitive problem. Some of these people do not even realize there is something wrong.

This means that, in addition to “long-hauler” patients with COVID-19 who are saying, “I have a problem and it won't go away,” there are probably another proportion of people who do not even realize they have an issue. The aim of this research is to quantify it to some extent.

We have another paper that hopefully will be accepted soon that looked at community dwellers with and without COVID-19. We asked about socioeconomic stressors, demographics and social determinants of health, as well as the same neurological quality of life questions that we asked in this study. Things that predicted abnormal neurological quality of life scores were much more often the stressors than the COVID-19 infection. We may underestimate, in some of the “long-hauler” patients, the impact of pandemic-related life and stressors that are feeding into this and confounding the picture. We need to pull apart how much of this is due to the biology of the virus vs. things like high unemployment or being stuck inside all the time or social isolation or job loss. We found that economic stressors like financial instability or insecurity or unemployment were the biggest predictors of health.

Healio Neurology: What are the next steps for this research?

Frontera: We have to figure out what mechanisms underpin the symptomatology or even the objective abnormalities we’re seeing. I think that is the phase that people are going into right now. Is it some kind of inflammatory issue with blood-brain barrier disruption? Is it that some people also have pulmonary disease and ongoing hypoxia? Is it some autoimmune mechanism? There are a lot of different theories about what might be contributing to this. It also could be static; it is possible that people sustained most of their injury during the time that they had severe COVID-19 infection. We know from the literature on acute respiratory distress syndrome that 50% of people who had the syndrome and were discharged have cognitive abnormalities. It could be a static insult that happened during the severe COVID-19 infection that is hard to get over, though there are cognitive rehabilitation strategies for people who experience something like this. However, that is not a slam dunk, either. A lot of the funding that NIH is putting out right is focused on drilling down on that mechanism.


Frontera JA, et al. J Neurol Sci. 2021;doi:10.1016/j.jns.2021.117486.