Long-Term Functional Abnormalities Common in Severe COVID-19 Cases


Abnormal scores on cognitive testing persisted in 50% of patients without a pre-COVID history of cognitive abnormalities, irrespective of the presence or absence of a neurological complication during hospitalization.

Jennifer Fontera, MD

Jennifer Fontera, MD

Newly published data from a prospective longitudinal study showed that at least 80% of patients hospitalized for COVID-19 who had no baseline functional abnormalities, developed at least one abnormal measure of functional, cognitive, or neuropsychiatric outcome at 12-month follow-up. The study investigators concluded that these results may not be generalizable to mild/moderate cases of COVID-19.1

The study evaluated the long-term trajectory of neurologic recovery in patients with and without neurological complications during index hospitalization for COVID-19 from March 10, 2020, to May 20, 2020. Modified Rankin Scale (mRS) scores analyzed using ordinal logistic regression, were the primary end point. Of the 242 included patients, 47% (n = 113) had neurological complications during index hospitalization and 53% (n = 129) had no neurological complications during hospitalization.

Led by Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine, direct patient responses to outcome assessments were obtained from 74% (84 of 113) of neurological patients and 85% (110 of 129) controls, while surrogate responses were utilized in 26% of neurological patients and 15% of controls (P = .199). Because some interviews were completed by surrogates, and some patients were too impaired to participate in cognitive or NeuroQoL testing, not all metrics were completed by all patients.

At 12-months, 87% (197 of 227) of patients who completed all follow-up batteries had at least 1 abnormal metric. More specifically, 75% (176 of 235) had a mRS greater than 0, 64% (150 of 236) had a Barthel Index of Activities of Daily Living less than 100, and 50% (80 of 161) of patients without a prior history of dementia/cognitive abnormalities had an abnormal telephone Montreal Cognitive Assessment (t-MoCA) score. Excluding patients with pre-COVID mRS greater than 0, 82% (107 of 130) of patients had at least 1 abnormal metric at 12 months.

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NeuroQol scores greater than 1 standard deviation above the mean occurred in 7% (16 of 225) for anxiety scores, 4% (9 of 225) for depression scores, 9% (20 of 223) for fatigue scores, and 10% (22 of 221) for sleep scores. Comparing those with and without neurological complications, only fatigue scores differed significantly in the univariate analysis (14% vs 4%; P = .010). In multivariate logistic regression analysis adjusting for age, ventilator status and baseline mRS, patients with neurological complications had a 3-fold significantly increased odds of severe fatigue than controls (adjusted odds ratio, 3.18 95% CI, 1.1-9.4; P = .037).

"The finding of higher rates of severe fatigue among COVID patients with neurological events is not entirely surprising given the high rates of chronic fatigue observed in a variety of neurological disorders including stroke, multiple sclerosis, dysautonomia, traumatic brain injury and neuromuscular disorders," Frontera et al wrote.

Frontera and her colleagues also evaluated outcome metrics in 174 patients who completed both 6- and 12-month follow-up interview (with neurological events: n = 86; without: n = 88). At 6 months, 88% (150 of 171) of the sample had at least 1 abnormal metric compared with 84% (141 of 168) of patients at 12 months. When excluding patients with pre-COVID baseline mRS scores greater than 0, results were similar, with 83% of the sample with at least 1 abnormal metric at 6 months vs 80% at 12 months (McNemar test, P = .503).

From 6 to 12 months investigators observed a statistically significant median improvement in t-MoCA scores, with median score increase from 18 to 19 (z = –2.437; P = .002). Additionally, NeuroQoL anxiety score improvements from 6 months (median score, 49.5) to 12-months (median score, 47.3)(z = –3.164; P = .002) were also statistically significant. Overall, 56% and 45% of patients, respectively, had t-MoCA scores and anxiety scores improved over time.

Although not statistically significant, investigators observed improvements in 48% of fatigue scores, 48% of sleep scores, and 38% of depression scores during the 6- and 12-month follow-ups. Conversely, the majority of patients showed no changes in mRS or Barthel scores during that time period.

Improvements in t-MoCA scores over time should generate a degree of optimism regarding recovery from long-COVID, particularly since "brain fog, confusion, and dysexecutive function appear to be common protracted post-acute sequelae," the study investigators noted. "While the pathogenesis of post-acute cognitive dysfunction is likely multifactorial, possibilities include post-hypoxic brain injury, blood brain barrier disruption with ongoing inflammation,autoimmune mechanisms or even neurodegenerative disease."

Frontera has been a leader within the field of COVID-related neurodegenerative research. She led a recently published study of 251 hospitalized patients with COVID-19, which showed elevated levels in biomarkers that were similar to–or even higher than–those observed in patients with Alzheimer disease. For those who died in hospital, levels of total tau (P <.001), phosphorylated tau (P = .022), glial fibrillary acidic protein (GFAP; P = .001) and neurofilament light (NfL; P = .006) were significantly elevated at the time of admission. For those who were discharged to home, t-tau (P = .009), GFAP (P <.001) and NfL (P = .044) were significantly lower.2

1. Frontera JA, Yang D, Medicherla C, et al. Trajectories of neurologic recovery 12 months after hospitalization for COVID-19: a prospective longitudinal study. Neurology. Published online March 21, 2022. doi:10.1212/WNL.0000000000200356
2. Frontera JA, Boutajangout A, Masurkar AV, et al. Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia. Alzheimers Dement. Published online January 13, 2022. doi:10.1002/alz.12556.
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