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Up to 2 years after infection, people who had COVID-19 continued to face increased risks of neurologic and psychiatric sequelae compared with people who had other respiratory infections, a retrospective study showed.

Health records of nearly 1.3 million people -- mostly in the U.S. -- showed that risks of cognitive deficit (brain fog), dementia, psychotic disorders, and epilepsy or seizures were increased at 2 years for adults who had COVID, reported Paul Harrison, FRCPsych, of the University of Oxford in England, and colleagues.

Risk of anxiety and depression rose in the first 6 months among adult COVID patients but faded over time, the researchers wrote in .

"The excess risk of some disorders, in particular anxiety and mood disorders, disappeared within 2 to 3 months, with no overall excess number of cases over the 2 years," co-author Maxime Taquet, PhD, also of the University of Oxford, said at a press briefing.

"More worrying news, however, is that the risk of other disorders -- including brain fog, dementia, psychotic disorders, and epilepsy and seizures -- remained elevated throughout the 2 years, with more new cases still being diagnosed 2 years after the infection," he added.

Children who had COVID also were more likely to be diagnosed with neurologic and psychiatric sequelae than their matched counterparts, but their likelihood of most diagnoses was lower than that of adults. Unlike adults, children did not have an increased risk of mood disorders (HR 1.02, 95% CI 0.94-1.10) or anxiety disorders (HR 1.00, 95% CI 0.94-1.06) at 6 months.

As dominant SARS-CoV-2 variants changed, post-COVID symptoms shifted. "The emergence of the Delta variant was associated with an increase in risk for several conditions; however, it's important to note that the overall risk of these conditions is still low," Taquet said.

"With Omicron as the dominant variant, although we see much milder symptoms directly after infection, similar rates of neurological and psychiatric diagnoses are observed as with Delta, suggesting that the burden on the healthcare system may continue even with variants that are less severe in other respects," he added.

The study, which extended previous work evaluating adult outcomes 6 months after SARS-CoV-2 infection, is "the first to attempt to examine some of the heterogeneity of persistent neurological and psychiatric aspects of COVID-19 in a large dataset," noted Jonathan Rogers, MRCPsych, and Glyn Lewis, PhD, FRCPsych, both of University College London in England, in an .

"It highlights some clinical features that particularly merit further investigation, but it must be complemented by prospective studies that provide more validation of outcomes," the editorialists emphasized.

Harrison and co-authors identified 1,487,712 patients in the international TriNetX electronic health records database who had a COVID-19 diagnosis from January 2020 to April 2022. Of these patients, 1,284,437 were matched with an equal number of people who had another respiratory infection on demographics, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status.

Both cohorts included 185,748 children, 856,588 adults ages 18-64, and 242,101 adults ages 65 and older. The study sample had a mean age of 42.5, and 57.8% were women. Alpha, Delta, and Omicron subgroups were identified as patients with a first diagnosis of COVID-19 when a particular variant was dominant in the U.S.

The researchers assessed risks of 14 neurologic and psychiatric diagnoses after SARS-CoV-2 infection, comparing these outcomes with the matched cohort. Two-year risk trajectories included 6-month constant HRs, risk horizons for each outcome (the point at which an HR returns to 1), and the time to equal incidence in the two groups.

Cognitive deficit, dementia, psychotic disorders, and epilepsy or seizures were increased at 6 months in adults 18-64 and remained elevated at the end of the 2-year follow-up period. Risks of mood and anxiety disorders returned to baseline after 1 to 2 months (mood disorders at 43 days; anxiety disorders at 58 days) and eventually reached the incidence of the matched group (mood disorders at 457 days, anxiety disorders at 417 days).

Children showed an increased risk of cognitive deficit; insomnia; intracranial hemorrhage; ischemic stroke; nerve, nerve root, and plexus disorders; psychotic disorders; and epilepsy or seizures at 6 months, with HRs ranging from 1.20 to 2.16. Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days).

The risk of any first neurologic or psychiatric diagnosis was higher among people 65 and older than others. A sizeable proportion of older adults who received a neurologic or psychiatric diagnosis in either cohort subsequently died, especially those diagnosed with dementia or epilepsy or seizures.

Risk profiles were similar just before the Alpha variant emerged compared with just after. Risks of ischemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders increased just after Delta emerged, as did the death rate. With Omicron, there was a lower death rate than just before emergence of the variant, but risks of neurologic and psychiatric outcomes remained similar.

The study had several limitations, Harrison and co-authors noted. Self-diagnosed and asymptomatic COVID cases were unlikely to be recorded in electronic health records or included in the study. In addition, the researchers did not assess the severity or length of each condition after diagnosis or compare this against other respiratory infections.

Nonetheless, the results may have important implications for patients and health services, as they suggest that new cases of neurologic conditions linked to COVID may occur for a considerable time after the pandemic has subsided, Harrison said in a press statement.

"Our work also highlights the need for more research to understand why this happens after COVID-19, and what can be done to prevent or treat these conditions," he added.

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