COVID-19 survivors still at higher risk of neurologic disorders 2 years later

Older man with brain fog
Older man with brain fog

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Rates of "brain fog," dementia, psychotic disorders, and epilepsy or seizures remained elevated 2 years after COVID-19 infection, according to a study of nearly 1.3 million adults and children in the United States, Australia, Europe, and Asia.

The study team, led by University of Oxford researchers, mined data on 14 neurologic and psychiatric disorders from the international TriNetX electronic health records network. The database contains the deidentified hospital, primary care, and specialist records of about 89 million adult and pediatric patients from the United States and, to a lesser extent, Australia, the United Kingdom, Spain, Bulgaria, India, Malaysia, and Taiwan.

The cohort of 1,284,437 patients tested positive for COVID-19 on or after Jan 20, 2020, and were matched in a 1:1 ratio with patients with non-COVID respiratory infections. Follow-up ended on Apr 13, 2022. Of all patients, 185,748 were children, 856,588 were adults, 242,101 were older adults (aged 65 years or older), average age was 42.5 years, and 57.8% were female.

Brain fog, dementia still elevated at 2 years

The risk of most disorders remained significantly elevated after 6 months (except for encephalitis, Guillain-Barre syndrome, nerve-related disorders, and parkinsonism [Parkinson's disease]), but their risk horizons and time to equal incidence differed considerably.

The risk of common psychiatric disorders returned to baseline within 1 or 2 months (43 days for mood disorders, 58 days for anxiety disorders) and then equalized with that of controls by 1.1 years (anxiety) and 1.3 years (mood disorders). But the risk of brain fog, dementia, psychotic disorders, and epilepsy or seizures stayed elevated at 2 years.

Relative to adults, children's risk of mood disorders and anxiety wasn't elevated at 6 months (hazard ratios [HRs], 1.02 and 1.00, respectively), but their risk of brain fog, insomnia, intracranial hemorrhage, ischemic stroke, psychosis, epilepsy or seizures, and nerve-related disorders was increased, with HRs ranging from 1.20 to 2.16. Children's risk of brain fog lasted for no more than 75 days and was the same as that of controls by 1.3 years.

A large number of older adults in both cohorts with neurologic or psychiatric disorders died of any cause, particularly those with a dementia or epilepsy/seizures diagnosis. "The fact that similar proportions of patients with these outcomes died in both cohorts suggests that this high mortality reflects general physical ill health rather than being related to SARS-CoV-2 infection itself," the researchers wrote.

Risk profiles were comparable just before and after the emergence of the Alpha SARS-CoV-2 variant in each cohort. But for the Delta variant, an increased risk of ischemic stroke, epilepsy or seizures, brain fog, insomnia, and anxiety disorders—as well as death—was seen only just after its emergence. Amid Omicron, the death rate was significantly lower after its emergence, but the risk of neurologic and psychiatric disorders stayed the same.

Variant-related risk conclusions

The study authors said that the varied disorder risk patterns suggest different underlying mechanisms. "The differing profile of post-COVID-19 neurological and psychiatric diagnoses in children informs the risk-benefit association of policies aimed at preventing COVID-19 in paediatric populations," they wrote. "Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern."

They warned that the finding of similar neurologic and psychiatric outcomes during the Delta and Omicron waves suggests that the healthcare burden might remain heightened even if future variants are less severe.

In a related commentary, Jonathan Rogers, MBBChir, and Glyn Lewis, MBBS, PhD, both of University College London, said that the study's conclusions about differences in outcomes between SARS-CoV-2 variants should be interpreted with caution.

"Pressure on health-care services, awareness of long-term sequelae of COVID-19, and different thresholds for seeking SARS-CoV-2 testing are all likely confounders that have had a role in altering the supposed risks across time periods, which were used by the authors as a proxy for variants," they wrote. "However, overcoming such limitations in time-series analyses is very difficult and Taquet and colleagues' study provides preliminary evidence."

The study, they said, "highlights some clinical features that merit further investigation, but it must be complemented by prospective studies that provide more validation of outcomes."

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