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COVID-19 survivors face a sharply elevated risk of developing psychiatric or neurologic disorders in the six months after they contract the virus — a danger that mounts with symptom severity, new research shows.

In what is purported to be the largest study of its kind to-date, results showed that among 236,379 COVID-19 patients, one third were diagnosed with at least one of 14 psychiatric or neurologic disorders within a 6-month span.

The rate of illnesses, which ranged from depression to stroke, rose sharply among those with COVID-19 symptoms acute enough to require hospitalization.  

“If we look at patients who were hospitalized, that rate increased to 39%, and then increased to about just under 1 in 2 patients who needed ICU admission at the time of the COVID-19 diagnosis,” Maxime Taquet, PhD, University of Oxford Department of Psychiatry, Oxford, United Kingdom, told a media briefing.

Incidence jumps to almost two thirds in patients with encephalopathy at the time of COVID-19 diagnosis, he added.

The study, which examined the brain health of 236,379 survivors of COVID-19 via a US database of 81 million electronic health records, was published online April 6 in The Lancet Psychiatry.

High Rate of Neurologic, Psychiatric Disorders

The research team looked at the first-time diagnosis or recurrence of 14 neurologic and psychiatric outcomes in patients with confirmed SARS-CoV-2 infections. They also compared the brain health of this cohort with a control group of those with influenza or with non-COVID respiratory infections over the same period. 

All study participants were older than 10 years, diagnosed with COVID-19 on or after January 20, 2020, and were still alive as of December 13, 2020.

The 14 psychiatric and neurologic conditions examined included intracranial hemorrhage; ischemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders; substance use disorder; and insomnia.

The investigators used hospitalization, intensive care admissions and encephalopathy as an indication of the severity of COVID symptoms.

The study benchmarked the primary cohort with four populations of patients diagnosed in the same period with nonrespiratory illnesses, including skin infection, urolithiasis, bone fractures, and pulmonary embolisms.

Results showed that substantially more COVID-19 patients were diagnosed with a neurologic or psychiatric disorder than those with other respiratory illnesses.

“On average, in terms of the relative numbers, there was a 44% increased risk of having a neurological or psychiatric diagnosis after COVID-19 than after the flu and a 16% increased risk compared to other respiratory tract infections,” Taquet told reporters.

Health services should be prepared for an increase in psychiatric and neurologic issues in the months to come, he said, adding that further investigations are needed into why, and how, the coronavirus affects brain health.

Largest Study to Date

Although previous research suggests a link between the two, this is the largest study of its kind, examines a wider range of neurologic outcomes, and spans the longest timeframe to date, said study co-investigator Paul Harrison, BM BCh, associate head of the University of Oxford Department of Psychiatry.

There was a lower incidence of mood and anxiety disorders vs neurologic disorders in patients with severe COVID-19 symptoms, a finding that Harrison said may indicate pandemic-related psychological stress is driving these disorders vs biological factors.

“This paper follows up on an earlier study we did where we found much the same association, and our view is that a lot of the mental health consequences of COVID are…to do with the stress of knowing that one has had COVID and all the implications that go with that, rather than it being a direct effect, for example, of the virus on the brain, or of the immune response to the virus on the brain,” he added.

In contrast, neurologic diagnoses were more likely to be “mediated by some direct consequence of the COVID infection,” he added.

Psychosis and dementia, for instance, were less frequent in the overall COVID-19 population but became much more frequent among those with severe symptoms. The research team said these findings, along with those related to the incidence of ischemic stroke, were “concerning.”

“We found that 1 in 50 patients with COVID-19 go on to have an ischemic stroke in the 6 months after the COVID-19 illness,” Taquet told reporters. “And that rate increased to 1 in 11 patients if we look at patients with encephalopathy at the time of the COVID-19 diagnosis.”

Rates of brain hemorrhages also rose sharply among those with acute symptoms. Just over 1 in 200 total COVID patients were diagnosed with this neurological condition, but that jumped to 1 in 25 of those who experienced encephalopathy at the time of their COVID-19 diagnosis.

Need for Replication

Study co-author Masud Husain, PhD, University of Oxford Cognitive Neurology Department, told reporters that while there is evidence from other neurologic studies that the virus can access the brain, there has been little sign the neurons themselves are affected.

“There isn’t much evidence that the virus itself attacks neurons in the brain, but it can cause inflammation, and it can activate inflammatory cells in the brain,” he said.

“And those effects are probably very important in some of the biological effects on the brain. In addition, of course, we know that the virus can change clotting and the likelihood of thrombosis in the blood, and those effects can also impact upon the brain,” he added.

Harrison it would be helpful to replicate the results garnered from the US database in other populations.

“It goes without saying that replication of these results with other electronic health records and in other countries is a priority,” he said, adding that investigations are essential into how and why the virus affects brain health.

Harrison cited a UK Research and Innovation-funded study called COVID CNS that will follow patients with neurologic and/or psychiatric issues during acute COVID in hopes of exploring possible causes.

Beyond a Reasonable Doubt

Commenting on the findings, Sir Simon Wessely, Regius chair of psychiatry, King’s College London, UK, said in a release: “This is a very important paper. It confirms beyond any reasonable doubt that COVID-19 affects both brain and mind in equal measure.”

Some of these effects, including stroke and anxiety disorders, were already known, but others such as dementia and psychosis were less well known, he added. 

“What is very new is the comparisons with all respiratory viruses or influenza, which suggests that these increases are specifically related to COVID-19, and not a general impact of viral infection,” Wessely said. “In general, the worse the illness, the greater the neurological or psychiatric outcomes, which is perhaps not surprising.    

“The worst outcomes were in those with encephalopathy — inflammation of the brain — again, not surprising.  The association with dementia was, however, small and might reflect diagnostic issues, whilst so far there doesn’t seem early evidence of a link with Parkinsonism, which was a major factor after the great Spanish Flu pandemic, although the authors caution that it is too early to rule this out.”

Lancet Psychiatry. Published online April 6, 2021. Full text

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