New research highlights COVID-19’s long-term effects on the brain, and finds that about a third of patients who survived in the six months after becoming ill were diagnosed with at least one neurological or psychiatric disorder.
The neuropsychiatric ailments that followed COVID-19 varied widely, from stroke and dementia to anxiety disorders and sleep disorders. Virtually all were more common among patients who were sick enough to be admitted to the hospital with COVID-19, and the risk was even higher for those admitted to an intensive care unit.
Patients who develop encephalitis, a dangerous swelling in the brain, are likely to have serious neurological diseases in the aftermath of COVID-19.
But even those not hospitalized were more likely to get a diagnosis for one or more neuropsychiatric disorders than people who had the flu or another respiratory illness, researchers found.
The findings, published this week in the journal Lancet Psychiatry, come from the biggest effort to detect the neuropsychiatric side effects of a coronavirus infection. It occurs when increasing numbers of patients who have apparently cleared an infection cause a persistent constellation of symptoms, including mood disorders, cognition, and sensation.
The phenomenon, called by patients ‘long COVID’, threatens to prolong the impact of the pandemic. Scientists, calling the syndrome Post-Acute Sequelae or COVID, or PASC, are scrambling to understand how a disease most visible to the lungs can leave such a variety of startling symptoms in the aftermath.
But first they need to determine how widespread these symptoms are, and prepare them for the possible onslaught of patients taking care.
“This article is important because it is the largest dataset anyone has looked at,” says Dr. Avindra Nath, who is doing research on the brain and immune system at the National Institute of Neurological Disorders and Stroke. “In that sense, it’s huge.”
Among 236,379 COVID-19 survivors, 24% had a confirmed mood, anxiety, or psychotic disorder in the six months after becoming ill. For 36% of the patients, the psychiatric diagnosis was their first.
The number of strokes, nervous disorders and dementia was also higher than normal in the COVID-19 survivors compared to patients treated for other medical problems.
Ischemic strokes, in which a blockage restricts the flow of oxygen to the brain, were seen in the six months after their initial illness in 2.1% of former COVID-19 patients. And almost 3% were diagnosed with nerve disorders or nerve roots.
Dementia was diagnosed in 0.67% of post-COVID patients, a rate that rose nearly 1.5% among those admitted to the hospital, and to nearly 5% among those who had encephalitis.
Among COVID-19 survivors aged 66 or older, 2.7% were diagnosed with dementia within six months, researchers found.
Worldwide, nearly 130 million SARS-CoV-2 infections have been confirmed and survived. Although the brain-related problems in the study only occur in patients who develop COVID-19 symptoms, they suggest that the pandemic will leave a large population of patients with persistent problems.
“I think the health consequences on this health are going to be huge,” said Dr. Anna Cervantes-Arslanian, a neurologist studying the after-effects of infection at Boston University Medical School.
I think the consequences for public health of these findings are going to be huge.
Anna Cervantes-Arslanian, a neurologist at Boston University Medical School
The study reveals much preliminary evidence of an increase in brain disorders that normally take years to detect, including dementia and Parkinson’s disease-like tremors, Cervantes-Arslanian said. And it documents the high dose of post-COVID depression and anxiety, common diagnoses that can occur during a person’s lifetime.
Only time and further study will learn how much COVID-19 can swell the ranks of patients with neurological and psychiatric problems, and how long it can last, she said. But ‘this paper raises alarm.’
A team of psychiatrists, neurologists and epidemiologists from the University of Oxford searched the medical records of nearly a quarter of a million people who were diagnosed with COVID-19 and were looking for new or repeated diagnoses of 14 specific disorders. They watched when the diagnoses were made and how their appearance differs with the COVID-19 severity.
Many viruses are known to leave behind clusters of mystifying symptoms. The Oxford researchers therefore also had to determine whether the ability of SARS-CoV-2 to disrupt brain function is unique.
To do this, they created large comparison groups of similar patients who were ill with flu or other respiratory infections. They then searched their medical records for evidence of a neuropsychiatric diagnosis in the six months after their initial illness. Overall, they found that the chance of having one of the 14 disorders was 44% higher for COVID-19 survivors than for those who had the flu. It was also higher for those who had another respiratory infection, but the difference was modest enough that it could be a statistical attack.
A second comparison group consists of patients who sought medical attention for skin infections, kidney stones, fractures of large bones or blood clots in the lung.
The rates of neuropsychiatric side effects were consistently higher among the COVID-19 survivors than for those in the other groups. There was one notable exception: patients who recovered from another respiratory infection also increased subsequent strokes (both the ischemic strokes that block blood flow to the brain and the intracranial hemorrhages that involve a cerebral hemorrhage).
More than 80% of the COVID-19 patients whose medical records were reviewed were never admitted to the hospital. Despite this, almost 32% of them were diagnosed with one of the 14 neuropsychiatric diseases within six months.
How can I explain why a disease that usually starts as pneumonia can have so many downstream effects on the brain?
Some possibilities lie in the eye: the fear caused by the pandemic, and the social isolation that accompanies it, are themselves depressing and anxious, and in turn have provoked unhealthy behavior.
Getting sick with COVID-19 can be a frightening and traumatic brush with death, especially if it involves intensive hospital care. And when other important organs are damaged – as in the most severe cases of COVID-19 – the brain can rarely escape the collateral damage.
But scientists suspect that more subtle mechanisms may also be at work.
First, the virus, or even viral fragments, can sneak past the barrier that normally protects the brain from infection and invade the organ that oversees everything from reason to body temperature.
Second, the immune overreaction that COVID-19 often elicits can drive immune cells and proteins that stay out of the brain into the sacred space, damaging delicate tissue and disrupting operations there.
And lastly, the affinity of SARS-CoV-2 to attack the lining of blood vessels and promote the formation of blood clots can cause a unique devastation in the brain, which depends on miles of small blood vessels to function properly.
Nath said there is a lot of preliminary evidence to support all three mechanisms in COVID-19 patients. But this is limited by the fact that the functioning of the living brain is so difficult to capture in real time.
An examination of the brains of deceased COVID-19 patients supervised by Nath found immune proteins and cells in many places, along with many damaged blood vessels. That autopsy study found no evidence of virus in the brain. But others did, and Nath acknowledged that the virus in his work may have been removed at the time of the patient’s death, or that it was not detectable with the available tests.
Ultimately, Nath said, the mystery of what causes the brain to cause COVID damage could focus on what creeps in through the chaos agents and what structures pull them inside.
“Most neuroscientists are interested in the fact that all coronaviruses affect the nose: they can end up in the brain by moving the olfactory nerve very efficiently,” he said.
That nerve, or other cranial nerves, can be the virus’ springboard for the limbic system of the brain, the deep structures where emotions such as fear and anxiety are processed, and from which depression and anxiety disorders can result.
Or the virus may take a different turn and continue with the prefrontal cortex, the seat of cognition and emotional regulation, both of which are frequently affected in post-COVID syndrome.
It can also lead to the brainstem, which controls a number of involuntary functions, including temperature regulation, heart rate and blood pressure. Many patients with a long COVID report ‘dysautonomia’, or difficulty regulating these functions.
The diversity and frequency of side effects captured by the new research could send scientists in various directions to find a common cause, Cervantes-Arslanian said. However, the findings support the suspicion that ‘there is definitely a brain invasion’ in the SARS-CoV-2 infection. The neuropsychiatric symptoms following COVID-19 have a real biological underpinning, ‘she added.