Dr. Juliette Madrigal has seen a fair number of patients in recent months suffering from anxiety while ill with COVID-19. While it seems reasonable that people with a potentially life-threatening disease would get anxious, Madrigal is increasingly convinced that the anxiety is a side effect that the coronavirus has on the brain.
“I’ve been seeing the anxiety in 20-something-year-olds, who will tell me that they know they’re fine, that they know they have a mild case,” said Madrigal, a primary care physician in Marble Falls, Texas. “They’ll tell me, ‘I know this is not going to be the death of me, but I feel very anxious.'”
It’s not the only neurological problem Madrigal is seeing in COVID-19 patients.
“We’ve also seen quite a few patients complain of what we now call ‘COVID Brain,'” she said. “People are complaining of feeling confused and about a loss of short-term memory.”
Patients and physicians have noticed neurological problems related to the coronavirus almost from the beginning of the pandemic. Early on, many patients reported a loss of their sense of smell. One study found that 41% of those with COVID-19 experienced a loss of smell.
Most patients recover their sense of smell within a month, although the loss lingers indefinitely for some. Scientists aren’t yet sure what causes the loss of smell. However, research published in the New England Journal of Medicine that examined the brains of deceased COVID-19 patients found signs of inflammation in the olfactory bulb.
Indeed, scientists are just beginning to unravel how COVID-19 affects the brain. And it increasingly appears that the disease can change the brain in different ways.
While the loss of memory or smell is serious enough, COVID-19 likely causes even worse neurological problems. A recent study published in the Lancet found that of 125 people who had COVID-19 and were diagnosed with a neurological problem, 57 had suffered a stroke, and 10 had suffered psychosis. Other ailments diagnosed included intracerebral hemorrhages, dementia-like symptoms, and inflammation of the brain known as encephalitis. Another Lancet article identified COVID-19 patients who had developed Guillain-Barre syndrome, a disorder in which the body’s immune system attacks the nerves.
Many of these studies have small sample sizes, making it challenging to connect neurological diseases with the coronavirus. But Alysson Muotri, a professor in the Departments of Pediatrics and Cellular and Molecular Medicine at the University of California, San Diego, is confident that there is a connection.
“Although most of the individual studies are small, collectively, they converge on similar clinical and pathological observations all over the world,” Muotri said. “Plus, we have strong experimental observations to back this up. I believe most scientists and physicians will agree that COVID has a neuro component at this stage.”
Increasing research suggests that COVID-19 causes strokes by creating a “cytokine storm.” This occurs when an infection causes the body’s immune system to flood the bloodstream with inflammatory proteins known as cytokines. Not only do cytokines have an inflammatory effect, but they also have a coagulant effect. That is, they create blood clots. Many studies have found elevated levels of a clot-dissolving protein called a “D-dimer” in patients with COVID-19 who have experienced strokes.
That would mean that the coronavirus doesn’t have to invade the brain to cause a stroke. Indeed, a recent article in the British Medical Journal did not find the virus in the cerebrospinal fluid of two patients who experienced both COVID-19 and a stroke. And a National Institutes of Health study of blood vessel damage in 19 patients who had COVID-19 found no trace of the virus in those brain tissue samples.
Still, the virus would likely have to invade the brain to cause other neurological problems, such as psychosis, dementia, or anxiety.
Muotri has been able to show in laboratory experiments that the coronavirus can infect inside the brain. He and his fellow researchers used brain organoids, which are brain tissues created from human stem cells. They then exposed the organoids to the coronavirus and found that it infected the brain cells.
Perhaps most importantly, they found that 48 hours after infection, the virus reduced the number of synapses in the brain cells by about 50%. Synapses are the parts of the brain that enable nerve cells to pass electrical or chemical signals to each other.
“This observation is so important because it reveals a potential mechanism to explain the neurological symptoms in COVID-19 patients,” Muotri said.
Muotri’s research also found that Sofosbuvir, an antiviral drug approved by the Food and Drug Administration, was able to stop the virus from replicating in the brain.
Learning how the coronavirus affects the brain will be crucial in determining proper treatment. If strokes and intracerebral hemorrhages are due to inflammation caused by the immune system’s response to COVID-19, then anti-inflammatory drugs are a likely treatment. But if the virus invades the brain, then antiviral drugs, such as Remdesivir or Sofosbuvir, might prove more effective.
Yet Muotri warns that scientists may be a long way from solving this puzzle.
“We are just scratching the surface,” he said. “It might take years to figure this out.”
