COVID-19 may be primarily a respiratory illness, but its reach extends far beyond the lungs. Since the pandemic’s onset, it has become clear to neurologists that the pervasive disease can impact even our most precious organ—the brain. The neurologic and psychiatric complications of COVID-19 are incredibly diverse and sometimes persist long after patients recover from their initial infections. Studying the mechanisms behind how these complications arise is urgently needed for helping those struggling with lingering symptoms, writes Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology, in a recent “Perspective” article published in Science.
“Many patients are desperate to get back to their normal lives, and it’s very frustrating for them that we lack targeted therapies for their conditions,” says Spudich. “Until we understand the pathophysiology, we can’t appropriately guide their treatment.”
For the past two decades, Spudich studied the effects of HIV on the brain, fascinated by how the tiny virus can cause long-lasting consequences in infected individuals. Then, 2020 brought the onslaught of a new virus, shortly followed by a growing number of clinical reports of infected patients also developing brain-related problems. In collaboration with colleagues at Yale, she has since pivoted much of her focus to learning more about the neurological impacts of SARS-CoV-2.
Neurological consequences of COVID are diverse
One aspect of the virus that has been very surprising to Spudich is the heterogeneity of the symptoms it causes. Even with mild cases, COVID-19 can cause confusion, delirium, sleepiness, poor cognitive function, intense headaches, and uncomfortable skin sensations. In more severe cases, patients have suffered complications as serious as strokes.
While researchers initially focused on complications during the acute stage of the disease, as the pandemic progressed they soon realized many of these complications could be long lasting.
“There are many, many reports now of people having persistent symptoms for months. That’s being termed ‘long COVID,’” says Spudich. “Often, they’ve had complete resolution of their fevers and breathing problems, but they continue to have problems with thinking, concentration, memory, or difficulty with strange sensations and headaches.”
Infection can lead to immune-mediated injury
At the beginning of the pandemic, researchers were concerned that neurological symptoms may be attributed to SARS-CoV-2 potentially invading and replicating in brain cells and directly injuring the brain. However, the vast majority of current evidence reveals that this is not the case.
“In our paper, we accumulated evidence that has been systematically investigated and summarized how the brain is affected during acute COVID-19,” says Spudich. “We found that most of the research points to immune-system mediated injury rather than the virus actually entering the brain and killing cells there.”
Researchers can look for the presence of pathogens in the nervous system through studying cerebrospinal fluid (CSF)—the liquid around our brain and spine. Of the many studies that have been conducted worldwide, very few have detected SARS-CoV-2 remnants in the CSF. Furthermore, autopsy studies—which can sometimes detect viral fragments in the brain—have also failed to find remaining particles.
However, even in the absence of a replicating virus, COVID-19 may still contribute to immunologic changes. Specifically, studies have pointed to an elevation in markers of immune activation and inflammation in the CSF and brain that may underlie symptoms. For example, immune cells release certain proteins to fight infection, but those can also have off-target effects that interfere with neurological function.
“We believe that in some people who get COVID and suffer neurological symptoms, the immune system is causing changes in the nervous system that end up making them symptomatic,” says Spudich.
Often, [patients have] complete resolution of their fevers and breathing problems, but they continue to have problems with thinking, concentration, memory, or difficulty with strange sensations and headaches.
Serena Spudich, MD
Furthermore, scientists believe some symptoms may be caused by autoimmunity—in which the immune system is turned on to fight an incoming pathogen, but mistakenly recognizes the body’s own cells as targets.
“In these cases, the immune system goes awry and attacks its own brain cells or peripheral nerve cells, causing neurologic or psychiatric consequences,” she says.
Long COVID's mechanism puzzles researchers
The persistence of problems after the acute infection clears in patients is an even more puzzling phenomenon. Because the presentation of long COVID is very heterogeneous and the clinical tests patients go through often come back normal, it is an especially difficult condition to study. “Most of these patients are hearing from their doctors that nothing is wrong with them,” says Spudich. “The rest of our publication is focused on trying to explore what some of the causes of long COVID might be.”
Long COVID may result from persistent neuroinflammation triggered during the acute infection, or from other kinds of changes related to autoimmunity. But there is currently a lack of clear evidence supporting either hypothesis. Because long COVID presents in a wide variety of ways, it will take many different specialists working together to understand its pathophysiology. “Our paper was partly trying to draw attention to this topic and galvanize more research investigation,” says Spudich.
For many sufferers of long COVID, their condition may impair their ability to work and significantly reduce their quality of life. The numbers of people who have filed for time off of work due to the condition are “staggering,” she says, and further research is essential for helping individuals get their lives back. For example, if research finds that excess inflammation or an autoimmune attack in the brain is the culprit behind certain long-term neurological symptoms, this would help scientists develop more targeted therapies. “It’s important that we understand the pathophysiology and what we call ‘biological phenotypes’ to help treat people correctly,” she says.
Spudich also believes further research is necessary for understanding whether having long COVID predisposes individuals to further problems down the road. There is a lack of data, for example, about whether patients are at greater risk for developing dementia or other neurological consequences.
“We are trying to resolve the situation people are facing at this moment, but we also need to interrupt whatever this ongoing process could be so that there aren’t more long-term consequences for what’s going on in the nervous system,” she says.
Looking to unravel SARS-CoV-2's mysteries
In her lab, Spudich is continuing to use the tools she developed over the years to better understand how HIV affects the brain for unraveling the mysteries of SARS-CoV-2. She works closely with multiple colleagues at Yale, including, Shelli Farhadian, MD, PhD, assistant professor of medicine (infectious diseases) and of neurology, and Lindsay McAlpine, MD, BSc,fellow in neurology.
Through looking at the different cells and proteins that surround the brain and can be measured in the CSF, they are studying how they function differently in people who have long COVID compared with those who didn’t develop further complications. They are also using MRI imaging to study the structural and functional brain differences between these groups. Spudich hopes that their work will not only provide answers to those struggling with the effects of COVID-19, but also shed light on other poorly understood viral infections such as Lyme disease.
“There are amazing research tools available to us now that allow us to study immunology, look for tiny fragments of the virus, and observe changes in the brain structure or the way it functions,” she says. “It will take time, funding, effort, and investment, but I am confident we will get answers.”