Covid and the brain: A neurological health crisis

Brain fog. Memory lapses. Difficulties focusing or sustaining attention. All these cognitive issues have plagued some who have otherwise gotten over a bout of Covid-19. In this video, Stanford neurologist Michelle Monje describes her work showing how even mild respiratory infections with the SARS-CoV-2 virus may lead to lingering problems with the brain.

“I think the rates of persistent cognitive symptoms in people who have recovered from Covid is, frankly, alarming,” Monje says. Some estimates from early in the pandemic (before vaccines were available), report as many as one in four people experiencing these issues. “We need to understand how to intervene and offer effective therapy, or there are going to be just millions of people suffering.”

Monje, who has long treated and studied cancer patients with similar symptoms following chemotherapy, says that the damage isn’t necessarily caused by the virus itself. Instead, her work suggests that inflammatory molecules released in the lungs of someone with Covid may trigger a reaction of immune cells in the brain.

These brain cells, called microglia, then start a cascade of signals that alter the behavior of other brain cells, eventually slowing communication between neurons. The good news, Monje says, is that the similarities to what she calls “chemobrain” may mean that many of these persistent cognitive problems will improve with time, just as chemobrain does.

READ MORE: Neuroinflammation During RNA Viral Infections, Annual Review of Immunology

This video is part of Reset: The Science of Crisis & Recovery, an ongoing series exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation.

Video transcript

Michelle Monje (neuroscientist and neuro-oncologist, Stanford University): “Inflammation in the brain can cause dysregulation of a number of different cell types and have lasting consequences to cognitive function. Understanding that when the pandemic struck and we saw how profoundly immunogenic, how profoundly inflammatory even relatively mild cases of Covid could be, I really worried about a neurological health crisis. And I think we’re watching that unfold right now. The rates of persistent cognitive symptoms in people who have recovered from Covid is frankly alarming. We need to understand how to intervene and offer effective therapy, or there are going to be just millions of people suffering with these persistent cognitive symptoms.

“I’m not an epidemiologist. I’m not a virologist. I’m a neurologist. But I am alarmed by the neurological possible consequences of this pandemic and alarmed by the neurological disease that’s already evident in many, many, many survivors of Covid.

“Even from early in the pandemic, it was very clear to neurologists that Covid infection results in a remarkably high rate of persistent neurological symptoms, including quite a high rate of persistent cognitive symptoms. That includes things like difficulty paying attention, difficulty with the speed of information processing, difficulty with concentration and memory. And that is something that we should all be paying a lot of attention to — that is really, really concerning, it’s debilitating. People are just not returning to their previous level of function. And that’s a major problem with 265 million people worldwide infected with Covid [as of January, 2022; over 526 million cases by May, 2022], and some estimates of as many as 1 in 4 people, at least prior to the time of vaccination, experiencing these cognitive symptoms. This is a neurological health crisis.

“I’m a neuro-oncologist and one of my clinical specialties is to take care of people following cancer therapy who have persistent brain fog: cognitive impairment as a result of their cancer and its therapy. And this so-called chemo brain, or chemo fog, is very similar to what people are describing after Covid. And so this so-called Covid fog shares almost the identical symptoms. And what we’re finding in the laboratory is that the two types of brain fog also share a lot of the very same cellular changes that we think are underpinning this sort of fogginess.

“We know that with severe Covid infection, that many things can go wrong, that severe disease is associated with blood clots that can cause stroke with even direct infection of the brain, and with the consequences of multi-organ disease and damage. But even after mild Covid, people were reporting persistent cognitive trouble. And I wondered whether the inflammatory response just to the respiratory infection might be enough to trigger neuroinflammation — inflammation in the brain — and consequently dysregulate these cells that are so important to keep in balance for healthy cognitive function.

“What we discovered in the laboratory in mice that have relatively mild respiratory Covid and then in human samples, Covid elicits such a profound inflammatory response in the brain. And as a result of that, brain cells that need to work together in order to communicate and function normally were dysregulated. In severe cases of Covid, there can be direct infection of the brain, but in many cases, there’s no evidence of virus in the brain.

“What’s happening to affect the brain instead is a consequence of the immune response to the virus. And what we studied was how the immune response to infection that was limited to the respiratory system could cause inflammation in the brain through signaling molecules that go from the lung, through the blood and to the brain. We found pretty high levels of inflammatory molecules called cytokines and chemokines in the central nervous system, just from mild respiratory infection.

“And together with that, we saw inflammation in a particular kind of brain immune cell, which is called a microglia. When microglia and astrocytes become reactive, they then can cause dysregulation of another kind of glial cell that form the insulation around axons — quite literally like the insulation on a wire. When that happens, the neurons (the communicating cells in the brain) can’t communicate with each other in their normal way — not as quickly and not as well. And so that can cause dysregulation of the whole circuit and cause cognitive impairment. This pathophysiology is particularly prominent in Covid.”

Covid and kids

Michelle Monje: “Now a lot more kids are becoming infected with Covid. And so one of the next things we’d like to explore in the laboratory is to understand how early life exposure to even mild respiratory Covid might influence both brain development, brain plasticity and cognition. As a parent, as somebody who takes care of children in the clinic, after Covid exposure I’m very attentive to how school is going, to whether they’re complaining about not being able to remember things, if they’re having difficulty finding their words, to describe certain things in conversations, their overall level of fatigue. I think there’s many things to pay attention to as a parent, as a teacher, as a physician.

“It’s not clear what neurological diseases people may be at increased risk for down the road. And so it’s of some real urgency to understand that, to understand these neurobiological underpinnings of this initial response to Covid, to know what people may be more susceptible to, and to reset these cells to a more normal state.

“The risk of long-term neurological disease really gives me pause and makes me not at all ready to decrease mitigation efforts. I still feel that we need to be vigilant. We need to not fatigue of these measures, as difficult as they are. We need to really maximize vaccination and hope to minimize the long-term damage that this pandemic is going to do for generations.

“I think the lessons from chemo brain are really encouraging, because the biology that we uncovered in the context of cognitive impairment are all potentially reversible. And that’s really hopeful. In more severe cases of Covid, particularly when there are clots and strokes and direct brain infection, irreversible damage can happen. But in these more mild, acute Covid cases, this is all potentially recoverable. It’s of real urgency to understand the neurobiology, to understand the basic underpinning of what is going wrong, so that we can develop therapies to intervene and restore normal balance in the brain. Otherwise, I think that there will be really profound long-term consequences of this pandemic on neurological health.”