Q&A: Neurological symptoms of COVID-19 remain an ‘evolving story’

Literature on the neurological manifestations of COVID-19 continues to emerge, as does the medical community’s understanding of how COVID-19 impacts the course of underlying neurological conditions like MS and epilepsy.

Research published in Neurobiology of Disease demonstrated that SARS-CoV-2 spike proteins triggered a proinflammatory response in brain endothelial cells that may influence a change in the function of the blood-brain barrier, a finding that showed the “direct impact” of the SARS-CoV-2 spike protein on endothelial cells in the brain. Another paper, this one in Annals of Clinical and Translational Neurology, found that encephalopathy and other neurologic manifestations occur often in patients with COVID-19, regardless of respiratory disease severity.

Healio Neurology spoke with Jeremy Payne, MD, PhD, of Banner Health University Medical Center Phoenix, about what the neurological complications of COVID-19, the long-term effects of these complications and what questions remain about this aspect of the disease.

Q: What are the main neurological symptoms in patients with COVID-19?

A: We’re still learning about them; it’s an evolving story. Often, with these complex systemic diseases like COVID-19, the neurological complications take some time to manifest. Early on, it seemed pretty clear that one of the cardinal symptoms was loss of smell and taste, and that still seems to be one of the consistent distinguishing features unique to COVID-19. There was some literature suggesting that we might see some MRI changes, particularly in the olfactory regions of the brain, maybe because that’s the port of entry into the brain. I don’t know that we’ve fully fleshed that out since those case reports.

Certainly, we saw early on that stroke seemed to be overrepresented in those patients. I have a collection of patients for whom stroke is really only best explained by aggressive COVID-19 infection. We also see increased coagulation; that is probably one of the big threads that ties all these organs together. Some of the lung injury likely has a lot to do with increased coagulation and inflammation of the lungs. Certainly, increased coagulation is a recipe for stroke.

What’s interesting now, more than 6 months into the pandemic, is that we’re starting to realize there are some long-term pervasive neurologic symptoms mostly involving encephalopathy. You’ll see that in the literature referred to as people reporting brain fog and concentration issues, maybe some longer-term headaches they hadn’t had before, trouble with focus and concentration. That seems to be a pretty core phenomenon in patients who have prolonged COVID-19 symptomatology after recovering from the primary infection. There’s some concern, too, that you could look at some of the symptoms as similar to chronic fatigue syndrome, another cluster of symptoms that we don’t really understand. With chronic fatigue syndrome, one of the key theories has always been that there’s been exposure to some kind of infectious agent, whether it’s a post-Lyme infection or post-viral infection. Longer term, with COVID-19, we might see systemic inflammatory processes still smoldering in the background that somehow affects the brain’s ability to focus and do some of these complex, higher-level organizational things that are correlates of feeling like we’re able to focus and pay attention.

Q: What are the short- and long-term neurological consequences of COVID-19?

A: What I’ve seen, in the patients I’m now starting to see in clinic, or people I know or colleagues who have confided in me about their symptoms, are issues with all of those symptoms, really – primarily difficulty concentrating and focus, the sense of fatigue, things that people colloquially refer to as ‘brain fog,’ persistent muscle aches, headaches, sense of taste and sense of smell not returning. I don’t dare speculate yet about the longer-term consequences.

We’re still in a phase, I think, where it’s accepted that people who have had COVID-19 may not return to work in a 100% productive manner. If we think about chronic fatigue syndrome, some patients who have that never return to work in a 100% productive manner. Those symptoms seem to last. We still really don’t understand what that is, or why it is, or what really to do about it. It becomes controversial because it’s not something we can see. We still don’t see, with chronic fatigue syndrome, objective evidence in ways that we all accept. One of my worries would be is if some of these COVID-19 symptoms don’t get better; what does that mean? People are starting to worry, for example, in the cardiac literature. We’re seeing similar changes in cardiac muscle function that we would see after, say, a cardiac myositis, a primary viral infection of the heart. Hopefully, those patients recover their cardiac function — but they don’t always. They go on to have long-term heart failure symptoms. A lot of patients do recover their full heart contractility, but it may take a year or two. I think it’s still too early to know, long-term, but I think we’re all a little bit concerned that some of the central nervous system features associated with COVID-19 may not get 100% better, given what we’ve seen with some of those other diseases.

It’s interesting. Our residents and medical students, especially residents who get interested a particular topic — for example, residents who decide they are interested in stroke — early on, there will be a paper that comes out that says one thing, and it’s super exciting because it’s practice changing. They start to realize that, 2 years later, another paper comes out that says exactly the opposite; in fact, it turns out that a discussion point bounces back and forth for quite some time until we finally settle down on what we accept is probably the truth. That’s how science works and that’s how it’s supposed to work. I think, at this point, I’ve seen very contradictory statements regarding the long-term neurological complications of COVID-19.

It’s too early to tell which patients will experience more long-term symptoms. Part of that answer might be that older patients, in general, are at higher mortality risk and higher risk for more obvious complications. For example, if an older person develops longer-term heart or kidney failure, or pulmonary complications, we’re much less likely to talk about their brain fog, because we accept that you can’t think straight if you have poor cardiac function. However, I think what we lose is the idea that it might truly be an independent symptom in those patients. In younger patients who recover better from some of those other systemic organ complications, the neurological complications like encephalopathy might be a lot more obvious because they’re not masked by the other diseases. I think it’s going to take years to sort that out. I’m not sure we’re in a position to truly understand the risks of those longer-term manifestations.

I think the pulmonologists, who were really the first people to confront COVID-19 in the hospital, are now among the first group of outpatient practitioners trying to understand the longer-term consequences of this disease. I think, in neurology, we’re going to start seeing that much more in the next 6 months or so.

Q: How does COVID-19 lead to these neurological symptoms?

A: Encephalopathy, and that aspect of brain function, is complex, sophisticated and fragile. Often in neurology, independent of COVID-19 or anything else, we commonly get asked things like, “Do I have Alzheimer’s disease?” We inquire about a patient’s reason for asking this question and they say, “I can never remember where I put my car keys or what I went to the store for.” It turns out the answer to that, for most people, is that you’re forgetful because you’re actually inattentive, you’re distracted, you’ve got a thousand things going on in your brain at any given time. It also turns out that, if you’re sick in any way — you’re fatigued, you’ve got things on your mind, you’re hungry, your bladder’s full — that’s the first thing that your brain struggles with, because it’s the most complicated. It’s this ensemble effect. It’s the idea of going to the symphony and perhaps, as a non-musician, you can tell that something is slightly off or there’s something indefinable about that particular performance that makes it transcendent. The music just all falls into place and you can’t quite say why, but it’s all just perfect. Our ability to think clearly, and have focus, and remember things that we hadn’t planned on memorizing, is like a perfect performance by the symphony. It requires all of the brain to be feeling good about itself and working harmoniously. Many things screw that up for us; COVID-19 will be one of them. Is that because of structural damage to the brain or is it because of this persistent inflammation that is messing up the way the brain functions from time to time or is there some kind of very, very specific lingering effect of the virus directly? I don’t think we know. In fact, mechanisms of memory and attention and focus are so complex that we don’t fully understand that, either.

Q: Have we developed strategies for dealing with these neurological complications?

A: I don’t know that we have anything specific for these patients, beyond what we typically administer for these types of symptoms. I’ve been telling my colleagues, those who have told me that they’re having some of this brain fog after a COVID-19 infection, to do all of the things that we know help with focus and attention and achieving that transcendence with any performance — get lots of rest; focus your mind by dealing with the things that are distracting you; and put good fuel in the vehicle: eat well, get a little bit of exercise to the extent that you can, avoid alcohol, avoid any medications that might cloud the way your brain works. Take care of the instrument as best you can. I think that’s our best weapon, as we don’t really have great pharmacologic targets. It’s not new, and it sounds a little basic, but one of the best things that I’ve learned throughout my time as a PhD in neuroscience is that we don’t really understand how the brain works.

Some of the complications, such as the loss of taste and smell, are quite specific, something the virus did, but some of the other issues, like the brain fog and the overall fatigue and inattention, it’s hard to know if that lives in a particular part of the brain, if it’s a structural change or just what happens when there’s this ongoing inflammation, perhaps, if your immune system doesn’t feel like it’s fully cleared that virus.