Clinical Guidelines: Neurologic Manifestations of COVID-19

Between the beginning of the COVID-19 pandemic and May 2022, more than 527 million cases of SARS-CoV-2 have been confirmed. COVID-19 represents an ongoing challenge to the field of neurology, as neurologic complications of the disease are leading to an increase in demand for both acute and long-term neurologic evaluation and management. Three experts from Northwestern Medicine Neurology — Igor J. Koralnik, MD, Eric M. Liotta, MD, and Edith L. Graham, MD — have been investigating the pathogenic mechanisms of acute and long-term COVID-19, as they may inform clinical evaluation and management. They discuss their guideline "Therapeutic Approaches to the Neurologic Manifestations of COVID-19," published in Neurotherapeutics in July 2022.

Clinical Guidelines: Neurologic Manifestations of COVID-19
Featured Speakers:
Eric Liotta, MD, MS | Igor Koralnik, MD, FAAN, FANA | Edith Graham, MD

Edith L. Graham, MD 
Assistant Professor of Neurology (Multiple Sclerosis and Neuroimmunology) 
Northwestern Medicine.

Igor J. Koralnik, MD 
Chief of Neuro-infectious Disease and Global Neurology 
Archibald Church Professor of Neurology
Northwestern Medicine. 

Eric M. Liotta, MD, MS 
Associate Professor of Neurology (Neurocritical Care) and Surgery 
Northwestern Medicine.

Clinical Guidelines: Neurologic Manifestations of COVID-19

Andrew Wilner, MD (Host): This is better edge, a Northwestern Medicine Podcast for physicians. I'm your host, Dr. Andrew Wilner, associate professor of neurology at the University of Tennessee Health Science Center and division director of neurology at Regional One Health in Memphis, Tennessee. Today we are discussing the neurologic complications of COVID 19 and the strange phenomenon of long COVID. We have three expert guests today, Dr. Eric Liotta, Edith Graham and Igor Koralnik. Dr. Liotta is associate professor of neurology and surgery. Dr. Graham is assistant professor of neurology and a specialist in multiple sclerosis and neuro immunology. And Dr. Koralnik is the archable church, professor of neurology and chief of neuro infectious disease and global neurology. All of the faculty work at the Feinberg School of Medicine at Northwestern Medicine. Welcome Dr. Liotta, Graham and Koralnik.

Dr. Igor Koralnik: Thank you for having us.

Dr. Edith Graham: Thank you.

Dr. Eric Liotta: Thank you.

Andrew Wilner, MD (Host): Well, to start as neurologists, we are particularly interested in how this COVID virus affects the central and peripheral nervous system, as well as the relatively new phenomenon of long COVID. Dr. Koralnik as a neuro infectious disease specialist, what do we need to know about COVID and its neurologic complications?

Dr. Igor Koralnik: Well, this is an excellent question. This is why we wrote this paper that we're discussing today. We are seeing two very distinct population of patients here at Northwestern Medicine affected with COVID 19. The first population of patients is severely sick hospitalized with COVID pneumonia. And sometime they are intubated in our ICU. And we have seen that approximately 82% of those will have some neuro manifestation during the acute phase. In addition, we have a second very distinct population of patients who had only a mild respiratory presentation of COVID 19.

Sore throat cough, a bit of fever that went away, but then thereafter are presenting with these lingering symptoms called the long COVID syndrome. And we are seeing them in our clinic. And this is why we've wrote this neurotherapeutics paper on how to care for both population of patients.

Andrew Wilner, MD (Host): Okay, well, thank you for that introduction. And it's very interesting that there are these two groups of patients. Now, as a neurologist, one question that I have, you mentioned 82% of the sickest patients in the hospital have some complication, some neurologic complication from COVID. So how do you know what percentage of those is due to the virus itself? Or is it just because they're sick and intubated and bad things are happening? What does the virus do?

Dr. Eric Liotta: Well, some of those complications like difficulties with sense of smell or taste may be more directly related to the virus. And a number of those complications could be more of an effect of what the virus is doing systemically with the inflammation or problems with clotting throughout the body. In particular, probably the important complication in the hospitalized patients is something that's called encephalopathy or this global brain dysfunction that can range from confusion all the way up to coma.

And it looks like encephalopathy is more likely due to the effects of the virus on the body causing inflammation or problems with blood clotting or dysfunction of the blood vessels themselves and not so much a direct invasion of the virus into the brain.

Andrew Wilner, MD (Host): Okay, thank you for that, Dr. Lido, what about stroke? That's another big problem.

Dr. Edith Graham: Yeah, so stroke is reported in about one to 3% of the hospitalized patients. And it does seem like it's more frequent in the critically ill. So it's about 6% of those patients. It seems like the most common mechanisms of stroke in the patients with COVID encephalopathy are either what we call cryptogenic. So it's not really clear what the mechanism is or cardio limbic. And we know that as a complication of COVID 19 people can have abnormal heart rhythms, or they can have dysfunction other dysfunctions of the heart, like heart failure. And it also looks like something about COVID 19 causes a predisposition to clotting.

So these patients have a tendency to form clots, and it also looks like there may be a dysfunction at the actual lining of the blood vessels themselves that can lead to lead to stroke. The strokes that we see in people with COVID 19 can range anywhere from. Very punctuate infarcts that we find incidentally on imaging when we're working up another syndrome, maybe like dizziness, all the way up to a large vessel occlusion that would present in a dramatic fashion.

Andrew Wilner, MD (Host): Okay. Well, let's stick with this very sick. Group of patients, Dr. Koralnik. You mentioned that in your paper, there are recommendations for treatment. Now I remember for example, back in the beginning of this pandemic. We were some physicians anyway were very enthusiastically anticoagulating patients in the hospital because of this. You mentioned Dr. Lader, there's a tendency for a hyper coagulable state causing a stroke. So, what do we do? Do we have treatment algorithms now and prophylactic algorithms for encephalopathy and stroke?

Dr. Edith Graham: Early in the pandemic, physicians were very frequently anticoagulating people because of a anecdotal experience with frequent clotting. But there has since been a number of clinical trials under the umbrella of the recovery trials that looked at the utility of anticoagulation and COVID patients. And it actually turns out that in the sickest patients, the critically ill patients, if you anticoagulate them without a specific indication, having a D V T or a pulmonary embolism, the bleeding risk is actually balances any benefit you get against thrombotic complications.

But it looks like in patients who need to be hospitalized, but have more mild disease. So they have elevated d dimers. They don't require to be in the ICU and maybe they're just on a little supplemental oxygen. It does look like anticoagulation benefits them up to 14 days. So we wouldn't want to just anticoagulate and every single COVID patient that's in the hospital, cuz it doesn't look like it actually benefits all of them.

Similarly, in the line of stroke, some people thought about, well, what about if we just give everyone an aspirin? And it turns out that prophylactic aspirin therapy was looked at as well. And that didn't really result in a net benefit against stroke either.

Andrew Wilner, MD (Host): Doctor, that's great. Let me push a little further. You mentioned that for the mild patients in the hospital, anticoagulation could be a good thing, but for the sickest ones, it probably isn't. Is that right?

Dr. Edith Graham: Well, if the sick ones have atrial fibrillation or they have DVTs, then you would anticoagulate them for those routine indications.

Andrew Wilner, MD (Host): Yes, unless there was a Specific indication, but what happens when the mild ones become the sick ones?

Dr. Edith Graham: Well, when the mild ones become the sick ones, then they transition from where you would've given them the anticoagulation in the trial to where you would discontinue it.

Andrew Wilner, MD (Host): So you would say, okay, well you are no longer in, in category A, you're in category B. So even though we started anticoagulation, for example, five days ago, it's better that we stop it now, is that correct?

Dr. Edith Graham: Hypothesis is that the anticoagulation is helping with micro thrombosis rather than the necessarily the macro thrombosis and that maybe when you've progressed to a severe disease state, that you've already have such a burden of micro thrombosis that that balance is no longer your favor with anticoagulation. The clinical trials that looked at this, weren't really designed to explore mechanism. So a lot of why are we observing one treatment being successful and one group and not the other is very based on hypothesis and maybe other disease models rather than being directly investigated in that clinical.

Andrew Wilner, MD (Host): Well, clearly we still have a lot to learn about the pathogenesis of COVID 19. Well, we're about halfway through our program. Why don't we switch to a discussion about long COVID, who would like to tell us about that?

Dr. Edith Graham: I can certainly speak to long COVID.

Andrew Wilner, MD (Host): Dr. Graham. Thank you.

Dr. Edith Graham: So long COVID or as the medical term is P ASC, which is post acute sequelae of COVID 19, is defined as at least one symptom of COVID 19 lasting for greater than four weeks. Some other institutions have varying definitions, but we like to use the four week one, which was initially used by the CDC earlier in the pandemic. And the trouble with this definition or so the trouble with really defining this population is that is really a heterogeneous group. And there is not just one presenting symptoms.

So some symptoms and long COVID are more common than others, notably cognitive dysfunction is seen frequently and so is fatigue as well as headaches, dysautonomia. And then prolonged anosmia. Okay. But really each patient that comes into our neuro COVID 19 clinic is just a little bit different. So some people ask what's their chance of getting long COVID after having a COVID infection. It's somewhere around 30% and it varies in length depending on the patient.

Fortunately we know that with the new variance coming out, it, there is a little bit less of a chance of getting long COVID with our newer variants. But it's still definitely a real risk. And we also know that one way to mitigate the chance of getting long COVID is to be fully vaccinated, including having a booster. While this is a.

Andrew Wilner, MD (Host): Thank you for that. I was going to ask you, does vaccination help prevent long COVID since you can get COVID even though you're vaccinated, although usually it's not severe. So the answer is yes, vaccination does help.

Dr. Igor Koralnik: Yes. And there is actually data about it. Some large studies come from the UK showed that vaccination decreased the risk of long COVID by 15%, but it's still a significant risk. A smaller study from Italy and healthcare worker showed that three vaccination or two vaccination, and one booster reduced the risk of getting long COVID to 16%. That means you can still have long COVID. And we see those patients coming to our clinic. We see also patient having a second or a third infection and developing long COVID despite vaccination booster, and is coming to our clinic.

Andrew Wilner, MD (Host): And so far, there's no other predictor, men, women age there, there's no indication if I get COVID tomorrow, you could say, well, you're in a high risk group of long COVID or a low risk group. Do we have any data on that?

Dr. Edith Graham: We do. There was a study of over, 200,000 patients who had COVID and they found that the patients who had long COVID. Actually more likely to be younger, be female and to have had severe illness. The severe illness part makes sense, but the younger patients and the female sex doesn't make a whole lot of sense in some ways.

Dr. Igor Koralnik: So if I may add to it, when we publish our first initial paper with the Edith Graham, being the first author, the first a hundred patients in the clinic we saw as ED said, that 70% of the patient were female. 16% had history of autoimmune disease before COVID. And these were a patients who had a mild disease, never hospitalized for pneumonia or hypoxemia. So we think that there is an autoimmune predisposition of developing long COVID. Since we know that women are more likely than men to develop rheumatoid arthritis, MS, Lupus and so on. And those patients had a higher rate of autoimmune disease prior to COVID.

Andrew Wilner, MD (Host): Okay. Now, before we turn to treatment, I wanna know is long COVID due to the damage done of the acute disease. We talked earlier about micro thrombosis and the capillaries, for example, or is there an ongoing chronic infection?

Dr. Eric Liotta: Yeah. So it may depend a little bit, whether you're a hospitalized patient or a non hospitalized patient. I think the people who are hospitalized and deal with severe illness, they're not only experiencing COVID, but all of the complications of critical illness. So there are probably separate mechanisms of brain injury that an outpatient might not experience. But we know that for the it's more complicated than just pulmonary disease or being hypoxic. Because we see that there's patients who never really have significant pulmonary disease or never need to be in the hospital who develop long COVID symptoms of particularly cognitive symptom.

Dr. Edith Graham: One of the other questions that comes up with the neurologic sequelae of COVID 19 is whether or not SARS covi two is a neurotropic virus. So whether or not it infects the brain itself. And this to date is a little bit more theoretical than proven that whether or not it could. Potentially there is some more infection lower in the brain stem and the ponds or me where there are ACE two receptors in higher concentrations. But otherwise there, it's not known to be a virus that does infect the brain.

Dr. Igor Koralnik: So, to answer your question, whether there's a persistent infection going on in the body, this is something that we're trying to answer in our lab. Since, as the CDC is tracking pockets of infection in the us by looking in sewage water for the RNA of the virus. We think that the virus may be hiding in hidden reservoir, like the gut. And since if it can be found in the sewer, then that's probably coming from the gut and we are starting to test the stool sample from our patients for the presence of SARS Covi two to either antigen or PCR. And we finding that some patients indeed have ongoing infection.

Dr. Eric Liotta: I would add along that line that we recently published a paper that demonstrated patients who had been hospitalized and continued to test positive for the viral RNA by nasal swab actually had worse outcomes in terms of mortality and had more complications in terms of encephalopathy in the hospital. And one of the hypotheses we proposed in that paper was that there could be either a latent reservoir in the body or another dysfunction of the immune system where it's not clearing the virus completely in certain individuals.

Dr. Igor Koralnik: And to that extent, we think that the persistent infection may drive this dysregulation of the immune response that we are seeing in the blood of our patients. And this regulation of the immune response may lead to autoimmunity, either mediated by auto antibodies or by auto reactive T cell. And it is an area of active investigation in my lab and in other centers.

Andrew Wilner, MD (Host): Now for patients with long COVID, is there a treatment?

Dr. Edith Graham: So if we're going off the theory that there is potentially a persistent virus infection in the body, could you use something like antiviral? So now we have a couple of antivirals out, like Paxolivid. And Monopuravir, well, we only have currently a treatment regimen of five days and that's only indicated for active infection. And we also know that patients who get Paxolivid may have rebound viral activation after stopping the course. So how would you know exactly how long to treat them for?

That would be a difficult question to answer. But for the current treatments that we have, they do focus more on symptomatic control of whatever their current symptoms are. So if it's headache, we may give the patient nortriptyline or sometimes I even give a short course of endamethocid, which has been shown to improve headache with. With just short courses of a couple weeks. If it is something like blood pressure, dysregulation or Dysotinomia, then we may be looking at other treatments like staying well, hydrated, compression stockings, graded exercise programs or even medications that may support the blood pressure. So it really depends on what their symptom coming into the clinic is, as to how we're gonna address it.

Andrew Wilner, MD (Host): Well, to wrap up Dr. Koralnik, tell us where I can read your paper and what's next in your research?

Dr. Igor Koralnik: So this paper was published in Neurotherapeutics Journal. It is online and you, everybody can download it for free. We have a lot of different ways. Taking care of our patients like Dr. Graham said, for example, brain fog, which is the major and most developed manifestation that our patients complain of in the clinic is treated by first determining what is their cognitive dysfunction. Using tool that we use in the clinical, the NIH toolbox patients are then referred to our neurocognitive specialists to pinpoint exactly what is wrong with them.

And then for cognitive rehabilitation at Shirley Orion Ability Lab here in Chicago, and we've already sent, you know, close to a hundred of patients. And the preliminary result seems encouraging that cognitive rehab is really helping them. We are doing other studies with other members of our department, for example, trying to figure out what is the component of sleep in cognition. And the fatigue in those patients. And we are carrying out actigraphy study to understand if there's a dysregulation of the sleep, wake pattern in the, those patients that may lead to fatigue.

And the problem with cognition. We also doing those studies in the lab trying to figure out if there are biomarkers of cognitive dysfunction and the brain inflammation in our patients and this is an ongoing effort. We are also looking at this immune dysregulation as a root cause of long COVID in the same patient population. And would it be possible obviously to treat those patients with antiviral medication, if this was proven?

Basically there's a multi-prong effort going on in neurology and as well as in the Comprehensive COVID Center, which is a multidisciplinary clinic which is a center that has 12 subspecialty clinic, including pulmonology, cardiology, gastroenterology, EMT, and so on where patients can get help for all their lung COVID related symptoms.

Andrew Wilner, MD (Host): Do you accept referrals from the community for long COVID?

Dr. Edith Graham: We do. There is a great need for more people to help with treating these patients because the wait times can be a couple months or more, but we absolutely accept new referrals.

Dr. Igor Koralnik: And we have full access to the clinic by not requiring physician referral. We don't need to have patients showing the proof SARS Covi two positive tests. Since we know that at the beginning of the pandemic, many people couldn't be tested or were not tested on time and therefore don't have a positive test, but they are seen in our clinic. We don't require also proof of insurance for people to come either in person or in televisit. Anybody who has access to a phone or a computer all over the states can see us. And we have seen so far more than 1,450 patient in the clinic since the beginning of the pandemic.

Andrew Wilner, MD (Host): Well, that's fantastic. You're providing such great accessibility for people with COVID symptoms. Well, we've reached the end of our time, but before we close, is there anything any of you would like to add?

Dr. Eric Liotta: Well, I think the pandemic has offered. I think an opportunity to understand a acute illness, even just beyond COVID. I think particularly what it highlighted for the hospitalist, the intensivist is the magnitude of disability that results from that encephalopathy that we talked about. And has really highlighted for me that we need a lot more research in that area to really understand how to treat it and prevent long term disability and particularly cognitive disability. Our treatments as you maybe highlighted a little earlier in the podcast are pretty limited.

We don't even know if we should be giving these patients immunomodulatory therapy. We do know that things like excessive sedation actually worsens encephalopathy and cognitive outcome. And that things like actually family visitation can reduce encephalopathy and we think improve outcome. So it's a very complex syndrome that we're dealing with. And we are really just scratching the surface of understanding it and discovering interventions.

Andrew Wilner, MD (Host): Dr. Liotta. Thank you for that. Doctors Liotta, Graham and Koralnik. Thanks for this very informative discussion and for joining me on Better Edge.

Dr. Igor Koralnik: Thank you very much again for having us.

Dr. Eric Liotta: Thank you very much.

Dr. Edith Graham: Thank you so much.

Andrew Wilner, MD (Host): To refer your patient or for more information, head on over to our website at to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner. Thank you for listening.