Decoding Long COVID’s Impact on the Brain with Igor Koralnik, MD

Erin Spain, MS: Our understanding of how viral infections can affect the brain has changed dramatically in recent years. The COVID-19 pandemic and the lingering neurological symptoms experienced by many patients with long COVID helped accelerate research in this area and led to the creation of dedicated clinical programs like the Neuro COVID-19 Clinic at Northwestern Medicine. My guest today. Dr. Igor Koralnik  is Chief of Neuro-Infectious Diseases and Global Neurology in the Department of Neurology at Feinberg and leads that clinic. His team has studied the long-term neurological effects of COVID-19, and developed tools to support patient recovery. He joins us today to talk about what we're learning from his COVID-19 research in the US and through collaborations in Columbia, Nigeria, and India, and about recent findings from his lab identifying a common virus in the brains of patients with Parkinson's disease that may influence how that disease develops. Welcome to the show, Dr. Koralnik. 

Igor Koralnik, MD: Good morning, Erin, and thank you for having me in your podcast for the second time. 

Erin Spain, MS: That's right. We had you on the show last in April, 2021, and at that time we were just beginning to understand that the neurological symptoms could persist after COVID-19 infection. So now here we are five years later. How has our understanding of long COVD, especially how it affects the brain,

Igor Koralnik, MD: So we have made a lot of progress since the early days of the COVID-19 pandemic, and we have now. Seen 3,300 patients in the Neuro COVID clinic at Northwestern Medicine. And this gives us the opportunity to understand better the neurologic manifestation of long COVID and do research associated with those. So in a series of publication, we have looked at different issues that those patients have. And for example, we have looked at the. Impact of COVID-19 severity on the neurologic manifestation of long COVID. Because in the literature at the beginning, all patients were put in the same bag. In a sense. Those who had severe pneumonia intubated in the ICU with severe complications of encephalopathy, seizures, cytokine storm and sometimes stroke with those who had a minor. Neuro respiratory representation with just cough and sore throat got better, but after that, also developed brain fog and fatigue. And so we studied the first 600 patients who came in the clinic, a hundred had been hospitalized with COVID pneumonia and 500 were non hospitalized. And we looked at the difference of demographics, comorbidities, symptoms, and so on, and we saw that all long COVID patients had not been created equal, really.We had on one hand those who were post-hospitalization, who were older, 54 in average. Who had broad neurologic and cognitive dysfunction, and also lack of insight into their neuro problem, potentially caused by CNS damage during their accurate illness could be caused by hypoxemia multiorgan failure, cytokine storm intravascular clotting, and so on. On the other end of the spectrum, those people who had only a mild initial presentation were never hospitalized, never required oxygen for pneumonia. And they were a decade younger, 45 years old in average. They were also more frequently women, 66% women instead of 58% on those who were hospitalized. And they had limited neurologic findings, but a deficit mainly in the. Tension task that we give them on objective testing, and they had a preserved insight into their neurologic problem. So the possible mechanism for those people would be maybe autoimmunity, viral persistence mitochondrial dysfunction. And also maybe a predisposition to neuropsychiatric vulnerability. So this is also crucial because it's not a one size fits all, and you're not going to be able to treat those two different population of patients with the same therapeutic modality. 

Erin Spain, MS: This idea that these are younger people, oftentimes in the prime of their life, they're working, they have families, then have this mild infection and we're talking weeks, months, years of brain fog and these other types of symptoms. How does this impact these folks in their day-to-day lives? 

Igor Koralnik, MD: Immensely for some, and this was the next study that we did with a different fellow who was working in the clinic at that time. And we looked at the impact of age on neurologic manifestation of bro COVID because we saw in the hospitalized population that those who were older tended to have worse COVID, 19 pneumonia and worse outcome. So we wanted to find out if it was also the case in those who were not hospitalized, for example. We studied the first 1300 patients who came to the clinic. 200 were. Post-hospitalization and 1100 were not hospitalized and we compared the young 18 to 44 years old, middle age, 45 to 64 years old and old, 65 and older. And so we saw that, old patient as expected, had a higher prevalence of comorbidities and also abnormal finding on the neuro exam. But it was actually the young and the middle aged patient who had higher frequency of long COVID related neuro and non neuralgic manifestation. And they also had altered quality of life and cognition in selected domains. So this study showed us that manifestation of COVID actually predominantly affect. Adults in their prime. And obviously these are the people who are working, you know, driving the, that the creative force in our society. And it unfortunately has profound public health and socioeconomic impact. And that was a paper that we published, Annals of Neurology in 2025. 

Erin Spain, MS: So you're studying these people, but you're also using some tools, some that existed that you've been able to incorporate into therapy for these folks. Can you talk about that? What are you able to offer these people that come to the clinic and are experiencing these persistent symptoms? 

Igor Koralnik, MD: So first we offer validation that their symptoms are real because so many times we have patients coming in the clinic and tell us that we are the only one you know, who actually listen to them and take them seriously because obviously on the outside they look good. The CAT scan is normal. The MRI is normal. Blood work is normal and a lot of time they hear from their physician that everything's fine with them. They should do relaxation yoga and everybody's stressed during the pandemic. And that's gonna get better. But in fact this is almost like adding insult to injury for those people who really have severe brain fog and objective cognitive dysfunction and inability to work in many cases. So what we do first, we diagnose. What they have in terms of their cognitive alterations by giving them an objective cognitive test called the NIH toolbox, which is a tablet based test that's developed actually at Northwestern in conjunction with the NIH and other collaborators where we test their processing speed, attention, executive function and working memory, we can see what modality is most severely affected. Usually it's attention, especially in young people. And we treat them with cognitive rehabilitation, which I explain to them is like PT for the brain, basically. We send them to our collaborators at Shirley Ryan Ability Lab across the street from Northwestern. It's a six to eight weeks program of cognitive rehabilitation depending on their cognitive alteration. It's administered by speech language pathologist. And we have uh, seen that this uh, is really helping them in their day-to-day function. 

Erin Spain, MS: You were also interested in understanding whether being vaccinated for COVID before infection changes, some of these neurological symptoms and people that experience symptoms later on. you published about this in brain communications. Tell me what you learned about that relationship between vaccination and long COVID effects on the brain. 

Igor Koralnik, MD: Certainly because you may remember at the beginning of the pandemic there was an urban legend going on that maybe vaccination cure long COVID or vaccination causes long COVID we didn't know. And so we also studied the first 1300 patients who came to the clinic. We thought that the vaccination before infection would actually lessen the burden of neurologic manifestation of long COVID. But unfortunately it was not the case. We basically compared pre vaccination infection with post vaccination breakthrough infection and this. Two populations were essentially similar, and that means that vaccination prior to infection does actually not affect the nor manifestation of long COVID. It's a study that was led by three medical students at Northwestern, that was published in Brain Communications in 2025. And in fact, other people have shown that the more episode of COVID-19, somebody has the higher the risk of developing long COVID. It's as if you have a river that goes up and up and at some. at some point the river goes over the dam and floods the system, right? And so we think that long COVID is an autoimmune disease, which is mediated by auto er, reactive T cells or auto antibodies. And every episode of COVID-19 raises. Autoimmunity in the system, and at some point the patient will become symptomatic. Not everybody obviously develops long COVID. But a study from the National Center for Health's statistic that was carried out in conjunction with the CDC as a household pulse study showed that. About 18% of all US adult had developed long COVID at some point, and about 5% currently suffered of long COVID. At the last time point of the study, which was in step number 2024, that means At that time, about 14 million US adults suffered from long COVID. 

Erin Spain, MS: Are people able to recover and then do they relapse when they're exposed to another version, another variant of COVID. 

Igor Koralnik, MD: So it is true that some people develop long COVID after the first COVID-19 episode. But some people develop long COVID after the third or fourth or fifth episode, and those who develop long COVID tend to have worsening if they develop another COVID-19 episode. And it's patient dependent. Obviously there are people who get COVID many time and never develop lingering symptoms. And just for the listeners, long COVID is defined as persistent symptoms more than three months after a COVID-19 episode that affects one or more organ systems. So we need to have a three month time limit and some people will still improve and sometimes they are. Completely fine after six months, but there are people who come to see us and there have been three, four years, sometime five years with those symptoms, 

Erin Spain, MS: So right now, as you mentioned, you can offer this cognitive rehabilitation therapy. But so far there isn't some sort of pharmaceutical answer to this problem. 

Igor Koralnik, MD: Unfortunately not. And we and others are doing research on that. So in terms of possible cause of long COVID one that has been looked at, is viral persistence? Does the virus remain in the system? And causes those lingering symptoms. And there have been numerous studies treating patients with longer periods with paxlovid, this antiviral medication to try to see if treatment of a latent infection could improve symptoms. And unfortunately, they have been largely negative. There is a study that is currently, enrolling at Northwestern that is sponsored by a pharmaceutical company called BIO V, which is funded by the Department of Defense using a new compound called beum. It is a novel anti-inflammatory medication that penetrate through the nervous system, and it is not immunosuppressant. And this is in a compound that is exploratory at this point. But we enrolling patient with long COVID in this study. It's a multicenter study we will see if this is efficient. In the meantime, unfortunately there's no magic bullet for long COVID, but we can help some. By patient with their different symptoms, we can help them with their headache. We can check if there are any other cause for their fatigue. For example we are doing home sleep test in those patients with fatigue to rule out obstructive sleep apnea. And we have seen that about 50% of the patient who come to see us with brain fog or fatigue also have some. Amount of obstructive sleep apnea, which was not diagnosed before. And this is something that we can treat with CPAP, for example, or an appliance. And we send them to the sleep clinic for evaluation and management. This is not caused by COVID or long COVID, but this is something that they may have had for a long time that was not diagnosed, and now we are able to diagnose them and treat them and also by the way prevent longstanding and irreversible cardiopulmonary complication for those patients. 

Erin Spain, MS: You are not only talking about patients here in the US. With your research, you've expanded internationally through collaborations in Columbia, Nigeria, and India. Why was it important to you to study long COVID from a global neurology perspective? 

Igor Koralnik, MD: I'm the chief of the division of Neuro Infectious Diseases and Global Neurology. So I was always interested in global neurology for many years. Since the beginning of the pandemic, we had the opportunity to collaborate with um, physician and scientist in Nigeria at the Lagos University teaching hospital in uh, medicine Columbia, and in JP Raan India, , and in three separate studies we have seen that long COVID also existed in those countries, which was not, definitely diagnosed before, especially in neurologic manifestation of long COVID and we published three different papers with those different collaborators. The difference between the US and those countries is that here we were first deluged with patients and then we did the research over there. You have to do the research in order to show that there's a patient population that needs to be taken care of.  Since we had all this data, we decided to compare the different countries with each other. And so this is a study of more than 3,100 patients from my clinic in the US, Nigeria, Columbia and India. And we compared those populations and we showed that there are some interesting differences in a nutshell, the richer the country, the higher the burden of Neurologic manifestation of COVID. So the. Symptom burden was higher in the US and Columbia and lower in Nigeria and in India. And when we discussed with the various collaborators in their countries, we also saw that people in Nigeria and India attended to report brain fog and less anxiety and depression and issues of mental health. And it seems that the most likely explanation are social, cultural parameters. So it is culturally accepted in the US to talk about mental health and cognitive issues, and it's not really the case in India and Nigeria.And cultural denial of mood disorders and cognitive problem is frequent in those countries. also you have to understand that people have to put this in context of their ongoing other, problems that they may face in their environment. And so for somebody living in Nigeria and India, a little bit of brain fog may mean not that as bad compared to other things that they may have to face in their environment. 

Erin Spain, MS: Clinicians in those countries might have to ask more probing questions when a person comes in to possibly diagnose them with long COVID. Is that right? 

Igor Koralnik, MD: Certainly. And it indicates that it's also not one size fits all. You have to use diagnostic tools and also approach to treatment that are culturally adapted for the environment in which you work. However we can still help those patients the same way as we're helping them here.And for example, we have a study going on in INE Columbia at the present time where we are also treating those patients with brain fog, with cognitive rehabilitation, obviously in Spanish. And the same collaborators at the Shirley Ryan Ability Lab are taking care of our patients helped us set up this treatment in Colombia as well, and we're doing now the same thing in Nigeria, but not only taking care of patient with long COVID brain fog, but also with those with post-concussion after mild traumatic brain injury because the brain fog of. Post-concussion syndrome is about the same for the patient as the one from Long COVID. And there are millions of people in Nigeria, for example, who have uh, traumatic brain injury after driving motorcycles without a helmet and having motor vehicle accidents. And those people are well known. Unfortunately, there's no specific treatment that's given to those people at the present time, and so by the way of long COVID, we are actually bringing cognitive rehabilitation in Sub-Saharan Africa that could benefit millions of people with post-concussion syndrome. 

Erin Spain, MS: So It's been six years since those first cases of COVID-19 appeared in the United States, but COVID is still circulating in our communities. It's still happening. There's fewer people getting vaccinated. From your perspective, are there still the same amount of people coming in with long COVID symptoms, or do you think this is something that people aren't necessarily thinking of right away when maybe they're experiencing some of these cognitive issues? 

Igor Koralnik, MD: That is right. People tend to have forgotten about COVID-19 and long COVID. They think it's a fact of life. I think that it's unfortunate that many post COVID clinic have actually closed their doors. So that means that, or comprehensive COVID 19 Center at Northwestern Medicine is. Busier than it used to be even for some uh, specialty like pulmonology and neurology.And since we can't see patient in televisit in every state, like we were able to do it at the height of the pandemic, now people have to travel long distance to come to see us. so it is true that it's been six years, but there are still no short answers for long COVID despite all the research. The research that we are doing also in our lab is looking at the root cause of long COVID. And the hypothesis is that it is a small vessel disease that is triggered by infection with the virus and the spike protein of the virus binds the ACE two receptor on the lining of the. Vessels, which are the endothelial cells. And one way to measure that was to do optical coherence, tomography and geography. It is a technique used by ophthalmologist to look at the back of the eye. Basically at the retina, it's a cat scan of the retina. And in a non-invasive fashion, just having the patients looking through a machine, we're able to. Do a segmentation of the full retinal slab and visualize the microvascular patterns in the this area. And we have seen in a pilot study that patient with nor manifestation of long COVID have a decrease. A vessel length density in the deep capillary plexus compared to healthy controls, which is consistent with decreased micro capillary perfusion. So that means that if there is decreased perfusion, there's less oxygen going to this in the back of the eye. That may explain the blurry vision that some of the patients have, and since we think that the eye is the window. On the brain and other organs because the capillaries are the same, then that may explain some of the problems that those patients have because of this microvascular dysfunction that can cause a symptom without the virus having to infect the bran In and of itself. so we are now doing a study looking at what we think is physical biomarker of long COVID, which is the altered retinal capillary perfusion together with what we think is a functional biomarker of long COVID. Which is a papillary reflex because those patients also have dystonia and blood biomarkers of long COVID that we have shown in the lab to be associated with mitochondrial dysfunction. Because if there's not an oxygen going into the tissues, then maybe the mitochondria are suffering and we can measure that using proteomics. And this is a study that we're doing in conjunction of using a new. App that we have created for the circumstance. It's a symptom tracker app that has been actually integrated into my chart, which is an interface between the patient and their electronic health record where they can enter their daily symptoms. Brain fog, yes. Fatigue, yes, no, and so on, and also their percent recovery. Compared to before COVID-19. So today they may feel 50% recovered tomorrow, 60% and so on. And so when they do that at home, we can see it on the back end through Epic. we have published recently that using this app we see that the pattern of recovery is not linear. There's a lot of improvements and relapses and ups and downs, which indicates that even in patient who improve, it's going to be a very bumpy road. And we've seen that women, unfortunately, are less likely than men to improve as well. 

Erin Spain, MS: This finding that women seem to be impacted more or have a more severe case of long COVID, it lasts longer, harder to recover. Do we know why this is, that there's this gender disparity. 

Igor Koralnik, MD: So we know that women are more likely than men to develop autoimmune diseases such as multiple sclerosis. Rheumatoid arthritis, lupus, and so on, and all the evidence points that long COVID is a novel autoimmune disease that mainly affects the nervous system. And this is why 66% of patient in long COVID clinic everywhere are women. And we have seen that they tend less to improve than the men. And they also, in the new research that we are just doing in the lab the first results show that they're also more severely impacted than men. So unfortunately women are also less likely to be taken seriously sometime, especially when their neurologic exam is mostly normal or their CAT scan or MRI are normal. so they have been subjected to gender discrimination by health profession. it's important for, providers to know that women are more ly impacted by long COVID and that they deserve attention and care for their symptoms.  

Erin Spain, MS: So You have been doing a lot of work on long COVID, but that's not the only disease that you are interested in. You've been exploring =how= other viral infections might contribute to neurodegenerative diseases like Parkinson's disease. Tell me about your work in identifying the human  pegivirus and the brains of some patients with Parkinson's disease. 

Igor Koralnik, MD: So you are right. We're interested in every virus and how every virus or the entire viral can affect the nervous system. And we have developed a novel assay in my laboratory called RO Fine, viral. Fine. Allow us. To detect 565 species of virus in any clinical sample. It is a target enrichment platform followed by. Metagenomic sequencing and analysis in a specific bioinformatic pipeline that allows us to do that. And we had the opportunity to study 10 brains from Parkinson's patients and 14 controls who died from other causes. And in this sample, we had three locations in the brain and we found that 50% of the brain of Parkinson's patient contained this virus called the human pegivirus and none of the controlled sample. And we also found the human  pegivirus in 30% of cerebrospinal fluid samples of those patients.Parkinson's is a neurodegenerative disease for which there is no cause, except a small percentage of patients have some genetic predisposition. But for the majority environmental factors have been hypothesized, including viruses, and when we looked at this human  pegivirus first, it's a bloodborne virus that infects, people who don't have any disease.We can find it in a small percentage of blood donors, but it was not known to affect the brain. And in few  case report is been shown to cause acute infection of the brain which result in encephalitis, for example. But it was really not on the spectrum for Parkinson's disease. And when we study those patients, and also we had access to a large database of blood sample from Parkinson's patient, we can see that this virus.Change the immune signaling in the brain of those patients and in a way that may. Leads to neurodegeneration in some who are predisposed. So at this point, it is exploratory. We don't say that this virus causes Parkinson. It may be associated in Parkinson's to the pathogenesis of Parkinson's disease in some patients, but it is still very tantalizing because the pegivirus is a close relative of the Hepatitis C virus.It's also a Flav virus for which medication are readily available. That cure Hepatitis C, and we just recently published a paper in the journal viruses where we did computer modeling of anti hepatitis C medication. Against two protein of the   pegivirus in sco and we saw that there's good evidence that those medication could also potentially be active against the human pegivirus. In addition, there are some large epidemiological study that have been done showing that people who have been treated with anti hepatitis C medication for hepatitis C have a lower risk of developing Parkinson's. that Begs the question, what would happen if somebody with Parkinson gets treated with anti hepatitis C medication, obviously, you may say that if they already have full-blown Parkinson's and a lot of death of neurons in their brain and they have already sustained a lot of neurodegeneration that may not really be useful at this time. Also, those medication are not targeting the nervous system. Obviously they're targeting the liver. But if it was possible to find those patient early on, right before they develop irreversible neurodegeneration, it would be potentially helpful for them. So we are doing more research. we have obtained a brain sample from another brain bank, not in the us. This time in Sydney, Australia, we have obtained a brain sample from Parkinson's. Patient and controls there as well. And we are looking if this is. Also the case that the human pegivirus virus  is present in those samples. 

Erin Spain, MS: Again, you mentioned that you're extending this work globally into Australia. Can you explain again why it's so important to look at these conditions with this global lens and to do this research in places outside of the us? 

Igor Koralnik, MD: Viruses are equal opportunity offenders, right? They are not worrying if people live in Africa or India or Australia. And they affect us just the same, but these are different populations. Sometimes they are subjected to different strain of viruses, or, for example, in Nigeria, the infectious milieu is different than the one that we have in the US.People as subjected to more infectious disease, and that may change the way they react to viruses. And that may also teach us different things about the pathogenesis of those viruses in this setting. The rate of mutation associated with the Parkinson's disease, the genetic mutation is also different in Africa than in the US. And that can also teach us how those people with certain mutation respond or do not respond against viruses. 

Erin Spain, MS: When you take a step back and look at all of this work that has emerged in the last five, six years, what is it teaching us about how viral infections can affect brain health in the long term? 

Igor Koralnik, MD: It teaches us that every 40 years is a. Same thing. There's a new pandemic. When I was a med student, it was the HIV pandemic and now the COVID-19 pandemic. In the meantime, we also had a Zika epidemic in certain parts of the world, and that tells us that there always going to be a. New and emerging pathogens, viruses mainly that are going to come along and mans us in various place in the world and sometime the entire world. And that we need to be vigilant and hopefully we'll be able to deal with the next pandemic better because we've been prepared with the COVID-19 pandemic. I want people to know that there's help for people who are affected, that research is being done, that even if we don't have a magic bullet to cure all symptoms of long COVID, we're still looking for the root cause. We can help. People with their cognition, we can help them with their fatigue. We can help them with their headache and dizziness, and so they should not lose hope. We continue to see patients in our comprehensive COVID center at Northwestern. Most busy clinic are neurology and pulmonology. Patients can come to see us without physician referral, and we'll be happy to care for them. 

Erin Spain, MS: Thank you, Dr. Igor Koralnik for your time today and this really fascinating look at the research you've conducted over the past six years on long c, o, and COVID-19 research. Thank you.  

Igor Koralnik, MD: Thank you for having me 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Igor Koralnik, MD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.