NeuroVoices: Joanna Hellmuth, MD, MS, on Recognizing, Characterizing Post-COVID Cognitive Changes


The cognitive neurologist at the University of California, San Francisco discussed recently published data on the presence of cognitive post-acute sequelae of COVID-19 and the need to legitimize these conditions.

Joanna Hellmuth, MD, MS

Joanna Hellmuth, MD, MS

Even in the mildest cases of COVID-19, some individuals have developed new post-acute sequelae (PASC) that includes persistent cognitive symptoms. Although this variance is not understood, investigators hypothesized that understanding the clinical features associated with cognitive PASC may inform groups at greater risk and highlight possible underlying mechanisms. A recently published analysis included 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild COVID-19 infection who underwent structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF).1

Among participants with cognitive PASC, 43% (n = 9) reported delayed onset of cognitive symptoms starting 1 or more months after their first COVID-19 symptom. Participants with delayed onset of cognitive PASC were younger than those with acute onset of cognitive PASC (median, 39 v 50 years; P = .04). Compared to cognitive controls, participants with cognitive PASC had a greater median of preexisting cognitive risk factors (2.5 vs 0; P = .03) with no differences in the presence of specific cognitive risk factors.

Senior author Joanna Hellmuth, MD, MS, cognitive neurologist, University of California San Francisco, feels as though these results highlight the importance of understanding and legitimizing milder cognitive conditions such as post-COVID PASC. In a new iteration of NeuroVoices, she described the reasons for the study, ties between HIV-associated neurocognitive disorder and PASC, the need to conduct thorough clinical examinations of patients and characterize the pathogenesis of the virus. Hellmuth also discussed whether assessments such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) can be used to understand mild cognitive changes.

NeurologyLive®: Why did you conduct this study and what were some of the notable findings?

Joanna Hellmuth, MD, MS: Prior to the pandemic, I studied HIV-associated neurocognitive disorder, which is a virally associated cognitive disorder that happens in about one-third of people living with HIV. Clinically, it’s almost indistinguishable from the cognitive changes we’re seeing in COVID. Coming in with that background, I took a cognitive neurology approach to the pandemic. My colleagues approached me and said we’re doing a research study on long COVID, and we’ve noticed that a lot of the participants in our study are noticing cognitive changes, so we’re wondering if you could help us out and start a substudy within our larger study. In 2020, I started a study called the Coronavirus Neurocognitive Study to try to understand these cognitive changes.

While taking it on a clinical research path, I was also seeing many patients in my cognitive neurology clinic. I see many people with HIV-associated cognitive changes, but also Alzheimer disease and all other things that cause cognitive disorders. I started to get many referrals for young and old people, as well as people in between, who had these cognitive changes after COVID. What was striking to me was that this cognitive disorder looked so much like HIV-associated neurocognitive disorder. Universally, it’s mild in most people. It is not the severity of dementia, but it is this mild, persistent cognitive disorder that many experience, with the exact same clinical pattern that was seen in HIV.

I came in knowing that it was likely a biologically based construct, as opposed to an artifact of just anxiety, depression, or stress from the pandemic. I wanted to answer questions about its pathogenesis. Those are the major questions that we have in the field of HIV-associated neurocognitive disorder. Until we understand what’s causing it, we’re not going to understand how to intervene and treat it, or even prevent it before it occurs. To me, this was an opportunity to try to understand virally associated neurocognitive disorders in a way that we haven’t before. This is not really a recognized discipline within neurology. At the moment, it falls between the fields of infectious disease and cognitive neurology. Neither have taken it on, so I’ve had this niche space squished in between the two.

I saw this as an opportunity to, in a rigorous and systematic way, evaluate people reporting cognitive changes after COVID and try to understand what’s causing this. Because so many people have been affected by COVID, we can study these disorders on a scale that we haven’t for all the others. It’s hard to get a collection of cases to study them.

Back in 2020 when I started the Coronavirus Neurocognitive Study, we wanted to take rigorous clinical characterization and match it up with the biologic measures of what’s going on. One thing we’ve learned in the pandemic is that there’s a constellation of neurologic symptoms. These sorts of long-COVID symptoms or what the NIH is calling the “post-acute sequelae” or “PASC.” These PASC symptoms are very diverse. Some people have fatigue, some have neuropathic pain, some are having pot symptoms. That’s just within neurology. My approach was to look at the cognitive syndrome as a cognitive syndrome. Let’s not try to look at all of PASC. Patients may or may not have other symptoms, we’re characterizing all of them, but the universality is that the patients are coming into this study because they have either COVID-associated cognitive changes that are persistent, or they just got COVID-19 and they say they’re doing great with no cognitive changes at all.

This isn’t a loosey-goosey question. We assess this in a rigorous way, with a structured interview that lasts about 2 hours. We ask them many questions about whether they’re experiencing their cognitive symptoms in specific domains, so that we have a clear understanding of what the patient is dealing with. All of the patients also get an in-person neurologic examination. They all get gold-standard, in-person neurocognitive testing with a neuropsychologist. We do blood draws, and then we offer the option of lumbar puncture to patients as well as CSF collection. A lot of what we’re reporting in this recent paper is some of the bigger findings from the clinical data, but also the CSF findings, which we thought were notable. The goal of this study is pathogenesis and looking into what is causing this. Until we know what is causing this, people are still going to think it’s just a psychological condition of people being stressed out. Also, we’re not going to know what to do to in terms of intervening and treating this effect.

What are some of the complexities in assessing patients who’ve had COVID-19 for PASC?

My approach is much like any other patient that comes into my clinic reporting with cognitive changes. First, you want to define the condition. We know that there are many things that can contribute to cognitive disorders. We know that there are many things that can contribute to cognitive disorders. We want to do a thorough job of crossing these off the list if we can. You want to look at all the reversible or contributing factors. You want to look at vitamin B-12, thyroid, do an RPR, as well as an HIV test. You want to evaluate if they have sleep apnea. Are they on psychoactive medications causing this? If you come to my clinic with a cognitive complaint, you deserve a brain scan of some kind. That way I can tell you, I found all these conditions, including in those who say they developed them after getting COVID-19. I found people with brain tumors. You need to check for everything first because so many people are getting COVID-19, that a lot of the usual stuff is getting wrapped up under the banner of COVID-19-related cognitive changes.

Let’s first exclude that from what’s going on. It might be COVID-associated but might not be caused by COVID. You must rule out everything else, which is why I like to look at pre-existing risk factors. We had a paper come out and one of the things we looked at was cognitive risk factors in people who went on to develop COVID-associated cognitive changes and those who did not. We found that the people who developed more COVID-associated cognitive changes had more cognitive risk factors, things like learning disabilities, ADHD, and cerebrovascular risk factors. It may be that some of these people are selectively vulnerable. At this point, that’s not actionable information, but I think that’s helpful to get the landscape of what the brain is prior to developing COVID. We’re all individuals born with very different brains. You want to understand that brain that then developed a cognitive disorder. Once you do that, you want to assess cognitive domains.

If you’re doing a thorough cognitive evaluation, you want to ensure that this is an executive functioning disorder exclusively, as opposed to another disorder. Again, people of all ages are getting these cognitive changes. I’ve seen teenagers, I’ve seen eight-year-olds. For that older population, you want to make sure that these aren’t new, executive functioning issues because of cerebrovascular disease. That’s kind of the incipient to vascular dementia, or something else like that. Additionally, you want to check if they have amnestic issues as opposed to executive function-related memory issues, potentially being a sign of early Alzheimer disease. You want to get a good clinical characterization of what’s going on.

Can we utilize cognitive assessments that are used in Alzheimer trials?

For objective data, you want to do a good neurologic examination, again, to make sure that you’re not getting signs that would point to another condition. We then refer all our patients to our in-house neuropsychological team to do cognitive testing, because it’s always nice to have a baseline for what an individual is. One of the challenges people face is thinking that cognitive testing is the end-all, be-all. I should step back and say, know not everyone has access to a neuropsychologist like we do at the Memory and Aging Center, and a lot of people ask me, what about the MMSE? What about the MoCA? Is that helpful? It’s important to think that these tools were developed to detect dementia in older people. We know that these cognitive changes in COVID can happen to any age group that I’ve evaluated. Again, I’m not a pediatric neurologist, but I’ve seen in this in those aged 18 and onward.

This was developed to have thresholds for dementia. We need to think, how would a younger person with a milder executive functioning disorder perform on an MMSE or McCA compared to a 72-year-old who is worried about Alzheimer disease? When you think about it that way, you realize that maybe these aren’t the best tools. Firstly, we know the MMSE doesn’t have a lot of executive functioning components, so it probably isn’t your go-to tool. If they have happen to have deficits, fine, but if they don’t, that doesn’t mean they’re doing great.

We published a paper in early 2021 looking at a few individuals that had both the MoCA and MMSE who went on to do a full cognitive battery. These were people who were not hospitalized with COVID, but who had reported significant cognitive issues. What we found was that they scored perfectly on the MoCA, but when you did more detailed cognitive testing on executive function, problems came out. The issue with the MMSE is that a lot of those thresholds are dialed to detect dementia. The digit you need to pass the MoCA is 3, while we know that is not normal. That is backwards for most age groups.

The approach I’ve taken is that you can do an MMSE and if you get less than 30, that may be telling. If people score perfectly, that doesn’t give you any useful information. We looked at more of the data within our study and have confirmed that these may not be great discriminators. I’m not going to make a value judgment about it, but our field of cognitive disorders has been focused on dementia, understandably, because of its huge impact on society financially and emotionally to the healthcare system. That has come at the expense of not validating and recognizing these milder, cognitive disorders that impact younger people who are working, people who have potentially decades left in the lives.

We tend to discount those disorders. We say, "well you don’t have dementia!" But in medical school or even in neurology residency, we’re not taught how to manage these or what do to for these people. From HIV, we know this is real, we know this impacts people’s lives. We know the same thing is happening with COVID, but on a much larger scale and people are not being validated by the field of medicine. Doctors don’t know what to do when they see these milder, cognitive disorders. They have not gained the medical legitimacy and even neurological legitimacy of other medical conditions. Reflect on the terminology we use. What’s the phrase people use to talk about COVID-related cognitive changes? Brain fog, right? Not a medical term, but sort of a loosey-goosey term.

There are people my age and older who remember back when you would play sports, you hit head on the field and you were a bit dazed, and it was called “getting your bell rung.” You would go back in there. We don’t call it that anymore. Mild traumatic brain injury has gained the neurologic legitimacy of other medical conditions. We treat it like a medical condition. Right now, brain fog is kind of in that space of gaining medical legitimacy. Part of what we’re doing in our study is approach this rigorously, so that we may provide the data to make people feel more comfortable. This is a legitimate neurologic disorder, and we need get to the point where we can develop effective treatments and interventions. Physicians need to feel like they have the tools to diagnose something more than “I think I have cognitive changes, help me out.” We can hopefully have a paradigm shift in the way we approach these milder cognitive disorders.

Transcript edited for clarity.

1. Apple AC, Oddi A, Peluso MJ, et al. Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19. Ann Clin Transl Neurol. Published online January 19, 2022. doi:10.1002/can3.51498
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