NeuroVoices: Joanna Hellmuth, MD, MS, on COVID-19 Pathogenesis and Long-Term Cognitive Changes

The cognitive neurologist at the University of California, San Francisco provided insight on the research needed to explain more about COVID-19’s pathogenesis and the realistic possibility of developing neurocognitive disorders.

This is 2-part interview. To view part 1, click here.

Recently published research has identified key risk factors and abnormal cerebrospinal fluid (CSF) levels associated with cognitive symptoms after mild COVID-19 infection. The small study compared clinical characterizations of 22 patients who reported cognitive post-acute sequelae (PASC) and 10 patients who did not report cognitive symptoms. Each patient underwent structured neurocognitive interviews, neuropsychological testing, and optional lumbar puncture (LP) for CSF collection.

These cognitive issues, widely labeled as “COVID fog,” have led to the speculation that there’s a neuro-inflammatory effect happening in the brain, and, that other neurocognitive disorders such as Alzheimer disease may develop in patients who present even the mildest cases. Senior author Joanna Hellmuth, MD, MS, does not believe this is the case, however, like many others, she acknowledged that they won’t be able to see the true impact of the virus for a number of years. Hellmuth, a cognitive neurologist at the University of California, San Francisco, claimed that her clinical background in treating patients with HIV-associated neurocognitive disorders helped understand more about COVID-19 and the presentation of cognitive changes.

In a new iteration of NeuroVoices, Hellmuth discussed the current knowledge of COVID-19 and its association with neurocognitive disorders. She detailed what was observed in her study, how it compares to previously published data, and the types of research needed to further understand its pathogenesis. Additionally, the expert provided an in-depth explanation on why she assessed CSF and what the data revealed.

NeurologyLive®: Is the belief that PASC will develop into mild cognitive impairment or other predementia disorders?

Joanna Hellmuth, MD, MS: What we can reflect on is what we know about the field of HIV-associated neurocognitive disorders and the neuropathogenesis of HIV. SARS-CoV-2 and HIV are different viruses, but knowing those differences can help set the story. HIV gets into the brain very early in the course of the disease, days to weeks after infection, and typically stays in the brain unless anti-retroviral therapy is started soon. There’s a latent viral reservoir in the brain of HIV. It can be suppressed with antiretroviral medications, but there’s slightly some low level of viral replication that’s constantly causing a persistent immune activation, either in the body or in the body and the brain of people living with HIV.

For SARS-CoV-2, we don’t have great evidence that the virus is neuro invasive in most people. It might be, but LP studies typically done in hospitalized patients typically show that about 6% of people who are severely neurologically ill with COVID might get virus in the brain. The neuropathy studies have not routinely shown evidence of virus in the brain. There’s one preprint published that the jury is still out on. I think we don’t really know yet whether SARS-CoV-2 is typically a neuroinvasive virus. Knowing that, we might guess that HIV probably has more pathogenesis in the brain.

We can say, "Well what happens to people with HIV-associated neurocognitive disorder? Are they more likely to go on to develop dementia?” What we know is that people with HIV-associated neurocognitive disorder are not more likely to have a positive amyloid PET scan than those who aren’t. I have some data that’s unpublished looking at the CSF biomarkers in older people with HIV-associated neurocognitive disorders. At this point, I’ll say that we don’t have a lot of evidence that people with HIV-associated neurocognitive disorder are at an increased risk for dementia. Knowing that, my hypothesis would be that SARS-CoV-2 is not setting people up for dementia as a whole, even though there’s probably some individuals who have neuro invasive virus. Maybe not with a latent viral reservoir, but these people may have sustained quite a bit of damage, particularly in the ICU setting where hypoxia is also a factor involved.

Then we get into all the other factors that can increase risk for Alzheimer disease. We know that the cerebrovascular needs to be healthy, and that unhealthy cerebral vasculature itself can increase risk for Alzheimer disease. I’m not going to say it’s not going to cause it. For some people, it might. But my hypothesis would be that for most people who develop HIV or COVID-associated cognitive changes, that it’s not likely to set them up in the future for an incipient neurodegenerative disease. That being said, we have no idea. Everyone knows about measles and subacute sclerosing panencephalitis (SSPE), that’s years and years later after measles infection. The jury is still out on encephalitis lethargica and the flu pandemic of 1918. It’s unclear if those two were associated. Again, that was an effect that happened many years afterwards. I think there’s always the chance that many millions of people who are getting COVID might be more at risk for this, but I’m hopeful that’s not the case for the majority of people.

Can you detail the reasoning for your cerebrospinal fluid analysis? What were some of the biggest take-home points from those data?

My approach is one of trying to understand pathogenesis. First, you have to rigorously clinically characterize participants and patients, so you understand what you’re dealing with. The question is, what pathogenically is causing what we’re seeing clinically? Again, taking a cognitive neurology approach, we need to collect objective data. We need to collect blood samples and cerebrospinal fluid. We have an IRB to do brain scans, but we don’t have the funding for that yet.

By looking at CSF, we have a window in what’s going on in the central nervous system. For someone with cognitive disorders, there’s a reasonable hypothesis that maybe there’s something going on in the central nervous system that might be different. It might be similar to what’s going on in the periphery or the rest of the body. Firstly, what we did in this study was look at the basic CSF laboratory findings in people with COVID-associated cognitive changes versus not. We understood that many clinicians do not have access to the specialized research analyses that we additionally do.

The first pass was, are they different? Or are they similar? Again, these are very small numbers of individuals. We ended up reporting on 17 LPs in individuals, 13 of which who had persistent cognitive changes that we could not attribute to another cause. We had 4 individuals with COVID who did not have any cognitive changes in the acute period. Very small numbers, we need to acknowledge that. What we found was that 77% of people with COVID-associated cognitive changes who underwent LP had CSF abnormalities on basic tests, whereas 0% in the COVID control group did. In 2 of the people, we saw elevated protein levels. We looked for any other cause of these elevated protein levels and did not find them in their medical histories. Our best guess is that we are attributing these elevated proteins to perhaps inflammation in the brain, but we don’t know. It could be another process.

The rest of the individuals had oligoclonal banding patterns. People may ask why we checked this. We don’t have any suspicion that any of the people in the study had multiple sclerosis. We know that in HIV, the immune system is involved in these cognitive changes. The hypothesis being that something similar is happening in COVID. We know that there’s a lot of autoimmunity in COVID, and that the virus itself is sort of predisposed by the way its structured for our bodies to develop an autoimmune process after being exposed to this antigen. One of the questions is, are we seeing different antibody levels in the blood compartment and in the brain? Are we seeing different patterns of expected versus unexpected antibodies? We didn’t find any different IgG levels in the blood or the brain, but what we did find is that 8 out of the 13 individuals had a matched oligoclonal banding in the blood and in the brain fluid.

We don’t know if those oligoclonal bands are produced in the brain or not, but they’re likely produced systemically. There was also some low level of transit in the brain, but what that suggested is that there’s a systemic inflammatory process happening in people with COVID-related cognitive changes. We also found that 1 of the 13 individuals with COVID-associated cognitive changes had unique oligoclonal bands within the cerebrospinal fluid. That suggests a CNS-specific, inflammatory process that’s happening in this individual.

To contextualize this, we did not see elevated cell count, nor did we see any changes in the immunoglobulin index of people. There are many other factors that were not disturbed in these individuals. All we can say right now is that there were different abnormalities within the CSF, they certainly point to an immunologic direction, not with a persistent viral infection. Nothing in our study suggested that they have SARS-CoV-2 actively in the brain. We would probably see elevated white cells if that was the case. If this is true, and this is an artifact of other factors, what does this imply? All of these people were LP’d a median of 10.2 months since they were infected with COVID. This is a long time after they got COVID. To me, this implies that perhaps there are more specific abnormalities in either antibodies in the blood in the brain, or other inflammatory or immune activation factors in the brain. We’ve already gone to that second step and are looking at those factors in these individuals. It’s not conclusive, it’s a small study, but what it suggests is that immunologic factors may underlie these cognitive changes in people with COVID.

What COVID-related research still needs to be conducted?

Everyone has their particular focus, and mine has been people who develop cognitive changes after COVID who are not hospitalized. You can imagine there’s a lot of confounds in an ICU patient who later goes on to develop cognitive changes versus that non-hospitalized population, which I’ve been focusing on. It provides a pure background on investigating these questions of pathogenesis. From my perspective, the cognitive changes after COVID are quite broad, and so many people are developing them. Some people are getting Guillain-Barre (syndrome), some are getting pots, and those are incredibly impactful on people’s lives.

I’ve taken the choice to study something that is milder but affects many more people. If you have Guillain-Barre or pots, these are thing that can be more objectively quantified by testing and patients get legitimized by their medical provider. "You have a real neurologic problem.” Whereas non-hospitalized patients who develop cognitive changes, for the large part, have not been legitimized by the field of medicine. In part, because us neurologists don’t know what to do with these patients. We are not given tools to diagnose them. Right now, all we have is the World Health Organization criteria for the post-acute sequelae of COVID, which is all self-reported symptoms.

In the absence of that, I see an importance in developing more objective data to feed to scientists and clinicians so that they feel more empowered to legitimize their patient. One of the damages that’s happened now is that we’re in this environment where people have an eroding trust in science and medicine. Every time a person goes to the doctor or neurologist and says, "I had COVID and I’m having cognitive changes," we sort of just raise our hands and say, "We don’t know what do to.” It erodes that trust even further. We’re continuing in the science to legitimize this and there’s some exciting things that we’re coming up with, but the first thing everyone can do is not denounced these patients, because you don’t know what’s going on.

There’s a strong likelihood that this is a neurologic condition. Some people it might be a manifestation of stress or anxiety, or other factors. But when all of those have been ruled out, or even if they have stress or anxiety because they have cognitive disorders, we need to tell patients that we don’t know what this is but that we’re working on it. We will be there by your side, working with you to try to understand this. We need to not do more damage in this pandemic. Certainly, there’s a lot that needs to be done from a clinical research side, but until that catches up, we as clinicians need to do our part to make patients feel legitimized. We may not know what to do for them, but that doesn’t mean that this isn’t a neurologic condition.

Transcript edited for clarity. For more iterations of NeuroVoices, click here.

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