Is Brain Inflammation the Missing Link? Brain Inflammation Collaborative & Dr. Ina Stephens

[00:45] Dr. Linda Bluestein: Welcome back to Bendy Bodies with the Hypermobility MD. I'm your host, Dr. Linda Bluestein, and today I'm joined by my guest co-host, Dr. Ina Stephens, Associate Director of the UVA Health EDS and Hypermobility Disorders Center. We are so proud to partner with the UVA Health EDS Center to bring you conversations that connect cutting-edge science with practical, compassionate care for our community.
[01:21] Today we're joined by two incredible guests from the Brain Inflammation Collaborative. Christy Jagdfeld is a CPA, longtime patient advocate, and caregiver who has spent more than 15 years leading nonprofit organizations, advancing patient education, fundraising, and research initiatives. She co-founded the Brain Inflammation Collaborative to help drive a more coordinated, collaborative approach to infection and inflammation-related chronic illnesses.
[01:47] We're also joined by Dr. Megan Fitzgerald, a neuroscientist whose career has spanned developmental neuroscience, neural stem cells, and regenerative medicine. After developing long COVID, she redirected her research towards understanding the biology of post-viral illness, bringing together her scientific expertise and lived experience. Her work with the Patient-Led Research Collaborative, and now the Brain Inflammation Collaborative, focuses on bridging the gap between patients, clinicians, and scientists to better understand how inflammation affects the brain and nervous system.
[02:19] You'll notice later on in the conversation, I had an internet problem and I had to leave, unfortunately. But Dr. Stephens jumped in for me and finished out the episode beautifully. This is a fantastic conversation about brain inflammation, neuroscience interactions, and why collaboration across disciplines may be the key to moving the field forward. This podcast is for education only and is not a substitute for personalized medical advice. Stay to the end for a hypermobility hack. Here we go.
[02:49] Well, I am so excited to be here today with guest co-host Dr. Ina Stephens, with Christy Jagdfeld, and Dr. Megan Fitzgerald. Thank you all so much for joining me today.

[03:00] Christy Jagdfeld: Thank you for having us.

[03:00] Dr. Megan Fitzgerald: Thank you for having us.

[03:03] Dr. Ina Stephens: Great to be here today.

[03:05] Dr. Linda Bluestein: Good. Well, I'm so excited for this conversation. I think so many people are going to go, brain inflammation — what is this? And hopefully by the end of this conversation, they're going to have a much better understanding of what we're talking about and why the Brain Inflammation Collaborative is such an important organization. So Christy, let's start with you. What led you to create this organization?

[03:31] Christy Jagdfeld: My daughter was diagnosed with POTS in 2010, and it took us about two years before we were able to get some idea of what was going on. I joined Dysautonomia International as a volunteer, and as we got going, we kept learning more and more about what was going on. She ended up having EDS, mast cell, and PANDAS. At that time it was difficult to tell which symptom was attached to which diagnosis. I ended up becoming treasurer of Dysautonomia International, but wanted to do more and ended up going to PANDAS Network for a while as a treasurer.
[04:17] One of the things that stood out is that a lot of the advocacy groups weren't really working together the way that I thought they could. I wanted to have a place where research could take place while helping patients at the same time. So I met another co-founder through PANDAS Network, because I don't have a science background and I needed someone that could handle that piece of it. I threw the idea out to her and we got started in 2022, and it's been really quite the journey. Pediatrics was one thing we really wanted to include, so it took us a little bit longer to get started, but that's the gist of why the organization was founded.

[04:59] Dr. Ina Stephens: And for those that are not familiar, can you just briefly tell us what PANDAS is?

[05:03] Christy Jagdfeld: PANDAS is a neuropsychiatric disorder that happens after a strep infection. Typically it's children, but you can get it as an adult. It's often a stronger strain of strep, though they're not really sure why some people react this way, but you have a lot of behavior changes — OCD being really a big one. Those were some of the things that didn't match up with the POTS and EDS diagnosis. So we had further questions, and that's when the PANDAS diagnosis came into place.

[05:34] Dr. Ina Stephens: That's definitely something that has come up from time to time. I think we need to do a full episode on PANS and PANDAS at some point. Okay, so Dr. Fitzgerald, how did your scientific and personal experience shape this work?

[05:51] Dr. Megan Fitzgerald: I'm happy to speak about that. So I'm a translational neuroscientist and the scientific director at the Brain Inflammation Collaborative. I came to EDS research relatively recently. My training was in neuroscience and neurology, and I was doing work in regenerative medicine and neuropsychiatric disease in a hospital-affiliated lab when I became sick with COVID in March of 2020. Like so many of us who were sick then, I developed long COVID. I was fairly severe, and I became involved in the infection-associated chronic condition space, originally with the Patient-Led Research Collaborative, and then I joined the Brain Inflammation Collaborative about two years ago, very inspired by Christy's passion to include pediatrics in our research.
[06:38] I can say as well that my interest in EDS as well as long COVID is not purely academic. I am hypermobile, and before I joined this community — unwillingly, like so many of us — I didn't know that this was something that could be associated with these sorts of complex chronic conditions. It had been evaluated by clinicians. I'm obviously hypermobile and it was termed benign hypermobility, and I was very athletic, so it was never a concern for anyone.
Together with Christy, we're really interested in studying the overlap between all of these chronic conditions. The Brain Inflammation Collaborative runs a platform called UnHIDE, which is a digital health platform that brings patients, clinicians, and researchers together to capture real-world data for more than 30 conditions that we believe share at least some overlapping biological mechanisms. EDS is one of these conditions, and some of the data that we're seeing — which hopefully we'll get to speak to — is really striking.

[07:44] Dr. Linda Bluestein: I actually had a good chance to look at your whole website and I found it really fascinating — I took a lot of deep dives into it. I feel that one thing is really important for our audience that's listening. If you could — and Megan or Christy, whoever would like to answer — really explain to our listeners what you mean by brain inflammation. Are you using this as kind of an overall term? Is it neuroinflammation? Maybe distinguishing it a little bit from other known causes of neuroinflammation like encephalitis, or even brain edema that can happen post-traumatic. Just getting into a little bit of the science of what you mean by brain inflammation, including potentially imaging studies or biomarkers. I know that's a big open-ended question, so go ahead.

[08:37] Dr. Megan Fitzgerald: I can get started on this. I'm aware that when clinicians hear "brain inflammation," those are the conditions that they think of — edema, overt signs that you can see on MRIs or other imaging modalities. We're talking about something that is a little bit more subtle. This is something that I had seen in my work, gosh, since the beginning of my career — things like microglial activation that you can't see using MRI or any large imaging modality like CT scans.
[09:12] So it can be difficult to assess this in living patients, even though we are developing — or learning more about — some signs that can be accessed in peripheral blood and things like that. We're talking about microglial inflammation, and we're talking about mast cell infiltration and mast cell activation. Because that affects not just the periphery and symptoms that a lot of us experience there, but there are also mast cells in the brain that can become activated as well. So these are the more subtle signs that we are talking about when we say brain inflammation colloquially, or neuroinflammation.

[09:51] Christy Jagdfeld: And that's something that — when we picked the name for the organization — was really difficult. We went back and forth between neuroinflammation, because that's what researchers and clinicians probably prefer, and patients perhaps more so the "brain inflammation" piece of it. So it was a discussion that we had and didn't take lightly, but we landed on brain inflammation.

[10:15] Dr. Linda Bluestein: I have a kind of follow-up question to this, if that's okay. In terms of what I know about brain inflammation and looking into it as an infectious disease specialist, a lot of the literature is on animal models, on mouse models, autopsy specimens — even of humans, patients with post-infectious phenomena such as long COVID. But in the living human being there's very little data, and that's difficult to do. We can't really cut open somebody's brain or get a little biopsy just to get some data — that's not quite ethical. So I'm really interested to know if you all have been looking into different biomarkers that have already been identified in the mouse model, or that have been seen in some of the autopsy specimens, and what you think is potentially available to be used or interesting in terms of developing further research. Can you talk a little bit about that?

[11:21] Dr. Megan Fitzgerald: I think one of the most interesting advancements is, as you're saying, it's impossible to study this in living patients. I had done a considerable amount of work in mouse models as well as in autopsy cohorts for exactly that reason — you had to use tissue, you couldn't see this using any imaging modalities. But some of the newer MRIs going up to 7-tesla are able to pick up things that we were not able to see just five or ten years ago. So I'm really encouraged about some of those developments because that gets right at what is happening in the central nervous system. And I know that there are a couple of studies being undertaken on POTS and EDS where that specifically is being asked. Hopefully they will provide some answers — those studies are trying to get funding and writing grants and are underway right now.
[12:19] In terms of blood biomarkers, that's tricky. There are a number that are also in development. As far as I've seen, I haven't seen data that is super convincing in terms of measuring what is going on in the brain from the periphery. But that's not to say that it's not happening right now. Certainly a lot of these immune markers and general inflammation markers, in terms of cytokines that have been explored, do correlate with these conditions — but they're not diagnostic. So you can look and say, okay, these people have peripheral markers of inflammation, they have these symptoms that would suggest they probably have central inflammation — like fatigue, brain fog, things like that — and then on autopsy studies these things are typically confirmed. It's just difficult to do in living patients.
[13:19] And this isn't just for our world. The TBI world is affected by this as well. There are a lot of neurological conditions that can only be really accurately diagnosed postmortem, unfortunately. So it's not a struggle that just our communities face — it's something that anyone with a brain-related disorder is dealing with. This is a place where we hope to see a lot of progress over the next ten years or so. I think there are a lot of researchers now who are tuned into how neuroinflammation can impact the conditions that we're living with — these complex chronic conditions ranging from autoimmune disease to EDS. One of the most encouraging developments I've seen over the last five years is that a lot of the symptoms we experienced were psychologized, and now there is widespread acknowledgement that these are really being driven by the same inflammation that's causing the symptoms we're experiencing in our bodies.

[14:13] Dr. Ina Stephens: That's the key message right there. You just hit the nail on the head.

[14:17] Christy Jagdfeld: That's really why the Brain Inflammation Collaborative was created — trying to get at, you know, I have several family members that have chronic illness, and the mental health pieces that were obvious were going along with the PANDAS or even psoriatic arthritis. You have this autoimmune response that creates inflammation and you may be having anxiety, depression, panic attacks — and it's not because you're worried that you're sick. That's not it at all.

[14:47] Dr. Megan Fitzgerald: And I think one of the most interesting developments — and again, this is preclinical — there are some studies of endosomes in the blood that are coming from CNS, central nervous system inflammation. That's an area that I have a PubMed alert set up for, and people might be interested in looking into some of that. But it is preclinical at this stage. It's not something that can be done in the doctor's office yet.

[15:16] Dr. Ina Stephens: Can you explain what you mean by endosomes?

[15:21] Dr. Megan Fitzgerald: These are little packages of materials that, on a cellular basis — when I say little, I mean microscopic, subcellular, smaller than a cell, very very microscopic — packages of materials that can be released from the cell or used for cell-to-cell communication. I'm trained as a microscopist, so just to frame that. What some researchers are trying to do is see if these packages released from cells can be detected in the blood, and whether in neuropathological states there are differences in patients with these conditions versus controls. And can these be detected in the periphery? So you're trying to detect things that are there at very, very low levels — and that's one of the technical challenges, as well as the scientific challenge of figuring out exactly what this is going to look like from one condition to the next and one patient to the next.

[16:17] Dr. Ina Stephens: I thought it was so interesting what you were saying about the microglial activation and the role that plays with brain inflammation, because that could also explain why something like low-dose naltrexone is effective for so many people suffering from these conditions — because it does help with the microglia.

[16:37] Dr. Megan Fitzgerald: And in the PET world, again in imaging, which is very promising, they are developing some new ligands. Ligands are things that bind to cells. In PET — and I don't know if any listeners have gone in for a PET CT or a PET test — they will inject you with something that's radioactive, and whatever it binds to shows up, it's detected on a camera image. What's really interesting with microglial inflammation is that they're developing some new PET ligands — that's what they call the compound that they would inject, which has a radioactive component that can be detected with their PET cameras — and these ones specifically bind to activated microglia. I've seen some of the results for some of the original trials for these, particularly in long COVID, and it does look promising. It's not in widespread use yet, but I think it's really interesting because again, five or ten years ago I was looking at postmortem studies and counting little processes that the microglia were shooting out to determine whether they were activated or not. You can absolutely see it under a microscope, but there's no way you're ever going to get that level of resolution in a living patient.

[17:42] Dr. Linda Bluestein: And you're seeing this both in human data as well as in animal data?

[17:47] Dr. Megan Fitzgerald: The human studies, yeah. For long COVID, the microglial inflammation, yes. And just overall systemic inflammation as well.

[17:56] Dr. Linda Bluestein: I think there's some really interesting data looking at defects with neurotransmitter transmission across the microglial cells, across the neurons. A lot of that is right now still very much an animal model — and postmortem — but I think that's where we're going to be able to really say this is exactly what's going on and get to some kind of directed treatment. That's obviously the goal. Are you involved, Megan and/or Christy, in any ongoing randomized controlled trials looking at human data with some of these imaging studies or looking at biomarkers?

[18:42] Dr. Megan Fitzgerald: What we're looking at at the Brain Inflammation Collaborative is patient-reported symptom data. I do other work with, for example, the NIH's RECOVER Initiative, but the remit of the Brain Inflammation Collaborative's work is to really look for patterns in real-world data from patient-reported symptoms. We are trying to facilitate some biospecimen collection with different collaborators, but what we're set up to do on our own is handle the symptom tracking and the validated surveys. What other researchers can do is see whether their biospecimens change over time, and we're handling the tracking on our end.
[19:24] But I don't want to minimize the data that we can glean from patient-reported data as well. There's a tremendous amount of information there, and we're able to do this at a scale that wasn't available until recently. We have thousands of patients in the platform and we're seeing some really interesting patterns in this data already — just from self-reported data.

[19:49] Christy Jagdfeld: Well, one of the things that we found important is not only to connect the patients to the researchers — and maybe we can do customized questionnaires and researchers can ask specific questions — but also giving back to the patients, where they can track their symptoms and coordinate all of their health journey in one place. So you may have the symptoms you're tracking for the day, but you also have notes: something happened to you that day, you had surgery, you had an injury, you had a virus. You can make a note, and you can track your treatments and your interventions. And then when you go to see your clinician, you can print a report that shows the month, what happened, what did your symptoms do with your different treatments, with your surgery and afterwards — all of those things.
They can also connect their electronic health records so that they can see all their lab reports in one place. And Megan, you could talk a little bit about the validated survey assessments — that's how we get a lot of the questions that are asked within the platform. But patients are able to get a score that goes along with these assessments and they can track their scores over time. So if they have a clinician that uses some of these scoring systems or is interested in it, they can talk to them about it and say, this is what my score has done over the last year.

[21:18] Dr. Megan Fitzgerald: Two scoring instruments that we have that I think might be interesting particularly to this community and audience: we have the Beighton, which is a measure of hypermobility. Participants can take this remotely and report their scores, and we can track this longitudinally over time. Longitudinal data is so important because then we can see how people are doing, not only at brief momentary assessments, but as their conditions progress and as time goes on. And before these sorts of digital health platforms were around, this would have relied on return visits and follow-up appointments, which are expensive and burdensome to the community. Now people can do this remotely from the comfort of their own home, at their own time and convenience.
[22:15] Another one that we have is the Short Form 36, which is a well-validated quality of life instrument used across many disease areas. And so we can compare people with, for example, EDS to the general US population. People who enroll in UnHIDE — it's open to anybody, healthy people can use it as well, and it's a great way to support a loved one who may have a chronic condition — but many people in our platform have conditions like ME/CFS, long COVID, EDS, and autoimmune diseases.
[22:48] Now, the people who have EDS in our platform, as compared to the general US population, have physical functioning, energy, pain, and general health scores that are less than half of American population norms across the board. So that's not a subtle difference. These are the kinds of numbers that you see in really severe diseases. And I think it's important to emphasize that this is real-world data from people living with EDS today. It's not just a select trial population or a highly selected research cohort. It represents what EDS looks like when overlaid with these other chronic comorbidities in the community.
[23:27] The energy and fatigue scores were really striking to me. The average score was about 11 out of 100 for people who had EDS, compared to a population norm of around 61. That's really profound. It maps onto what we know about the overlap with ME/CFS and dysautonomia, just showing how these are not separate problems — they're part of the same picture. That's really the power of the platform that we're developing. Quality of life isn't just about one symptom set; it's about the cumulative burden of managing multiple complex conditions simultaneously. And many of these conditions are still poorly understood and underdiagnosed.

[24:05] Dr. Ina Stephens: I want to point out really quickly, because I can usually anticipate the questions, I think there are going to be some people who say, "Wait, the Beighton score? I hate the Beighton score." I just want to point out that the SF-36 is a great tool. The Beighton score has been shown time and time again to not really correlate with function. We know that over time it goes down, and you can have injuries and surgeries and things like that. So it's good that you're asking for that and having people do it. But I think some people are going to say, "Wait a minute, that doesn't really correlate with how I'm feeling."

[24:38] Dr. Megan Fitzgerald: We have seen that in some of our patient comments as well. We do allow for a self-reported Beighton scale, so if there are aspects of it that they cannot do — like bend over and touch the floor — that can be eliminated and not calculated into their score. I've seen this in the data in the first preliminary analysis, and I was like, okay, so this is what the patients were talking about when I saw this dataset. I think it is powerful because it's in there, but it also shows we need to develop a better tool. It is not correlating as well as I would have thought with measures like the SF-36, the Fatigue Severity Scale, and these other validated tools that we have in there — nor is it correlating with how patients are feeling. So we have it in there and we can track it longitudinally over time as well.
It's going to be really interesting to see, because flexibility changes even in a healthy population. But I think we can actually prove that this is maybe not the best measure for people who are really severely impacted. It might be picking up people at the beginning of their illness trajectory, but after they've been sick for a while, people can no longer perform some of the tests. There's just a lot happening in people's bodies that can make it less and less reliable over time. So we are seeing that in the data as well.

[26:05] Christy Jagdfeld: And I think that's important to note — we've talked about this being a place where we can help, where we can improve the scoring and maybe come up with a better scoring instrument.

[26:19] Dr. Ina Stephens: Right, for generalized joint hypermobility — it's not a scoring tool for EDS, it's for generalized joint hypermobility. And speaking of EDS, do you all think that hypermobile EDS, HSD, POTS, MCAS, ME/CFS, long COVID, and so on, are these separate diseases? Do you think that neuroinflammation is something that happens with most people with mast cell activation? How does this fit in with autonomic dysfunction and all of these other things? Do they have shared biological pathways? What do you think is the story there?

[26:59] Dr. Megan Fitzgerald: That's a lot of questions. For MCAS specifically, I do think that is neuroinflammation, or at least causes neuroinflammation. Are they all the same condition? Are they separate conditions? I think that's something our data can tell us, and I'm really interested to look at that, because we do have people who have only a single one of these diagnoses without the trifecta of four or five diagnoses. So I want to see over time, do they accumulate these diagnoses, or are there people who just stop at one? I don't know the answer to that, and I don't know that it is known yet.
This is something Christy is going to the EDS conference pretty soon, and this is something I think our dataset can really help to answer. Maybe some people can arrest the course of a progressive condition, or maybe some people just have the genes for one of these conditions. I don't know yet.
[28:03] One thing I can add is that we also saw neurodivergent people have higher rates of EDS in our dataset — people with ADHD and autism spectrum disorder in particular. For me that was a little bit of an unanticipated finding, but when I started reading about it I realized this actually fits into the literature really well. And I do wonder — is EDS kind of a link with the connective tissue disorder, or is the immune system causing the connective tissue issues? I think there's a lot we can look at, both in our dataset as well as in pathobiological studies. But I hope those studies will be informed by what we're seeing in terms of diagnosis and symptoms in a dataset of over 4,000 participants — about 4,200 adult participants. This is a large dataset of people with multiple comorbidities and I think we can look at that pretty closely and hopefully answer some more of those questions. The only one I feel confident saying right now is that I do think MCAS is neuroinflammation, or causes neuroinflammation.

[29:07] Dr. Linda Bluestein: I have some questions about how you're gathering the data for the surveys. The first question is: the patients who are putting their data in and giving you a diagnosis — have they been formally diagnosed by a physician with, say, dysautonomia, autonomic dysfunction, mast cell, EDS, or long COVID? Or are they giving you their symptoms and saying, "I think I have this"? That's question one. And then — you mentioned measuring this over time — how often are you asking people to put in survey data? Is it monthly? Every couple of months? Weekly? And is it just about how they're feeling physically, or does it capture emotional changes as well? Or is it primarily when something happens, like they got another virus and they're putting in new data? Sorry, lots of questions there.

[30:20] Dr. Megan Fitzgerald: A lot of this is up to the patients themselves. We aren't policing anybody — we want people to get a good return on investment for the data they're providing. As Christy mentioned earlier, we provide patients with charts of their symptoms so they can take these to their doctors. We also have score reporting now so people can see how they are scoring on these validated assessments over time.
[30:45] Each of these validated surveys has a different cadence that we tried to think out pretty carefully — what's the minimum amount of data we really need on the research side versus what would be too much of a burden for people to put in. So each of these has a slightly different cadence so that people aren't getting slammed with five or ten different surveys to answer at once. We have over a dozen surveys in the platform and they are given at a certain cadence. Some are one-time only, and then others are repeated over time. Some are asked every three months, and others every six months. The Beighton, for example, is only done annually. We have different cadences for every survey depending on feedback from the patient community as well as from researchers we work with.
[31:36] Patients are encouraged to log their symptoms daily, primarily for their own benefit — so that if they start a new treatment, they can see how they're responding to it, or if they had a triggering event, how have their symptoms responded. We do have access to the symptom data on the research side as well, so we can see how those trajectories are changing over time. But in general, we try to be very cognizant of patient burden. These conditions, as you all know, are very fatiguing, and we don't want to add any more burden. We want to make people's lives easier.

[32:12] Dr. Linda Bluestein: Survey fatigue is definitely a real thing, so I was wondering how you manage that. Thank you.

[32:23] Dr. Megan Fitzgerald: And I can say — thank you to anyone who's in the platform and filling this out. Please be aware your data is so valuable. We cherish it.

[32:32] Christy Jagdfeld: That's a really good point. We are very thankful for all of the patients that do take the time to fill it out. And one of the things — just to answer that question a little further — is we didn't want anybody to get missed if they weren't diagnosed, because you know how hard it is to get diagnosed. So we wanted people who suspected it, and you can always go back if you get another diagnosis and add that to your list. And to Megan's point, looking at some of the survey data, we might be able to see, well, it looks like this person may have EDS but was never diagnosed with it. What does that look like? There are so many doctors out there that really just think they're not seeing these patients.

[33:18] Dr. Ina Stephens: That's the ironic thing. Before we go to break, I just want to point out that the SPIDER tool is something that, although you don't necessarily need other things to add, might be something to consider, in that it has different domains — neuromuscular pain, fatigue, GI, dysautonomia, anxiety, depression, and urogenital. So that would capture a lot more than the Beighton score, which is for generalized joint hypermobility. We're going to take a quick break, and when we come back I want to really dig into what we actually know for sure, what we suspect, and what we still need to prove. We're going to talk more about brain inflammation with this incredible group after the break. We'll be right back.

[34:46] Dr. Linda Bluestein: Okay, we are back, and I know that Dr. Stephens has some great questions for these brilliant guests.

[34:54] Dr. Ina Stephens: Well, just during the break we were talking a little bit about how important it is to really study this. I feel like there is so much that we need to know — from the basic science to the surveys to clinical data — and there's virtually an unlimited amount that we need. But this is just question number one: if we had unlimited funding, what type of research would you want to do right now? How would we perform this research? Where do you think the most necessary next steps are?

[35:31] Christy Jagdfeld: There's really so much there. I really think that coordinating the research capabilities is key — there are so many different projects that have started. How can we better work together to use the dollars more wisely? That's not really answering your question about the science specifically, but it makes the whole point that we keep having different organizations start different projects and the money gets spread across all of these places. How can we collaborate together to make that better? But Megan, I don't know if you have anything specific about research that comes to the forefront in your mind.

[36:02] Dr. Megan Fitzgerald: I have so many ideas. I'll reiterate what I spoke about earlier regarding the extracellular vesicles — I can abbreviate them as EVs. It was one of those moments I had earlier this year where I had been hearing about this and was a little skeptical, thinking this is too good to be true. I emailed a couple of colleagues and asked to see some of the raw data, and it was really cool. They're also looking at these EVs for intrinsic abilities to stimulate tissue repair — so not only as a diagnostic biomarker, but also as something we can use to actually help treat these conditions. That's one reason it's such an exciting field that I'd love to see considerably more funding go into.
[37:06] Immune profiling of these conditions is another one — we know that there's so much immune dysregulation that happens, and we're at a point where we have drugs that can target specific aspects of immune dysregulation, but we don't know which patients they're going to work for. We need to figure that out. The first step is determining what manner of immune dysregulation a patient presenting with heterogeneous complex conditions is experiencing and what they're best going to benefit from. So those are the two things I would put money into right now — something to diagnose as well as something to use the potential treatments that we have right now for these complex chronic conditions. And I'm sure I'll think of many more things tonight if there were infinite money.

[37:56] Dr. Ina Stephens: No, great. I very much agree with both of you. The more heads together and the more that we can all collaborate — this is our source of funding, let's all put our heads together and get one great study going. We really need to get to the basic science of this to figure out, as we say in infectious disease, we need to know the bug and the drug. We need to know the biomarker and who is going to respond to what appropriate therapy.
[38:32] Taking care of these patients can sometimes feel like — and I know, Dr. Bluestein, we talk about this a lot — we try this and see if it works, and we try this and hope it works. We need to know which patients. And I am so appreciative of this large survey you're doing. Being able to categorize those with certain comorbidities and who may fit into a certain phenotype — even if we don't have a biomarker yet — potentially that phenotype may respond to a certain therapy or intervention.

[39:07] Christy Jagdfeld: Well, and I think the pediatric piece is important to put money into as well. There is very little pediatric research. It's difficult — you have a lot of regulations around the pediatric piece, and that was part of why our platform took a little bit longer to launch that part of it. But I think what's happening with these kids, my daughter being a good example — as a baby she had different things, and as a toddler, and our doctor explained everything away, whether it was that she was more aware of her body, she was having autonomic issues, or it was growing pains, a small stomach, you name it, it was always explained away.
[39:50] What are the things that could help people become educated about the chronic illness space so that when there is an infection, or things do escalate, you aren't blindsided? And all of your pediatricians and regular doctors have no idea how to help you. If we can get some education around what it looks like before some of these diagnoses happen — there are signs, and most patients that I talk to will tell you that.

[40:21] Dr. Ina Stephens: I am so glad that you brought up the pediatric piece, because that was my next question. I'm really interested in the research, obviously being a pediatrician. The challenge is that these children are developing these issues during key developmental times — not only physically, but their brain is developing. Could this potential infection or disease entity cause changes in their neurodevelopment over the course of their lifetime? And how is that going to manifest as an adult? I think it's very unpredictable and we need to be able to help these kids. I take care of a lot of these children, and they're missing huge pieces of their lives because they are so ill.

[41:22] Christy Jagdfeld: We have a teen group that we just started, partly to test some of our surveys and get feedback, but also to figure out how do we reach teens, how do we recruit, how do we message them. It's so isolating as a teen to have this happen, and being able to speak to other teens who are in similar situations really helps.

[41:46] Dr. Megan Fitzgerald: I couldn't agree more with both sides. For me as an adult — I got long COVID and it was months off of work, it was awful for me and my family, particularly because I was the primary caregiver of my son who was a toddler at the time. But one of the things that was in my head is: what if this happened to me when I was in high school? I was an athlete — I would no longer be able to play sports. I would miss college application deadlines. I would miss exams. All of these things that we have across childhood and adolescence are so regimented in terms of timelines. You miss events with your friends, and it's just such a different time of your life socially.
[42:33] The impact on kids and their families is just tremendous. And then you have a whole lifespan ahead of you with this question mark: am I going to be able to work productively? Am I going to be able to handle a full college curriculum, or med school, or some of these massive decisions that you have to make in your early life? Most kids who are blessed with good health don't even have to think about this. But for kids with chronic conditions and diseases, it's heartbreaking that they have to think about this and they might be judged more harshly by their peers who don't understand what's going on — and even by some of the adults in their lives and in their school systems who really don't understand what these kids are going through.

[43:22] Dr. Ina Stephens: But then even beyond the social side, there are those critical developmental periods.

[43:24] Dr. Megan Fitzgerald: Exactly. And I don't know if the audience is aware — if pregnant women get an infection during certain trimesters of pregnancy, it can lead to long-term developmental consequences. These same things can happen throughout postnatal life and postnatal development too, because the brain is developing and changing in this amazingly regimented way throughout postnatal life into our early 20s. So what happens when there's a massive inflammatory event — maybe it's an infection that triggers something, or an autoimmune disease at onset? What happens longitudinally? That has really been understudied across the world, completely understudied.
[44:13] In the studies that we do have, they tend to be observational — there was a war at this time, there was a famine, let's see what happened 40 years later to kids who had to grow up like that. And we're unfortunately going to go through a great cultural experiment with COVID as well, seeing what happened to people who were infected. It's one of the reasons the RECOVER Initiative that's tracking them is so important. But the Brain Inflammation Collaborative is looking with a much wider lens on associated conditions so we can really start understanding the impact of these critical periods of development — both the social side and the neurodevelopmental side. Intellectually, this is something I've spent my career on, but then also just being a patient now and having that insight — what these families are going through is just tremendous.

[44:58] Christy Jagdfeld: It really is. And just to any kids who are going through this — my hat's off to you for the bravery that these kids are showing just getting through the day, and the resilience that they're showing. It's tremendous.

[45:11] Dr. Ina Stephens: Well, Megan, I have to say I am so appreciative that you've just brought up all these points, because this is literally what I am seeing every day in taking care of these kids. These are questions that I'm being asked as a pediatrician, as an infectious disease specialist: what is going to happen for my child in the future? Is there anything to potentially prevent this from happening? Is there any research going on that's looking at preventative strategies for these children who may be hit with long COVID or a post-infectious phenomenon?
[45:45] They're obviously struggling tremendously. There is data now showing that children after a COVID infection are actually at higher risk to develop long COVID than adults are, and that about six million children are currently living around the world with long COVID. That's a huge piece of the population. We have to help them through this. We've got to help them neurodevelopmentally.
[46:11] And then the other piece — I'm very interested to know if you're getting some of this in your survey data — are you looking at children who developed a huge inflammatory response to COVID-19, what we called MIS-C, the multi-system inflammatory syndrome? It's very much like a tremendous inflammatory response, and even after they've recovered and don't develop long COVID, what kind of problem that tremendous inflammatory response may have caused. Are you looking at children in this survey study? How many of these patients are children, and are you looking at anything differently for them?

[47:05] Dr. Megan Fitzgerald: We only built the pediatric platform less than a year ago. And if you're conducting pediatric research, it is complicated both from an ethical point of view — because you have to get the parents on board as well as the child — and you also have to make sure that you're tailoring materials appropriately for each age group. So you've got the 13-to-18-year-olds, the 7-to-12-year-olds, and the 2-to-6-year-olds. We aren't looking at infancy in our study — it starts at 2 years old. Infants are even more challenging because they develop so quickly. So those are the different age ranges we've segmented by in our digital health study. It took a while to build the platform and tailor it for each of those age groups. We do have about 100 pediatric participants enrolled across our different diagnoses, and we are actively trying to recruit more pediatric participants across the whole pediatric span of life right now.
[48:09] I can't emphasize enough how important it is to understand what's happening. We do ask questions from both parents or caregivers as well as from the participants themselves. I do think that in some research they're only looking at one side of the coin — usually the parent-reported symptoms — but we thought it's really important whenever possible to get responses from the participants too, so it's not just an observer point of view. We want to hear from the kids and teenagers themselves, in their own words, how they're experiencing these symptoms.
[48:41] One reason for that is — if a patient comes to you, Dr. Stephens, you can be asking questions in the terminology that is most resonant with that patient depending on what stage of life they're at. How do kids describe brain fog, for example? It's one of our surveys, because it's a symptom that's very common and can be really disabling for kids who are trying to focus in school and trying to fight through this. But "brain fog" itself is such a term that kind of trivializes it, and kids might not even use that term or be familiar with it. So we're trying to understand — and that's one of our active surveys — how kids talk about neurocognitive impairments that they might be noticing and experiencing. We worked on that with a researcher at Columbia, Dr. Mara Koboldina, who is actually a Lyme disease specialist.

[49:30] Dr. Ina Stephens: Interesting. That brings up another whole point about how a child describing their symptoms — or even sometimes parental report, or report from teachers — can sound like: does this child have something like Tourette syndrome? Does this child have something like ADHD? Because it could almost be described in a very similar way. So we importantly need to develop further biomarkers and imaging studies that can really show a true difference between all these different disease and syndrome entities. A child comes in maybe with the complaint of brain fog, but they don't know how to say that. What the teacher is saying is that this child is not paying attention in school. And so the thought is, oh, this child must have ADHD. Maybe that's really not what's going on. It may be a component, but it may not be the whole story. Really being able to tease out all these pieces is where we need evidence-based diagnoses, evidence-based treatments, and evidence-based outcomes. I think we're on the track for that, but we still have a long ways to go.

[51:04] Christy Jagdfeld: Yeah, and I think it's really important that it has been elusive for a very long time — it's been 12 years for my daughter. In the meantime, it's really important to be able to succinctly put a child's description into a form that clinicians can use. And to Megan's point — how does a 6-year-old, how does a 10-year-old, how does a 22-year-old describe brain fog? They're all going to be different. A clinician needs to be able to use that information until we do have these markers and imaging to go further. Maybe it will still be elusive for another 10 years — I don't know the answer to that. But in the meantime, I think it's important to have these descriptions.

[51:51] Dr. Ina Stephens: Well, I have to say, I think that with the two of you doing this and the Brain Inflammation Collaborative, this platform and this longitudinal symptom data that you're collecting — which is huge, and you're telling me up to 4,000-plus patients — we're going to get somewhere. This is just the beginning. I'm excited to collaborate with you. I think we have a lot of work to do, but we have it laid out for us, and that's what's most important. I just don't want patients to give up hope. I sometimes hear that and I see that, and I want to say to our listeners out there that people are really energized to try to find solutions. We know what the patients are dealing with. We know how they're suffering. We know how the families are suffering. And we have to be able to find ways to help.

[52:57] Christy Jagdfeld: For sure. And I think the research piece of it — we need that data collected. This also empowers people who are just looking for an outlet. Please join our platform. There are a lot of benefits across the board.

[53:14] Dr. Ina Stephens: Well, I know that Dr. Bluestein — her internet unfortunately probably went on a lag — but I know we're getting close to our time here and I want to be appreciative of your time as well. I know that Dr. Bluestein always likes to end with what we call a hypermobility hack. So do each of you have a hypermobility hack for our listeners?

[53:43] Dr. Megan Fitzgerald: I can go ahead. A lot of our community has complex chronic conditions, so they might have EDS alongside something like ME/CFS or long COVID. And with ME/CFS and long COVID, one of the most disabling symptoms is called post-exertional malaise. You do something — it might not even be exercise. It might be just getting out of bed for people who are really severe, or for people who are more moderate, doing a load of laundry. Nothing that a healthy person would consider exercise, but it's exertion and it can trigger flu-like symptoms. You want to avoid that because that's an increase in inflammation.
[54:21] At the same time, there are certain exercises that can be really beneficial for hypermobility as well as for POTS. So what I would say for people who do have these complex comorbidities is to make sure to pace. If you want to try any of these exercises — they can be beneficial for a number of symptoms people might be experiencing — pacing is just incredibly important. What that means is start off very small with a very small movement, just a little bit, maybe 10% of what you hope to achieve eventually. See how it goes. I do think this is the power of symptom tracking apps like the one that we have, because you can really say: this was my treatment this day, I did a little exercise, and you can see how that looks in your own health data for a couple of days or even a week afterwards. Then you can build up from there. The pacing component is really important whenever you're introducing exercise into ME/CFS or long COVID. But at the same time, I have seen people who do benefit from certain targeted exercises — not graded exercise therapy, not anything like that, but using your own wisdom and knowledge of your body to try to track your progress and help manage comorbidities like EDS and POTS.

[55:38] Dr. Ina Stephens: I love that. That is a great hack. And it's not just a hack, it's a treatment modality that I talk about every day. Thank you, Dr. Fitzgerald. How about you, Christy?

[55:51] Christy Jagdfeld: Mine's not quite as detailed, but I did talk to my daughter a little bit about this. There were actually two things. She had a lot of trouble with temperature regulation, and we had this gel neck and shoulder wrap that you keep in the freezer and take out. Whenever things seemed really, really hard, she would put that on and get her core temperature back, and things were a little bit easier.
[56:18] The other thing is she is super sensitive to mattresses and sleeping surfaces. She's actually sleeping at someone else's house right now for an internship, and she bought one of those eggshell or memory foam toppers. It has made all the difference for her. She's extremely sensitive to hard surfaces. So those are probably her two favorite things.

[56:46] Dr. Ina Stephens: Oh, those are great hacks. There are so many little tools and things that patients have shared that have helped tremendously. I'm going to ask if you could send a link to what exactly this product is for the show notes, because I know that Dr. Bluestein has a whole list of her products that you can access through the show notes and even on the Bendy Bodies Amazon link. So if that can help any of the listeners, that would be great. And the last thing I know is so important — how can people find you? How can people get involved? How can they potentially sign up to be part of this survey and part of this research? How can they learn more about the Brain Inflammation Collaborative? Please, go ahead.

[57:49] Christy Jagdfeld: To sign up for our research, you can go to unhidenow.org and there's a sign-up button. There's some information about eligibility and an overview of the study itself, but the easiest thing is to click the sign-up and you will consent, create an account, download our app, and be able to start tracking symptoms immediately.

[58:12] Dr. Megan Fitzgerald: We also have another website called braininflammation.org, and that is our main educational and informational site. We have the separate unhidenow.org for our science piece of it.

[58:25] Christy Jagdfeld: Yes, and we have contact us forms if you ever want to get in touch with us as well.

[58:29] Dr. Ina Stephens: Great. Well, thank you both so much. We really appreciate talking to you, and I'm personally really looking forward to working with you in the future.

[58:57] Dr. Linda Bluestein: Thank you for listening to this week's episode of the Bendy Bodies Podcast. You can also help us spread the word about connective tissue disorders by leaving a review, sharing this episode, or sending it to someone who needs it. These small actions truly make a difference in raising awareness about conditions that are still widely misunderstood. And don't forget, full video episodes are available every week on YouTube at Bendy Bodies Podcast.
[59:34] As many of you know, my passion is helping people better understand and navigate symptomatic joint hypermobility. In addition to my clinical and educational work, I offer one-on-one coaching, professional mentorship for healthcare professionals, and expert witness services. If you'd like to learn more, please visit the services page at hypermobilitymd.com.
[59:54] You can find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, X, and LinkedIn, all @HypermobilityMD. As part of our collaboration with the UVA Health EDS and Hypermobility Disorders Center, we also want to share a few helpful resources. For questions or appointment inquiries, you can contact them at [email protected]. That's the letter R, [email protected]. Or call 434-243-8200.
[1:00:26] Our incredible production team is Human Content. You can find them on TikTok and Instagram at Human Content Pods. We love bringing on guests with unique perspectives to share. However, these unscripted discussions do not necessarily reflect my views or opinions. Furthermore, perspectives expressed within Bendy Bodies media, including this podcast, do not reflect the views or opinions held by Human Content Inc. Although we may share healthcare perspectives on this podcast, no statements made on Bendy Bodies should be considered medical advice. Listening to or watching this podcast does not constitute a doctor-patient relationship. Please always consult a qualified healthcare provider regarding your own care.
[1:01:03] For information about the Bendy Bodies program disclaimer and ethics policy, submission verification and licensing terms, HIPAA release terms, or to get in touch with us, please visit bendybodiespodcast.com. Bendy Bodies Podcast is a Human Content production. Thank you for being a part of our community, and we'll catch you next time on the Bendy Bodies Podcast.