Busting Common EDS & MCAS Myths with Dr. Dacre Knight

[00:10] Dr. Linda Bluestein: I think understanding that you can have damage in your body but not have pain, and you can have pain and not have damage, is a very important concept for people to understand and an important myth to discuss. Welcome back, every bendy body, to the Bendy Bodies Podcast. I'm your host, Dr. Linda Bluestein, the Hypermobility MD. A Mayo Clinic-trained physician dedicated to helping you navigate Ehlers-Danlos syndrome, joint hypermobility, and complex chronic illness. Today, I'm joined again by Dr. Dacre Knight, who is not only an expert in EDS, HSD, POTS, and mast cell disorders, but is also joining me as a recurring co-host. Today, we are going to be talking about some common myths related to EDS, HSD, POTS, and MCAS.

As always, this podcast is for educational purposes only and is not a substitute for personalized medical advice. Stick around until the very end so you don't miss any of our special hypermobility hacks. Let's get started.

Well, I am so excited to be back with Dr. Knight, who is the medical director of the UVA Health EDS and Hypermobility Disorders Center. Thank you so much for joining me again.

[01:37] Dacre Knight: Thank you. Yeah, always a joy and a pleasure to be here.

[01:39] Dr. Linda Bluestein: Wonderful. Well, I'm super excited about this conversation because we hear so many different myths, right? Myths about EDS, myths about joint hypermobility and POTS and MCAS and all the things. So we're going to talk about a lot of those myths today and see how many of them we can bust.

[02:04] Dacre Knight: Mythbusters, the EDS version, right?

[02:04] Dr. Linda Bluestein: Yes, exactly, Mythbusters EDS version. So I want to start with one of the really important ones, and then we're going to get into some more general things — maybe things you feel like you really want to say, hey, this is a myth that I hear all the time, let's just clear this up once and for all. But let's start with something kind of specific, which is why people say, oh, well, EDS isn't serious unless it's vascular. I feel like this is a myth that persists. And of course we know that vascular EDS is very serious, but so are the other forms of EDS. So what are your thoughts about that myth?

[02:41] Dacre Knight: Well, for sure. And that is a myth indeed, because how do we put it in context of what's serious? I think that's the question, because historically, my take on it is that medicine has defined severity by immediate mortality risk, right? We think about emergency situations, chest pain, right? Call 911. And so there's kind of this relationship, but it hasn't really had that relationship with long-term disability.

And that's where we see the hEDS and the hypermobility disorders fit in, because while yes, vascular EDS and some of those other rare severe types certainly are dramatic and life-threatening, these other types — the common types — they can certainly cause chronic multi-system impairment that is less visible. But it certainly has a tremendously profound impact, and that impact is long-lasting.

[03:36] Dr. Linda Bluestein: And I'm sure you've had patients and/or heard stories about people who have passed away related to complications from EDS, right? So even though hypermobile EDS itself is not technically considered life-threatening — although my life insurance company sure did view it that way when I was trying to get life insurance and they saw hypermobile EDS on my medical records and they didn't want to insure me. So that was interesting.

[04:08] Dacre Knight: Yeah. Well, that's the whole point of what we try to do — recognize it when it is manageable, right? Because it's not severe until it is. And we don't want to let it be severe.

Dr. Linda Bluestein: Right. Exactly. And there are people that have, because they've ended up with central lines and things like that, and then they get an infection or get septic or whatever — there's a number of cases that I am aware of, of young people, people in their 20s, that have passed away due to complications from hypermobile EDS. So it's just so important for us to know that these conditions are definitely serious. They can carry some very serious complications. And for our clinician colleagues to be aware that, especially as we talked about in a previous recording, especially when we don't address things at an earlier stage, that can lead to other sequelae that can really be problematic.

[05:02] Dacre Knight: Absolutely. And as we just said, we don't want it to be problematic. So that's why we have to do our due diligence to recognize these things as early as possible.

Dr. Linda Bluestein: And there are a lot of myths around genetic testing also. So what do you want to say about the myths about genetic testing?

Dacre Knight: Well, I think what underlies this topic is the question about testing in general — when we come to treatment or testing, we want the quickest answers. We want the most complete answers. We want the best description of what's going on. And the problem is genetic testing, while it can be very accurate, very specific, and if we're looking at specific mutations or variants on specific genes, it can answer a lot of questions.

We have certain subtypes and identified mutations for those subtypes, but it cannot rule out conditions like hypermobile EDS where the genetic basis is still unknown. And hypermobility spectrum disorders are likely much more multifactorial than just genes. There may be an influence of epigenetic or environmental exposures that affect our genes, and so that differs from person to person depending on whatever conditions they're living in. So while genetic testing is helpful, it's not always as helpful as we want it to be.

[06:32] Dr. Linda Bluestein: And when do you think that genetic testing is indicated in people who are presenting with symptomatic joint hypermobility? Because I feel like, at least for me, that needle has moved over time. So what are you currently doing about that?

[06:51] Dacre Knight: Well, as the proverbial needle moves, I would love to see it continue to move in the direction where we have more testing capabilities — quicker, easier, more accurate genetic testing — because I think it can fit in well into a precision model of healthcare where we're able to do some testing to figure out the differences from one person to the next. We're not all the way there yet, but I'm hopeful that's where we'll get.

So right now, where we are is we have to look at the patient and their medical history and their family history to infer any red flags that may be evident. History of sudden death in someone young in the family, history of aneurysms in immediate family members — when we talk about immediate family, meaning parents, siblings, and children. Those can inform us whether there is a genetic disease that may be present, that may be found on genetic testing. But ultimately, if we have a negative test result, that doesn't mean you don't have EDS or hEDS or hypermobility spectrum disorder. So we always have to be thinking about that next step too.

[08:01] Dr. Linda Bluestein: And I think that's another one of those myths that continues out there, which is that a geneticist is required in order to diagnose hypermobile EDS or HSD. Neither of us are geneticists, and of course we have diagnosed plenty of people with hypermobile EDS and with HSD. So I think it's just important for people to be aware that what really is required is a person who has, first of all, the ability to diagnose — so the person has to be an MD, a DO, it could be a nurse practitioner or a physician assistant. Those are basically the four categories. And then the person has to have the right knowledge and training and time to do the proper assessment in order to make the diagnosis, but they don't have to belong to any particular specialty.

Dacre Knight: Right. And certainly in areas where there is still a huge unmet need, it's really any specialty who's willing to take the time to learn and understand and educate themselves on the diagnostic evaluation, the criteria, and things like that — it can really be any of those, like you mentioned.

Dr. Linda Bluestein: Yeah. Because that's another myth — that these conditions are rare. That's probably the biggest myth there is. And also that a lot of clinicians won't be seeing patients with these conditions. But I would argue that every clinician, regardless of your specialty, virtually every clinician is going to see people who are somewhere on the spectrum of symptomatic joint hypermobility, whether they meet the full current 2017 diagnostic criteria for hypermobile EDS or not. Of course, we have the road to 2026, so we'll see what that new criteria looks like. But regardless of your specialty, if you're a clinician and you're listening to this right now, I pretty much guarantee that you have these patients in your practice. And once you start seeing them, you won't be able to unsee them.

[09:55] Dacre Knight: And ideally then you can provide them the tools and resources to help them. I think patients just understanding that there is someone who's learned and listened to them and has the knowledge to try to help them, rather than just referring them on to the next provider — that's a huge bonus for those patients.

[10:18] Dr. Linda Bluestein: So a lot of times patients will come to me for their first appointment and they will share results from direct-to-consumer genetic testing. I really worry about the accuracy of those results, and I have discussed that with both Dr. Claire Francomano and Dr. Paldeep Atwal. What are your thoughts on those types of testing processes?

[10:40] Dacre Knight: Yeah, I'm in the same group of thinking as they are. And I generally find them less helpful than helpful in my practice. There are a couple of things at hand. One that you mentioned is it's hard to discern the reliability of that testing site and what they're doing and how they're doing their testing — and that can vary. I mean, there can still be some good ones out there. But there's also this added anxiety that comes with unexplained test results and what they mean.

And that's not to say that we want to ignore the fact that there may be something at hand. We just want to go through it in the right process where patients can get the counseling and feedback that may come with any result. That's part of the whole consenting process we go through when we consent patients for genetic testing — their awareness of what they may or may not find, and the ramifications of testing.

So I'm generally pleased to see that the technology is expanding and growing in availability and the cost is coming down. But I think we still have to be very careful of how we're doing it. And as the analogy of snake oil salesmen has been around for many years, there are still plenty of people who would be very willing to take your money if they are espousing these great visions of all the answers being explained to you through whatever testing service they offer. So just be careful of it. And we certainly as providers want to have everyone as informed as possible, and we can counsel them when they see us.

[12:34] Dr. Linda Bluestein: Yeah. And I've noticed too that they'll often have a little asterisk at the bottom — "not to be used as medical information" or something like that. But at the same time, they'll say, "this gene is consistent with hypermobile EDS." And it's like, well, wait a second, we don't know the gene or genes for hypermobile EDS yet. So that's something that definitely needs more study and exploration, because people are desperate and they are resorting to more and more of those kinds of tools on their own.

[13:11] Dacre Knight: Yeah. I've seen that a lot for sure.

[13:12] Dr. Linda Bluestein: What other myths do you hear commonly about EDS and HSD?

Dacre Knight: Well, a lot of what I was just talking about earlier is related to the impact of the disease. And I think we talk about invisible illnesses — that's a very good description — but I think there's a better way that we can explain it as researchers and clinicians.

This is part of some of the research we're doing at the University of Virginia: to understand that, at least if we can try to add some clarity on the impact of disease — if nobody believes us that the symptoms are real and the symptoms are severe — how can we define it as the impact on someone's not only quality of life, but also what they do as an occupation? And clearly there will very likely be an impact on their work, on their workability. This is some of the recent data we've been collecting — how these conditions impact someone's ability to work, whether it's work hours lost or job promotions not achieved. There are a number of ways we can look at it. Other conditions in a similar sequence have highlighted that too.

So the long-term disability effect, as I was alluding to earlier — that is a myth that it's not serious. Yes, we need to put all the funding and effort we can into understanding dementia and cancer and all of these other things. But there's certainly no reason to ignore this and minimize it, because there is a profound effect on patients' lives.

[14:50] Dr. Linda Bluestein: And often very, very young people's lives. So they have many decades ahead of them. If we can get them feeling better and functioning better, that's a huge win for many, many decades. And if not, then it is important for everyone — the family, the person themselves — to understand that these conditions can be extremely disabling. So you're already researching this at UVA, since you started there not too long ago.

[15:18] Dacre Knight: Right. Well, these are some of the research ideas we'd already started from Mayo Clinic and we've just continued on that. And I know others are interested in this too. We have a large dataset that we can interrogate, and I think that will be effective because, really just as you mentioned, we as human society are only as good as how we can help those who are the sickest or the weakest, who are the most in need. So what can we do at least to highlight that there is a need here to begin with? And then we can hopefully focus more resources and funding into getting better research and better treatments into the future.

[16:04] Dr. Linda Bluestein: Fabulous. Let's shift gears a little bit and talk about dysautonomia and specifically POTS, because postural orthostatic tachycardia syndrome is something that we see a lot in our patients with Ehlers-Danlos syndromes and hypermobility spectrum disorders, et cetera. We know that POTS is often dismissed as, oh, well, you're just deconditioned. So what would you say to clinicians who think that POTS is just deconditioning?

[16:32] Dacre Knight: Yeah, it is that and a lot more. And I think that is probably linked to some early research linking symptoms to deconditioning — reduced fitness overall. And then clinicians and laypeople focus on heart rate changes. So we get specific parameters and specific diagnostic criteria, and we could go into a whole other discussion about the pros and cons and the advantages and pitfalls of diagnostic criteria. But one of the big pitfalls I would say is seen here in this area of POTS, and that is that the broader autonomic disorders and the broader systemic context are lost in that.

[17:18] Dr. Linda Bluestein: Yeah, that's really important. I think that sometimes people get sent to the cardiologist and the cardiologist may or may not do orthostatic vitals in the office. They might do them briefly — they don't do them for the full 10 minutes after the person is standing. Or even if they do diagnose the person with POTS, this has happened with a lot of my patients where they are left to believe that they have a cardiac problem and not a neurologic problem. And like you said, not understanding that this actually affects your entire autonomic nervous system — the automatic nervous system, which controls your digestion, your breathing, your heart rate, blood pressure, temperature regulation, et cetera.

So yeah, I feel like it's so important for other providers to realize that, especially since we've had the COVID pandemic, POTS and other forms of dysautonomia are much more common than they used to be. And it is a spectrum like everything else. So it's really important to recognize when people are somewhere on that spectrum, because there's a lot that we can do to help those patients.

[18:31] Dacre Knight: Yeah, that couldn't be more true. There has been some very good research coming in on the COVID effects of causing autonomic dysfunction. And I think we then have a better understanding altogether that, while the criteria is useful — certainly for clinicians, and maybe those inexperienced clinicians, to know when things are present or not present — we have a better characterization overall outside of those criteria of what patients look like and what their symptoms are.

Because I think what we go back to a lot, and we want to encourage patients on this message too, is that the symptoms are there whether the criteria is met or not, right? Your symptoms are your symptoms. And if the criteria is the issue, that's the criteria — that's not a fault of your own as a patient. It's upon us as clinicians to understand those symptoms and what they may be related to, and ultimately how we address them.

[19:34] Dr. Linda Bluestein: Yeah, most definitely. Because that's the thing with the criteria — okay, if your heart rate is supposed to go up by 30 beats per minute but it only goes up by 28 beats per minute, does that mean you don't have POTS? And that could be very frustrating for a lot of people. I know people who have been assessed for POTS, told they had POTS, and then went back for a follow-up, did a repeat tilt table or something, and were told, "Oh, you no longer have POTS." And they're like, "Wait — what do you mean? I still feel terrible. How could I no longer have POTS?"

[20:03] Dacre Knight: I was discussing this very topic with some colleagues, and there's actually now some pretty good data on it looking at those heart rate figures. For some groups of younger patients, they looked at using 100 beats per minute as a cutoff — which we typically define as tachycardia, right, anything 100 and above. Then the question is: is there a difference in symptoms with that predefined tachycardia measure? Is there a difference above it versus below it? And the fact was there was no difference in the symptoms and the overall presentation just based on that heart rate cutoff of 100 beats per minute. So we have to be very careful when we make those judgment calls.

[20:44] Dr. Linda Bluestein: Right. And then the other thing I'm thinking of as you're saying that — a lot of people, even if we leave them supine, and I like to have people lying down for like 10 minutes before I check their baseline vitals before I get them up — a lot of people are anxious about the fact that you're going to be doing this, either a tilt table test or orthostatic vitals. So maybe their heart rate is going to be faster than it would normally be anyway. So looking for that difference of 30 or 40 beats per minute depending on their age might be harder to find.

[21:17] Dacre Knight: Or how about patients who have maybe already had some idea that this may be what they're suffering from and they either take it upon themselves to learn about it and then treat it? So it improves some of their symptoms a little bit. Maybe they're taking extra salt or fluid or things like that, and then they go get testing and the testing's normal. And then what do you say about that? Well, okay — you're treated, or you have the condition. Being told that you don't have the condition isn't correct. So it really has a lot of nuance to it.

[21:48] Dr. Linda Bluestein: Right. And I know there was a study that looked at patients with POTS and showed that, at least in some people, their heart rate increase actually started before they actually did the tilt. And some were saying, well, that must be psychological. But if you think about it, there's a lot that goes into your heart rate. It could be a conditioned response — well, every time I stand up, my heart rate goes up, and now they're going to do this to me. It's kind of like if you have insomnia and then you get in bed — you're not going to sleep well because you associate your bed with not sleeping well.

[22:20] Dacre Knight: Yeah, exactly. And that's why in some of our best research studies we have to control for placebo and other variables as best we can, because it clouds the picture. And the same is true when it comes to diagnostic testing. So yeah, we have to be very mindful of that.

[22:38] Dr. Linda Bluestein: And when it comes to POTS, as you were saying, clearly this is a multi-systemic problem. It's not just a heart rate problem, although the heart rate is definitely one of the things we see impacted. I often use the COMPASS-31 as one of my scoring or monitoring tools. Do you use that or do you use something different? Because I know there are multiple different tools out there.

[22:59] Dacre Knight: Yeah, I use the COMPASS-31 too, and none of them are perfect, but I think it does give us some objective measures so we can get an idea of what's going on. And that's really the way we need to consider diagnostic testing in general — it is added information. It's all helping us paint a clinical picture, but we ultimately have to use our judgment in how we piece that data together as clinicians.

[23:24] Dr. Linda Bluestein: Let's switch gears and talk a little bit about mast cell activation syndrome. Talk about something that definitely can be controversial, right?

[23:39] Dacre Knight: Oh yeah, that's right.

[23:39] Dr. Linda Bluestein: Yeah. It is so tricky because there are schools of thought where you'd have to meet more strict criteria, and there are schools of thought where maybe we need to be capturing more people, casting a wider net, because some of the treatments can be so safe. And why do you think that MCAS is so controversial?

[23:54] Dacre Knight: Well, I think controversy lies in lack of understanding and knowledge just to start with, right? And lack of evidence — that's always a very vulnerable area to start a controversy between conspiracy theories and anything else. So I think that's a starting point.

Diagnostic criteria are out there, but they're still evolving. Testing is certainly imperfect. And the symptoms themselves overlap with so many other things. We talk about mast cell symptoms and you can't target just one organ or just one body system because it really — I mean, we talk about EDS and HSD being connective tissue from head to toe, but with mast cell it really goes across the board. And so I think that's why.

[25:03] I'm an advocate of: let's do the research, let's get the knowledge improved, and let's understand these conditions better. And I think we understand them not by ignoring them, but by looking into them and keeping an open mind and bringing in all considerations that we can.

[25:21] Dr. Linda Bluestein: Yeah, totally agree. We need so much more research when it comes to these three components of — if you want to call it the triad or the trifecta, some people call it the evil triad. So many people are being impacted and having their quality of life affected. We desperately need more research, more information. And that's why it's so exciting what you're doing at the University of Virginia, because I think your work has already helped a lot of people, but it's going to help a lot more.

[25:52] Dacre Knight: Well, that's what we want to do. And you know, that's what we want to do here with this podcast — help and educate. And you had a very good session with Dr. Afrin. I think anyone who is brave enough to go into the field of understanding mast cell activation is doing a great service to us all, because as I just said, you can't shy away. Ignoring the problem is not going to make the problem go away.

And it is a real problem when there is controversy, because what we end up with is really two schools of thought as you described — one has been labeled as a group with very strict criteria that is underdiagnosing patients, and then that group sort of frames the other group as having criteria that's too loose and overdiagnosing it. And whatever the case may be, patients are the ones left to suffer when they're on either end. So we really have to narrow that gap.

I applaud anyone who's willing to take the time to study and look into it, because there is a lot of effort going into understanding mast cell activation better. And personally, I share a similar approach to your guests who have discussed mast cell activation — Dr. Molderings and Dr. Afrin — in that I personally just really want to help the patient. What can we do to that end that's safe and effective and is going to afford them the best outcome? To get them back to functioning with ease, without all of these symptoms that may be related to mast cell activation.

[27:40] Dr. Linda Bluestein: I agree. I often tell people, let's worry less right now about whether you actually meet the criteria for mast cell activation syndrome, or whether we're going to call this mast cell activation unspecified, and let's start to work on improving some of your symptoms. We can focus on the labels later. And I know some people would disagree with that approach — they feel like the diagnosis is important to establish first. But like you said, at the end of the day, it's about the patient and what we can do to improve their quality of life. Because usually by the time they get to us, they're really suffering, and they've been suffering for many, many years, and in some cases decades.

[28:22] Dacre Knight: Yeah, exactly. And we don't want to see any more suffering. The misconception with taking the right or wrong approach — just like we were talking about genetic testing — is that if the lab tests are inconsistent or negative, the misconception is then the disease must not exist. But the reality is that there are so many other complexities to the disorders we're discussing — HSD, hEDS, and mast cell activation. These are biologically complex and episodic. And so the testing is not going to give us all the answers that we want it to at this point. I'm hopeful for the future when we get there, but right now, we're not there.

[29:14] Dr. Linda Bluestein: Wow. You just hit the nail on the head. I think that's so important. So often people think that we live or die by the test results, but every test has limitations, right? Whether it's imaging or labs or whatever the case might be. That's so important. You said this at the beginning of our last conversation — about listening to the patient and William Osler's quote: listen to the patient, they're telling you the diagnosis.

[29:39] Dacre Knight: Yeah, that's it. And we have to think about every patient because every patient has a different story. And you know, I honestly dislike the concept of spectrum diseases — autism spectrum, hypermobility spectrum — because I think it exhibits our lack of knowledge and we just throw "spectrum" out there and it captures everyone. Eventually I am hopeful that we'll get to a point where we have better classifications.

But right now we do have to understand that it is a spectrum because there are certainly different presentations — some more severe, some milder. And so we as clinicians have to understand the clinical patterns and what treatment response may be elicited with whatever treatment tools we have in every individual setting.

[31:08] Dr. Linda Bluestein: We're back with Dr. Knight, and I just wanted to talk a little bit more about mast cell activation syndrome and mast cell activation, just because I feel like this is an area that is so full of myths. I'm thinking back to when I first heard about mast cell activation syndrome. I was thinking, wait a minute — it feels like they're lumping just everything, right? You could have constipation, you could have diarrhea, you could get full easily, you could eat a lot, you could gain weight, you could lose weight. Like, this is everything. So how do you think we should be thinking about mast cell mediated disease?

[31:56] Dacre Knight: Well, I think we should start with that thought in mind — that there are a lot of things that can be lumped together. And that's generally the approach we take with matters related to EDS and HSD: there can be so many things that it's causing, so we want to start by casting the widest net, right, to try to include as much as we can. We talked about Occam's razor before. But in doing that, that net is also meant to catch anything else that could be causing those symptoms — other organic dysfunction in the body, other organ systems, other autoimmune diseases, other allergic immunologic conditions that can fold into it.

So I think that's the right approach. We do lump things in general, but what we want to get to is: okay, we can work on differential diagnoses all day long, but what is that going to get us towards in terms of the next step in treatment? Fortunately, in this area of controversy related to mast cell activation syndromes, a variety of treatments can be used, and some of the first stages of treatment are relatively safe. So I'm comforted by knowing that we can start with treatments that are safe and easily accessible enough, and we can find some responses in those patients. But there can certainly be more severe cases that are treatment resistant, and then it gets pretty quickly tricky.

[33:34] Dr. Linda Bluestein: And it makes sense, right? Because mast cells are present where we interface with the environment — on the skin, in the digestive tract, in the genitourinary tract. They can create a lot of havoc in the body. And of course, lying next to nerves and affecting connective tissue — we know this is so intertwined, which makes it really challenging to sort things out. But it's also a very exciting time to be in this space.

[34:04] Dacre Knight: Well, yeah. And that's really what excites me the most about what we're doing here at the University of Virginia, and what I'm working on with other colleagues at other institutions across the country and with my colleagues still at Mayo Clinic. That is understanding the human body — the human condition — better in general.

We are far from knowing everything there is that can be causing problems and symptoms in any human being. And if we get to a place where we are understanding the pathophysiologic mechanisms — meaning the steps and sequence to disease — and we get a better understanding of that, then when we get to better treatments, I think we arrive at a better understanding of precision medicine at our disposal. We are better at understanding one individual's condition and experience versus another based on what you hear about as the omics — their protein structures, their genetic makeup, the exposures and environmental conditions they've been exposed to. There is so much we can do with that. And that's what really excites me the most about this research and going into this field — I think we're unlocking some very big answers for anyone working in the medical field.

[35:31] Dr. Linda Bluestein: Most definitely. I also want to talk about pain, because we know that is such a common presenting concern for a lot of patients who have hypermobile EDS and HSD especially, but of course other forms of EDS as well, and other connective tissue disorders like Marfan syndrome, Loeys-Dietz, et cetera. I know that when I first learned — I was working as an anesthesiologist, I had been in practice for a number of years, but I was having so much pain myself. And I actually watched a lecture by Dr. Dan Clauw, who you probably know.

Dacre Knight: Yeah.

Dr. Linda Bluestein: Fibromyalgia.

Dacre Knight: Guru.

[36:09] Dr. Linda Bluestein: So I was watching a lecture by him on YouTube and it just blew me away, because I hadn't really studied pain processing for many years since my residency. And when I heard that pain does not equal structural damage — that there are all these other factors involved in pain processing — that was really a pivotal moment for me in improving the pain I had in my body.

And I think this is one of the biggest myths that is important to correct. It's not that you're making it up. It's not "in your head" in the sense that you made it up. But understanding that you can have damage in your body and not have pain, and you can have pain and not have damage, is a very important concept for people to understand and an important myth to discuss.

[37:02] Dacre Knight: Well, yeah, absolutely. And this is a huge paradigm shift in medicine in general and our understanding of pain. And I don't think we've really grasped it all. I don't think we've accepted that shift so much in medicine and healthcare.

And really, I should ask you, Dr. Bluestein, since you're the expert on this — I've actually learned a lot from the papers you've written on this. I think this is where a lot of our patients get misunderstood. As you mentioned, thinking about pain as structural damage — there must be a smoking gun somewhere. And in the cases of our patients with these hypermobility disorders, there's not a smoking gun, but yet there still is something there. And we are actually getting better at characterizing that in studying the conditions of pain in the lab. This is my invitation to you to share the understanding of our progress in characterizing nociplastic pain over the years.

[38:06] Dr. Linda Bluestein: Yeah. It's fascinating because nociplastic pain — so there are different types of pain, right? There's nociceptive pain, which is more directly related to actual or potential tissue damage. Neuropathic pain, which is pain that's in the nervous system. And then nociplastic pain, which is more like the software of the nervous system being dysfunctional.

And you can have nociplastic pain alongside nociceptive pain. So maybe you have arthritis in your knee, or you've dislocated your patella many, many times, and you've had these pain sensations — the nociceptive neurons sending pain signals to your brain — and that sensitizes your central and peripheral nervous system. But what's fascinating about that is how the mast cells are involved. Mast cell mediators are involved in pain processing. So oftentimes what starts the problem and what perpetuates the problem are not one and the same. But by treating the mast cells, oftentimes we can make the pain better.

It's so interesting to learn about how everything is interconnected. And for me, learning about pain processing — at that time I was doing so much catastrophizing, and by changing how much I was catastrophizing, that could change my experience of pain. Because pain is an experience, right? It's whatever the person who is experiencing it says it is. There is no such thing as non-real pain. All pain is real. And it is influenced by so many different factors. So it's not purely psychological — that's not true — but it's not purely biological either. That's not true either. It's biopsychosocial. We need to recognize all of those factors involved in pain if we want to help people have less pain and function better.

[40:13] Dacre Knight: And that's what comes to my mind a lot too — that it is an experience. So maybe you can add to that: why we can't measure pain. There's not a simple answer to that. There are so many things involved in pain, right?

Dr. Linda Bluestein: Right. There are so many things involved in pain. And a lot of people think of pain as just going from the periphery to the brain. There's that classic example where a person has their finger close to a fire and the pain signal goes from their finger up to their brain and tells them, move your hand. But pain signals also go from the brain out into the periphery. So we can actually either dampen those signals or amplify them depending on what's happening in our nervous system. It's important to understand that pain is bidirectional.

And the research in this space now is really fascinating. The centers of the brain involved in pain include things like the amygdala, which is the fear center of the brain. So when we are more fearful, we are going to feel more pain. I remember when I was in so much pain and still working in the operating room, really struggling and having a lot of problems. My doctor was saying things to me like, well, you need to do deep breathing. And not understanding that stress affects all pain. It doesn't matter what the pain is coming from — when we're more stressed, we are going to feel more pain. Our pain experience is going to be worse.

So there are things we can do that make the pain experience worse, and there are things we can do to make the experience at least a little bit better. Learning some of those tools can be really, really helpful — like some of the neural retraining type programs that are out there. There are quite a few, and I've had a lot of people have really good success with those, as well as medically treating things. And we're going to be talking next time about our favorite treatments, and I'm excited for that conversation.

[42:17] Dacre Knight: Definitely. This is just a fascinating conversation. I as well have had patients that have had success with this pain neuroscience education and things like that that you're describing. And we love those success stories, because those are generally accessible — we're not talking about major surgeries and things like that to find improvement. So I love those stories of success for sure.

[42:41] Dr. Linda Bluestein: Yeah, me too. It seems like — they take different approaches, right — but they're trying to teach the nervous system that the body is safe. When we're in that sympathetic mode, we tend to feel more pain, we're going to feel more anxious, and then that kind of feeds on itself and can really exacerbate the problems.

[43:02] Dacre Knight: And that's why it's so difficult when we talk about advancing technology and improving our resources and capabilities — we don't have a biomarker for pain. We can't image it. We can't get a lab test for it, because there are so many things it's connected to. Things are influenced by so many other things in what you're describing — even just stress. If something relates to stress, how can you control for that every time?

[43:30] Dr. Linda Bluestein: Exactly. And that leads perfectly into my next question, which is about why symptoms fluctuate so dramatically. I think a lot of times family members don't understand. They think, oh, the person must be exaggerating or faking if they can be pretty good one day and then really, really miserable the next day.

[43:54] Dacre Knight: Yeah. And that's what we ultimately want to get at — to get to a place where patients have less of these cycles, less of the flares. And I think we get there by first educating, and then patients understanding their own condition and their own bodies and their own behaviors and what may lead into those cycles and those flares, because there's a lot.

Going back to mast cell treatments too — one of the things we try is to avoid triggers. Okay, that's certainly easier said than done. But if you can identify triggers, great. And it's the same thing with flares and symptoms. There can be any number of triggers when it comes to flares, whether it's a POTS flare, a mast cell flare, a pain flare, fatigue, brain fog. And those things are usually related to the day-to-day activities that someone is doing. They can be very small too.

We have this description of chaos theory — the butterfly flapping its wings, somewhere along the way causing a tornado. I think that's the best analogy we have here. The butterfly flapping its wings in day-to-day life: maybe you were exposed to some allergy you didn't know you were exposed to, or you didn't sleep well and you may not even notice it because your body was in pain and maybe it wasn't enough to wake you up, but your quality of sleep just wasn't that great. Any number of those small things can have manifold effects down the road or into the next day.

[45:42] Dr. Linda Bluestein: I love that example because this happens with me all the time — I have a patient I'm talking to and they're telling me their symptoms are worse. And not only are their symptoms worse and that's bothering them, but what bothers them even more is that they can't figure out why.

Dacre Knight: Yeah.

[45:59] Dr. Linda Bluestein: And sometimes we're not going to figure out why, no matter what. Other times, as you start to dive into it more, they might actually realize, oh, actually I did do more than I thought. And like you said, it could be a really small thing. But have you observed that — that not knowing cause and effect? It makes sense for human nature that we want to know why this thing occurred so that we can maybe change the outcome next time. But do you see that?

[46:27] Dacre Knight: It adds to the frustration, right? With the condition they're already experiencing — so much frustration involved already: frustration with the healthcare system, frustration with their symptoms, frustration with lack of control. And so that in turn is only going to add to stress levels. And as we just described, that stress can cause compounding effects on the body. Increased cortisol, glycemic control issues, blood sugar all over the place, sleep all over the place. And when we're already in this very careful balance of homeostasis — your body trying to reach that point where your circadian rhythms are on point, your sleep-wake cycle is on point — any slight thing that pushes it over the edge is just going to lead to a tornado.

So we have to put a lot of emphasis on patients getting to the point where they understand these conditions and the effect they may have on their body. So then they learn how to recognize patterns within their body and with things that they're doing and where those patterns may lead into symptoms. It's not easy, but we have to start somewhere.

[47:43] Dr. Linda Bluestein: Yeah. We definitely do. And we also know that a lot of people with EDS and HSD react poorly to medications or react poorly to supplements. Do you have any thoughts about that?

[48:00] Dacre Knight: Well, yeah. And just like we're talking about flares — everyone's experience with flares can be different as far as what triggers them and what kind of conditions they're living in, what kind of stress or jobs they're doing — it's the same thing with medications. Those may not be affected as much by behavior and daily activities, but there are certainly a lot of differences from one person to the next in how they're metabolizing medications, how they're taking them, what they're taking them with, and what other medications they're taking them with.

As an internist, I see this a lot and get asked about medication interactions frequently. That's something we have to take our time with patients on. And while we want to avoid polypharmacy to begin with — which is just the description of excess medications where you're taking one medication to counteract another and another to counteract that — I think we have to start from the bare minimum and understand that everyone's response may be unique. So a failed response is not necessarily a failed treatment; it's just an opportunity to find a better treatment.

[49:09] Dr. Linda Bluestein: Okay. And what do you see as the mistake that providers make most frequently? We talked before about how a lot of times people are not very curious. So that's something that people could work on — being more curious and being more open-minded and not minimizing people's symptoms. But if you had to pick one thing, what do you think the biggest mistake is that most clinicians make?

[49:38] Dacre Knight: Well, I think it's a mistake that when patients come in with these conditions — there's so much complexity to it — it's almost like analysis paralysis. The clinician looks at all of these things going on and immediately just shuts down, like, this is more than I can handle. And I hear patients say that all the time. The physician just outright doesn't accept patients with mast cell activation, outright doesn't accept EDS.

And I understand that the complexity is there. It's frustrating as a clinician if you don't understand how to treat something or address it correctly — you feel like you're not doing your job. We go into this to try to help people. And if you can't help someone, it's frustrating. But I don't think the answer is to ignore it or push it away or send it on to the next person.

I think we all have to keep an open mind about what symptoms may be caused by. And I think we then have to take some time to understand these conditions. That's what we're trying to do here — make this understanding something that's within grasp of clinicians. Because in the end, we realize that yes, there is a lot of complexity to it, but there are also patterns within these conditions, and there are also treatments, and there are success stories. And it's so rewarding to me to find patients who have gone through so many hoops and gotten nothing, and then we find successful treatment. I think that sense of satisfaction and reward when you treat someone correctly is something that would be shared by many other clinicians.

Dr. Linda Bluestein: I love that. Because I think that is what has kept me going as well — those success stories. It just makes you feel like, yeah, that's why we went into this profession in the first place. So it is really rewarding. And I think you're right that there's maybe a component almost of learned helplessness that can happen where you look at all of these symptoms and you think, oh my God, there's just no way that I can do anything for this person.

[52:01] Dacre Knight: Yeah. And you're certainly not going to do anything by just ignoring it. And you're not going to do anything good by just sweeping it under the rug.

[52:14] Dr. Linda Bluestein: Maybe if nothing else, if people can say, I believe you, I hear you — if you don't know enough to even point someone in the direction of resources, I certainly hope people will point people in the direction of this podcast. And the UVA Center would obviously be another great resource. But if nothing else, simply saying "I believe you" really means a lot to a lot of patients. Because I've had a shocking number of people tell me things like, well, I can't be in this much pain because my doctor told me that I shouldn't be in this much pain.

Dacre Knight: No, that's a real gem you've hit on, Dr. Bluestein, and I agree. I think the way we frame this is that we as human beings are all worthy of love and compassion. And as doctors, that's generally what we want to provide. So there are some things that are within reach that can show love and compassion.

And as far as education goes, I think this is a good opportunity for me to make a plug for our research symposium that we'll be hosting at the University of Virginia. That's April 9th and 10th, and we will have a virtual option for attendance. Registration is free, but we have some excellent speakers from all over. We would love to share the knowledge and education that we'll be hosting. So we can get that registration information into your show notes here.

[53:42] Dr. Linda Bluestein: We will definitely add the link to the show notes. And is this a symposium for providers? Is it for patients? Who is the intended audience?

[53:51] Dacre Knight: Yeah, well, it's funny you ask that because we built this as a research symposium — there are so many research opportunities, so much research going on, so much that we want to share and discuss. But there are also clinicians who wanted to be involved and who are seeing patients. We know that clinical care is evolving too. So researchers and clinicians, and then our patients started getting wind of this and we realized there's so much patient interest. And that's great. There are so many knowledgeable patients out there and patients who are hungry for knowledge. So it's really geared to all of the above — researchers, clinicians, patients, community members. We want to make it accessible and speak to all of those groups.

[54:33] Dr. Linda Bluestein: Amazing. I'm really looking forward to that. That's going to be a great event. So on this podcast, we have now hit over a million streams, which is very exciting. And some episodes have been listened to by tens of thousands of people. So I would love for you to share what you think patients should be doing differently — one big thing that you think, if patients could do differently, could make a significant difference in terms of their outcomes.

[55:08] Dacre Knight: Yeah. And by adding this, I certainly don't want to bring up too much anxiety that someone is doing anything wrong, because added anxiety is self-limiting on its own. But as a DIY pro tip, I would say: as we referred to earlier in this episode, getting to understand your symptoms and the conditions in which your symptoms present — characterizing those and what they may be related to. Whether it's a journal or just taking mental notes or taking notes on your phone, that's probably a very good way of doing it because it does two things.

One, it's something you can share with a provider so they're not just in that analysis paralysis — they've got some objective things they can look at and can't brush this aside as too complex or nonspecific. And the other thing is it helps patients grasp an understanding of how things may relate to one another and how they may relate to your body. Because ultimately, as we've said before, we want to empower patients with these skills and self-management tools. Their own bodies and their own experiences are so unique that we have to keep the patient as the focus and as part of the treatment team itself to achieve the best outcomes.

[56:29] Dr. Linda Bluestein: Yeah, I love that. And I have a hack — we always end with a hypermobility hack. If you have one, great. Otherwise, I have one.

Dacre Knight: Go for it.

[56:41] Dr. Linda Bluestein: Okay. So it's funny because my hack actually fits very well into what you just said. We're already starting to think alike. That's a little scary. So my hack is that when you are telling your story or reporting your symptoms or explaining your conditions, it's helpful to have layers — different versions. So you might have like the half-page, 2-minute version, just a few sentences, and then a little bit longer version, and then all the details — if somebody wants 50 pages, you're going to have that. If somebody wants your whole binder, you're going to have everything in your binder. Your imaging, your labs, all of that stuff.

But be prepared to have multiple different ways that you can tell your story so that if somebody needs the key pieces of information in a very short time, you can do that. If they have a little bit more time, you can do that too. Be concise, but share the details that the person needs. And ideally, use a detective-type lens and a curiosity-type lens — try to act like a reporter so that you're reporting more of the facts, like "this is what I feel in my body," rather than labeling. I really like people to tell me what it is that they feel in their body, because otherwise we might prematurely label something and be headed down the wrong path when in reality maybe it's something completely different that's causing the problem.

[58:13] Dacre Knight: Yeah, I love that idea too — having what you might call an elevator speech of your situation and condition at the time. Whether it's someone in a healthcare setting where you may not have much time, how you can get it to them quickly. Or — you see on Reddit something that says "too long, didn't read" — so you've got the TL;DR ready to go, but then you've got all the details to back it up. That's great.

[58:41] Dr. Linda Bluestein: Yeah. And I know you mentioned you gave a talk recently on AI. Well, AI could be a great tool for this. You could take all your stuff — the really, really long version — and ask AI to help you reformat it. Because AI is really good at reformatting things. You obviously have to be careful when using it for a lot of other things, but for reformatting, it can be really great.

[59:10] Dacre Knight: Oh yeah. We've talked about this in the setting of hEDS and HSD, because patients develop such a long complex story. I've had them plug it into their large language model of choice and get a summary back, and it's delivered to me packaged perfectly. So easy to understand. I love it. It's great.

[59:25] Dr. Linda Bluestein: Yeah, it's great for us because it'll have like "neurologic" and then, depending on how you want to format it, it can help you break out your symptoms by system. That can be really, really helpful for your provider to quickly get a sense of what's going on.

[59:43] Dacre Knight: And as a place to continue questions and ask things as they may relate to any of those topics — good to have as a roadmap to go through for that visit. Absolutely.

[59:55] Dr. Linda Bluestein: Well, thank you so much for joining me again today. As always, I really loved this conversation, and I know that you have a lot going on. I'm so excited about the symposium, so thank you for sharing that with us. We'll be sure to put a link in the show notes so people can learn more about that. And of course, we will also include the phone number and the links to learn more about the UVA Health EDS and Hypermobility Disorders Center. That's wonderful.

[1:00:20] Dacre Knight: Yes. Thank you so much. It's exciting to see where this goes, and I'm looking forward to our next conversation.

[1:00:28] Dr. Linda Bluestein: Well, as always, I really enjoyed talking to Dr. Knight. He is such a wealth of information and has such different perspectives. So it's really great to get to talk to him. Thank you so much for listening to this week's episode of the Bendy Bodies Podcast. If you'd like to go deeper, I share additional education, clinical insights, and resources in my newsletter, the Bendy Bulletin, which you can find on Substack at hypermobilitymd.substack.com. 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. As many of you know, I offer one-on-one coaching and mentorship for both individuals living with connective tissue disorders and people caring for them. You can learn more about these options on the services page at hypermobilitymd.com. You can find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, X, and LinkedIn, all at @hypermobilitymd.

As part of our collaboration with the UVA Ehlers-Danlos Syndrome Center, we also want to share some of their helpful resources. For questions or appointment inquiries, you can contact the UVA EDS Center at [email protected]. Again, that's the letter R as in Robert, [email protected]. You can find answers to common questions at uvahealth.com/support/eds/FAQ.

Our incredible production team is Human Content. You can find them on TikTok and Instagram @humancontentpods. As you know, we love bringing on guests with unique perspectives to share. However, these unscripted discussions do not necessarily reflect the views or opinions held by me or the Bendy Bodies team. Although we may share healthcare perspectives on the podcast, no statements made on Bendy Bodies should be considered medical advice. Please always consult a qualified healthcare provider regarding your own care.

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