Symptom connections in ME/CFS, Long Covid, EDS & Fibromyalgia - Orthostatic Intolerance, pain, PEM & MCAS

Lucinda Bateman (0:06): We need all clinicians to recognize all of these illnesses.

Gez Medinger (0:12): Everyone's experience in the kaleidoscope of their symptoms are built by a different set of the interacting pathologies underneath.

Nancy Klimas (0:22): If you don't think in a complex way with such a complex illness, I don't think we have a chance to make people better that have been ill for a long time.

Emily Kate Stephens (0:35): Welcome to Make Visible, the podcast shining a light on complex chronic illness, I am your host Emily Kate Stephens. Welcome to our 40th episode of Make Visible. I am joined by Gez Medinger, and today we are going to bring you a little bit of a review of some of the work that we have done so far, along with, I guess, some of the knowledge that Gez and I have gathered along this journey. Gez, how are you doing?

Gez Medinger (1:10): You know, I was having some thoughts about this question. I'm sorry to just give you a long answer to the "How are you, but I want to actually interrogate the concept of "How are you? in complex chronic illness because it very much depends who's asking, right? As to the answer that it is okay to give, and this podcast is a safe space because you get it, and I'm pretty sure that everybody else listening gets it. So that means I can say, you know what, it's a struggle at the moment, but that's okay. Depending on who's asking, it's a really tricky question to answer, that isn't it? Because what the answer that people want is good thanks. That's the answer they want. But you're betraying yourself if you just try and pass off with that. And equally, it's not appropriate in every scenario. When someone asks, you'd say, actually, really pretty bad thanks, because suddenly that throws the whole world of small talk off. So it is a very loaded, difficult question. How are you? And I'm sure everyone listening has had their own experiences with this. And it's not a question that most of the time, as much as we want to be asked it, we don't want to be asked it by everyone because it can put us in a really tricky position of social mores.

Emily Kate Stephens (2:18): Very much working out how much and how little to share. Like Lizzie Mooney said in the episode last week, that people can try and sympathize, but they don't understand. And you can see people's eyes glaze over when you start saying, "I actually haven't been able to get out of bed for the last week, but I'm doing a bit better today, and then there's that situation because you're up and out, and a lot of the time that you are asked how are you, it is those days that you're up and out. You're presenting a good front on that day. I do sometimes compare it to the kind of masking that goes on in neurodivergent people because there is very much that holding it together when you're out in the world, and then it's all crumbling. How are you behind closed doors? Is the interesting thing

Gez Medinger (3:09): exactly? It's the social stigma that comes with chronic illness to some degree, and how okay are we with having that conversation each time, or changing someone's perceptions of us? And again, it depends on the person who's asking, and it depends on the place they're asking, and it depends on the context. But of all the questions that can be thrown at you with just three words, it's surprisingly tricky.

Emily Kate Stephens (3:29): And it's probably the one that gets thrown at you the most often. But tell me honestly, in our safe space here,

Gez Medinger (3:36): yeah,

Emily Kate Stephens (3:37): how are you doing?

Gez Medinger (3:38): Holding things together with spit and sawdust is the honest answer. I'm doing a couple of new long COVID treatments that are taking it out of me at the moment. At the same time, I'm doing far too much work. And actually, apart from long COVID, life's pretty good. And I'm just in this tricky position of trying to make the most of it whilst not overdoing it, and also trying to leave enough space and room in there to have the treatment. And so it's juggling 18 balls at once.

Emily Kate Stephens (4:03): When you and I have spoken to each other, maybe not on air, but we've said before that perhaps this warrants a whole episode for discussion. This trying to establish how much of life you should or need to live versus what you need to leave behind. Some people would say that you need to stop completely, but you have said in the past that you have radically rested, and yet still six years on, you're in this situation. It's that I need to have the joy. I need to find the things that bring me alive versus how much you need to retract, and if we talk about that nervous system stress, the stress that's put on your body, perhaps going out and doing the things that give you joy can alleviate a certain amount of stress, and it's this crazy balance of trying to find the things that don't push you into the post-expressional malaise, but that give you

Gez Medinger (4:59): something. Well, like last week's episode where Lizzie Mooney was talking about the knitting and doing the things with her hands because her hands felt safe and because they didn't create problems symptom-wise. So, what is it that can bring you joy that has a very low spoon or symptom cost? And that's an ongoing adventure to try and work out because it probably won't be the same things that used to allow to give you joy before, so you've got to try all sorts of new things, and maybe in in there somewhere there'll be a little nugget.

Emily Kate Stephens (5:27): I was on holiday last week, so that definitely gave me some joy. I love being outside. I love being able to swim. I swam a lot. I was at the beach, and I did go surfing a couple of times, which is something that used to bring me so much joy.

Gez Medinger (5:44): How was it? How was the surfing? Because surfing

Emily Kate Stephens (5:46): is it's heavy duty. It's a real challenge. It's a real challenge, and obviously I've got this back problem at the moment. And actually, I found this incredibly frustrating because I was comparing myself to myself seven years ago, and I had this phenomenal instructor who just said, "Stop comparing yourself, even to yourself, and be here in the moment. It does not matter if you can't pop up the way that you used to pop. Enjoy each wave, and just be present, and practice non-attachment, which is something a lot of people try to practice in yoga class. Be there, present in the moment. Take from it whatever you take from it, without that judgment of, oh, but I used to be much better at this. And actually, that kind of mindset put me in the water and made me let go of some of the I've got to be where I used to be, which still creeps in, and it definitely jars my nervous system because I'm this week not in a big PEM crash, but I've got a few symptoms that I know are my warning signs that I have to watch out.

Gez Medinger (6:50): Well, look after yourself, Emily.

Emily Kate Stephens (6:51): I will. So this week we are going to review a few of some of the real highlight people that we have had on this show, and that's actually almost doing a disservice to some of the other people. We have spoken to so many incredible people, but we wanted to bring a few clips here that give an overarching viewpoint from people so well versed in these conditions that is very much cross condition that we deal with. So we are bringing you here some voices that talk about symptoms or circumstances that befall the majority of people or a large proportion of people with complex chronic illness. So we are going to dig a little into old episodes that give you an overview of orthostatic intolerance, chronic pain, post-exertional malaise, mast cell activation, and today I wanted to start with almost an overview piece of our entire situation in terms of homeostasis. This is Nancy Klemas, who is an immunologist and the director of the Institute of Neuroimmune Medicine at Nova Southeastern University, and she's been operating in this space for decades. And here she talks about the way that the whole body has shifted out of balance, and what she does with her team to try and bring people back into balance.

Nancy Klimas (8:26): We think of this whole thing as homeostatic networks being screwed up, so that when you're healthy, everything's in the balance. Your endocrine system, your immune system-it's all in this little balance. And if you listen to the monitors talk, they would talk about a well, like a little valley between two mountains, and if you got the flu, you get out of balance. You'd crawl up this mountain a little bit, but when you're better, you drop that back down into your healthy well, right? And the idea that a chronic homeostasis thing is going on, the chronic illness, is that you climb the mountain and you drop the ball down into the next well, and now you've got a chronic unwell person, but very stably sick. That the things that are wrong are going to be the same things. What hormones are wrong, whatever. This is this is unwell, but stable, and this is well, and stable. And now I got to find a way to climb up the mountain and drop the ball back into the other well. That's sort of the theory behind our computational modeling group, and I think it makes good sense. And then you can deal with all the complexity. When you talk about gender differences, women are different in some very significant ways. Women are far more inflammatory; the immune system is more reactive. Women get all the autoimmune diseases far more differently than men do. Right? Men are swimming in this anti-inflammatory thing called testosterone that inflates stuff down, so they so they have a biologic advantage on inflammation. So when we look at our models of these diseases, actually they model differently for men and women. They model differently for postmenopausal, perimenopausal, and premenopausal women, and actually the models predict different interventions for each of those stages of life, and it's because they're interactive with the endocrine system as high in a row, and your estrogen and testosterone levels are in the model, and they they they drive a bunch of the imbalance that's involved in the illness is it

Emily Kate Stephens (10:24): predominantly the hormone differences that

Nancy Klimas (10:28): it's what the hormones do to everything else. You know, if it was just hormones, every guy would just start testosterone, but it's not because it's one of the easiest things to fix is is hormone levels. So if all you do is fix that one thing. You don't make people better, but it puts the stage in place to be able to bump the other things that were completely out of balance and leaning into the wrong levels of all these hormones to stay out of balance. So in our models, we have to kind of fix the hormones and fix the immune system, and fix the adrenal, the cortisol system. Right. Yeah, but it's cool because if you don't think in a complex way with such a complex illness, I don't think we have a chance to make people better that have been ill for a long time.

Emily Kate Stephens (11:21): If you take those sort of three three sections of the system, what what therapeutics or interventions are you currently able to use that target each of those that enable returning some kind of homeostasis or coming back into that?

Nancy Klimas (11:37): Yeah, so one thing to clinics without the benefit of having evidence-based medicine in ME/CFS saying do X Y Z, and you just walked into a clinic. The first question is, what clinic should you walk into, right? Because you're going to get a different treatment depending on whose door you walk through. So it's kind of important when you know all these different systems are whacked out to walk through the door of someone who's looking at the whole thing, and not I'm the endocrinologist, and I'm the immunologist, and I'm the cardiologist. You

Emily Kate Stephens (12:08): are an immunologist, but you do seem to approach this from very, very

Nancy Klimas (12:12): integrative medicine. But when I moved from my other university, where I ran the immunology clinic, and that's what I saw was nothing but immuno emily problems, and I came here. We re envisioned the whole clinical thing. So it's going to be multidisciplinary. So you can see immunologists, cardiologists, and all this at the same time. Yeah, you're like, you know, actually no, because most of the cardiologists really don't know what to do with this, you know, and and neither do the neurologists or all these other specialists to see these folks. Who was doing the best job were people that were in integrative or functional medicine. So we ended up with eight, and I think I think we have eight right now. And I'm the only one that's not bordering integrative or functional medicine in different,

Emily Kate Stephens (12:58): which means combining. It

Nancy Klimas (13:00): is so interesting because look at my gray hair. I trained in medicine before you triaged anybody anywhere. You just took care of them. You know, I'm born in internal medicine and immunology, so the internal medicine training would have been. I got trained in cardiology, emily. I got trained in all those things. You only push someone off to some specialist if you were over your head, but now it's like triage and just everybody gets on top of every kind of specialist. But for long COVID and for MCS, it's a tough situation because somebody has. Even if you do that, who's taking all those consults and knitting it back into a management plan? Instead, you see people stepping on each other, prescribing drugs that shouldn't be put together. Order two different things, or whatever. I just want integrative medicine conceptually because it's a whole body way of thinking. We do complex medical disease integrative medicine. Most integrative medicine is all about wellness, diet, nutrition. We do this and do that, exercise, exercise, exercise. We do something differently because we're starting over. They're pretty darn sick, and trying to help them, you know, get up to better and better levels. So I think with our with our with our treatment style in our group and other integrative medicine type folks, it's kind of a layered approach. Get them up a little notch, and then get them up the next little notch until you bring someone out of the well into a much more functional space.

Emily Kate Stephens (14:34): Gez, I love this approach of trying to chip away at the things that are going on in our bodies, and I love that there are people out there who know how to treat these conditions. What are your thoughts?

Gez Medinger (14:47): Well, the the thing that I found particularly engaging that tweaked my little metaphor buttons was her description of homeostasis and how it's a valley between two mountains, like a V shape. And normally, what happens is the ball gets pushed up the mountain when you're ill or something, and then it just the body just rolls it back down to the bottom. Gravity sorts it all out. But imagine there's a hole or a well halfway up one of these mountains, and the ball falls into that, and it's stuck in there. So what we're trying to do to extend her metaphor a little bit, the way I've looked at it, is trying to create enough interventions that create little steps inside that well that bit by bit by bit you can lift that ball up and push it over the edge and then it will roll all the way back to the bottom of the valley and you will find complete homeostasis again, i.e. recovery. The challenge, of course, is that everybody's well is different and everybody's steps are going to be made out of different stuff. So I have been furiously fabricating stephens out of every material I can possibly get my hands on for the last six years, trying to step on all of them to climb out. I'm very much on board with this idea of how do you help the body to help itself. But where it gets really tough, of course, is that this is a very complex multi-system condition. Everyone's experience and the kaleidoscope of their symptoms are built by a different set of the interacting pathologies underneath. Also, it seems, and so when you have this sort of challenge, it makes research very difficult, and it makes finding your own personal solution very difficult too. Because what works for someone else down the road isn't going to work for you. What I like about this metaphor is that it runs counter to the idea of the magic bullet, because the magic bullet is this thing that works for everybody, and is just going to immediately, no matter what your constellation of symptoms are, it'll just sort you out. A bam, all done. And looking at it in this way, it seems very simplistic, but I think it's actually much more realistic in terms of the nature of these complex connect conditions are what's actually going on in them, and the failure of the body to find homeostasis again. I think looking at the problem in that way is perhaps more productive in some ways to helping to work out how to approach and treat

Emily Kate Stephens (16:55): it. I'd like to pick up on two points that you just said there. One of them is said that you've tried a multitude of different things over six years to, and then paraphrasing, to find your own way out of this condition. And I feel like you and a lot of people are very much on their own on this journey, trying to work their way out. Whereas I think if you have the guidance of someone like Nancy Climates, who has been treating people with these conditions for decades to actually start putting those steps together with you, guiding you, holding your hand? They might actually be able to give better guidance on which are the correct steps for you, because I think there are people like you who have worked incredibly hard to try and build those steps, and perhaps part of what it is is the efforts that you've had to put in to trying to find your own way. That is somehow detrimental to the effects of some of those steps, because there is so much work that needs to go into actually even the research, and we're talking about cognitive impact as well as physical impact of trying to work it out. And you and I both we've both spent the last six years trying to work it out. So I definitely think that having your hand held by someone who knows what they're doing is just so invaluable, and we're so lucky that we've got to speak to so many of these incredible people, and yet even you and I, who have spoken to so many of these incredible people, do not have access to actually be treated. We've not found our person. I don't

Gez Medinger (18:31): know. No, and it's very much geographical, and it's to some degree financial. And there's all of these things that that fit into it. Whether you have access to some of these people, and obviously the people who are particularly good, it's very difficult to get an appointment to go and see them, even if you are geographically in the same space. And even beyond any of those questions, there are far more people suffering than there are doctors to treat them. And until medical science changes and starts putting big chapters in textbooks about complex chronic illness, when it understands complex chronic illness well enough to do so. I don't think that's going to change any time that soon. So we do still have this burden of responsibility to try and find our own way through this condition.

Emily Kate Stephens (19:12): All of the people that we are bringing you clips from today have put a huge amount of effort into research and publication, and trying to actually create guidelines and best practices for other conditions going forward. And the next specialist that we're bringing you is Dr. Peter Rowe. And when I put this episode up, I had an incredible number of people write and say, "I have been treated by Dr. Rowe, and it is so incredible the way that he is able to actually treat people. Dr. Peter Rowe is a professor of pediatrics at Johns Hopkins University. So I love that he is able to try and mitigate some of the worst outcomes in younger people because one of the most heartbreaking things about last week's episode was how a child had their entire teenage years obliterated by these conditions. Now he is an expert in orthostatic intolerance, and that is something that is so prominent in so many of these conditions and this autonomic dysregulation that comes from it. There are a whole raft of symptoms that are broken out into different specialties. But here he gives an overview of how orthostatic intolerance relates to fatigue. Not only that, how it relates to ME/CFS and the crossover that he has found with Ehlers-Danlos syndrome. You became interested in these disorders that were characterized by fatigue and autostatic intolerance, and that's really one of your areas of expertise is this orthostatic intolerance. Can you, first of all, for our audience, explain to us what orthostatic intolerance is and how it contributes to these fatigue-related conditions?

Peter Rowe (21:15): Sure. So orthostatic just means upright, and if you're intolerant of upright posture, you can get a variety of symptoms that are mostly related to not getting adequate blood flow to the brain, or the body's response to not getting enough blood flow to the brain, which includes a sort of high adrenaline state. Orthostatic intolerance syndromes can include drops in blood pressure, so that you have orthostatic hypotension or reflex response that leads to fainting, you can have increases in heart rate, or you can have neither a change in blood pressure or heart rate, but still have big reductions in the amount of blood flow that gets to the brain. So the symptoms really count.

Emily Kate Stephens (21:58): Why? If you've not got the drop in the blood pressure or the heart rate. What what drives or what causes that change in blood pressure?

Peter Rowe (22:10): So it's likely to be a combination of things. One is that people who have orthostatic intolerance tend to have a greater gravitational shift of blood into the lower half of the body when they're upright, for reasons that are that are not entirely clear. Some of them have very stretchy blood vessels, and so there's a connection between orthostatic intolerance and people who have joint hypermobility. The same connective tissue that makes them stretchy also is affecting the wall of the blood vessels, so that they can pool a lot more blood in the lower half of the body. Other contributors can be a reduction in total blood volume. So our patients tend to have about a 10 to 15% reduction in the amount of blood they have in the circulatory system. Again, for reasons that are unclear. And then the third problem with patients, other than the excessive pooling and the low blood volume, is that they get an exaggerated adrenaline response, and and by adrenaline I mean both adrenaline and noradrenaline, epinephrine and norepinephrine. So the body sort of has a big reaction to that, and those catecholamines can also cause rampant heart rate, palpitations, and a bit of a number of other symptoms.

Emily Kate Stephens (23:27): And that's particularly interesting in the conditions that you deal with, because actually, I think it was in the 1990s that you started, early 1990s, that you started to realize that your patients that were coming in with chronic fatigue syndrome, as it was then known, even without the fainting, without the syncope, were experiencing these shifts in heart rate, in blood pressure, and this orthostatic intolerance. You've started noticing that as would you say it's a symptom of NECFS or it's a driver because it was so correlated?

Peter Rowe (24:07): Yeah, both both a symptom, and we think it's a driver because if you can treat it effectively, almost everybody with NECFS gets better to some degree.

Emily Kate Stephens (24:17): This is fascinating, isn't it? Because the symptoms that you just mentioned in orthostatic intolerance are such primary symptoms in ME/CFS, and then it was in 1999 that you wrote the paper where you connected the orthostatic intolerance, ME/CFS, and telescopes or this hypermobility, and the idea that the flexibility in the blood vessels is the same as that hypermobility in hypermobile Elisabeth. Can you tell me about your work in that from 1999 onwards?

Peter Rowe (24:57): Yeah, so we initially thought that the orthostatic intolerance was such a huge driver that we could get everybody better, and that was probably foolish thinking. But along the way, some of the people that didn't do as well, we noticed were much more likely to have a pre-existing diagnosis of Ehlers-Danlos syndrome, and we we thought, gosh, let's let's look into this more carefully, and we looked at the next 100 patients consecutively. We found 12 who were confirmed by a geneticist to have Ehlers-Danlos syndrome, and all of them had orthostatic intolerance and ME/CFS. So this was the first paper that really tied together those three diagnoses. We went on after that to say, all right, if they've got the full spectrum of EVS, what about people who have just joint hypermobility without meeting the criteria for ELISTAMH And that study enrolled 58 consecutive patients and controls, and we showed that there was if you had a diagnosis of ME/CFS, you were three and a half times more likely to be hypermobile. That was not an accident. That's a genetic trait that was present throughout childhood. Why it then tends to appear as people reach adolescence most commonly is a bit unclear. So there are other factors you probably need a second hit, possibly an infection or something else. Maybe the changes of pubertal development.

Emily Kate Stephens (26:26): So there's this genetic predisposition to the joint hypermobility, and that is genetic. That is from birth.

Peter Rowe (26:33): Correct.

Emily Kate Stephens (26:34): And then you're saying that what happens is there's the susceptibility there that when you take that viral hit, some kind of trauma, to to the it drives us into ME/CFS. Is that right? That

Peter Rowe (26:49): seems to be the case. Yeah. And

Emily Kate Stephens (26:50): then subsequently, work that you've done suggests that 60% of your ME/CFS patients actually have that joint hypermobility. So, is is joint hypermobility something that we can actually view as a marker for more of a predisposition to MECFS?

Peter Rowe (27:11): We think so. Yeah, it's a risk factor.

Emily Kate Stephens (27:13): That's that's the word I was not. And

Peter Rowe (27:15): important to recognize that not everybody it's who's hypermobile is likely or or will to get ME/CFS. You know, many people who are ballet dancers and and swimmers and other athletes are hypermobile. It gives them an advantage. Think of Michael Phelps, for example, but he doesn't have ME/CFS, right? He's the hypermobility doesn't always confer a very high risk, but it's clearly much more.

Emily Kate Stephens (27:43): Gez, I really enjoyed his explanation of orthostatic intolerance. There is a description of the very, very mechanical action of it in an episode with Dr. Boone Lim, which I think might be episode two. People want to go and dig into it. Do go and have a listen to that. But as an entry point to try and understand what is going on in your body and those symptoms that you might be able to attribute to orthostatic intolerance, because there are things that one can do to treat orthostatic intolerance. I really appreciated his insights.

Gez Medinger (28:19): Yeah, absolutely. And pots and all static intolerance are not quite the same thing, but they are essentially similar. Incredibly debilitating in terms of the impact that they have on your ability to function day to day. But you are exactly right. Anything that you do that requires standing or being upright in some way is going to really make you feel terrible or bring on a whole sex. It goes into

Emily Kate Stephens (28:42): more detail about the way in which people with orthostatic intolerance, what happens then when they raise their arms. So why so many people cannot take a shower and wash their hair because you're standing up and raising your arms at the same time? Do listen to the episode. It's just a fantastic insight into what's going on in your body.

Gez Medinger (29:02): Yeah, I completely agree. The amazing thing about it is that it's one of the few sort of subsets, or symptom subsets, or pathology subsets, or how would we want to call the constellation of conditions that exist inside complex chronic illness. That actually there are effective treatments for, well established, well evidenced, widely accessible because there are plenty of doctors who are familiar with orthostatic intolerance way more than there are with some of the other like MCAS we're going to talk about in this episode later. You're going to have a lot more joy trying to find a doctor who's familiar with orthostatic intolerance and will prescribe medication accordingly than you will for MCAS.

Emily Kate Stephens (29:38): There are such lifestyle medicine that you can take without necessarily prescriptions that can help.

Gez Medinger (29:45): Absolutely. So whilst it is debilitating, it's one of the few few conditions inside complex chronic illness where actually people can improve by huge amounts relatively quickly by making a combination of lifestyle measures and medications. In some cases, there's there's also just more philosophically or theoretically, this idea of how does a virus cause POTS or orthostatic intolerance? It makes sense that if you have hypermobility or earless dam loss, you can understand the mechanism by which your blood vessels can't constrict enough to hold your blood pressure up. So that makes perfect sense. But if you've never had hypermobility of any kind and you just caught a virus, and now suddenly you're off statically intolerant. Well, what's happening there? And there are all sorts of theories floating around on this. The one that is the most compelling is probably the one about overstimulating or blocking the vagal signaling or the normal adrenergic reaction of the body, which means that the way that our body tries to control our vasoconstriction essentially is is compromised. So it's sort of it's sort of think of it this way: it's like the virus has gone in there and it's messed with your ECU, which controls what your blood vessels are doing, and so it's a it's a signaling problem rather than a mechanical problem, if that makes sense. But again, we've still got theories, and we haven't got enough evidence yet to really nail down what's causing it in those sorts of people.

Emily Kate Stephens (31:06): Very true. We actually have quite a few episodes talking about orthostatic intolerance, and another such person is Lucinda Bateman, who is the founder and medical director of the Bateman Horn Center. But she was instrumental in creating the 2015 diagnostic criteria for ME/CFS, but has worked across what she now sort of terms ME/CFS and related conditions, as in she has this bucket for the conditions that have that viral relation and ME/CFS, and then a look at the chronic pain conditions as well, which sit side by side, and in this kate today, she talks about the differences between having chronic pain conditions and the posterism malaise that is prevalent in the ME/CFS and related conditions.

Lucinda Bateman (32:07): I've been a fibromyalgia specialist all this time too. Yeah, and we all kind of use these case definitions, but we use them in the way that makes the most sense to us. And the way I divide someone I call fibromyalgia only, and ME/CFS is the ability to return to exercise, and the nature of the flare of symptoms after you do more activity. And I'll tell you what I mean by fibromyalgia alone.

Emily Kate Stephens (32:36): Yeah, please.

Lucinda Bateman (32:37): So fibromyalgia. You have hundreds of fibromyalgia patients that need help with symptom management, they need help with sleep, and they need help with pain modulators, and they usually have a lot of stressors going on in their life. I think Emily SP almost purely stress-induced illness.

Emily Kate Stephens (32:54): Physical or mental stress?

Lucinda Bateman (32:55): All stress.

Emily Kate Stephens (32:57): Okay.

Lucinda Bateman (32:58): Yeah, I think mental stress too. You could not separate them very well, right? If someone is a single mom working nights and in a job where she doesn't have any control and has a hard time making ends meet, what are the stressors? Is it the night shift? Is it not getting sleep? Is it yeah? You can't separate them all out. Yeah, but over time, I'm just stunned by my fibro patients and what they've been through, and they're just strong people who have trudged through difficulties. It's weird because it's not like they're weak people. It's like they're people who wouldn't lie down when things got hard, so they push themselves through very difficult conditions and develop widespread pain and fatigue and sleep problems and brain fog and stuff, but the difference is, and the and the literature holds this out. If you take someone who has fibromyalgia and you gradually help them rehab physically, they get better control over their illness. They can't do hard exercise, but they do moderate movement and strength training and low impact exercise doesn't make their illness go away, but it helps their mood, it helps their sleep, it helps their fatigue, and they get an overall better management of their illness. They don't really get post-exertional malaise; they can get post-exertional pain amplification. Right. So if they exercise too hard, all the muscles hurt, and that kind of thing. So they have to kind of be careful because they have a pain amplification problem. So that's one group, and I love seeing patients with that because I can totally help them get into a much better place. It's very satisfying. On the other hand, or what I consider ME/CFS and other conditions where people are vulnerable to developing chronic pain conditions. If you have ME/CFS and you have post-exertional malaise, you can't implement what we would implement for a patient with fibromyalgia, even if you meet fibromyalgia criteria, because you can't exercise, and exercise sets you back. So to me, that's the the big difference. And they're not like completely separate illnesses. Think about what happens to someone with post viral injury. They they lose sleep, they lose their job, they go through all these stressors. Sometimes they don't have pain initially, but they go on to develop chronic widespread pain or pain conditions, and maybe because of how horrible it is for them in the first year, all those stressors-the same things that can cause widespread pain. I don't know the answer, but what I want to say about that paper is the most important thing about that paper is it saying, "Look, clinicians, there are many things you can treat in people with ME/CFS. So identify these comorbid conditions and take what we know about chronic pain management and start to treat your patient.

Emily Kate Stephens (35:50): And in that, just for our listeners, we're talking about the overlapping chronic pain conditions, and that also goes back to what you said earlier in terms of dealing with orthostatic intolerance, or exactly, so you're trying to address these comorbidities,

Peter Rowe (36:13): right,

Emily Kate Stephens (36:15): as a method to alleviating some of the problems of ME/CFS,

Lucinda Bateman (36:20): right, exactly, and one of the reasons pain was left out of the IOM criteria as a primary criteria. So the IOM criteria they have those core criteria that everybody has to have, and then they say, oh, and there are a lot of other common symptoms, and pain, chronic pain is down in that list of other symptoms, and it's because there's a broad spectrum of how pain affects people with ME/CFS, as this paper demonstrates. And I know there are some people who don't really have pain who have ME/CFS unless they're in post-exertional age. That they don't have pain all the time, but if they overdo, then they get a flare of pain, and then there are all these pain comorbidities. And our thinking in making this case definition, is we already have a great literature for chronic pain and fibromyalgia. We don't have to redo that with the IOF criteria.

Emily Kate Stephens (37:15): And straight off the back of that interview, let us go to Todd Davenport, who is a professor at the University of the Pacific, and he is a doctor of physical therapy, whose advisor to the Work Well Foundation has been such a huge resource for many, many other practitioners in terms of understanding post-exertional malaise. And here he explains how they can actually see that impact that exertion has on the body of people who develop post-subversional malaise. When you're dealing with this patient group, what does that term exercise actually mean you're not talking about necessarily going for a run.

Todd Davenport (38:05): Yeah, absolutely. That's that's actually the the easiest way to find these conditions and a common hallmark of these conditions, which is post-exertional malaise, is to go for a run. So I start with a patient story that I hear very frequently, which is, I got sick. Didn't get better for a while. Took me a while to improve, and then when I approved, it was only maybe 80% wasn't quite all the way back. So I decided I can't can't really live with that last 20% I've got to do something, and since I'm tired, I'll do what seems to make sense, which is I'll I'll go out to the gym, or I'll go out for a run, or a walk or a solid session in the garage. There, put in my favorite exercise video and just give it a go. And frequently, people in response to that will say that made me sick all over again. I felt worse than I did when I was sick. Or for example, people with long COVID will say where I had COVID again in response to that.

Emily Kate Stephens (39:00): That's exactly my experience. Yeah.

Unknown (39:02): So as you mentioned, exercise is very fraught. There's a whole science behind this. Probably one of the few areas of science that's been replicated pretty repeatedly in ME/CFS, and beginning to see the same types of studies in long COVID. And crediting my colleagues at the Workwell Foundation, Stacy Stephens, Jared Stephens, Mark Van Ness and Chris Snell. We've been working on a paradigm called the two-day cardiopulmonary exercise test for a number of years in order to really understand the effect of exercise on the body. And what we're seeing are some characteristic reductions in the body's ability to use oxygen to burn fats and sugars as part of complex chronic conditions. And we think that has to do with the activity limitations that we observe, and also the corresponding inability to exercise, and also the signs and symptoms that we see after people exert.

Emily Kate Stephens (39:51): This is work that you've been focusing on for a long time, but actually, you started this with the Work Well Foundation within about 2022. That specific piece looking at the abnormal response in post-examination.

Unknown (40:02): This this is work that's been going on for gosh, what year is it? Almost 30 years.

Emily Kate Stephens (40:07): Right.

Unknown (40:08): And of course, I came later to this. Part of my origin story is that Stacy showed me two two CPET reports, and and she insisted they were the same person, separated by 24 hours, and they just didn't look like this. They looked like two completely different people, and so that was that was my whole because of what happened as a

Emily Kate Stephens (40:26): result of the exercise.

Unknown (40:27): Exactly, two two look like two different people. You do not expect people to look totally different 24 hours apart.

Emily Kate Stephens (40:35): And what are the differences that you observe in that? What does the exercise actually physiologically do to these patients?

Unknown (40:41): So what we notice is a decline in the ability for a person to consume oxygen at what we call the ventilatory anaerobic threshold, which is the transition point between the body using oxygen and the body no longer able to use oxygen efficiently. On the second test, we notice that the utilization of oxygen tends to drop and tends to drop more precipitously and earlier at a lower workload on the second test, suggesting that people are less efficient with using oxygen. And the other thing that we notice is that people don't exert as much torque against the pedals, which we refer to as work rate or workload, and those things happen together. And the thing that's notable about ventilatory anaerobic threshold is that you can't fake it. Peak values-they're-they're a little harder. You've got standard criteria to ensure someone achieves a max test. But but the ventilatory anaerobic threshold, you go back and literally plot breath by breath, and you identify it based on a breath by breath plot after the fact, so a person doesn't know that they're they're going through that point when they're going through it.

Gez Medinger (41:55): Thoughts? So I think the brilliant thing about what a preferred is talking about is with the two-day CPET test. You can't argue it or fake it. It is absolutely written down there in very firm black marker pen what the results are, and it is a direct insight into what the body is doing when you stress it. And to me, it's a brilliant riposte to the community of scientists who continue to advocate for for the pace trial, and that in order to get better in these conditions, you just have to do more. And when you get results like this, I can't really understand how you can have that position because here is a very demonstrable result of what happens when you do more, and it's not good. The big questions we've still got to answer is well, why? What's actually the mechanisms? What are the mechanisms going on in the body that lead to this outcome? And we're getting closer. There's a lot of work, a lot of research happening into mitochondrial dysfunction, which seems to be connected to how the cells are using the oxygen and why the aerobic limit is dropping and why is trying to metabolize anaerobically. So, for example, I did an interview with Professor Klaus Burth, who's got a really exciting theory on what's happening at the mitochondrial level and why this is essentially going wrong. If anyone's interested, there's a long interview on my YouTube channel, but it's quite technical. So, I did a breakdown video called "Mitochondrial Dysfunction Explained, and that's only eight to 10 minutes long. So that's quite a nice, easy way of explaining the theory that might perhaps fit into what we're seeing with these CPEP tests. But again, we need more research, more money into this research because this is a very fundamental part of the physiology that has gone haywire, and it's one of the things that affects my quality of life most severely. I probably wake up panned half of the days in the week because I'm perpetually right on the cusp of overdoing it, and I won't be the only one out there.

Emily Kate Stephens (43:55): No, and you can feel it at a cellular level. You really mentioned the mitochondria, but when you are in those crushes, you can feel that every cell in your body is not able to produce enough energy. And actually, in that interview, Professor Davenport goes on to explain immediately after that his hypothesis of what is actually taking place in the in the body. I'm very interested to overlap that with classwork and correlation there.

Gez Medinger (44:21): Quite auto correlation.

Emily Kate Stephens (44:23): Yeah, but that's what I love about the voices that we've pulled together today is the basis in science. It's not airy fairy theory. These people see this on a microscopic, scientific, validated level, and those people that suffer from PEM, you know that feeling, and that's essentially what I'm talking about having this week. I have slight PEM, but I just know now how to manage it.

Gez Medinger (44:51): Yeah, and it's probably much less bad than it was when things were brutal in the middle. All right.

Emily Kate Stephens (44:56): Oh my God, I wouldn't be able to get out of bed these two days. I wouldn't be able to lift my head from the pillow. So how have I gone having mitochondria cells that were not able to uptake the ATP or produce the energy required to being functioning again? And I hope that that gives other people hope that you can go from that complete crash to a position where you're not constantly experiencing it, you can get out of PEA, but we need we need to work out how.

Gez Medinger (45:29): Yeah, and we need to work out what the phenotypes are inside this condition and how they interact differently with this or not. The kinds of PEM that people experience is that because the mechanism is different, or is it the manifestation is different? And so we're going to speak about MCAS shortly, and the same thing is very true there. So we have a huge constellation of possible symptoms from MCAS, but it's the same fundamental mechanism just happening in different parts of the body. So is the same true for the constellation of symptoms that we experienced with PEM? We don't know yet, and I would love to know.

Emily Kate Stephens (46:02): The more that we delve in, there also seems to be more overlap between the way that our cells are responding or not responding. Let's go into MCAS mast cell activation. This is a clip from an interview with Dr. Theo Harris-Haridis, who calls himself the mast cell master. He's also a professor at the Institute of Neo Immunization in Nancy Klamath's team, but he has done decades of research. It's one of those things that is so rarely identified. I still have intense mast cell activation every single day. They try to sometimes send me to an allergist, but then the allergist clinic has denied my appointment. There are not people within our health system here who know how to deal with it. And my conversation with Theo Harris Theoharides was absolutely mind blowing in terms of the breadth that this mart cell activation is actually impacting us, so some of the things that I've attributed to completely separate drivers could potentially have been tied into mast cell activation. This mast cell activation is possibly something that is fairly underrepresented or misunderstood amongst the general population, and I'm not just talking about patients. I'm talking about physicians as well, because I know that you have talked historically about how people approach their physicians with a certain condition, and you have the understanding that perhaps that is mast cell activation.

Theoharis Theoharides (47:44): Well, couldn't be a better time to be having this conversation because I was actually invited to write a review on mast cell activation comorbidities and lookalikes. I'm raising a lot of the issues that I'm sure you have in mind, many of those that your audience have in mind. So let me start by the fact there are many misnomers. So we talk about allergies, ectopic diseases, mast cell activation, mast cell activation unspecified, mast cell activation syndrome, conditions with mast cell activation, etopic inflammation, and the list goes on and on. So, the scientific, the medical community has just not gotten it together as of yet to really define who we're talking about. And of course, patients are left scratching their heads as to what do I really have. I'm giving a lecture about multiple activation in multiple chemical sensitivity syndrome that seems to be just like muscle activation. In fact, I think it is, and I'm not suggesting we change the nomenclature necessarily. We don't really have to rediscover the wheel about what is the basis for many of these conditions.

Emily Kate Stephens (48:56): But we need to gain that understanding that they might possibly all have the same

Theoharis Theoharides (49:00): basis. So, 15 years ago, I actually taped an episode out of the blue. I was actually giving a lecture in Copenhagen, and two patients approached me, and they had complex problems along the lines of what we discussed. So we created an episode, which is YouTube, and it's called "My Mystery Symptoms and Must Cells. So. there was no question then, and there's even more no question now that the mast cells are everywhere. So let's start with the fact that they're everywhere. They're in every tissue in the body, especially tissues exposed to the outside, like eyes, nose, mouth, lungs, skin, gut, but also inside the brain, and in fact, that critical part of the brain that connects the hypothalamus that regulates everything in our body with the pituitary that releases all the hormones in the body. It's called the median eminence. It's a little stock connecting the two. Has more mast cells per unit volume than our skin, yet our brain doesn't get allergic reactions. We used to think that a cell, which has 1000 secretory granules, can store and release about 100 molecules. As of about a year ago, now we're to 350 molecules that can release, and yet we're still dealing only with histamine and maybe leukotrienes that constrict the bronchi. We're at a loss about how those other molecules are released, when they are released, and to make things even worse, if we were to assume that a mast cell will be triggered by a particular trigger, whatever the trigger might be, the first hormone released under stress, called corticotropin releasing factor in Europe or corticobar releasing hormone CRF or CRH in the states, resets the reactivity of the mast cells. That means that individuals that may have had some history of allergic light problems. Let's call them that for now. They undergo a major surgery event or car accident. God forbid, someone dies in the family, and now they're allergic to everything. "Quote unquote allergy. So we know that the mast cells are not static, and they will respond to pretty much anything. And there's no question from work other colleagues have done that they respond to pathogens. There can be bacteria, there can be fungi, there can be viruses. And not only they stimulate the mast cells, but they also reset the reactivity of the mast cells. Hence, people that might have been done with COVID, for instance, now they have all kind of symptoms that are reminiscent of activation of the mast cells.

Emily Kate Stephens (51:52): And I think what's interesting there is in the things that you mentioned is you're not only talking about something that infiltrates the body in a pathogenic way. You also mentioned. You said God said someone died in the family. So you're talking about psychological impacts, trauma in that sense, and not differentiating that against the physical.

Theoharis Theoharides (52:18): Not at all. Both physical and emotional stress will release those hormones, especially CRF. The difference is that, while, for instance, someone had, let's say, eczema, which would be more allergic by, might undergo a major stressful event, and now they're kind of will be covered with eczema. We've seen hundreds of patients like that. But what we're entering an era where the triggers are hidden. So if someone, let's say, were sick with COVID or they had monoculosis at some point, and now we have viral reactivation, that will trigger the mast cells, and now they might either respond to triggers had been quiet for a very long time, or new triggers that are showing up now.

Emily Kate Stephens (53:04): Does it always tend to be one big trigger, like a COVID, like a virus, or that kind of analogy of a glass of water and you add a bit more and you add a bit more? So, can the do the mast cells operate in that way? So you have a virus, and then you have emotional trauma, and then you have something that you were already triggered by. Maybe it's a chemical, maybe it's a cleaning chemical.

Theoharis Theoharides (53:37): No, I agree with you. Eventually, just the glass overflows. It's just that if there is a distinct event, it's easier for a patient to understand it and convey. Let's say the physician of I remember that everything started after that. And as you said, there can be an incidence after an incidence after incidence, eventually leaving out. So it can be those small increments. With medicine, we always look for triggers because it's easier to say, "Well, there's a trigger, but we don't really look for inhibitors. I mean, my mast cells are on fire, yours may. So why? Is it one

Emily Kate Stephens (54:17): of the things that has affected you,

Gez Medinger (54:19): Jazz? Absolutely. So this came out of some of the research I did at the very start of when I got into this field in 2020 and 2021 was looking at what pre-existing conditions people had and the huge preponderance of people who are atopic. That is to say, they had asthma, hay fever, or eczema, and I am one of them. I have a hay fever and I used to get eczema. If you are a topic, there is a very high probability that you will be suffering from mass cell activation if you are suffering with a post-viral condition. And one of the things that made it very clear to me was how much better my symptoms got when I a changed my diet and avoided high histamine level foods or histamine liberating foods, and b started taking antihistamines, and I still take antihistamines to this day. And if I stop, then my skin flares up, and I still have issues with my skin now-inflammatory issues with my skin-that I know when my long COVID is bad because my skin's worse. It demonstrates itself, it manifests itself, and when I'm better, the inflammation and my skin returns to normal. All

Emily Kate Stephens (55:19): inflammation related, isn't it? You're just presenting on your body,

Gez Medinger (55:23): yeah,

Emily Kate Stephens (55:24): your inflammation

Gez Medinger (55:25): exactly. But the thing about NCAS is that it can manifest in all sorts of different ways. And yes, there are normal-ish symptom groupings. So there are the allergic symptoms that can manifest as skin rashes, but you can also have a tightening of the chest, and you can have difficulty breathing. The asthmatic type reaction as well. There are headaches which are common as well. The list of symptoms is actually mind-boggling, and this makes it particularly hard to diagnose and particularly hard to test because yes, technically there are tests, but good luck getting one that is reliable. Simply because actually the the way that those tests are run rely on cold chain transport, which is very unreliable. And even if you do get a positive test, like great, just take some antihistamines because that's all you could do anyway. So it's it's a really complex subject.

Emily Kate Stephens (56:13): Do you see the overlaps between here? So headaches is a chronic pain condition. It could also be to do with EDS or orthostatic intolerance. It could also be mast cell activation and PEM. Or PEM problems breathing are given a name of asthma, but they could actually be related to all of those things. It can also be the orthostatic, the cardiac, the the overlaps, the way that it's all separated out is problematic in us trying to understand what is actually going on in our body.

Gez Medinger (56:46): I completely agree. So I made a little while ago saying, is it dysautonomia or MCAS? Because there are so many of the symptoms that overlap, and and what I hear in the community is people labeling their symptoms as one or the other. And when you dig a little bit deeper, you often start to think actually you might be mislabeling that, and I think your problem is more disautonomic than it is MKC, or more MCASC is dysautonomic. And the easiest way to tell is usually what the triggers are, because the triggers are more distinct than the symptoms. So if your triggers are exercise or activity or orthostatic function related, or heat, or anything that requires the automic system to do things, or indeed timing of eating, because digestion is autonomically challenging as well. Then dysautonomia might be what's causing some of your symptoms and autonomic dysfunction. But if the triggers are more environmental, then MCAS might be more more likely. So when I say environmental, I mean things like pollen levels, or fuel, or chemical sensitivity, or what you eat, or what you drink. So the triggers are sometimes an easier way of working out which of those two are affecting you more. But the tricky thing is that most of us have got both.

Emily Kate Stephens (58:01): Yeah, and to play devil's advocate, I would say that some of those things that you have said, such as exercise, also could be a trigger for MCAS because essentially one of the biggest triggers for MCAS is stress. So for me, I can see it in my eczema in my hands when my stress levels are immediately get more symptomatic in terms of my eczema, and stress can form in so many different ways. And even if that is just the stress of your digestive system trying to eat too late at night, so I agree with you. Look at the triggers and try and break them down. But there's still this massive gray area of what has that trigger done to your physical or emotional state.

Gez Medinger (58:41): It's a very complex picture, and not one that immediately lends itself to instant comprehension. Unfortunately,

Emily Kate Stephens (58:49): no, longer than six years it might take to get. It's still pretty murky.

Gez Medinger (58:53): Yeah. So there was one other part that Dr. Theo mentioned that I particularly liked, and that was his the glass getting full analogy, and the question of these cumulative stresses that might end up with you ultimately in this particular example suddenly developing MCAS symptoms. Sometimes this is a bit of a controversial topic to talk about the things that we might have done in our old life that made it more likely that we were to develop complex chronic illness. So because it seems like victim blaming, or it might be taking away the responsibility from the thing that really tipped tipped everything over the edge. But the way I look at it is that let's say you've got your glass, right, and when the glass is completely full, that's the point at which the body falls into dysfunction, or the ball gets stuck in the well halfway up the hill, or the mast cells suddenly go haywire and they start behaving in ways they weren't previously. So the virus, or whatever the event might have been-bacterial infection for some, virus for others-may have put 60% water into the glass. But for the people who, previous to that point, had got nothing in the glass, that's fine. They never actually overflowed. They could have been up to 20% already. But for those of us who maybe lived a life where it was full of stressors, this sort of nervous system and metabolic and emotional levels-I'm speaking for myself here-the previous few years to catching COVID for me were incredibly stressful in every different dimension, and so the body itself was under a huge amount of stress. I was at peak marathon training fitness as well when I caught the virus, was really maxing out how much water I was putting into that glass at that time. It didn't take much of a kick actually for that 60% sender over the top, and because I'd already pre-filled it. A part of what fills that up will be genetic predisposition, so the nature of my immune system, the nature of my inflammatory response, the nature of my nervous system of the way

Emily Kate Stephens (1:00:41): that you manage stress in the body,

Gez Medinger (1:00:44): and also the burden of all of the previous infections I've had, the fact that I've had Epstein Barr before will have contributed to how my body responds to the fact that I've had chickenpox. Every single infection you've ever done shapes your immune system. So it's this very complex picture of everything that goes into that glass before the final straw,

Emily Kate Stephens (1:01:02): yeah,

Gez Medinger (1:01:03): and that's why I think we see a lot of people who fit a similar picture. It doesn't exclude the people who don't, but we do see a lot of people who who fit a similar picture in terms of whether they're suffering from fibromyalgia or whether they're suffering from ME/CFS or indeed any other complex chronic illness.

Emily Kate Stephens (1:01:19): Yeah, that they either pushed it quite hard in life, or had quite a lot of stresses on them, or that they had been through quite a traumatic time physically or emotionally previously. I agree. I hope that that gives a little bit of an overview of what you can go back and delve into in our back catalog. A lot of it is evergreen content from some of those people who have been practicing for years, and then even those people are still doing the research and coming up new theories, new treatments, new therapies, new strategies. And I love the interplay between so many of these physicians. So you will have reference to Todd Davenport in Kate and Powers' episode because they all review each other's work, review the information that comes before, and are really, really trying to develop that into something that going forward we might have some kind of cohesive understanding or possibly even a treatment plan for some of us. You can but hope. Thank you so much for joining me today. I am going to leave you all with some words of wisdom and a little, I guess, call to action from Lucinda Bateman, who is doing the research but just asks all of you to help with all of the resources from all of the people that we have shared today. I'll add them in the show notes, take their resources, and go forth and see if you can try and get better results from your clinicians.

Gez Medinger (1:02:54): Advocacy model.

Lucinda Bateman (1:03:04): What would be your hope right now? Your immediate hope in terms of the direction that we need to be heading in terms of research. I'm going to say that even more than research, and this is reflected in Bateman Horn Center's mission, is we need all clinicians to recognize all of these illnesses. Put this huge effort into provider education, and I think everybody needs to join this. Every patient should teach their own clinicians and engage them, and share with them, and find ways to teach them one-on-one about this illness, because there's no point in doing research if people don't get diagnosed. We can't carry out research, and we can't complete research if there are people to study.

Emily Kate Stephens (1:03:59): Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy-limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you, visit our website at makevisible.com.

Unknown (1:10:42): What?