Why Are You So Exhausted? with Dr. Brayden P. Yellman

[01:00] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast with your host and founder, Dr. Linda Bluestein, The Hypermobility MD. Today we will be speaking with Dr. Brayden Yellman about ME/CFS. This is such an important conversation because chronic fatigue and ME/CFS are different from one another, as he will be explaining to us, but we see this so commonly in people that have symptomatic joint hypermobility. So whether you have one of the Ehlers-Danlos syndromes or some other type of condition, I think you're going to find this really helpful.
[01:33] Dr. Yellman serves as the medical director at the Bateman Horne Center of Excellence. With a strong background in managing complex multisystemic illnesses, Dr. Yellman began his career as a clinical rheumatologist focusing on conditions such as systemic sclerosis, inflammatory myositis, and vasculitis. In 2019, he shifted his focus to ME/CFS, fibromyalgia, long COVID, autonomic dysfunction, mast cell activation, and other infection-associated chronic conditions, recognizing the urgent need for specialized clinical care and research in these areas.
[02:07] Dr. Yellman is dedicated to advancing medical education, patient care, and research, working alongside leading experts to improve diagnostic and treatment approaches for these underrecognized conditions. His work at the Bateman Horne Center has contributed to numerous clinical studies and collaborations with major research institutions.
[02:26] I am so excited to have this conversation with Dr. Yellman. As always, this information 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. Here we go.
[02:44] Okay, I'm here with Dr. Yellman, and we are going to be talking about ME/CFS and how that relates to hypermobility and connective tissue disorders like EDS. So, Dr. Yellman, it's so great to finally meet you.

[02:58] Dr. Brayden P. Yellman: Thank you for having me.

[03:00] Dr. Linda Bluestein: Can you start out by explaining to us what ME/CFS is and how that differs from general fatigue?

[03:07] Dr. Brayden P. Yellman: Sure. So ME/CFS is a term that stands for myalgic encephalomyelitis, or chronic fatigue syndrome, as it was formerly called. We don't generally go by the name chronic fatigue syndrome anymore because that understates the degree of fatigue and really functional impairment that patients will feel and experience with ME/CFS. This is a term that's been used to describe what we're now starting to call in the medical field infection-associated chronic conditions. But it really is referring to a longstanding chronic illness that develops after certain insults to the body. Specifically, we have identified insults to the immune system as triggers for this illness.
[03:57] So many times that is an infection. It can be viral infections. A really famous cause of this would be COVID-19 as a trigger for chronic illness long after that COVID infection has technically resolved. But it can also be bacterial. It can be parasitic infections. It can be other assaults to the immune system, such as a traumatic brain injury or certain major events in life that activate the immune system. Surgeries, for example — even vaccines, as great as they are and as well as they work most of the time, are designed to activate the immune system. And if it activates in an improper way and doesn't entirely shut down or calm down in the ways that we would hope, it's possible that people can develop ME/CFS.
ME/CFS is currently a kind of grab bag term that we use for a whole clinical syndrome, a full-body multi-system illness, and it does not have what we would call a biomarker, which makes it a little harder to diagnose. We can't just send a certain lab test or get imaging that gives us this diagnosis. So instead, we rely on the Institute of Medicine's core clinical criteria from 2015 — what we call the Institute of Medicine criteria — that essentially captures five criteria that are present in all people with ME/CFS. There are plenty of other comorbid conditions and other complications that people can have, but these seem to be core criteria for those of us who've been treating people with ME/CFS or infection-associated chronic conditions for our careers.
[05:37] The first of those criteria is a severe and profound fatigue that is unlike anything a person had ever experienced prior to becoming ill. They must have it for at least six months, but I think the important part here is that fatigue is functionally impairing to the degree where people cannot do the same things that they could do prior to their illness. And we're talking about huge differences — inability to work, inability to go to school, inability to learn things. Sometimes it goes all the way to inability to perform normal activities of daily living. It can become very severe, even to the point where people become essentially bedbound.
[06:18] The second criteria is the presence of what we refer to as post-exertional malaise, or PEM. This is really the core, pathognomonic criteria for this illness, and I'm going to come back to that in just a second.
[06:40] The third criteria is really nonspecific, but always present, and that is unrefreshing sleep. That can be all kinds of sleep disorders, but even when someone gets enough sleep — maybe they even spend ten hours asleep — no matter what, they still are not refreshed by sleep the way they were before. We may also see problems with insomnia. People describe being wired but tired. The more tired they get, the more activated their sympathetic nervous system is. We see people struggle with falling asleep to begin with, with staying asleep, with waking up frequently, having nightmares — lots of different types of sleep disruptions. So the third criteria is unrefreshing sleep.
[07:24] The fourth and fifth criteria, as defined in 2015 by the Institute of Medicine, require that you only have one of the two. But I would say having treated this illness exclusively for over six years, almost everybody indeed has both. One of those criteria is cognitive impairment. And this is somewhat different from the cognitive impairment we see in a lot of other illnesses. It is waxing and waning. It is not progressive. It is often very much focused on trouble with maintaining attention, concentration, and focus. So people will think they're having memory issues, but it's really that they're not encoding or paying enough attention to begin with, or are unable to process information. It will often manifest with people having significant word-finding issues. They'll often describe brain fog, or a sort of inability to access thoughts and bring them forward. And it can manifest in a lot of other waxing and waning ways. The only other kind of cognitive dysfunction that I can think of that's waxing and waning in this way is what we think of as delirium in the geriatric population. It can be a little like that, but it also has a lot of features in neurocognitive testing that are similar to how we define ADD or ADHD.
[08:45] The fifth clinical criteria is that of orthostatic intolerance — not functioning as well in an upright position. So either standing or sitting with your feet on the floor as compared to laying down supine, or even sitting with your legs elevated on a couch in a horizontal position. This is a grab bag term that's really identifying the presence of dysautonomia, or dysregulation of the autonomic nervous system's ability to control where blood flow is going and where it's getting to when you're in an upright position — when you're challenged with orthostasis. These are things that we don't have to think about normally, but become challenging when our autonomic nervous system is dysregulated. This is where things like the diagnosis of POTS, or postural orthostatic tachycardia syndrome, or orthostatic hypotension, or some of the other terms we use, fall under this category of dysautonomia and orthostatic intolerance.
[09:44] I mentioned I would return to post-exertional malaise — the second criteria, the pathognomonic criteria — because it is so important. This is a unique situation that really only occurs in ME/CFS, and it is characterized by a fatigue and impairment that is more profound and more long-lasting, and associated with significant worsening of all symptoms that a patient experiences in ME/CFS, as well as the presence of new symptoms. And it occurs, best we can tell, as a result of energy expenditure that exceeds someone's shortened or reduced limit for energy.
[10:28] So if you imagine something like a cell phone battery being at 100% for normal healthy people, that cell phone battery may be starting out at 50% for someone with ME/CFS. And it may be a very old cell phone — the kind that you can literally watch that battery tick down from 50 to 49 as you're using the phone. Just using very simple apps drains that battery quickly. That is what is happening to what we refer to as the energy envelope for people with ME/CFS. They spend energy on physical exertional activities, or even just on maintaining an upright position as compared to a supine position in that orthostatic challenge. They may be spending energy on cognitive tasks, whether that's processing things cognitively, whether it's social interaction, or even whether it's emotional processing. On a cellular level, people are still spending a lot of ATP, or energy, to have emotions — good emotions or bad emotions. Even opening presents on Christmas morning is using a lot of ATP on a cellular level.
[11:36] So it's a different level for different people and it can change throughout the course of an illness, but there's this sort of limit on how much energy is available. And if someone exceeds that limit, they can enter post-exertional malaise — this totally different physiological status. That's the way to think about this: it is an entirely different physiological state where their function is severely impaired.
[12:02] And I think it's important to point out that post-exertional malaise happens with a delay in onset. There is generally a 12- to 24-, sometimes 36- or even 48-hour delay between the energy expenditure that exceeds this limit and when the symptoms of post-exertional malaise really kick in. That's critical because there are people with orthostatic intolerance who may have POTS but maybe not ME/CFS, who may go out on a hot summer day — as I used to as a teenager in Texas in 105-degree weather — and mow the lawn. You can start to get dehydrated, feel lightheaded and dizzy, and have POTS symptoms, and then you need to go lie down because you start to feel sick. That is not post-exertional malaise. Now, that may still trigger post-exertional malaise the next day or 12 hours later, but that immediate response is a direct response to the orthostatic challenge. Post-exertional malaise is different from, and even more severe than, that — it is an entirely different physiological state.
There was a recent study done at the American College of Rheumatology looking for post-exertional malaise in rheumatological conditions. They published on self-reported post-exertional malaise in rheumatoid arthritis, osteoarthritis, and Sjögren's syndrome. And I can assure you, having practiced rheumatology, that the fatigue experienced in those illnesses is nowhere near what we experience in post-exertional malaise. It does not meet that definition. And once you've sat down and observed what this means for people, you'll never be confused again. I wish people had the opportunity to talk to people who've been through severe post-exertional malaise, because it's really an edifying experience specifically for clinical providers.
[13:58] One of the things we think about when it comes to post-exertional malaise, one of the ways we sort of screen for it clinically, is by asking about functional status in patients. I just don't think we ask that enough in clinical medicine. I was taught by Dr. Lucinda Bateman in these terms, and I've always followed this: we ask patients about their hours of upright activity. So very specifically, time in an upright position with their feet on the floor versus laying down or having their feet elevated. And we ask about things that they can and can't do.
There are sort of two states. There's what is your hours of upright activity on a quote good day — which is really maybe not a good day because they're ill, but it's their baseline status. It's the best day they may have in a month. And how many good days do you have a month? Oh, well, I have four or five days where I'm doing okay. I can be upright for three to four hours and I can walk to the mailbox. I can have a conversation for 15 minutes. I might be able to drive 10 minutes to get my kids to school. But they still can't exercise. They can't do three chores in a row. They can't read for more than 20 minutes before comprehension starts to go away. So we ask these types of questions, both with activities of daily living and just other things that are core to living life — how can you do those things, and how long can you do them before you start to fade out?
[15:26] And then that same patient may say, I also have ten really bad days per month where we assume they're in post-exertional malaise. I am upright for less than an hour a day. I can get up and make it to the bathroom, but then I have to climb back in bed. If someone brings me a meal, I can eat it there, but I can't really get up and prepare anything. I definitely can't walk out to the mailbox. I've heard people even say, if the house was on fire, I think I could get out — I'm not entirely sure — and I wouldn't get any farther than the curb. This is not just "I'm tired and don't want to" — this is an inability to do things.
[16:05] Getting the number of hours of upright activity and what they can and cannot do on good and bad days is a very simple, quick way to get a sense of someone's functional impairment and the degree to which this is disruptive to their life. And I would encourage all clinicians worried about ME/CFS, worried about long COVID, and other infection-associated chronic conditions to ask these questions in clinic.

[16:27] Dr. Linda Bluestein: Those are great questions. And I know on your website there is a link to a video that goes into detail about the battery analogy, the cell phone battery analogy. That's a great video. We can link that in the show notes so people can check that out as well.
[16:40] For patients who are struggling to get a diagnosis, or struggling to get their clinicians to pay attention to these kinds of symptoms — if they just listened to all of this and they're saying, "Oh my gosh, this sounds like me, but none of my doctors are taking me seriously, and I really struggle to explain the degree to which I have these problems" — they may hear those questions that you just mentioned and then spontaneously provide that information to their physician. But do you have any suggestions for ways that they can really get this message across to their clinicians about how significantly these symptoms are affecting them? Because I know delays in diagnosis are a really big problem.

[17:23] Dr. Brayden P. Yellman: Yeah. Prior to long COVID, it was an average of at least five years to get a diagnosis of ME/CFS. That's shortened a little bit because of greater awareness of ME/CFS, given that long COVID is often becoming ME/CFS or meeting criteria for ME/CFS in patients. So it's getting a little more notoriety. We've gone from very few physicians understanding these conditions to what's a lot better — which is maybe 10% of the general physician population.
[17:54] There's no one simple answer to that. It's something that we as a nonprofit struggle with every day. How can we mainstream this illness more? How can we provide better care? What's the right specialty to care for this? Is the medical system even set up to deal with complex chronic illness, or is it all about acute illnesses and a chief complaint and you have ten minutes to say what's going on?
[18:11] A lot of our patients — anybody with this illness, really — are given that ten-minute window to come in and express what's going on. What I would say is it's easy to get lost in a myriad of symptoms, what we call a review of systems in medical language — what's going on cardiovascularly, what's going on respiratorily, what's going on with the skin dermatologically, et cetera. Don't get as focused on the symptoms. Bring in a good summary of the functional impairment. "I used to run every day, five miles. I now, on an average day, have five good days. I have eleven bad days. I have days where I cannot physically get out of bed. I'm certainly upset that I can't, but I'm not just depressed, I'm not just anxious — something else is going on. I physically cannot do these things."
[19:18] Physicians and providers will get lost in that review of systems. But if you can very clearly state: this is how much time I can be upright, this is how long I can stand, I have an MBA and I've been to grad school and now I can only read for 15 minutes and I can't understand beyond that — I get distracted and have to pull over when I'm driving if I've driven for more than 15 minutes, or when I'm in a sensory-overwhelming environment. Giving those kinds of examples. "This is where I was. This is how I'm impaired now. This is my functional status." That is really going to help get a physician's attention.
[19:50] Now, that's not necessarily going to get us to the diagnosis, and that's where you have to bring a little bit of extra information to the table. On our website — not to plug the Bateman Horne Center necessarily, but we try to, as a nonprofit, have a lot of free resources for patients who are worried they have this, because clearly we can't take care of everybody. There's a test that we use, a passive standing lean test, or what we've referred to as the NASA lean test, which is a very simple test that you can actually do at home with some help from family members and then bring in to a clinician.
[20:31] We have a form you can print off, fill out, and bring in to show a clinician what your vital signs do. This is a test where we have people lay down in a dark room — no phones — for 15 minutes. We have them stand up, not wearing any shoes, and lean against a wall. Their heels are about 6 to 12 inches from the wall, and they're just standing there, palms forward, leaning against the wall. We measure using a pulse oximeter for heart rate, we use a blood pressure cuff to measure blood pressure, we look at oxygen level, and then observe what's happening to a patient who is just standing and leaning against a wall.
[21:09] Sounds really easy. I have to admit, I have POTS myself. Thank goodness I don't have ME/CFS or long COVID. I couldn't believe as an athlete how difficult it was to lean against the wall. And the reason is because it takes away the impact of the skeletal muscle in the lower extremities — that squeeze and its involvement in venous return to the heart, in preload to the heart, in actual circulation — while also challenging you orthostatically. And so it's a great way to elicit what we know is going on underneath: difficulties with circulation, with getting blood flow into the brain, to the muscles, et cetera, in an upright position as compared to laying down.
[21:50] You will see people's heart rate go way up. That's where we make a diagnosis of POTS — a rise in heart rate of greater than 30 beats per minute over the course of that ten minutes. Alternatively, we also see lots of changes in blood pressure, and one of the most common ones we see is a narrowing of the pulse pressure. So that's the difference between the systolic pressure — the high number when the heart is squeezing — and the diastolic pressure — when the heart is relaxing. That pulse pressure gets smaller and smaller. So if you start at 120 over 80, kind of the traditional normal blood pressure, that may drop a little bit systolically — you may get 110 — but that diastolic is going to go up from 80 to maybe even 98 or 100. So you might get 110 over 98. There's a narrowing of that pulse pressure.
[22:37] One thing that's important to remember on that test too: it's great to fill this out to show what's happening to your body and bring that into a physician, but also to explain to them that the pathology in this case is not the heart rate increase. The pathology is not the narrowing of the pulse pressure. Those are your body's secondary adaptive mechanisms for the actual pathology, which is the inability to have adequate circulation in that upright position compared to laying down. And there are some great ultrasound studies that show, on a heads-up tilt table test — which is very similar to a NASA lean test — that there actually is a global reduction of cerebral blood flow on the average of about 25% in those with these infection-associated chronic conditions, compared to 6 to 7% in healthy controls.
[23:25] So bringing a NASA lean test into your clinician and showing them what your heart rate does, what your blood pressure is doing just by standing up — that is something they can put in your chart. That is something that is objective in their minds, because there's not a biomarker. So anything you can bring in that is some form of objective evidence is really helpful.
[23:45] I would also say — and this is its own discussion topic — it's very common for people with these conditions to have something called mast cell activation syndrome. That's not part of the IOM diagnostic criteria, but it's very common among many patients with ME/CFS. Trying to identify symptoms of mast cell activation syndrome, finding objective evidence of those things, and showing pictures of rashes, et cetera, to your physician can also be really helpful.

[24:13] Dr. Linda Bluestein: And we definitely talk about the triad of EDS, POTS, and mast cell activation syndrome a lot on this podcast. So I'm really glad that you mentioned that so early on. That's very important.
So I do NASA lean tests in my office, usually at the first visit, and I do give people instructions so that they can do it at home if we didn't have time, or if they're consulting with me in a more informal fashion and they're going to be going in for an appointment with somebody else.
[24:41] With deconditioning, you would also see some changes potentially. I mean, if someone even just had the flu or something and they're kind of still recovering — I know you mentioned that you need to have the fatigue and post-exertional malaise for at least six months, so that kind of takes out the portion of people who are acutely recovering. But I guess what I'm wondering is, with the NASA lean test, are there certain things that you're looking for that would help you determine if the results are indicative of ME/CFS versus POTS versus deconditioning?

[25:19] Dr. Brayden P. Yellman: Well, somebody who's severely deconditioned could show some notable dysautonomia on a NASA lean test, but even so, I would argue that they generally don't meet criteria for POTS or orthostatic hypotension, or have drops in their pulse pressure that are greater than 25% of the overall blood pressure, for example. So that's sort of a starting point. It's challenging, but when you put things together with a medical history, I think it becomes a little more clear.
[25:53] So if someone gets a viral illness, if someone has a head injury, if someone has a surgery and then they are never the same after that — they used to have no problems with conditioning, they were generally healthy people, and all of a sudden they're not — I think that's an important clinical characteristic to think about.
[26:08] I would also say we get so worried about whether it could be deconditioning that we forget there's a person that's suffering in front of us either way. Let's say, just in a thought experiment, that someone was just severely deconditioned. That's probably only likely if they've been laid up in an ICU for a very long time, where it would be clearly obvious that's the case. But let's say someone was deconditioned and we mistakenly made a diagnosis of POTS, as it were, or we started giving them orthostatic support. Let's say we gave them IV fluids in a situation where we knew they could handle it from a cardiovascular perspective. Let's say we gave them fludrocortisone, we gave them arterial support with midodrine or droxidopa, we used pyridostigmine to enhance venous return, we used compression clothing. And they felt better. Are we really doing any harm to patients? And then as they get better, if they do — especially if it's deconditioning — you can wean those therapies off. They don't have to be long-term therapies. They can be a short bridge to someone actually exercising and getting better.
[27:22] In the case of ME/CFS, which I promise is going to be way more likely — this is what we almost always see, this is what's actually happening — those support measures are still going to help people with their functional status. The problem is you're just not going to be able to quickly wean them.
[27:40] And I think this is an important point to bring up here as well. You always have to be really careful how you say this, so I want to be very clear to everyone: there is very strong evidence that exercise does help dysautonomia, does help in deconditioning, no matter the cause. However — and this is the huge caveat — it is not helpful if that level of exercise causes post-exertional malaise, which is why that is such a pathognomonic and important feature. If someone experiences post-exertional malaise as a result of the exercise — and that may be very, very little exercise, it may not even meet our definition of exercise, it may just be walking one block or going up the stairs — if that's going to cause post-exertional malaise, you're actually doing harm to patients. You're worsening their long-term functional prognosis. They're not able to see the improvements of exercise.
[28:36] So when I treat people with dysautonomia who have post-exertional malaise, these therapies are designed to help extend that leash, extend that energy envelope, to where they can do some things without experiencing post-exertional malaise. Generally in the first year of therapy, even for people who are very responsive — and not everybody is — we need that pharmacotherapy support. We need that exogenous fluid and salt support to really help people learn to live within their energy envelope and learn to live without experiencing post-exertional malaise. And then only then, when they've stabilized, when they've been able to avoid PEM with those supports, can we start to ask: can we pull back on therapies, or alternatively, should we start by introducing careful, observable exercise? Trying to keep a max heart rate below a certain range, trying to be very careful about avoiding post-exertional malaise — can we introduce a little bit of physical therapy or exercise safely without triggering PEM and gradually make improvements?
[29:43] A lot of times we can, but that is just never first line. It's never something we really successfully get to in the first year of therapy. That step comes later. We'd love it to come sooner because, hey, it's non-pharmacological — it sounds like it's a great first-line therapy — but it never really works that way in those who have post-exertional malaise. So if you have POTS, if you have dysautonomia, if you have deconditioning — does exercise help? Yes, but only if you don't have post-exertional malaise as a result.

[30:11] Dr. Linda Bluestein: So we are going to take a quick break, and when we come back, we are going to talk about the fact there are no biomarkers, but are there some laboratory tests that can be helpful? And I also want to ask you about upper cervical instability and if that impacts the clinical picture, and genetic testing and a few other things. We'll take a quick break and we'll be back in just a minute.
[31:30] Okay, I'm back with Dr. Yellman, and I know you mentioned that there are no biomarkers for ME/CFS, which is a huge problem — and there are no biomarkers for hypermobile EDS or HSD either. So these are all clinical diagnoses, which really makes it so tricky. Are there any lab tests that can be beneficial? I know that I've read some things about natural killer cells and that the function of those can be impaired in ME/CFS.

[31:56] Dr. Brayden P. Yellman: That's very true. I generally think of those specific tests — those immunological panels — as being helpful in the research arena, but not so much in clinical medicine. They're hard to know exactly what to do with. They could theoretically be supportive if you really have concerns about making a clinical diagnosis, but I generally do not order them.
[32:17] I would say it's important to do a basic traditional lab workup for someone presenting with symptoms of chronic illness. So anything that you would think of on that workup should go into an ME/CFS workup as a basic way to make sure we're not missing something else. Basic CMP and CBC, maybe inflammation markers with ESR and CRP, definitely looking at thyroid, hemoglobin A1C. Sometimes we'll check cortisol, although there's a debate back and forth about how helpful that is — it can be low-normal or sometimes high-normal depending on the clinical circumstances and how physiologically stressed that patient is. But it's important to make sure someone doesn't have Addison's disease, for example. You don't want to miss something like that in a fatiguing illness. You want to make sure there are no signs of malignancy or chronic active infection. And those are just going to look really different. I think we're all trained as clinicians in identifying those things.
[33:19] But I would not make this an extensive — what I used to call in rheumatology — a shotgun panel, where you're just looking for everything and testing every autoantibody under the sun. I think this is true of neurodegenerative conditions as well. They have a way of presenting themselves. They're pretty obvious on clinical exam in the way they're going to present. So I would really encourage clinicians to trust their physical exam, to trust their history, to trust clinical medicine. Do the basics, make sure you've dotted your i's and crossed your t's, but it doesn't have to be an extensive laboratory evaluation.
The same goes with imaging. Some of these conditions, I think, get seen by some clinicians as diagnoses of exclusion — like you have to exclude every other illness under the sun to make a diagnosis. And that's just not true. This is a diagnosis to be made. If you look at those IOM criteria, if you really know how to ask about post-exertional malaise, if you assess hours of upright activity, if you assess good days and bad days and a functional questionnaire — I mean, we do this just screening patients to even come in to our nonprofit, to make sure we're serving the patients we're really trying to serve — it's really easy, honestly, to make these diagnoses.
[34:57] This sense that we need to rely on a biomarker for a clinical diagnosis is misplaced. Would it be extremely helpful for research? Would it make it easier for clinicians who are not well-versed in infection-associated chronic conditions to make a diagnosis? Certainly a biomarker would be great, but it is not really there right now. These extensive workups slow the opportunity to get to a diagnosis and start actually doing something about it for patients. And doing something for patients can be as simple as giving them a diagnosis and perhaps supporting a little time off from school or a little bit of extra support at work. These are things people need now. They need to start pacing and realize that they can't keep pushing themselves into post-exertional malaise, and they need accommodations. Any clinician can do that. So this is a diagnosis to be made. Getting hung up in a lab workup is a fallacy.

[35:55] Dr. Linda Bluestein: And I think for any clinicians listening to this, I'm also going to link in the show notes a paper that you are a co-author on — with multiple other co-authors who have also been on this podcast: David Kaufman, Irene Ruju, Tanya Dempsey. In that paper, there was a great table with some pretty extensive questions so that you really could get a sense of someone's post-exertional malaise and that kind of thing. So I will link that in the show notes as well so people can access that information.
[36:26] And what about genetic testing? Is that something that you ever find to be helpful?

[36:32] Dr. Brayden P. Yellman: Well, with hypermobile spectrum disorders and hEDS — which is really our most common version of presenting with a bendy body, as it were — this is a multigenic situation. There's not a single genetic test that is going to guarantee you have this particular illness. And I think it also doesn't take into account the environmental impacts of that genetic background and how things change over time, how insults to the immune system may activate mast cell activation, which is theoretically implicated in actually progressing hypermobile spectrum disorder. There's this interaction that we're still trying to learn about — whether those are even two distinct entities, and how they affect one another.
[37:16] So when I see a patient, I'm certainly assessing for hypermobility on exam. I'm certainly looking at the Beighton criteria. I'm certainly looking at the EDS Society diagnostic clinical criteria, although those are somewhat insufficient and I understand are being reviewed for consideration of new diagnostic criteria. But I don't send an extensive genetic panel.
[37:40] That being said, there are situations where you do want to make sure you're not missing vascular EDS, which is a very specific type of EDS where there's a really high risk of complications, including complications for surgery. So if I have a patient, for example, who I've been with for several years, who we are really worried about their neuroanatomy — maybe they have craniocervical instability or a tethered cord and they're looking at getting a surgical intervention for that — then I might test for vascular EDS to make sure we know we're not getting into a more complicated surgical situation that could have a bad outcome. I think that changes management.
[38:19] There is an argument to be made for testing for vascular EDS or other subtypes — or even Marfan syndrome or Stickler syndrome — when you are helping a patient apply for disability. But the problem is the absence of those things doesn't really mean that they don't have functional impairments. So that can be its own tricky web. So do I do it sometimes? Yes, but it's certainly not something I think has to be done from the perspective of a clinician caring for people. Is it more important as we continue to research? Yeah, it is.

[38:53] Dr. Linda Bluestein: In terms of upper cervical instability, have you made any observations in your patient population in terms of how often you see that overlap? And if you see that sometimes — if they do have severe enough upper cervical instability and they actually go for fusion-type surgery — whether their ME/CFS actually improves?

[39:17] Dr. Brayden P. Yellman: That is a sort of newer topic that has entered into the care of these conditions. Upper cervical instability, as you're referring to, we often call craniocervical instability. That's where the skull sits on C1, the first cervical vertebra. And then there's also issues with atlantoaxial instability, which is C1 upon C2. We're talking about an area that should be very stable with the surrounding connective tissues and not be moving around a lot. When there is a connective tissue disorder — perhaps when there is active mast cell activation in these areas — these connective tissues may become more lax, and there can be more motion at these sites. That can be horizontal motion, it can be vertical motion. It can allow for things like the brainstem to sink down a little more with gravity and upright positioning.
[40:03] Ultimately, we think that in some of these cases of instability — and in certain positions, in certain barometric pressures, with certain volume statuses for patients, all of which are dynamic conditions that can affect symptoms — there can be neurological irritation, impingement, pressure upon areas of the brainstem or the cranial nerves that actually drives symptoms of ME/CFS. That actually drives, for example, dysautonomia-based symptoms, whether that is vascular dysautonomia and orthostatic intolerance, or gastrointestinal dysautonomia with severe gastroparesis, nausea, and vomiting, et cetera.
I would also mention a close association between craniocervical instability, atlantoaxial instability, and something called acquired tethered cord — the base of the spinal cord getting tethered to the surrounding soft tissue structures, creating a downward pulling pressure and a little bit of tension in that spinal cord, perhaps even anchoring the brainstem into a neuroanatomically disadvantageous position where you're actually contributing to this type of worsened dysautonomia. That is often found comorbid with it. And then of course, in the background, we have some emerging understanding of how the venous and lymphatic vasculature also affect these conditions in dynamic and changing ways, making things more complicated.
[41:27] These are complicated diagnoses to make. There's really no agreed-upon type of imaging that is sensitive and specific for them. Different specialists — of which there are very few — can have very reasonable arguments for different ways of doing things. There's no standard of care. And yet, when you're caring for these patients over time, there are many patients who have bad orthostatic intolerance. If you treat aggressively enough, you can significantly improve that orthostatic intolerance with pharmacotherapies, behavioral therapies, and other supportive therapies. And then there are others where you provide all the same therapies that work across populations, and even though each therapy individually seems to move the needle a little, you see that patient's overall functional status is not getting better — or perhaps even slowly getting worse over time.
[42:26] At some point you come to this realization that there is a subset of people who have something upstream of their dysautonomia that is preventing clinical progress with all of the therapies we know otherwise work. That's when I start to consider or look for neuroanatomical reasons or complications that could be driving this inability to move forward. So I don't generally see a new patient and say, let's start looking for craniocervical instability. I really think of it as something we want to save for when we can't make any further progress with all the tools we have in internal medicine to help people first. When there's something clearly still not moving forward, that's when we go looking for these neuroanatomical complications. That's generally when we find them.
[43:10] So of course, I'm going to have a bias about how often I find it because I think I'm looking at the right people. And yes, in those circumstances, when we do find tethered cord, when we do find CCI, and we cannot move people forward clinically otherwise, I do see some of these neuroanatomical interventions make an enormous difference in patients' lives.
[43:25] I want to be clear: these surgeries are not a cure. You still have ME/CFS, you still have the immune dysfunction, you still have the metabolic dysfunction that is behind what we think is post-exertional malaise, to the best of our understanding of that entity. But you may take away the primary driver of symptoms of dysautonomia in particular, if you remove those neuroanatomical complications.
[43:56] Sometimes that does involve a craniocervical fusion, which is a really, really big deal — something we want to save only for the most severely ill patients who are just not making any further progress. But sometimes if you also notice a concurrent tethered cord, I have seen a lot of cases now where people will go for a tethered cord release, and upon releasing the tethered cord — which is a way safer, easier surgery relatively compared to a CCI surgery — their dysautonomia symptoms get better over time. In other words, that anchoring of the spinal cord may not be pulling the brainstem into quite as disadvantageous a neuroanatomical position. And while CCI still exists, it may not be as unconquerable as far as its constant ability to exacerbate dysautonomia and drive symptoms.
[44:50] For example, if that tethering goes away, the brainstem slightly shifts to a point where it's not as irritated. You can then layer on very specific, careful physical therapy to help provide better cervical support. There are things that people can do from a positioning perspective, a motion perspective, to try to protect or prevent the brainstem from getting back into those neuroanatomically disadvantageous positions. And they can live with CCI without the same severity of symptoms they had prior to that tethered cord release. So I often look for that first and try to approach it on a slightly more conservative basis.
[45:23] All of this is on the scale of tens of patients, not hundreds. We still have a lot to learn about these situations. But there are times when people get stuck and there's no way to move forward otherwise — and that's when we start looking. I think we're learning more about how to have good outcomes in these situations.
[45:42] I think it's important to point out that I would never send someone to one of these surgeries without really feeling that I've done a great job controlling mast cell activation. I think that's important to clinical outcomes and to healthy recovery. So there's a lot we're still learning. It's really complicated. There's no standard of care, but it is relevant, and we're going to be learning more about this in the upcoming years.

[46:03] Dr. Linda Bluestein: And actually, it's funny timing because the episode that came out yesterday — now this will be released in a few weeks — was with Dr. Petra Klinge, who obviously is a neurosurgeon and does lots and lots of tethered cord surgeries. And I've also interviewed Dr. Paolo Bolognese. So I'll link both of those episodes also in the show notes so people can learn more about tethered cord and cervical instability, CCI and AAI, as well.
[46:29] And I want to talk about treatments. You have already mentioned fludrocortisone, midodrine, IV fluids, and a number of different things. There are no FDA-approved treatments for ME/CFS, correct? So these are all off-label — which is the same situation as EDS, where there are no on-label treatments and everything's off-label. Could you talk about how you approach the treatment of these symptoms and what you find most effective?

[47:06] Dr. Brayden P. Yellman: So I agree that most of the tools that we use are in some ways considered off-label. But I would actually point out — and forgive me if I'm not as up to speed as I should be — I know there have been studies from David Systrom's work that have shown that pyridostigmine absolutely helps in ME/CFS and long COVID situations. They've been reviewed, and I know they were under review by the FDA. We're relatively certain that at some point, if it hasn't already happened, pyridostigmine will become an FDA-approved or recognized treatment for ME/CFS. So I did want to point that out.
[47:45] But you really start with the comorbid conditions. You don't look at someone with ME/CFS and just treat it as ME/CFS. You have to start breaking things down into subcomponents. And I think this is true in the care of lots of complex chronic illnesses — I think it's true of my rheumatology colleagues when they're looking at something like lupus, which is a multi-system illness, and thinking about what systems are affected and how are you going to help with those specific issues.
[48:09] Are there FDA-approved or recognized treatments for POTS and orthostatic intolerance? Yes. That's where IV fluids, compression clothing, oral fluid and salt loading, fludrocortisone, midodrine, and droxidopa really come in — those are kind of recognized for that comorbidity.
[48:30] We have a long way to go in our understanding and dissemination of knowledge when it comes to mast cell activation syndrome. But if that is present, we actually have a lot of tools that are known to be mast cell stabilizers and that can affect mast cell numbers, et cetera, and can really help reduce the symptoms and secondary and tertiary comorbidities associated with that illness.
I also screen patients for a degree of what I generally refer to as sympathetic overdrive — this constant activation of the sympathetic nervous system. Yes, sometimes that is directly a result of the physiological stressors they're undergoing in dysautonomia, but there can be an additional component that's really difficult to treat. So I will use things that we know calm down the sympathetic nervous system. Clonidine has been used for years and years for blood pressure. In this kind of situation it can really drop blood pressures when they're raised because someone is in urosepsis, or having a heart attack, or because they have high cortisol levels, because they're under physiological stress. It's an alpha blocker — it's blocking sympathetic signaling. Same with beta blockers. That's really why we use beta blockers: not because slowing the heart rate is a treatment for POTS specifically, but because it reduces cortisol response, catecholamine response, and the overall secondary symptomatology of that huge surge of physiological stress that people are experiencing.
It sounds blasphemous, and a lot of people disagree with me, but this is a field where I think benzodiazepines are really helpful for sympathetic overdrive. We always refer to them as not being great medicines because they don't address the core underlying features of anxiety — it's the neurotransmitter levels that are different. But when someone's having POTS symptoms, when they can't be upright and their body's sending distress signals, that peripheral nervous system effect of benzodiazepines is beneficial. It helps people tolerate other medicines that they don't otherwise tolerate. I've seen people who take a Tylenol and don't sleep for two days. And is that the pharmacological response to acetaminophen, or is that a hypersensitive neurological response to it that can be mitigated with tools we have? Absolutely the latter.
I also assess for the impacts of hypermobility, of small fiber polyneuropathy, of fibromyalgia, of gastrointestinal dysmotility, of possible vascular complications like May-Thurner or Nutcracker syndrome or median arcuate ligament syndrome. I assess for the neuroanatomical complications we just discussed, and you kind of break it all down into those components and try to provide individualized treatments for each of those comorbid conditions. Some of those are FDA-approved, some are just accepted in the field, and then there is a lot that's still off-label but also safe — things we've been using for thirty years in medicine.
[51:26] For example, I'm thinking about the use of very low-dose aripiprazole — two milligrams or less seems to be really helpful for reducing sensory sensitivities to bright lights, loud sounds, and multiple things going on in a sensory environment around us. We know that two milligrams of aripiprazole or less is generally safe and well-tolerated. We use dextromethorphan — over-the-counter dextromethorphan — up to 15 milligrams three times a day, sometimes less. And some people find that it helps reduce the incidence, duration, or intensity of their post-exertional malaise, or helps them avoid post-exertional malaise to begin with. Is this an off-label treatment that clinicians should feel scared to use? I mean, it's dextromethorphan. There are a lot of examples like that, off-label but still really helpful, that we can use without fearing harm to our patients or fearing legal retribution.

[52:25] Dr. Linda Bluestein: And when it comes to benzodiazepines, given the potential risks for dependence and things like that, are there any certain precautions that you take, or do you dose them in a certain way to help mitigate that?

[52:43] Dr. Brayden P. Yellman: I will say in treating people with ME/CFS and using benzodiazepines — do people develop a physical dependence? Of course they do. But they also develop physical dependence on all kinds of medications. Look at venlafaxine, for example, and how hard it is to get a patient off of that.
[53:03] What I haven't seen is psychological addiction or psychological dependence. I just haven't seen it in ME/CFS patients with these drugs. It sounds concerning when they say, "I take lorazepam and that really helps my symptoms." But if you really get down to why they're having the symptoms in the first place, in what ways it's helping, if you're really paying attention to how they're using it, when they're using it, giving them clear instructions — I just haven't seen misuse of these drugs at all.
So yes, a physiological dependence is not great. Is there an association with long-term benzodiazepine use and potentially earlier dementia? Yeah, there are concerns there. But I would argue: if you have a patient with untreated orthostatic intolerance for years and years, and you don't identify that, and there is actually globally reduced cerebral blood flow — might that ultimately be a risk factor for cognitive decline in the future? We don't have the data, but I think it's reasonable to assume it could be.
So I would apply the same precautions we would have for using benzodiazepines in any other circumstance, but not this terrible fear, this idea that they have no place in medicine anymore. I liken it to NSAIDs and to opioids. At one point, NSAIDs were considered the greatest, and then they caused gastrointestinal ulcers and renal disease, and then you can't use them at all. And then you use opioids, and now we find out how awful opioids are. There's a time and a place for everything to be used responsibly, and you just have to consider the circumstances. So I take that approach to benzodiazepines as well. Again, this is not to say this is the only treatment or the major treatment, but it's a tool that we've been using for years and years in medicine that we shouldn't forget about.

[54:44] Dr. Linda Bluestein: Yeah, I think that's an excellent point because the pendulum tends to swing so far in one direction and then so far in the other direction. And a lot of people tend to look at things very black and white, but these cases are so complex and patients have such poor quality of life in so many instances. So we have to really weigh the risks and benefits of everything that we're doing and really think about the person in front of us and how we can really help them to feel better. Are we really doing them a disservice if we don't prescribe something just because we're afraid of potential problems like that? So I think those are excellent points.

[55:26] Dr. Brayden P. Yellman: Yeah, you can make the same argument for how we are perhaps undertreating pain now with our fear of using opioids in the acute setting. That's very different than chronic use, but that's another conversation.

[55:39] Dr. Linda Bluestein: Definitely. I've seen some really troubling things along those lines, and it really is crazy. So before we wrap up, I just want to ask if there's anything in particular that you're excited about from a research standpoint, or any particular projects that you're working on.

[56:00] Dr. Brayden P. Yellman: We always have several projects cooking in the background. It's hard to say too much until we get a little further into them. But in general, a couple of things I'm mostly excited about.
[56:15] One of the black boxes in this field has been how do we address — and you probably haven't heard me say anything about it yet — the metabolic aspects of this illness. The clear inability to provide as much ATP, to have as much aerobic metabolism before we switch into anaerobic metabolism. And that is clearly part of the illness. Is it the driver? Is it secondary? We're still trying to learn that. What's its role in PEM? Is it why we have PEM? These are all things still to be discovered. There's been a lot of great research done in that field. But we are finally starting to crack the egg just a little bit on some treatments that might be beneficial for improving just the overall weight of fatigue — the heaviness, the absence of energy. That's a really exciting area where we may see some progress in the next five years.
[57:06] And then in general, as horrible as COVID-19 was acutely, and also from a long COVID perspective, there is a silver lining: it has mainstreamed and legitimized these illnesses. More clinicians are aware of this type of symptomatology. More clinicians are ready to listen to patients, to not dismiss them, to not just say, "You have the yuppie flu," or "You're just being lazy," or "You're just tired," or "You're just depressed," or "You're just anxious." There is a tide changing, and people with these illnesses are going to be treated like they should have been treated all along — with a little more respect and with some real empathy for what they're going through. They will start to receive, at a very basic level, what we talked about before: just support from their clinicians to have time off of work, to not feel like they're crazy when they can't do things, to have their family members speak to the clinician and understand what their loved one is going through so they don't gaslight their own family member. There's a real change happening there as well. So those are some things to be excited about.

[58:17] Dr. Linda Bluestein: And the gaslighting is definitely a huge problem that people really suffer from. And I always like to end every episode with a hypermobility hack. Do you have a hack that you can share with us?

[58:31] Dr. Brayden P. Yellman: So this is really for patients when you're talking to your clinicians, and I think it's going to help all of us learn a little bit more about the dynamics of hypermobility.
[58:41] When you have a symptom that is intermittent, or that waxes and wanes, or that's worse at certain times versus others, think about your position in space. What is your body doing? Are you upright? Are you partially reclined? Are you laying down? Are your legs elevated? Are they on the floor? Is your back flexed or extended? Is your neck rotated? Are you flexing or extending your neck? It also seems to be important — for patients that I see being in Salt Lake City, Utah — whether you're at altitude or at sea level. What is the barometric pressure?
These types of details, when you have symptoms that come and go, that worsen and get better, are things that we've found to be relevant. And there are different relevances for different patients. Understanding, "hey, the longer I'm upright as the day goes on, these symptoms get worse," or, "I wake up with severe symptoms, but as I get into an upright position, things start to improve" — looking for those kinds of patterns, and how position and biomechanical arrangement in space, what your posture is, where your head is rotated, et cetera — these are details that can really help clinicians figure out what's going on in a very dynamic situation where the anatomy is, to some degree, different for everybody with connective tissue disease. So think about those variables when you're examining your symptoms and how they affect you.

[1:00:18] Dr. Linda Bluestein: I love that. And I'm in the Denver area right now — in Littleton — so I'm a little under 6,000 feet, and I just had some friends here. This guy was super fit and we went up to about 8,000 feet, and oh my gosh, it was amazing, the difference. So those are great tips. I really appreciate that. And where can people learn more about you and the fabulous work that you're doing?

[1:00:43] Dr. Brayden P. Yellman: The best place to learn more about what we've talked about today is probably our nonprofit's website. This is the Bateman Horne Center of Excellence — B-A-T-E-M-A-N H-O-R-N-E Center. We have all kinds of YouTube videos and educational resources that are designed for clinicians, for families, for patients. We have links to how to do the NASA lean test at home. You could really lose yourself on that website. As a nonprofit, it's really our mission to try to get this information out so that more people can access it. It's all free, and we're always updating it. So please take a look there for any additional learning that you may want to pursue.

[1:01:32] Dr. Linda Bluestein: Well, I'm so grateful to you for taking the time to chat with me today. I know that you're very busy. I know people are really going to enjoy hearing this conversation and will find it very informative. So thank you again.

[1:01:44] Dr. Brayden P. Yellman: Thank you, Linda. It was a pleasure.

[1:01:51] Dr. Linda Bluestein: Well, that was such a great conversation with Dr. Yellman about ME/CFS — something that I feel is so misunderstood. We know that delayed diagnosis is really, really common and very problematic. So I hope that you will share this episode with other people who are potentially suffering from ME/CFS, or with clinicians who might be seeing this population.
[1:02:13] I want to thank you for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. You can help us spread the word about joint hypermobility and related disorders by leaving a review and sharing the podcast. This really helps raise awareness about these complex conditions.
[1:02:29] If you would like to dig deeper, you can meet with me one-on-one. Check out the available options on the services page of my website at hypermobilitymd.com. You can also find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, Twitter, and LinkedIn at hypermobilitymd. You can find Human Content, my producing team, at humancontent pods on TikTok and Instagram. You can also find full video episodes up every week on YouTube at Bendy Bodies Podcast.
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