The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
Discuss the article on the Forums.

The Stanford Paradox... Could it be showing a link between EIA and PEM?

Discussion in 'General ME/CFS Discussion' started by Amelie, Aug 18, 2017.

  1. TLDR version available here. :D

    So I recently saw this entry on Health Rising ( ), and it got me thinking...

    We already know that physical activity can act as a pseudo-allergen for people who, like me, are diagnosed with Mast Cell Activation Syndrome (MCAS), as well as those who suffer from other types of Mast Cell Activation Disorders (MCAD).

    We also know that there is another health condition, still largely unexplained, called “Exercise Induced Anaphylaxis” (EIA), where someone doing physical activity will suddenly present the same symptoms as someone going through anaphylaxis, to the point where the reaction can be life threatening.

    And we also know that not every allergic reaction (or pseudo-allergic reaction, as the case may be) involves anaphylaxis. Some of the milder symptoms may include vertigo, dizziness, nausea, gastrointestinal issues, itching, fatigue, brain fog, flushing, sweating, and so forth.

    Before being diagnosed with MCAS (i.e. during the 7 years I’ve lived with a CFS/ME diagnosis), I used to describe my “post-exertional malaise” (PEM) as being the rough equivalent of feeling drunk or drugged. I had a lot of brain fog, dizziness, nausea, sometimes palpitations. At times, I could get a bit of paresthesia in the hands and feet; but basically, I just felt generally “unwell” and weakened.

    Sometimes, the only immediate PEM I felt was a slight sense of general weakness and tiredness. Instead, it was the day after, and/or the day after that, that most of the symptoms would occur. But once they did, it could take me days, weeks, or even months to recover.

    So, the reaction itself could be either immediate, delayed, or both. However, once the pseudo-allergic reaction to physical activity was triggered, it almost always took me a very long period to be able to recover from it.

    Most of the time, it depended on my level of exposure to the pseudo-allergen. i.e. Physical activity in more intense doses (ex: going to a medical appointment) would typically take me a longer time to recover from than in smaller doses (ex: taking a bath at the end of a “better day”).

    Therefore, this study is really making me wonder if the PEM that is found in patients with a CFS/ME diagnosis, MCAS, and perhaps even a certain number of other patients suffering from other types immunological disorders couldn’t be, in fact, a variant of EIA. At the very least, in a certain subgroup of these patients.

    Whereas EIA might involve the more immediate and sometimes life-threatening symptoms of anaphylaxis, post-exertional malaise might involve a milder, pseudo-allergic reaction to physical exertion (of virtually any kind and/or intensity), accompanied by a delayed systemic immune reaction.

    Because, while physical exercise has been shown to decrease systemic inflammation, fatigue, and increase physical endurance in patients with fibromyalgia, systemic lupus, Crohn’s disease, and so forth; there have been exceptions within those groups.

    And those exceptions are often dismissed as suffering from anxiety, and/or having developed some type of phobia towards physical activity causing them to entertain catastrophic thoughts regarding the potential negative impact that said physical activity could have on their ability to properly function, the intensity of their pain, and all of their other symptoms.

    We tend to believe that they just have a harder time tolerating certain levels of discomfort compared to other patients suffering from the same illnesses, and/of finding the motivation to put in the required efforts to fight the deconditioning they acquired during the more acute stages of their illness.

    Sometimes, however, the burden of the overall disease is still recognized, and those patients are encouraged to implement certain techniques to avoid depleting their energy reserves within the day. Since one of the most popular models uses spoons as energy units to illustrate how pacing works, patients suffering from many chronic illnesses will often nickname themselves “spoonies”.

    And when you read entries from blogs belonging to spoonies that are homebound or bedbound, what you may find are patients describing a reality that is very close to what is experienced by patients with a CFS/ME diagnosis.

    Should they meet a doctor familiar with CFS/ME fatigue, they will tend to be given both diagnosis. Ex: a patient suffering from both CFS/ME as well as systemic lupus.

    So, with time, it seems that the concept of what Myalgic Encephalomyelitis is has moved away from the epidemic infectious illness that was initially described following the Royal Free Hospital outbreak, to instead include all the cases where such a disabling fatigue, accompanied by an aberrant response to physical activity, has been found.

    That type of CFS/ME fatigue, combined with PEM, is often believed to be what differentiates CFS/ME from all other chronic illnesses where chronic fatigue is involved. And I’ve seen people go as far as suggesting that the 2 days CPET (cardio-pulmonary exercise testing) protocol developed by Staci Stevens should be used to diagnose patients as having CFS/ME.

    Except I did the 2 days CPET protocol back in 2012.

    On the very first day of the test, I was already a little more exhausted than usual from all the traveling I did to get from the area of Montreal (Qc) to Ithaca (NY); so my anaerobic threshold was already abnormally low at 2.1 METS (which is about the effort required for washing hands, or leisurely typing on a computer).

    Thus, we didn’t see a huge difference between day 1 and day 2 in terms of the anaerobic threshold itself (7.46 ml/kg/min vs 7.27 ml/kg/min).

    Except, my VO2 Max values decreased from:

    Day 1: 6.2 METS, to
    Day 2: 5.7 METS.

    Those results are highly typical of patients diagnosed with CFS/ME.

    I did the same test again in 2014 in Ottawa (as part of a research project to see if the technicians of the hospital the test was being done in were sufficiently comfortable applying Steven’s protocol), and while there were a few issues with some of the data collected (they somehow failed to identify the anaerobic threshold on the very first day), the reviewing doctor still concluded that the results of:

    Day 1, were compatible with mild to moderate deconditioning, and
    Day 2, were compatible with a pulmonary vascular disease which is mild to moderate.

    So, we could still see that “something” was going on there between day 1 and day 2.

    And the interesting thing is that, no matter where the “mast cell degranulation threshold” in response to physical activity would be in a MCAS patient like myself (assuming that’s indeed what is happening), having the patient reach maximal effort would technically ensure that they would reach it, and mast cell degranulation in response to physical activity would inevitably occur.

    Of course, this would likely happen only in patients for whom physical activity might be a trigger for mast cell degranulation. Some patients with MCAS - just like some patients with lupus, fibromyalgia, Crohn’s disease and so forth – can be slightly more tired than the general population, yet they seem to be able to tolerate physical activity, and/or even get some relief from their symptoms with a gentle exercise routine or program.

    But I couldn’t. Physical activity above a certain level of intensity almost never failed to trigger PEM and worsen my symptoms, like all patients that are being diagnosed with CFS/ME.

    And since January 2016, I’ve been receiving Xolair (Omalizumab) treatments, 300mg s/c injections q. 4 weeks.

    Few months later, in October 2016, I was spending the whole day in New York, visiting the city and being able to walk 20 km in a single day (with some rest periods to eat or sit down a bit), without suffering from post-exertional malaise on the day itself, or the next!

    Before those treatments, I could not even walk the distance between my partner’s car and the doctor’s office if I had a medical appointment in a hospital. Thus, he had to push me in a wheelchair. At home, I needed someone to cook and prepare all my meals for me, because all I was able to do was re-heat them in the microwave, and even that required rest afterwards. I was virtually homebound, and if I hadn’t been living with a partner, I never would have been able to care for myself.

    So, I believe that this is a pretty dramatic improvement achieved in barely 10 months of treatments.

    Today, I can do 1 hour of fast paced walking + 45 minutes of light weight lifting as part as my rehabilitation program routine twice a week, and 1 hour of dance practice every day of the week without having to “pay for it” afterwards.

    I can’t say for sure if physical activity still triggers some level of mast cell degranulation. Basically, all I know is that PEM is no longer a phenomenon that I can consciously detect following physical exercise (or nowhere near the level I used to). And other triggers, such as exposure to sunlight, car vibrations, environmental and food sensitivities and intolerances, and so forth aren’t triggering any of my other symptoms anymore.

    So, I am sharing all of this right now, because I believe that the link between exercise induced anaphylaxis (EIA) and post-exertional malaise (PEM) in CFS/ME patients, and perhaps other “spoonies” suffering from a vast array of chronic infectious and non-infectious diseases, might genuinely be worth exploring.

    Basically, what I’m wondering is, could it be possible that there are many other diseases out there that could trigger secondary mast cell activation syndrome in some (genetically predisposed, perhaps?) patients? And/or many other diseases out there where mast cell activation might play a pivotal role in the overall pathogenesis and/or the chronicity of the disease?

    Among those mast cell activated patients, could some of them also suffer from a pseudo-allergic response to physical activity?

    Essentially, what if, for the vast majority of systemic lupus patients, for example, physical activity DID reduce inflammation, and thus brought them some relief from their symptoms, including the fatigue?

    What if, because of those patients with a normal and positive response to physical activity, we’ve always assumed that physical activity was perfectly safe for all systemic lupus patients?

    What if we’ve unwittingly been missing that, in some systemic lupus patients, a pseudo-allergic response to physical exertion occurred. And that pseudo-allergic reaction instead contributed to the systemic and chronic inflammation found in their illness, thus worsening their symptoms and the fatigue itself?

    What if the fatigue, that many seem to believe is exclusive to ME/CFS, was a form of disease process common to many different chronic health issues involving the immune system, and we’ve made the mistake of assuming it was unique to a single group, turning a common disease process into a single clinical entity/disease instead?

    And if my theory, based on my own extremely limited understanding of those pathologies, made any sense, could it be possible that this is exactly what is shown to happen here, in this very particular study?

    Because recently, another study by Dr. Theoharides’ team ( ) showed that, when mast cells (that are neither damaged nor dying) are activated, their mitochondria will move closer to the cell’s surface, where they will released their mitochondrial ATP and DNA extracellularly.

    Some of these components – the mitochondrial DNA at the very least – can travel through the blood circulation, and then even reach and go through the blood-brain-barrier (BBB).

    Once released into the extracellular space, that study has shown that these mitochondrial components are mistaken by the immune system for pathogens. Their presence triggers, once again, mast cell degranulation, thus causing them to send signals to the other cells of the immune system to go fight and destroy those pathogens.

    And here, if I understand correctly, Dr. Wang hypothesized that those peripheral blood mononuclear cells (PBMCs) are in a state of activation caused by “something” – an “innate pathogen” released during mast cell degranulation, perhaps? – that causes them to switch from catabolism to anabolism, where they become more reliant on glycolysis for their ATP needs.

    In patients affected by EIA and MCAD, we know that physical exertion of any kind can be a potent trigger for mast cell degranulation.

    And mast cells just so happen to be the little sentinels of the immune system, responsible for signaling those PBMCs (lymphocytes T, B, NK, monocytes…) through the release of cytokines, chemokines, and other mediators.

    Interestingly enough, I believe that CFS/ME patients have also been associated with very high concentrations of cytokines in their blood, too.

    So, if we go with the theory that a pseudo-allergic reaction to physical activity is what could be happening in CFS/ME patients (just like it is what we assume is happening in a subgroup of MCAD patients), perhaps a patient diagnosed CFS/ME’s response to physical activity could look a little like this:
    1. physical activity triggers mast cell degranulation;
    2. during mast cell degranulation, the mitochondria move to the cell’s surface, where they release their mitochondrial ATP and DNA extracellularly;
    3. the mitochondrial ATP and DNA enter the tissues and blood circulation, where they are mistaken for pathogens, thus triggering mast cell degranulation (autocrine inflammatory response);
    4. during mast cell degranulation, mast cells signal PBMCs to go attack and destroy those innate pathogens (paracrine inflammatory response);
    5. to destroy the mitochondrial ATP and DNA, the PBMCs switch from catabolism to anabolism;
    6. thus, PBMCs become more and more reliant on glycolysis and non-mitochondrial sources of ATP production.

    During that whole process, the body of a person with a CFS/ME diagnosis (and or MCAD), would therefore be consuming massive amounts of ATP to satisfy its energy requirements, including:
    - providing the energy needed to maintain its vital functions,
    - providing the energy needed to perform the physical activity itself,
    - providing the energy needed for mast cell degranulation, triggered by the physical activity,
    - providing the energy needed for mast cell degranulation, caused by the presence of extracellular mitochondrial ATP and DNA in the tissues and plasma,
    - providing the energy needed for the other cells of the immune system involved in the body’s defense against pathogens to go attack and destroy the extracellular ATP and DNA released by the mitochondria, and
    - providing the energy needed for the other cells and organs of the body to deal with the overall organic stress caused by systemic inflammation.

    So, assuming we would ask that particular patient to perform two CPET within 24 hours of each other, we just might get the following results:

    Day 1 : Physical activity triggers a pseudo-allergic reaction leading to systemic inflammation.

    Assuming the patient is well rested on day 1, it is highly possible that the results obtained during the first day of testing would be compatible with physical deconditioning, given that CFS/ME patients tend to greatly avoid or limit their exposure to whatever triggers their symptoms on a day to day basis.

    Day 2 : Since the body usually needs from 24 to 48 hours to recover from an allergic reaction, either the person would be barely recovered, and still need some rest to replenish their energy reserves. Or, their PBMCs might still be fighting an “ongoing infection”, thanks to the mast cells having confused their own extracellular mitochondrial ATP and DNA for pathogens.

    With those ATP levels already partially depleted at the very beginning of the exercise, and/or the PBMCs still activated and attacking the extracellular mitochondrial ATP and DNA; if you ask the patient to do another CPET, it makes a lot of sense that both the anaerobic threshold and the VO2 Max would be reached that much faster.

    It’s not that the patient would have a hard time producing the ATP required to sustain the physical effort during the exercise, but rather that a huge amount of ATP – both mitochondrial and non-mitochondrial – has already been produced and used up before the patient even had a chance to begin the exercise!

    And to make matters worse, you are also exposing that patient to the same pseudo-allergen that triggered the whole inflammatory response on the first day.

    You can therefore assume that if you were to ask the same patient to perform yet another CPET on a third day, they’d once again be getting a worse result than they did on day 2. Albeit, the difference between the two might be less spectacular (perhaps similar to my own test results, since I was already in a state of mast cell activation on day 1).

    And it would be getting worse, and worse… Until at some point, such prolonged exposure to a pseudo-allergen might lead to alterations in the number, structure, and function of the cells of the organs and systems affected by the chronic pseudo-allergic reaction.

    Using graded exercise therapy in CFS/ME patients would therefore make just about as much sense as using graded gluten exposure therapy to treat coeliac disease patients, and then wonder how come they’re not doing any better.

    Come on now, we’ve been increasing the gluten you must eat each day SLOWLY… Surely you must feel better each time you’re eating gluten now!

    So, there is a very good reason why MCAD doctors encourage their patients to exercise only within their own safe personal limits. Prolonged or constant exposure to something triggering mast cell degranulation does not make someone feel better!

    And should this theory be making any sense, it might also mean that the immune system of CFS/ME diagnosed patients would produce and invest huge quantities of mitochondrial energy (ATP) and non-mitochondrial energy (ATP) into attacking and destroying their own mitochondrial energy (ATP).

    Good job! That’s ATP well spent!

    And, of course, we haven’t even begun to consider all the multi-systemic symptoms and malaise that can be triggered through mast cell mediators release following exposure to the pseudo-allergen (physical activity) into the equation.

    Nor have we spoken about the risk of the patient being exposed to other triggers for mast cell degranulation while at rest. If we take example on MCAD patients: heat or cold, certain smells, sunlight, positive and negative stress, certain chemicals (even completely non-toxic and 100% natural ones), the vibrations from a car, noises, etc. Thus, maintaining those high energy (ATP) production and consumption levels, even while the person is at rest.

    So, the density of those folds in the cristae of the mitochondria being increased in those exhausted patients suffering from PEM being observed here? Yeah. I would think so.

    If, for a MCAS patient like myself, getting dressed is enough to trigger a pseudo-allergic reaction, I have no trouble imagining it happening in CFS/ME-diagnosed patient as well.

    Therefore, the more it goes, the more I am getting highly confused and intrigued regarding what the difference between Chronic Fatigue Syndrome and Mast Cell Activation Syndrome might be.

    First, the chronic fatigue and PEM found in MCAS patients have a very good chance to be a mast cell mediated inflammatory response.

    Either that, or I was, indeed, suffering from both CFS/ME and MCAS.

    If that is the case, however, this would mean we might have found a monoclonal antibody, Omalizumab, with mast cell stabilizing effects, that just happens to be effective against both CFS/ME fatigue and PEM in a patient with a 2.1 MET anaerobic threshold, and a VO2 Max that decreased 8,8% in response to physical activity.

    Otherwise, the most common symptoms consistently reported here by patients with a MCAD ( ) greatly resemble many of the symptoms found in the Canadian and International Consensuses (yes, I did fit those criteria, too).

    MCAS also happens to be linked to POTS and EDS, in such a way that they may be sharing a common genetic mutation. It’s also often found in patients with fibromyalgia and/or IBS. Lyme disease might be a potential trigger for mast cell activation… And all these conditions are also highly linked with CFS/ME diagnosed patients.

    And the thing is, unless monoclonal, MCAS is no more a disease than CFS is. It is a syndrome. All it really means is “mast cells are abnormally degranulating in an exaggerated manner spontaneously, randomly, or in response to triggers that should not be causing an allergic response”.

    But, as a patient with the idiopathic form of MCAS, I have absolutely no clue why my mast cells are (mis)behaving that way. Innate or acquired genetic mutation? Another underlying disease we have missed that’s causing the aberrant mast cell activation? Who knows?

    So, I’m thinking mast cell activation might just be something that could be found in a hundred of different chronic diseases involving the immune system! Including possibly subgroups of people with Lyme Disease, ME (according to Dr. Hyde’s definition), systemic lupus, Crohn’s disease, and so forth.

    And among those patients, perhaps some of them have developed a severe chronic “allergy” to physical activity, and were never those lazy, unmotivated individuals that are refusing to activate themselves (Ha! Good one! Turns out they’re likely more activated and most people will ever get to be! ; ) ).
    Last edited: Aug 19, 2017
  2. Wonko

    Wonko Senior Member

    The other side.
    Interesting, but several times longer than I can read, let alone process, ATM

    2 things jump out at me tho

    Exercise lowering inflammation is the opposite of my experience or as far as I know anyone who uses free weights (I don't any more but did). I routinely puff up on any day not dedicated to rest.

    Your theory may be able to explain cases of PEM induced by physical activity, I don't know yet, not being able to absorb enough of it yet, but it seems to specifically exclude PEM caused by other factors. I experience PEM caused by other factors, given that I can, mostly, limit my physical activity to keep PEM levels under control what typically causes PEM in my case is cognitive exertion, this is the dominant cause of PEM for me now.
    Subtropical island, JaimeS and Amelie like this.
  3. msf

    msf Senior Member

    I read most of it, and got the gist I think, but I think that PEM will eventually be shown to be driven by changes in gut permeability.

    One question this raises (which you may have already answered in your post) is the following: if ME is a form of mast-cell disorder, why do only some people with ME show clear symptoms of mast-cell deregulation? Do they have two different types of mast-cell disorders, or just a more severe version of the condition you are proposing?

    Oh, and I would consider turning your post into several blogs, and saving this thread for discussion. I am doing the same thing with a few ideas I´ve had. On that note, my blog also referenced Dr. Wang´s work, but I wasn´t aware that she has talked about an ´´innate pathogen´´ - could you tell me where this quote is from?
    Last edited: Aug 18, 2017
    JaimeS and Amelie like this.
  4. jpcv

    jpcv Senior Member

    SE coast, Brazil
    Congratulations, I can see your treatment is going very well, i would never have tehe energy and focus to write such a long article ! As a matter of fact, i almost crashed after reading it !;)
    I´m inclined to accept that ME/CFS are /is a syndrome rather than a single disease; maybe those cases decribed by dr Hyde that show brain lesions and important neurologic symptms could be the manifestation of one single infectious disease...
    But how to accept that diferent pathogens cause the same disease: Me/cfs can develop after a viral infection and after Giardia infection, like the outbreak that occured in Norway.

    regarding the release of ATP: Dr Naviaux recently in Stanford symposium told that extracelular release of ATP signals an alert to the cells that could shift its metabolism.
    JaimeS, Amelie, Wonko and 1 other person like this.
  5. @Wonko, I'm not necessarily excluding PEM caused by any other factors. Simply proposing a model of what might be happening in, perhaps, a subgroup of patients with PEM and/or the type of fatigue that is found in people with a CFS/ME diagnosis.

    Basically, I'm trying to understand how we were able to get rid of my CFS/ME-like fatigue and PEM through the use of a medication with mast cell stabilizing properties.

    I've also been thinking about the similarities between exercise-induced anaphylaxis and post-exertional malaise for quite some time now, but it's the very first time I see a research article suggesting that a CFS/ME patient's cells are producing over twice the amount of non-mitochondrial ATP (most likely via glycolysis) compared to a healthy individual, rather than suffering from energy production issues.

    Hence my excitement! Especially since they were studying the mitochondria of PBMCs specifically, and Dr. Wang brought up this theory (that was raised by Dr. Maureen Hanson during a personal conversation): "It is possible that those immune cells (PBMCs) are activated, maybe due to a virus infection or other pathological conditions. It has been shown that when activated, immune cells shift from catabolism to anabolism which requires more energy, and become increasingly dependent on glycolysis for ATP production."

    Aerobic energy production also seems to be working perfectly well! A little too well, in fact, since the cristae of the mitochondria are very dense. And this might indicate that the energy demands for aerobic energy production are very high.

    @msf, As for the innate pathogen, this comes from Dr. Theoharides' article:

    Here's another article based on the same study that's perhaps a little easier to read:

    From the abstract: "Allergies, asthma and autism have reached epidemic proportions, but the reason(s) why remain elusive. Recent evidence indicates that mitochondria, commonly known for their cellular energy production, undergo fission and translocation to the cell surface where they secrete some of their components extracellularly. These include DNA and ATP, which are misconstrued by the body as “innate pathogens” leading to an autoinflammatory response that may explain many sterile inflammatory disorders, especially autism"

    Basically, I've been looking at the results found in Dr. Wang's study and comparing them with those found in Dr. Theoharides' study, and wondering if mast cells triggered by physical activity might react in a similar way than when they are exposed to allergens and/or the pro-inflammatory peptide substance P.

    Also, what I'm thinking is that gut permeability might be a symptom or the result of mast cell activation disorders, not the source of aberrant mast cell mediators release.

    Now, do those changes in gut permeability caused by mast cell activation also lead to PEM and fatigue? Highly possible!

    Like I said, I didn't even begin to approach the multi-systemic symptoms, disorders, and associated conditions that might be linked to aberrant mast cell activation.

    Basically, I see mast cell activation as a disease process that might be happening in a number of different chronic diseases where inflammation is believed to play a role in the disease's pathogenesis.

    This is what I believe Myalgic encephalomyelitis to be:

    So, I do very much think that a subgroup of ME patients, i.e. those that fail to recover from the enteroviral infection, might have had a genetic predisposition or some other factors that might lead them to suffer from a secondary mast cell activation disorder that will contribute to the chronicity and severity of the disease.

    But they've also suffered from vascular brain injuries caused by the viral infection. So even if you were to find a way to stabilize the mast cells, it doesn't mean that every single symptom would magically go away, either.

    This might explain why so many symptoms of ME overlap with CFS.

    Same thing with Lyme disease. There's been some evidence that the bacteria responsible for Lyme disease can induce mast cell activation and cytokines release:

    I've also read a few testimonies from patients saying that they got some relief from their symptoms with treatments typically used to stabilize mast cell activation.

    But Lyme disease remains a distinct infectious disease.

    Still, should there be an innate or acquired genetic predisposition to develop a secondary mast cell activation disorder, it's possible that the patients with Lyme disease that fail to recover from the infection might also suffer from abnormal and aberrant mast cell activation.

    ME is ME.

    Lyme disease is Lyme disease.

    But what if both could trigger a chronic Mast cell activation disorder?

    And what if what we've been calling CFS all along, happens to be a mast cell activation disorder accompanied by an exercise-induced mast cell degranulation process?

    Which could explain why so many symptoms between those diseases overlap and are so close to what we've come to call "CFS/ME", and entity that includes patients with ME (as per Dr. Hyde's definition) and without ME.

    I was never infected by an enterovirus. I did have shingles followed by mononucleosis 2 years later, though. Perhaps those were my triggers, maybe not.

    I don't think that different pathogens can cause the same disease per say.

    But I think that different pathogens might just cause the same or at least a very similar immunologic response within the body in predisposed patients.
  6. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

    Toronto, Canada

    Very interesting connecting of some dots.

    Fwiw, I've experienced perhaps 4 or 5 exercise induced anaphylaxis - each time was within a couple of minutes of finishing a triathlon - my tongue swelled, my throat swelled - after the first few times, I started to wander over the ambulance folks (that are always at the races) in case it got worse - after perhaps 8 - 10 minutes, the swelling would go down.

    I've also been diagnosed with coxsackie, from the enterovirus family and tend to agree with Dr Hyde's contention of ME as an enteroviral infection, and CFS other undiagnosed illnesses.
  7. Something I've just realized! And my apologies if that wasn't clear, but excessive or very intense physical exercise can indeed increase inflammation in healthy individuals as well!

    When I'm talking about people suffering from chronic diseases getting relief from their symptoms through exercise, I'm talking about a regular, gentle exercise program, where the intensity of the effort is slowly increased from day to day. Not asking them to lift heavy weights or run on a treadmill for 1 hour! ;)
    Wonko likes this.
  8. Wonko

    Wonko Senior Member

    The other side.
    In that case my unreasonable and excessive desire to undertake the activities required to eat a boiled egg with toast and a make cup of tea in the morning may constitute intense physical exercise, for me, as my hands, forearms and god knows what else swell up from just doing that - in just the same way as they used to when I was lifting weights. - possibly it wasn't the weights that were the problem,maybe it was the eggs :)
  9. msf

    msf Senior Member

    Thanks for the in-depth response, but you didn´t seem to answer my question: if what you are suggesting is true, why do some ME patients have obvious mast cell issues (to the extent that they are eventually diagnosed with MCAS), whilst others (who also have PEM) do not?

    I was aware of the mast-cell connection with Lyme, but do you know if any other infections have been linked to mast cell issues?
  10. @ScottTriGuy , more likely than not, you probably do fit Dr. Hyde's definition (though there are other criteria, like certain types of brain vascular injuries that can be seen with a SPECT scan).

    I typically try to be very careful in how I say that I don't believe that ME and CFS are the same thing, mostly because that doesn't mean that people who do not fit the ME criteria are not just as every bit as sick, disabled, and symptomatic as ME patients.

    But here's the thing, the first time the term ME was used, it was to describe a viral outbreak that happened in the Royal Free Hospital the same year as other poliomyelitis epidemics.

    I understand that there are some doctors who, back then, thought that because it primarily affected women, this was just a case of mass hysteria.

    What I don't understand, is that with all the current advances in society, that theory still seems to carry some weight, and the recognition of the epidemic nature of ME hasn't been yet fully recognized by the medical community.

    Iceland disease, Lake Tahoe (where the same class of virus has been found), all of these very much appeared to be viral epidemic outbreaks.

    And yes, I do agree that those don't account for ALL the cases of "CFS/ME" where no enteroviruses have been found...

    But maybe that should give us a clear sign that, perhaps, just perhaps, those aren't the exact same diseases.

    The best way to treat ME would be through prevention and immunization.

    Then, through quick identification of the infectious agent involved, and anti-viral treatments.

    And then, ONLY then, should we be stuck with palliative treatments aimed at treating long term complications.

    A secondary chronic Mast cell activation disorder might just be one of those long term complications (but likely not the only one).

    So, by putting all those diseases together on the basis that they all share a very similar clinical presentation, and treating them as a single entity, we might just have been failing to recognize that many enteroviruses besides the 3 known polioviruses might just be highly dangerous, and cause illnesses that are very close to polio (except they don't typically result in death and/or paralysis).

    I'm overjoyed that so much effort is being put into better understanding what causes the fatigue and PEM in CFS/ME diagnosed patients, especially because I think that it will likely benefit a huge number of spoonies out there with often unexplained multisystemic symptoms, manifestations, issues, and associated conditions.

    But I'm very scared that doctors might forget to look into the different viral causes behind the illness of some of those patients that somehow ended up developing that particular kind of CFS/ME-like fatigue and PEM.
    sue la-la, ScottTriGuy and Daisymay like this.
  11. Sorry @msf! I didn't understand what you meant by that question!

    Well, first you have to define what you mean by "obvious mast cell issues".

    I didn't have "obvious mast cell issues", not the same way most MCAS patients that will experience flushing, intense rashes, and/or anaphylaxis have.

    - I have fatigue with PEM.
    - I have brain fog and intense cognitive executive functions impairments.
    - I have dystautonomia, as my blood pressure fails to increase with physical exercise.
    - I have IBS.
    - I have fibromyalgia.
    - I have a hard time with variations in heat or cold.
    - I have paresthesia in my hands and feet.
    - I have those weird sore throats often accompanied by earaches (almost always on the left side).
    - I start being dizzy, shaking, slightly nauseated, and overall feeling like I'm more or less drugged or drunk when exposed to a room where there's a lot of chatter, or a car's vibrations, or direct and indirect sunlight.
    - My hands and feet can tend to turn bluish and cold, or on the contrary sometimes will be hot and a little red.
    - I have a bunch of weird sleep disorders (sleep paralysis with hypnagogic and hypnopompic hallucianation, idiopathic hypersomnia...), including something that looks a lot like nocturnal frontal lobe epilepsy.

    Who ever said I had obvious mast cell issues? ;)

    Actually, I do have dermographism, which is something I never knew I had until the doctor had me do a skin test allergy, and we discovered that my skin will lightly swell and become red just by scratching it with the tip of the needle (so skin allergy tests aren't very helpful in my case). That's a more obvious mast cell issue...

    Otherwise, I have multiple food intolerances and environmental sensitivities... So again maybe that's more obvious.

    And yet you have patients with MCAS that can eat whatever they want and do not suffer from any environmental intolerance or allergies, either, but will become symptomatic for no apparent reason, when physically exercising, or then again just being out in the sun!

    There are mast cells and mast cell mediators receptors virtually anywhere on the body. So depending on what's dysfunctional and which organs they affect, the symptoms those dysfunctional mast cells can cause can be as diverse and seemingly unrelated as they can be!

    Dr. Afrin more or less says that if the patient presents with bizarre multisystemic symptoms and manifestations that do not seem directly related to one another, very much consider the possibility of mast cells involvement.

    Not a single MCAS patient looks exactly the same.

    I used to think that having red patches on my chest after taking a bath, that didn't itch or hurt, and disappeared within the hour after I no longer had any exposure to heat and moisture was normal.

    Turns out it's a sign of mast cell activation! Who knew, right? Vasodilatation is supposed to occur in a more uniform manner, not show up in patches.

    So, many skin manifestations in MCAS patients can very easily be missed and/or fail to be reported, because either the patient has never noticed them, or they've always believed it was normal (since it didn't give them any other issues).

    The rosacea on my cheeks might be an associated condition.

    The ADHD, too.

    So really, if you share some of those symptoms as a patient with a CFS/ME diagnosis, you might just be showing signs of MCAS.

    Truth is, I do not know exactly why I don't show the more classical signs of MCAS. All I know is that most of my symptoms can probably be explained by mast cell activation, and I respond very well to mast cell stabilizers.

    Otherwise, besides Lyme disease, I'd have to do a bit more research to see if Mast cell activation disorders been linked with other specific infections. I think I've seen something about Dengue and Influenza at some point, but I would have to look further.

    Technically, mast cells orchestrate the system's defense against viruses, bacteria, fungi, and parasites... Except they aren't supposed to continue to get triggered once the infection is over.
    Last edited: Aug 18, 2017
  12. Wonko

    Wonko Senior Member

    The other side.
    Interesting, a couple of things in your post are things that happen to me I thought were normal, or normal for those with M.E. - I'll look into mast cells, thank you.
  13. You're welcome, @Wonko

    If you are looking for more in depth information, I would highly suggest this chapter written by Dr. Lawrence B. Afrin:

    Otherwise, those articles provide excellent summaries, and are much more concise. :D
    Page 5 and 6 of the document (numbered 151 and 152), will offer you a good overview of the symptoms and clinical findings typically found in MCAS patients.
    sue la-la, Daisymay and Wonko like this.
  14. anciendaze

    anciendaze Senior Member

    Just one more aspect to make things strange: a number of patients with confirmed diagnoses of hypokalemic periodic paralysis (HKPP) can experience a feeling that their muscles are being put through a grinder during exercise, after which they appear to have rhabdomyolysis. This is confirmed by the danger of damage to kidneys this presents. There is a higher rate of kidney failure in that group.

    In at least one patient I know, the period to recover from overexercise is three days, which sounds like PEM. He also recognizes "brain fog" during this time.
  15. @anciendaze, alright, I've been trying to see if HKPP and MCAS might be linked, and this is getting way too specific and complex for me! Lol!

    All I've found thus far that MIGHT mean something, are basically that:

    - A mutation in the CACNA1F calcium voltage-gated channel subunit alpha1 F gene can cause Hypokalemic periodic paralysis.

    - "The CACNA1F gene encodes for the Cav 1.4 VGCC, which is expressed in the retina and localizes at ribbon synapses in cone and drop photoreceptors (Mortans et al., 2005), as well as in the inner nuclear and ganglion cell layer (Mc Rory et al., 2004). The channel is also detectable in plasma and mast cells, although its role in the immune system is not fully understood."

    ( )

    - Cav 1.4 VGCC would be an L-type calcium channel
    ( )

    And so, I typed "Cav 1.4 VGCC mast cells" and "L-type calcium channel mast cells" to see what I could find, and now I have a headache from trying to read and understand any of these... Lol!

    Ah... Help?! Is this in any way relevant, at all? Does anyone understand any of this?

    Rhabdomyolysis is also extremely interesting, though!

    "Striated muscle injury is at the core of mechanisms producing vast systemic insults in rhabdomyolysis. Central to the development of the syndrome is intracellular ATP depletion.4 This triggers a cascade of cellular disruptions, such as Na+ K+ ATPase pump dysfunction, impaired calcium transport, and release of free oxygen radicals.5 Intracellular calcium levels increase in unregulated fashion, leading to persistent muscle contraction.6 Eventually, there is cell death. Intracellular components such myoglobin, creatine kinase (CK), lactate dehydrogenase (LDH), uric acid, aldolase, and electrolytes (e.g., potassium) are released into the bloodstream.4


    The most common causes of non-traumatic rhabdomyolysis are hypermetabolic exertional stress injury. Strenuous exercise will increase serum CK in normal humans. Exertional rhabdomyolysis, or "hyper-CK-emia" occurs in individuals who have a sudden increase in overall levels of physical activity and can demonstrate CK levels more than five times normal. There is an increased incidence in males, African-Americans, and individuals with high muscle mass.9 The majority of these individuals do not have muscle soreness, weakness, and myoglobinuria, and have CK levels that rapidly return to normal. When hyperCKemia and myoglobinuria occur in a patient with muscle soreness and weakness, the patient has exertional rhabdomyolysis. A common factor in exertional rhabdomyolysis cases is repetitive exercise or exertion beyond when fatigue would compel an individual to normally stop (for example, new military recruits and participants in long-distance running events). It is exacerbated by high ambient temperatures.

    Exertional rhabdomyolysis occurs when exertional energy requirements exceed ATP production. Depletion of ATP within the myocyte during exertion causes a release of calcium into the cell and, therefore, cellular necrosis. The myocytes then become permeable, swollen with fluid, and leak their components into the intracellular matrix. This results in intravascular volume depletion from third spacing and lactic acidosis. There is a resultant rapid increase in serum creatinine. The prognosis for exertional rhabdomyolysis is better than for other forms of rhabdomyolysis and less often results in acute kidney injury. However, exertional rhabdomyolysis exacerbated by severe heat injury will increase risk of renal injury.

    Anyone may develop exertional rhabdomyolysis when under enough mechanical and environmental stress. However, exertional rhabdomyolysis can also be triggered by genetic influences that predispose the individual to the development of exercise and heat-related illness. These genetic abnormalities cause abnormal intracellular skeletal muscle calcium regulation via disorders of carbohydrate metabolism, lipid metabolism, or mitochondrial disorders. Recognized genetic causes include McArdle's disease, CPT2 deficiency, and AMPD deficiency.9 In McArdle's disease, the individual lacks the enzyme to break down muscle glycogen to continue to fuel cells after circulating ATP are spent. Carnitine palmitoyl transferase (CPT2) deficiency causes an increase in open-state probability of RYRI calcium channels, so there is a much lower threshold for high calcium levels within cells to cause cell breakdown. In adenosine monophosphate deaminase deficiency (AMPD), a critical enzyme for muscle energy metabolism is present in abnormally low levels, therefore decreasing exercise capacity and shortening the time to tissue ischemia. Polymorphic variations in angiotensin-converting enzyme, CK muscle isoform, and myosin light-chain kinase have also been associated with exertional rhabdomyolysis.9 Hereditary causes are listed in Table 2."

    Of course I don't think that is quite what is happening in patients with CFS/ME or MCAS diagnoses, since mitochondrial ATP is relased extracellularly apparently without any cell injury or death, and I think most of the lab tests they are suggesting in this article tend to be normal in CFS/ME and/or MCAS patients.

    Still, there are certain similarities for sure!

    Actually, other diseases, like mitochondrial diseases, for examples, are probably highly likely to cause PEM-like symptoms.

    Except the energy production or consumption issues will usually have a known cause, and/or be more objectively shown through lab results.

    I don't think a pseudo-allergic reaction to physical activity is the only possible explanation for PEM associated with all inflammatory diseases. More perhaps in those few cases where exertion is not supposed to cause PEM, and lab tests fail to show clear sign of exertional stress injuries.

    While it seems some sort of PEM and cellular injury is supposed to be very much expected in exertional rhabdomyolysis.
    echobravo likes this.
  16. anciendaze

    anciendaze Senior Member

    Here is an excerpt from an exchange with a medical doctor who is also concerned about ME/CFS. The discussion started when I referenced the work by Systrom's group described in Cort's post on Health Rising:

    Your comment about a lack of clear clues baffles me, as Systrom's group has very clear objective evidence of low ventricular fill pressures, which in turn points to vascular dysfunction. This is episodic in response to exercise or orthostatic challenge rather than constant. It is also a clear indication that the condition may well be reversible.

    Autonomic function, including vascular dysfunction which can produce syncope, has a clear relation to cerebral hypoperfusion which is well-known to affect mental function. I believe we are dealing with autoantibodies interfering with a normal process called functional sympatholysis which takes place when exercise produces localized hypoxia in muscles. Only part of this takes place in nerve cells. After erythrocytes dump oxygen, if there is still local hypoxia, they dump significant amounts of ATP into the bloodstream. (Cells can use excess ATP to survive temporary hypoxia.) This also causes veins downstream to dilate, increasing the pressure difference across the muscle, and presumably increasing blood flow to that muscle. In the pathological situation that dilation response stays stuck on.

    I've described this in earlier messages. It ties metabolomic results to hemodynamic problems. Frequent onset following acute viral infection ties in with autoimmune activity, and viruses which infect immune cells in particular. The pieces connect.
    Note that I am not talking about too much or too little ATP. ATP is being produced by blood cells and dumped outside the cells that need it for anaerobic metabolism. It is not coming from the mitochondria of the muscle fibers. This fits data on excess ATP combined with low available energy. The human body is not a single beaker in which you mix stuff up, it is a highly-structured and dynamic environment.

    (There is a technical medical term for the biological condition where dynamics are not important, that patient is called dead.)

    Depleting a particular class of B-cells with Rituximab/Rituxan to reduce symptoms ties in with the idea of autoimmunity, I would be very interested in learning if depleting only B-cells infected with EBV would benefit patients.

    With reference to your comment about MCAS, I will point out that mast cells line boundary tissues like skin or mucous membranes. Nothing about immune response in the vascular system should seem at odds with this, particularly if you are dealing with exercise-induced damage as happens with the extreme case of rhabdomyolysis. This need not be mechanical damage, and a great deal is known about damage by episodic hypoperfusion and local hypoxia, together with reperfusion injury following ischemia.

    I will also mention the correlation between connective tissue disorders and MCAS. The HKPP patient I know best also has serious connective tissue problems. Tests for antibodies have shown several, though there are many that would not be tested for unless the patient showed signs of cancer.

    I'll have to look at your references later, as I'm now trying to move to a new location in town. I suspect many of you would groan at the idea have having to pick up and move yourselves. Fortunately, I have help.
    echobravo likes this.
  17. Isaiah 58:11

    Isaiah 58:11 Senior Member

    A Sun-Scorched Land
    This confuses me because I often have this too when exposed to tap water, sunlight, some florescent lights, and I don't know what else. Any doctor I have shown a picture to and asked they said it was an allergy and they were unconcerned because it is mild. On me, it seems to almost always be symmetrical and I have certain spots that flare up more frequently both under and over clothing regardless of the apparent irritant. I never thought it looked like a typical allergy rash because rather than welt-y it looks like a flush, but when you look closely you see thousands of pin-prick red spots. Mine is milder, but the following picture gives an idea: Is this in any way similar to what you are referring to? [​IMG]

    I appear to have rhabdomyolysis on occasion. My "episodes" have most often happened after trying to push myself through what was a normal activity the day before - sort of PEM in the extreme? I have never made it for help at a point when I felt like my life was in danger, but I have been tested maybe a week later and was found to have high CK. I have also had high CPK; I am not sure if those are equivalent. The last neurologist I saw said perhaps it was myositis, but in 12 excruciating years I have never received a firm diagnosis on anything and now have so little muscle you can see rather too much of my skeleton. Your post intrigues me because once, seemingly randomly, my kidney tests came back abnormal. I wonder if that was a coincidence or the two things are related.

    I have long known that the CPT2 deficiency described on Wikipedia describes me nearly exactly, but I am female and the only doctors who were ever mildly curious said they could not find a genetic specialist (outside of oncology) that would see adults. I do have an abnormal carnitine/acylcarnitine ratio but, if I recall, it was different than the one I once read about in CPT2.
    From Wikipedia: This exclusively myopathic form is the most prevalent and least severe phenotypic presentation of this disorder.[4] Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin),[5] myoglobinuria, recurrent muscle pain, and weakness. It is important to note that muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks.[4] Symptoms are most often exercise-induced, but fasting, a high-fat diet, exposure to cold temperature, or infection (especially febrile illness) can also provoke this metabolic myopathy.[4][5] In a minority of cases, disease severity can be exacerbated by three life-threatening complications resulting from persistent rhabdomyolysis: acute kidney failure, respiratory insufficiency, and episodic abnormal heart rhythms. Severe forms may have continual pain from general life activity.[4] The adult form has a variable age of onset. The first appearance of symptoms usually occurs between 6 and 20 years of age but has been documented in patients as young as 8 months as well as in adults over the age of 50. Roughly 80% cases reported to date have been male. ​

    I am not sure what you mean by connective tissue disorders, but I was diagnosed as EDS by the same doctor who diagnosed me with what he called CIRS/ME/CFS (I was acute onset and meet the Hummingbird Foundation criteria.) and in the last few years have had massive amounts (>250) of anti-CCP antibodies.

    My point in replying to all this is two-fold: Either you all are right on as far as things that are overlapping and coexisting with ME or, perhaps, you can all tell me what is actually wrong with me and that I have been misdiagnosed.
  18. anciendaze

    anciendaze Senior Member

    Your image did not come through. Even with it I would hesitate to guess the cause. We have more evidence of strange immune activity in your other tests.
    Your signs and symptoms do show a real disease, and the question of how medical doctors will diagnose this remains up in the air. I would not put you in the general CFS bin, which often serves as a wastebasket for unpromising cases that are not life-threatening.

    A diagnosis of EDS is nothing to take lightly, there are all kinds of complications and associated conditions. You should probably be talking to patients in that community to find out if you match a pattern they recognize. You should definitely have a doctor experienced in EDS.

    BTW: there is an association between EDS and MCAS.

    True rhabdomyolysis is dangerous because of the risk of kidney failure. It will also produce long-term damage to muscles. This is nothing to take lightly. Serious cases produce a change in urine color after exercise that may disappear before the patient reaches a doctor.

    It may be that you have damage that falls short of those diagnostic criteria, but is enough to provoke autoimmune activity. Another possibility that comes to mind is late-onset muscular dystrophy. This can be determined conclusively by a muscle biopsy.

    There is a real chance you have a known autoimmune disease like rheumatoid arthritis or several others for which etiology remains unknown. This is a job for an expert.
    Isaiah 58:11 likes this.
  19. Murph

    Murph :)

    Hi @Amelie! Great post but a bit heavy on the old eyes and brain. Might I ask if you would go back and edit a tl;dr into your post for those of us (I'm going to guess many of us) for whom it's a bit long?

    If you're proposing PEM is an activation of the immune system, I very much tend to agree. I can't really think what else it might be, to be honest. I'd like to know more about your ideas. Perhaps some subheadings could be another way to break up the text?
    Subtropical island likes this.
  20. Isaiah 58:11

    Isaiah 58:11 Senior Member

    A Sun-Scorched Land
    I agree. Do you happen to know of one? I do have lasting muscle problems and I am aware of the EDS complications (my father had an aorta problem). I have been ill since late 2003 and was admitted to the hospital in 2005 with a suspected neuromuscular degenerative disorder because of symptoms paired with high CK but discharged with no diagnosis and told to follow up with a doctor who refused to see me. Since then I have seen only God knows how many primary care doctors (and been discharged by one of them!), 4 neurologists, a rheumatologist, a cardiologist, a clinical toxicologist, and so on. Now I am stuck on high deductible insurance, so I can't just make appointment after appointment hoping that this will finally be the person who helps me. [Sigh] I really do need help. But don't we all?

See more popular forum discussions.

Share This Page