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New Exercise Study Brings Both Illumination and Questions
Simon McGrath looks at new objective evidence of abnormal response to exercise in ME/CFS patients, and the questions that researchers are still trying to answer ...
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Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity

Discussion in 'Phoenix Rising Articles' started by Mark, Jul 29, 2013.

  1. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    A valid point, I think. But I usually find that my energy levels appear normal the day after exertion. I become weak and fatigued as part of PEM. I have an initial, short-lived (a few hours at most) spell of fatigue immediately after exertion, which then fades and I feel OK again until PEM (including fatigue) sets in.

    How it seems to me is that the exertion causes hyperlactaemia, which then has various downstream effects including overloading the liver.

    This paper 'Lactate physiology in health and disease' may be of interest:

    http://ceaccp.oxfordjournals.org/content/6/3/128.full
  2. Simon

    Simon

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    Hi Gus
    You're quite right that the abstract only mentions fatigue, but the paper itself mentions both malaise and sympotoms more more generally:

    Fatigue is usually defined subjectively, the objective measures in this test were really markers of the fatigue/malaise, rather than measuring them directly. It could be argued that the earlier onset of the anaerobic threshold at test 2 is an objective marker of fatigue, though the paper doesn't do that (instead it suggests there is a problem with metabolism ie much less output for a similar consumption of oxygen at VT.
    ahimsa, Valentijn, beaker and 2 others like this.
  3. Sea

    Sea Senior Member

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    Any chance we could have access to the full paper?
    MeSci likes this.
  4. Simon

    Simon

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    Interesting. Do you think that this mulitple smaller problems paradigm is underpinned by a common underlying defect?

    In a way, deconditioning, or deconditioning plus minor specific health problems could create a such a situation with lots of small problems that individually don't look that out of the ordinary but collectively cause a big problem. So could many other underlying defects ag with the autonomic nervous system. Just thinking out loud here.

    Thanks.

    And yes, there is a difference between the problems that many of experience day-to-day, and the objective deficits found in this study after a second maximal exercise test: the Big Bazooka approach. Much as I'm fascinated with this later study, I wish there were a test that could identify objective problems in more real-world conditons.

    Hope the sleep tests throw up something useful for you.
    ahimsa and beaker like this.
  5. Ember

    Ember Senior Member

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    Look again at the study's cohort, Simon. The study's subjects both met Fukuda and reported PEM. Fukuda doesn't require PEM. Therefore, the results of this study don't generalize to Fukuda- defined CFS.

    You write that both the CCC and ICC “require self-reported symptoms...rather than objective markers of exercise dysfunction.” The ME/CFS Guidelines, however, both require Post-Exertional Malaise and/or Fatigue and include among their list of tests for abnormalities in ME/CFS “Cardiopulmonary Exercise Testing: AMA Guide for Evaluation of Permanent Impairment. Lower cardiovascular and ventilatory values at peak exercise help determine functional capacity, and peak oxygen consumption levels determine disability categories.” Such testing, of course, doesn't involve the Stevens protocol.

    The ME Primer, on the other hand, requires Post-Exertional Neuoroimmune Exhaustion (PENE), which is confirmed under its Laboratory/Investigative Protocol using the Stevens protocol. “In a 2 consecutive day comprehensive 8-12 minute cardiopulmonary exercise stress test (measuring heart, lung, and metabolic function), only ME patients have significantly worse scores the second day & abnormal recovery from exertion:”
    * Exercise tolerance test with expired gas exchange - (2 consecutive days) – measure cardiovascular, pulmonary & metabolic responses at rest & during exercise: peak oxygen consumption VO2 or VO2 at anaerobic threshold (AT) - decline of 8% or greater on test 2 indicates metabolic dysfunction, post-exercise blood analysis - increase in sensory, adrenergic and immune genes - increase in metabolite receptors unique to ME

    Staci Stevens is a member of the International Consensus Panel, and the ME Primer uses the Stevens protocol to operationalize PENE. Those studies published as of last October are included in the Primer's description of the pathophysiology of PENE (pp. 2-4). This study (received October 27, 2011) builds on that research.

    Given that the International Consensus Panel uses the Stevens protocol to operationalize PENE, a cardinal feature of ME, and calls for the removal of ME patients from the more encompassing CFS classification, Dr. Unger should indeed be using this protocol, as you suggest, in her multi-site study.
  6. Bob

    Bob

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    Thanks Simon, for a great article. It's very helpful.

    This really is an interesting study, and if the findings can be reliably replicated, then the results will be exceptionally useful for so many reasons.

    I like the way they used healthy but deconditioned individuals as a control group, and then objectively demonstrated that CFS patients (biologically) react differently to exertion when compared to deconditioned healthy individuals. This, in itself, is essential evidence to demonstrate that CFS is not a simple state of deconditioning, due to a fear and avoidance of activity etc. An objective biomarker would transform the field of ME/CFS.

    Like others have mentioned, this research ties in with Julia Newton's objective findings that muscles from CFS patients produce a lot more acid than healthy controls.

    Both these research studies lead to so many vital questions about ME/CFS, such as the one that Firestormm asked earlier in the thread: is oxygen not getting into our cells? And if it isn't, what is the reason?
    Another question is: do we have dysfunctional mitochondria and, if so, what viruses potentially affect the function of mitochondria?

    Repeating other people's comments again, I think much more biomedical research should be focused on the post exertional reaction in ME/CFS patients, as it is at the heart of the illness.
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  7. Allyson

    Allyson *****

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    Thanks SImon - great reading
    yes low blood volume mwy be one cause and that is easily tested for

    Likewise POTS/OI - common symptoms of ME and could contribute to this in a major way - not enough blood to your heart and other muscles when exercising? not going to help anything.

    POTS/OI are easily tested for but strangely very few PWME are ever tested for them - correctly that is - one BP reading sitting or lying then again standing is NOWHERE close to accurate - yet this is how I was measured and fobbed off for years - now I Know I DO have OI/POTS and managing them helps the ME a LOT.

    cheers

    ALly
  8. Firestormm

    Firestormm Guest

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    I wonder if you could use this test on patients and controls before, during, and after something like GET with the aim of seeing if the loss of exercise ability can indeed be recovered by gradually increasing the exercise to the initial test level. I don't mean necessarily to prove if GET is useful or not; but really to see when and if a person's exercise ability returns to initial levels i.e. to see how long on average this 'PEM' lasts.

    I also think it is important as a next step to try and better understand the knock-on effects of this inability to exercise as well on day 2 with the appearance of other symptoms generally subscribed to 'malaise'. It could be that the exhaustion on day 2 (or 3 whatever) leads to a person feeling sicker; there may be nothing demonstrable e.g. sore throat, swollen glands though perhaps sore muscles, pain and headaches might be more relevant - though subjective - or cognitive performance; but it would be very useful to study the after-effects of this 'over-exertion' in some way.

    'Malaise' has been a useful term as is does describe the feeling rather well but I think we can now seek to better understand what this might encompass and explain why: the 'starvation' of oxygen could be responsible for so much more; and if it is then in what way.

    And as part of para 1 above we could also look at establishing how long this post-exertion state lasts. Get a better understanding of how long recovery takes, comparing resting for example, with gradual increases in exercise. It might help to determine - as I said - how long our cells/whatever are taking to recover. Not recover to a healthy state; but recover to a state that allows us to 'over-exert' in this way again. Then run the same study. Then run the after-study. See if this inability persists and try and gauge for how long - as well as in other studies better determining why.

    Just random morning thoughts :)

    Health Rising also have an article about this study published yesterday:

    Busted! Exercise Study Finds Energy Production System is Broken in CFS
  9. beaker

    beaker CFS/ME 1986

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    Thanks for the article and link to the abstract -- I passed it on to my dr.
    They did this type of testing back in the early Ampligen studies. It is sad that it has taken this long to get a study like this completed and published.
    Glad to see it though.
  10. alex3619

    alex3619 Senior Member

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    Hi Simon , with regard to reduced level of function in a system of problems, while its possible there is a common underlying dysfunction, its more likely to define a family of dysfunctions. In other words, CFS with PEM/PENE is a family of disease with similar final symptoms. However that does not mean that most of us do not have the same thing.

    If a large number of system failures are involved, over many organs and tissues, then the impact of individual variations including comorbid diseases and genetics will be large. At the very least I expect to see variations based on individual genetics for a range of issues, including methylation and other aspects of metabolism.

    CFS could be the touchstone that creates a paradigm shift in medicine. That alone will create huge resistance in medicine in my view. If CFS represents the final common symptoms of a variety of disorders, then a single fully reliable test based on causation is unlikely. However I think repeat exercise testing might represent a reliable test on consequences, measuring the final outcome.

    I am not convinced even ME is a single disease entity. I suspect it might be at least two different but similar diseases. Only in an ME outbreak are you fairly sure that patients will have the same disease, and then only for that one outbreak.

    I really hope there is one single common mechanism though ... but its hope, not science at this point. If there is one cause, there can be one really reliable treatment. If its many causes, treating or curing it is going to be a long tough road, even after effective treatments for subgroups become widespread.

    However if there is are common outcomes, then symptomatic treatment can vastly improve, even if the underlying cause is not cured.
  11. Simon

    Simon

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    Yes, Fukuda + PEM, though as I said in the blog the results don't generalise to Fukuda+PEM either since it was a convenience sample, and subjects had to sign up to a double maximial exercise test, which not everyone will want to do.

    But this is not a mandatory test? Also, that test is to test functional capacity, separate from symptoms or fatigue (and is used widely to do the same in many illnesses).

    Does this mean the Stevens protocol is mandatory to diagnose ICC ME, or is that an optional test? Mandatory would be worrying as a lot of people have relapses way below maximal exertion (also, VO2 max was not significantly different on test 2 for CFS patients for this new study).They are also quoting the unreplicated Lights study on increased mRNA expression; again surely not mandatory? I'm pretty sure that neither study - certainly not this one - used ICC criteria, so I'm not sure how anyone can be certain these are definitive tests and that falling below a particular threshold is exclusionary.

    I do think this new test could be very important but needs replicating, especially as the dramatic fall in VTO2 is a new finding: the CDC study, with a larger and more representative sample would be the ideal place to do this.
    MeSci likes this.
  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Just been searching my files to see if I had anything on 'recovery' time, and this video apparently cites an average of 4 days:



    (I haven't watched it but found the link in a WordPress article)

    I haven't had time to search for links for the following but they should be easy enough to find. Sorry about poor formatting but the info is copied from pdfs.

    from 'A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS' by Twisk and Maes:

    from 'Chronic fatigue syndrome and mitochondrial dysfunction' by Myhill, Booth and McLaren-Howard:

    from 'Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls' by Thambirajah AA, Sleigh K, Stiver HG, Chow AW:
    from 'A real-time assessment of the effect of exercise in chronic fatigue syndrome' by Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH:
    from 'Time course of exercise induced alterations in daily activity in chronic fatigue syndrome' by Black and McCully:
    This study: 'Immunological Changes After Both Exercise and Activity in Chronic Fatigue Syndrome:
    A Pilot Study' by White PD, Nye KE, Pinching AJ, Yap TM, Power N, Vleck V, Bentley DJ, Thomas JM, Buckland M, Parkin JM (interesting combination!) found that the journey to hospital for testing changed some immunological markers, a potential confounding factor when baseline values are taken on arrival at hospital instead of before leaving home.

    from 'Physical activity before and after exercise in women with chronic fatigue syndrome' by Sisto SA, Tapp WN, LaManca JJ, Ling W, Korn LR, Nelson AJ, Natelson BH:
    from 'International Consensus Primer for Medical Practitioners':
    from 'Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)' by Norman E Booth, Sarah Myhill, John McLaren-Howard:
    from 'DIAGNOSING AND TREATING CHRONIC FATIGUE SYNDROME (CFS)' by Dr Sarah Myhill:
    (There is more detailed info about (possible) reasons for slow recovery in this document.)

    Also from the above document, I am including this about 'boom and bust' for anyone who needs more understanding of the necessity of pacing:
    There is other excellent advice in the above document but IMO an over-emphasis on D-ribose, which many people cannot tolerate, and it can be risky, e.g. causing hypoglycaemia.
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  13. Ember

    Ember Senior Member

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    So then it can't be claimed that “the results of this study showed that it should detect 90% of CFS cases, or 10% of Fukuda-defined CFS cases would be missed.”
    The ME/CFS test is not: “While there is not one definitive test for ME/CFS, many tests may indicate abnormalities.”
    PENE, among other symptom patterns and abnormalities, is confirmed by testing according to the ME Primer's Laboratory/Investigative Protocol (p. 11):
    Pressure should be brought to bear.
  14. Firestormm

    Firestormm Guest

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    MeSci thank you for that lot! :) Blimey. Lot of effort there. Appreciate it. I shall come back later and read more deservedly. That Pinching/White study is in full here. Interesting as you say. Shame it doesn't appear to have been replicated or even taken on board elsewhere.
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  15. Simon

    Simon

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    Thanks, MeSci, you have been busy

    That immune one in particular, featuring Peter White and Anthony Pinching looks so interesting (esp the effect of travel on immune markers), but is yet another case on a tantalising pilot (n=9) that never got replicated (maybe some of the authors didn't want to pursue that line of inquiry). Similarly, the Black study and heatshock study both only have 6 CFS patients :(.

    There is a good deal of debate about mitochondrial function. This new Snell paper quotes an earlier study that found reduced performance at day 2 but normal oxidative phosphorylation. The new MRC study at Liverpool will be using new and more sensitive techniques to focus in on mitochondrial functioning.

    On a more positive note, the Klimas/Fletcher labs are working on a good day/bad day study of immune markers, as well as looking at them post-exercise, and I'm hoping the study will be of a decent size. The Horning/Lipkin study (n=loads) is also measuring some immune markers - not post-exercise or post-travel but generally - and the study size as well as rigorously matched controls should produce robust data on immune markers.
  16. Simon

    Simon

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    Blog updated: more information on 'uniqueness' of findings, plus another supporting study

    After getting more information from Chris Snell, I added this, with more published studies:
    Nb a lot of repeat test studies have at least 7 days between first ad second tests, so don't provide a useful comparison.

    I've also mentioned a study by Betsy Keller, presented at the IACFS 2011 conference, and about to be submitted for publication. Like the new study it finds declines in both VT VO2 and workload, though the workload findings are nowhere near as dramtic as this new study. n=12, results highlights:

    Significant decreases from test 1 to test 2 were:
    13.5% for VO2ma; 9.4% for Wmax
    18.8% for AT [VT] and 17.3% for ATwork [work output at VT]

    However, there was no change in maximum RER indicating that subject effort was maximum and also comparable during both tests
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  17. MeSci

    MeSci ME/CFS since 1995; activity level 6

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  18. Firestormm

    Firestormm Guest

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    Simon I have something I would like your opinion and that of others on in relation to this kind of testing; and that relates to safety.

    Let me take this from Jennie's wonderful blog, it doesn't cover all my point, but does exemplify it to some extent:

    When we talk about 'exercise' and most especially GET we express concern and alarm that some practitioners, clinicians, might lack the necessary understanding of ME and push people to exercise above their safe ability etc.

    With the Snell test, as I understand it, patients are told to push it as much as they can for the duration of the test, and it could be said that, in order to prove you have ME you must crash on the next day.

    Is this safe? Is it safe for everyone or for only some? Is it safe for the undiagnosed? How might it be viewed in light of widespread concerns over the misuse of GET?

    We are essentially saying 'Prove you have ME by crashing' and that this is the best (one of the best) objective measures. Is it not rather extreme? Could it be achieved any other - less intrusive - means?

    Any thoughts? I refer of course to the scenario of having this test in it's current state used outside of research in a clinical setting as part of a process for diagnosing ME; and to calls for it being incorporated in the existing CDC data collection project.

    I believe that you said yourself, Snell's work needs replication. So maybe we are not there yet with something that could or even should be considered for mass-use?

    There is also the cost of course but I would like to talk a bit about concerns over safety and whether or not such a test could possibly be considered suitable for all with ME or who need a diagnosis.

    Thanks :)
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  19. Simon

    Simon

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    I think the Snell work is fascinating and potentially a very imprtant way to reveal what goes wrong in our illness.

    However, until there is hard safety data I don't think it's appropriate to use as a standard diagnostic tool. I do think the CDC study would be a great place to look for validation/replication, and measure sustained response to exercise eg for a couple of weeks afterwards. Would also be good to know what proportion of clinic patiens would refuse the test (we don't know if self-selection is a big factor).

    And I agree about your point re GET: many patients object to it because it pushes them too hard, and that can causes relapses. No GET currently recommended includes anything like maximal exertion (though obviously is over a much longer period).

    Disclosure: I have relapses at way less than maximal exertion, so would refuse even a single maximal CPET, let alone 2 in 24 hours.
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  20. Firestormm

    Firestormm Guest

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    Thank you and for the italicised final sentence. I think I would agree with you there as well. And it would be useful to know how many patients if offered the choice would decline such a test in the field as it were as this would impact on any clinical outrolling of it as a diagnostic test.

    Not sure how reasonable it would be to ask the CDC to introduce such an unreplicated test but I don't remember off hand how far committed to their protocols and study they are to be honest. Might be too late and anyway, Unger seems to have been advised not to do it. Certainly would support another independent study of this and other studies that try and pin down PEM. No argument there :)
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