Exercise, PEM or PENE, and general medical research

[anciendaze]

We now have two reputable exercise laboratories which have separately published results of two-day cardiopulmonary exercise tests showing the reality of a drop in anaerobic threshold of ME/CFS patients on the day after a first exercise challenge. This is so striking the researchers involved said they went back and recalibrated their equipment, because they had trouble believing what they were seeing.

I am not here to dive into the on-going scrum about using this test for diagnosis. I want to ask a different question. These are basic physiological measurements. The researchers have been doing exercise testing for many years, yet still expressed surprise bordering on shock at these results. Why has this not been previously documented? Is it plausible that a million or more people with this condition in the general population have never showed up in tests run for other purposes?

One answer would be that this is a new disease or epidemic outbreak, with characteristics never seen before. (I doubt this, but I'm willing to consider the possibility.) Another possibility is that reasoning of the sort "healthy people exercise more" => "exercise improves health" has never been widely tested because expressing doubt on the subject would weaken the effect of medical exhortation about exercise, which is generally a "good thing" for most people, most of the time. If it had been carefully tested, and if incidence of ME/CFS has remained roughly constant, then the absence of earlier results of this kind -- in any medical condition -- would be inexplicable. (I'll admit to having a prejudice here, but I'll listen to reasoned arguments.)

I can certainly report that doctors have advocated exercise for me -- even when I had flu-like symptoms. At the time, I thought they knew what they were talking about, but I've since seen enough evidence about patients with myocarditis presenting with similar symptoms to wonder how they can be so sure this is not such a case, where exercise can actually be fatal. The fact that a patient has recently passed a physical is not much of a guarantee. I've also seen patients have heart attacks a week or two after a physical with lab work and an EKG that said they were in good cardiovascular health. This is not a rare sequence of events. Most clinical tests only detect damage after it has occurred. They have poor predictive value, if there is no previous damage.

My suspicions were aroused by publication of a study claiming aerobic exercise was beneficial for both MS and ME/CFS, without ever checking for any effect on anaerobic threshold. The "subanaerobic exercise" challenge they used was based on data from the healthy population. They had no idea if this truly was below anaerobic threshold for the patients they studied. Since anecdotal material about the effects of overexertion on MS patients is widespread, I wondered if this was an isolated lapse or evidence of a systematic pattern of research neglect.

What I'm asking here is for help in researching the state of the art. How much effort has gone into distinguishing exercise as a measure or consequence of health from exercise as a treatment promoting health in any medical context? If I reach a conclusion I will post a blog entry covering the subject. You can either post references here or you can send me a PM. You can even send email to my handle on this forum via gmail.com.

 

[alex3619]

@anciendaze, I substantially agree with your views. Yet there are social, political and bureaucratic issues here, plus the possibility that these findings have been seen as far back as the 1980s just not published in a useful way.

CPET goes back to at least 1949. The CPET technology hit mainstream sometime post 1963, after the publication of the Bruce Protocol. I am not sure exactly how pervasive it became in the different decades, but by the 1980s it was probably in every major hospital in the Western world.

I suspect that the critical connection that was not made is the requirement for two day testing. Many many ME and CFS patients have reportedly been claimed to have bad CPET results. Some have claimed to have had repeat testing, but this was private patients and those involved in proprietary research.

It took the Pacific Fatigue Labs researchers (now at the Workwell Foundation) to finally publish and properly investigate this.

Doctors have difficult issues to face. They have to provide good service for the costs. Many probably saw CPET as test that could not be justified, and were thinking along the lines that I was that since it wasn't published as useful, and was such an obvious test, it is probably the case that its not useful.

Insurance providers, and government bureaucracy out to cut costs, wants to limit testing. Testing costs money. Doctors are under pressure to conform, and only perform tests that are approved.

I have only begun to scratch the complexity here. So many issues are involved. So much of it is not publshed. As such we are largely guessing as to the actual issues.

One thing is not a guess. This is an obvious technology to apply, at least in hindsight, and has been around since 1949 at least. Something went very very wrong in the medical community.

I hope you get enough information to write your blog. I am thinking about this.

 

[WillowJ]

There was an article in the NY Times, stating that of the population in general, 10% did not benefit from exercise.

I don't have that citation handy, but while looking for it, I found this:
http://www.nytimes.com/ref/health/healthguide/esn-exercise-ess.html

 

[anciendaze]

Just a sampling of what turns up if you search for myocarditis and comorbidity: association with H1N1 influenza; effect of the particular antipsychotic drug clozapine; comorbid occurrence in rheumatology. This at least suggests there is some reason to consider possible myocarditis in three separate classes of illness for which you need to make differential diagnoses with ME/CFS. For patients with myocarditis there is no question about the dangers of overexertion.

Added: Somehow I left out Lyme disease and myocarditis. Another infectious cause is Rocky-Mountain Spotted Fever. If we have a diagnosis of exclusion, it seems the effort required to exclude possible differential diagnoses must be considerably greater than is currently recommended. I'm still waiting for official word on excluding Lyme in my own case, beyond having doctor say "Nah! You can't have Lyme. You live in Florida." prior to testing, as guidelines suggest.

This is interesting, but more or less irrelevant to my basic question: has medical research systematically overlooked a fundamental physiological response because "everyone knew" it did not happen?

 

[Valentijn]

This is interesting, but more or less irrelevant to my basic question: has medical research systematically overlooked a fundamental physiological response because "everyone knew" it did not happen?

I don't think it can be that simple. Patients knew very well that if they were active on day 1, they'd be very sick on day 2. We've undoubtedly been telling that to our doctors for decades.

I think the real obstacle has been the lack of belief. Psychosomatic theories dictate that our symptoms should be ignored and trivialized, not taken at face value and investigated. And, as mentioned above, exercise must cure everything!

 

[alex3619]

Ramsay and other researchers knew about the second day issue. Yet they didn't use CPET so far as I am aware. In the early days of CPET research it was primarily developed for heart disease. I think this might have biased people to seeing it as a heart test, though later on it was expanded to lung disorders. I wonder if it was its use in exercise testing for athletes that led to a wider use of the technology.

This is about dogma over reason, bias over science, prejudice (in the sense of prejudgement) and ignorance (as in lack of information) over knowledge. I think it might go to the heart of why humans stuff up. In the end it might be a false victory of intuition over reason ... people are just very sure, without evidence or sound reason. Let us not forget that patients also missed this, including me, though I did consider testing I never made the connection and presumed the science would have been done ... in my naive days when I thought the obvious things would have been tested.

Yet there is no doubt there are exacerbating factors, including the rise of psychogenic claims about ME from about 1970, right when CPET would have become very widespread. The rise of economic rationalism in which optimization of cost became a huge factor was also the 1970s, as was the beginning of the rise of the biopsychosocial model.

There might also be more prosaic reasons, such as this being a limited test, with limited testing facilities, so it might have been heavily prioritized to heart patients. Yet MS patients were able to get tested.

Let us also not forget that comparatively few doctors are scientists. How scientists and doctors think is very different.

PS We might have to consider medical ethics too. Most doctors who were concerned about ME patients might have been unhappy forcing us to exercise.

PPS Was it the 1970s that saw the rise of exercise as a cure-all? This is when the notion of aerobic exercise became popular.

 

[alex3619]

All these factors are why I have been saying the medical profession has some responsibility for all this. This happened on their watch, globally, over more than a half century. Its also no coincidence that these are some of the factors I have been looking into for my book.

I also wonder if we might have been considered statistical outliers even when problems were found. The ideas of statistics are often over-applied to individual patients. We are not all carbon copies, but statistical thinking promotes some weird biases that we are only just beginning to understand.

 

[anciendaze]

I'm going to change my question in hopes of getting some definite answers. Let's just examine the literature for any test, for any condition, which showed a prolonged drop in anaerobic threshold following exercise. Did researchers simply assume that people who did not drop dead experienced increased capacity for aerobic exercise without actually testing this assumption? If they did test the assumption there should be papers which would allow us to see how patients with this problem were overlooked. If testing was done, and patients were not overlooked in testing, we have evidence of a new illness or epidemic.

Either outcome of such a search of medical literature would be highly significant.

 

[Valentijn]

Did researchers simply assume that people who did not drop dead experienced increased capacity for aerobic exercise without actually testing this assumption? If they did test the assumption there should be papers which would allow us to see how patients with this problem were overlooked. If testing was done, and patients were not overlooked in testing, we have evidence of a new illness or epidemic.

I think there was some testing done with a 2-day CPET, in some normal and ill populations. But very little.

For the most part, I think the researchers didn't assume that the patients with other diseases would significantly improve lung or heart functionality by exercising more. They likely assumed that the poor results were not due to deconditioning, and they would be just as bad the next day, or the next week.

It all comes down to researchers' beliefs about the different diseases.

 

[Marco]

All valid questions predicated on the ME/CFS findings being genuine and unique.

One member @kermit frogsquier raised questions on another thread and suggested that these studies lacked appropriate controls e.g. :

As an addendum to the above -

Look, regarding Snell's results and the findings he has published in patients who were claimed to have ME/CFS - none of them will mean anything if another group of researchers does just a single study showing you can get the same results in very sedentary healthy controls. It is the control arm of the study that is important. That is not to say that the ME patients didn't have those findings, that is only to say the findings are not unique, and that is what is important.

If that happens - no one in the medical community will pay CPET testing any attention, even those very abnormal 1 day CPET tests that really do show a massive difference in ME patients will probably be dismissed. This is why both I and others (see message board above) are worried that Snell is doing more harm than good.

Snells claims of not just quick recovery in healthy controls, but improved supposed maximal exercise on consecutive days, fly in the face of what others have written about sports science in respect to very unfit people.

http://forums.phoenixrising.me/inde...e-test-for-assessing-diagnosing-me-cfs.31059/

I'm aware of two conditions (Gulf War Illness and Post Concussion Syndrome) where patients have been documented as having delayed exacerbation of symptoms after exercise rather than just exercise intolerance although I don't know if anaerobic threshold was measured. I'm pretty sure though that a 2 day CPET wasn't used.

A final point is that we can't rule out that other conditions might show the same pattern if tested but it hasn't been investigated because 'fatigue' isn't the major or pressing problem. If anywhere, you would expect such investigations in relation to 'energy' disorders such as primary mitochondrial diseases or diabetes. Might be worth a look?

 

[Mark]

There was an interesting Horizon (UK TV documentary) called "The truth about exercise" a year or two ago, which featured researchers at Nottingham University; I keep meaning to follow up on this and contact them about it because there is an easy and interesting ME/CFS study that's suggested by what was presented in the programme. Googling it now, it looks like it was actually a different group of researchers who found genetic markers that can predict who will benefit from exercise and who will not, although my recollection of it was that it was the Nottingham researchers who were talking about that.

I would really like to know whether there's a bias in the ME/CFS population to one or other of these genetic groups. If there was a strong association, which seems at least feasible, that would be a massive result. Maybe we could organise an informal study ourselves by getting the genetic testing done for a few patients and seeing what a small sample shows. Ideally I would like to get these researchers interested in exploring the reported drop in VO2 max in ME/CFS and see if they can find gene(s) for that. I really must try to get in touch with them. Here are some links about it:
http://www.rvc.ac.uk/News/PressReleases/pr1002_Genes.cfm
http://blogs.nottingham.ac.uk/pressoffice/2012/03/01/exercise-challenged-by-science/

The first link above mentions that some people don't get a very big improvement on V02 max after exercise! I don't know how the timing of that testing relates to the 2-day testing, but the interesting questions raised in this thread are important for us to understand as advocates, so I hope you'll keep on looking into it and get some answers.

As I understand it, CPET is well-established but 2-day test/re-test CPET is effectively a new protocol originating from Pacific Labs. So the sceptics argument on this is that this is a new test, and we don't know enough about how it might work for the general population - or for other sedentary and disease groups - to know whether this finding is definitive of ME/CFS. However, I think I heard Dr Snell (or someone else) counter this by saying that the whole point of Vo2max testing is that it should be repeatable and a consistent measure, and the whole point of using it is that it should be near-enough exactly the same a day, 2 days, 5 days or whatever days after the exercise. The only thing that should change is that over the long run it goes up with exercise. Thus in the short-term it really should be a stable measure, and studies in the past have (I think) supposedly validated that it is, which is why it's become a standard test.

So in other words, the 2-day test itself is a new protocol, but the idea of V02max falling like this a day or two after exercise is pretty much anathema to the whole concept of the test.

I think it's very important for us to have a good understanding of how solid the 2-day CPET results are though, and what are the caveats and possible roadblocks for that science. I don't think that science is done and dusted yet - it appears to be strong and important, but the case remains to be proven scientifically (mainly because nobody, certainly not from outside of the ME/CFS world, seems to be showing an interest in replicating the studies, which is what is really needed). We have recently had some sceptical arguments presented on here against the CPET test, as some members may recall, but unfortunately the critic provided no relevant evidence to support his claims. Still, I think it would be very useful for us to have a good handle on what the potential problems with this research might be, and what might need to happen for it to be more widely accepted, so I think it would be good to get some expert views on the research from people who might raise concerns...then we could all put this research in its proper context. To me it seems that the research is promising, but it's at the stage where it's crying out for attempted replication by researchers from outside the ME/CFS world, and perhaps we should be trying to set up studies by someone from the world of general exercise research, and providing them with a small group of patients to pilot a study.

 

[Valentijn]

I'm aware of two conditions (Gulf War Illness and Post Concussion Syndrome) where patients have been documented as having delayed exacerbation of symptoms after exercise rather than just exercise intolerance although I don't know if anaerobic threshold was measured. I'm pretty sure though that a 2 day CPET wasn't used.

GWI is identical in symptoms to ME/CFS, just with a more specific onset. They're probably the same illness, or extremely closely related.

 

[Valentijn]

I would really like to know whether there's a bias in the ME/CFS population to one or other of these genetic groups. If there was a strong association, which seems at least feasible, that would be a massive result. Maybe we could organise an informal study ourselves by getting the genetic testing done for a few patients and seeing what a small sample shows. Ideally I would like to get these researchers interested in exploring the reported drop in VO2 max in ME/CFS and see if they can find gene(s) for that. I really must try to get in touch with them. Here are some links about it:
http://www.rvc.ac.uk/News/PressReleases/pr1002_Genes.cfm
http://blogs.nottingham.ac.uk/pressoffice/2012/03/01/exercise-challenged-by-science/

It looks like the actual study is at http://jap.physiology.org/content/108/6/1487

I've downloaded it, and will make a list of the relevant genes, then check that against the 23andMe data I have for 19 ME patients who have PEM. I'll post the results back here, but it might take a day or two depending on how much data there is to go through

 

[MeSci]

Haven't had time to read all the posts yet but found this review paper which may be relevant to some aspects of the question - on exercise and Respiratory Tract Viral Infections. I had always thought that it was advisable to rest during viral infections but the evidence seems to be mixed.

A lot of the paper is about prior exercise's effect on the likelihood/duration of infection; from a quick look there isn't much about exercising during an infection.

I'm finally getting round to typing out my one-off exercise results from a student self-experiment at my Open University summer school carried out in the year that I became ill. I haven't got a detailed health diary for that year - only snippets - but one entry reports a resting pulse rate of 100 in the late evening, prior to the summer school test. Yet I was told that my results indicated excellent metabolism! There is no 'VO2 max/peak' etc in there but hopefully someone can pull something useful out of it.

I'm having to type it in small bursts due to the annoying effects of ME causing my eyes and brain to pack up after a short spell of concentration.

I think I will be posting the results in my blog for people to see if there is anything useful there if they want.

 

[Cheshire]

Here's a desperating paper by BPS physiotherapists.


Several submaximal exercise tests are reliable, valid and acceptable in people with chronic pain, fibromyalgia or chronic fatigue: a systematic review
http://download.journals.elsevierhealth.com/pdfs/journals/1836-9553/PIIS1836955314000794.pdf

I didn't get it all, most of the article is about trial outcomes. But what seems clear is that they have strong preconcived expectations about the whole stuff. As usual, they mix up everything (fibro, ME/CFS ...) and when a tool could be usefull they dismiss it (the poor results are due to non comitment caused by unrational fear of exercice, high heart rates are a consequence of anxiety...)

Of course, nowhere are they talking of the two day cardiopulmonary test. And anyway, I'm sure they would attribute any abnormality to movement phobia, anxiety and neuroticism...

My question is: does this test see the difference between someone pushing oneself and someone pretending to? In other words, is it possible to cheat?

 

[Marco]

Not to hi-jack the thread but this might be highly relevant in terms of replicating the CPET work. We all know that there is overwhelming evidence of autonomic dysfunction in ME/CFS with reduced parasympathetic and increased sympathetic activity even at rest. The same is true for type II diabetes. This autonomic dysfunction can be measured as a reduction in heart rate variability.

The following paper validates the use of a Heart Rate Variability Threshold (HRVT) measurement as a proxy for the anaerobic threshold (as explained in the text below).

This is potentially a simpler and cheaper way to measure the anaerobic threshold which could take studies such as a 2 day CPET out of the specialist exercise physiology labs. Not a trivial matter when diabetics with cardiac autonomic neuropathy (CAN) are prone to 'sudden cardiac death' (a nicely descriptive term if I ever heard one) .and exercise needs to be prescribed with some caution (in an ideal world).

Noninvasive method to estimate anaerobic threshold in individuals with type 2 diabetes

While several studies have identified the anaerobic threshold (AT) through the responses of blood lactate, ventilation and blood glucose others have suggested the response of the heart rate variability (HRV) as a method to identify the AT in young healthy individuals. However, the validity of HRV in estimating the lactate threshold (LT) and ventilatory threshold (VT) for individuals with type 2 diabetes (T2D) has not been investigated yet.

Conclusion

The HRVT identification by the proposed autonomic indicators (SD1 and RMSSD) were demonstrated to be valid to estimate the LT and VT for both T2D and ND.

While several studies have identified the AT through the responses of blood lactate [2,7,8] ventilation [9] and blood glucose[7] others have suggested the response of the heart rate variability (HRV) as a method to identify the AT in young healthy individuals [10]. The HRV is a non-invasive measure of the oscillation between consecutive cardiac cycles (as measured between each R-R complex). This technique has been used for the noninvasive evaluation of the sympathetic (SNS) and parasympathetic nervous system (PNS) activity both during resting and low intensity exercise[11].

During low to moderate exercise intensity the heart rate (HR) increase is mainly controlled by the PNS withdrawal [12]. On the other hand, at higher intensities (e.g. above AT), there is a reduction in the parasympathetic modulation concomitant to an increase in sympathetic activity [13,14] and thus a decrease in HRV is observed [15]. Such transition between the increase in the SNS activity and the vagal tone withdrawal occurs close to 60% VO2max, being close to the intensity at which the lactate (LT) and ventilatory (VT) thresholds have been observed for healthy young individuals [10,15]. However, the validity of the HRV in estimating the LT and VT for individuals who may have autonomic dysfunction associated with T2D [16-18] has not been previously examined.

The main findings of present study evidenced the HRV as an effective parameter for exercise evaluation in individuals with T2D, due to its noninvasive characteristic as well as because it evaluates variables associated with autonomic function. According to Yeckel et al. [30] the autonomic dysfunction usually precedes the occurrence of T2D. In addition, an elevated sympathetic activity is associated to a higher risk for cardiovascular events such as infarction and stroke [32,33]. The HRVT seems to identify an exercise intensity that represents the transition from a lower to a higher sympathetic activity and thus to an increased probability for the occurrence of cardiovascular events T2D individuals. Therefore, the identification of the HRVT intensity may be a safe and useful procedure for exercise evaluation and prescription.

Another benefit of HRVT identification is the avoidance of elevated financial costs usually associated with invasive methods. Exercise tests involving blood collection and biochemical measures, and/or the use of expensive apparatus for expired gases analysis, as well as trained professionals dealing with such protocols are expensive and thus of difficult access to a major part of the population.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033241/

 

[anciendaze]

@Marco

Heart-Rate Variability (HRV) is one of the features which turns up in testing for leading indicators of heart problems based on advanced theories of heart dynamics developed in the 1980s. This could hardly be called new research. It also shows up as a predictor of disturbed sleep. There is a strong correlation with problems in autonomic function including baroreflex sensitivity. This has direct relevance to problems of orthostatic intolerance, though medical language may obscure this. Orthostatic intolerance, dysautonomia and baroreflex are keywords I regularly use in searches.

I will admit that most research has been directed at people who have previously had either heart attacks or known comorbid conditions predisposing them to heart attacks. Current clinical practice seems to involve expressing concern for this possibility after patients have had a heart attack, but ignoring such evidence without a recognized comorbid condition.

Some research I've seen in the past, but don't have at hand, suggests the question of improvement in HRV as a proxy measure of cardiovascular health in response to exercise is not well-documented, except in people known to be healthy. I'll extend my request for research answering either this question or the earlier question about anaerobic threshold. How well have assumptions about improvement of either measure of cardiovascular function, in patients who start with poor measures, been tested, irrespective of a diagnosis of ME/CFS?

 

[MeSci]

I don't think it can be that simple. Patients knew very well that if they were active on day 1, they'd be very sick on day 2.

or day 3, 4, 5, 6 or even 7!

I always feel OK on day 2, at least until late evening and sometimes beyond that. It has been day 3 when I've been hit for most of my ME 'career'.

 

[Marco]

Reduced heart rate variability and autonomic dysfunction which appears to closely correlate with anaerobic threshold appeals to me as a concept because it both explains 'exercise intolerance' but also might help explain PEM/PENE in response to mental exertion whereas a purely cardiovascular issue such as myocarditis doesn't immediately appear to.

Yes, a 20 min personal phone call can be stressfull (some more than others) but I'm pretty sure that I've never breached the anaerobic threshold during them.

Cort reported (hopefully accurately) some time ago that Nancy klimas stated that her patients' ANS 'tanked' in response to exercise and this was folllowed by an immune response. There may be some mileage in this.

 

[anciendaze]

Incidentally, I am perplexed by the quoted comment about the control arm of these studies. If significantly reduced anaerobic threshold 24 hours following exercise is common among seriously deconditioned, but otherwise healthy, people where is the documentation for this claim? This should not depend on two particular groups of researchers, it should already be part of normative physiological data. Neither should it come as a surprise, as this did.

The only example without a definite pathology which comes to mind is overtraining syndrome, which takes place at much higher performance levels. If ME/CFS patients cross such a threshold -- at very low power outputs -- that is an extremely significant finding. If healthy, but deconditioned, people experience similar low thresholds, which cause setbacks in recovery, then the whole field of physical therapy for deconditioning needs to be reevaluated.