Gulf War Illness (/CFS): two subgroups in response to exercise challenge?

June 28, 2013

Simon McGrath examines the latest research publication from Professor Baraniuk and Dr Rayhan

fMRI image

An fMRI image showing activation of brain areas during a cognitive test. From the PLoS One paper

Exercise challenge is fast the becoming THE key method when studying illnesses characterised by Post Exertional Malaise, such as Gulf War Illness (GWI) and ME/CFS. A paper just published looks at how exercise affects pain, cognitive performance, heart rate and brain functioning in patients with GWI. These patients also happened to meet the criteria for CFS, albeit only based on questionnaire diagnosis, making this study particularly interesting from an ME/CFS perspective.

Professor James Baraniuk and his colleague Dr Rakib Rayhan actually used a repeat challenge, with bicycle exercise on successive days, and looked for differences between 28 GWI patients and 10 controls, both before exercise and after. What they found was…initially, not much, it seems.

Pain was higher at baseline in GWI patients, as expected given that pain is one of the symptoms of GWI. And it appears that pain for GWI patients got worse after exercise, unlike controls. But they didn’t find the expected drop off in performance on the exercise bike at the second test (this fits with the latest results for CFS patients presented by Christopher Snell at the FDA workshop). And cognitive performance didn’t deteriorate after exercise (it was already low) – and brain functioning wasn’t so different either. Overall, increase in heart rate on standing (POTS) was unaffected by exercise too.

Detective work pays off

rakibR

Dr Rakib Rayhan

The study looked like a disappointment, until Rakib Rayhan did some digging through the data and noticed a marked difference amongst GWI patients. One subgroup (of 10 patients) showed tachycardia on standing (POTS) after exercise, while the remainder, 18, did not. The tachycardia patients, dubbed START for “Stress Test Associated Reversible Tachycardia”, also had much higher levels of anxiety and other problems such as gastrointestinal symptoms. The other GWI subgroup, labelled STOPP (with the PP standing for ‘Phantom Perception’ of pain), had an increase in pain after exercise compared with controls. However, the STOPP group pain increase doesn’t appear to be significantly different from START, and I suspect the label was chosen mainly because it makes a snappy acronym :) (though see below for some fMRI evidence that extra ‘pain’ regions are activated in STOPP patients).

What made these START and STOPP groups so interesting was that when they re-analysed the fMRI data they found the two groups had very different brain activation patterns during cognitive testing, and the patterns changed in a different way for each subgroup after exercise. For controls, the expected brain areas assoicated with working memory lit up during pre-exercise memory testing, but GWI patients activated these areas and aditional ones too (a similar phenomenon has been seen in CFS patients); it’s possible that GWI patients needed to use more brain areas to get the same job done. Intriguingly, START and STOPP groups activated different additional areas.  After exercise, there was less activation in the brain of controls as well as GWI patients, and bizarrely no activation in the START group.

Intriguingly, for the STOPP group, the additional regions lighting up in response to cognitive exercise increased are play important roles in processing pain perception. Before exercise the extra activity was in the bilateral anterior insula, after exercise it was the medial frontal gyrus. However, these regions have functions other than pain perception too so their activation may not relate to pain perception.

Rayhan and Baraniuk also looked at brain structure, and found lower volumes of grey and white matter in certain regions compared with controls – again the pattern was different for START and STOPP patients.

The researchers theorise that these differences in post-exercise tachycardia, brain functioning and brain structure mark out two distinct phenotypes. Which is amazing as originally they’d thought the tachycardia testing wouldn’t go anywhere: “I thought this would be a waste of the nursing staff’s time,” said James Baraniuk, adding that they did not expect the veterans to be different from the control group – or for there to be subgroups within the veterans. Instead, “It became a fundamental way of splitting the two veteran groups“.

Except…

Other experts are less convinced, noting that most of the subjects in the Georgetown study were self-selected and that their number was relatively small: 28 veterans with symptoms and 10 participants without symptoms. For the START subgroup, the comparison was between 10 controls and 10 patients and findings on such small samples can prove unreliable. Also, the authors say the bizarre finding of no brain activation during cognitive testing post-exercise may be an artefact of their method – but presumably some of the other findings could be artefacts too. The results need verifying.

Dr Drew A Helmer, director of the Department of Veterans Affairs’ War-Related Illness and Injury Study Center, called the Georgetown studies “very preliminary” but also “a very important step forward.”

Replication (as always) is key

The authors themselves emphasise the need for replication and validation, and they are hoping to get funding for a replication study on a new sample of patients. Given Dr Helmer’s comments on the potential importance of the findings, perhaps his Department will fund the work. The results from this will give a far clearer picture of whether or not there are indeed two types of GWI patients – if there are, it could prove very important indeed, as they note:

Identifying biomarkers such as these for phenotypic designation is one way to begin untangling the pathophysiological and molecular mechanisms underlying idiopathic disease states such as Gulf War Illness.

Those idiopathic illnesses, of course, include ME/CFS.

Update on the replication study, and relevance to CFS, from Dr Rakib Rayhan on Monday 1 July:

We are hopeful that this leads to a replication study in the near future. Ideally, we would like a very large sample of controls and GWI subjects for greater power and validation of current findings. Due to the overlap in symptomology, we feel that this protocol of brain scans before and after exercise perturbation holds tremendous promise to possibly try to understand central nervous system mechanisms in CFS.

 

Simon McGrath tweets about ME/CFS Research

 

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23 comments

{ 23 comments… read them below or add one }

Marco June 28, 2013 at 11:55 pm

Nice review Simon.

Methodological issues aside (and thanks for keeping us all grounded in this respect) I do wonder how many significant findings may be obscured by simple group comparisons where the patient cohort may be heterogenous.

"However, the STOPP group pain increase doesn’t appear to be significantly different from START, and I suspect the label was chosen mainly because it makes a snappy acronym"

A particular pet hate of mine (PACE, FINE, NICE, SMILE, BACME etc) and particularly naff in this context I felt.

Simon June 29, 2013 at 2:03 am
Marco

Nice review Simon.

Methodological issues aside (and thanks for keeping us all grounded in this respect) I do wonder how many significant findings may be obscured by simple group comparisons where the patient cohort may be heterogenous.

Thanks, Marco

I'm sure heterogeneity is a big reason for the lack of progress. Looking for subgroups is a good way of addressing this in smaller studies, so long as there is proper follow-up on any findings. Ultimately the answer is much bigger studies, which we are beginning to see, such as Mady Hornig's huge pathogen study and the CDC multi-clinic study which specifically aims to uncover heterogeneity.

Firestormm June 29, 2013 at 2:12 am

Thanks Simon. Struggled with this one (well nothing new there!). So they did the original experiment, found nothing 'odd', and THEN drilled down into the data to find these 'sub-groups'.

Hmm… I see what you meant the other day. Still, if the next experiment is better designed with these 'sub-groups' in mind then replication might have a better chance of succeeding.

FWIW that cognition test? Forget it. I couldn't comprehend the rules and the test was a nightmare :)

Simon June 29, 2013 at 9:28 am
Firestormm

Thanks Simon. Struggled with this one (well nothing new there!). So they did the original experiment, found nothing 'odd', and THEN drilled down into the data to find these 'sub-groups'.

Hmm… I see what you meant the other day. Still, if the next experiment is better designed with these 'sub-groups' in mind then replication might have a better chance of succeeding.

FWIW that cognition test? Forget it. I couldn't comprehend the rules and the test was a nightmare :)

That's exactly how it appears, and hopefully there will be replication that builds on this study.

Sorry the test was so hard – I only included it because I thought it migh be fun…

MeSci June 29, 2013 at 9:39 am

Another intriguing article – thanks, Simon. I won't even attempt the test at the moment – brain too fuzzy due to congestion. I'm sure that results will vary a lot depending on whether or not we have brain fog at the time!

Firestormm June 29, 2013 at 9:44 am
Simon

That's exactly how it appears, and hopefully there will be replication that builds on this study.

Sorry the test was so hard – I only included it because I thought it migh be fun…

MeSci

Another intriguing article – thanks, Simon. I won't even attempt the test at the moment – brain too fuzzy due to congestion. I'm sure that results will vary a lot depending on whether or not we have brain fog at the time!

All a question of timing. Am sure it's doable. Its got me hooked now – so I shall be back to try it again :)

beaverfury June 30, 2013 at 9:00 pm
Simon

Thanks, Marco

I'm sure heterogeneity is a big reason for the lack of progress. Looking for subgroups is a good way of addressing this in smaller studies, so long as there is proper follow-up on any findings. Ultimately the answer is much bigger studies, which we are beginning to see, such as Mady Hornig's huge pathogen study and the CDC multi-clinic study which specifically aims to uncover heterogeneity.

Thanks, Simon.

I'm ignorant of science methodology unfortunately, so i'm thankful for others more informed and balanced judgement.

I would have thought the American government would have a huge desire to follow up and replicate such experiments for the benefit of their military…and that me/cfs patients would benefit downstream.
But upon further reading it seems that this is not necessarily the case.

Cort, over on HR writes,

'It’s not clear how many of this studies findings will apply to ME/CFS but one thing’s for sure – GWI patients have received the same, if not worse kind of neglect from the federal establishment that the ME/CFS community has endured. Six months ago Dr. Stephen Coughlin, an immunologist at the Veteran Affairs Office, resigned while accusing the VA of manipulating and hiding data and basically doing everything it could to ensure Gulf War Illness was not taken seriously. Coughlin asserted the VA did not want anything published that might prove GWI is a neurological condition.'

It's 23 years since the start of the Gulf war! Progress is certainly slow.

Mark July 1, 2013 at 11:50 am
beaverfury

Cort, over on HR writes,

'It’s not clear how many of this studies findings will apply to ME/CFS but one thing’s for sure – GWI patients have received the same, if not worse kind of neglect from the federal establishment that the ME/CFS community has endured.

Similar kind of neglect, fair enough. But worse?? I've heard several researchers – including Baraniuk, Klimas and Mikovits I think, from memory – say that they find it much easier to get funding for their GWI research than for their ME/CFS research. Rayhan said at Invest in ME that they would love to repeat their GWI study for ME/CFS patients, but expected to find it much harder to get funding for that. I even get the impression that some researchers interested in ME/CFS are doing GWI studies instead in the hope that what they find will be applicable to ME/CFS as well. So my impression would be that GWI has been neglected 'almost as badly' as ME/CFS rather than 'the same, if not worse'. Comparison of historical research funding stats would be interesting.

Simon July 1, 2013 at 1:08 pm

I've updated the main blog to clarify some of the differences in brain activation during that cognitive test. For the STOPP (Phantom Pain Perception) subgroup, the areas activated in addition to the ones expected for woking memory both have a role in pain, which is another reason the authors chose the pain label. However, pain was not significantly different between START and STOPP groups, and those brain regions are involved in other activity apart from pain perception.

Here's an update too on the future from Rakib Rayhan:

We are hopeful that this leads to a replication study in the near future. Ideally, we would like a very large sample of controls and GWI subjects for greater power and validation of current findings. Due to the overlap in symptomology, we feel that this protocol of brain scans before and after exercise perturbation holds tremendous promise to possibly try to understand central nervous system mechanisms in CFS.

beaverfury July 2, 2013 at 1:03 am
Mark

Similar kind of neglect, fair enough. But worse?? I've heard several researchers – including Baraniuk, Klimas and Mikovits I think, from memory – say that they find it much easier to get funding for their GWI research than for their ME/CFS research. Rayhan said at Invest in ME that they would love to repeat their GWI study for ME/CFS patients, but expected to find it much harder to get funding for that. I even get the impression that some researchers interested in ME/CFS are doing GWI studies instead in the hope that what they find will be applicable to ME/CFS as well. So my impression would be that GWI has been neglected 'almost as badly' as ME/CFS rather than 'the same, if not worse'. Comparison of historical research funding stats would be interesting.

I pulled this from the net- Sorry if it doesn't link. I just googled 'cost of gulf war'.

http://www.fas.org/sgp/crs/natsec/RS22926.pdf

Costs of Major U.S. Wars

Congressional Research Service
1
A Trillion Dollars for Wars Since 9/11
Since the terrorist attacks of September 11, 2001, Congress has appropriated more than a trillion
dollars for military operations in Afghanistan, Iraq, and elsewhere around the world. The House
and Senate are now considering an additional request for $33 billion in supplemental funding for
the remainder of FY2010, and the Administration has also requested $159 billion to cover costs of
overseas operations in FY2011.

Holy crap! A trillion dollars! That's $1,000,000,000,000…. Or, a thousand billion dollars. Or a million million if you like.
And that's only up to 2010.

I don't know what the situation in USA is, either with GWI research or me/cfs research.

It seems like there's nothing the USA military can't do when undertaking war. I would be interested to know if they back a real desire to solve GWI with sufficient funding?
I know that funding money doesn't always equate to results, and that the researchers themselves are doing their utmost to solve the problem.

MeSci July 2, 2013 at 2:16 am
beaverfury

I pulled this from the net- Sorry if it doesn't link. I just googled 'cost of gulf war'.

http://www.fas.org/sgp/crs/natsec/RS22926.pdf

Costs of Major U.S. Wars

Congressional Research Service
1
A Trillion Dollars for Wars Since 9/11
Since the terrorist attacks of September 11, 2001, Congress has appropriated more than a trillion
dollars for military operations in Afghanistan, Iraq, and elsewhere around the world. The House
and Senate are now considering an additional request for $33 billion in supplemental funding for
the remainder of FY2010, and the Administration has also requested $159 billion to cover costs of
overseas operations in FY2011.

Holy crap! A trillion dollars! That's $1,000,000,000,000…. Or, a thousand billion dollars. Or a million million if you like.
And that's only up to 2010.

I don't know what the situation in USA is, either with GWI research or me/cfs research.

It seems like there's nothing the USA military can't do when undertaking war. I would be interested to know if they back a real desire to solve GWI with sufficient funding?
I know that funding money doesn't always equate to results, and that the researchers themselves are doing their utmost to solve the problem.

Governments always seem to be more willing to invest in taking lives than in saving them.

Whoops – controversial…

Emma July 2, 2013 at 10:50 am

Thanks for this, Simon!

This passage…

"But they didn’t find the expected drop off in performance on the exercise bike at the second test (this fits with the latest results for CFS patients presented by Christopher Snell at the FDA workshop)."

…made me a bit worried. Did Chris Snell report at the FDA workshop that his team does NOT find the drop on Day 2 of the Stevens Protocol Exercise Test in ME/CFS patients??

I have so much been hoping that the second day drop in oxygen use and anaerobic threshold would hold up as biomarkers to distinguish ME/CFS patients and to possibly measure outcome in future treatment trials. I just saw the newly published paper by Snell/Stevens/et al:
http://ptjournal.apta.org/content/early/2013/06/26/ptj.20110368.abstract

And I read this at the Prohealth report on the FDA workshop:

"Test results for CFS/ME patients
Dr. Snell’s group was not able to distinguish CFS patients from controls during an exercise test, until they looked at the aftermath. People with CFS were sick after the test. Strikingly, their ability to utilize oxygen decreased on the second day of testing. This was in direct contrast to healthy controls, who were able to utilize oxygen better on the second day. Later, this study was replicated using 56 patients. While the results were not as dramatic, the second larger study showed that there was a big drop-off in metabolic efficiency. CFS patients produced less work for more effort and had a greater buildup in lactate.

Summing up
Post exercise morbidity distinguishes deconditioning from CFS. CPET is a valid and accepted form of testing – there are just over 400 clinical trials around the world that currently include CPET (clinicaltrials.gov). CPET should be used as an endpoint to evaluate the efficacy of any drug treatment in clinical trials."

Was there something Snell said at the FDA workshop that indicated that the Stevens Protocol does NOT work in distinguishing ME/CFS patients (or hopefully measuring treatment efficacy)?

Thanks for keeping us up to date on everything!

Simon July 2, 2013 at 11:52 am
Emma

Thanks for this, Simon!

This passage…

"But they didn’t find the expected drop off in performance on the exercise bike at the second test (this fits with the latest results for CFS patients presented by Christopher Snell at the FDA workshop)."

…made me a bit worried. Did Chris Snell report at the FDA workshop that his team does NOT find the drop on Day 2 of the Stevens Protocol Exercise Test in ME/CFS patients??

I have so much been hoping that the second day drop in oxygen use and anaerobic threshold would hold up as biomarkers to distinguish ME/CFS patients and to possibly measure outcome in future treatment trials. I just saw the newly published paper by Snell/Stevens/et al:
http://ptjournal.apta.org/content/early/2013/06/26/ptj.20110368.abstract

And I read this at the Prohealth report on the FDA workshop:

"Test results for CFS/ME patients
Dr. Snell’s group was not able to distinguish CFS patients from controls during an exercise test, until they looked at the aftermath. People with CFS were sick after the test. Strikingly, their ability to utilize oxygen decreased on the second day of testing. This was in direct contrast to healthy controls, who were able to utilize oxygen better on the second day. Later, this study was replicated using 56 patients. While the results were not as dramatic, the second larger study showed that there was a big drop-off in metabolic efficiency. CFS patients produced less work for more effort and had a greater buildup in lactate.

Summing up
Post exercise morbidity distinguishes deconditioning from CFS. CPET is a valid and accepted form of testing – there are just over 400 clinical trials around the world that currently include CPET (clinicaltrials.gov). CPET should be used as an endpoint to evaluate the efficacy of any drug treatment in clinical trials."

Was there something Snell said at the FDA workshop that indicated that the Stevens Protocol does NOT work in distinguishing ME/CFS patients (or hopefully measuring treatment efficacy)?

Thanks for keeping us up to date on everything!

Thanks!

It's a bit ambiguous at the moment. The data presented at the FDA workshop, and what Chris Snell said too, indicated that the big drop-off seen in max oxygen consumption in the very small pilot wasn't replicated. But they did find a substantial drop in efficiency on day 2, so the CFS patients were producing less 'power' on the bicycle on day 2, despite using similar amounts of oxyge However, the newly published study, which appears to use the same data, says peak oxygen consumption also fell on Day 2 (ie the same finding as the small pilot).

So the good news is that the new paper definitely distinguishes between CFS and controls. However, it seems to do this in a different way to the original pilot study that got so much attention.

Hopefully things will become clearer when we get to see the full text of the new paper.

Separately, fMRI studies by Julia Newton's groups indicates muscle metabolism abnormality on muscle flexing alone. My view is that whatever the results of the latest Snell paper, we don'thave a definitive exercise test until we have consistent replication of any finding.

SOC July 2, 2013 at 12:22 pm

There are multiple physiological measures in exercise testing to be considered. What the people doing exercise testing are currently sorting out is which of those measures are clearly and predictably different in ME/CFS patients — which would be beneficial for diagnostic purposes — as well as which others might be useful for other purposes such as investigating causality, or evaluating treatment.

For example, a diagnostic marker has to be distinct enough that there isn't an overlap in the measure between healthy people and ill ones. For a diagnostic marker to be useful, every ill individual needs to fall outside the healthy range on that measure.

OTOH, discovering that the average (on some measure) of the patient group is significantly different from the average of healthy controls tells us that something is indeed different about the patient group, and what areas (relating to that measure) should be investigated for treatments and/or causality.

A current example of a useful measure that is not diagnostic is NK cell function. Every ME/CFS patient (as far as we currently understand it) does not have NK cell function outside the normal range, so it is not currently considered diagnostic. However, many of us do have low NK cell function, which indicates there's something wrong in that arena. Also, if a patient does have low NK cell function, treatments for poor NK cell function can be given and their effectiveness tracked by measuring change in NK cell function.

One thing we're hoping for, but which no one has published about afaik, is what measure will be useful in evaluating the effectiveness of any fundamental treatment for ME/CFS. For example, my AT is low which is common in ME/CFS, but not universal enough to be a diagnostic. Still, if a treatment increased my AT, that would be really useful for me. However, symptomatic treatments that have moved me from bedbound to 60-70% functional and feeling hugely better (no pain, no flu-like symptoms) have not budged my AT one iota. So if we used AT as a measure of the effectiveness of a treatment, the treatments that have helped me a lot would be considered ineffective because they didn't change my AT. o_O

Lots more work to be done. Thanks to Dr Snell and any others who are trying to tease apart this knotted ball of confusion that is ME/CFS.

MeSci July 3, 2013 at 2:28 am
SOC

For example, a diagnostic marker has to be distinct enough that there isn't an overlap in the measure between healthy people and ill ones. For a diagnostic marker to be useful, every ill individual needs to fall outside the healthy range on that measure.

OTOH, discovering that the average (on some measure) of the patient group is significantly different from the average of healthy controls tells us that something is indeed different about the patient group, and what areas (relating to that measure) should be investigated for treatments and/or causality.

I think that there are few diagnostic markers for any condition that are 100% specific and 100% sensitive, so something in the 90s would be great. But of course there are probably subgroups, and co-morbidities (which will be more numerous the later the diagnosis is attempted), and there is always the inescapable circularity/tautology of having to rely on incomplete knowledge and having to make assumptions, which themselves may not be correct!

This is not unique to ME, and we will never have a perfect solution.

It keeps scientists in work at least.:)

Simon July 3, 2013 at 9:52 am
MeSci

I think that there are few diagnostic markers for any condition that are 100% specific and 100% sensitive, so something in the 90s would be great. But of course there are probably subgroups, and co-morbidities (which will be more numerous the later the diagnosis is attempted), and there is always the inescapable circularity/tautology of having to rely on incomplete knowledge and having to make assumptions, which themselves may not be correct!

This is not unique to ME, and we will never have a perfect solution.

It keeps scientists in work at least.:)

Agree with that,esp the circularity of not having a validated gold standard.

90%+ is pretty good, but with one caveat:
Doctors don't usually have problems distinguishing between ME/CFS patients and healthy sedentary controls so the issue is specificity. Would be great to have a test that reliably distinguishes between ME/CFS and and other chronically fatiguing illnesses.

Snow Leopard July 19, 2013 at 6:14 pm

It is important to note that these studies don't imply any directionality. The brain changes may simply reflect the changes in the body, since we are talking about two parts of a single system.

Similarly exciting changes in brain activity can be measured before and after a thirsty person has a drink.

The problem I have with these brain imaging studies is they tell us very little about potential treatments.

Simon July 20, 2013 at 3:38 am
Snow Leopard

It is important to note that these studies don't imply any directionality. The brain changes may simply reflect the changes in the body, since we are talking about two parts of a single system.

I'm a bit puzzled by this. Measuring differences in brain activity during a congitive test, compared with baseline, seems a reasonable way to identify brain areas that might be involved in that test. Or have I missed something?

My bigger concern is whether the findings are real and replicable.

Similarly exciting changes in brain activity can be measured before and after a thirsty person has a drink.

Isn't that what would be expected? Given the fundamental importance of water to a thirsty person, I would have predicted exciting changes in brain activity in response to a drink.

The problem I have with these brain imaging studies is they tell us very little about potential treatments.

The authors are arguing that their fMRI test separates the patients into meaningful subgroups, which will aid research:

The authors

Separating subjects into groups based upon a stressor response may generate more homogenous subgroups for study of mechanisms and treatments.

Heidi July 22, 2013 at 3:18 pm
Simon
Emma

Thanks for this, Simon!

This passage…

"But they didn’t find the expected drop off in performance on the exercise bike at the second test (this fits with the latest results for CFS patients presented by Christopher Snell at the FDA workshop)."

…made me a bit worried. Did Chris Snell report at the FDA workshop that his team does NOT find the drop on Day 2 of the Stevens Protocol Exercise Test in ME/CFS patients??

I have so much been hoping that the second day drop in oxygen use and anaerobic threshold would hold up as biomarkers to distinguish ME/CFS patients and to possibly measure outcome in future treatment trials. I just saw the newly published paper by Snell/Stevens/et al:
http://ptjournal.apta.org/content/early/2013/06/26/ptj.20110368.abstract

And I read this at the Prohealth report on the FDA workshop:

"Test results for CFS/ME patients
Dr. Snell’s group was not able to distinguish CFS patients from controls during an exercise test, until they looked at the aftermath. People with CFS were sick after the test. Strikingly, their ability to utilize oxygen decreased on the second day of testing. This was in direct contrast to healthy controls, who were able to utilize oxygen better on the second day. Later, this study was replicated using 56 patients. While the results were not as dramatic, the second larger study showed that there was a big drop-off in metabolic efficiency. CFS patients produced less work for more effort and had a greater buildup in lactate.

Summing up
Post exercise morbidity distinguishes deconditioning from CFS. CPET is a valid and accepted form of testing – there are just over 400 clinical trials around the world that currently include CPET (clinicaltrials.gov). CPET should be used as an endpoint to evaluate the efficacy of any drug treatment in clinical trials."

Was there something Snell said at the FDA workshop that indicated that the Stevens Protocol does NOT work in distinguishing ME/CFS patients (or hopefully measuring treatment efficacy)?

Thanks for keeping us up to date on everything!

Thanks!

It's a bit ambiguous at the moment. The data presented at the FDA workshop, and what Chris Snell said too, indicated that the big drop-off seen in max oxygen consumption in the very small pilot wasn't replicated. But they did find a substantial drop in efficiency on day 2, so the CFS patients were producing less 'power' on the bicycle on day 2, despite using similar amounts of oxyge However, the newly published study, which appears to use the same data, says peak oxygen consumption also fell on Day 2 (ie the same finding as the small pilot).

So the good news is that the new paper definitely distinguishes between CFS and controls. However, it seems to do this in a different way to the original pilot study that got so much attention.

Hopefully things will become clearer when we get to see the full text of the new paper.

Separately, fMRI studies by Julia Newton's groups indicates muscle metabolism abnormality on muscle flexing alone. My view is that whatever the results of the latest Snell paper, we don'thave a definitive exercise test until we have consistent replication of any finding.

I'm disappointed to see here what seems like Snell waffling– or, even more disappointing, what seems like Snell trying to confuse the issue.

I think the two-day exercise test is so important because it demonstrates that THERE EXIST people whose VO2 max drops on the second day. Because of this, you could consider PEM to be a clinical entity in itself. Everything I read up until this (Snell waffling) seems consistent with that.

–PEM defined that way might be unique to people who seem to have something wrong with them but do not have another disease label other than Fukuda etc. Thus: a new clinical entity.
–PEM defined that way might turn out to be a symptom shared by some/all CFS people with (say) MS and/or cardiomyopathy and/or ALS or who knows. This would be evidence for something severely wrong with CFS people and would suggest what it might be.
–PEM defined that way is evidence that people with PEM will be made worse or killed by exercise. That is most definitely a treatment suggestion.

It would work best for our purposes if someone simply divided people into two groups– those whose VO2 max falls on second day and those who don't, and then study the first group.

Of course this happens in those lab(s) that test a large number of private individuals for disability. What is happening to that evidence?

Simon, would it be possible for you to write a summary from this perspective? (I am completely confused by the different labs, different studies, different buzz words, etc. even though there seems to be a very limited number of labs/studies.) Thanks for your analysis so far. I'm terrified that something apparently so clear-cut is going to get obfuscated out of existence, and that it is already too complex for the casual reader.

Heidi July 22, 2013 at 3:36 pm

Also, it is hard to express my irritation with STOPP "Stress Test Occurring Phantom Perception".

First of all, they operationalized it into "tender point exams." That's all it is. Those are controversial as to what they even represent.

Maybe in the study it was meant to represent changes in pain threshold. Yeah maybe it does. Maybe it doesn't. But then you call it "Stress Test Occurring Pain Threshold Decrease"–look, it almost spells STOP.

What the heck is a "phantom perception"? Translation: the observer gets to decide if the subject has "real" pain or not. (Newsflash: the word "pain" means a subjective perception, unless you are a behaviorist/solipsist).

The observer apparently then gets to decide if the subject has "real" injury (for example, if exercise causes injury to nerves) or not. Instead of, you know, studying the subject to look for injury.

The term seems to evoke "phantom limb pain."

Phantom limb pain is pain, not a phantom. The limb is the phantom, not the pain. The pain exists in the nervous system.

People who, for example, actually have limbs, do not have phantom limb pain, nor phantom pain, they have limb pain.

You could have "phantom pain" if a disembodied soul had pain. Then you could surmise that "pain" does not "exist in the nervous system" but was instead, for sure, "phantom pain."

Disgusting.

Simon July 23, 2013 at 6:09 am
Heidi

I think the two-day exercise test is so important because it demonstrates that THERE EXIST people whose VO2 max drops on the second day. Because of this, you could consider PEM to be a clinical entity in itself. Everything I read up until this (Snell waffling) seems consistent with that.

–PEM defined that way might be unique to people who seem to have something wrong with them but do not have another disease label other than Fukuda etc. Thus: a new clinical entity.
–PEM defined that way might turn out to be a symptom shared by some/all CFS people with (say) MS and/or cardiomyopathy and/or ALS or who knows. This would be evidence for something severely wrong with CFS people and would suggest what it might be.
–PEM defined that way is evidence that people with PEM will be made worse or killed by exercise. That is most definitely a treatment suggestion.

It would work best for our purposes if someone simply divided people into two groups– those whose VO2 max falls on second day and those who don't, and then study the first group.

Simon, would it be possible for you to write a summary from this perspective?

Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.

SOC July 23, 2013 at 8:48 am
Simon

Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.

I, for one, am eagerly awaiting your blog on this paper. :)

Heidi July 24, 2013 at 12:11 pm
Simon
Heidi

I think the two-day exercise test is so important because it demonstrates that THERE EXIST people whose VO2 max drops on the second day. Because of this, you could consider PEM to be a clinical entity in itself. Everything I read up until this (Snell waffling) seems consistent with that.

–PEM defined that way might be unique to people who seem to have something wrong with them but do not have another disease label other than Fukuda etc. Thus: a new clinical entity.
–PEM defined that way might turn out to be a symptom shared by some/all CFS people with (say) MS and/or cardiomyopathy and/or ALS or who knows. This would be evidence for something severely wrong with CFS people and would suggest what it might be.
–PEM defined that way is evidence that people with PEM will be made worse or killed by exercise. That is most definitely a treatment suggestion.

It would work best for our purposes if someone simply divided people into two groups– those whose VO2 max falls on second day and those who don't, and then study the first group.

Simon, would it be possible for you to write a summary from this perspective?

Welcome to the forum, Heidi

I will be blogging on the new Snell paper shortly, which will hopefully help.

However, the VO2max effect itself is probably of limited value. First, those willing to undertake a double VO2 max test are probably unrepresentative of CFS patients as a whole. And the effect is quite small, so it looks like there is a lot of overlap between healthy controls and CFS patients.

Wheras the reduced power output, and efficiency at Ventilatory Threshold on Day 2 test might be altogether more important. Still picking my way through a fairly detailed paper so not sure yet.

Thanks for the welcome, the clarification, and of course for reporting on these papers.

I am astonished that the VO2 max thing was not what I thought. Wow. So nothing is ever simple after all… I hope that my surmise/assumption/guess will be true–that some second-day tests are so messed-up that PEM can be characterized from them. And I hope that something simple can be made from that.

Really appreciate your analyses, Simon.

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