Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity

July 29, 2013

Hooked up for a CPET

Hooked up for a CPET

Simon McGrath reports on Dr Snell’s new study demonstrating that ME/CFS patients have a reduced capacity to exercise when they repeat a maximum exercise test one day on – unlike healthy controls.

One of the biggest problems of getting ME/CFS taken seriously is that often we ‘look’ normal, even though we feel lousy, and most lab tests produce ‘normal’ findings. How do we prove to the world that we are sick?

A defining feature of ME/CFS is Post-Exertional Malaise (PEM) and a couple of studies have clearly demonstrated PEM in patients [see box]. However, PEM is a subjective experience and one that can only be measured by patient self-report, which won’t satisfy everyone.

Dr Chris Snell, Staci Stevens, Dr Todd Davenport, and Dr Mark VanNess’s new study aimed to objectively demonstrate the problem of post-exertional malaise, by using a repeat Cardiopulmonary Exercise Test (CPET). As they formally hypothesized in their paper: “an exacerbation of symptoms following the first test would be reflected in physiological responses to the second”.

The study

The 51 CFS patients were all women, met Fukuda criteria and also reported PEM. Controls, also female, were similar in age and BMI, and were fairly sedentary. In fact, the results of the first CPET revealed that the controls were in the bottom 10% of published population norms and would count as deconditioned. CFS patients were barely different from controls so were also deconditioned, but, crucially, they were ill while controls were healthy, casting doubt on the idea that deconditioning is responsible for CFS.

CPET: Cardiopulmonary Exercise Testing explained

CPET is the Gold standard for measuring physical capacity, used by athletes wanting to measure the effectiveness of their training programs. It’s also used medically e.g. to diagnose cardiovascular, breathing and muscle disorders.

cPETb

The principle is to get someone to exercise to exhaustion, using a protocol that starts easy and gets increasingly difficult until the subject can do no more. The key measures for this study are the Volume of Oxygen consumed (VO2) and the amount of work done, measured in Watts on the exercise bike.

Anaerobic/Ventilatory Threshold

A critical factor is the anaerobic threshold, the point at which the body has to supplement normal aerobic (oxygen-burning) metabolism with much less efficient anaerobic metabolism, creating lactic acid. This threshold is measured in CPET by finding the point where carbon dioxide (CO2) starts to be produced faster than Oxygen, and is called the Ventilatory Threshold, or VT (strictly, VO2 VT).

CPETaVO2 max versus VO2 peak

One challenge of CPET is detecting if the person is using maximal effort, as opposed to trying pretty hard. Data showed that CFS patients and subjects here all went deep into anaerobic exercise and met at least one other measure of high effort. However, as it’s almost impossible to be completely sure, the study reported ‘peak’ measures instead of maximum, e.g. VO2 peak, not VO2 max.

Note there are equivalent thresholds for work output, in watts: W max, W peak and W VT

More: Lannie’s blog on PR about her CPET at Pacific Fatigue Labs.

Day 2 results separated patients from controls

Day 2 CFS patient...

A Day 2 CFS patient…

The big differences between the groups emerged on the second maximal CPET test, 24 hours after the first. On average, controls did slightly better on Day 2 (something that has been observed in other studies too) while patients did substantially worse. Interestingly, VO2 peak did not differ significantly between patients and controls, but peak Watts output was significantly lower, as was VTO2 . The biggest difference of all was for Watts output at VT, down for the patient group by over half.

The study found the repeat test could separate CFS patients from controls in this sample with 95% accuracy (3 errors in total). They also used a statistical technique called ‘cross-validation’, which indicated the test would achieve a 90% accuracy in an independent sample (though see issue with convenience sample below).

This ability of a 2-day repeat test to discriminate healthy but sedentary controls from CFS patients is critical. In theory, doctors can manage this easily enough without a CPET test. However, where there is doubt about the reality of symptoms, as can happen with disability insurance claims, an objective test can demonstrate that a patient really is sick. As Workwell Foundation notes, it’s useful in legal or medical disputes; the reduced performance on VT is “impossible to fake”, adds Dr Snell.

“the post-exertional state in CFS is characterized by objectively measurable deficits in submaximal metabolism and workload that would be nearly impossible for patients to fabricate”

In some ways the findings are unexpected, as it was the same group’s earlier finding of a substantial drop in VO2 max on the second test that caused such a buzz amongst patients. And the big drop in output at VT wasn’t seen in a study (albeit a small one) by a separate research group, though a smaller drop was seen for VT, and VO2 max in a study presented at an IACFS conference. I asked Chris Snell if he was surprised by the finding. “No”, came the reply: the initial study was small making the findings less robust, and he said that a much bigger effect on VT than VO2 max has been seen in the clinic too.

Evidence of Post-Exertional Malaise from subjective studies

As well as the objective evidence from this new paper, PEM has been shown by self-report measures too. A 2010 study from Pacific Fatigue Labs found that only 1 of 25 female CFS patients recovered from a maximal exercise test 48 hours later while all 23 sedentary controls did. Another study using a moderate exercise test found that fatigue and pain increased in the 48 hours after exercise in CFS patients – while it returned to normal in that time for both healthy controls and Multiple Sclerosis patients.

Committed to Maximal CPET

Given that it’s hard enough for people with ME/CFS to do one maximal test, let alone two, these results create the temptation to just run the second test as far as the Ventilatory Threshold and forget about VO2 max. But Chris Snell stressed that the Workwell Foundation remains committed to the repeat-maximal approach. First, VT can’t be measured on the fly so they wouldn’t know when to stop the test. And perhaps more importantly, the post-exertional effect appears to differ by patient, with some showing a greater effect on peak measures and others at VT.  Dr Snell suggested that varying post-exertional responses may well reflect different underlying pathologies.

Unique to ME/CFS?

Is this the killer test that uniquely identifies CFS patients? Dr Snell has reported that their clinic has tested patients with numerous illnesses including Multiple Sclerosis and Congestive heart failure, but have only seen the problem in ME/CFS patients. Published studies show normal repeat CPET performance for sarcoidosis, angina, Chronic Airflow Obstruction, Pulmonary Hypertension and heart disease. I’ve seen no studies showing failure to reproduce CPET results in other illnesses, but it’s probably too soon to say if this is unique to ME/CFS, or just very unusual.

What might cause the exercise problems?

The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS. Lower oxygen carrying capacity could result from low blood volume, while low oxygen consumption could also result from autonomic dysfunction and reduced ventilation. But research into the causes is needed.

No study is perfect…

  • There were only 10 controls, though as the repeatability of CPET results is firmly established (with 94% reliability between tests), in some ways controls mainly serve to demonstrate that the protocol is working properly.
  • The CFS patients were a convenience sample, rather than, for example, consecutive referrals to a secondary clinic. This, and the fact that patients had agreed to a repeat maximal exercise test, means the results might not generalize to the patient population as a whole.
  • The earlier study by this group, and the other studes from independent groups, didn’t find the dramatic changes with workload at the ventilatory threshold, so further replication would help to confirm the nature of the changes.

These findings, which make visible the hallmark ME/CFS problem of post-exertional malaise, have potentially huge importance. Replication of this study, perhaps with a more representative sample of CFS patients and some sick controls, should in my view be a priority for the research community. Stage two of the huge CDC multi-clinic study could provide the perfect opportunity for this.

Simon McGrath tweets on ME/CFS research:

 

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155 comments

{ 155 comments… read them below or add one }

LaurieL July 29, 2013 at 5:40 pm

This is a start!!! Albeit not one any of us were expecting, but woohoo!! It really is a start, and if they can identify sub groups, and then correlate with the subgroups, we could very well get confirmatory results, and testing, and legalities tied down, and finally, some type of healthcare, oh…and the very least, a howdy doo. :thumbsup:

Kina July 29, 2013 at 6:27 pm

Simon — another excellent article.

Nielk July 29, 2013 at 8:12 pm

Thank you Simon for your clear presentation of this study. It is apparent that this two day test can be beneficial for those who are building a case for the diagnosis of me/cfs but, does this mean that if one does not show a positive outcome of this test, that they do not qualify for a diagnosis of me/cfs. Does this back up the need of the ccc or Icc criteria having the mandatory symptom of pem/pene?

Valentijn July 30, 2013 at 2:24 am

Great article, Simon! :thumbsup:

Sasha July 30, 2013 at 3:14 am

Great article, Simon – this is very important research.

I have a concern, though, about its wide use as a diagnostic tool and that's whether the test itself could provoke a relapse. Do the authors have anything to say about this in their paper, or any follow-up data?

Simon July 30, 2013 at 3:35 am
Nielk

Thank you Simon for your clear presentation of this study. It is apparent that this two day test can be beneficial for those who are building a case for the diagnosis of me/cfs but, does this mean that if one does not show a positive outcome of this test, that they do not qualify for a diagnosis of me/cfs. Does this back up the need of the ccc or Icc criteria having the mandatory symptom of pem/pene?

Thanks!

The results of this study showed that it should detect 90% of CFS cases, or 10% of Fukuda-defined CFS cases would be missed. They didn't assess patients according to other criteria so it doesn't say anything about CCC and ICC – both of these require self-reported symptoms eg post-exertional malaise, rather than objective markers of exercise dysfunction. It would have been interesting to see follow-up symptomatic data for this study, as well as the objective data, to see how well the two correlated.

Sasha

Great article, Simon – this is very important research.

I have a concern, though, about its wide use as a diagnostic tool and that's whether the test itself could provoke a relapse. Do the authors have anything to say about this in their paper, or any follow-up data?

That's a very important point, and no, it wasn't addressed in the paper. A number of people who have undertaken the test have reported they recovered without any permanent deterioration, including Lannie and Jennie Spotilla, but I do think that if the test is to be widely used there needs to be systemmatic data on the likely impact on patients, both post-exertional symptoms and any relapses.

And thanks.

Thanks Valentijn, Kina :)

MeSci July 30, 2013 at 3:39 am

VO2 max versus VO2 peak

Thanks, Simon. I'm trying to familiarise myself with this and foggy brains need repeated readings for it to sink in.

Could you clarify for foggy brains what VO2 is, please? I know that VT02 is the ventilatory threshold, but VO2?

alex3619 July 30, 2013 at 4:39 am

I think the repeat exercise testing is some of the most important research that has ever appeared into ME. Until we have something better I think this should be considered the Gold Standard in ME functionality testing, although I do thing we need studies showing it works in CCC and ICC defined cases to address possible criticism.

This does exclude more severe patients though. If this research can be advanced and other markers found as a result, then testing on bedbound patients might become possible … but for now it isn't.

"The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS." I think this statement is critical. Its looking increasingly likely that well defined CFS is a heterogenous collection of different problems. Traditional medicine has looked at single-cause disease. For a heart to not supply sufficient blood for everyday use, for example, it must have seriously degraded capacity. I have been asking a question for some years now: what happens if you lose much less capacity, say 10 to 20% in many interacting systems? Rather than failure at one critical point, its the entire system that would be degraded, and testing each individual part would show up as normal.

Consider a chain of things A to D. (This could be mitochondria, muscle function, heart function, circulation function for example.) Now suppose heart function is down 60%, then the circulation output would be down 60% as its on the critical path. Consider however if all of them were down by just 20% each, which might not be considered normal. What is the outcome? (0.8)^4 = approx 41% capacity. This is almost the same as a 60% fall in heart function, if measured over the entire chain of mechanisms.

user9876 July 30, 2013 at 5:36 am

It would be interesting to do immune system testing at the same time prior to tests, after first test, after second test and after different recovery times.

Also I was wondering how this fits in with Julia Newtons work looking at lactic acid in muscle tissue. I was thinking this may relate to the VT02 threshold

Sasha July 30, 2013 at 5:44 am
user9876

It would be interesting to do immune system testing at the same time prior to tests, after first test, after second test and after different recovery times.

That was done by the Drs Light, wasn't it? And showed huge effects in PWME vs healthy & MS controls. Was that immune stuff or endocrine & other stuff?

Simon July 30, 2013 at 6:58 am
MeSci

Could you clarify for foggy brains what VO2 is, please? I know that VT02 is the ventilatory threshold, but VO2?

Sorry, thought I'd explained CPET well, but omitted the most important bit of info (would like to blame my illness for this but don't think that's the case).

VO2 is Volume of Oygen consumed.
VO2 plain and simple is measured in litres, but as VO2 depends so much on a person's size, it's usually expressed as mls O2, per minute, per kilo of body mass. For example, in this study the VO2 peak (volume of oxugen consumed) was 21.5 ml O2/min/kig – which is very low.

So VO2 max, VO2 peak and VTO2 are all volume of oxygen consumed per minute per kilo of body mass, at maximum, peak and ventilatory threshold. VTO2 is probably better called VO2 VT, but VTO2 is often used instead.

user9876

It would be interesting to do immune system testing at the same time prior to tests, after first test, after second test and after different recovery times.

Also I was wondering how this fits in with Julia Newtons work looking at lactic acid in muscle tissue. I was thinking this may relate to the VT02 threshold

I think the former is being done by Nancy Klimas, though I suspect she only uses a single maximal test. As Sasha notes the Lights looked at immune markers – or rather mRNA of immune marker proteins and found a small difference in CFS for the CD4 protein mRNA. They used a single 'moderate' exercise protocol, rather than a maximal one (though was probably close to maximal for the most severely affected patients they used,and these patients accounted for most of the effect seen).

Interesting idea about Julia Newton's lactic acid test, though her group didn't use a maximal test, and didn't use a repeat test either. The Snell study here didn't find a difference in VT for the first test, only on the repeated test.

Sasha

That was done by the Drs Light, wasn't it? And showed huge effects in PWME vs healthy & MS controls. Was that immune stuff or endocrine & other stuff?

Mostly it was looking at mRNA expression of adrenergic nerve pain/fatigue receptors where the effects were much bigger than the CD4 (immune marker) difference they found.

Esther12 July 30, 2013 at 7:18 am

Thanks Simon.

peggy-sue July 30, 2013 at 8:57 am

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later – and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.
It really is incredibly hopeful to, finally, see the right things being looked for and tested.

Artstu July 30, 2013 at 9:08 am

I wish I could be tested. In the cold below 12 deg C I can repeat more or less the same test again and again for a couple of weeks, and do similar average miles for average heart rates, in fact I can see gains in mileage and lower heart rates.

Firestormm July 30, 2013 at 9:35 am

Simon. Another cracker and very nicely presented on the full version I must say. Loved the cartoon :D

I couldn't get my head round this paper so thank you for persevering. Kind of what makes this place so great. If I can't figure it out then chances are someone else can :)

Having just returned from hospital and spoken with some physiologist science boffin about my 'mass of data' it would appear that initial suggestions are that my poor brain cell is being starved of oxygen during the night. It's too soon to say 'apnea' but we talked a bit around the topic; and I am left wondering to what degree oxygen starvation generally could be responsible for my muscle problems also (and lack of energy too I suppose) during the night and during the day.

It seems that oxygen is tied up with much that might be wrong. If my cells are not getting the oxygen they need then, as you said above, the outcome is more lactic acid and pain and discomfort for me. An inability to operate my muscles or for my muscles to recover from exertion. But above looks at inability to recover from exercise; and not ability to exercise in the first place – I am wondering then if those controls were experiencing the degree of muscle pain and ache etc. that I do constantly. Maybe this is where Prof. Newton's work comes into focus. Are 'we' just not getting enough oxygen, or not processing it, or not being able to process it?

All good stuff old bean :)

MeSci July 30, 2013 at 9:36 am
Simon

VO2 is Volume of Oygen consumed.
VO2 plain and simple is measured in litres, but as VO2 depends so much on a person's size, it's usually expressed as mls O2, per minute, per kilo of body mass. For example, in this study the VO2 peak (volume of oxugen consumed) was 21.5 ml O2/min/kig – which is very low.

So VO2 max, VO2 peak and VTO2 are all volume of oxygen consumed per minute per kilo of body mass, at maximum, peak and ventilatory threshold. VTO2 is probably better called VO2 VT, but VTO2 is often used instead.

Beautifully clear, thanks, Simon! :)

MeSci July 30, 2013 at 9:42 am
peggy-sue

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later – and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.
It really is incredibly hopeful to, finally, see the right things being looked for and tested.

I find that PEM takes longer to appear when I am relatively well, and at best it becomes almost imperceptible. Before I started getting these improved phases, my PEM occurred 2 days after exertion, almost like clockwork.

The fact that further exertion seems to put the PEM on hold, and that it then comes back with a vengeance, makes me extremely curious to know what is happening physiologically.

Answers to such questions could be invaluable.

Simon July 30, 2013 at 11:07 am
peggy-sue

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later – and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.

MeSci

I find that PEM takes longer to appear when I am relatively well, and at best it becomes almost imperceptible. Before I started getting these improved phases, my PEM occurred 2 days after exertion, almost like clockwork.

The fact that further exertion seems to put the PEM on hold, and that it then comes back with a vengeance, makes me extremely curious to know what is happening physiologically.

Answers to such questions could be invaluable.

Interesting point about the variability in PEM: mine doesn't even wait for 24 hours before it hits but clearly for others, including yourselves, it takes much longer, and that could complicate things.

Without changing their setup much, it would be interesting to ask patients how long before their PEM typically occurs, and correlate that with changes seen between test 1 & 2. They already have illness duration data, so could include that in the analysis too. (I don't know if they have looked at that separately).

Gijs July 30, 2013 at 11:50 am

This study do not proof PEM post-exertional malaise but post-exertional fatigue! Read the abstract correctly. Verry important finding.

MeSci July 30, 2013 at 11:59 am
Gijs

This study do not proof PEM post-exertional malaise but post-exertional fatigue! Read the abstract correctly. Verry important finding.

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

Simon July 30, 2013 at 2:05 pm
Gijs

This study do not proof PEM post-exertional malaise but post-exertional fatigue! Read the abstract correctly. Verry important finding.

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

As a corollary to extreme fatigue in CFS, post-exertional malaise (PEM) or exacerbation of symptoms following physical exertion, is considered one of the most common and recognizable aspects of the illness.6, 7 The Canadian Consensus Document on CFS goes so far as to mandate evidence of symptom expression following physical activity.4 The presence of postexertional symptoms in the clinical presentation of CFS suggests that cardiopulmonary exercise testing (CPET) can be reliably employed to elicit symptoms in CFS while also serving as both an indicator of clinical status and a quantifiable model of physical exertion.

… The purpose of this study was to establish the discriminative validity of objective measurements obtained during CPET to distinguish individuals with CFS from non-disabled sedentary individuals. To control for potential individual differences in preparation for testing and the cyclical nature of CFS symptoms, the present study employed a dual test paradigm comprised of 2 CPETs, each separated by 24 hours. It was hypothesized that an exacerbation of symptoms following the first test would be reflected in physiological responses to the second test.

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.

Sea July 30, 2013 at 3:10 pm

Any chance we could have access to the full paper?

Simon July 30, 2013 at 4:24 pm
alex3619

"The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS." I think this statement is critical. Its looking increasingly likely that well defined CFS is a heterogenous collection of different problems. Traditional medicine has looked at single-cause disease. For a heart to not supply sufficient blood for everyday use, for example, it must have seriously degraded capacity. I have been asking a question for some years now: what happens if you lose much less capacity, say 10 to 20% in many interacting systems? Rather than failure at one critical point, its the entire system that would be degraded, and testing each individual part would show up as normal.

Consider a chain of things A to D. (This could be mitochondria, muscle function, heart function, circulation function for example.) Now suppose heart function is down 60%, then the circulation output would be down 60% as its on the critical path. Consider however if all of them were down by just 20% each, which might not be considered normal. What is the outcome? (0.8)^4 = approx 41% capacity. This is almost the same as a 60% fall in heart function, if measured over the entire chain of mechanisms.

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.

Firestormm

Simon. Another cracker and very nicely presented on the full version I must say. Loved the cartoon :D

Having just returned from hospital and spoken with some physiologist science boffin about my 'mass of data' it would appear that initial suggestions are that my poor brain cell is being starved of oxygen during the night. It's too soon to say 'apnea' but we talked a bit around the topic; and I am left wondering to what degree oxygen starvation generally could be responsible for my muscle problems also (and lack of energy too I suppose) during the night and during the day.

It seems that oxygen is tied up with much that might be wrong. If my cells are not getting the oxygen they need then, as you said above, the outcome is more lactic acid and pain and discomfort for me. An inability to operate my muscles or for my muscles to recover from exertion. But above looks at inability to recover from exercise; and not ability to exercise in the first place – I am wondering then if those controls were experiencing the degree of muscle pain and ache etc. that I do constantly. Maybe this is where Prof. Newton's work comes into focus. Are 'we' just not getting enough oxygen, or not processing it, or not being able to process it?

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.

Ember July 30, 2013 at 5:00 pm
Simon

The results of this study showed that it should detect 90% of CFS cases, or 10% of Fukuda-defined CFS cases would be missed. They didn't assess patients according to other criteria so it doesn't say anything about CCC and ICC – both of these require self-reported symptoms eg post-exertional malaise, rather than objective markers of exercise dysfunction.

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.

Bob July 30, 2013 at 6:46 pm

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.

Allyson July 30, 2013 at 11:22 pm

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

Firestormm July 31, 2013 at 12:20 am

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

beaker July 31, 2013 at 12:25 am

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.

alex3619 July 31, 2013 at 3:15 am

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.

Simon July 31, 2013 at 5:30 am
Ember

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.

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.

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.

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).

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.

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.

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.

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 July 31, 2013 at 6:24 am
Firestormm

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 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:

Blacket al. (2005b) concluded that ME/CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4–10 days.

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

when the concentration of ADP in the cytosol increases and the ADP cannot be recycled quickly enough to ATP, another chemical reaction takes place. This becomes important if there is any mitochondrial dysfunction. Two molecules of ADP interact to produce one of ATP and one of AMP (adenosine monophosphate). The AMP cannot be recycled [6] and thus half of the potential ATP is lost. This takes some days to replenish and may account for the post-exertional malaise symptom experienced by patients.

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:

Basal hsp27 was significantly higher among CFS patients compared to controls, and decreased immediately post-exercise, remaining below basal levels even at 7 days. A similar pattern was observed for HSP60, which gradually decreased in CFS patients but increased in controls post-exercise.

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:

Following exercise, physical symptoms did get worse but not until a five-day delay in CFS patients.

from 'Time course of exercise induced alterations in daily activity in chronic fatigue syndrome' by Black and McCully:

Over the first 4-10 days of walking the subjects with CFS were able to reach the prescribed activity goals each day. After this time, walking and total activity counts decreased. Sedentary controls subjects were able to maintain their daily walking and total activity goals throughout the 4 weeks. Unlike our previous interpretation of the data, we feel this new analysis suggests that CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4-10 days. The inability to sustain target activity levels, associated with pronounced worsening of symptomology, suggests the subjects with CFS had reached their activity limit.

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:

There was a significant reduction in overall average activity after the treadmill test, with the greatest decrease on days 12 through 14.

from 'International Consensus Primer for Medical Practitioners':

Activation and worsening of symptoms can be immediate or delayed by several days. When exercise is repeated the next day, abnormalities are more severe…prolonged recovery period: usually 24 hours,often 48 but can last days, weeks or cause a relapse….Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.

from 'Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)' by Norman E Booth, Sarah Myhill, John McLaren-Howard:

The most characteristic and disabling symptom of M.E. is the postexertional malaise following activity or exercise, either physical or mental, often one to three days later…The replacement of the lost adenine nucleotides can take several days. This may explain one clinical feature of ME/CFS, namely delayed fatigue.

from 'DIAGNOSING AND TREATING CHRONIC FATIGUE SYNDROME (CFS)' by Dr Sarah Myhill:

delayed fatigue (mental and physical) – i.e. symptoms persist for 24 – 96 hours if you over-do things.
This is because when mitochondria are stressed, all the energy molecules (ATP, ADP and AMP) are drained out and cells have to wait 1-4 days for new energy molecules to be made via the pentose phosphate shunt.

(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:

all CFSs tend to push themselves to their particular limit every day and therefore do not give themselves a chance to get better. This means they have one day doing as much as possible, then three days to recover. Whilst you are on this roller coaster ride of activity and dives, you cannot hope to improve overall.
Fatigue and pain are the symptoms that prevent the body from damaging itself. Ignore these at your peril!

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.

Ember July 31, 2013 at 6:55 am
Simon

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.

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.”

Simon

But this is not a mandatory test?

The ME/CFS test is not: “While there is not one definitive test for ME/CFS, many tests may indicate abnormalities.”

Simon

Does this mean the Stevens protocol is mandatory to diagnose ICC ME, or is that an optional test? … I'm not sure how anyone can be certain these are definitive tests and that falling below a particular threshold is exclusionary.

PENE, among other symptom patterns and abnormalities, is confirmed by testing according to the ME Primer's Laboratory/Investigative Protocol (p. 11):

Laboratory/Investigative Protocol: Diagnose by criteria. Confirm by laboratory and other investigations. A broad panel of tests provides a more robust basis to identify symptom patterns, abnormalities and orient treatment.
[...]
PENE: 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

Simon

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.

Pressure should be brought to bear.

Firestormm July 31, 2013 at 9:48 am

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.

Simon July 31, 2013 at 12:50 pm

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.

Simon August 1, 2013 at 2:51 am

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:

Unique to ME/CFS?

Is this the killer test that uniquely identifies CFS patients? Dr Snell has reported that their clinic has tested patients with numerous illnesses including Multiple Sclerosis and Congestive heart failure, but have only seen the problem in ME/CFS patients. Published studies show normal repeat CPET performance for sarcoidosis [n=20, new], angina [n=14, 3 tests in 3 days], Chronic Airflow Obstruction [n=11, 2 tests in 3 days], Pulmonary Hypertension [n=42, >200 tests total as most patients did multiiple repeat tests over extended period] and heart disease[n=17]. I’ve seen no studies showing failure to reproduce CPET results in other illnesses, but it’s probably too soon to say if this is unique to ME/CFS, or just very unusual.

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

MeSci August 1, 2013 at 3:45 am

Just thought I would add a link to the thread I posted on 2nd July about the Snell study as there is lots of discussion there too, in case anyone hasn't seen it:

http://forums.phoenixrising.me/index.php?threads/new-dr-snell-paper-on-exercise-and-cfs.24050/

Firestormm August 1, 2013 at 6:10 am

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:

3 June 2013

Oh CDC, You So Crazy

…Dr. Unger said that the clinicians in the multi-site study felt a two-day exercise test was “not advisable.” She elaborated that patients travel some distance to get to the physicians involved in the study and that a two-day test was not feasible. It was not clear to me whether the concern was the time required or the physical impact on the patients. I was very surprised that the clinicians (Natelson, Klimas, Peterson, Kogelnik, Bateman, Lapp, Podell) were the ones who advised against using the test because most (if not all of them) have used two day testing for some of their patients….

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 :)

Simon August 1, 2013 at 8:52 am
Firestormm

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:

…Dr. Unger said that the clinicians in the multi-site study felt a two-day exercise test was “not advisable.” She elaborated that patients travel some distance to get to the physicians involved in the study and that a two-day test was not feasible. It was not clear to me whether the concern was the time required or the physical impact on the patients. I was very surprised that the clinicians (Natelson, Klimas, Peterson, Kogelnik, Bateman, Lapp, Podell) were the ones who advised against using the test because most (if not all of them) have used two day testing for some of their patients….

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?

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.

Firestormm August 1, 2013 at 9:25 am
Simon

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.

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 :)

jeffrez August 1, 2013 at 9:34 am
Firestormm

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 :)

All very good points. From that perspective, the test is actually medically unethical, as it violates the "do no harm" dictum.

SOC August 1, 2013 at 10:18 am
jeffrez

All very good points. From that perspective, the test is actually medically unethical, as it violates the "do no harm" dictum.

Not exactly. :) Doctors do surgical biopsies and spinal taps when necessary for diagnosis. Both these procedures cause some degree of "harm". Some amount of trade-off is accepted.

The relevant difference between the CPET test and GET is that the CPET is a one-time diagnostic(theoretically) from which one can recover, although it takes time. GET is presented as a continuing therapy, constantly stressing the system and not giving it time to recover.

That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy — no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET — what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?

jeffrez August 1, 2013 at 11:28 am

Sometimes people don't recover, though, or more commonly, don't recover fully. I think as long as that very real danger exists, it's a bit unethical to test in this way. I guess as long as the patient in an experimental or research setting consents that's one thing, but if a test like this were to become standard for diagnosing CFS/ME, I think it would have the potential to cause a lot of harm, and that obviously less dangerous testing through blood, etc. (or even spinal puncture) would be preferable. It would be psychologically very distressing if nothing else for patients to know they had to subject themselves to a 2- or more day exercise test to get any validation from the doctors.

Bob August 1, 2013 at 11:36 am

At the most recent CFSAC meeting, Beth Unger seemed to suggest that they might be including (one-day) post-exercise resting heart rate measures for the CDC's study. (I think it was suggested that CFS/ME patients' heart rates take a long time to return to normal after exercise.) Perhaps this is a good compromise, if she won't include two-day testing for ethical and practical reasons, but I'm not familiar with any post-exercise resting heart rate studies.

Bob August 1, 2013 at 11:43 am
SOC


That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy — no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET — what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?

I agree that this is very important research, and that CPET testing should be carried out with willing volunteers, who know that they will not suffer from long-term consequences from an exercise test.

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)

Butydoc August 1, 2013 at 12:12 pm
Bob

I agree that this is very important research, and that CPET testing should be carried out with willing volunteers, who know that they will not suffer from long-term consequences from an exercise test.

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)

I completely agree with Bob. Unless there is a likelihood of some positive therapeutic benefit, I personally wouldn't subject myself to the almost certain crash that would happen from this type of test. I spoke to people at Pacific labs and was told that some people have crashed for as long as a few months. This seems like a poor trade off just to prove my disease exist.

Gary

Simon August 1, 2013 at 12:36 pm
Butydoc

I completely agree with Bob. Unless there is a likelihood of some positive therapeutic benefit, I personally wouldn't subject myself to the almost certain crash that would happen from this type of test. I spoke to people at Pacific labs and was told that some people have crashed for as long as a few months. This seems like a poor trade off just to prove my disease exist.

Gary

Few months? Don't think I've ever got over a relapse that fast. Never mind the malaise, I typically lose over half of my function, and it comes back very slowly. And of course, people like me will self-select themselves out of such a test, making it very hard to know how safe the test would be in general use – as opposed to those willing to volunteer, who are probably people who know their worst case loss is a few months. If I knew that was the worst case for me, I would be more willing to give it a go.

urbantravels August 1, 2013 at 1:01 pm

I had the test for disability documentation. I can't speak to how they did it for clinical trials, but the disability test includes a symptom questionnaire that asks you about symptoms for a week after the test. I did have PEM symptoms for more than a week, but I think a week's cut-off is practical for the purpose of documenting disability…meaning that being sick for a week after exertion is enough to interfere with your ability to work full-time consistently week to week, and after that going on to be sick for more days isn't relevant for that purpose. Also, self-report of symptoms, as we all know, isn't measurable and objective, so it has only a little usefulness in the context of the whole test. It's more in the nature of supporting evidence.

I had no permanent or long-term setback from the test. I think I was fully back to baseline within 5 or 6 weeks and the really bad symptoms only lasted about 4 days. I am fortunate in having no particular responsibilities beyond basic self-care, so with preparation (lots of food laid in and everything otherwise arranged so I didn't have to go out or do anything but rest) the recovery period was long, but not agonizing or stressful. I was hitting my pain pills far more than usual due to muscle pain – that is, flu-like muscle pain, not muscle strain from unaccustomed exercise, although of course I had that too. Easy to tell which muscles got overworked from a bike test. But the muscle strain went away real fast compared to the PEM muscle pain.

The worst crash symptoms actually did not fully set in until four days after the test. I actually felt OK on the second day in terms of general malaise symptoms – better than I expected. In fact, I got home OK (short flight Sacramento –> Los Angeles, accompanied by my dad) and was all settled in for my recovery period before I started feeling really sick.

But – and this is important – I still had a *huge* plummet in my performance (workload at ventilatory threshold went down 60%) from Day 1 to Day 2 even though I certainly didn't *feel* 60% worse at that point. From this, I think it's possible that PEM symptoms do not track exactly with the decrease in your energy production capability – the decrease in ability to seems to happen quickly, but all the inflammatory-type symptoms may take longer to fully build up.

I don't know how this fits with the Lights' findings that pro-inflammatory cytokines go up within hours of an exercise challenge. It may be that the cytokines don't have their full effect for a while after they start being produced. Or, it could be that the cytokines continue to rise after the Lights' relatively short follow-up time…meaning that what the Lights are measuring actually isn't yet enough to provoke major symptoms, but it indicates the disease process is kicking off. Or that the body can clear the cytokines for a while at first but is eventually overwhelmed by them. I don't think this is a fault in their research. They are not looking at the entire life cycle of a PEM episode, but for a biomarker that distinguishes people with the disease from people without it.

SOC August 1, 2013 at 2:22 pm
Bob

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)

Good point. I was a bit too flip there with the "we get up, we move on". Every crash I had in my viral-ish days left me little bit worse. Because my illness wasn't as well-managed in those days, I never lasted long enough between crashes to recover that little bit back. Every crash made me a tiny bit worse, and the accumulation was a slow but steady downhill slide.

I guess I was thinking of participating in research — I would plan ahead for a crash and do everything I could to ensure I had the opportunity to go into mega-rest mode for up to a couple of weeks afterward. This is what I've done for other important things — my mother's funeral, for example. Not exactly "we get up, we move on" :whistle:. More like, we sometimes do what we have to do.

No ME/CFS patient should be required to do a two day CPET. The potential consequences are too high to require that from anyone. I hope some people at all stages of ME/CFS will choose to do the test for the sake of forwarding our knowledge. I also hope those patients will be under the care of a good ME/CFS doc who will help deal with the symptoms involved in the crash — autonomic dysfunction, infections, cardiac problems, whatever they are. To plan research on severe patients without that kind of post-test support borders on unethical.

urbantravels August 1, 2013 at 2:40 pm

That's sort of what I was trying to say in my post – creating a big cushion of rest and recuperation both before and after an expected stressor can help minimize the effects and possibly shorten the crash period. So it's important to be able to do that. I'd hate to have a big exertion and resulting PEM happen on top of one of those sort of "snowballing" crash periods. when something keeps happening to set you back a bit more each time. Pile a huge PEM on top of that and you might have a very protracted crash on your hands.

I'm not sure what deathly things could happen to you once you are done with the test and are recuperating at home that would require specialist medical intervention. I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.

urbantravels August 1, 2013 at 2:43 pm

More like, we sometimes do what we have to do.

I always tell healthies that I'm actually capable of rapid movement in an emergency, though I couldn't sustain it for long and would pay consequences later. I kept saying "I could run from a bear if I had to" so often that my friend asked me if bear attacks were a big problem in my neighborhood. :eek:

SOC August 1, 2013 at 2:50 pm
urbantravels

The worst crash symptoms actually did not fully set in until four days after the test. I actually felt OK on the second day in terms of general malaise symptoms – better than I expected. In fact, I got home OK (short flight Sacramento –> Los Angeles, accompanied by my dad) and was all settled in for my recovery period before I started feeling really sick.

I found this particularly interesting. In the days when I was still doing the push-crash thing, my delay was 4 days, which seems longer than most people are reporting. I usually hear of people crashing 24-48 hours after over-exertion. I did wonder if the 2-day CPET would catch my more delayed reaction, but it sound like it did for you, which is promising.

That was a clear and complete description of your reaction to the test. Thanks for that! Your description of a shorter "acute" phase of PEM, followed by a longer phase where you get back to baseline resonates with me. It's very much the way my (now rare) crashes work, but I've never described it that clearly.

SOC August 1, 2013 at 3:08 pm
urbantravels

I'm not sure what deathly things could happen to you once you are done with the test and are recuperating at home that would require specialist medical intervention. I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.

I'm thinking of things like viral reactivations or some kind of resurgence of infections. That seemed to happen to me with crashes when I had a pack of chronic infections. Antivirals and abx might be helpful under those circs. I'm also wondering if some people have some kind of autonomic crash after overexertion that could be alleviated with, I dunno, IV saline or meds…?

For me, the one-day tests have not been bad. You described it quite well. No long-term effects. I never did one when I was in the bedbound stage, though, so I don't know what it might have done to me then. Still, having done one before I was bedbound, I don't think I would have been afraid of trying it when I was. It might have been miserable, but I've been miserable with this illness, so that's not a big deal. I wouldn't have expected any permanent damage.

Bob August 1, 2013 at 3:33 pm
SOC

Good point. I was a bit too flip there with the "we get up, we move on".

Yes, I had the feeling that you'd experienced worse crashes than it appeared from your comment.

SOC

I guess I was thinking of participating in research — I would plan ahead for a crash and do everything I could to ensure I had the opportunity to go into mega-rest mode for up to a couple of weeks afterward. This is what I've done for other important things — my mother's funeral, for example. Not exactly "we get up, we move on" :whistle:. More like, we sometimes do what we have to do.

Yep, we all plan for big days, by resting before-hand etc., but a day visiting family, for example, is completely different to a maxed out exercise test. I've been through long periods of my illness where I only have to take a short walk and I crash severely. I can't think of anything worse for me than a maxed out exercise test!

Obviously many patients might feel confident that an exercise test is OK for them to participate in. But we've all got to safely make that decision for ourselves.

urbantravels

I think people often imagine a huge risk of permanent damage from taking the exercise test and I just don't see that happening. But the only way to know for sure would be to do long-term follow-up on a group of patients.

Each individual is different. A number of us here seem to be saying that an exercise test would be really bad for us. For myself, it could mean years of added distress if I had a bad crash. And it's very likely that I would have a bad crash if I exercised to the max, just once. Two days could be asking for a life time of hell. Remember that we're all different, and so the extent and severity of flare ups, in reaction to exertion, is different in all of us.

I'd like to see this research taken forwards, but it's got to be done safely, and not every one will be suitable to get involved.

urbantravels August 1, 2013 at 5:49 pm

Well, then the reasonable question would be: for those who have had crashes lasting months or longer, how often have they started from baseline (i.e you were at your personal average level of unwellness, not already extra unwell) and been triggered by one single episode of over-exertion?

peggy-sue August 2, 2013 at 11:52 am

My worst "crash" was after a 3 month prolonged overdoing under severe stress, while my Dad was dying (in a hospital 70 miles away). I did not stabilise to a new, but lower baseline than I had been at before, for 6 years.

I have just come home from a 6 day period of big overdoings – travelling a long way to cram as many friends and family members into the short space of 4 days (2 full days travelling).
I got home early Tuesday am. (this is now Friday afternoon)

I haven't crashed yet. I will monitor what happens and report. :)

Normally, I try to ignore it as much as I can. I had a lot of fun and it was very mentally uplifting. I anticipate a bout of depression as part of it (getting happy has its costs:cry: ) But I most sincerely hope it does not happen.

I generally find resting as much beforehand, taking a carnitine supplement daily while away, and carrying on with the carnitine supplement when I get back really does help to minimise suffering, and I have been doing that.

SickOfSickness August 2, 2013 at 12:45 pm

I would like to see the results if they waited longer between tests… 36 hours, 48 hours, perhaps more.

Some doctors are bound to say that the results can be faked. The terrible ones who think we want to be sick.

peggy-sue August 2, 2013 at 1:15 pm

SickofSickness said;
"Some doctors are bound to say that the results can be faked. The terrible ones who think we want to be sick."

You mean the ones that are already "faking" their results? Possible. They would, I'm sure, expect everybody else to be as deceitful as they are. :p

However, I don't think these are the sorts of results that CAN be faked, SoS. Honestly! :)

urbantravels August 2, 2013 at 2:16 pm

It's important to define what information you are looking for and why. Since the two-day exercise test is cumbersome, expensive, stressful, and contraindicated for many people, I certainly don't want and don't expect it to become the standard diagnostic test to confirm the presence of ME/CFS…or at least the ONLY test available.

A blood test for cytokines after a mild exercise challenge may become accepted as diagnostic. That would be quicker and cheaper and much more widely applicable. (Actually I've no idea how cheap it is to measure what the Lights are measuring, which is, as I understand it, activation of the genes that produce certain cytokines, not the cytokines themselves.)

Here's one problem though, drawn from my personal experience, that goes beyond the need to diagnose. For a disability claim, they may acknowledge that you have CFS, but refuse to accept that it is as severe as you say it is, or severe enough to prevent you from working. So in that situation, you need some way to objectively demonstrate how much your functional capacity is impaired by the disease, not just the fact that you have it. Being able to measure the severity of disease would also be useful for research. The really tricky bit would be developing a test that shows impairment of functional capacity without requiring the patient to do anything, or a test that "measures" a PEM without provoking a PEM. Unless it turns out that the most severe patients are in a more or less permanent state of PEM, which might be measurable.

Valentijn August 3, 2013 at 1:17 am
urbantravels

It's important to define what information you are looking for and why. Since the two-day exercise test is cumbersome, expensive, stressful, and contraindicated for many people, I certainly don't want and don't expect it to become the standard diagnostic test to confirm the presence of ME/CFS…or at least the ONLY test available.

A blood test for cytokines after a mild exercise challenge may become accepted as diagnostic. That would be quicker and cheaper and much more widely applicable.

This is why it's especially important to have this test included in the research. By seeing which patients have the non-deconditioned abnormal response, they can look to see what non-exercise-induced markers are present in those patients. Then every patient can benefit by having the results of a blood test stand in as indicating vulnerability to exertion, versus having to do the two day exercise challenge themselves to prove that they're ill.

They are NEVER going to take our word for it that exertion makes us sick. There has to be objective, unfakeable, physical testing clearly associated with the quick-and-painless testing methods that we want to be developed.

peggy-sue August 3, 2013 at 3:45 am

Personally, I'd rather risk a pretty massive crash before I'd have a lumbar puncture.
(Actually, I'm not sure I'd not prefer to die than have a lumbar puncture, but that's just me.)

MeSci August 3, 2013 at 4:02 am
SOC

Not exactly. :) Doctors do surgical biopsies and spinal taps when necessary for diagnosis. Both these procedures cause some degree of "harm". Some amount of trade-off is accepted.

The relevant difference between the CPET test and GET is that the CPET is a one-time diagnostic(theoretically) from which one can recover, although it takes time. GET is presented as a continuing therapy, constantly stressing the system and not giving it time to recover.

That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy — no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET — what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?

I agree with much of what you say, but not all. Some people do not recover from crashes, but become permanently even more impaired. If people are managing part-time work or self-employment, a crash can have a serious impact on income for a person who may already be on the breadline. This happened to me in 2010 when over-exertion caused a crash that landed me in hospital. I ended up building up a large credit card debt which I have only just paid off thanks to maturation of small occupational pensions accrued before I became ill.

No one has a right to make someone suffer such adversity just to prove that they are genuinely ill (and I do receive two disability-related 'benefits' – the disability element of Working Tax Credit, and a reduction in my council tax, and these have entitled me to a few further benefits such as free medications).

MeSci August 3, 2013 at 4:05 am
SOC

Good point. I was a bit too flip there with the "we get up, we move on". Every crash I had in my viral-ish days left me little bit worse. Because my illness wasn't as well-managed in those days, I never lasted long enough between crashes to recover that little bit back. Every crash made me a tiny bit worse, and the accumulation was a slow but steady downhill slide.

I guess I was thinking of participating in research — I would plan ahead for a crash and do everything I could to ensure I had the opportunity to go into mega-rest mode for up to a couple of weeks afterward. This is what I've done for other important things — my mother's funeral, for example. Not exactly "we get up, we move on" :whistle:. More like, we sometimes do what we have to do.

No ME/CFS patient should be required to do a two day CPET. The potential consequences are too high to require that from anyone. I hope some people at all stages of ME/CFS will choose to do the test for the sake of forwarding our knowledge. I also hope those patients will be under the care of a good ME/CFS doc who will help deal with the symptoms involved in the crash — autonomic dysfunction, infections, cardiac problems, whatever they are. To plan research on severe patients without that kind of post-test support borders on unethical.

I replied to your earlier message before seeing this one, SOC. Let me know if you want me to edit it, as I agree with you now! :)

MeSci August 3, 2013 at 4:23 am
urbantravels

I had the test for disability documentation. I can't speak to how they did it for clinical trials, but the disability test includes a symptom questionnaire that asks you about symptoms for a week after the test. I did have PEM symptoms for more than a week, but I think a week's cut-off is practical for the purpose of documenting disability…meaning that being sick for a week after exertion is enough to interfere with your ability to work full-time consistently week to week, and after that going on to be sick for more days isn't relevant for that purpose. Also, self-report of symptoms, as we all know, isn't measurable and objective, so it has only a little usefulness in the context of the whole test. It's more in the nature of supporting evidence.

I had no permanent or long-term setback from the test. I think I was fully back to baseline within 5 or 6 weeks and the really bad symptoms only lasted about 4 days. I am fortunate in having no particular responsibilities beyond basic self-care, so with preparation (lots of food laid in and everything otherwise arranged so I didn't have to go out or do anything but rest) the recovery period was long, but not agonizing or stressful. I was hitting my pain pills far more than usual due to muscle pain – that is, flu-like muscle pain, not muscle strain from unaccustomed exercise, although of course I had that too. Easy to tell which muscles got overworked from a bike test. But the muscle strain went away real fast compared to the PEM muscle pain.

The worst crash symptoms actually did not fully set in until four days after the test. I actually felt OK on the second day in terms of general malaise symptoms – better than I expected. In fact, I got home OK (short flight Sacramento –> Los Angeles, accompanied by my dad) and was all settled in for my recovery period before I started feeling really sick.

But – and this is important – I still had a *huge* plummet in my performance (workload at ventilatory threshold went down 60%) from Day 1 to Day 2 even though I certainly didn't *feel* 60% worse at that point. From this, I think it's possible that PEM symptoms do not track exactly with the decrease in your energy production capability – the decrease in ability to seems to happen quickly, but all the inflammatory-type symptoms may take longer to fully build up.

I don't know how this fits with the Lights' findings that pro-inflammatory cytokines go up within hours of an exercise challenge. It may be that the cytokines don't have their full effect for a while after they start being produced. Or, it could be that the cytokines continue to rise after the Lights' relatively short follow-up time…meaning that what the Lights are measuring actually isn't yet enough to provoke major symptoms, but it indicates the disease process is kicking off. Or that the body can clear the cytokines for a while at first but is eventually overwhelmed by them. I don't think this is a fault in their research. They are not looking at the entire life cycle of a PEM episode, but for a biomarker that distinguishes people with the disease from people without it.

I have been trying to work out the sequence of events from my own exertion, but don't have time to go through all my notes and do a proper analysis, as I am still having to work self-employed to keep the wolf from the door. It's very frustrating.

But so far I have observed:

1. Initial muscle pain that lasts up to about 48 hours, often much less
2. No obvious worsening on 2nd day
3. Mild head and neckache, arm muscle tightness, calf muscle twitching, apparent solute diuresis (evidenced by polyuria that does not respond to desmopressin) Mild upper abdominal pain? Looser bowel movements? Swollen cervical lymph nodes and submandibular glands with very pale skin over them? Twingeing maxillary lymph nodes? Itchy and blocked ears?
4. Poorer sleep, mild-moderate toothache.

There are other symptoms that I haven't included and I am not 100% sure of the chronological order.

Possible explanations for some observations:

  • Excess lactic acid production overloads the liver, hence upper-abdominal pain
  • Hyperlactaemia acidifies gut, hence loose bowel movements, possibly including loss of some nutrients that way
  • Solute diuresis involving excretion of excess lactic acid as sodium lactate and other salts
  • Consequent mineral deficiency leading to toothache and poor sleep

After my first severe episode of hyponatraemia I started suffering dental damage and also had my only-ever fracture, from a minor fall, supporting my theory of mineral loss, hence the fact that I now take a bone mineral supplement. I don't get these severe effects any more.

MeSci August 3, 2013 at 4:32 am
peggy-sue

Personally, I'd rather risk a pretty massive crash before I'd have a lumbar puncture.
(Actually, I'm not sure I'd not prefer to die than have a lumbar puncture, but that's just me.)

I wouldn't go that far, but I would only agree to a lumbar puncture to diagnose a possible life-threatening illness that needed urgent treatment. It's a dangerous procedure, the after-effects can be very nasty, and if they go wrong (which some do) it can be catastrophic.

MeSci August 3, 2013 at 4:47 am
urbantravels

I always tell healthies that I'm actually capable of rapid movement in an emergency, though I couldn't sustain it for long and would pay consequences later. I kept saying "I could run from a bear if I had to" so often that my friend asked me if bear attacks were a big problem in my neighborhood. :eek:

I can sometimes react quickly, and sometimes not. If I could always react quickly I would not have broken my wrist in 2008. I could have stopped myself from falling. I would not have sprained my ankle badly on a step more recently. Again, I could have stopped myself from falling. When I am dizzy, or disorientated, or weak, or ataxic, I cannot react on the way I need to, and the same would be likely to apply in a life-threatening situation. Yes – when not already suffering adverse effects from over-exertion, I can – to a degree. But the distance I would be able to run, or, for example, my ability to climb over a fence or up a tree, would be limited by my ability to keep producing ATP fast enough, which would vary according to my state of health but would probably always be less than what it would be without ME.

I also cannot rescue all the wild animals caught by my cats as I used to, which is upsetting. I even accidentally killed a mouse I was trying to rescue, due to weakness, slow reaction times and poor coordination.

I had to turn down my brother's invitation to go on his motorbike to see the solar eclipse a few years ago, as I know there was a danger I would not be able to hold on for long enough, so could end up falling into the road.

This inability to protect myself and others due to my illness is frightening.

MeSci August 3, 2013 at 4:54 am
urbantravels

It's important to define what information you are looking for and why. Since the two-day exercise test is cumbersome, expensive, stressful, and contraindicated for many people, I certainly don't want and don't expect it to become the standard diagnostic test to confirm the presence of ME/CFS…or at least the ONLY test available.

A blood test for cytokines after a mild exercise challenge may become accepted as diagnostic. That would be quicker and cheaper and much more widely applicable. (Actually I've no idea how cheap it is to measure what the Lights are measuring, which is, as I understand it, activation of the genes that produce certain cytokines, not the cytokines themselves.)

Here's one problem though, drawn from my personal experience, that goes beyond the need to diagnose. For a disability claim, they may acknowledge that you have CFS, but refuse to accept that it is as severe as you say it is, or severe enough to prevent you from working. So in that situation, you need some way to objectively demonstrate how much your functional capacity is impaired by the disease, not just the fact that you have it. Being able to measure the severity of disease would also be useful for research. The really tricky bit would be developing a test that shows impairment of functional capacity without requiring the patient to do anything, or a test that "measures" a PEM without provoking a PEM. Unless it turns out that the most severe patients are in a more or less permanent state of PEM, which might be measurable.

I wonder whether blood could be used for a test similar or roughly analogous to that which was conducted on muscle biopsies – subjecting them to the equivalent of exertion in vitro.

alex3619 August 3, 2013 at 10:09 am
MeSci

I wonder whether blood could be used for a test similar or roughly analogous to that which was conducted on muscle biopsies – subjecting them to the equivalent of exertion in vitro.

I have been making similar comments. We need more research in this area. This appears to be the case with fibromyalgia, its probably the case for ME as well. We need this investigated.

Firestormm August 3, 2013 at 10:10 am
alex3619

I have been making similar comments. We need more research in this area.

Me three :) Think we have a couple of threads capturing our thoughts on this kind of testing.

SOC August 3, 2013 at 11:22 am
MeSci

I replied to your earlier message before seeing this one, SOC. Let me know if you want me to edit it, as I agree with you now! :)

No problem. :) I wasn't clear the first time around, so it's reasonable people would call me on it to clarify.

SOC August 3, 2013 at 11:46 am
MeSci

But so far I have observed:

1. Initial muscle pain that lasts up to about 48 hours, often much less
2. No obvious worsening on 2nd day
3. Mild head and neckache, arm muscle tightness, calf muscle twitching, apparent solute diuresis (evidenced by polyuria that does not respond to desmopressin) Mild upper abdominal pain? Looser bowel movements? Swollen cervical lymph nodes and submandibular glands with very pale skin over them? Twingeing maxillary lymph nodes? Itchy and blocked ears?
4. Poorer sleep, mild-moderate toothache.

During crashes I don't have the initial muscle pain, but I do get joint and muscle aches different from overuse muscle pain. They don't usually hit the first day, either.

Before I cleared my chronic infections, crashes used to give me swollen cervical lymph nodes and salivary glands. In the worst crashes, I'd look like a chipmunk, the side of my face were so swollen. The good news is that now I don't get swollen node and glands with crashes, so I'm assuming that they were related to the infections. The toothache thing also disappeared. Doc and dentist think, and I agree, that the toothache was from swelling in the jaw area, not directly dental.

I still get the itchy and blocked ears. I'm wondering if it's a histamine thing…

MeSci

I can sometimes react quickly, and sometimes not.

For me, there's definitely an element of muscle stiffness (probably from lack of exercise) and clumsiness (which could be related to muscle stiffness or neurological problems) that prevent me from being agile and athletic. I've fallen down stairs 4 or 5 times in as many years. :eek:

Still, if I had only 15 minutes to get out of a burning airplane, for example, I could do it as well as 50% of the other passengers. There'd just be hell to pay later.

MeSci August 3, 2013 at 12:34 pm
Firestormm

Me three :) Think we have a couple of threads capturing our thoughts on this kind of testing.

Can you point me to any? Not sure if I have seen them or not. Don't worry if you can't find them easily.

MeSci August 3, 2013 at 12:40 pm
SOC

I still get the itchy and blocked ears. I'm wondering if it's a histamine thing…

I think there's some evidence that it's lymph-related. I may have saved the info somewhere, and I think it's been discussed on here as well.

SOC

For me, there's definitely an element of muscle stiffness (probably from lack of exercise) and clumsiness (which could be related to muscle stiffness or neurological problems) that prevent me from being agile and athletic. I've fallen down stairs 4 or 5 times in as many years. :eek:

Still, if I had only 15 minutes to get out of a burning airplane, for example, I could do it as well as 50% of the other passengers. There'd just be hell to pay later.

I wish I could be as confident. I thought I could react quickly in emergencies but experience has suggested to me that it won't always be the case.

I have very nearly fallen down the stairs a couple of times due to no longer knowing instinctively where my feet and legs are in relation to the ground. One occasion was pretty scary – I grabbed the handrail and involuntarily swung round about 90 degrees, holding on for dear life. That would have potentially been a bad fall, and it shook me up, with visions of breaking my neck as I might well have gone down headfirst and hit the wall at the bottom. It was a close thing. I have been very careful since then.

Simon August 3, 2013 at 12:58 pm
MeSci

I wonder whether blood could be used for a test similar or roughly analogous to that which was conducted on muscle biopsies – subjecting them to the equivalent of exertion in vitro.

That would be great.

Perhaps more likely is something like the Lights work on gene expression after moderate exercise, which also has the advantage, compared with maximal tests, that it represents real-life situations where patients actually experience PEM. They now have a substantial NIH grant to try to replicate the findings of very different results in ME/CFS patients so perhaps when that study reports there will be an altogether more moderate test with objective findings of abnormal response to exercise.

Mij August 3, 2013 at 2:05 pm
Bob
SOC


That said, I agree that 2-day CPET testing is not ready to be used as a universal diagnostic. First, it needs to be confirmed. Second, there's still a lot we don't know about it and its usefulness. My hope is that using 2-day CPET testing in research will provide enough information that someone will be able to develop a less "destructive" test for diagnosis.

I have never done the 2-day test. I did the one-day maximal test while I was mild-moderate and had a moderate crash that was a week or two long. Not fun, but not catastrophic. I've had as bad, and worse, crashes from other activities and infections. It wasn't so bad that I wasn't willing to do it again about 5 years later. The second test was not maximal, though, only to VT and was easy — no crash afterwards.

We've all had crashes. We get up, we move on. I'm willing to crash (as a one-time event), if necessary, to improve the knowledge base in this illness, especially if it's a planned crash so I can arrange my schedule, and maybe stick a few meals in the freezer. ;)

Maybe we need to hear, all in one place, from some of the people who did the 2-day CPET — what their condition was before the test, if they crashed and for how long/badly, what their condition was after the crash. Anybody willing to chime in with their experience?

I agree that this is very important research, and that CPET testing should be carried out with willing volunteers, who know that they will not suffer from long-term consequences from an exercise test.

But I don't agree that "we get up, we move on" after crashes. Obviously, it's different for everyone, but my ME is very reactive and my crashes tend to be severe, deeply distressing and long-lasting, and I spend my whole life trying to avoid them. I would never agree to any exercise testing unless I was in a very stable period of remission and I was absolutely confident that the exercise was within my safe limits. (Safe enough to avoid a crash.)

It is very interesting how we are all different. From my experience having ME for 22yrs would make me a good candidate for this test. I always stay within my boundaries because PENE is something I try to avoid at all costs, it's just too distressing.
I have gone through periods when I felt up to 80% improved fir a couple of years but if I do the SAME amount of exercise as when I'm feeling 40% the PENE is always the same. How I'm "feeling" makes no difference in exercise capacity, so the test result will show abnormalities no matter how well I am feeling at the time of exercise, there will be a unique physiological change upon doing just a small amount. If I'm going through a viral episode the PENE will come on within 2-3hrs, so like someone else wrote earlier is that we need immune testing added to the mix.

urbantravels August 3, 2013 at 2:06 pm

I think there's a distinction between the ability to produce a short burst of *energy* versus coordination and reflexes. I'm definitely klutzy since I've been sick – I've broken a lot of dishes and water glasses, walked into tables and chairs, etc. etc. But on a bike for the exercise test I managed to put in maximal effort without falling off or anything. No need for coordination or reflexes there – just hang onto the bike handles for dear life and pedal straight ahead.

Of course any given emergency or survival situation is probably going to require a combination of energy, strength, and coordination, so I'm not sure I could make good on my bear-eluding promises, unless it was on a straight even track. And it was a really short sprint. Hmm, this analogy may not be so good after all. Maybe I should go with "escaping from a burning building." Or "getting out in case of an earthquake." Not like those would require balance and coordination or anything..well, I now have no analogies, except "I could do an exercise test on a stationary bike if I had to."

Mind you nobody *requires* you to take the two-day exercise test to prove disability. It's just pretty much the only tool you can use that gives an objective measurement of functional capacity, impossible to fake or exaggerate. And I'd also add that no disability insurer is *required* to take any note of this test or consider it proof of anything, since it is not an "officially" accepted test of disability from CFS. The Social Security Administration, in its guidance on CFS claims, says an "exercise test" may be submitted as supporting evidence but is careful to point out that no test is considered *proof* of CFS or its severity. They could, at their complete discretion, ignore a Stevens test completely, or decide it is invalid or irrelevant. Hypothetically.

Without going any further into matters of which I should not speak…although I have seen a number of reports from people who prevailed in disability claims by taking the test, I feel obliged to point out that it is not a dead lock or a guarantee.

rosie26 August 3, 2013 at 3:55 pm

I think in ME we are in PEM all the time aren't we. (sorry I am struggling cognitively today). As our threshold for exercise is so low. We are feeling unwell everyday, always something wrong.

As for what day extra PEM sets in after exercise, for me it can happen anytime. There is no predictability. I can head out to an appointment and find myself doing a quick run to catch a bus and that short burst of a run can set me back in an hours time, my inflammation starts intensifying, I feel extremely sick. And there is also the accumulation upon accumulation PEM as well. That can result in a major relapse.

Cheers to the ME sufferers who put themselves up for the exercise testing. x

Firestormm August 3, 2013 at 4:16 pm

rosie26 I think I tend to equate 'exercise' with physical exercise. And therefore it's more likely to be worrisome and in need of more careful consideration. I'd probably plan some time out to better account for any PEM even if my exercise now equates to a brisk walk.

But a period of 'mental exercise' also can lead to consequences. So unless I have to – see below – I try and break it all up with distractions. Takes me longer but I am the tortoise now to the hare and usually get there in the end.

It is hard to judge what activity or intensity is going to be more likely to lead to a 'flare' and subsequent need for rest. I think through experience we tend to learn our own limitations at any given time and can make judgements accordingly.

Establishing routines if we can that fit to our own abilities is key but retaining some flexibility is also necessary. And that kind of makes it harder to commit to regular things – though I am ever full of praise for those who can.

I was just saying to Simon that I anticipated after my night's stay in hospital, the travel and disruption; and then a 3 hour intense meeting on Wednesday; that I would be in need of at least a few days of cleared decks. It still though comes as a surprise and I find it very annoying when the 'flare' hits.

Not always predictable the degree to which it can affect us – is it? And it's never just about the physical exertion; it's also the mental and emotional that we need to consider.

MeSci August 3, 2013 at 4:22 pm
rosie26

I think in ME we are in PEM all the time aren't we. (sorry I am struggling cognitively today). As our threshold for exercise is so low. We are feeling unwell everyday, always something wrong.

I think that people who are relatively badly-affected may always feel unwell, but I don't, and suspect that many others don't, as long as we adopt measures to prevent it, e.g. suitable diet and supplements and careful pacing. When I feel 'well' I have negligible bodily discomfort and my brain and body are able to do what I ask of them, which has to be not too much so as to avoid PEM later. So I am not recovered, but feel what I regard as 'fine', a lot of the time. I wonder how often sufferers and health workers mix up the two conditions – well and recovered. Is 'well' the right word for feeling OK?

SOC August 3, 2013 at 6:13 pm
MeSci

I think that people who are relatively badly-affected may always feel unwell, but I don't, and suspect that many others don't, as long as we adopt measures to prevent it, e.g. suitable diet and supplements and careful pacing. When I feel 'well' I have negligible bodily discomfort and my brain and body are able to do what I ask of them, which has to be not too much so as to avoid PEM later. So I am not recovered, but feel what I regard as 'fine', a lot of the time. I wonder how often sufferers and health workers mix up the two conditions – well and recovered. Is 'well' the right word for feeling OK?

I'm in the same place since I cleared my known chronic infections and, equally importantly, learned to use my HR to pace my activities. Without HR-based pacing, I was always overdoing (while doing very, very little) and constantly had symptoms.

alex3619 August 3, 2013 at 8:30 pm

In terms of general markers that might apply to ME patients, I discussed this a while ago on a thread on NADPH.

http://forums.phoenixrising.me/inde…surement-at-riordan-clinic.15641/#post-252023

Little Bluestem August 3, 2013 at 11:26 pm
MeSci

After my first severe episode of hyponatraemia I started suffering dental damage and also had my only-ever fracture, from a minor fall, supporting my theory of mineral loss, hence the fact that I now take a bone mineral supplement. I don't get these severe effects any more.

This is interesting. I have never had severe hyponatraemia. I don't know if I have had mild hyponatraemia.

I have had two filling replaced this spring. X-rays show that another is deteriorating. I was diagnosed with osteoporosis.

Valentijn August 3, 2013 at 11:55 pm
SOC

I'm in the same place since I cleared my known chronic infections and, equally importantly, learned to use my HR to pace my activities. Without HR-based pacing, I was always overdoing (while doing very, very little) and constantly had symptoms.

Heart rate has been a huge help to me too. I use a pulse oximeter since it's small and easy to take with me (it even came with a carrying pouch to go around my neck).

MeSci August 4, 2013 at 4:41 am
Little Bluestem

This is interesting. I have never had severe hyponatraemia. I don't know if I have had mild hyponatraemia.

I have had two filling replaced this spring. X-rays show that another is deteriorating. I was diagnosed with osteoporosis.

Standard general-health blood tests in the UK include blood sodium, and I would guess that this would be the case elsewhere. Can you see if you have more results for this? If not, you could ask for a test. In the UK I would expect patients to be told if their blood sodium was worryingly, or consistently, low.

But maybe different people are prone to deficiency in different minerals. Lactic acid can also be excreted as a salt of potassium, for example.

SOC August 4, 2013 at 11:29 am
Valentijn

Heart rate has been a huge help to me too. I use a pulse oximeter since it's small and easy to take with me (it even came with a carrying pouch to go around my neck).

I use a pulse oximeter now, too. When I was going over my AT walking across the room, I wore a chest belt HR monitor because I needed to watch every little activity to avoid going over my AT. Now I only need to check occasionally during the day.

pamb August 4, 2013 at 2:47 pm
peggy-sue

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later – and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.
It really is incredibly hopeful to, finally, see the right things being looked for and tested.

Hi Peggy Sue,
Thanks for sharing this interesting bit of information, that the longer your illness goes, the longer the delay before PEM hits. My husband has been ill for 13 years now and we've seen so many symptom changes over the years I've lost track. But, I had never considered PEM delayed longer than 2 days. We'll start watching and see if we are able to note a similar pattern. I can see it may be tricky as there as so many opportunities in a week to over due it.

Pam and John

urbantravels August 4, 2013 at 4:04 pm
MeSci

Standard general-health blood tests in the UK include blood sodium, and I would guess that this would be the case elsewhere. Can you see if you have more results for this? If not, you could ask for a test. In the UK I would expect patients to be told if their blood sodium was worryingly, or consistently, low.

Sodium is part of the standard electrolyte panel. Everybody gets this as part of a routine physical. I'm usually at the low end of the normal range on sodium, occasionally a point or two below the normal range, but nothing worrying. A truly low value is definitely something that would be treated, in anyone.

Ember August 4, 2013 at 5:48 pm
SOC

I'm also wondering if some people have some kind of autonomic crash after overexertion that could be alleviated with, I dunno, IV saline or meds…?

According to Jennie Spotila, Dr. Dan Peterson offers IV saline to help patients recover from exercise testing:

Disability evaluation and exercise testing will now be performed in two locations: the XCEL Physical Therapy Clinic in Ripon, California and Sierra Internal Medicine in Incline Village, Nevada (Dr. Dan Peterson’s clinic). Stevens says that the relocation actually enhances the quality of care that Workwell can provide patients. Working in Dr. Peterson’s office will not only offer patients access to his expertise in ME/CFS, but patients can receive IV saline to help them recover from the CPET.

Perhaps this CPET support will become standard procedure.

MeSci August 5, 2013 at 2:09 am
urbantravels

Sodium is part of the standard electrolyte panel. Everybody gets this as part of a routine physical. I'm usually at the low end of the normal range on sodium, occasionally a point or two below the normal range, but nothing worrying. A truly low value is definitely something that would be treated, in anyone.

OK. Hopefully in the US they have a better idea of how to treat it than here in the UK, where they have no clue about how to assess a person's hydration status and are therefore prepared to restrict fluids in an already-dehydrated patient!

MeSci August 5, 2013 at 2:13 am
Ember

According to Jennie Spotila, Dr. Dan Peterson offers IV saline to help patients recover from exercise testing:

Perhaps this CPET support will become standard procedure.

That's interesting, Ember. Presumably he checks people's sodium and fluid levels first? This may seem a silly question, but in the UK doctors often do very silly things!

peggy-sue August 5, 2013 at 3:52 am

Reporting on my current status, after my very busy holiday catching up with family and friends (24th-29th of July).
Today being 5th August, I noticed yesterday that somebody has turned the gravity up. I think payback is starting. I have wet washing in the machine, but have ignored it for 2 days – I am clearly "catastrophising" ;) – or in other words, my guts are telling me that hanging it up will be a really big job of overdoings.
That's a delay of 6 days since I got home.

Ember August 5, 2013 at 6:08 pm
Sasha

That was done by the Drs Light, wasn't it? And showed huge effects in PWME vs healthy & MS controls.

Gene expression isn't available as a clinical test at this point, but you may find Dr. Bateman's discussion of the Light AR, Bateman L, Jo D, et al. (2012) study interesting (5:00 – 18:00). Dr. Bateman discusses individual patient responses, attributing the low-level results of one of her patients in her 60s to her being a master of pacing and good health practices.

The initial study by the Drs. Light highlights the comparison with MS controls:

Although both CFS and MS patients reported greater physical and mental fatigue than controls, the CFS group reported more fatigue and pain at pre-exercise than the MS group, and their postexertional symptoms increased more and were still increased after 48 hrs while the MS group recovered by 24 hrs. Gene expression of metabolite-detecting receptors increased following exercise only in the CFS group, and only in this group was there a correlation between P2X4 increases and severity of post-exercise fatigue and pain. Thus, the pathology of CFS may include a susceptibility to disproportionate fatigue in response to exercise stress that is uniquely expressed in this patient group. The pattern of gene expression may have potential for use as a biomarker for diagnosis and treatment responses.

Dr. Bateman suggests test combining and says that serial CPET testing “is hopefully going to be a signature of this illness as well.”

Snowdrop October 20, 2013 at 8:58 pm
pamb

Hi Peggy Sue,
Thanks for sharing this interesting bit of information, that the longer your illness goes, the longer the delay before PEM hits. My husband has been ill for 13 years now and we've seen so many symptom changes over the years I've lost track. But, I had never considered PEM delayed longer than 2 days. We'll start watching and see if we are able to note a similar pattern. I can see it may be tricky as there as so many opportunities in a week to over due it.

Pam and John

This is my situation also. This is the first I've heard mention of the longer than 2 days PEM delay but I've come to realise that for me it's more like 4-5 days. Again, I'm not as alone as I thought.
SD

SOC October 20, 2013 at 9:14 pm
Snowdrop

This is my situation also. This is the first I've heard mention of the longer than 2 days PEM delay but I've come to realise that for me it's more like 4-5 days. Again, I'm not as alone as I thought.
SD

By the time I started paying attention to PEM — about 4 years after the initial flu-like illness — I was having about a 4-5 day delay before PEM. I'm starting to think the 3-5 day delay is more common that is currently believed.

MeSci October 21, 2013 at 3:25 am
SOC

By the time I started paying attention to PEM — about 4 years after the initial flu-like illness — I was having about a 4-5 day delay before PEM. I'm starting to think the 3-5 day delay is more common that is currently believed.

That's perhaps the opposite to what I have found. I said earlier in this thread that after I made appropriate changes to diet and supplements my PEM became more delayed (and almost imperceptible). It was hard to be sure as it had become so mild, but the delay seemed to have increased to about a week, from an initial two days.

peggy-sue October 21, 2013 at 5:29 am

I first read an article by the Dr. David Smith who has his own pet theory about ME?CFS quite early on in my internet trawlings to find out more about what the heck was wrong with me.

He's the chap who reckons it can be cured by mixing SSRIs and Tricyclics (officially contraindicated because of the risk of heart failure).

But his website had an article on pacing and how to calculate payback.
I wasn't neccessarily going to believe it.
I had read and dismissed a lot of garbage on the net (LP, Mickel, Reverse etc.)

But it did give me something to watch and observe, see if that was what did happen.

His "calculation" was that;

For every year you have been ill, PEM will delay by another day.

For every year you have been ill, the PEM will last that number of days
times the lenght of time you spent overdoing yourself.

so, for example,

a 2 week bout of 'flu after 6 years of being ill will give rise to payback of

14 x 6 days, (3 months) delayed by 6 days from the end of the 'flu.

I am not sure if it carries on getting delayed much after a week…. I have not observed that at all.

I've been sick 11years, my last big bout was still only delayed by 6 days.

I'm still getting over it – it was a very big and lengthy overdoing, in unbearable heat.

(but it was such a good time I had;
full of fun and laughs and confidences… and most important of all, love.:love: )

MeSci October 21, 2013 at 6:32 am
peggy-sue

I first read an article by the Dr. David Smith who has his own pet theory about ME?CFS quite early on in my internet trawlings to find out more about what the heck was wrong with me.

He's the chap who reckons it can be cured by mixing SSRIs and Tricyclics (officially contraindicated because of the risk of heart failure).

But his website had an article on pacing and how to calculate payback.
I wasn't neccessarily going to believe it.
I had read and dismissed a lot of garbage on the net (LP, Mickel, Reverse etc.)

But it did give me something to watch and observe, see if that was what did happen.

His "calculation" was that;

For every year you have been ill, PEM will delay by another day.

For every year you have been ill, the PEM will last that number of days
times the lenght of time you spent overdoing yourself.

so, for example,

a 2 week bout of 'flu after 6 years of being ill will give rise to payback of

14 x 6 days, (3 months) delayed by 6 days from the end of the 'flu.

I am not sure if it carries on getting delayed much after a week…. I have not observed that at all.

I've been sick 11years, my last big bout was still only delayed by 6 days.

I'm still getting over it – it was a very big and lengthy overdoing, in unbearable heat.

(but it was such a good time I had;
full of fun and laughs and confidences… and most important of all, love.:love: )

I'm glad you had some fun, peggy-sue

But that David Smith stuff sounds like BS to me. (Bad Science :lol:)

I took an SSRI and a tricyclic at the start of my ME and they turned me into an insomniac zombie unable to speak or swallow properly and with numbness in my hands which made it hard to use them. When I stopped them both I seemed to come alive again, once more aware of the beauty of nature, which I had become oblivious to and which had always been a source of pleasure for me, and one of the few things that I could still enjoy after becoming ill. All pleasure had been numbed by these drugs.

A lot of us don't get colds or flu. I still did in the early stages, and actually felt relatively well when I had them. I appear to have been immune to them for many years now.

It can be confusing when a website or other source has some good info/advice and also some BS. If you know one or more things to be correct, you may tend to assume that the rest is too. But it ain't necessarily so…(Cue music).

peggy-sue October 21, 2013 at 8:47 am

"It can be confusing when a website or other source has some good info/advice and also some BS. If you know one or more things to be correct, you may tend to assume that the rest is too. But it ain't necessarily so…(Cue music)."

Exactly, MeSci.

But his website was the first thing I found on the internet which had any pacing advice at all.

I could see the rest was BS, same as I read up about LP and Mickel and Reverse, and dismissed them as BPS -
(Bad Pseudo Science:p)

This was before I found any ME forums.

Pacing made sense, so I started applying pacing principles. They helped. A lot.

I don't get colds or 'flu often either. I felt what he said about that was daft.
apologies for using 'flu as an example of an overdoing!:redface:

alex3619 October 21, 2013 at 9:21 am

(Bad Pseudo Science:p)

:lol:

SOC October 21, 2013 at 2:26 pm
MeSci

That's perhaps the opposite to what I have found. I said earlier in this thread that after I made appropriate changes to diet and supplements my PEM became more delayed (and almost imperceptible). It was hard to be sure as it had become so mild, but the delay seemed to have increased to about a week, from an initial two days.

I wonder if it might be related to OI issues compared to energy production issues. Both could cause PEM, but on different time scales.

In my case, PEM occurred about 4 days after exertion in the time before I had any OI symptoms. As OI developed, the PEM delay got shorter and shorter. Since I've been treating OI, my PEM delay has lengthened again, although that may not be as certain since management has helped me to mostly avoid significant PEM over the past few years. It's hard to know for sure what's going on with such a small amount of data.

It might be interesting if researchers doing 2 day CPET also recorded when post-test PEM hit their "victims". ;)

alex3619 October 21, 2013 at 3:11 pm

The problem with PEM and current science is that it is still a syndrome. We don't understand it. I suspect its a composite symptom cluster with multiple issues, each of which has their own time scale. Some aspects of it are being unravelled though, from mitochondrial and delayed energy production issues, to more immediate muscle lactate responses.

Given that this involves metabolism, nerve signals, hormonal signals and immunological signals, each with its own time frame, the way to think of PEM might be one to many overlapping curves, each with its own maximum intensity spike\s, and what we experience is the combination of these effects. In terms of waves, this means intensification or nullification based on how the waves superimpose on each other. Three big waves coincide and whammo, you have big symptoms.

Which leads me to a question I have not thought about much, are there stages to PEM, with different symptoms in those stages?

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