Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity

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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.

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).

VO2 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

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 and equipment 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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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?

 

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

Good question, Alex, and well worth some research. If only we had the funding.

I've wondered a lot lately about the definition of PEM. It seems that if you've experienced it, it's easy to identify. It's entirely different from fatigue, or exhaustion, or any other symptom in the same class. I've had exhaustion along with PEM/PENE, but it was clearly much more than just exhaustion. I frequently wonder if most of our doctors, and researchers even more so, don't really get it.

I sometimes think some patients who believe they have PEM, actually have other types of fatiguing symptoms and/or exercise intolerance which, while disabling in their own right, are different from PENE -- post-exertional neuro-immune exhaustion.

Now that I've cleared a number of viruses (for the time being, anyway), my experience of PEM is different -- much less flu-like and multisystem collapse, and more mostly exhaustion. Is it just less severe PEM, or do I only get some fatiguing symptoms but not true PEM? Is it that it would just take more now for me to get the whole system collapse thing, or that I wouldn't get there at all, although I would have extreme mental and physical fatigue? Frankly, I'm not going to experiment with testing to destruction unless it's for some valuable scientific research. I kinda like not being crashed.

I'd love to see more research on PEM --- What is it, exactly? Are there stages to PEM? Are there different flavors of PEM? Do different types of exertion -- physical, mental, emotional -- cause different types of PEM or is it all the same PEM?

 

I'd love to see more research on PEM --- What is it, exactly? Are there stages to PEM? Are there different flavors of PEM? Do different types of exertion -- physical, mental, emotional -- cause different types of PEM or is it all the same PEM?

Quark, strangeness and charm versions of PEM?

http://en.wikipedia.org/wiki/Quark,_Strangeness_and_Charm

http://en.wikipedia.org/wiki/Quark

There are six types of quarks, known as flavors: up, down, strange, charm, bottom, and top.[4] Up and down quarks have the lowest masses of all quarks. The heavier quarks rapidly change into up and down quarks through a process of particle decay: the transformation from a higher mass state to a lower mass state. Because of this, up and down quarks are generally stable and the most common in the universe, whereas strange, charm, top, and bottom quarks can only be produced in high energy collisions (such as those involving cosmic rays and in particle accelerators).

 

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

I started taking Yohimbe, a bark extract, about two weeks ago, and I haven't had any PEM while on it despite exceeding my limitations pretty badly, by flying back home (10+ hours in the airplane, 3-4 hours in airports). My heart rate was elevated for most of the trip, 100-105 on the airplane, and 105-130 after getting off the airplane, which would usually mean a bad crash.

So I still have my abnormal reaction to exertion shown by raised heart rate and/or dropping oxygen levels, but I don't seem to be crashing afterward. Basically there have been a couple recent papers by the Lights, showing a three-fold increase in ADRA2A expression after exertion in ME patients, but not in well-matched sedentary controls. And ADRA2A is capable of accounting for much of the symptoms of PEM, as well as suppressing norepinephrine production, which can cause orthostatic intolerance.

So I switched from taking an NRI to taking Yohimbe, which is a very potent antagonist of ADRA2A, and my OI symptoms have remained under control, in addition to thus far avoiding PEM. Gut motility has also improved, to the extent that I've had to cut my daily magnesium dose in half. I've had none of the muscle twitches or cramps that I would usually get from cutting back magnesium.

So in my very brief experience thus far, it seems possible that the up-regulation of that one gene after exertion can account for all of my PEM symptoms, both physical and cognitive, as well as a few other symptoms. Hence my experience says there's just one stage, with a single trigger - though there's obviously something triggering that abnormal reaction, since gene expression is normal prior to exertion.

Of course, there's also symptoms immediately following over-exertion (pain, weakness, etc), but I think those are a separate issue from PEM.

 

Gut motility has also improved, to the extent that I've had to cut my daily magnesium dose in half.

I tried one magnesium tablet once and it gave me bad diaree. I never did it again. As I treat the step after ADRA2A upregulation with the immuneregulator I use that makes sense to me now.

Keep digging valentijn

 

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?

A message by beaverfury here yesterday contains a link to a paper that excites me greatly as I believe that it may provide an important clue to how exertion can perpetuate ME autoimmunity, and perhaps also how the gut can be involved in the process of PEM being caused.

Unable to get the full text of that paper, I did some searching and found this one.

Put together with this paper that shows how excessive gut permeability could lead to, and perpetuate, autoimmune disease, some good clinical research addressing these issues in combination could perhaps scotch the psychoquacks' nonsense once and for all, and prove how GET can not only exacerbate symptoms on various timescales but also make recovery impossible.

 

I started taking Yohimbe, a bark extract, about two weeks ago, and I haven't had any PEM while on it despite exceeding my limitations pretty badly, by flying back home (10+ hours in the airplane, 3-4 hours in airports). My heart rate was elevated for most of the trip, 100-105 on the airplane, and 105-130 after getting off the airplane, which would usually mean a bad crash.

So I still have my abnormal reaction to exertion shown by raised heart rate and/or dropping oxygen levels, but I don't seem to be crashing afterward. Basically there have been a couple recent papers by the Lights, showing a three-fold increase in ADRA2A expression after exertion in ME patients, but not in well-matched sedentary controls. And ADRA2A is capable of accounting for much of the symptoms of PEM, as well as suppressing norepinephrine production, which can cause orthostatic intolerance.

So I switched from taking an NRI to taking Yohimbe, which is a very potent antagonist of ADRA2A, and my OI symptoms have remained under control, in addition to thus far avoiding PEM. Gut motility has also improved, to the extent that I've had to cut my daily magnesium dose in half. I've had none of the muscle twitches or cramps that I would usually get from cutting back magnesium.

Anything suggested by the great Valentijn has to be worth looking into. So I did me some searching for info on Yohimbe.

Looks like it's not for me, unfortunately.

For example this page says

Yohimbe bark has traditionally been used in Africa as an aphrodisiac

No thanks! I can do without that complication.

This lot is further cause for concern for me:

Yohimbe has been associated with high blood pressure, increased heart rate, headache, anxiety, dizziness, nausea, vomiting, tremors, and sleeplessness. Yohimbe can be dangerous if taken in large doses or for long periods of time.

OK, it only says 'associated', but I already have high blood pressure, and the others are common ME symptoms. It may be that further searches will reveal actual evidence, but it's 'No' to Yohimbe for me.

 

My reaction to the mention of Yohombin was an immediate; "eeeeeeeek!"

(something from the recesses of pharmacology studies and from work)

I couldn't remember what it was, or what was scary about it, but I remembered it was scary.

Early on in being ill, I found that mental overdoings could cause physical PEM and vice versa.

I'm not quite so sure this still happens. Sometimes, if I've been very happy, I will get a payback of being really down.

Mostly nowadays, PEM is an exacerbation of everything, my "baseline" level of functioning reduces.

I get that peculiar difficulty with breathing that Alex describes - as if the air hasn't got enough oxygen in it - (I do not know what thin air at altitude feels like, I'm only imagining) and that while I am labouring to breathe, it's still not doing what it it supposed to!

PEM should be a priority for research.

 

OK, it only says 'associated', but I already have high blood pressure, and the others are common ME symptoms. It may be that further searches will reveal actual evidence, but it's 'No' to Yohimbe for me.

It is heavily marketed as a male erection type drug, probably due to improvements in circulation. Many sources go way overboard in trying to make it look effective, to the extent that my bottle of it says "Not for use by females"

Anyhow, I do about 1/4 of the recommended daily maximum on the bottle, split into two doses. So a quite small dose. My heart rate has lowered, not raised, probably due to my pulse pressure rising to a normal level. I haven't experienced any side effects yet.

But yeah, if you don't have a problem with norepinehprine getting low, then your ADRA2A gene might not be getting overexpressed after exertion, or your body is compensating differently than the hypotensive folks. In which case, Yohimbe might not help, and might cause problems.

I haven't had any increase in libido, and no signs of growing a penis yet

 

But yeah, if you don't have a problem with norepinehprine getting low, then your ADRA2A gene might not be getting overexpressed after exertion, or your body is compensating differently than the hypotensive folks. In which case, Yohimbe might not help, and might cause problems.

Or maybe a med prevents the drop.

 

My reaction to the mention of Yohombin was an immediate; "eeeeeeeek!"

It has been banned from OTC sales in some countries, as well as in Australia. Possibly due to it raising norepinephrine and potentially epinephrine quite a bit, if taken in large doses. But pretty much the only thing it does is down-regulate three closely related genes, one of which is over-expressed in ME patients (and another of which might be involved in fibromyalgia).

Ideally it probably should be regulated due to the impact it has on the central nervous system, and it can be prescribed by a doctor in some countries. But here in the Netherlands, it's illegal to manufacture or sell it as a supplement, and it's not available in any form as a prescription. So once again, the medical system drops the ball, and we do the best we can with what's available.

The only other drugs which act as antagonists to ADRA2A are less powerful and far less specific. So probably much more side effects, and issues with tolerance, withdrawal, etc. And it's a nice alternative for people who can't get a doctor to give them any prescription, for whatever reasons.

 

I finally remembered to check my blood pressure properly: 130/88 with a pulse of 72. That means my pulse pressure is 42, whereas prior to starting Yohimbe it mostly stayed around 35, and my pulse was usually around 85 when rested.

 

I finally remembered to check my blood pressure properly: 130/88 with a pulse of 72. That means my pulse pressure is 42, whereas prior to starting Yohimbe it mostly stayed around 35, and my pulse was usually around 85 when rested.

As the pulse of atletes is lower than of normal people the psych could conclude you are less deconditionded now.

 

As the pulse of atletes is lower than of normal people the psych could conclude you are less deconditionded now.

But ... but ... drugs can't help me! Only exercise! A psychologist and an extremely egotistical neurologist said so, hence it must be true

 

It is heavily marketed as a male erection type drug, probably due to improvements in circulation. Many sources go way overboard in trying to make it look effective, to the extent that my bottle of it says "Not for use by females"

Anyhow, I do about 1/4 of the recommended daily maximum on the bottle, split into two doses. So a quite small dose. My heart rate has lowered, not raised, probably due to my pulse pressure rising to a normal level. I haven't experienced any side effects yet.

But yeah, if you don't have a problem with norepinehprine getting low, then your ADRA2A gene might not be getting overexpressed after exertion, or your body is compensating differently than the hypotensive folks. In which case, Yohimbe might not help, and might cause problems.

I haven't had any increase in libido, and no signs of growing a penis yet

Trouble is, I don't know what my adrenaline/noradrenaline(aka epinephrine/norepinephrine - how on earth does one pronounce these?!) levels are. I have doubts over whether a UK doctor would be willing to test them. Or do you test them yourself?

Glad you've managed not to change sex yet!

 

Trouble is, I don't know what my adrenaline/noradrenaline(aka epinephrine/norepinephrine - how on earth does one pronounce these?!) levels are. I have doubts over whether a UK doctor would be willing to test them. Or do you test them yourself?

I got mine tested privately at a local lab which has blood platelet testing as an option, with my US ND signing off on it. They also do international testing, but you'd still have to get blood drawn somewhere. But it's a fairly common test, so I'd be surprised if there aren't private labs in the UK offering it.

If you have low blood pressure and/or low pulse pressure (difference between systolic and diastolic values), then norepinephrine is a reasonable culprit. But if un-medicated pulse pressure and blood pressure are high or normal, then low epinephrine seems unlikely.

 

I got mine tested privately at a local lab which has blood platelet testing as an option, with my US ND signing off on it. They also do international testing, but you'd still have to get blood drawn somewhere. But it's a fairly common test, so I'd be surprised if there aren't private labs in the UK offering it.

If you have low blood pressure and/or low pulse pressure (difference between systolic and diastolic values), then norepinephrine is a reasonable culprit. But if un-medicated pulse pressure and blood pressure are high or normal, then low epinephrine seems unlikely.

OK, thanks. I can take my own blood samples if no special technique is needed (e.g. if it is particularly important to avoid leakage from blood cells - I don't have the expertise for that). But it sounds as though it's unnecessary in this case.

 

Adrenaline is pronounced a-dren-a-lin
Noradrenaline is pronounced nor-a-dren-a-lin

the "e" at the end should not be pronounced or alter the sound of the word.

Epinephrin(e) norepinephrin(e) are pretty much the same..

e-pin-e-frin

nor-e-pin-e-frin

I think.... but as we all know, that can be dodgy in PWME .

 

Adrenaline is pronounced a-dren-a-lin
Noradrenaline is pronounced nor-a-dren-a-lin

the "e" at the end should not be pronounced or alter the sound of the word.

Epinephrin(e) norepinephrin(e) are pretty much the same..

e-pin-e-frin

nor-e-pin-e-frin

I think.... but as we all know, that can be dodgy in PWME .

But which syllable(s) is/are stressed in the latter two?

They seem such cumbersome (if perhaps more accurate) words. I can't imagine saying that someone is an epinephrine junkie or that they enjoy epinephrine rushes!

 

Anyhow, I do about 1/4 of the recommended daily maximum on the bottle, split into two doses. So a quite small dose. My heart rate has lowered, not raised, probably due to my pulse pressure rising to a normal level. I haven't experienced any side effects yet.

Do you have a brand suggestion? When I did a brief hunt at my favorite supplements site, all the brands I saw looked a bit dodgy. If I'm going to try something a little risky, I like to stick with brands I'm fairly confident have in the bottle what is claimed to be there.

Do you mind saying how much is 1/4 of the max dose on your bottle?

I need to find a doc who will test norepinephrine. Unfortunately, there's not an ND or similar anywhere near here. All "evidence-based medicine" in my neck of the woods. If only that phrase actually meant what it says....