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 study conclusion said:
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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Do you have a brand suggestion? When I did a brief hunt at my favorites 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.
I've been using Yohimbe Fuel from Twinlab, and it seems to work quite well.

I also tried Yohimbe Bark from Gaia Herbs, which my mom thinks is a good brand, and that also seemed to work. But it's an extract with an alcohol base, which might have been causing me some problems until I switched to Twinlab (headache and feeling a bit hung over).
Do you mind saying how much is 1/4 of the max dose on your bottle?
Twinlab says 400mg of bark per capsule, twice per day, which they claim is 8mg of Yohimbine (the active part of the yohimbe bark) per capsule. I do 1/4 of a capsule twice per day, so that's about 100mg of bark and 2mg of Yohimbine twice per day. Which gives me a daily total of 200mg of bark and 4mg of Yohimbine.

A smaller dose might work, but I haven't tried it yet. Basically the 100mg dose isn't causing me any problems, and the stuff is dirt cheap, so I'm not worried saving cash. 4 bottles will last me over a year :D
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....
In the US, it shouldn't be too hard to find a doctor who is somewhat willing to investigate things. It might help to check websites for someone who likes to treat complex and chronic disease . . . autism, IBS, fibromyalgia, etc. Even if you can't find someone who knows much about ME/CFS, you might be able to find a doctor who isn't afraid of a challenge.
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!
Actually I would say:

But maybe that's more of an American thing. I'd have trouble putting the emphasis just on a single vowel.
I would stress the E s. pronounced "eh" as in enjoy.

I never say epinephrin(e) or norepinephrin(e).

:confused: I do have a slightly Scottish accent - I also rrr-oll my rrr-s :p
AfME report following presentation evening in Bristol. 07 February 2014:

"...After the film, Prof Mark VanNess spoke about the work he and his team are doing at the fatigue laboratory in the Health, Exercise, and Sport Sciences Department, University of the Pacific, California.

Working with people who have mild to moderate M.E., they are finding objective, rather than self-reported or subjective, evidence for the kind of fatigue that is specific to M.E.

Using cardiopulmonary exercise testing, Prof VanNess has proven that people with M.E.:

  • experience significant post-exertional malaise, though he prefers to call it post-exertional amplification of symptoms
  • have significantly impaired ability to generate energy from aerobic activity.
The key is that subjects are tested over two days. People with M.E. and healthy controls, all volunteers, spend 10 minutes on the treadmill on the first day, and then again 24 hours later. Results show that on the second day the metabolic function of people with M.E. has dropped by around 25%, such a marked decrease that, Prof VanNess told us, exercise physiologists protested that the machine must not be calibrated properly.

As a result of the data he has gathered, Prof VanNess has concluded that therapeutic interventions for people with M.E. should avoid aerobic exercise. Instead, they should be offered analeptic activity, intended to retrain the short-term (anaerobic) energy system to increase range of motion and improve functional strength. Crucially, he said, the ratio of activity to rest should be one to three, and physical therapists should be trained and experienced in this type of physical therapy.

Prof VanNess and his colleagues wrote an article for the CFIDS Chronicle, which explains these findings in more detail. He has also published numerous papers in peer-reviewed journals on his topic, including:

Conversely, or at least some have interpreted it that way, here is Nancy Klimas (hint: I suggest you watch the trailer and interpret it for yourselves):

Posted 1 week ago

Exercise and ME/CFS with Dr Nancy Klimas

Dr. Nancy Klimas, one of the most respective authorities on chronic fatigue syndrome in the world, emphatically states:

“It is very important for my patients to know how to approach exercise in a safe way…. if they don’t exercise, they will only get worse."

With the kind assistance of Dr Klimas and Connie Sol, the physiologist on staff at the Neuroimmune Institute (, we have created a series of three videos on VO2 Max exercise testing, the consult and the implementation of the program for sufferers.

Klimas Exerice and Vo2 Max.jpg

Also included in the video are two bonus segments with Dan Moricoli on how he has employed the system to go from a housebound, virtually bed bound, status to a near normal lifesytle.

DVDs of the video are available for worldwide delivery for only $19.99. To order a DVD via PayPal go to:

The three part series plus a personal view on the program by Dan Moricoli
Dr. Nancy Klimas, one of the most respective authorities on chronic fatigue syndrome in the world, emphatically states:

“It is very important for my patients to know how to approach exercise in a safe way…. if they don’t exercise, they will only get worse."
Really? Then how have I improved so much without 'exercise'? And re the previous message, how have I improved in strength (don't know what 'functional strength' means) without exercise?

I have been active, in my essential daily tasks, as usual, but not 'exercised' because there is no energy to spare after the essentials.
Conversely, or at least some have interpreted it that way, here is Nancy Klimas
Thanks for posting both bits of info, Firestormm.

Whenever I've seen Nancy Klimas talk about exercise, her emphasis is always on what is 'safe' for patients to do. She uses CPET tests and heart rate to determine what she considers to be safe for individual patients. So perhaps Klimas' exercise prescription is not so different to what VanNess recommends, but I don't know enough about either's recommendations to be able to compare them.

I don't approve of the suggestion in Klimas' video that exercise is therapeutic, and leads to improvement, for obvious reasons.

All the power walking and squats etc seen in the video are utterly inappropriate for an ME patient. (I think most of us would expect that level of activity to provoke a post-exertional flare-up.)
Many of us participate in gentle activity, but if a 'patient' can do power-walking and squats etc, then I question if they actually have ME. (They don't seem to have much disability.)
In my opinion, the level of exercise that is shown in the video is way out of proportion, in terms of what patients can be expected to do.

Is it a promotional video for Klimas' clinic?
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The Klimas approach is at least extremely useless for severe illness. If not dangerous even with the safeguards.
I don't know how the ill patients managed exercise and daily living too.
I have found brushing my teeth, getting dressed and feeding myself challenging.
Showing people out power walking seems ridiculous to me.
It would seem that they really don't have any idea of the symptoms we face and their severity.
The Klimas approach is at least extremely useless for severe illness. If not dangerous even with the safeguards.
I don't know how the ill patients managed exercise and daily living too.
I have found brushing my teeth, getting dressed and feeding myself challenging.
Showing people out power walking seems ridiculous to me.
It would seem that they really don't have any idea of the symptoms we face and their severity.
Snowdrop, did you see the chap who was talking at the end, I can't remember his name. I actually remember speaking very similarly to him when I was at my worst, but I don't do that any longer, and it isn't through exercise specifically.

I don't know what it is - but I think slowly building up again, and learning to manage, being able to sweep things aside and rest when I need to etc. all have helped me to improve over time. I think speech is one of more noticeable improvements commented on by others like my family.

I have worked hard to regain some of my ability to function mentally again I think, through reading, writing (well typing really) and stuff, and I do take walks now, but I don't have any rigidity in my life really, I have routines but they are flexible of necessity.

I think acceptance has finally paid dividends as well. Learning not to fight but not to surrender to it either. Of course I can't always avoid a crash but I can be more aware of when one is likely, and be prepared for it.

Actually I am overdue a shower... been waiting for a phone call but better have one now before bed I think. Good luck to you :)
I really am not wanting to be over critical of someone wanting to help our community.
But I confess to being really sceptical about this.

As well as what I said above I forgot (ironically) to mention the cognitive aspect of this illness as it pertains to draining my energy resources. I have been astounded to realise just how much I've been affected. It's taken me a long time to realise that I tire not just from physical effort and even cognitive effort but also from emotional effort. I have become emotionally flat simply because I don't have the energy to produce an emotional response.
Physical exercise works well for the healthy in maintaining their overall function but I'm not sure about how well it works for us.

I would like more information. More transparency. How did these two people get to Dr Klimas' clinic if they were so ill/bedbound.
Then after getting there how did they manage to do anything on the bike never mind coming back the next day.

And I'm not accusing anyone here but I'd like to know what kind of financial compensation the patients had for doing this advertising of the treatment. I'd also like to know if they were doing other treatments at the same time.

I'd be very happy if this worked as brilliantly as it seems to do but I have reservations until I know more.
Perhaps there are some brave souls who will give it a go and report back.

And regarding my own illness/recovery. I spent a great deal of time resting. Many months. I couldn't consider any other treatment including supplements because I didn't have the energy or even ability to organise my mind to deal with that. I am now a little better cognitively and physically and am able to try simplified methylation. This has made a small improvement.
One of my cognitive measures involves being able to do a single Sudoku without tiring.

It seems to me that there are other things going on that are wrong eg the hippocampus low N-acetylaspatate. Does simply exercising solve all these other findings?
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Videos from the event at Bristol are now on YouTube (Courtesy of Tate Mitchell via Co-cure). I don't know if this has been posted before:

Mark VanNess 'Exercise and ME/CFS' at Bristol Watershed. Part One

Prof Mark VanNess from the Workwell Foundation explains how damaging aerobic exercise can be for patients with ME/CFS. Their 2 day testing protocol demonstrates an astonishing post exertional amplification of symptoms in ME patients; a hallmark symptom of ME. This damage to the aerobic energy system means that it is utterly counter productive to try to use aerobic exercise to improve health in these patients.

The evidence from their research is so unexpected and contrary to accepted views of exercise and graded exercise, both in ME and in other illnesses, that many people actually find it difficult to hear and take on-board what he is saying. Fortunately you can go over what he says repeatedly and follow up the links on the Workwell Foundation website to watch or read other information.

Interestingly, he reflects on comments made in the film, explaining that these are consistent with their evidence from cardiopulmonary testing. He also explains how patients can try to find a more appropriate way of managing their activities of daily living and exercise, by trying to avoid causing any worsening of symptoms and so allowing their bodies a better chance of healing. He explains about analeptic exercise, which means restorative; not causing relapse!
In case anyone is unaware of the type of protocol Workwell uses for treatment (not testing) exercise, the VanNess video gives an example. First, exercise does not last for more than thirty seconds at a time. Second, there is at least a threefold break before doing any more, which in this case is about ninety seconds I guess. Third, the exercise is light strength improving calisthenics, without any aerobic component. As he stresses, the aerobic system is broken, it cannot be retrained. Those who have tried have failed.
Do folk watch all these videos and can they take in what is being said?
I might be odd, but I detest having to watch videos on youtubey things, I don't bother any more.:(

You have to spend ages and ages, paying close attention to a load of introductory waffle, then when a point of interest is made - it's gone in a flash and you've missed it.

I like information in the written form. I can skip the bits I don't need to pay attention to, and spend time on the bits that are important, I can go back to the beginning bit if it does turn out to be relevant...
I saw all three tonight, while the sound does fade for a second here and there if the speaker turns their face from the microphone, the sound was fine otherwise. I found myself pausing the videos on key slides ... there is good written info, some of which I was interested in, including Speight on fallacies, my pet topic.
I watched that one too, though like @peggy-sue I really hate videos and audio things :p

In addition to what @alex3619 mentioned (30 second intervals, anaerobic activities only, 3 times as much rest as activity), he listed 4 stages (starting at 30:45 into the video):
Stage 1: Stretching and Strengthening
Stage 2: Stretching with Resistance Training
Stage 3: Dose-Controlled Interval Training (short, anaerobic)
Stage 4: Maintenance

He mentioned that it might take someone a year to progress from one stage to another, and based on the example it looks like it's normal to take months. He also said this activity would have to be compensated for by cutting out other activities.

An example of the Interval Training -
Goal: 1x4 reps increased to 2x8 reps
Activities: Breathing, step-ups, wall push-ups, modified chair dips, toe raises

Then for maintenance, the patient would maintain that level of activity and add stair intervals. For the example given, the woman wanted to be able to walk downstairs and then upstairs so she could go shopping without crashing, and she could use a heart rate monitor and rest on the landing to help accomplish that.

All in all I think it was pretty reasonable and realistic, both regarding the activities and the expectations (get down a flight of stairs without becoming extremely ill, versus "recovery"). He was almost derisive about GET, or any other deliberate aerobic activities.

There's also a nice chart he shows at 13:15, which describes how disabled someone is based on their VO2max results, according to the American Medical Association. Mine's 11.9 mL/kg/min which puts me right in the middle of the "severe" group :p
In case anyone is unaware of the type of protocol Workwell uses for treatment (not testing) exercise, the VanNess video gives an example. First, exercise does not last for more than thirty seconds at a time. Second, there is at least a threefold break before doing any more, which in this case is about ninety seconds I guess. Third, the exercise is light strength improving calisthenics, without any aerobic component. As he stresses, the aerobic system is broken, it cannot be retrained. Those who have tried have failed.
This is just what Connie Sol (at Dr Klimas' office) told me about how to exercise. No aerobic, less than 2 mins (for me, based on testing), 5-10 mins supine rest between sets, no more than 3 sets per session. Only stretching and strengthening.

My problem with it, to be honest, was that it drove me nuts to do 1 min of exercise, rest 5 mins three times. That's about 20 mins for 3 mins of wimpy exercise -- besides having to get up and down off the floor. Life was hard enough at the time and I gave up on that particular "annoyance". It might help in the long run, but my personality rebelled. :oops: