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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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

 

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.

 

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).

 

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.

 

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.

 

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

 

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.

 

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.

 

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!

 

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!

 

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.

 

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.”

 

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

 

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.

 

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.

 

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. )

 

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. )

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

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

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).

 

"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)

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!

 

(Bad Pseudo Science)

 

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".