On Christopher Snells 2012 ME/CFS Exercise Challenge Lecture

On Christopher Snells 2012 ME/CFS Exercise Challenge Lecture, this came in via Tom Kindlon and Jan van Roijen (via the CO-CURE maillist):

I have omitted a lot of the discussion on the advantages/disadvantages of various scientific methods etc. and stuck mainly to the items that I would assume a non-scientific interested person would wish to know.

If you’re of a scientific bent, you would probably get more benefit from watching the actual lecture. All credit to Professor Christopher R Snell of the Pacific Fatigue Laboratory, California (USA).

If you’re a sufferer, I recommend watching from 54:00 through to 59:20 – they go through a brief summary of energy conserving techniques, which could be very useful! Following this there is a case study of how they applied some of these techniques to a 17 year old sufferer to allow her to manage the condition better.


Clinical exercise testing in CFS/ME research and treatment: A summary

On an exercise test where a person has to exercise until they are exhausted, a healthy person will recover usually within a day, definitely within 48 hours (on the outside).

When they did this with CFS patients, they had only one person recover within 48 hours – the average recovery was 4 days.

CFS patients also had symptom flares as a result of this test.`

`````` There are problems with the PACE trial:

* they very selectively reported results

* they only took high-functioning CFS patients

* they used the 6-minute walking test (see below)

* patients at the end of the trial, were still walking at a severely disabled speed, even when they had improved the distance they could walk. If a patient who needed a heart transplant could only walk this speed due to a lung problem, they would not be allowed onto the transplant list because they would not be deemed well enough to actually survive.

* there is no mention of any improved functioning in any other area for any of the trial participants


There are problems with the 6-minute walking test (as used in the PACE trial as a measure of functioning) and other similar tests

* they assume that the patient does not exercise to exhaustion, or anywhere near exhaustion. All the understanding of the results are based on the assumption that it was just a casual exercise experience that they could easily repeat.

* it does not work for specific groups of unhealthy people, it is designed only for a healthy population, so results from an unhealthy group can’t be interpreted validly. This is because they rely on the heart rate as a measure of energy production, but the way the heart rate and energy production are linked in a healthy person is not necessarily the same in a sick person. Many studies in fact show that the link between them in certain diseases is very different – meaning you cannot rely on these tests in sick individuals, without first carrying out studies to determine what the connection is.

* the american heart association says not to use tests with heart-rate measures, as many people use heart-rate controlling medication (eg: for POTS, migraines)

The best way to assess physical function is to use

“cardio-pulmonary exercise testing”, which is to measure:

* oxygen consumption (as oxygen is used directly to produce energy, this will always be a correct measure). This is effected by lungs, heart and muscles.

* the “anaerobic threshold” – which is the point at which the carbon dioxide you breathe out is greater than the oxygen you take in. In a healthy person this is 50-60% of max. oxygen consumption; in an athlete it may be as high as 90%. In CFS patients it is very very low, and going above it makes you worse – and is very easy to do

* you can prove beyond doubt that someone is not faking these results because you are measuring the amounts of oxygen and carbon dioxide in the air they breathe in and out.

* you can establish beyond doubt that the persons capabilities in the test have nothing to do with motivation/effort because the “effort” of the person is shown in the oxygen intake/carbon dioxide given out

* these are a good measure of function, they are very reliable and accurate

* there are alreasy established measures of this for many other healthy people and disease states, meaning you can compare ME patients to others easily


Exercise will not cure ME/CFS. But – people who do not exercise will suffer the effects of a sedentary lifestyle, so if you can do some exercise without making symptoms worse, it is probably beneficial to do so

Post exertional malaise occurs across all the spectrum of ME/CFS patients – regardless of how severe they are

It does not show up in an single exercise test – you need to test again (they do it 24 hours later). This allows them to measure the post-exertional effect. (Many ME/CFS patients could be assessed as normal on a single test, due to eg: having rested beforehand, it is the second test which shows they are ill)

It is hard to separate the effects of deconditioning from the effects of CFS with a single test

* but with multiple tests you can see what CFS has done.

At 37 minutes there is a table of results for ME patients


The second test shows:

* ME/CFS patients do worse on the second test; they are significantly worse (in terms both of workload they accomplish, and the oxygen/anaerobic measures)

* non-ME/CFS patient will improve on the second test (graph at 42mins).

* ME/CFS patients have a drop in the oxygen consumption, but a much much worse drop in the amount of work actually achieved. This shows that the exercise on the second test is less effcient

* the drop in peak-oxygen consumption is actually less for severe patients than for milder patients; but severe patients start out with a much lower oxygen consumption than a milder patient.

* the drop in workload done is more in severe patients than milder patients

* The theory is that there is a basic level of oxygen consumption that you need to survive, and the more severe you are the closer you are to this base level. So severe patients cannot drop any lower or they would die, so they reduce workload instead.

This is a reproducable, reliable test which shows the extent of the post-exertional malaise; other research groups have replicated these results

Their tests show objectively for CFS patients:

* an atypical recovery

* an abnormal stress-test

* post exertional malaise

There are many theories as to why post-exertional malaise occurs

Their research shows ME/CFS patients

* have a reduced physical working capability

* the aerobic energy generation (the production of energy in the presence of oxygen) is impaired

* activity exacerbates symptoms ( every ME/CFS patient has post exertional malaise)


Their research can be used as an objective proof of disability (for example, for disability assessments and clinical trials)

It is quantifiable – ie: it can measure accurately to a degree how ill the patient is

It reveals abnormality across many systems


Cognitive behavioural therapy is not a cure for ME/CFS – but it can be useful to help patients manage/adjust to their illness

ME patients can go a very long way into the anaerobic threshold (longer than most people manage) because they have adjusted to being ill; but this results in huge PEM. So short-term, patients can often manage a lot more than they can manage long-term.


Avoiding activities above the anaerobic threshold will help patients avoid PEM

* heart rate monitors can help; they are set to go off just before you hit the anaerobic threshold, to get you to rest instead of using too much energy

* activity logs can help; you can identify activities which make you worse (what activities make you ill? How do you feel the next day? Do you get PEM? Can you carry out other normal activities and these activities?)

* “rates of perceived exertion” can help; this is a fancy way of saying, if it feels like a lot of effort, it is a lot of effort – stop!


Resting will help recovery from going into the anaerobic threshold

If you go above the anaerobic threshold, you will have to pay back far more energy


Physiotherapy can help – but physios often need to be re-trained to understand ME/CFS

* reconditioning will not work with ME/CFS patients


They have a therapy called “energy conservation therapy” – I think this is basically working out how to manage your life now with less energy. It involves

* pacing

* body positioning (ie: sit instead of stand to use less energy)

* protecting joints

* using assistive devices

* planning activities (to make sure you don’t over-exert)

* using any energy saving thing you can do etc.


They also have a “theraputic exercise program” (nothing like GET!) – this can be aided by trained physios

* learning to breathe properly

* training the anaerobic system, not the aerobic system

* exercise must be recovered from within 24 hours – if you take longer than that to recover, it is harming you, not helping

* stretching

* only doing a little bit at a time

* only ever increase amounts if you aren’t experiencing symptom increase – decrease amounts if you experience symptoms


He closed with the comment:

“It doesn’t really matter what you call it, there are hundreds and thousands of people who are really really sick; if the medical profession is not helping them, their government representatives are not helping them; they need help urgently.”

Christopher Snell 2012 Lecture – "Clinical exercise testing in CFS/ME research and treatment"

Christopher Snell 2012 Lecture – "Clinical exercise testing in CFS/ME research and treatment"


After mentioning the lecture in the last post, I'm giving this very excellent lecture of his an post of its own.

I think the lecture is very helpful and ties in nicely with the work done by Kathleen and Alan Light (see Alan Light's 2007 and 2011 lecture).

If I had some more energy, I would write down some take home message – but alas, this has to suffice for now.

Update:
This came in via Tom Kindlon and Jan van Roijen.

"At least two subgroups of patients with CFS can be identified by gene expression changes following exercise"

A follow up to their previous studies by "The Lights".

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC.

Department of Anesthesiology The Brain Institute Department of Neurobiology and Anatomy Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT 84132, USA.

Abstract

OBJECTIVES:

To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.

DESIGN:

Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate).

Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise.

Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen.

Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise.

Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.

RESULTS:

No gene expression changes occurred following exercise in controls.

In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h.

These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered.

History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup.

FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.

CONCLUSIONS:

At least two subgroups of patients with CFS can be identified by gene expression changes following exercise.

The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine.

The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A.

FM-only patients can be identified by baseline increases in three genes.

Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Daily physical activity & symptom fluctuations in CFS patients

Daily physical activity & symptom fluctuations in CFS patients
…
Conclusions:
The more patients with CFS are sedentary and the better activity is dispersed, the fewer symptoms and variations they experience on the same and next day.

Inversely, more symptoms and variability is experienced when patients were more active that day or the previous day.

(via)

ME/CFS Exercise Study: Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome

This study by David Jones and others from Newcastle (never heard of them) is interesting, because just like Alan Light, these researchers found two subgroups in ME/CFS, when they challenge the patients with exercise.

Abstract
Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome
(via niceguidelines.blogspot.com)

Background:  Chronic fatigue syndrome (CFS) patients frequently describe difficulties with repeat exercise. Here we explore muscle bioenergetic function in response to 3 bouts of exercise.

Methods:  18 CFS (CDC 1994) patients and 12 sedentary controls underwent assessment of maximal voluntary contraction (MVC), repeat exercise with magnetic resonance spectroscopy and cardio-respiratory fitness test to determine anaerobic threshold.

Results:  CFS patients undertaking MVC fell into 2 distinct groups.

8 (45%) showed normal PCr depletion in response to exercise at 35% of MVC (PCr depletion >33%; lower 95% CI for controls).

10 CFS patients had low PCr depletion (generating abnormally low MVC values).

The CFS whole group exhibited significantly reduced anaerobic threshold, heart rate, VO2, VO2 peak and peak work compared to controls. Resting muscle pH was similar in controls and both CFS patient groups.

However, the CFS group achieving normal PCr depletion values showed increased intra-muscular acidosis compared to controls after similar work after each of the 3 exercise periods with no apparent reduction in acidosis with repeat exercise of the type reported in normal subjects.

This CFS group also exhibited significant prolongation (almost 4-fold) of the time taken for pH to recover to baseline.

Conclusion:  When exercising to comparable levels to normal controls CFS patients exhibit profound abnormality in bioenergetic function and response to it. Although exercise intervention is the logical treatment for patients showing acidosis any trial must exclude subjects who do not initiate exercise as they will not benefit. This potentially explains previous mixed results in CFS exercise trials.

So, to recap the little information the abstract gives: The CFS group exhibited significantly reduced anaerobic threshold, heart rate, VO2, VO2 peak and peak work compared to sedentary controls. Resting muscle pH was similar in controls and both CFS patient groups.

One half of the patients (remember, small study!) had low PCr depletion (Phosphocreatine?). (Are these the POTS patients?)

The other half of the patients showed normal PCr depletion (Phosphocreatine?) in response to exercise. However, this group showed increased intra-muscular acidosis compared to controls after similar work after each of the 3 exercise periods with no apparent reduction in acidosis with repeat exercise of the type reported in normal subjects. This group also exhibited 4-fold prolongation of the time taken for pH to recover to baseline.

I wonder how these groups map unto the two groups Alan Light found. Again, the "no apparent reduction with repeat exercise" is basically the same thing that other researcher see, that ME/CFS is something substantially different than deconditioning.

We observed that CFS patients as a group have reduced cardio-respiratory reserve with a lower anaerobic threshold than sedentary controls. This finding replicates previous studies [3]. One implication of a lowered anaerobic threshold would be increased reliance on anaerobic as opposed to aerobic metabolism with a predicted consequence of increased short term acid generation within muscle due to over-utilization of the lactate dehydrogenase pathway. This prediction was confirmed by the use of MR spectroscopy methodologies which demonstrated increased post-exercise acidosis in the CFS group as a whole. The effect was not, however, uniform across the CFS patient group. 

In the CFS subjects where normal PCr depletion was seen in the context of a normal MVC, exercise induced profound and sustained acidosis. This replicates our previous findings [18] in a second cohort of patients with CFS. Importantly, minimum pH values attained by this group of CFS patents were actually lower than those previously shown by us in the fatigue-associated chronic disease primary biliary cirrhosis (PBC) [28]. We would suggest that the increased reliance upon anaerobic metabolism during even relatively lowlevel muscle contraction, shown by a decreased intramuscular pH, is at least partly a consequence of the decreased aerobic capacity (reduced anaerobic threshold and VO2peak) seen in CFS, and in this regard the physiology of fatigue in CFS closely mirrors that in PBC.

There are aspects of the abnormality in acid homeostasis in CFS which differ to those seen in PBC and which may significantly contribute to the severity of fatigue in CFS. We have previously reported that when PBC patients undergo repeat exercise the degree of acidosis seen within muscle reduces with each exercise episode, suggesting the retention of some compensatory capacity for excess muscle acidosis in PBC (28). One mechanism for this is increase in proton flux, and the speed of onset of maximum proton excretion, with repeat exercise. This phenomenon, which is also a feature of mitochondrial disease where increased proton efflux after exercise helps compensate for reduced aerobic capacity [35], was absent from the CFS patients. These findings suggest that CFS patients are unable to compensate for the increased reliance upon anaerobic energy sources during muscle contraction in comparison to other conditions with reduced aerobic capacity. The net effect of these combined effects can be seen in terms of cumulative acid exposure determined from the area under the curve for pH. Using this approach total post-exercise acid exposure is of the order of 50-fold higher in CFS patients exercising to the same degree as normal controls, with no reduction in this pattern of sustained high level acidosis with repeat exercise. We believe that the local and systemic sequelae of this sustained acid exposure contribute significantly to the expression of fatigue in CFS.

The reasons for slowed recovery from muscle acidosis in CFS are at present unclear but there are a number of possibilities. Our finding of a slow recovery time appears to be at least in part a result of slow kinetics of proton excretion and may point to potential mechanisms by which the increased muscle acid exposure occurs. Acid is actively transported from the muscle by Na-H antiporters which are in turn under autonomic regulation. Indeed, conditions which increase sympathetic tone such, as hypertension [36], or following sympathetic denervation [37] change acid handling in muscle. It is possible that impaired function of acid transporters occurs in CFS and that this related to the autonomic dysfunction found frequently in those with CFS [2, 19-22]. It is also possible that reduced vascular run off (related to autonomic dysregulation) may also contribute. Furtherwork is needed to explore the underlying mechanisms fully. Importantly, many of the pathways for acid excretion from muscle cells can be upregulated by exercise therapy suggesting a possible mechanism for benefit with graded exercise therapy (although our caveats about stratification should be noted).  

"I think the Lights should take this finding on board when they find increased acid sensors - that it's most likely because there's increased acid!" 

Alan Light 2011 Lecture: Gene Expression Biomarkers for Chronic Fatigue & Fibromyalgia Syndromes

As a follow-up to the last post, here is his 2011 lecture (about 1 hour) by Alan Light for OFFER Utah about his very excellent ME/CFS gene-expression study.

This is objective data that there is biological reason for the symptoms [in ME/CFS and Fibromyalgia].

You may want to switch to 1080p HD to best view the slides.
(Part 1 Part 2 Part 3 Part 4 Part 5)

My take-home messages:

1. 70% of ME/CFS patients have Fibromyalgia (FMS) symptoms. And Fibromyalgia gets worse after exercise, even if the definition for FMS does not specify for it. And a majority of FMS patients (but not all) have ME/CFS symptoms.

2. TRPV1 contributes to the body's temperature set point.

3. Alan Light found a sensory definition of fatigue (The nerves at the muscle tell the brain "You are tired") in ME/CFS that contributes to the desire to use the muscles less. It is related to "actual" muscle fatigue ("The muscle is about to fail"), but it is not the same.

4. In both ME/CFS and FMS there is a 40% subgroup, that has a Ad2A (vasoconstriction) decrease. That gene is responsible for preventing orthostatic intolerance (OI / POTS). 70% patients with this gene expression profile have orthostatic intolerance, and 20% without have POTS (it might depend when and how you measure POTS).

5. FMS without CFS patients look like controls after execercise, but have different baseline levels. P2X4, TRPV1 and IL10 are expressed higher at baseline.

6. Gene expression as biomarker for ME/CFS and Fibromyalgia? Specificity 94% (6% of false negatives) and sensitivity of 65% (35% of false positives), good but not excellent biomarker, could be improved. Might be clinically available within 2 to 3 years.

7. The orthostatic subgroup should be treated differently.

8. Pregabalin or Gabapentin decrease the level of pain and of mental fatigue - maybe.

9. The cause could be increase of sensitivity of fatigue and pain, or dysfunction of the sympathetic nervous system.
(My comment, this the only flaw of Alan Light's work I can think of. He is leaving out one possibility: Of course it could be that there is an actual increase of fatigue and pain due to a pathologically increased muscle exhaustion in ME/CFS and FMS patients. If the nerves are sensing something, it could actually be there – doh!)

10. This is objective data that there is biological reason for the symptoms.
(Translated to English: "The psychosomatic school can go and f*ck themselves.")

As an addendum:
Don't miss Christopher Snell's 2012 lecture, which ties in nicely!

Alan Light 2007 Lecture: The Physiology of Chronic Pain and Fatigue

OFFER Utah (warning, their website plays music...) has a lot of lectures regarding ME/CFS on their OFFER Utah Youtube Channel. They have some very good and interesting lectures (and some less so). If you haven't already, you should subscribe to their Youtube channel, add the feed to your RSS-Reader, etc. ...

One very interesting video is this 44 minutes lecture by Alan Light:

"The Physiology of Chronic Pain and Fatigue" Dr. Alan R. Light.

This presentation by Alan R Light was made during the 2007 OFFER Provider's Conference. This lecture shows basically where Alan Light came from and his studies that lead up to the ME/CFS post-exertional gene-expression study "the Lights" (he and his wife Kathleen Light) have done together with Lucinda Bateman.

I had these take home messages:

1. Acute pain and fatigue sensing are protective and evolutionary important to prevent depletion or injury of important systems. If an living being has an impairment in sensing of pain and fatigue, it will usually die quite quickly. So there are multiple pathways in a living being to measure this information.

2. There are many concepts of fatigue. For ME/CFS fatigue is not sleepiness, fatigue is not failure of the muscle, but a sensory event – one could move the muscle with enough willpower.

3. The sensing of muscle-pain and fatigue happens by nerve sensory-endings located between the muscle and the blood vessels. Several metabolites (Lactate, ATP, pH/protons) are measured together by receptors (e.g. P2X4, P2X5, ASIC3, TRPV1) working together.

4. Fatigue and pain share receptors, but are not the same.

5. The sympathetic nervous system can restrict blood vessels to muscles that are not fatigued and increase blood flow to muscles that are.

6. Mononuclear blood cells have these receptors too, as they need to go "where the action is", where damage is, where things are going wrong and they are circulating through the muscles that are used.

7. Enhanced muscle pain is caused by cytokines, and if the blood flow is not increased (if the sympathetic nervous system does not regulate it properly), the metabolites in the muscles build up, and with it fatigue and pain.

8. The NIH (and the medical profession at general) are not interested and it is very difficult to get funding for these studies. All his research depends on the support by the university of Utah. There is some old medical "knowlegde" ("these receptors don't function at physiological ranges" etc.) that needs to be challenged and updated. This research that should have been done 25 years ago and the NIH is dragging its feet.
(I find it ironic that it is Alan Light's research in ME/CFS that improves the understanding in biological and medical sciences of how pain and fatigue work – after all the damage that Strauss et. al. have done with their psychosomatic bullshit, after all the damage Wessely and Sharpe are still doing today)

Don't miss Alan Light's 2011 follow-up lecture!

And don't miss Christopher Snell's 2012 lecture, which ties in nicely!