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!" 

Be your doctor's copilot

"A new Northwestern Medicine study shows the attending physician in the intensive care unit could use a copilot, too. The mortality rate plummeted 50 percent when the attending physician in the intensive care unit had a checklist -- a fairly new concept in medicine -- and a trusted person prompting him to address issues on the checklist if they were being overlooked. Simply using a checklist alone did not produce an improvement in mortality."

Simply using the checklist alone didn't work because they weren't using it. That's the funny thing about checklists...

So be your doctor's copilot.

The Epidemic of Mental Illness

A large survey of randomly selected adults, sponsored by the National Institute of Mental Health (NIMH) and conducted between 2001 and 2003, found that an astonishing 46 percent met criteria established by the American Psychiatric Association (APA) for having had at least one mental illness within four broad categories at some time in their lives. The categories were “anxiety disorders,” including, among other subcategories, phobias and post-traumatic stress disorder (PTSD); “mood disorders,” including major depression and bipolar disorders; “impulse-control disorders,” including various behavioral problems and attention-deficit/hyperactivity disorder (ADHD); and “substance use disorders,” including alcohol and drug abuse. Most met criteria for more than one diagnosis.

If you look for mental illnesses, you will find them in people. That doesn't mean that these people are mentally ill – if there is an epidemic, it is an epidemic of doctors who psychopathologize people.

The sad thing is, very few of these illnesses are genuine "psychiatric" or mental illnesses. Most are environmental, living beings are usually not "ill by themselves". Illness is most usually caused by nutrition, pathogens or society (and society being overrated as a cause of illness), very seldom are genes the root cause of illness.

And I can see how the CDC/NIH/Strauss psychopathologized ME/CFS patients...

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!

David Bell Lecture: 25 Year Follow-up in Chronic Fatigue Syndrome

David Bell has given a very interesting lecture (albeit a bit longish, but very rewarding to watch) on how his patients do after 25 years, and the Massachusetts CFIDS/ME & FM Association has done an excellent job of publishing it on their web-page:

Here is a short summary (about 1 page), and long summary (about 10 pages). You can view the video of the lecture (55 minutes) and the video of the Q&A session (42 minutes) – both links open a video in flash-format in a new window. MassCFIDS has made a fine presentation of the lecture with a side-by-side video of the speaker, an index and the slides.

I had two take-home-messages:

1. After the "acute" phase of ME/CFS, which can last several month to years, patients fall in one of three categories.

Dr. Bell felt that the single most useful criterion in gauging overall well-being was how many hours someone spent engaged in upright activity each day: "hours of actually doing something, like work, school, or cleaning; not just sitting around, vegging-out watching TV." Some people with CFIDS/ME log only one to five hours of cumulative activity a day, he said (those hours generally aren't consecutive; people might be active for only a few minutes at a time). Healthy people, or controls, averaged 15 hours of daily activity; the remitting patients, about 13, fairly close to the level of "normals." 

With the exception of those who had recovered, however, no one seemed totally okay this time around. Forty percent (40%) had essentially no symptoms and apparently normal activity, but they were not as well as controls. Among the 20% who remained disabled, many experienced increasing debility over time. The remaining 40% (the remitters) still had symptoms, but their activity level was close to normal; that sounds like a good outcome, but in fact many ultimately experienced a return of symptoms or an erosion in activity level.

So, after the acute phase:

• 20% never get well, most of them are bedbound
• 40% get well (albeit not completely), stay that way and have left the disease almost behind
• 40% improve after the acute phase, but never get "really well" and very slowly deteriorate over the years

And the "gradual-onset" patients might be patients that had an asymptomatic "acute" phase:

Also on the topic of XMRV, Dr. Bell suggested the possibility that many people may have been exposed to this virus without developing symptoms. … He said he wouldn't be surprised if it turned out that some people who were fine at age 20 became symptomatic as they aged, perhaps developing CFIDS/ME at age 40 or later. This is another subject for future research.

2. About half of the ME/CFS patients either have arranged themselves ("I'm fine, I don't have problems." despite being still seriously restricted), or they don't talk with their doctors about their symptoms ("I don't mention my problems, no way!").

"Health-identity confusion" seemed to plague those in the remitting category. They considered themselves to be in good health, but all still had symptoms and abnormal lab tests indicating that something was physically amiss. On the symptom scales, the remitting patients' scores fell about half-way between those of controls and those of chronic patients. A healthy person's score on one symptom might be zero (0), e.g., a chronic/persistent person's score might be 10; and a remitter's, in the middle at five.  

Bell remarked, that many patients will say, "I'm opting out of this system." … "When I called them, I asked, 'Have you told your current doctor that you have this illness?'  A lot of them said something like, 'I'm not going to subject myself to that!"

A quote I picked up over at cpnhelp.org

"When Going Thru Hell, Just Keep Going"
Winston Churchill

The international consensus criteria for Myalgic Encephalomyelitis are on their way

In the introduction to the [Alan Light] paper, the authors cite a manuscript submitted that describes international consensus criteria for myalgic encephalomyelitis, listing the following authors: BM Carruthers, MI van de Sande, KL DeMeirleir, NG Klimas, T Mitchell, D Staines, AC Powles, DS Bell, R Vallings, and Speight. This may be the first public acknowledgement of a current effort to define criteria for ME. 

The international consensus criteria for Myalgic Encephalomyelitis are on their way. This is good news, considering that Nancy Klimas and David Bell are on board. These two will bring a good clinical perspective to this disease. (The others I don't know, with the execption of DeMeirleir, whose name I have heard before.)

I have ME/CFS

I have ME/CFS, and/or possibly Fibromyalgia*, so the updates here will be erratic – you have been warned.

* I would dearly love to have a proper test to find out what I have (or haven't). Even better would be if the etiology of ME, CFS and Fibromyalgia were known – or the etiologies of all sub-groups, if there are differences.