The ME/CFS Zoo Hypothesis

A constant question regarding ME/CFS (and fibromyalgia) goes something like this:

Is it one disease, or is it a "spectrum", or is it multiple (distinct) diseases that look the same?

I that regard: I find the "Blind men and an elephant" parable helpful – and would like to expand it.

First of all, let me recount from the Wikipedia page a slightly modified summary of the parable:

In various versions of the tale, a group of blind men touch an elephant to learn what it is like. Each blind men feels a different part, but only one part, such as the trunk, or an foot, or the tusk.

A Jain version of the story says that six blind men were asked to determine what an elephant looked like by feeling different parts of the elephant's body. The blind man who feels a leg says the elephant is like a pillar; the one who feels the tail says the elephant is like a rope; the one who feels the trunk says the elephant is like a tree branch; the one who feels the ear says the elephant is like a hand fan; the one who feels the belly says the elephant is like a wall; and the one who feels the tusk says the elephant is like a solid pipe.

Afterwards the blind men talk to each other and learn that they are in complete disagreement. Some of the stories differ in how violent the conflict becomes, and how (or if) the conflict among the men and their perspectives is resolved.

In some versions, they stop talking, start listening and collaborate to "see" the full elephant. When a sighted man walks by and sees the entire elephant all at once, they also learn they are blind. While one's subjective experience is true, it may not be the totality of truth.

My impression is that many in the ME/CFS "community" think that most of the studies are equally "true" – I think that is the first mistake. To stay in the parable: Some of the blind men have never touched an elephant (or any other animal, for that matter) and simply make things up. Here you have blind men who describe not an elephant, but maybe an park bench, or an found umbrella, or maybe an object that exists only in their fantasy (and even describing that they suck). Yes Virginia, I'm talking about Lombardi, Mikovits and Ruscetti. There are others. Like those blind men trying to describe the color of the elephant. Somehow, now I have to think of the names Meirleir, Maes and Gerwyn.

And even if you sieve out all the blind men describing inanimate objects (or worse, make-believe objects), you get some who grabbed some random animal in the zoo and tried to described it. Now if they can describe two (or more) of those animals, and the differences between them, and if they do not try to make you believe that they describe the whole animal, I think they are much more trustworthy than those who want to make you believe they describe only an elephant, and that they know the entire elephant.

If you have someone who says "Here I found two animals with distinctly different tusk, one has leather like skin, the others is furry", well then we are on to something. Currently I have seen few people who would fit that bill: Alan Light (et al.), and maybe Julia Newton (come to my mind).

But one thing should be clear, all those harping about how we need better criteria to "sieve out all non-elephants" (to stay within the parable) should know that:
a) Your are an "blind men" yourself
b) You might be an "non-elephant" yourself
c) The studies you trust might describe non-elephants
d) The studies you trust might describe non-elephant animals that are different from you

Yes, better (and more stringent) criteria might be helpful, but what we need are ways to look at "a collection of zoo animals" (parable again), and learn to differentiate them properly, both in a research setting, and in a clinical setting.

Is ME/CFS an mental illness – an comment

I made an comment at an (otherwise not noteworthy) article:

Three researchers – Mikovits, Ruscetti and Lombardi – published one (possibly fraudulent) study, a study that didn't help up to scrutiny – that doesn't mean that ME/CFS is an mental illness.

You should look into the work of Alan Light, a Research Professor of Anesthesiology at the University of Utah.

His topics are:
- Cellular Neuroscience
- Neurobiology of Disease
- Molecular Neuroscience
- Brain and Behavior

He has done some research into pain (and now fatigue) of – among other diseases – ME/CFS. His work shows differential gene expression in peripheral blood cells of ME/CFS patients after an exercise challenge – this indicates increase pain and fatigue in sensory nerve endings at the muscle level.

Two of his lectures (available on YouTube) are in my view recommendable to come up to speed to his research:

2007 Lecture: "The Physiology of Chronic Pain and Fatigue"
http://parakoch.blogspot.de/2011/06/alan-light-2007-lecture-physiology-of.html

2011 Lecture: "Gene Expression Biomarkers for Chronic Fatigue & Fibromyalgia Syndromes"
http://parakoch.blogspot.de/2011/06/alan-light-2011-lecture-gene-expression.html

In my opinion the findings by Alan Light rule out mental illness as an probable disease model for ME/CFS.

[I reworked the comment slightly for this blog]

Seriously?

Dear Jo Nijs,

I have a question regarding one of your results.

You state that:
"From the available literature, it is concluded that musculoskeletal factors are unlikely to account for pain from CFS."

My question originates from the 2009 study "Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects." that you cite in your paper.

I was under the impression that the data by the author Alan Light actually suggest that it are the sensory nerve endings on the muscles that sense increased fatigue (and in extension pain) in CFS (and Fibromyalgia).

E.g. as Alan Light says here in a lecture (at minute 4:11):
http://www.youtube.com/watch?v=x3Hylumohfo&t=4m11s

I would like to ask what suggest that the increased expression of sensory genes in peripheral blood cells is a phenomenon occurring centrally, and what makes you think that changes in peripheral blood are a central phenomenon and therefore "unlikely" to originate from musculoskeletal factors.

Kindest regards

I really had to watch my language with such fine research from such fine researchers.

"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.

Got a mail from Alan Light

Alan Light send me a mail response to some ideas I had. Well he dashed  (short, precise and friendly) one of my pet theory. Oh well, he really knows much more than me :-)

I need to digest it first. It is really nice that to have access to such great researchers.

Anyway, his email contained a footer. This was in it:

No virus found in this message.
Checked by AVG
Version: 10.0.1411 / Virus Database: 1522/3957 - Release Date: 10/17/11

Made me smile :-)

XMRV is on its way out

"This has been a difficult and disappointing process for them and for CFS patients, but hopefully we have all learned lessons that will guide future research and lead to discovery of the cause and cure of this disease".

So Mikovits/Lombardi/WPI have retracted a part of their Science paper. And the results of the blood working group look like contamination.

“I commend them on their scientific integrity and commitment to the scientific process,”

The WPI have pushed the ME/CFS issue, even if they are wrong with regards to XMRV. I think they find out what has happened to cause these results and will publish it – it just takes some time.

Lots of Newspapers Covering ME/CFS Today

I have read the articles from the major US sources, and all spoke of CFS like a serious physical disease. It was all in the context of the XMRV studies coming up negative, but they only quoted "real" ME/CFS docs and researchers, so barely a breath of psychological mumbo-jumbo anywhere.

The really good news is that the Lights & Bateman get a Million dollars to do more research into ME/CFS.

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!

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.)