"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.

"The Concept of Incomplete Fibromyalgia Syndrome"

The Concept of Incomplete Fibromyalgia Syndrome:
Comparison of Incomplete Fibromyalgia Syndrome With Fibromyalgia Syndrome
by 1990 ACR Classification Criteria
and Its Implications for Newer Criteria and Clinical Practice.

Yunus MB, Aldag JC.
From the Department of Medicine, University of Illinois College of
Medicine at Peoria, Peoria, IL.

J Clin Rheumatol. 2012 Feb 12. [Epub ahead of print]

Abstract

BACKGROUND:
The 1990 American College of Rheumatology (ACR) classification criteria for fibromyalgia syndrome (FMS) has 2 components:

(a) widespread pain (WSP)
and
(b) presence of 11 or more tender points (TP) among possible 18 sites.

Some clinic patients fulfill 1 component but not the other.

We have considered these patients to have incomplete FMS (IFMS).

The purpose of this study was to examine the clinical and psychological differences between IFMS and FMS (by 1990 ACR criteria) because such comparison may be helpful to diagnose patients in the clinic.

METHODS:
Six hundred consecutive patients referred to our rheumatology clinic with our diagnosis of FMS were examined by a standard protocol to determine whether they fulfilled the 1990 criteria for FMS.

Both IFMS and FMS groups were compared in demographic, clinical, and psychological variables using appropriate statistical methods.

RESULTS:
One hundred twelve (18.7%) patients did not satisfy the 1990 ACR criteria and were classified as IFMS.

Symptoms in IFMS and FMS were similar, generally with less frequent and less severe symptoms in the IFMS group.

In IFMS, no significant difference was found among the WSP and TP component subgroups.

Both TP and WSP were correlated with important features of FMS.

CONCLUSIONS:
Fulfillment of the ACR 1990 criteria is not necessary for a diagnosis of FMS in the clinic.

For diagnosis and management of FMS in the clinical setting, IFMS patients, along with consideration of the total clinical picture, may be considered to have FMS, albeit generally mild.

(via Co-Cure)

"Pain Negatively Affects Cognition in Fibromyalgia"

Pain Negatively Affects Cognition in Fibromyalgia

February 6, 2012 (Miami Beach, Florida) — Pain is the primary factor contributing to cognitive impairment in patients with fibromyalgia syndrome, over and above depression, anxiety, fatigue, sleep complaints, and medication use, reported Stefan Duschek, PhD, from the University of Munich, in Germany, here at the 6th World Congress of the World Institute of Pain.

Patients with fibromyalgia scored worse than healthy control subjects on mathematical thinking and attentional control. "A large part of the variance on these tests was explained by pain," said Dr. Duschek in an interview with Medscape Medical News. "The most important factor underlying these deficits is pain, nothing else; it's not depression, it's not anxiety, but pain."
…

I'd be surprised if it is significantly different in ME/CFS.

Of interest, patients taking opiate medication performed better than those who were not (P < .05). "Our hypothesis was the opposite — that opiates disrupt cognitive function — but it makes sense; it reduces pain intensity so people can concentrate better," said Dr. Duschek.

(via)

Sinusitis associated with fatigue and pain

I found some older studies (warning: they try to push endoscopic sinus surgery), but they are interesting nevertheless:

ScienceDaily (Aug. 14, 2003) — Washington, D.C. – A new study published in the August 11 issue of the Archives of Internal Medicine demonstrates a possible link between unexplained chronic fatigue and sinusitis, two conditions previously not associated with each other. Also newly noted was a relationship between sinusitis and unexplained body pain.
…
Through his private internal medicine practice, Chester questioned 297 patients, noting unexplained chronic fatigue in 22%, unexplained chronic pain in 11%, and both in 9%. While these numbers are consistent with previous studies, Chester observed an unusual connection between patients with chronic pain or fatigue: prevalent sinus symptoms. Sinus symptoms were nine times more common on average in patients with unexplained chronic fatigue than the control group, and six times more common in patients with unexplained chronic pain. In addition, sinus symptoms were more common in patients with unexplained fatigue than in patients with fatigue explained by a mental or physical illness, suggesting the syndrome of unexplained fatigue is more closely associated with sinusitis than are other types of fatigue.
…
15 out of the 65 patients in Chester's study met criteria for chronic fatigue syndrome (CFS), a severe form of unexplained chronic fatigue associated with body pains and other symptoms. Most CFS patients had sinus symptoms and many noted a sudden onset of their illness, similar to people with sinusitis. "We clearly need to do more research to see if sinus treatments alleviate fatigue and pain. This study does, however, offer hope for possible help in the future." said Chester.

ScienceDaily (Sep. 23, 2008) — A new analysis led by researchers at Georgetown University Medical Center suggests many patients with sinusitis have aches and pains similar in severity to people in their 80s and those with arthritis or depression. …  "We found that the daily experience of bodily pain was much more common in patients with sinusitis than in the overall population," explains Chester. "Confirmation that aches and pains occur with sinus disease is a relief to many patients who thought they had two separate illnesses."

So what did the meta analysis find?

A subgroup analysis of 11 studies measuring outcomes using the 36-Item Short Form Health Survey (SF-36) demonstrated a moderate-sized combined effect of 0.47 (95% confidence interval, 0.38-0.56; I = 0%), corresponding to a mean +/- standard deviation improvement of 9.7 +/- 3.4 units on the SF-36 vitality domain scores.

A improvement of 10 points on the SF-36 score isn't bad, but it is not a cure to ME/CFS...

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!