Kathleen Light - New Fibro; ME/CFS Review?

I can't tell of this is a new review or not. Its stated as accepted for publication in July 2011 but copyright is 2012 plus its not in the library.

A very interesting paper which discusses the overlap and differences between Fibromylagia and 'CFS'?


Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome

Abstract

In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information. This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels. The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed.

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http://www.hindawi.com/journals/prt/2012/427869/

Thank you, Marco,

The Kathleen Light paper looks really interesting and I've printed it off to read more carefully. I hope in the meantime someone more knowledgeable than I can give us a simple summary of the paper and its implications.

cheers, Lynne

Did Light et al use Reeves/CDC-2005 criteria in all their CFS studies?

Increases in P2X4, P2X5, TRPV1, and ASIC3 plus exaggerated COMT, ?-2A, and ?-2 adrenergic receptor expression following moderate exercise have been a unique profile in CFS and CFS+FMS patients, not evident in any other patient group with chronic fatigue or pain that we have examined to date. Both the adrenergic receptor and ion channel gene expression was directly correlated with the severity of postexertional fatigue and pain reported by the CFS group. It is notable that our gene expression responses did identify a subgroup among the CFS patients showing decreases rather than increases in ?-2A adrenergic receptors lasting for 48 hours; this subgroup did not show increases in any other genes, and they were much more likely to have a clinical history of orthostatic intolerance than other CFS patients. These clinical and gene expression differences provide a helpful starting point for individualized treatment options. Surprisingly, despite their shared fibromyalgia and the fact that both groups reported postexercise increases in pain and fatigue, the FMS-only group was unlike the CFS+FMS group and showed no postexercise increases in these genes.

[...]

We have interpreted these observations as indications of dysregulation in the primary metabolite-detecting neural pathway that senses products of muscle activity including protons, lactate, and ATP. Large-scale increases in P2X4, P2X5, TRPV1, and ASIC3 receptors in the DRG would potentially increase sensitivity to even low levels of these metabolites such that even activity as mild as upright posture and slow walking in CFS or CFS+FMS patients could produce sensations of fatigue and muscle pain that normal individuals would only feel during extreme activity.

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Interesting indeed. However ...

To date, the only research examining leukocyte gene expression responses after exercise in patients with FMS-only and patients with CFS plus comorbid FMS has been by our University of Utah research team [8890]. The 1994 Fukuda et al. criteria plus the Reeves criteria [9] were used to define CFS, including persistent or relapsing fatigue of 6 months duration or longer that results in substantial restriction of life activities, and is accompanied by at least 4 of these 8 additional symptoms: unusual worsening of fatigue, pain, or general unwellness following exertion, impaired memory or concentration, muscle pain, joint pain, unrefreshing sleep, change in headaches, sore throat, and tender lymph nodes.

9. W. C. Reeves, D. Wagner, R. Nisenbaum et al., Chronic fatigue syndromea clinically empirical approach to its definition and study, BMC Medicine, vol. 3, article 19, 2005.

88. A. R. Light, A. T. White, R. W. Hughen, and K. C. Light, Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects, Journal of Pain, vol. 10, no. 10, pp. 10991112, 2009.

89. A. R. Light, L. Bateman, D. Jo, et al., Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia, Journal of Internal Medicine. In press.

90. A. T. White, et al., Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis, and healthy controls, Psychosomatic Medicine. In press.

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The "Reeves criteria" has been heavily criticized for sensitivity and specificity issues, but I guess it can no longer be said that "only the CDC use it". It is just the Fukuda criteria with additional screening tools but somehow inflates the prevalence estimates 5-10 fold, allows CFS disability to be wholly emotional, conflates with depression, used in all the CDC's recent personality and childhood abuse research, etc. Light et al's discussion of methodological issues seems focused on depression and employing additional types of stress testing.

They mention that in their larger more recent study, 30/48 (63%) of CFS patients were on antidepressants, which seems unusually high, although 11/49 (23%) of people in their "healthy" control group were on antidepressants for clinical depression and it does not seem to be a factor in the results. However, I still think it is important to also include stress anxiety disorder controls in such research, but overlap in mechanisms wouldn't necessarily mean CFS is a stress-anxiety-induced disorder as both conditions could just have similar downstream effects from the body being under stress due to different factors. Also, CFS may involve an actual rise in metabolites, not just increased sensitivity to them which may be dismissed by some as the biological correlates of psycho>somatic perception? I think in some of their papers they have discussed actual rises in metabolites too.

[EDIT: Thanks oceanblue for pointing out Dolphin's post on one of these studies (Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome, and Fibromyalgia) where 46/48 (~96%) of the CFS patients also met Canadian criteria. That eases my concerns, but I would still like to see stress/anxiety controls!]

Our research group [55] demonstrated short-term reduction in clinical pain ratings in patients with FMS (including 40% with comorbid CFS) and TMD following ?-receptor blockade with low-dose propranolol (which blocks both ?-1 and ?-2 receptors). Subsequently, Tchivileva et al. [56] used a double-blind crossover design to compare one week of propranolol versus placebo treatment, and similarly found that total pain ratings of TMD patients were decreased by the ?-adrenergic antagonist; they also found that propranolol did not alter sensitivity to experimental pain in all TMD patients, but did reduce it in those with the COMT haplotype linked to decreased enzyme production.

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According to 23andMe I have the COMT Val(158)Met SNP in question so perhaps low-dose propranolol would be useful. As post-exertional symptoms are one of my worse symptom categories and limits me substantially, I hope more research is being done into possible treatments, assuming that such treatment does not have negative consequences elsewhere (the gene expression may be an indication of the body's attempt to force a reduction of activity for a good reason that is not negated by merely intervening with receptor blockade).

I'm not sure if they mean either the 1994 or 2005 definitions, or whether patients meet both (most likely)?

Criteria

I think the reference to Reeves et al., 2005 is an error. Here are the three studies.

One of the writing team might have heard "CDC criteria" were used and looked them up.

Otherwise, I'd say it was more likely Reeves et al., 2003 (people get them confused):

BMC Health Serv Res. 2003 Dec 31;3(1):25.
Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.
Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group.

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Reeves et al., 2005 take quite a bit of work with specific questionnaires. Wouldn't get 96% satisfying Canadian criteria without something odd happening.

A. R. Light, A. T. White, R. W. Hughen, and K. C. Light, Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects, Journal of Pain, vol. 10, no. 10, pp. 10991112, 2009.

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[..]

All CFS patients met the CDC criteria
for CFS (Fukuda et al, 1994). Prior screening had excluded
all other known causes for persistent or relapsing fatigue
in these CFS patients. Exclusion criteria included active
upper respiratory infections, use of corticosteroids, SNS
agonists, or prescription analgesics known to affect
SNS, HPA, or cytokine activity, and/or uncontrolled cardiovascular
or pulmonary disease.

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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.
J Intern Med. 2012 Jan;271(1):64-81. doi: 10.1111/j.1365-2796.2011.02405.x. Epub 2011 Jul 13.

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All CFS patients met the CDC criteria for CFS
[1], and 46 (96%) met the Canadian Criteria for ME/CFS as well [2] .

[..]

1. Fukuda, K., S.E. Straus, I. Hickie, M.C. Sharpe, J.G. Dobbins and A. Komaroff. The chronic
fatigue syndrome: a comprehensive approach to its definition and study. International Chronic
Fatigue Syndrome Study Group. Ann.Intern.Med 1994; 121: 953-959.

2. Carruthers, B.M.J., A.K.; De Meirleir, K.L.; Peterson, D.L.; Klimas, N.G.; Lerner, A.M.; Bested,
A.C.; Flor-Henry, P.; Joshi, P.;Powles, A.C.; Sherkey, J.A.; van de Sande, M.I. Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome: Clincal Working Case Definition, Diagnostic and
Treatment Protocols: A Consensus Document. Journal of Chronic Fatigue Syndrome 2003; 11:
7-115.

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Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls.
White AT, Light AR, Hughen RW, Vanhaitsma TA, Light KC.
Psychosom Med. 2012 Jan;74(1):46-54. Epub 2011 Dec 30.

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Twenty-two patients with CFS (6 of these are the same patients from our previous
publication (15)) who met the Centers for Disease Control and Prevention
criteria for CFS (1),

[..]

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The
chronic fatigue syndrome: a comprehensive approach to its definition and
study. International Chronic Fatigue Syndrome Study Group. Ann Intern
Med 1994;5:2506Y8.

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Thanks for this Marco