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What is the current thinking/evidence on abnormal muscle function in ME?

I'd love to believe the "it's just deconditioning" hypothesis, but my muscles now respond to exercise and to increases in exercise so differently from how they used to when I was training for a half marathon before I got ME.

" I was training for a half marathon before I got ME."

I could spend hours in a morning dry stone walling and be called to shower before lunch before I got tired.
Now just having the shower leaves me aching and needing to rest.


This seems interesting.
http://www.cortjohnson.org/blog/2013/07 ... syndrome/.
Not processing oxygen well, at the mitochondrial level?
(My question mark. On this I don't buy *anything* too quickly.)

It fits my symptoms.
"Officer, someone has vandalised my Krebs cycle!"

(edit for spelling.)

Thanks Chris - that's really interesting. It would be great if more research could be done in this area.

Dear clare35

There is evidence of weak muscles, deconditioning, reduced heart size, and a reduction in mitochondria (a component of cells associated with energy). However, once scientific studies have taken into account deconditioning and abnormal perception of effort, muscle function is in fact normal.

I also agree that it’s ‘not just deconditioning’. Graded Exercise Therapy (GET) appears to work for people not because it’s reversing deconditioning, but because it’s changing the perception of effort.
The most scientifically convincing explanation is therefore not to do with any particular muscle abnormality, but rather an abnormality in the perception of the post-exertional fatigue, malaise or pain. This is a complex interplay that involves muscles, nerves, and the brain so can’t realistically be put down to one thing. I also wonder if the frustration (or downright stress) of not being able to do what one could before also amplifies the perception?

I hope this gives you reassurance that you are right: the answer is not straight forward, and is a complex interplay between various body systems.

All the best with your health.

Dear Jessica

Thank you for your reply - but unfortunately it left me more confused!

You comment that "once scientific studies have taken into account deconditioning and abnormal perception of effort, muscle function is in fact normal".

However, the 2013 study in Physical Therapy (the link in Chris's post) seemed to suggest that there were clear differences in people with ME compared to the 'couch potato' controls.

Could it be 'absence of evidence' rather than 'evidence of absence' as far as abnormal muscle function in ME is concerned - i.e. that insufficient robust studies have currently been done in this area?

I'm also puzzled by your comment that GET appears to work "because it's changing the perception of effort" and that the abnormality "in the perception of the post-extertional fatigue, malaise or pain" is "a complex interplay that involves muscles, nerves and the brain".

If the muscles are in fact normal (as you suggest from the scientific studies), then is GET working on the nerves or the brain - and if so, how?!

I'm puzzled by the mechanism here.

In my ongoing N of 1 study (as a highly-motivated previously very fit person extremely motivated to ignore and over-ride muscle symptoms whenever I possibly can and to act as if I don't have ME), what is the magic ingredient that I can get from GET or the mechanism that I can activate via GET which will enable me to get back to running 5-8 miles five times a week, commuting for 3 hours a day, working 12 hour days and running a half marathon again?

I would be grateful for any further light you can shed on this puzzle.

http://www.meactionuk.org.uk/documented ... me-cfs.htm

In 1983, UK researchers documented evidence of a consistent pattern of complexity, including “malaise, exhaustion on physical or mental effort, chest pain, palpitations, tachycardia, polyarthralgia, muscle pains, back pain, true vertigo, dizziness, tinnitus, nausea, diarrhoea, abdominal cramps, epigastric pain, headaches, paraesthesiae and dysuria” (Keighley and Bell, JRCP: 1983:339-341).



In 1984, Arnold et al demonstrated excessive intracellular acidosis of skeletal muscle on exercise in ME/CFS patients, with a significant abnormality in oxidative muscle metabolism and a resultant acceleration in glycolysis (Proceedings of the Third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York: 1984: 12-13).



In 1985, UK researchers demonstrated muscle abnormalities in ME/CFS patients: “The post-viral fatigue syndrome, also known as ME, has been recognised recently as a distinct neurological entity with increasing evidence of the organic nature of the disease. The most important findings were type II fibre predominance, subtle and scattered fibre necrosis and bizarre tubular structures and mitochondrial abnormalities. About 75% of the patients had definitely abnormal single fibre electromyography results” (Goran A Jamal Stig Hansen JNNP 1985:48:691-694).



In 1987, Archer demonstrated that: “Relapses are precipitated by undue physical or mental stress. However compelling the evidence for an hysterical basis may be, there is further, equally compelling, evidence of organic disease. Some patients do have frank neurological signs. Muscle biopsies showed necrosis and type II fibre predominance” (JRCGP: 1987:37:212-216).



It was documented as long ago as 1988 that there was “general agreement that (ME’s) distinguishing characteristic is severe muscle fatigability, made worse by exercise. It becomes apparent that any kind of muscle exercise can cause patients to be almost incapacitated (and) the patient is usually confined to bed. What is certain is that it becomes plain that this is an organic illness in which muscle metabolism is severely affected” (Crit Rev Neurobiol: 1988:4:2:157-178).



In 1988, UK researchers Archard and Bowles et al published the results of their research into muscle abnormalities in ME/CFS: “These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that persistent viral infection has an aetiological role. These results provide further evidence that Coxsackie B virus plays a major role in ME, either directly or by triggering immunological responses which result in abnormal muscle metabolism” (JRSM 1988:81:325-331).



Also in 1988, Teahon et al published a study of skeletal muscle function in ME/CFS; it showed significantly lower levels of intracellular RNA, suggesting that ME/CFS patients have an impaired capacity to synthesise muscle protein, a finding which cannot be explained by disuse (Clinical Science 1988: 75: Suppl 18:45).

Dear Jessica,

You state that:

“Graded Exercise Therapy (GET) appears to work for people not because it’s reversing deconditioning, but because it’s changing the perception of effort. The most scientifically convincing explanation is therefore not to do with any particular muscle abnormality, but rather an abnormality in the perception of the post-exertional fatigue, malaise or pain. This is a complex interplay that involves muscles, nerves, and the brain so can’t realistically be put down to one thing. I also wonder if the frustration (or downright stress) of not being able to do what one could before also amplifies the perception?”

You will be well aware that this explanation is held only by a small group of psychiatrists and like minded colleagues, whereas the great majority of researchers around the world consider post-exertional malaise to be physical in origin and do not recommend GET as a primary therapy.

I would be grateful if you would explain how all the following peer reviewed research evidence can be explained by this explanation of post-exertional fatigue.

These research papers invalidate the assertion that the problem is merely wrong perceptions and show that post-exertional fatigue is a verifiable physical phenomenon and that increasing exercise beyond what patients find tolerable is contraindicated by the objective evidence.

Also I would be grateful if you would provide me with references to papers showing MECFS patients do indeed have abnormal perceptions of fatigue and pain and that these wrong perceptions can cause the pathological findings referred to in the papers below, a necessary requisite for any theory.

Thank you for your time,

Genevieve

http://www.workwellfoundation.org/wp-co ... Final1.pdf

Workwell Foundation announces the publication of a new study supporting previous findings that a 2-day Cardiopulmonary Exercise Test (CPET) protocol objectively documents postexertional malaise (PEM), the most commonly recognized symptom in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).The study revealed a statistically significant performance decrease on Day 2 in workload at ventilatory threshold (VTWL), workload at peak exercise (WLpeak), volume of oxygen consumed at ventilatory threshold (VTO2) and volume of oxygen consumed at peak exercise (VO2peak). In short, individuals with CFS/ME were unable to reproduce their Day 1 performance on Day 2.The statistical classification analysis points to a diagnostic biomarker for CFS/ME with a 95.1% accuracy.

Here is the relevant paper:
http://ptjournal.apta.org/content/early ... 0368.short
“Discriminative Validity of Metabolic and Workload Measurements to Identify Individuals With Chronic Fatigue Syndrome”
Christopher R. Snell, Staci R. Stevens, Todd E. Davenport (tdavenport@pacific.edu)and
J. Mark Van Ness

And the research evidence cited here:

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract

Myalgic encephalomyelitis: International Consensus Criteria

“Malaise – a vague feeling of discomfort or fatigue” [42] is an inaccurate and inadequate word for the pathological low-threshold fatigability and post-exertional symptom flare. Pain and fatigue are crucial bioalarm signals that instruct patients to modify what they are doing in order to protect the body and prevent further damage. Post-exertional neuroimmune exhaustion is part of the body’s global protection response and is associated with dysfunction in the regulatory balance within and between the nervous, immune and endocrine systems, and cellular metabolism and ion transport [43-47]. The normal activity/rest cycle, which involves performing an activity, becoming fatigued, and taking a rest whereby energy is restored, becomes dysfunctional.

Numerous papers document abnormal biological responses to exertion, such as loss of the invigorating effects of exercise [20], decreased pain threshold [48-50], decreased cerebral oxygen and blood volume/flow [51-54], decreased maximum heart rate [55], impaired oxygen delivery to muscles [56], elevated levels of nitric oxide metabolites [57], and worsening of other symptoms [58]. Patients reach the anaerobic threshold and maximal exercise at a much lower oxygen consumption level [59]. Reported prolonged effects of exertion include elevated sensory signalling to the brain [60] that is interpreted as pain and fatigue [61], elevated cytokine activity [62], delay in symptom activation [63] and a recovery period of at least 48 hours [58]. When an exercise test was given on two consecutive days, some patients experienced up to a 50% drop in their ability to produce energy on the second evaluation [64]. Both submaximal and self-paced physiologically limited exercise resulted in post-exertional malaise [49].

43. Jason LA, Helgerson J, Torres-Harding SR, Carrico AW Taylor RR. Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. Eval Health Prof 2003; 26: 3-22. [PMID: 12629919]
44. Jason LA, Taylor RR, Kennedy CL, et al. A factor analysis of chronic fatigue symptoms in a community-based sample. Soc Psychiatry Psychiatr Epidemiol 2002; 37: 183-89. [PMID: 12027245]
45. Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Myalgic Encephalomyelitis – A persistent enteroviral infection? Postgrad Med J 1990; 66: 526-30. [PMID: 2170962]
46. Lloyd AR, Hickie I, Boughton CF, Spencer O, Wakefield D. Prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990; 153: 522-28. [PMID: 2233474]
47. NijsJ, MeeusM ,McGregorNR, MeeusenR, deSchutterG, vanHoofE, DeMeirleirK. Chronic Fatigue Syndrome: Exercise Performance Related to Immune Dysfunction. Med Sci Sports Exerc 2005; 37: 1647-54. [PMID: 16260962]
48. Meeus M, Roussel NA, Truijen S, Nijs J. Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med 2010; 42: 884-90. [PMID: 20878051]
49. VanOosterwijckJ,NijsJ,MeeusM,LefeverI,HuybrechtsL,LambrechtL,PaulL.Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome; an experimental study. J Intern Med 2010; 268: 265-78. [PMID: 20412374]
50. Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain threshold in chronic fatigue syndrome. Pain 2004; 109: 497-99. [PMID: 15157711]
51. Yoshiuchi K, Farkas I, Natelson BH. Patients with chronic fatigue syndrome have reduced absolute cortical blood flow. Clin Physiol Funct Imaging 2006; 26: 83-6. [PMID: 16494597]
52. Goldstein JA. Chronic Fatigue Syndrome: The Limbic Hypothesis. Binghamptom, New York: Haworth Medical Press; 1993:19, 116.
53. Streeten DH. Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci 2001; 321: 163-67. [PMID: 11269790]
54. Neary PJ, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imag 2008; 28: 364-72. [PMID: 18671793]
55. VanNess JM, Snell CR, Dempsey WL, Strayer DR, Stevens SR. Subclassifying chronic fatigue syndrome using exercise testing. Med Sci Sports Exerc 2003; 35: 908-13. [PMID: 12783037]
56. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med 2000; 170: 3270-7. [PMID: 11088089]
57. SuárezA,GuillamóE,RoigT,etal.Nitricoxid emetabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt) 2010; 19: 1073-7. [PMID: 20469961]
58. VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in women with chronic fatigue syndrome. J Women’s Health (Larchmt) 2010; 19: 239-244. [PMID: 20095909]
59. Vermeulen RCW, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med 2010; 8: 93. doi:10.1186/1479- 5876-8-93. [PMID: 20937116]
60. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implication of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann NY Acad Sci 1998; 840: 684-97. [PMID: 9629295]
61. 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. J Pain 2009; 10: 1099-112. [PMID: 19647494]
62. WhiteAT, LightAR, HughenRW, BatemanL, MartinsTB, HillHR, LightKC. Severityof symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiol 2010; 47: 615-24. [PMID: 20230500]
63. Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH. A real- time assessment of the effect of exercise in chronic fatigue syndrome. Physiol Behav 2007; 92: 963-8. [PMID: 17655887]
64. Snell CF, VanNess JM, Stayer DF, Stevens SR. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). In Vivo 2005; 19: 387-90. [PMID: 15796202]

Professor Julia Newton's team found that muscle tissue grown from biopsies taken from ME patients and subjected to electrical impulses to mimic exercise produced 10 times as much lactic acid as muscle cultured from healthy people. Obviously there's no 'perception' going on there because there's no brain or CNS hooked up to the muscle.

Here's a link to the Times article:

http://forums.phoenixrising.me/index.ph ... ers.22880/

This would seem to argue against the idea that trying to train the brain to perceive effort differently is likely to work (quite apart from the question of whether one believes that there is any evidence that GET is effective at all - it seems to me that the heavy criticism of the PACE trial, in particular, has never been adequately addressed).

I'm so glad that everyone chipped in here to show the weight of evidence for muscle abnormalities that are present. It is important that in this forum we have a balanced, intelligent discussion of the science out there with the experts otherwise this forum sadly would be truly a waste of time.

Jessica, I must say I am confused by this statement: "I also agree that it’s ‘not just deconditioning’. Graded Exercise Therapy (GET) appears to work for people not because it’s reversing deconditioning, but because it’s changing the perception of effort."

I'm afraid I haven't seen any studies showing that GET (with or without CBT) works in any objective manner which impacts physical functioning. In fact, the studies which use actometers show quite the opposite - there is no physical improvement in CDC defined ME/CFS patients, despite scoring better on questionnaires. [1]

I do try to keep up with all of the research in this area, and have reads dozens, if not hundreds, of papers on the subject. Hence if you can cite a study which used objective measurements that account for Post-Exertional Malaise (such as actometers) and show an improvement, I would appreciate it very much if you could cite those sources so I can add them to my collection

Thank you,
-Valentijn

[1] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G (2010). How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine 40, 1281-1287.