Neuromuscular strains in ME/CFS

ME Research UK research article, 2 August 2016: Neuromuscular strains

In the diagnosis and assessment of ME/CFS, there is a great need for simple objective measures that can differentiate the condition from other chronic illnesses, particularly after 24 or 48 hours when the effects of exercise can become most apparent. To date, researchers at Antwerp University Hospital have found upper limb muscle recovery is be slower in ME/CFS patients (read more), and they have also shown that ‘timed-loaded standing’ with a dumbbell (intended to simulate the performance of the torso during everyday activities) is shorter in women with ME/CFS than others, revealing a relative lack of endurance in the muscles of the trunk and arm (read more).

Similarly, an ongoing program of research at Johns Hopkins University has also shown that simple physiological challenges can have abnormal effects. These researchers have uncovered preliminary evidence that ME/CFS patients’ symptoms can be aggravated by ‘neuromuscular strain’, and that young people with the illness have more areas of the body with an ‘abnormal range of motion’ than healthy youngsters. In fact, in the young patients, they found that adding a longitudinal strain to the nerves and soft tissues provoked symptoms, suggesting that the nervous system and connective tissues of the ME/CFS patients is less compliant, i.e. more sensitive to mechanical movement, than normal.

Continuing its investigations, the group’s most recent report describes work on 60 people with ME/CFS and 20 controls, who underwent either a real neuromuscular strain for 15 minutes  (passive supine straight leg raise or SLR) or a sham leg raise that minimised strain. The SLR, which involves raising and holding up one leg while the person lies on their back on an examination table, is most often used for low-back examinations; in fact, it is a test of nerve root irritation, most often seen in sciatica or lumber disc herniation (read more). In this case, however, it was used only to give a mild to moderate strain to the muscles and nerves.

Their most interesting finding was that ME/CFS patients undergoing the SLR, which actually strained their muscles and nerves, had more body pain and concentration difficulties during the procedure than those with the sham leg raise. Not only was the mean composite symptom score significantly greater during the manoeuvre (difference of 3.52 points) in the SLR group than the sham leg raise group, but it was also greater after 24 hours (4.30 points). Also, more patients in the SLR group reported at least a two-point increase in at least three symptoms after 24 hours (44 versus 18%, respectively). As the authors say, “a sustained longitudinal strain applied to the neural and soft tissues of the lower limb was associated with an increased intensity of cardinal symptoms during the manoeuver and for up to 24 hours afterwards”.

They explain the results by pointing to the fact that, in everyday life, the nervous system has to adapt to changes as the body moves, including changes in fibre length and the sliding of nerves within their protective coat of fascia (see a review). Passive SLR exerts a pulling force on a large range of structures (lower limb peripheral nerves, dorsal root ganglia, lumbosacral nerve roots, etc.) and probably gives an elongation strain to the entire length of the spinal cord. Such increased mechanical strain may also cause the spinal blood vessels to narrow, and may stimulate mast cells to release biologically active substances, such as histamine, that worsen both acute and delayed symptoms.

Prof Kevin Fontaine, a co-author of the report, says that the findings “have practical implications for understanding why exercise and the activities of daily living might be capable of provoking CFS symptoms…If simply holding up the leg of someone with CFS to a degree that produces a mild to moderate strain is capable of provoking their symptoms, prolonged or excessive muscle strain beyond the usual range of motion that occurs during daily activities might also produce symptom flares.”

Overall, the results suggest that increased mechanical sensitivity may be a factor in the symptoms people with ME/CFS experience after even mild exertion, and the researchers’ next steps are to tease out the particular effects of strains to muscles and nerves, and to elucidate whether neural or muscular factors predominate. Day-to-day impairments in basic functioning of people with ME/CFS – which can be easily measured objectively in the consulting room, and can be provoked by simple manoeuvres like  the SLR – tend to be overlooked by healthcare professionals today, but may well have diagnostic or pathophysiological value.

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Three approaches to CFS in the UK, Australia, & Canada: lessons for democratic policy

Research abstract:

Decisions about diagnostic categories through clinical practice guidelines (CPGs) represent a central type of informal policy-making which affect the scope of publicly-regulated health services and directions for future research. We examine the development of three diverse sets of CPGs for chronic fatigue syndrome (CFS) in the United Kingdom, Canada, and Australia in order to examine diverse approaches to the development of such guidelines by medical professionals and other ‘experts’ in concert with inputs from the public, particularly those affected by the disease condition.

We argue that the CPGs formulated for CFS in the United Kingdom, Australia, and Canada reflect three contrasting modes of policy development, and that the differential levels of acceptance of these guidelines by a range of relevant parties provide guidance as to which mode of policy development is likely to be most effective and acceptable particularly in the domain of controversial or contested domains within medicine.

Three approaches to Chronic Fatigue Syndrome in the United Kingdom, Australia, and Canada: Lessons for democratic policy, by Rachel A. Ankeny, Fiona J. Mackenzie in Big Picture Bioethics: Developing Democratic Policy (Chapter in: Contested Domains, Part IV. (The International Library of Ethics, Vol. 16. pp 227-243) July 28, 2016

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Human herpesvirus 6 and 7 are biomarkers for fatigue

Research highlights:

  • Salivary HHV-6 and HHV-7 can be used for assessment of physiological fatigue.
  • Activation and differentiation of macrophages are needed for viral reactivation.
  • Salivary HHV-6 and HHV-7 do not increase with pathological fatigue.
  • Salivary HHV-6/7 can distinguish between physiological and pathological fatigue.

Research abstract:

Fatigue reduces productivity and is a risk factor for lifestyle diseases and mental disorders. Everyone experiences physiological fatigue and recovers with rest. Pathological fatigue, however, greatly reduces quality of life and requires therapeutic interventions. It is therefore necessary to distinguish between the two but there has been no biomarker for this.

We report on the measurement of salivary human herpesvirus (HHV-) 6 and HHV-7 as biomarkers for quantifying physiological fatigue. They increased with military training and work and rapidly decreased with rest. Our results suggested that macrophage activation and differentiation were necessary for virus reactivation. However, HHV-6 and HHV-7 did not increase in obstructive sleep apnea syndrome (OSAS), chronic fatigue syndrome (CFS) and major depressive disorder (MDD), which are thought to cause pathological fatigue.

Thus, HHV-6 and HHV-7 would be useful biomarkers for distinguishing between physiological and pathological fatigue. Our findings suggest a fundamentally new approach to evaluating fatigue and preventing fatigue-related diseases.

Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue, by Ryo Aokia et al in Biochemical and Biophysical Research Communications [Available online 7 July 2016]

comment:

Japan: fatigue biomarkers show difference between chronic fatigue syndrome and ordinary fatigue

 

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Genetic evaluation of metabolic enzymes in CFS

Research abstract:

Chronic fatigue syndrome (CFS) is a disease that can seriously impair one’s quality of life; patients complain of excessive fatigue and myalgia following physical exertion. This disease may be associated with abnormalities in genes affecting exercise tolerance and physical performance. Adenosine monophosphate deaminase (AMPD1), carnitine palmitoyltransferase II (CPT2), and the muscle isoform of glycogen phosphorylase (PYGM) genes provide instructions for producing enzymes that play major roles in energy production during work.

The aim of this study was to look for evidence of genotype-associated excessive muscle fatigue. Three metabolic genes (AMPD1, CPT2, and PYGM) were therefore fully sequenced in 17 Italian patients with CFS. We examined polymorphisms known to alter the function of these metabolic genes, and compared their genotypic distributions in CFS patients and 50 healthy controls using chi-square tests and odds ratios. One-way analysis of variance with F-ratio was carried out to determine the associations between genotypes and disease severity using CF scores.

No major genetic variations between patients and controls were found in the three genes studied, and we did not find any association between these genes and CFS. In conclusion, variations in AMPD1, CPT2, and PGYM genes are not associated with the onset, susceptibility, or severity of CFS.

Genetic evaluation of AMPD1, CPT2, and PGYM metabolic enzymes in patients with chronic fatigue syndrome, by P.E. Maltese, L. Venturini, E. Poplavskaya, M. Bertelli, S. Cecchin, M. Granato, S.Y. Nikulina, A. Salmina, N. Aksyutina, E. Capelli, G. Ricevuti, L. Lorusso in Genetics and Molecular Research Vol. 15, no. 3, 15038717 [Published July 29, 2016]

 

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Key research needs in ME/CFS – responses to US request for info

National Institutes of Health press release, 29 July 2016: NIH Request for Information on ME/CFS Research Efforts

On May 24, 2016, the Trans-NIH ME/CFS Working Group published a Request for Information seeking the public’s input on needs, opportunities and strategies for ME/CFS research and research training. Comments were invited from researchers, health care providers, patient advocates and health advocacy organizations, scientific or professional organizations, Federal agencies and other parties with an interest in advancing ME/CFS research efforts.

In particular, the Working Group sought perspective on the following issues related to ME/CFS research planning efforts:

  • Emerging needs and opportunities that should be considered as new ME/CFS research strategies are developed
  • Challenges or barriers to progress in research on ME/CFS
  • Gaps and opportunities across the research continuum from basic through clinical studies

This request was for information and planning purposes only. Responses were accepted through June 24, 2016. Follow the links below to read the comments. In all instances, emails and personally identifiable information have been removed. Names of healthcare providers, researchers and representatives from patient organizations remain. [A number of responses came from outside the US]

RFI responses from individuals pdf

RFI responses from patient advocacy organizations pdf

RFI responses from researchers and healthcare providers pdf

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Assessment of self-management methods for severe CFS

Research abstract:

Purpose: To assess the efficacy of fatigue self-management for severe chronic fatigue syndrome (CFS).

Methods:  This randomized trial enrolled 137 patients with severe CFS.

Participants were randomized to one of three conditions:

  • fatigue self-management with web diaries and actigraphs (FSM:ACT);
  • fatigue self-management with less expensive paper diaries and pedometers (FSM:CTR);
  • or an usual care control condition (UC).

The primary outcome assessed fatigue severity at 3-month follow-up. Analysis was by intention-to-treat.

Results:  At 3-month follow-up, the FSM:CTR condition showed significantly greater reduction in fatigue severity compared to UC (p=.03; d=.58).

No significant improvement was found at 12-month follow-up for the FSM:ACT or the FSM:CTR condition as compared to UC (p>.10). The combined active treatment conditions revealed significantly reduced fatigue at 3-month follow-up (p=.03), but not at 12-month follow-up (p=.24) compared to UC. Clinically significant improvements were found for 24-28% of the intervention groups as compared to 9% of the UC group. Attrition at 12-month follow-up was low (<8%).

Conclusion: Home-based self-management for severe CFS appeared to be less effective in comparison to findings reported for higher functioning groups. Home-based management may be enhanced by remotely delivered interventional feedback.

Efficacy of two delivery modes of behavioral self-management in severe chronic fatigue syndrome, by Fred Friedberg, Jenna Adamowicz, Indre Caikauskaite, Viktoria Seva & Anthony Napoli in Fatigue: Biomedicine, Health & Behavior Vol 4, no.3, pp 158-174 [Published online: 29 Jul 2016]

 

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The blood volume paradox in ME/CFS & POTS

Health Rising blog post: The Blood Volume Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS by Cort Johnson, 29 July 2016.

Kunihisa Miwa, a Japanese ME/CFS researcher, has been on something of a roll. Through no less than five studies he pioneered the small heart findings in chronic fatigue syndrome (ME/CFS). Systrom basically validated Miwa’s finding in his large study of people with unexplained exercise intolerance – some of whom had ME/CFS.

The Exercise Intolerance in ME/CFS, POTS and FM Explained?

Miwa appears to be something of a lone wolf; his ME/CFS studies were either authored just by him or by one other person. Miwa may not be working with a lot of researchers, but he’s certainly up to date; he refers to ME/CFS as ME in this and other papers, and the patients in this study had to meet not the Canadian Consensus Criteria, but the International Consensus Criteria developed in 2011.

Miwa recognized that the small hearts he found in his chronic fatigue syndrome (ME/CFS) patients were likely due not to some defect but to reduced blood flows. If the heart, like any other muscle, doesn’t work out it won’t grow, and the heart needs blood, and lots of it, to work itself into shape.

In this study (ME/CFS=8, HC=5) people Miwa examined some factors – renin (plasma renin enzymatic activity), aldosterone and antidiuretic hormone (ADH) – that affect blood volume. He also also did an echocardiograph and examined the effects of desmopressin – an ADH replacement – to see if it helped.

Results

The study confirmed… “that the vast majority of the patients with ME had a small heart shadow….and their cardiac function was actually impaired with a low cardiac output.”

As before Miwa found evidence of a smaller than usual heart (LV end-diastolic diameter) and reduced output (stroke volume index, cardiac index) in the ME/CFS patients. Mean blood pressure was also lower. More importantly, the factors designed to increase blood volume such as renin enzymatic activity (p<.06), aldosterone (p<.02), and ADH (p<.004) were significantly lower or nearly significantly lower (p<.05) in the ME/CFS patients.

The Low Blood Volume Paradox

Low blood volume has been a recognized issue in ME/CFS since Streeten and Dr. Bell nailed it way back in the year 2000. In fact the Streeten-Bell study – done on 15 randomly selected ME/CFS patients – may have described postural orthostatic tachycardia syndrome (POTS) before it showed up in the literature. Streeten and Bell found reduced blood pressure, reduced blood volume, increased norepinephrine levels and excessive tachycardia upon standing. (This study appears to precede any studies on POTS. If so, chronic fatigue syndrome may have birthed POTS.)

Demonstrating another overlap with ME/CFS and POTS Miwa’s findings mimic those of a 2005 POTS study (reduced blood volume, aldosterone and plasma renin activity).
Streeten would go on to show way back in 2001 that blood pooling in the veins as well as low blood volume was preventing sufficient amounts of blood from getting to the heart. Military antishock trousers were reportedly quite effective in reducing the problem.

(Military antishock trousers are inflated with a pump. They don’t seem to have ever be suggested as a viable treatment option but do indicate that blood pooling the veins is very important is very important). The excessive tachycardia, Streeten believed, was an attempt to increase blood flows to the brain.

Jump forward 15 years and David Systrom shows up with a large study years in the making which shows that unexplained fatigue associated with exercise is characterized by reduced preload (blood flows to the heart), reduced blood volume and blood pooling in the veins; i.e. exactly the same problem Streeten and Miwa found but being applied to a much larger set of patients.

Systrom suggested that problems with the veins were more important than blood volume but Hurwitz’s large study suggested that blood volume was most important factor in the low cardiac output found in ME/CFS. About half the patients in Hurwitz’s study had low blood volume and they were the sickest.

The fact that POTS, ME/CFS and some other disorders were included in Systrom’s study indicates this problem is present in an array of diseases. Miwa describers the tachycardia in POTS in the same way that Streeten did – as a reaction to the low blood levels reaching the heart. We know now, though, that POTS is more complicated than once thought, and that autoimmune processes targeting the receptors that effect heart rates are involved as well. .

Low blood volume appears to be common, though, in both ME/CFS and POTS. Ordinarily, low blood volume should trigger the renin-angiotensin-aldosterone system and ADH (vasopressin) to increase it, but in what’s called the renin-aldosterone paradox, both these systems appear to poop out in ME/CFS and POTS.

The Renin Aldosterone Paradox

Miwa doesn’t posit a clear answer to the renin-aldosterone paradox but suggests that central nervous system/HPA axis and “structural or functional brain abnormalities” are to blame. The top of the HPA axis chain – the hypothalamus – is part of the limbic system in the lower brain. It links the nervous and endocrine systems together via the pituitary gland. (The hypothalamus also regulates our circadian rhythms (and thus sleep) and the autonomic nervous system.

ADH (vasopressin) is produced in the hypothalamus and then carried into the blood via the pituitary gland. Aldosterone is produced by the adrenal glands in response to angiotensin II, ACTH, potassium or via messages from the stretch receptors in the heart that blood pressure has fallen.

Dr. Bateman’s Big Picture

In her talk “the Big Picture and ME/CFS” Dr. Bateman proposed a similar scenario. First, she focused on the Zinn’s findings from the Stanford Symposium which suggested that people with ME/CFS were asleep when they were awake, and awake when they were asleep. The Zinn’s proposed a “limbic encephalopathy” – a brain disorder concentrated in the lower regions of the brain – was present.

Dr. Bateman echoed that idea noting that the Japanese had found inflammation in the lower part of the brain, and that a Rhomberg test – an indicator of deep brain issues – is often positive in ME/CFS/FM.

Then she noted a bevy of hormones including ADH (vasopressin) are produced in the lower part of the brain. With his functional or structural brain abnormalities Miwa appears to be positing that this area is producing the low blood volume, and perhaps the vein problem in ME/CFS.

Treatment

Miwa proposes the use of desmopressin, a drug not often associated with ME/CFS. Desmopressin is a synthetic analogue of vasopressin. Vasopressin, which is decreased in both ME/CFS and POTS, increases blood vessel “tone” and blood pressure. Desmopressin doesn’t increase blood vessel tone but it does increase blood volume. It’s most frequently used in diabetes insipidus and for night-time bed-wetting.

The IACFS/ME Primer doesn’t mention desmopressin but a 2012 study found that desmopressin significantly reduced the heart rate in POTS patients. The authors of the POTS study found desmopressin effective in the short term, but would not recommend its daily use until further studies had been done. They did say it’s been proven safe for children with night-time bedwetting problems.

One risk of daily use is hyponatremia – low blood sodium concentrations – which might be exacerbated by the large amounts of water some patients drink. The authors concluded that desmopressin is

highly effective at acutely decreasing orthostatic tachycardia and standing tachycardia in patients with POTS, and this was associated with an improvement in symptom burden in these patients. Longer-term studies are needed to assess this therapy.

That’s significantly better than the finding that fludrocortisone – another drug commonly used in orthostatic intolerance – was no better than placebo.

New Studies
Researchers have been showing more interest in blood volume enhancement as of late. Medow’s study quantifying the effects of saline on ME/CFS should be out this year, and he just got a nice NIH grant to examine the effectiveness of oral rehydration salts in increasing blood volume in ME/CFS.

Oral rehydration salts (ORS) were developed by the World Health Organization to combat diseases such as cholera. They are cheap, easy to make and surprisingly effective.

Medow states in the grant that he believes that the ORS may bemore effective than IV saline infusions in increasing blood volume and improving blood flows to the brain.

Conclusions

We’ve made some progress since Bell and Streeten identified the low blood volume, problems with the veins, and rapid heart rates 15 years ago in ME/CFS. We know that smaller than usual hearts are also present in ME/CFS and POTS and people with idiopathic exercise intolerance (who have not been diagnosed with ME/CFS). Researchers are taking a deeper look at blood volume, and we know that the inflammation in the lower brain may have something to do with it.

If Dr. Bateman is right further brain studies will highlight this area. We should know in the next year or so.

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Gender differences in CFS

Research abstract:

BACKGROUND AND OBJECTIVES:
Chronic fatigue syndrome (CFS) is a chronic condition that predominantly affects women. To date, there are few epidemiologic studies on CFS in men. The objective of the study was to assess whether there are gender-related differences in CFS, and to define a clinical phenotype in men.

PATIENTS AND METHODS:
A prospective, cross-sectional cohort study was conducted including CFS patients at the time of diagnosis. Sociodemographic data, clinical variables, comorbid phenomena, fatigue, pain, anxiety/depression, and health quality of life, were assessed in the CFS population. A comparative study was also conducted between genders.

RESULTS:
The study included 1309 CFS patients, of which 119 (9.1%) were men. The mean age and symptoms onset were lower in men than women. The subjects included 30% single men vs. 15% single women, and 32% of men had specialist work vs. 20% of women. The most common triggering factor was an infection. Widespread pain, muscle spasms, dizziness, sexual dysfunction, Raynaud’s phenomenon, morning stiffness, migratory arthralgias, drug and metals allergy, and facial oedema were less frequent in men. Fibromyalgia was present in 29% of men vs. 58% in women. The scores on physical function, physical role, and overall physical health of the SF-36 were higher in men. The sensory and affective dimensions of pain were lower in men.

CONCLUSIONS:
The clinical phenotype of the men with CFS was young, single, skilled worker, and infection as the main triggering agent. Men had less pain and less muscle and immune symptoms, fewer comorbid phenomena, and a better quality of life.

Gender differences in chronic fatigue syndrome, by Faro M, Sàez-Francás N, Castro-Marrero J, Aliste L, Fernández de Sevilla T, Alegre J [Article in English, Spanish] in Reumatol Clin. 2016 Mar-Apr;12(2):72-77 [Epub 2015 Jul 17]

 

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Mixed results for MitoQ in FM & CFS study

Research abstract:

Fibromyalgia (FM), myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are disorders with similar symptom constellations including pain, fatigue, cognitive problems and sleep disturbance, among others.

These multi-system illnesses have many known abnormalities, few reliable treatment options and unknown causes. Oxidative stress has been linked to disorder severity, suggesting anti-oxidants may be of benefit. Coenzyme Q10 (Q10) has been shown to improve symptoms and biomarkers of FM, and ME/CFS if taken in combination with another coenzyme. However, Q10 is poorly absorbed by mitochondria.

MitoQ is a mitochondria targeted Q10 analog with superior absorption and accumulation by mitochondria in vivo. The current study tested the effect of 6-weeks of daily oral MitoQ (20mg) on FM and ME/CFS with two randomized, blinded, placebo-controlled crossover studies. A third open label cohort contributed data but did not receive placebo.

Results suggest MitoQ may reduce pain and increase working memory in FM. Further investigation in a more controlled environment is warranted.

The influence of Mitoq on symptoms and cognition in fibromyalgia, myalgic encephalomyelitis and chronic fatigue, by Cort Johnson & Joshua Grant

[This article has NOT been officially peer reviewed and is the opinion of the authors. Comments can be made publicly or privately on either Mendus.org or HealthRising.org]

Mendus is a platform to encourage people with health conditions share experiences, interact with research scientists, generate research questions and initiate research studies.

Founder Joshua Grant says:

We had a great turnout for the MitoQ study. Though not everyone finished, 144 people contributed data. Newcomers can still complete the study but I wanted to inform you that an official report is freely accessible here.

There were encouraging and disappointing results. MitoQ seems to work quite well for fibromyalgia, lowering pain and improving memory. For ME/CFS the higher dosage (those who also had placebo) showed no effects that could not be explained by placebo. However, our open label cohort (Group3) showed huge effects with the lower dose. You can read much more about our interpretation in the discussion section of the paper.

Did MitoQ mend us? by Cort Johnson, 8 Aug 2016

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Lower level of dynamic postural control in CFS & FM

Research highlights:

  • Fibromyalgia and chronic fatigue syndrome showed a lower level of postural control in gait initiation.
  • There was no significant difference between fibromyalgia and chronic fatigue syndrome in dynamic postural control.
  • Fibromyalgia patients showed a higher K value compared to the controls.

Research abstract:

BACKGROUND: Impaired postural control has been reported in static conditions in chronic fatigue syndrome and fibromyalgia, but postural control in dynamic tasks have not yet been investigated. Thus, we investigated measurements from a force plate to evaluate dynamic balance control during gait initiation in patients with chronic fatigue syndrome and fibromyalgia compared to matched healthy controls.

METHODS: Thirty female participants (10 per group) performed five trials of gait initiation. Center of pressure (CoP) trajectory of the initial weight shift onto the supporting foot in the mediolateral direction

(CoPX) was analyzed using General Tau Theory. We investigated the hypothesis that tau of the CoPX motion-gap (τCoPx) is coupled onto an intrinsic tauG-guide (τG) by keeping the relation τCoPx=KτG, where K is a scaling factor that determines the relevant kinematics of a movement.

FINDINGS: Mean K values were 0.57, 0.55, and 0.50 in fibromyalgia, chronic fatigue syndrome, and healthy controls, respectively. Both patient groups showed K values significantly higher than 0.50 (P<0.05), indicating that patients showed poorer dynamic balance control, CoPX colliding with the boundaries of the base of support (K>0.5).

INTERPRETATION: The findings revealed a lower level of dynamic postural control in both fibromyalgia and chronic fatigue syndrome compared to controls.

TauG-guidance of dynamic balance control during gait initiation in patients with chronic fatigue syndrome and fibromyalgia by O Rasouli, AK Stensdotter, AL Van der Meer in J Clin Biomech (Bristol, Avon) Vol 37, August 2016, pp 147–152  [Epub ahead of print]

 

 

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