Short-Term Effect of Aerobic Exercise on Symptoms in Multiple Sclerosis and Chronic Fatigue Syndrome

[Dolphin]

Free full text: http://ijmsc.org/doi/abs/10.7224/1537-2073.2013-005

Article Citation:
Yvonne C. Learmonth, Lorna Paul, Angus K. McFadyen, Rebecca Marshall-McKenna, Paul Mattison, Linda Miller, and Niall G. McFarlane (2014) Short-Term Effect of Aerobic Exercise on Symptoms in Multiple Sclerosis and Chronic Fatigue Syndrome. International Journal of MS Care: Summer 2014, Vol. 16, No. 2, pp. 76-82.
doi: http://dx.doi.org/10.7224/1537-2073.2013-005

Short-Term Effect of Aerobic Exercise on Symptoms in Multiple Sclerosis and Chronic Fatigue Syndrome: A Pilot Study

Yvonne C. Learmonth, PhD; Lorna Paul, PhD; Angus K. McFadyen, PhD; RebeccaMarshall-McKenna, PhD; Paul Mattison, MD; Linda Miller, MPhil; Niall G. McFarlane,PhD

Background:

This pilot study was conducted to determine whether a 15-minute bout of moderate-intensity aerobic cycling exercise would affect symptoms (pain and fatigue) and function (Timed 25-Foot Walk test [T25FW] and Timed Up and Go test [TUG]) in people with multiple sclerosis (MS) or chronic fatigue syndrome (CFS), and to compare these results with those of a healthy control group.

Methods:

Eight people with MS (Expanded Disability Status Scale score 5–6; Karnofsky score 50–80), eight people with CFS (Karnofsky score 50–80), and eight healthy volunteers participated in the study.

Pain and fatigue levels and results of the T25FW and TUG were established at baseline as well as at 30 minutes, 2 hours, and 24 hours following a 15-minute stationary cycling aerobic exercise test.

Repeated-measures analysis of variance (ANOVA) and covariance (ANCOVA) were used to analyze the findings over time.

Results:

At baseline there were statistically significant differences between groups in fatigue (P = .039), T25FW (P = .034), and TUG (P = .010).

A significant group/time interaction emerged for fatigue levels (P= .005).

We found no significant group/time interaction for pain levels or function.

Conclusions:

Undertaking 15 minutes of moderate-intensity aerobic cycling exercise had no significant adverse effects on pain or function in people with MS and CFS (with a Karnofsky score of 50–80) within a 24-hour time period.

These initial results suggest that people with MS or CFS may undertake 15 minutes of cycling as moderate aerobic exercise with no expected negative impact on pain or function.

From the College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK (YCL, LP, RMM, NGM); Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA (YCL); AKM-STATS, Statistical Consultants, Glasgow, Scotland, UK (AKM); Multiple Sclerosis Service, NHS Ayrshire and Arran, Scotland, UK (PM, LM); and School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, Scotland, UK (LM).

Correspondence: Yvonne C. Learmonth, PhD, Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 906 S. Goodwin Ave., Urbana, IL 61801; e-mail: ycl@illinois.edu.

 

[Dolphin]

When one sees the results, they are not as clear cut as the authors make out. At 8 patients in each cohort, I think this study was underpowered to find differences.

---
The authors appear to be fans of exercise for CFS. This is annoying as I know people like Lorna Paul and Rebecca Marshall-McKenna have been funded by ME Research UK in the past and should be aware of problems

Several weeks of aerobic exercise can be beneficial for people with CFS, including improving fatigue and physical functioning.4

There is minimal evidence of the effect of a short bout of aerobic exercise in CFS. Paul et al.12 found no clear symptom change following 15 minutes of aerobic exercise on a stationary cycle, yet it is acknowledged that symptoms may increase following modest exercise, physical activity, or exercise testing.2 In addition, it has been shown that the physiological response (final heart rate and perceived exertion) to a short bout of exercise may differ between those with CFS and healthy individuals,12 yet results of such comparison between those with MS and healthy individuals have not been reported.

Participating in exercise over a prolonged period of time may have a positive impact on fatigue, pain, and mobility problems, while helping to prevent comorbidities associated with a lack of exercise.13 However, past evidence is unclear as to whether exercise may increase symptoms (ie, pain or fatigue) immediately following exercise in those with MS and CFS.2,9–11 Indeed, concern about a detrimental effect of exercise may deter people with these diseases from undertaking exercise, despite the absence of strong quantitative evidence that exercise may negatively affect symptoms over a longer period of time.

Discussion:

Taken together, these results are important because if people with MS and CFS do not experience any detrimental effects on fatigue and function following short durations of exercise, this may encourage maintenance of exercise programs and thus allow those with MS and CFS to experience the long-term benefits of exercise.

 

[Dolphin]

Who were the patients:

Participants with MS and CFS were recruited through the local National Health Service rehabilitation service.

So not necessarily a representative group.

People with CFS were eligible if they had been diagnosed with CFS and met both the Centers for Disease Control and Prevention research guidelines for CFS15 and the Canadian clinical guidelines for CFS.16

Good that Canadian ME/CFS criteria used.

To reduce some potential confounding factors, people with MS or CFS were excluded if they had experienced exacerbation of their symptoms in the 3 months prior to the study or if they had taken anticonvulsant therapy, disease-modifying drugs, or immune suppressants in the 4 weeks prior to the study.

So again possibly not representative.

 

[Dolphin]

An example of how underpowered the study appears:

pretreatment pain scores were not significantly different

The pre-treatment pain scores were:
Mean (SD)
MS: 3.85 (4.6)
CFS: 18.9 (17)
Healthy Controls: 8 (22.6)
On scale of 0-100.

 

[Dolphin]

Note that 3 out of 8 of the CFS group didn't perform the required exercise:

Two participants with MS (EDSS = 6; Karnofsky score = 70) and three participants with CFS (Karnofsky score = 60 [n = 1], 70 [n = 2]) were unable to maintain the desired wattage to achieve a 90% work rate; however, they completed the exercise test to the best of their ability.

3 out of 8 is 37.5% so a significant percentage.

 

[Dolphin]

As might be expected, the exercise had a greater effect on perceived exertion in the MS & CFS groups.

A one-way ANOVA revealed no differences in HR between groups; however, a significant difference emerged between the three groups for RPE scores (P = .01), with both clinical groups reporting higher RPE scores at the end of the test. The Tukey test revealed that these differences were only between the HC and MS groups and between the HC and CFS groups (Table 1).

 

[Dolphin]

Here's the table with the main results:

As one can see, there are some changes for fatigue and pain in the CFS group compared to the healthy controls which might reach statistical significance with a bigger sample.

They did say:

Additionally, there was a slight trend toward increased pain levels in both the MS and CFS groups.

 

[Bob]

With only 8 CFS patients participating, this is a meaningless study. But these look like the sort of results you'd expect for deconditioned/sedentary healthy people, rather than ME patients. I'd like to see the results at 48 hours, but if they are deconditioned/sedentary patients, then I guess the results would be similar.

 

[osisposis]

[QUOTEI think there are differences in CFS vs. ME/CFS , to me ME/CFS does point to allergy and infection, and menningitis and damage to the menninges. IL-33 involvement points to this. again, I'm here because of exposure in a WDB, aka toxic molds, chemicals,voc's,ect. it was a high moisture/humidity wdb that tore me up. this was 2001, in 2007 I started researching which didn't start so well because of brain dysfunctions but I kept at it. mast cells are major here, and alot of new and very recent studies point to this. I say this because I've done the research, lyme, virus,bacterial, and the secondary poisoning cause by mast cell degranulation and even the release of potents without degranulation is a big deal. to much to try to cover in a few but mainly I wanted to share this as I think I may be seeing some tie in here because I've been looking into IL-6 and IL-10. this first article jumped out at me, you have to look inbetween the lines here but I pulled out some interesting stuff. the other article "mast cell in inflammation" goes into some detail thats very valuable also. ][/QUOTE]

 

[osisposis]

IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927536/

We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity

Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

The hypothalamus, The hypothalamus is a brain region that gathers information on the body's nutritional status and governs the release of multiple metabolic signaling molecules such as insulin and leptin to maintain homeostasis.

This means that strategies to reduce the aberrant activation of inflammatory signaling in the hypothalamus are of great interest to improve the central insulin and leptin action and prevent or treat related metabolic diseases. Using a combination of pharmacological, genetic, and physiological approaches, our study indicates that physical activity reorganizes the set point of nutritional balance through anti-inflammatory signaling mediated by interleukin (IL)-6 and IL-10 in the hypothalamus of rodents. Hence, IL-6 and IL-10 are important physiological contributors to the central insulin and leptin action mediated by exercise,linking it to hypothalamic ER stress and inflammation.


Using a combination of pharmacological, genetic, and physiological approaches, our study indicates that physical activity reorganizes the set point of nutritional balance through anti-inflammatory signaling mediated by interleukin (IL)-6 and IL-10 in the hypothalamus of rodents. Hence, IL-6 and IL-10 are important physiological contributors to the central insulin and leptin action mediated by exercise, linking it to hypothalamic ER stress and inflammation.

Since the discovery of interleukin (IL)-6 releases from contracting skeletal muscle, accumulating evidence indicates that exercise induces metabolic changes in other organs, such as the liver, the adipose tissue, and hypothalamus, in an IL-6 dependent manner. IL-6 is most often classified as a pro-inflammatory cytokine, although consistent data also demonstrate that IL-6 has an anti-inflammatory effect and may negatively regulate the inflammation of acute phase response by increasing IL-10, IL-1 receptor antagonist(IL-1ra), and soluble TNF-receptors (sTNF-R) [17].



Discussion
Exercise as a Potential Target for Countering Hyperphagia and Obesity

Physical activity is a cornerstone in the prevention of obesity and related diseases. Although the energy expenditure aspects of such exercise may contribute to the effects of weight loss, it has been suggested that physical exercise may also contribute to negative energy balance by altering appetite and reducing food intake in rodents [21],[32] and humans [33],[34]. Our study shows that acute exercise per se did not evoke any meaningful effect, in terms of food intake in lean animals, but interestingly, it was crucial for suppressing hyperphagia mediated by overnutrition, reducing hypothalamic IKKβ/NF-κB activation and ER stress, thus improving insulin and leptin action in an IL-6- and IL-10-dependent manner (Figure 9).


These data are in accordance with Park and colleagues [36], who showed that exercise improved insulin and leptin signaling, increased STAT3, and reduced AMPK phosphorylation in the cerebral cortex and hypothalamus of diabetic rats, contributing to the regulation of body weight and glucose homeostasis.


IL-6 Is a Crucial Cytokine for Exercise to Restore Hypothalamic Insulin and Leptin Signaling.

Recently, we demonstrated that exercise requires IL-6 to increase hypothalamic insulin and leptin sensitivity [18] and increase the effects of leptin on the AMPK/mTOR pathway in the hypothalamus of rodents [21]. Furthermore, IL-6 is also released from the brain during prolonged exercise in humans [41]. In the present study, we showedthat the increment of IL-6 expression in the hypothalamus was crucial to exercise for reducing the inflammation and ER stress activation induced by overnutrition.


Thus, our data demonstrate that IL-6 plays an important role in the control of the ER stress effects in the hypothalamus of rats.

All these results are significant, since IKKβ and ER stress activation were strongly associated with insulin and leptin resistance in the hypothalamic tissue. Although we showed a consistent anti-inflammatory effect, mediated by IL-6, in the hypothalamus, we cannot exclude the possibility that IL-6 acts directly as an anorexigenic factor.


Hypothalamic IL-10: A Core Anti-Inflammatory Cytokine Induced by IL-6


Although our findings clearly show that IL-6 diminished hypothalamic IKKβ and ER stress activation and restored the central insulin and leptin action in an animal model of obesity, the question remains as to how IL-6 promotes these events in the hypothalamus. Following exercise, the high circulating levels of IL-6 are followed by an increase in two anti-inflammatory molecules, IL-1ra and IL-10 [25]. Therefore, IL-6 induces an anti-inflammatory environment by inducing the production of IL-1ra and IL-10. In our study, we found that exercise increased the hypothalamic levels of IL-10 but did not change IL-1ra expression in this tissue. Thus, we showed that the anti-inflammatory response mediated by IL-6 involves the increase of IL-10 expression in the hypothalamus.


IL-10 is an important immunoregulatory cytokine with multiple biological effects. In the cytoplasm, it has been demonstrated that IL-10 blocks NF-κB activity at two
levels: suppressing IKK activity and NF-κB DNA binding activity [26]. Moreover, IL-10 reduced ER stress in intestinal eptithelial cells, whereas IL-10−/− mice demonstrated that the expression of the ER stress response protein grp-78/BiP was increased in intestinal eptithelial cells under conditions of chronic inflammation [27].

In the CNS, the anti-inflammatory role of IL-10 has been extensively studied in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. The increase in IL-10 expression in the CNS during recovery from brain inflammation and the inability of IL-10 null mice to recover from acute CNS inflammation suggests that the presence of IL-10 within this target organ is required for disease remission [42],[43].




hus, the role of IL-10 in the control of food intake and energy expenditure deserves further exploration.


Hence, IL-6 and IL-10 are important physiological contributors to the central insulin and leptin action mediated by physical activity, linking it to hypothalamic ER stress and inflammation.

 

[osisposis]

The role of mast cells in allergic inflammation

http://www.sciencedirect.com/science/article/pii/S0954611111003325

 

[Seven7]

How is this even valid or relevant when is widely accepted that excercise can cause PEM in cfs after even 72H!!!!! They cannot conclude but tha WITHIN the 24h didn't make a difference, even if you go bed ridden right after that.

 

[osisposis]

low IL-10 has also been linked to fibromyalgia.

 

[MeSci]

Here's the table with the main results:
View attachment 7901

As one can see, there are some changes for fatigue and pain in the CFS group compared to the healthy controls which might reach statistical significance with a bigger sample.

Some of the standard deviations (SDs) are enormous, aren't they? Stats are my weakest point in science but I know there are some stats whizzes on here.

 

[Seven7]

@Dolphin it is legal to comment on paper or use the same data and write another paper??? Could any of us clarify the 24h period and publish something before we get detremental excercise prescribed. This is irresponsible (AND I DO EXCERCISE but I know what my AT is, and even like that I have issues and set backs).

 

[Simon]

This study provides important messages for those with MS and CFS and for health professionals involved in their care. Undertaking aerobic training on a stationary cycle for 15 minutes at a work rate sufficient to produce an HR of about 66% to 70% of the maximum age-predicted HR and an RPE of about 4 does not significantly affect pain and function in people with MS and CFS.

Think they are getting well ahead of themselves, as surely the only safe message is to researchers, that this is an interesting finding that needs replication on a bigger scale with representative patients. This ought to come before any messages about appropriate exercise regimes are put out to patients or their clinicians.

The abstract is a little better

Conclusions:

Undertaking 15 minutes of moderate-intensity aerobic cycling exercise had no significant adverse effects on pain or function in people with MS and CFS (with a Karnofsky score of 50–80) within a 24-hour time period.
These initial results suggest that people with MS or CFS may undertake 15 minutes of cycling as moderate aerobic exercise with no expected negative impact on pain or function.

However, the authors didn't cite a bigger study on MS, CFS patients and controls in response to moderate exercise, which found pain and fatigue increased at 24 hours in the CFS but not the MS group (from the Lights' stable)
Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls
Although focusing on gene expression this study - with 22 CFS, 23 MS & 23 controls - found that both pain and fatigue increased significantly over time in response to moderate exercise (c70% max heart rate, similar to the new study) and remained elevated at 48 hours in CFS patients though not in MS or controls [see figure 1]. (The study didn't measure function.)

When one sees the results, they are not as clear cut as the authors make out. At 8 patients in each cohort, I think this study was underpowered to find differences..

Yes, and the unrepresentative nature too, as you pointed out: additionally was 4 men/4women, aged 56 and BMI=29 so older, more male and more overweight than typical clinical samples.

 

[anciendaze]

There is considerable clinical recognition about the negative effects of overexertion in MS. What do they say about that? Second, do they offer any way CFS patients can tell if they are approaching anaerobic threshold? It now appears that exercise beyond this threshold is responsible for PEM. If patients have no way to avoid a threshold they cannot perceive, what use is advice?

For those who expect ME/CFS to show strong markers in terms of cytokines, I'd point out that MS generally does not offer these in a consistent and disease-specific way.

See,
Review: cytokines and the pathogenesis of multiple sclerosis

1. V. Navikas* and
2. H. Link

The cytokine abnormalities hitherto observed are not MS specific, because they can be found in other inflammatory CNS diseases, e.g., aseptic meningitis and even noninflammatory neurological diseases like stroke.

Elsewhere I've commented on the problematic nature of thresholds for laboratory measurements for autoimmune disease in the absence of clinical signs.

So, what determines a solid diagnosis of MS? We come back to clinical signs which are difficult or impossible to fake, and lesions seen on MRIs or found at autopsy. Is it possible for disease states to fall just short of these? Yes, and the way you tell is to wait for the patient to develop those clinical signs or lesions, or die unexpectedly.

 

[osisposis]

Think they are getting well ahead of themselves, as surely the only safe message is to researchers, that this is an interesting finding that needs replication on a bigger scale with representative patients. This ought to become before any message about appropriate exercise regimes are put out to patients or their clinicians.

The abstract is a little better


However, the authors didn't cite a bigger study on MS, CFS patients and controls in response to moderate exercise, which found pain and fatigue increased at 24 hours in the CFS but not the MS group (from the Lights' stable)
Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls
Although focusing on gene expression this study - with 22 CFS, 23 MS & 23 controls - found that both pain and fatigue increased significantly over time in response to moderate exercise (c70% max heart rate, similar to the new study) and remained elevated at 48 hours in CFS patients though not in MS or controls [see figure 1]. (The study didn't measure function.)


Yes, and the unrepresentative nature too, as you pointed out: additionally was 4 men/4women, aged 56 and BMI=29 so older, more male and more overweight than typical clinical samples.

 

[osisposis]

2012, Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls

Although this same study also examined gene expression of several immune markers, only the anti-inflammatory cytokine interleukin-10 (IL-10) had greater expression in CFS vs. the control group

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/

 

[user9876]

With only 8 CFS patients participating, this is an meaningless study. But these look like the sort of results you'd expect for deconditioned patients, rather than ME patients. I'd like to see the results at 48 hours, but if they are deconditioned patients, then I guess the results would be similar.

With only 8 in each group quoting the mean and SD is very dodgy at they can be very sensitive to an outlier. This may be particularly so when several in 2 groups didn't manage to do the test.