Sex differences in post-exercise fatigue and function in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

To assess biobehavioral sex differences in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) utilizing a low burden exercise protocol, 22 females and 15 males with ME/CFS and 14 healthy controls underwent two six-min walk tests.

Fifteen daily assessments were scheduled for fatigue and function ratings and heart monitoring. Six-min walk tests were conducted on days 8 and 9. The ME/CFS group showed high self-report fatigue and impaired physical function, whereas healthy controls did not show fatigue or function abnormalities.

In patients, no significant post-exercise changes were found for heart rate variability (HRV); however, heart rate decreased in ME/CFS males from Day 14 to Day 15 (p = 0.046). Female patients showed increased fatigue (p = 0.006) after the initial walk test, but a downward slope (p = 0.008) in fatigue following the second walk test. Male patients showed a decrease in self-report work limitation in the days after exercise (p = 0.046). The healthy control group evidenced a decrease in HRV after the walk tests from Day 9-14 (p = 0.038).

This pilot study did not confirm hypotheses that females as compared to males would show slower exercise recovery on autonomic or self-report (e.g. fatigue) measures. A more exertion-sensitive test may be required to document prolonged post-exertional abnormalities in ME/CFS.

Trial registration: NCT NCT03331419.

Source: Friedberg F, Adamowicz JL, Bruckenthal P, Milazzo M, Ramjan S, Zhang X, Yang J. Sex differences in post-exercise fatigue and function in myalgic encephalomyelitis/chronic fatigue syndrome. Sci Rep. 2023 Apr 3;13(1):5442. doi: 10.1038/s41598-023-32581-w. PMID: 37012343. https://www.nature.com/articles/s41598-023-32581-w (Full text)

Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunction

Abstract:

Objective: To test a model of non-improvement in chronic fatigue syndrome (CFS) utilizing self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined.

Methods: This prospective study in CFS collected all data remotely, including six months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, six months of weekly heart monitoring and three months of daily waking actigraphy data were collected. Improvement or non-improvement status was assessed using semi-structured interviews at 6 months follow-up.

Results: 148 individuals (87.2% female) were enrolled and 12.2% were lost to follow-up. Participants reporting non-improvement (n = 92), as compared to improvement (n = 38) showed greater autonomic dysfunction (lower heart rate variability [HRV], group difference = 5.93 (SE = 2.73) ms; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 (SE = 0.16); p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing.

Conclusions: This study provided evidence for linking patient-reported non-improvement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS.

Source: Friedberg F, Adamowicz JL, Bruckenthal P, Milazzo M, Ramjan S, Quintana D. Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunction. Psychosom Med. 2022 Apr 15. doi: 10.1097/PSY.0000000000001082. Epub ahead of print. PMID: 35420586. https://pubmed.ncbi.nlm.nih.gov/35420586/

Hydrogen water as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome: a pilot randomized trial

Abstract:

Background: Given the absence of effective medical treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the testing of a new intervention that may ameliorate potentially pathologic levels of oxidative stress, sympathetic arousal, and inflammation may yield symptomatic improvements.

Objective: To explore in a pilot study, the possible beneficial effect of molecular hydrogen (H2) for the symptoms and functional limitations of ME/CFS.

Methods: Twenty-three subjects were randomized to H2 or active placebo which involved drinking up to five glasses daily of hydrogen-enriched water or placebo water for 28 days. Assessments included: (i) self-report fatigue, physical function, and stress; (ii) salivary C-Reactive Protein (inflammation), Uric Acid (antioxidant status), and Alpha-Amylase (sympathetic function); and (iii) heart rate variability (parasympathetic activity). Data were analysed with Wilcoxon rank-sum tests.

Results: Completion rate for the primary outcome measure of fatigue severity was 100% for the 11 hydrogen participants and 91.7% (n = 11) for placebo participants. No significant changes were found on self-report or biological variables in the active vs. placebo treatment conditions. A small, but significant reduction in fatigue was found in the placebo condition. Adverse effects led to treatment discontinuation in 27.2% of H2 subjects. All severe- and moderate-intensity effects were found in the active treatment condition. Adverse effects were not significantly associated with any demographic or symptom variable.

Conclusions: Therapeutic molecular hydrogen did not yield improvement on any biological or symptom measure in individuals with ME/CFS. Dosage reduction might benefit any future trial of hydrogen therapy in this illness.

Source: Fred Friedberg & Dennis Choi (2022) Hydrogen water as a treatment for myalgic encephalomyelitis/chronic fatigue syndrome: a pilot randomized trial, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2022.2038519

Legitimizing myalgic encephalomyelitis/chronic fatigue syndrome: Indications of change over a decade

Abstract:

This commentary identifies recent scientific and clinical milestones that appear to have increased legitimization of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These milestones include government-funded reports recognizing the seriousness of ME/CFS, new initiatives for biomedical research sponsored by the US National Institutes of Health, official endorsement of the ME/CFS name, publication of practitioner primers, and the launch of a new peer-review fatigue journal. These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.

Source: Fred Friedberg (2020) Legitimizing myalgic encephalomyelitis/chronic fatigue syndrome: indications of change over a decade, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2020.1718292

Rethinking the Standard of Care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

For over two decades, the standard of care for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been cognitive behavior therapy (CBT) and graded exercise therapy (GET). Both interventions had been recommended by the US Centers for Disease Control and the UK NICE guidelines. Behavioral intervention as the clinical standard was given a considerable boost by the 5 million–pound PACE trial, a large multi-arm randomized trial of CBT and GET launched in 2007. This British government–funded trial was intended to definitively answer whether such interventions were beneficial in ME/CFS. In their 2011 and 2013 publications, the PACE trial authors announced with widespread publicity that 22% of their patients had “recovered” and 59–61% had clinically improved across the CBT and GET interventions.

Read the rest of this article here.

Source: Friedberg, F., Sunnquist, M. & Nacul, L. J GEN INTERN MED (2019). https://doi.org/10.1007/s11606-019-05375-y https://link.springer.com/article/10.1007%2Fs11606-019-05375-y

Defining recovery in chronic fatigue syndrome: a critical review

Abstract:

PURPOSE: In chronic fatigue syndrome (CFS), the lack of consensus on how recovery should be defined or interpreted has generated controversy and confusion. The purpose of this paper was to systematically review, compare, and evaluate the definitions of recovery reported in the CFS literature and to make recommendations about the scope of recovery assessments.

METHODS: A search was done using the MEDLINE, PubMed, PsycINFO, CINAHL, and Cochrane databases for peer review papers that contained the search terms “chronic fatigue syndrome” and “recovery,” “reversal,” “remission,” and/or “treatment response.”

RESULTS: From the 22 extracted studies, recovery was operationally defined by reference with one or more of these domains: (1) pre-morbid functioning; (2) both fatigue and function; (3) fatigue (or related symptoms) alone; (4) function alone; and/or (5) brief global assessment. Almost all of the studies measuring recovery in CFS did so differently. The brief global assessment was the most common outcome measure used to define recovery. Estimates of recovery ranged from 0 to 66 % in intervention studies and 2.6 to 62 % in naturalistic studies.

CONCLUSIONS: Given that the term “recovery” was often based on limited assessments and less than full restoration of health, other more precise and accurate labels (e.g., clinically significant improvement) may be more appropriate and informative. In keeping with common understandings of the term recovery, we recommend a consistent definition that captures a broad-based return to health with assessments of both fatigue and function as well as the patient’s perceptions of his/her recovery status.

Comment in:

 

Source: Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 Nov;23(9):2407-16. doi: 10.1007/s11136-014-0705-9. Epub 2014 May 3. https://www.ncbi.nlm.nih.gov/pubmed/24791749

 

Comments

Frank Twisk 2014 Jul 01 11:41 a.m.
A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Jun 17. doi: 10.1007/s11136-014-0737-1. Twisk FNM.

Abstract

Introduction

Adamowicz and colleagues recently proposed to use “a consistent definition of recovery that captures a broad-based return to health with assessments of both fatigue and function as well as the patients’ perceptions of his/her recovery status” for patients with chronic fatigue syndrome (CFS).

Methods

A qualitative analysis of case definitions for Myalgic encephalomyelitis (ME) and CFS and methods to assess the symptoms and clinical status of ME and CFS patients objectively.

Results

The criteria of CFS define a heterogeneous disorder. ME, often used interchangeably with CFS, is principally defined by muscle weakness, cognitive impairment etc., but above all post-exertional “malaise”: a long-lasting increase in symptoms, e.g. muscle pain and cognitive deficits, after a minor exertion.

The principle symptom of CFS however is “chronic fatigue”. Since post-exertional “malaise” is not obligatory for CFS, only part of the CFS patients meet the diagnostic criteria for ME, while not all ME patients qualify as CFS patients.

There are several accepted methods to assess characteristic symptoms and the clinical status of ME and CFS patients using objective measures, e.g. (repeated) cardiopulmonary exercise tests.

Conclusion

To resolve the debate about the clinical status, proposed effectiveness of therapies and recovery in ME and CFS, it is crucial to accurately diagnose patients using well-defined criteria for ME and CFS and an objective assessment of various typical symptoms, since subjective measures such as “fatigue” will perpetuate the debate.

Comment by Joan Crawford 2014 Jun 04 10:04 a.m. 
Part 2

I’d have liked to have seen this article proposing solid, objective measures be used in the future – ones that have face validity with patients and doctors. Moreover, future trials need to decide if the researchers are aiming at recovery from ill health to as near/close to pre-morbid health (as in like how you’d recover from a severe, debilitating infection) or if they are aim at improving functioning/quality of life as a goal in its own right. This difference ideally should be clearly identified.

The omission of the obvious mathematical/statistical flaws with the use of SF36 PF scale was notable. They miss that using 1SD below mean is not an OK thing to do to compare HC and patients. Doing this is a statistical nonsense. The HC data is massively skewed with a ceiling effect. The bulk of HCs score the max score of 100. (Bowling, 1999, Figure 1). The HC data is not normally distributed so using the mean is not terribly helpful here when comparing and setting standards for recovery. I think using the mode (the value that appears most often in the data sets) would be much more meaningful in this context. Similar will be true of the fatigue scores. There was also no mention of the lowering of the SF36 PF scale outcome measure cut off level in the PACE trial (White et al., 2011). There may well be good reasons for doing so but there was no critical review as to whether the reasons given by White et al were good enough to justify the changes between the proposed pre-trial paper measures (White et al 2007) and the final Lancet one. I notice that White was a co-author of the Knoop (2007) paper that selected a SF36 PF score of -1SD as recovered but in a later trial (White et al., 2011) this was reduced to 60 (-2SD). This is quite a leap by the same investigator.

I particularly do not like their pathologisation/speculation of the role of pre-morbid patient functioning. Action prone nonsense. No one can or are they ever likely to prove objectively that pwME/CFS were overactive/overambitious/action prone before getting ill. I hear people mourning the loss of activities, relationships and careers they cherished and enjoyed immensely. So now they cannot even talk about their pre-illness time without feeling psychologised? To not take a more critical view of this is a real let down for me. It’s subjective, speculative nonsense that is unprovable. Patients have a right to get annoyed when they are psychologised in this manner. It should be rather obvious that patients have ex-work colleagues and friends who worked as hard (or harder, longer, faster) than them who are still employed, with families, fit and well with fulfilling lives. PwME/CFS cannot do this because they are sick. Not because they overdid it a bit. That is burnout, not ME/CFS. I thought it remiss to not see the other side regarding how the impact of this speculation might affect patients. Moreover, there are plenty of not especially ambitious, couch potatoes who are ill!

How recovery in ME/CFS is operationalised in the future requires more critical thought and this must take into account how the patients define recovery and must be able to be demonstrated objectively (Haywood et al., 2011).

References:

Anthony, W. A. (1993) Recovery from mental illness: the guiding vision of the mental health service system in the 1990s. Psychosocial Rehabilitation Journal, 16, 11-23.

Bowling A., Bond, M., Jenkinson, C., & Lamping, D.L. (1999). Short Form 36 (SF-36) Health Survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. Journal of Public Health Medicine. 21(3):255-70.

Haywood, K.L., Staniszewska, S., & Chapman, S. (2011). Quality and acceptability of patient-reported outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): A systematic review. Quality of Life Research, In press.

Knoop, H., Bleijenberg, G., Gielissen, M. F. M., van der Meer, J.W. M., & White, P. D. (2007). Is a full recovery possible after cognitive behavioral therapy for chronic fatigue syndrome? Psychotherapy and Psychosomatics, 76, 171–176.

Lester, H., & Gask, L. (2006). Delivering medical care for patients with serious mental illness or promoting a collaborative model of recovery. British Journal of Psychiatry, 188, 401–402.

White, P.D., Sharpe, M.C., Chalder, T., DeCesare, J.C., Walwyn, R; on behalf of the PACE trial group. (2007). Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BioMed Cent Neurology, 7:6.

White, P.D., Goldsmith, K.A., Johnson, A.L., Potts, L., Walwyn, R., DeCesare, J.C., et al. (2011). Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomised trial. Lancet, 5, 377(9768), 823-836.
Comment by Joan Crawford 2014 Jun 04 10:01 a.m.edited 
Part 1

This paper has a great description of the differences between ‘recovery’ versus ‘adaptation/feeling better’. As a patient I describe this as the difference between ‘feeling better’ and ‘being better’ (i.e. recovered to point comparable with pre-existing health given age increase with ability to return to work/social life without the presence of limiting symptoms). These things appear to get muddled in many clinical trials. I suspect anyone feeling poorly will feel a bit or a lot better after a psychological intervention with a concerned, empathic individual, however, whether this has any impact on their underlying condition or activity levels needs to be shown by objective measures.

It was a disappointment that in this paper there was no push for more objective measures of patient functioning to be used in future research work. For example, pedometers, actigraphy, neuropsychological tests, 2 day exercise testing (if well enough at baseline), using simple dynamometers taking readings over 2 days, return to work/school (or ability to do if the person wished), move from incapacity/sickness welfare payments to job seeking benefits and so on. I’m perplexed when researchers claim that patients are recovered if they continue to receive incapacity/ill health payments. Perhaps in this condition it might be worth measuring whether saliva cortisol levels and NK cell functioning normalise. At a push even the simple 6 minute walking test could be helpful. Objective measures need not be expensive. Simple, reliable and cheap equipment such as pedometers are available for around $30 and can show really well if a patient who is doing better over time. This could be used quite simply to get around the issue of is the patient feeling better because they are actually doing less that is discussed in the review. It’s a shame that straightforward solutions like this were not suggested.

Within the paper the authors refer to Lester & Gask (2006), which includes a popular definition of recovery from within mental health context by William Anthony as: “‘a way of living a satisfying, hopeful and contributing life even with the limitations caused by illness. Recovery involves the development of a new meaning and purpose in one’s life as one grows beyond the catastrophic effects of mental illness’ (Antony, 1993: p. 21). I had not seen this definition before for recovery so it was educating to be made aware that this was a widely used concept. To me that defines adaptation, not recovery. I would not be happy with researchers who decided that that was a good place to start defining recovery from ME/CFS. I’d want the goal to be at a minimum to not feel ill or sick or debilitated and able to be free of disease symptoms and normal functioning for the patient for their age.

References and Part 2 above

Chronic fatigue self-management in primary care: a randomized trial

Abstract:

OBJECTIVE: To assess the efficacy of brief fatigue self-management (FSM) for medically unexplained chronic fatigue (UCF) and chronic fatigue syndrome (CFS) in primary care.

METHODS: A randomized controlled design was used wherein 111 patients with UCF or CFS were randomly assigned to two sessions of FSM, two sessions of symptom monitoring support (attention control; AC), or a usual care control condition (UC). Participants were assessed at baseline and at 3 and 12 months after treatment. The primary outcome, the Fatigue Severity Scale, measured fatigue impact on functioning. Analysis was by intention to treat (multiple imputation) and also by per protocol.

RESULTS: A group × time interaction across the 15-month trial showed significantly greater reductions in fatigue impact in the FSM group in comparison with the AC group (p < .023) and the UC group (p < .013). Medium effect sizes for reduced fatigue impact in the FSM group were found in comparison with the AC group (d = 0.46) and the UC group (d = 0.40). The per-protocol analysis revealed large effect sizes for the same comparisons. Clinically significant decreases in fatigue impact were found for 53% of participants in the FSM condition, 14% in the AC condition, and 17% in the UC condition. Dropout rates at the 12-month follow-up were high (42%-53%), perhaps attributable to the burden of monthly telephone calls to assess health care use.

CONCLUSION: A brief self-management intervention for patients with UCF or CFS seemed to be clinically effective for reducing the impact of fatigue on functioning.

Trial Registration clinicaltrials.gov Identifier: NCT00997451.

 

Source: Friedberg F, Napoli A, Coronel J, Adamowicz J, Seva V, Caikauskaite I, Ngan MC, Chang J, Meng H. Chronic fatigue self-management in primary care: a randomized trial. Psychosom Med. 2013 Sep;75(7):650-7. doi: 10.1097/PSY.0b013e31829dbed4. Epub 2013 Aug 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785003/ (Full article)

 

Chronic fatigue syndrome, fibromyalgia, and related illnesses: a clinical model of assessment and intervention

Abstract:

A clinically informative behavioral literature on chronic fatigue syndrome (CFS) and fibromyalgia (FM) has emerged over the past decade. The purpose of this article is to (a) define these conditions and their less severe counterparts, i.e., unexplained chronic fatigue (UCF) and chronic widespread pain; (b) briefly review the behavioral theory and intervention literature on CFS and FM; and (c) describe a user-friendly clinical model of assessment and intervention for these illnesses. The assessments described will facilitate understanding of the somewhat unusual and puzzling somatic presentations that characterize these patients. Using an individualized cognitive-behavioral approach the mental health clinician can offer significant help to these often stigmatized and medically underserved patients.

(c) 2010 Wiley Periodicals, Inc.

 

Source: Friedberg F. Chronic fatigue syndrome, fibromyalgia, and related illnesses: a clinical model of assessment and intervention. J Clin Psychol. 2010 Jun;66(6):641-65. doi: 10.1002/jclp.20676. https://www.ncbi.nlm.nih.gov/pubmed/20186721

 

Activity Logs as a Measure of Daily Activity Among Patients with Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Self-report data collected through interviews has been one of the primary ways of assessing symptoms of patients with chronic fatigue syndrome (CFS). An alternative way to collect data involves activity logs, which involves patients writing down the pattern, intensity, and qualitative nature of activity over several days.

AIMS: We examined the associations between activity, evaluation of activity and symptoms.

METHODS: Activity log data over a two day period of time were used in the present study using a sample of patients with diagnosed CFS.

RESULTS: Findings indicated that the percent of time spent feeling fatigued was positively associated with a higher percent of time in pain and doing activities that were fatiguing. However, time spent in meaningful activities was associated with less fatigue.

CONCLUSIONS: These findings and others suggest that activity logs can provide investigators and clinicians with valuable sources of data for understanding patterns of behavior and activity among patients with CFS.

 

Source: Jason LA, Timpo P, Porter N, Herrington J, Brown M, Torres-Harding S, Friedberg F. Activity Logs as a Measure of Daily Activity Among Patients with Chronic Fatigue Syndrome. J Ment Health. 2009 Dec;18(6). Doi: 10.3109/09638230903191249. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821173/ (Full article)

 

Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity?

Abstract:

This multiple case study of cognitive-behavioral treatment (CBT) for chronic fatigue syndrome (CFS) compared self-report and behavioral outcomes. Eleven relatively high-functioning participants with CFS received 6-32 sessions of outpatient graded-activity oriented CBT.

Self-report outcomes included measures of fatigue impact, physical function, depression, anxiety, and global change. Behavioral outcomes included actigraphy and the 6-minute walking test. Global change ratings were very much improved (n=2), much improved (n=2), improved (n=5), and no change (n=2).

Of those reporting improvement, clinically significant actigraphy increases (n=3) and decreases (n=4) were found, as well as no significant change (n=2). The nature of clinical improvement in CBT trials for high-functioning CFS patients may be more ambiguous than that postulated by the cognitive-behavioral model.

 

Source: Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Apr;65(4):423-42. doi: 10.1002/jclp.20551. https://www.ncbi.nlm.nih.gov/pubmed/19213007