Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study

Abstract:

Introduction: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation.

Methods: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM).

Results: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not.

Conclusion: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

Source: Bourke JH, Wodehouse T, Clark LV, Constantinou E, Kidd BL, Langford R, Mehta V, White PD. Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study. J Psychosom Res. 2021 Sep 21;150:110624. doi: 10.1016/j.jpsychores.2021.110624. Epub ahead of print. PMID: 34600309. https://pubmed.ncbi.nlm.nih.gov/34600309/

Sick of the Sick Role: Narratives of What “Recovery” Means to People With CFS/ME

Abstract:

Little is known about what recovery means to those with chronic fatigue syndrome/myalgic encephalomyelitis, a poorly understood, disabling chronic health condition. To explore this issue, semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10) after a guided self-help intervention, and analyzed via “constant comparison.” The meaning of recovery differed between participants-expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the “sick role,” with functionality prioritized. Others redefined recovery, reluctant to return to the lifestyle that may have contributed to their illness, or rejected the concept as unhelpful. Recovery is not always about eliminating all symptoms. Rather, it is a nexus between the reality of limited opportunities for full recovery, yet a strong desire to leave the illness behind and regain a sense of “normality.”

Source: Cheshire A, Ridge D, Clark LV, White PD. Sick of the Sick Role: Narratives of What “Recovery” Means to People With CFS/ME. Qual Health Res. 2020 Nov 11:1049732320969395. doi: 10.1177/1049732320969395. Epub ahead of print. PMID: 33176575. https://pubmed.ncbi.nlm.nih.gov/33176575/

Patterns of Daytime Physical Activity in Patients With Chronic Fatigue Syndrome

Abstract:

Objectives: To classify patients with chronic fatigue syndrome (CFS) by pattern of physical activity and determine the clinical associations of each type.

Methods: 579 out of 641 participants with CFS from the PACE (Pacing, graded Activity, Cognitive behavioural therapy: a randomised Evaluation) trial wore an Actiwatch (accelerometer) for between 3 and 7 days before any trial treatments, which provided a measure of physical activity. Participants’ activity was categorised into one of four patterns (pervasively inactive, pervasively active, boom and bust, or indeterminate) primarily using a priori definitions of activity. Clinical associations were sought with each group using an exploratory logistic regression with the indeterminate activity group being the reference group.

Results: 124 (21%) of the participants were classified as pervasively inactive, 65 (11%) as pervasively active, 172 (30%) showed a ‘boom and bust’ pattern of activity, and 218 (38%) had an indeterminate pattern. Pervasively inactive patients were more physically disabled, those in the pervasively active group were more anxious, and those in the boom and bust group had more sleep disturbance.

Conclusion: We were able to classify patients with CFS into groups by their daytime activity pattern. The different patterns of activity were associated with important clinical variables, suggesting that they might be helpful in determining prognosis and targeting treatments. These associations need replication.

A perspective on causation of the chronic fatigue syndrome by considering its nosology

Abstract:

The causes of chronic fatigue syndrome (CFS) remain unknown, with many failures to replicate new findings. This may be because the condition is hard to diagnose, difficult to classify, or because of its heterogeneous nature. Authors have problems in differentiating CFS from myalgic encephalomyelitis (ME), which leads many to label it as a hybrid CFS/ME or ME/CFS. Attempts to validate the many published criterion-based definitions have ended in failure. The International Classification of Diseases provide several different descriptions to choose from, although the latest 11th edition has narrowed this down. This paper describes conventional attempts to define and classify the illness, suggesting that this may be what leads to a failure to replicate putative causes. The approach to CFS/ME may require a shift in the assumption that the illness is homogeneous. An alternative approach is provided by studies suggesting that the condition is heterogeneous. ‘

CONCLUSION: The way forward may be to be over-inclusive regarding the diagnosis as a first step, while subdividing the condition into likely subgroups as a means of finding valid and reliable associations with potential causes. Studies of aetiology must involve prospective designs since cross-sectional studies cannot inform either aetiology or pathophysiology.

© 2019 John Wiley & Sons, Ltd.

Source: White PD. A perspective on causation of the chronic fatigue syndrome by considering its nosology. J Eval Clin Pract. 2019 Aug 1. doi: 10.1111/jep.13240. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31373106

The international collaborative on fatigue following infection (COFFI)

Abstract:

Background: The purpose of the Collaborative on Fatigue Following Infection (COFFI) is for investigators of post-infection fatigue (PIF) and other syndromes to collaborate on these enigmatic and poorly understood conditions by studying relatively homogeneous populations with known infectious triggers. Utilising COFFI, pooled data and stored biosamples will support both epidemiological and laboratory research to better understand the etiology and risk factors for development and progression of PIF.

Methods: COFFI consists of prospective cohorts from the UK, Netherlands, Norway, USA, New Zealand and Australia, with some cohorts closed and some open to recruitment. The 9 cohorts closed to recruitment total over 3000 participants, including nearly 1000 with infectious mononucleosis (IM), > 500 with Q fever, > 800 with giardiasis, > 600 with campylobacter gastroenteritis (CG), 190 with Legionnaires disease and 60 with Ross River virus. Follow-ups have been at least 6 months and up to 10 years. All studies use the Fukuda criteria for defining chronic fatigue syndrome (CFS).

Results: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction.

Conclusions: COFFI (https://internationalcoffi.wordpress.com/) is an international collaboration which should be able to answer questions based on pooled data that are not answerable in the individual cohorts. Possible questions may include the following: Do different infections trigger different PIF syndromes (e.g. CFS vs. irritable bowel syndrome)?; What are longitudinal predictors of PIF and its severity?

Source: Ben Z Katz, Simon M Collin, Gabrielle Murphy, Rona Moss-Morris, Vegard Bruun Wyller, Knut-Arne Wensaas, Jeannine L.A. Hautvast, Chantal P Bleeker-Rovers, Ute Vollmer-Conna, Dedra Buchwald, Renée Taylor, Paul Little, Esther Crawley, Peter D White & Andrew Lloyd. The international collaborative on fatigue following infection (COFFI). Fatigue: Biomedicine, Health & Behavior Vol. 0, Iss. 0, 2018. http://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1426086?journalCode=rftg20

Response to the editorial by Dr Geraghty

Abstract:

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty’s views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Source: White PD, Chalder T, Sharpe M, Angus BJ, Baber HL, Bavinton J, Burgess M, Clark LV, Cox DL, DeCesare JC, Goldsmith KA, Johnson AL, McCrone P, Murphy G, Murphy M, O’Dowd H, Potts L, Walwyn R, Wilks D. Response to the editorial by Dr Geraghty. J Health Psychol. 2017 Aug;22(9):1113-1117. doi: 10.1177/1359105316688953. Epub 2017 Jan 24. https://www.ncbi.nlm.nih.gov/pubmed/28805524

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study

Abstract:

Chronic fatigue syndrome (CFS) is characterized by fatigue after exertion. A systematic review suggested that transforming growth factor beta (TGF-β) concentrations are often elevated in cases of CFS when compared to healthy controls. This study attempted to replicate this finding, and investigate whether post-exertional symptoms were associated with altered cytokine protein concentrations and their RNA in CFS patients. Twenty-four patients fulfilling Centers for Disease Control criteria for CFS, but with no comorbid psychiatric disorders, were recruited from two CFS clinics in London, UK. Twenty-one healthy, sedentary controls were matched by gender, age, and other variables. Circulating proteins and RNA were measured for TGF-β, TNF, IL-8, IL-6 and IL-1β.

We measured six further cytokine protein concentrations (IL-2, IL-4, IL-5, IL-10, IL-12p70, and IFN-γ). Measures were taken at rest, and before and after both commuting and aerobic exercise. CFS cases had higher TGF-β protein levels compared to controls at rest (median (quartiles) = 43.9 (19.2, 61.8) versus 18.9 (16.1, 30.0) ng/ml) (p = 0.003), and consistently so over a nine-day period. However, this was a spurious finding due to variation between different assay batches.

There were no differences between groups in changes to TGF-β protein concentrations after either commuting or exercise. All other cytokine protein and RNA levels were similar between cases and controls. Post-exertional symptoms and perceived effort were not associated with any increased cytokines. We were unable to replicate previously found elevations in circulating cytokine concentrations, suggesting that elevated circulating cytokines are not important in the pathophysiology of CFS.

This article is protected by copyright. All rights reserved.

© 2017 British Society for Immunology

Source: Clark LV, Buckland M, Murphy G, Taylor N, Vleck V, Mein C, Wozniak E, Smuk M, White PD. Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study .Clin Exp Immunol. 2017 Aug 5. doi: 10.1111/cei.13023. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28779554

Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study

Abstract:

Objective Trends in recorded diagnoses of chronic fatigue syndrome (CFS, also known as ‘myalgic encephalomyelitis’ (ME)) and fibromyalgia (FM) in the UK were last reported more than ten years ago, for the period 1990-2001. Our aim was to analyse trends in incident diagnoses of CFS/ME and FM for the period 2001-2013, and to investigate whether incidence might vary by index of multiple deprivation (IMD) score.

Design: Electronic health records cohort study.

Setting: NHS primary care practices in the UK.

Participants: Patients registered with general practices linked to the Clinical Practice Research Datalink (CPRD) primary care database from January 2001 to December 2013. Main outcome measure Incidence of CFS/ME, FM, post-viral fatigue syndrome (PVFS), and asthenia/debility.

Results: The overall annual incidence of recorded cases of CFS/ME was 14.8 (95% CI 14.5, 15.1) per 100,000 people. Overall annual incidence per 100,000 people for FM was 33.3 (32.8-33.8), for PVFS 12.2 (11.9, 12.5), and for asthenia/debility 7.0 (6.8, 7.2). Annual incidence rates for CFS/ME diagnoses decreased from 17.5 (16.1, 18.9) in 2001 to 12.6 (11.5, 13.8) in 2013 (annual percent change -2.8% (-3.6%, -2.0%)). Annual incidence rates for FM diagnoses decreased from 32.3 (30.4, 34.3) to 27.1 (25.5, 28.6) in 2007, then increased to 38.2 (36.3, 40.1) per 100,000 people in 2013. Overall annual incidence of recorded fatigue symptoms was 2246 (2242, 2250) per 100,000 people. Compared with the least deprived IMD quintile, incidence of CFS/ME in the most deprived quintile was 39% lower (incidence rate ratio (IRR) 0.61 (0.50, 0.75)), whereas rates of FM were 40% higher (IRR 1.40 (0.95, 2.06)). Conclusion: These analyses suggest a gradual decline in recorded diagnoses of CFS/ME since 2001, and an increase in diagnoses of fibromyalgia, with opposing socioeconomic patterns of lower rates of CFS/ME diagnoses in the poorest areas compared with higher rates of FM diagnoses.

 

Source: Collin SM, Bakken IJ, Nazareth I, Crawley E, White PD. Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. J R Soc Med. 2017 Jan 1:141076817702530. doi: 10.1177/0141076817702530. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28358988

 

A UK based review of recommendations regarding the management of chronic fatigue syndrome

Abstract:

OBJECTIVES: Chronic fatigue syndrome (CFS) is a controversial illness, with apparent disagreements between medical authorities and patient support organisations regarding safe and effective treatments. The aim of this study was to measure the extent of different views regarding treatments, comparing patient support organisations and medical authorities in the UK.

METHODS: Two independent raters analysed two groups of resources: UK patient support websites and both medical websites and textbooks. A 5-point Likert scale was developed with the question ‘With what strength does the source recommend these treatments?’ The various treatments were divided into the following four groups: complementary and alternative medicine (CAM), pharmacological, rehabilitative, and pacing therapies.

RESULTS: There were significant differences between the scores for patient support organisations and medical sources for all 4 treatment groups. The results for supporting CAM were 74% (patient group) vs 16% (medical source) (p<0.001), 71% vs 42% for pharmacological (p=0.01), 28% vs 94% for rehabilitative (p<0.001) and 91% vs 50% for pacing treatments (p=0.001).

CONCLUSIONS: There were substantially different treatment recommendations between patient support organisations and medical sources. Since expectations can determine response to treatment, these different views may reduce the engagement in and effectiveness of rehabilitative therapies recommended by national guidelines and supported by systematic reviews.

Copyright © 2016 Elsevier Inc. All rights reserved.

 

Source: Mallet M, King E, White PD. A UK based review of recommendations regarding the management of chronic fatigue syndrome. J Psychosom Res. 2016 Sep;88:33-5. doi: 10.1016/j.jpsychores.2016.07.008. Epub 2016 Jul 17. https://www.ncbi.nlm.nih.gov/pubmed/27521650

 

Comment

Ellen M Goudsmit 2016 Aug 16 12:55 p.m.

It should be noted that the PACE trial did not assess pacing as recommended by virtually all patient groups. This behavioural strategy is based on the observation that minimal exertion tends to exacerbate symptoms, plus the evidence that many with ME and CFS cannot gradually increase activity levels for more than a few days because of clinically significant adverse reactions [1]. It does not make any assumptions about aetiology.

The authors state that “It should be remembered that the moderate success of behavioural approaches does not imply that CFS/ME is a psychological or psychiatric disorder.” I submit that this relates to CBT and GET and not to strategies such as pacing. It might be helpful here to remind readers that the GET protocol for CFS/ME (as tested in most RCTs) is partly based on an operant conditioning theory, which is generally regarded as psychological [2]. The rehabilitative approaches promoted in the UK, i.e. CBT and GET, tend to focus on fatigue and sleep disorders, both of which may be a result of stress and psychiatric disorders e.g. depression. A review of the literature from the ‘medical authorities’ in the UK shows that almost without exception, they tend to limit the role of non-psychiatric aetiological factors to the acute phase and that somatic symptoms are usually attributed to fear of activity and the physiological effects of stress.

I informed the editor that as it read, the paper suggests that 1. patients have no sound medical source to support their preference for pacing and that 2. the data from the PACE trial provides good evidence against this strategy. I clarified that the trial actually evaluated adaptive pacing therapy (a programme including advice on stress management and a version of pacing that permits patients to operate at 70% of their estimated capability.) The editor chose not to investigate this issue in the manner one expects from an editor of a reputable journal. In light of the above issues, the information about pacing in this paper may mislead readers.

Interested scientists may find an alternative analysis of the differing views highly illuminating [3].

[1]. Goudsmit, EM., Jason, LA, Nijs, J and Wallman, KE. Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: A consensus document. Disability and Rehabilitation, 2012, 34, 13, 1140-1147. doi: 10.3109/09638288.2011.635746.]

[2]. Goudsmit, E. The PACE trial. Are graded activity and cognitive-behavioural therapy really effective treatments for ME? Online 18th March 2016. http://www.axfordsabode.org.uk/me/ME-PDF/PACE trial the flaws.pdf

[3]. Friedberg, F. Cognitive-behavior therapy: why is it so vilified in the chronic fatigue syndrome community? Fatigue: Biomedicine, Health & Behavior, 2016, 4, 3, 127-131. http://www.tandfonline.com/doi/full/10.1080/21641846.2016.1200884

Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is characterised by persistent fatigue, disability and a range of other symptoms. The PACE trial was randomised to compare four non-pharmacological treatments for patients with CFS in secondary care clinics. The aims of this sub study were to describe the use of complementary and alternative medicine (CAM) in the trial sample and to test whether CAM use correlated with an improved outcome.

METHOD: CAM use was recorded at baseline and 52weeks. Logistic and multiple regression models explored relationships between CAM use and both patient characteristics and trial outcomes.

RESULTS: At baseline, 450/640 (70%) of participants used any sort of CAM; 199/640 (31%) participants were seeing a CAM practitioner and 410/640 (64%) were taking a CAM medication. At 52weeks, those using any CAM fell to 379/589 (64%). Independent predictors of CAM use at baseline were female gender, local ME group membership, prior duration of CFS and treatment preference. At 52weeks, the associated variables were being female, local ME group membership, and not being randomised to the preferred trial arm. There were no significant associations between any CAM use and fatigue at either baseline or 52weeks. CAM use at baseline was associated with a mean (CI) difference of 4.10 (1.28, 6.91; p=0.024) increased SF36 physical function score at 52weeks, which did not reach the threshold for a clinically important difference.

CONCLUSION: CAM use is common in patients with CFS. It was not associated with any clinically important trial outcomes.

Copyright © 2016 Elsevier Inc. All rights reserved.

 

Source: Lewith G, Stuart B, Chalder T, McDermott C, White PD. Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome. J Psychosom Res. 2016 Aug;87:37-42. doi: 10.1016/j.jpsychores.2016.06.005. Epub 2016 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/27411750