Intended for healthcare professionals


The long wait for a breakthrough in chronic fatigue syndrome

BMJ 2015; 350 doi: (Published 05 May 2015) Cite this as: BMJ 2015;350:h2087
  1. Andrew R Lloyd, professor1,
  2. Jos W M van der Meer, professor2
  1. 1Inflammation and Infection Research Centre, University of New South Wales, Sydney 2052, Australia
  2. 2Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
  1. Correspondence to: A R Lloyd a.lloyd{at}

Not over yet

There hasn’t been much good news for patients with the prevalent but enigmatic disorder chronic fatigue syndrome (also referred to as myalgic encephalomyelitis). Over decades, research into the pathophysiology has failed to find convincing evidence of either persistent infection or immunological, endocrine, or metabolic change, and has rejected simplistic notions of depression (typical or atypical) or primary sleep disorder. Several notable “breakthroughs” have failed independent replication. The most noteworthy is the recent rise and fall of xenotropic murine leukaemia virus related virus (XMRV) as the cause, which was ultimately established as a murine DNA laboratory contaminant.1 Similarly, an exhaustive array of randomised controlled trials seeking curative outcomes from antiviral, immunological, hormonal, antidepressant, and many other therapies have failed to show any benefit over placebo, or failed the replication test.

Where then is the progress? Firstly, there is reproducible evidence implicating certain infections as a trigger—notably, infectious mononucleosis caused by Epstein-Barr virus, but also infection with other pathogens.2 Secondly, there is clear evidence that a substantial proportion of patients have a coexisting mood disorder, and sometimes a sleep-wake disorder, and that these conditions may exacerbate or perpetuate the illness.3 Thirdly, independent studies using both structural and functional imaging techniques have identified alterations in the brains of patients with chronic fatigue syndrome, implicating the central nervous system as the site of pathophysiology.4 Fourthly, there is solid evidence from multiple controlled studies that patients can gain control of symptoms and functional improvement through multidisciplinary interventions incorporating graded exercise therapy and cognitive behavioural therapy. These interventions have clearly positive outcomes in systematic reviews and meta-analyses.5 6 7 For instance, the recent Cochrane review of graded exercise therapy5 states that “patients with CFS [chronic fatigue syndrome] may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed.”

How therapy works

Plausibly, graded exercise may reverse a perpetuator in the form of physical deconditioning. However, there is little evidence for loss of aerobic fitness in patients with chronic fatigue syndrome, and limited evidence for improved physical performance after successful graded exercise therapy.8 Instead, graded exercise has been proposed to act by desensitising an exaggerated central nervous system response to the physiological signals associated with exercise.9 In psychological terms, patients may avoid activity because of the prolonged exacerbation of symptoms that follows minor physical activity; this leads to an understandable conclusion that exercise is harmful or to a conditioned fear of such activity.10 In this respect, the recent mediation analysis of the outcomes of the PACE trial is of interest.11 This trial compared standard medical care, cognitive behavioural therapy, graded exercise, and adaptive pacing therapy, concluding that both cognitive behavioural and graded exercise therapy were more effective at reducing fatigue and improving physical disability than standard care or adaptive pacing.12 The mediation analysis suggested that both cognitive behavioural therapy and graded exercise worked by reducing avoidance of activity. This is broadly consistent with findings by others,13 although whether the effect simply relates to the behavioural change itself (that is, exercise) or reconditioning of the associated fear of activity remains unclear. In addition, a substantial proportion of patients do not avoid activity but have repeated boom-bust cycles of overactivity when feeling relatively well (the boom) followed by reduced activity when symptoms are exacerbated thereafter (the bust). These data argue for a personalised approach to both therapies.

Cognitive behavioural therapy for patients with chronic fatigue syndrome is based on the premise that inappropriate cognitive attributions (thinking patterns) and behaviours help perpetuate symptoms. It seeks to alter these attributions and modify the associated behaviour, targeting activity patterns and sleep-wake behaviours. For example, although primary sleep disorders do not explain chronic fatigue syndrome,14 patients typically report that their night-time sleep is unrefreshing, and as fatigue is the dominant symptom, patients may consider that increased sleep will relieve symptoms and aid recovery. This idea commonly leads to frequent daytime naps and a delayed sleep-wake cycle.

Prospects for cure

There has been recent contention about the possibility of cure after graded exercise and cognitive behavioural therapy. An analysis of the PACE trial suggested cure was possible, but recovery outcomes were defined post hoc using population norms with generous thresholds (such as the population mean plus one standard deviation for self reported fatigue).15 This analysis was criticised because of the limited assessments and less than full restoration of health,16 leading to a recommendation that trials use more accurate outcomes (such as clinically relevant improvement) defined in advance and capturing a broad based return to health with assessments of fatigue and function. Trialists must also consider patients’ perceptions of their recovery.17 In this context, the increase in volume of grey matter associated with clinical response to cognitive behavioural therapy, as reported in one study, needs further investigation.18 Even with the unduly liberal designation of recovery, less than one quarter of patients “recovered” in the PACE trial.

What then of the long awaited breakthrough? As is often the case in medical research, progress is predominantly made in modest increments not breakthroughs. The evidence for graded exercise and cognitive behavioural therapy is already clear, so this treatment should be made widely available. The next increments are to find ways to increase the symptom relief and functional improvement achieved by these treatments and to identify factors predicting clinically relevant improvement and non-response in order to increase the proportion of patients who benefit.


Cite this as: BMJ 2015;350:h2087


  • Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Commissioned; not externally peer reviewed.


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