 |
| Unfortunately, PACE isn't admitting anything. |
Dr. Lloyd, an immunologist associated with the University of South Wales, Australia, is a long-time proponent of exercise as the "cornerstone" of treatment for ME/CFS.
The reply by Dr. Jonathan Kerr, who is regarded as one of Britain’s foremost ME/CFS researchers and an expert in microbiology, inflammation and genetics, lays out the errors in Dr. Lloyd's endorsement of GET and CBT, not the least of which is that Lloyd's "evidence" is based entirely on a study so flawed that it should never have been published.
In the wake of the Columbia studies documenting progressive immune abnormalities in ME/CFS, and the IOM's unequivocal statement supporting the biogenesis of ME/CFS, it is clear that the proponents of psychological interventions and exercise as legitimate treatments have only one leg to stand on.
And that leg is increasingly in need of a crutch.
________________________________
The biological pathogenesis of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis
By Jonathan Kerr
The biological pathogenesis of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis
By Jonathan Kerr
This editorial (1) comes from authors from two of three CFS/ME centres whose prolific academic production in CFS/ME provides almost the sole support for a supposed psychiatric basis for the disease; these centres are Kings College London, Nijmegen Medical Centre in the Netherlands, and the University of New South Wales, Sydney, Australia. However, the scientific basis on which the treatments, Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET), are offered is critically flawed. The original PACE trial conducted by Kings College London, enrolled patients using the 1991 Oxford criteria (2), which allows inclusion of patients with affective disorders. This is in direct conflict with the internationally accepted 1994 CDC criteria which specifically excludes patients with affective disorders. This means that this study was performed using patients whose exact diagnoses are unknown. However, despite this flaw, global insurance companies do not pay sickness benefit to CFS/ME patients on the basis that effective treatments are available. Yet these interventions are not effective in CFS/ME.
CBT helps only a fraction of patients and GET has been shown to exacerbate the symptoms of patients with CFS/ME, which is logical as one of the cardinal symptoms of CFS/ME is post-exertional malaise, and so GET should not be used for CFS/ME patients. Furthermore, the Institute of Medicine in the USA has recently recommended that the name, CFS/ME, should be changed to Systemic Exercise Intolerance Disease (SEID) (3), which again reinforces the truth that exercise therapy should not be used for CFS/ME.
We know that CFS/ME can be triggered by a variety of infections, vaccines, exposure to organophosphate chemicals, and that the pathogenesis involves prolonged immune activation, which results in a flu-like illness that persists for months to years, and we all know how we feel during a flu-like illness, and there is no dispute that flu-like illnesses are caused by viruses. Several infection models have been presented which illustrate very well this progression in patients followed from the time of acute infection to development of CFS/ME. Parvovirus B19 triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*01, *04 and *07 alleles, is characterised by raised levels of circulating TNF-α and IFN-γ, and CFS/ME triggered by B19 has been cured with intravenous immunoglobulin (IVIG) which is the specific treatment for B19 infection (4). Coxiella burneti also triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*11 and certain IFN-γ polymorphisms, is associated with chronic immune activation and Q fever-associated CFS/ME is treated successfully with tetracyclines which are the specific treatment for Q fever (5). Epstein-Barr virus triggers CFS/ME, and patients with EBV-triggered CFS/ME have been successfully treated with valacyclovir (6), which is a specific treatment for EBV infection. In all of these models, the infectious agent persists long-term with chronic genomic persistence and antigen presentation, which appears to be important. The diversity of infectious triggers and individual responses likely account for the heterogeneity observed in CFS/ME, and the existence of subtypes, which are recognised to be important for the optimal management of patients.
Maybe the big breakthrough in CFS/ME comes when we are free to apply our significant existing knowledge of CFS/ME towards the best investigation and treatment of INDIVIDUAL patients, whom we know have different pathogenetic processes which account for the existence of disease subtypes. Disease subtypes are a feature of multiple chronic inflammatory autoimmune diseases and are taken into account in their management, and therefore CFS/ME is typical of such a biological disease.
References
1. Lloyd AR, Meer JW. The long wait for a breakthrough in chronic fatigue syndrome. BMJ. 2015;350:h2087. doi: 10.1136/bmj.h2087.
2. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med.1991 Feb;84(2):118-21.
3. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015
4. Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003;36(9):e100-6.
5. Sukocheva OA, Marmion BP, Storm PA, Lockhart M, Turra M, Graves S. Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens. QJM. 2010;103(11):847-63.
6. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-13.
_____________________________
Editorial
The long wait for a breakthrough in chronic fatigue syndrome
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h2087 (Published 05 May 2015) Cite this as: BMJ 2015;350:h2087
Andrew R Lloyd, professor,
Jos W M van der Meer, professor
Author affiliations
Correspondence to: A R Lloyd a.lloyd@unsw.edu.au
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.
Notes
Cite this as: BMJ 2015;350:h2087
Footnotes
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.
References
1. Van Kuppeveld FJ, van der Meer JW. XMRV and CFS—the sad end of a story. Lancet2012;379:e27-8.
2. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ2006;333:575.
3. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet2006;367:346-55.
4. Tanaka M, Ishii A, Watanabe Y. Neural mechanisms underlying chronic fatigue. Rev Neurosci2013;24:617-28.
5. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev2015;2:CD003200.
6. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ 2000;320:292-6.
7. Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health2013;53:154-65.
8. Moss-Morriss R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol2005;10:245-59.
9. Nijs J, Meeus M, Van Oosterwijck J, et al. In the mind or the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest2011;42:203-11.
10. Clark LV, White PD. The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS). J Mental Health2005;14:237-52.
11. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry2015;2:141-52.
12. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet2011;377:823-36.
13. Wiborg JF, Knoop H, Prins JB, Bleijenberg G. Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome? J Psychosom Res2011;70:306-10.
14. Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med2012;8:719-28.
15. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med2013;43:2227-35.
16. Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health2014. doi:10.1136/eb-2014-101961.
17. Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res2014;23:2407-16.
18. De Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain2008;131:2172-80.
CBT helps only a fraction of patients and GET has been shown to exacerbate the symptoms of patients with CFS/ME, which is logical as one of the cardinal symptoms of CFS/ME is post-exertional malaise, and so GET should not be used for CFS/ME patients. Furthermore, the Institute of Medicine in the USA has recently recommended that the name, CFS/ME, should be changed to Systemic Exercise Intolerance Disease (SEID) (3), which again reinforces the truth that exercise therapy should not be used for CFS/ME.
We know that CFS/ME can be triggered by a variety of infections, vaccines, exposure to organophosphate chemicals, and that the pathogenesis involves prolonged immune activation, which results in a flu-like illness that persists for months to years, and we all know how we feel during a flu-like illness, and there is no dispute that flu-like illnesses are caused by viruses. Several infection models have been presented which illustrate very well this progression in patients followed from the time of acute infection to development of CFS/ME. Parvovirus B19 triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*01, *04 and *07 alleles, is characterised by raised levels of circulating TNF-α and IFN-γ, and CFS/ME triggered by B19 has been cured with intravenous immunoglobulin (IVIG) which is the specific treatment for B19 infection (4). Coxiella burneti also triggers CFS/ME and this is predisposed to by carriage of HLA-DRB1*11 and certain IFN-γ polymorphisms, is associated with chronic immune activation and Q fever-associated CFS/ME is treated successfully with tetracyclines which are the specific treatment for Q fever (5). Epstein-Barr virus triggers CFS/ME, and patients with EBV-triggered CFS/ME have been successfully treated with valacyclovir (6), which is a specific treatment for EBV infection. In all of these models, the infectious agent persists long-term with chronic genomic persistence and antigen presentation, which appears to be important. The diversity of infectious triggers and individual responses likely account for the heterogeneity observed in CFS/ME, and the existence of subtypes, which are recognised to be important for the optimal management of patients.
Maybe the big breakthrough in CFS/ME comes when we are free to apply our significant existing knowledge of CFS/ME towards the best investigation and treatment of INDIVIDUAL patients, whom we know have different pathogenetic processes which account for the existence of disease subtypes. Disease subtypes are a feature of multiple chronic inflammatory autoimmune diseases and are taken into account in their management, and therefore CFS/ME is typical of such a biological disease.
References
1. Lloyd AR, Meer JW. The long wait for a breakthrough in chronic fatigue syndrome. BMJ. 2015;350:h2087. doi: 10.1136/bmj.h2087.
2. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med.1991 Feb;84(2):118-21.
3. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015
4. Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003;36(9):e100-6.
5. Sukocheva OA, Marmion BP, Storm PA, Lockhart M, Turra M, Graves S. Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens. QJM. 2010;103(11):847-63.
6. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-13.
_____________________________
Editorial
The long wait for a breakthrough in chronic fatigue syndrome
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h2087 (Published 05 May 2015) Cite this as: BMJ 2015;350:h2087
Andrew R Lloyd, professor,
Jos W M van der Meer, professor
Author affiliations
Correspondence to: A R Lloyd a.lloyd@unsw.edu.au
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.
Notes
Cite this as: BMJ 2015;350:h2087
Footnotes
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.
References
1. Van Kuppeveld FJ, van der Meer JW. XMRV and CFS—the sad end of a story. Lancet2012;379:e27-8.
2. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ2006;333:575.
3. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet2006;367:346-55.
4. Tanaka M, Ishii A, Watanabe Y. Neural mechanisms underlying chronic fatigue. Rev Neurosci2013;24:617-28.
5. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev2015;2:CD003200.
6. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ 2000;320:292-6.
7. Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Adolesc Health2013;53:154-65.
8. Moss-Morriss R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol2005;10:245-59.
9. Nijs J, Meeus M, Van Oosterwijck J, et al. In the mind or the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest2011;42:203-11.
10. Clark LV, White PD. The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS). J Mental Health2005;14:237-52.
11. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry2015;2:141-52.
12. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet2011;377:823-36.
13. Wiborg JF, Knoop H, Prins JB, Bleijenberg G. Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome? J Psychosom Res2011;70:306-10.
14. Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med2012;8:719-28.
15. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med2013;43:2227-35.
16. Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health2014. doi:10.1136/eb-2014-101961.
17. Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res2014;23:2407-16.
18. De Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain2008;131:2172-80.
