Source: The Lancet Vol, 367, #9507, pp 346-355 Date: January 28, 2006 URL: http://www.sciencedirect.com/science/journal/01406736 http://www.thelancet.com/journals/lancet/article/PIIS0140673606680732/fulltext Chronic fatigue syndrome ------------------------ Judith B Prins(a,*), Jos WM van der Meer(b) and Gijs Bleijenberg (c) a Department of Medical Psychology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands b Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands c Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands * Corresponding Author InformationCorrespondence to: Dr Judith B Prins, Radboud University Nijmegen Medical Centre, 840 Department of Medical Psychology, PO Box 9101, 6500 HB Nijmegen, Netherlands Summary During the past two decades, there has been heated debate about chronic fatigue syndrome (CFS) among researchers, practitioners, and patients. Few illnesses have been discussed so extensively. The existence of the disorder has been questioned, its underlying pathophysiology debated, and an effective treatment opposed; patients' organisations have participated in scientific discussions. In this review, we look back on several controversies over CFS with respect to its definition, diagnosis, pathophysiology, and treatment. We review issues of epidemiology and clinical manifestations, focusing on the scientific status of CFS. Modern neuroscience and genetics research offer interesting findings for new hypotheses on the aetiology and pathogenesis of the illness. We also discuss promising future issues, such as psychopathophysiology and mechanisms of improvement, and suggest multidisciplinary prospective studies of CFS and fatigue in the general population. These studies should pay particular attention to similarities to and differences from functional somatic syndromes and other fatiguing conditions. Chronic fatigue syndrome (CFS) is the term that is generally accepted by scientists and mostly by clinicians for the range of complaints that patients commonly refer to as myalgic encephalomyelitis (ME) or chronic fatigue and immune dysfunction syndrome. CFS is characterised by persistent and unexplained fatigue resulting in severe impairment in daily functioning. Sporadic CFS-like cases and epidemics were described first in the 19th and 20th centuries,1 but interest in CFS increased in the early 1980s with the advent of ME, a term that had been introduced 30 years earlier for an epidemic of neurological symptoms among staff at the Royal Free Hospital in London, UK. In the illness ME, apart from neurological symptoms, chronic fatigue was a main symptom. Initially, comparisons with neurasthenia were made,2 and a possible role of viruses and other microorganisms was examined.3-6 In the absence of a recognisable cause, ME was referred to as a psychiatric disorder7 or a 20th-century illness. Controversial views about the dichotomy of organic versus functional were presented.8 Since then, practitioners have disagreed on whether the illness really exists.9 Researchers, practitioners, and patients have not been able to agree on the name (ME or CFS), on case definitions, on the acceptability of diagnosing CFS as an illness, on the absence of underlying pathophysiology and the need to continue research in somatic causes, or on the effectiveness of cognitive behaviour therapy (CBT). All these issues are discussed here, including those of epidemiology, clinical manifestations, and management of CFS. We also look forward to future studies resulting from a few promising hypotheses. Definitions The first studies of CFS were limited by the lack of proper diagnostic features and definitions. From 1988 onwards, several case definitions of CFS were developed.10-12 In 1994, a consensus was reached on a revised case definition from the US Centers for Disease Control and Prevention13 (panel). The importance of criteria on non-specific accompanying symptoms has been questioned, since the number of additional symptoms depends strongly on the assessment method used and no differences have been found in fatigue severity between patients whose disease met the criteria and those whose disease did not.14-16 The CFS definition was shown to lack specificity by comparison of groups of patients who met the case definition but had different symptom severities.17 Also, heterogeneity has been found within samples of patients with chronic fatigue.18 Between 2000 and 2002, international experts joined forces and identified ambiguities in the case definition for CFS. Guidelines for systematic and uniform case ascertainment and specific instruments for classification were developed to resolve ambiguities.19 In 2003, another case definition was proposed in an attempt to exclude psychiatric cases.20 Although they differ, all case definitions select severely fatigued groups of patients. Since CFS is neither a distinct nosological disorder nor a discrete diagnostic entity, the main purpose of a case definition is to identify patients who are at the tail end of the dimension fatiguing illness. The most widely supported scientific case definition is the 1994 definition from the US Centers for Disease Control and Prevention, which is now considered the standard.13 ----------------------------------------------------------------------------- Panel: 1994 case definition for CFS from US Centers for Disease Control and Prevention Characterised by persistent or relapsing unexplained chronic fatigue * Fatigue lasts for at least 6 months * Fatigue is of new or definite onset * Fatigue is not the result of an organic disease or of continuing exertion * Fatigue is not alleviated by rest * Fatigue results in a substantial reduction in previous occupational, educational, social, and personal activities * Four or more of the following symptoms, concurrently present for ⩾6 months: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, pain in several joints, new headaches, unrefreshing sleep, or malaise after exertion Exclusion criteria * Medical condition explaining fatigue * Major depressive disorder (psychotic features) or bipolar disorder * Schizophrenia, dementia, or delusional disorder * Anorexia nervosa, bullaemia nervosa * Alcohol or substance abuse * Severe obesity ----------------------------------------------------------------------------- The main remaining problem for practitioners is the descriptive character of the definition. In all CFS case definitions, the illness is identified by means of symptoms, disability, and exclusion of explanatory illnesses, and not by means of physical signs or abnormalities in laboratory test results. Although descriptive definitions are common for psychiatric disorders, many practitioners feel uncomfortable using them as a sole method for diagnosis of somatic complaints. Consequently, there is a need for discussion among practitioners and researchers, and the difficulty of definition has never really been resolved. One thing the scientists agreed on was naming the illness CFS, whereas patients and practitioners preferred ME. Patients were reluctant to use CFS, because in the WHO 1992 classification, neurasthenia, which was associated with CFS, was linked to psychiatry and postviral fatigue syndrome (benign myalgic encephalomyelitis) was linked to neurology, although the descriptions of the two disorders were identical.21 During the past few years, the UK collaborating centre of the WHO Guide to Mental Health in Primary Care unified CFS and ME in a single psychiatric code. However, the WHO did not permit dual classification of the same disorder; ME remained classified as a neurological disorder and patients' organisations adopted the name CFS/ME. To resolve the difficulties related to the definition of CFS, the consensus criteria should be validated by study of cohorts of patients with the disorder in several countries in the near future. Epidemiology and prognosis The difficulties with definition have affected the results of epidemiological studies. Prevalence varies widely. For this reason, only studies using the 1994 case definition of the Centers for Disease Control and Prevention have been reviewed. Two US community-based CFS studies found prevalences among adults of 0.23% and 0.42%; the rates were higher in women, members of minority groups, and people with lower educational attainment and occupational status.22,23 A prospective primary-care study in the UK found a CFS rate of 2.6%. After exclusion of patients with comorbid psychological disorders, the prevalence is 0.50%,24 a rate similar to those in the community-based studies, which did not exclude such cases. The reason why rates from the two countries differ is not clear. Two studies22,25 have found incidences of 0.18% and 0.37%, which seem high. However, owing to differences in study methods, they cannot be compared with the prevalences mentioned above. The estimated prevalence of CFS is much lower among children and adolescents than among adults.26-28 A recent systematic review of the prognosis of CFS showed that full recovery without treatment is rare.29 Most prognostic studies were done in specialist centres with a bias towards severe cases. The duration of follow-up of prognostic studies ranged from 1 year to 5 years. The median recovery rate was 5% (range 0-31%) and the median improvement rate 39.5% (range 8-63). A better outcome was predicted by less severe fatigue at baseline and the patient's not attributing the illness to physical causes, whereas psychiatric disorder predicted poorer outcomes. Demographic data show that in most studies 75% or more of patients with CFS are female. The mean age at onset of CFS is between 29 years and 35 years. The mean illness duration ranges from 3 years to 9 years.29 Few reliable and valid epidemiological data on CFS are available. Future epidemiological studies should focus on both the incidence and prevalence of CFS in the general population. Clinical manifestations The main complaint of patients with CFS is persistent severe fatigue, but most have many concomitant symptoms and, in some, complaints of pain and cognitive dysfunction are just as prominent as the fatigue. Unprompted, patients mention an average of eight complaints and report symptoms of myalgia, impaired memory or concentration, gastrointestinal problems, headaches, and pain in muscles or several joints.30 Dizziness, nausea, anorexia, and night sweats are also reported.31 Many patients, especially those presenting to tertiary care, report an acute onset of symptoms after an infectious illness.5,32,33 In nearly all cases, the symptoms have resulted in substantial reduction in previous degrees of occupational, educational, social, and personal activities.34 Symptom characteristics differ between individuals diagnosed as having CFS and those with CFS in the general population.35 In the general population, the onset of fatigue is gradual in most individuals with CFS. Patients with tender lymph nodes and a sore throat were more likely to see a physician than those without these symptoms and might be over-represented in clinic-based studies. In studies comparing patients with CFS and distinct control groups, psychiatric, especially depressive, disorders are found in a minority of patients with CFS.9,36 Discussions about the prevalence of psychiatric disorders in CFS have been obscured by differing CFS case definitions, instruments for psychiatric disorders, and settings in which patients were seen, and an overlap between CFS symptoms and psychiatric disorders such as depression. These differences have resulted in overdiagnosis and underdiagnosis of psychiatric disorders. Despite these methodological and definition difficulties, Wessely and colleagues9 compared a large number of studies and concluded that there is abundant evidence for an association between CFS and psychiatric disorders, most commonly depressive disorders. Several possible explanations have been given, such as misdiagnosis of CFS as a psychiatric disorder or the reverse, comorbidity in the onset of both diagnoses, and psychological symptoms as a normal reaction to physical illness.9 This view has been contradicted by findings that CFS and depression differ. Depression cannot be included in a model of perpetuating factors.37 In treatment studies, antidepressants have turned out to be ineffective for CFS,38,39 and CBT is effective whether or not psychiatric disorders are present.36 Aetiology Many studies have investigated the aetiology and pathogenesis of CFS. More than half of the CFS studies between 1980 and 1995 concentrated on the physical aetiology of CFS, with a slight shift towards psychological and psychiatric research in the next few years.40 Many somatic and psychosocial hypotheses on the aetiology of CFS have been explored. Explanations for CFS were sought in viral infections, immune dysfunction, neuroendocrine responses, dysfunction of the central nervous system, muscle structure, exercise capacity, sleep patterns, genetic constitution, personality, and (neuro)psychological processes. Although several studies found abnormalities, only a few were diagnosed in large groups of patients with CFS and were independently confirmed in well-controlled studies, an exception being the subtle changes in the hypothalamopituitary-adrenal axis.41 The aetiology and pathogenesis are generally believed to be multifactorial.42 Distinction between categories of predisposing, precipitating, and perpetuating factors is useful for understanding of this complex disorder (figure). The assumption is that one or more factors of each of these categories is conditional but insufficient for development of CFS.43-47 Figure. 4P model Predisposing factors ------> Precipitating factors | | <--------+ V <------+ | CFS | | | | Perpetuating factors------------------------------+ | Prognostic factors --------------------------------+ Predisposing factors Personality and lifestyle are presumed to influence vulnerability to CFS. In a review of personality characteristics, neuroticism and introversion have been reported as risk factors for the disorder.48 Inactivity in childhood and inactivity after infectious mononucleosis have been found to increase the risk of CFS in adults.47,49 Genetics might have a role too, since women are more prone to CFS than men. Twin studies have shown a familial predisposition, but no genetic abnormalities have been found.50-52 Smith and colleagues' study,53 not in twins, found that CFS might be associated with HLA DQA1*01, but this finding must be confirmed in a large independent cohort. Precipitating factors Acute physical or psychological stress might trigger the onset of CFS.33 Three-quarters of patients with the disorder have reported an infection, such as a cold, flu-like illness, or infectious mononucleosis, as the trigger.33,54 A causal relation has been found between infectious mononucleosis and chronic fatigue.43,55-57 High rates of chronic fatigue after Q fever and Lyme disease have been found.56 However, no differences have been found in load of Epstein-Barr virus and immunological reactivity between individuals who developed CFS and those who did not.5,6 Precipitating somatic events such as serious injuries, surgery, pregnancy, or labour, which are reported as the onset of CFS by patients, have not been studied systematically. Psychological stress as a trigger of CFS has also been studied. Serious life events, such as the loss of a loved one or a job, and other stressful situations have been found to precipitate the disorder.58,59 Perpetuating factors Once CFS has developed, several maintaining factors can impede recovery. Psychological processes seem to be involved in the perpetuation of complaints in patients with CFS. These processes involve ideas or cognitions of patients about complaints and behavioural factors such as persistent avoidance of activities associated with an increase in symptoms. A strong belief in a physical cause of the illness, a strong focus on bodily sensations, and a poor sense of control over complaints contribute to an increase in fatigue severity and functional impairment.37,60-62 In a study of monozygotic twins discordant for CFS, the affected twins used more avoidance strategies than their non-fatigued co-twins.63 Inactivity of patients with CFS is caused by perceptions and expectations rather than by physical fitness.64,65 In CFS, discrepancies between perceived and actual cognitive performance have been found.66-68 A similar perception problem has been found for sleep disturbance.69-71 Twin studies have contributed particularly to evidence on the difference between perception and actual functioning of patients with CFS.63,67,69-71 Other perpetuating CFS factors that have been identified are social processes ranging from solicitous behaviour72 to lack of social support.73 Illness perceptions and illness behaviour can be reinforced by people in the patient's environment, such as a partner or family.74-76 Practitioners can contribute to the persistence of CFS by continuously encouraging unnecessary medical diagnostic procedures, by persistently suggesting psychological causes, or by not acknowledging CFS as a diagnosis, thus causing communication problems.77,78 Apart from the many disadvantages, long-lasting illness can also have more desirable consequences, such as care, attention, disengagement, or even financial benefits, which might also be considered perpetuating factors.72,79 Pathophysiology The nature of the underlying pathophysiology of CFS remains unclear. Many biological mechanisms have been hypothesised. Abnormalities in the central nervous system and immune system have been extensively studied. Evidence of discrete neuroendocrine abnormalities has been found. Neuroendocrine challenge tests have found a lower than normal cortisol response to increased corticotropin concentrations and upregulation of the serotonergic system. Studies of neuroendocrine function in patients with CFS have found no evidence for uniform dysfunction of the hypothalamopituitary-adrenal axis or stress hormones.41 Increasing evidence points to acquired neuroendocrine dysregulations in patients with CFS.80 Evidence for immunological dysfunction is not consistent. Many studies, some of which were not well controlled for non-specific stress effects, focused on cytokines and shifts in T-lymphocyte subsets and had variable results.81 The studies in monozygotic twins discordant for CFS have not provided support for immunological abnormalities.82 Nevertheless, at the tissue level, cytokines such as interleukin 6 might have an important role in CFS, because they are also involved in the stress response and are crucial inducers of sickness behaviour,83–86 which is characterised by avoidance behaviour, apathy, sleepiness, impaired memory and concentration, anorexia, mild fever, and increased sensitivity for pain. The role of RNAse L molecule in the type 1 interferon pathway is unclear.87-89 No specific pattern of cerebral abnormalities in patients with CFS has been found.90 Functional MRI studies in patients with CFS have shown that various areas in the brain are activated during erroneous performance in a motor imagery task, which suggests a motivational disturbance.91 Two studies have also found a reduction in the volume of grey matter in patients with CFS,92,93 but independent confirmation is needed. Abnormalities of the neuroendocrine and central nervous systems alone are not sufficient to explain the symptoms of CFS. More complex interactions between regulating systems are assumed to be at work and seem to involve the central nervous system, the immune system, and hormonal regulation systems.42,94 Diagnosis and management Guidelines for clinical management of CFS have received much less attention than those for its definition. Although CFS protocols have been developed,9,20 clinicians still express difficulty in diagnosing the disorder. Apart from having to cope with the definition difficulties, they also have to deal with patients who can present their complaints of severe fatigue in different ways. Some patients simply wonder what is going on, whereas others diagnose CFS/ME themselves, which can lead to irritation on the doctor's part, especially if he or she is uncertain or sceptical about the CFS diagnosis or even contests it.40,95 Some patients have been searching for a diagnosis for a long time. This diversity of presentations challenges the management skills of general practitioners and specialists. In all cases, the first step in the symptom-specific history is to gain insight into the patient's expectations and objectives. Many patients with CFS attribute symptoms to somatic factors,94 which cause them to expect too much of diagnostic tests. Some might have a hidden agenda involving insurance issues and invalidity-benefit claims. Identification of these issues and expectations at an early stage makes communication more transparent and prevents the doctor and patient from taking up entrenched positions.96 In a survey of patients with CFS, two-thirds were dissatisfied with the quality of medical care and pointed out the need for better communication and better education of doctors in the diagnosis and management of their illness.97 A thorough history, a meticulous physical examination, a mental status examination, and a minimum array of laboratory tests are necessary.13,19 Laboratory investigation is meant only to detect other disorders, not to find out whether a patient has CFS.98 Assessment of fatigue severity and functional impairment in the history of the patient remains difficult. If there is doubt about symptom severity or disability, brief questionnaire assessment might be considered to optimise the process of diagnosis.96 The diagnostic value of the accompanying symptom criteria in the case definition still has to be proven in a clinical setting.14 In the absence of sufficient symptom severity or disability for the diagnosis of CFS, appropriate acknowledgment of the patients' symptoms and suffering by the doctor prevents patients from radicalising disease opinions.40,98 Diagnosis of CFS alone is not sufficient. Education of the patient should include an explanation of the illness model, information about effective treatments, and motivation for therapy. More attention to these factors in the education of doctors is essential. Treatment Systematic reviews have investigated the effectiveness of several CFS treatments.99-101 CBT and graded exercise therapy (GET) are the only interventions found to be beneficial. The subtle changes found in the hypothalamopituitary-adrenal axis have led to two randomised controlled trials, on the basis of which the researchers have not concluded that steroids are the treatment of choice.102,103 For immunological interventions such as immunoglobulin, the evidence has been inconclusive. There has also been insufficient evidence of the effectiveness of pharmacological, supplementary, complementary, and other interventions.101 The conclusions from these reviews have not been refuted as yet.104-111 The model of perpetuating factors in CFS, which shows causal relations between both cognitive and behavioural factors and CFS symptoms,37 has been a promising starting point for elaboration on CBT.112,113 This therapy is a general form of psychotherapy directed at changing condition-related cognitions and behaviours. CBT for depression has not been effective for patients with CFS.114 This lack of efficacy is not surprising, since there are clear differences between depressed patients with CFS and patients with major depression.115 Central CBT components for CFS include explanation of the aetiological model, motivation for CBT, challenging and changing of fatigue-related cognitions, achievement and maintenance of a basic amount of physical activity, gradual increase in physical activity, and planning work rehabilitation or rehabilitation in other personal activities. CBT teaches patients with CFS how to acquire control over symptoms. In several randomised controlled trials, CBT for CFS has been compared with standard medical care and other treatments, such as immunotherapy, relaxation therapy, and support groups.116-119 The same has been done for GET.39,120-122 CBT for CFS is based on a behavioural model of avoidance and always includes a graded activity programme. GET is based on a physiological model of deconditioning and has no intention of explicitly treating cognitions. In a few GET studies, cognitions to encourage graded exercise have been modified.123 CBT is generally a more complex treatment than GET, which might explain why CBT studies show better improvement rates (around 70%) than those with GET (around 55%). A treatment advocated by patients is pacing, which is lifestyle management allowing optimum adaptation to the illness, including an appropriate balance of rest and activity.124 A current study in the UK is comparing pacing with CBT and GET, but no evidence for this treatment is available as yet. Most CBT studies strive for rehabilitation of patients with CFS. Our study had cure of CFS as its explicit goal of therapy.119 Cure has been defined as disappearance of symptoms and functional impairment, ability to return to work and to undertake other activities, no longer interpreting everyday bodily signs as indicating CFS, and letting go of the label 'CFS patient' 125 As in other chronic diseases, the meaning of cure varies tremendously among patients. At the beginning of CBT, recovery seems vague and unattainable for most patients. Therapists should broaden the patient's vision to a future life as a healthy person. A personal goal can never be achieved if it is not aimed for. By striving for rehabilitation only, therapists might deprive patients with CFS of a potential cure. Lasting benefits of CBT recovery or improvement have been shown by significant differences between the original groups of two randomised controlled trials at 2-year and 5-year follow-up.126,127 However, not all patients benefit from CBT or GET. Predictors of poor treatment outcome were membership of a self-help group, receipt of a sickness benefit, claiming a disability-related benefit, low sense of control, a strong focus on symptoms, and a pervasively passive activity pattern. Duration of illness, surprisingly, did not predict treatment outcome.119,128 Most CBT/GET studies had samples of patients with median duration of illness of about 5 years. If CBT were offered to patients at an earlier stage of the illness, medical and societal costs might be substantially reduced. Economic analyses of CBT and GET for patients with CFS and chronic fatigue have shown that the cost of therapy was higher than that of usual care, but the outcome was better. For more accurate estimatation of the cost- effectiveness of CBT in patients with CFS, future research should focus more on productivity costs and use a longer period of follow-up.129,130 The future Although adherents of biopsychosocial and pathological CFS models have made steps towards agreement on definition and diagnosis,131 some of the patients' organisations seem to share the opinion that the success of CBT confirms the bias that CFS has a psychogenic cause. This argument reinforces the old model in which diseases or complaints are considered as either somatic or psychiatric in origin. In modern medicine, the biopsychosocial approach should guarantee that both facets are attended to. The use of a psychological CFS model does not preclude neurobiological components. Until recently, studies on biological or psychological CFS mechanisms were directed at one feature of the illness and not at the integral syndrome. Pathophysiological research should follow two strategies. The first consists of distinguishing CFS from other disorders. The characteristics and pathophysiology of chronic fatigue in, for example, neurological disorders (multiple sclerosis, neuromuscular disorders, after stroke), in or after cancer, and in chronic inflammatory disorders such as rheumatoid arthritis, should be compared with those in CFS. The other strategy consists of investigating the similarities and dissimilarities in functional somatic syndromes.132,133 Modern neurosciences offer some explanatory models, which might bridge the gap between somatic and psychological models for CFS and other functional somatic syndromes that might show both similarities and differences. The challenge is to find out what is wrong in the molecular interplay at the level of the central nervous system. In the brain, hormones such as corticotropin-releasing factor, corticotropin, and cortisol interact with cytokines (such as interleukins 6 and 1) and neuropeptides (such as serotonin and dopamine). In this network of molecules, receptors are modulated also. Techniques such as bioimaging and proteomic strategies, and perhaps a systems biology approach,134 should be applied to try to elucidate such complicated interactions. In other models, chronic and severe disturbance of homoeostatic mechanisms is supposed to be the basis for deregulating systems in functional somatic syndromes. Psychobiological responses to extreme stress have been identified and related to resilience or vulnerability.135 Like fibromyalgia, CFS could be conceptualised as a stress disorder, in which adverse life experiences, stress regulation, and pain-processing mechanisms are highly inter-related.136 Psychobiological sensitisation mechanisms might be related to functional somatic syndromes. During chronic stress, the central nervous system, especially the limbic system, is supposed to increase sensitisation. In this setting, other areas of the central nervous system lose control and contribute to increases in symptoms and avoidance behaviour.137 Another important question is whether CFS is a homogeneous or heterogeneous disorder. Various researchers have called for investigations of subgroups by features such as chronicity, immunology, activity, and neurobiology.138,139 Mechanisms of improvement How a psychological treatment such as CBT contributes to physical improvement is not yet known. What elements in CBT are essential for recovery? Do cognitive and behavioural interventions need equal attention? Is graded exposure to exercise or increased physiological fitness essential for recovery? A recent randomised controlled trial has found that the treatment effect of GET is mediated by a decrease in symptom focusing rather than an increase in fitness.122 This finding is remarkable, since increased activity was assumed to be necessary for recovery. Studies on the process of change during CBT are necessary for the best treatment to be achieved. Perception seems to have a more central role than exercise. Since cortisol is related to cognitive appraisal, in which perception is the first step, CBT studies should pay more attention to changes in neuroendocrine functions as outcome measures. The important question is whether neuroendocrine and immunological abnormalities are reversible, for example after successful CBT. Or do these abnormalities predict a negative outcome of CBT? There is some evidence that neuroendocrine abnormalities revert with successful CBT.140 Tailor-made treatment Once we know more about the elements in CBT that cause the main improvements in specific groups of patients with CFS, more efficient and less expensive treatments can be developed. GET with low numbers of individual treatment sessions and telephone follow-up calls has shown promising results for patients without strong illness beliefs or concurrent emotional difficulties.123,128 Cooperation with patients' support groups has been suggested as a way to spread evidence-based advice among patients with CFS.128 For some patients, group CBT might be more efficient by combining patients' support and evidence-based interventions. However, group therapy for CFS also has disadvantages. It can lead to reinforcement of dysfunctional behaviour or resistance against psychotherapy. Furthermore, individualised CBT is more difficult to achieve for each patient in a group.141 When more knowledge is available about processes involved in improvement, research into CBT and GET might focus on tailor-made treatments with variable intensity or forms. Internet therapy or self-help instruction might be useful for some patients. Similarly, more insight into the neurobiology of CFS might lead to a new drug treatment, which might be used separately or in combination with CBT. Prospective fatigue studies Varying prevalence and incidence emphasise the need for prospective studies in the general population. We assume that CFS is not a stable disorder, and its prevalence is affected by symptom fluctuation, as suggested by data on the course.142,143 Fatigue and physical functioning of patients with CFS should be monitored for several years so that patterns of cure and relapse can be elucidated. More knowledge about the psychoneurobiology of CFS and change processes is needed to improve our understanding of this illness and to allow development of more efficient treatments. Search strategy and selection criteria ----------------------------------------------------------------------------- We searched the Cochrane Database of Systematic Reviews (Cochrane Reviews) and the Cochrane Database of Methodology Reviews (Methodology Reviews) up to April, 2005, and MEDLINE, PubMed, and PsycInfo from 1988 to the present. The keywords we used were 'chronic fatigue syndrome' and 'myalgic encephalomyelitis' in relation to epidemiology, aetiology, pathophysiology, diagnosis, definition, prognosis, prevention, and genetics. For the history of chronic fatigue syndrome, we searched the complete MEDLINE database and, when appropriate, publications from before 1988. In addition, we checked reference lists of articles identified by means of this search strategy and used relevant articles on these lists. We also used several book chapters and theses on chronic fatigue syndrome. ----------------------------------------------------------------------------- Conflict of interest statement We declare that we have no conflict of interest. JWM vd M has received grants from GlaxoSmithKline Netherlands and Optipharma for CFS drug studies. Acknowledgments We thank Elsbeth Prins for helping us select relevant publications. Back to top References 1. Shorter E. From paralysis to fatigue: a history of psychosomatic illness in the modern eraNew York: NY Free Press, 1992:. 2. Wessely S. Old wine in new bottles: neurasthenia and ‘ME’. Psychol Med 1990; 20: 35-53. 3. Bell EJ, McCartney RA. A study of coxsackie B virus infections, 1972-1983. J Hyg 1984; 93: 197-203. 4. Buchwald D, Sullivan JL, Komaroff AL. 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