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Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common (0.19–2%)1,–,4 and disabling condition in children and young people, with over 50% of affected children and young people bed bound at some stage and a mean time off school of 1 academic year.5 The importance of CFS/ME has been highlighted by both the Chief Medical Officer's report6 and the National Institute for Health and Clinical Excellence (NICE) guidelines.7
A variety of case definitions for CFS/ME exist (box 1), and studies, including those reviewed here, often use different definitions, particularly around the duration of symptoms. It is not clear whether the different case definitions have different implications for aetiology or prognosis. Paediatric CFS/ME is defined in the Royal College of Paediatrics and Child Health guidelines as “generalised fatigue persisting after routine tests and investigations have failed to identify an obvious underlying cause”.8 The NICE recommended that the fatigue should have lasted 3 months before a diagnosis is made and highlighted the fact that the fatigue must be disabling and was likely to occur in the presence of one other symptom7 (box 1). There is a philosophical discussion to be had on how diagnoses are made, particularly with diagnoses where no underlying pathogen has been identified, but it can be argued that “delineation of a syndrome is the first step towards elucidation of the chain of causation and redefinition of the whole group or subgroups within it”.9
Definitions for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) in children and young people
Royal College of Paediatrics and Child Health definition of chronic fatigue syndrome or myalgic encephalomyelitis
”Generalised fatigue persisting after routine tests and investigations have failed to identify an obvious underlying cause”
National Institute for Health and Clinical Excellence 2007 guidelines7
Fatigue with all of the following features:
New or had a specific onset (ie, it is not life long)
Persistent and/or recurrent
Unexplained by other conditions
Has resulted in a substantial reduction in activity level characterised by postexertional malaise and/or fatigue (typically delayed, for example by at least 24 h, with slow recovery over several days)
One or more of the following symptoms:
Difficulty with sleeping, such as insomnia, hypersomnia, unrefreshing sleep, a disturbed sleep–wake cycle
Muscle and/or joint pain that is multi-site and without evidence of inflammation
Painful lymph nodes without pathological enlargement
Cognitive dysfunction, such as difficulty thinking, inability to concentrate, impairment of short-term memory, and difficulties with word-finding, planning/organising thoughts and information processing
Physical or mental exertion makes symptoms worse
General malaise or ‘flu-like’ symptoms
Dizziness and/or nausea
Palpitations in the absence of identified cardiac pathology
A minimum of 3/12 fatigue is required before a diagnosis of CFS/ME is made
Centers for Disease Control and Prevention 1994 criteria
Minimum 6 months' duration
Four symptoms required: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern or severity; unrefreshing sleep; postexertional malaise >24 h
Exclusions: clinically important medical conditions, melancholic depression, substance abuse, bipolar disorder, psychosis, eating disorders, dementia
It seems reasonable to consider that fatigue and CFS/ME exist on a continuum10 and this article will consider the relationship between emotional disorders and fatigue, as much of the literature in the field relates to the symptom of fatigue rather than CFS/ME. We use the term ‘emotional disorders’ to reflect the fact that depression and anxiety disorders are associated with each other11 and there is high comorbidity between the two (27% of those with anxiety experience comorbid depression).12
An association between emotional disorders (anxiety disorders and depression)13 14 and CFS/ME has been described in children, but there is controversy over whether emotional disorders have a role in the aetiology or maintenance of CFS/ME, or arise as a result of it. In this article, we review the current evidence on this clinically important question for the prevention and treatment of CFS/ME.
The association between anxiety and depression and CFS/ME
Several case–control studies have described an association between paediatric CFS/ME and both anxiety and depression, in comparison with healthy controls and when compared with other chronic illnesses such as juvenile idiopathic arthritis (JIA) and migraine.15,–,20 However, drawing firm conclusions from this literature is difficult, as some studies have been quite small (table 1). The studies were set within tertiary referral centres and one was based within a psychology department,17 so the patient group may not be representative of children and adolescents in the general population. Comparison was made with normative population data,11 12 age- and sex-matched healthy controls from a local school,14 young people registered with a local general practitioner9 and with children referred to tertiary services with migraine14 and JIA.13 In one study,16 some patients had recovered, suggesting that the design of these studies may have introduced selection bias.
The only cross-sectional population study (N=4240) of CFS/ME in children4 described an association between anxiety and both CFS/ME (defined by the CDC criteria) and self-reported ‘chronic fatigue’ (defined as disabling severe fatigue of at least 6 months duration for which rest doesn't help). This is consistent with a case–control study in the same year which described higher anxiety in children with CDC-defined CFS/ME (and those with migraine) compared with ‘idiopathic CFS’ (clinically evaluated, unexplained chronic fatigue that fails to meet criteria for CFS) or controls,20 suggesting there may be a dose–response relationship between severity of fatigue and presence of anxiety, as the relationship is stronger in those meeting CDC criteria.
Which comes first?
There are a number of possible explanations for the association between CFS/ME and emotional disorders.
Emotional disorders might lead or contribute to children subsequently developing CFS/ME
It has been postulated in the adult CFS/ME literature21 that CFS/ME might occur as a result of depression via the mechanism of depression leading to reduced physical activity, and this leading to fatigue. This is plausible as children with CFS/ME attend less school and are more physically disabled22 than the normal population. However, it is also argued that perception of activity levels might be distorted in children with CFS/ME.23 As yet, there are no longitudinal data in support of this aetiological pathway in children and young people.
Emotional disorders may be secondary to CFS/ME
Alternatively, the experience of having CFS/ME might cause young people to become depressed or anxious. This idea is understandable in that a young person might become psychologically distressed while living with a chronic illness, particularly one that is poorly understood and stigmatising. Separation anxiety and social anxiety have been reported to be associated with CFS/ME and this might be due to children becoming increasingly dependent on their carers, and finding it hard to reintegrate with their peer group after long absences from school.12
Emotional disorders and fatigue may be associated because of overlapping diagnostic criteria
It has been suggested that depression and CFS/ME are associated because of overlapping diagnostic criteria, but this is hard to justify as differences have been described clinically and in terms of genetic risk factors.24,–,27 There is no overlap in the diagnostic criteria for anxiety disorders and CFS/ME, except that both can include tension headaches.
Common risk factors lead to the development of both emotional disorders and CFS/ME
Childhood trauma is a risk factor for subsequent depression and anxiety in adults,28 and is also associated with adult CFS/ME in retrospective studies.29 30 A relationship between sexual abuse in childhood and idiopathic chronic fatigue (although not CFS/ME) has been described,31 and replicated in a larger cross-sectional study.32 A large prospective twin study in the adult CFS/ME literature suggested that the perceived stressfulness of daily life is predictive of subsequent fatigue, an effect size that increases to a fivefold increase in risk after accounting for genetic factors.33 In one cross-sectional study of adolescent girls, those with fatigue report a greater number of negative life events in the previous year.34
It has been suggested that a relationship between stressful life events and CFS/ME might involve the hypothalmic–pituitary–adrenal (HPA) axis. One case–control study (N=40) showed lower mean, peak and total cortisol in response to synacthen in adolescents with CFS/ME.35 This reduction in cortisol is not seen in teenagers who have only been fatigued for 1 month,34 which raises the possibility that changes in the HPA axis may be related to the duration of fatigue. A recent study in adults29 has shown that mean waking cortisol levels are lower in adults with CFS/ME who have a self-reported history of childhood trauma than in both controls and individuals with CFS/ME without a history of trauma.
In contrast, evidence suggests that cortisol levels may be higher than normal in adolescents with depression, who show decreased suppression of cortisol in response to dexamethasone suppression test, and a non-significant tendency to higher basal cortisol levels.36 Again it is unclear whether this predisposes to or is a result of depression, but it is clear that the relationship between the HPA axis, CFS/ME, depression and life events is complex and has yet to be fully understood.
These four possible explanations of the association between emotional disorders and CFS/ME are not mutually exclusive, and it is likely that that the relationship between emotional disorders and CFS is more complex, with each contributing to the development of the other. This ‘aetiological vicious cycle’ theory has been proposed in the adult CFS/ME literature.21
The cross-sectional studies reviewed above do not enable us to determine which of these models best fits the relationship between CFS/ME and emotional disorders.
No sufficiently powered population-based longitudinal studies have investigated psychological risk factors in children with CFS/ME, but several longitudinal studies have investigated the relationship between ‘fatigue’ and depression and anxiety.
The first longitudinal study3 used a subset from the Office of National Statistics study of the mental health of children and adolescents in Great Britain. At time 1, 1096 adolescents were interviewed using the DAWBA.37 Fatigue symptoms, but not mental health, were followed up at time 2 (4–6 months later). Rates of ‘fatigue’ (1 month duration) and ‘chronic fatigue’ (6 months' duration) were measured at both time points. New cases of both ‘fatigue’ (166 found) and ‘chronic fatigue’ (nine found) at time 2 were found to be associated with anxiety or depression at time 1, with a much higher odds ratio for new cases of ‘chronic fatigue’. However, there were only nine new cases of ‘chronic fatigue’ at time 2, and since time 2 was 4–6 months after time 1, by definition the cases at time 2 would have had to be fatigued at time 1, so it is not possible to disentangle the direction of causality between chronic fatigue, depression and anxiety. Also, the DAWBA was not repeated at time 2, so new cases of anxiety or depression were not identified, and it was not possible to be certain whether fatigue is a risk factor for emotional disorders.
The second longitudinal study38 followed 1747 Dutch adolescents at three time points (T1 (spring), T2 (autumn) and T3 (the following spring)). The outcome was fatigue lasting 2 weeks, and just 653 adolescents completed all time points. Persistently fatigued (those severely fatigued throughout the study) participants had higher levels of depression and anxiety at the beginning of the study. Depressive symptoms (on the Beck Depression Inventory) and anxiety symptoms (State-Trait Anxiety Inventory for Children) at T1 and T2 were associated with new fatigue (scoring >35 on the fatigue subscale of the Clinical Interview Schedule) at T3.
The third study39 used school-based questionnaire surveys of 1880 adolescents, with time points 2 years apart. High scorers on the Short Mood and Feelings Questionnaire at time 1 were significantly more likely to report ‘severe fatigue’ (extreme tiredness occurring more than once a week) at time 2 (OR 1.9; 95% CI 1.5 to 2.5; p<0.001), adjusted for sex, year group, overcrowding and eligibility for free school meals.
These studies consistently demonstrate an association between fatigue and psychological distress, and suggest that the direction of causation might be that anxiety and depression lead to fatigue. It is not clear whether this finding would extend to CFS/ME as well as fatigue.
Does the adult literature for CFS/ME help?
Two longitudinal studies have investigated psychological factors as risk factors for CFS/ME in adults (although several have studied ‘fatigue’). The first study40 used the 1970 British cohort study (N=11 261), with General Health Questionnaire 12 (GHQ-12) results at age 16 as a marker of psychological distress, and self-reported CFS/ME at age 30 as the outcome. They found no evidence of an association between high GHQ-12 scores in 16-year-olds and lifetime self-reported CFS/ME (adjusted OR 1.0; 95% CI 0.4 to 2.4).
The second study41 used the 1946 British birth cohort to investigate the relationship between self-reported CFS/ME at age 53 (prevalence 1.1%) and previous psychiatric illness. They found that self-reported ‘depression, nervous or emotional troubles’ at age 36 gave an increased risk of CFS/ME at age 53 (OR 2.73; 95% CI 1.20 to 6.21; p=0.02). Having a psychiatric disorder as diagnosed using the Present State Examination at age 36 also increased risk (OR 3.47; 95% CI 1.39 to 8.66; p=0.008). They also demonstrated a dose–response relationship, in that increasing total score on the Present State Examination at age 36 gave an increasing risk of CFS/ME at age 53.
However, children and adolescents are not simply ‘small adults’, and it is not clear that what is true of CFS/ME in adults will also hold true in children. For example, the natural history of CFS/ME in children appears to differ, and children show a much greater response to treatment than do adults.42
From the current evidence, anxiety is seen more frequently in young people with CFS/ME than in the general population, or other chronically ill populations. The aetiological relationship between emotional disorders and CFS is likely to be complex, with each contributing to the development of the other. There is some evidence that both depression and anxiety predict future fatigue in adolescents. We can also be confident that a diagnosis of a psychiatric disorder in adults increases the risk of developing CFS/ME at later time points.
Paediatricians treating young people with fatigue or CFS/ME need to be alert to symptoms of emotional disorders and need to work with their colleagues in Child and Adolescent Mental Health Services, ideally in shared clinics, in order to offer these patients the best possible treatment. Similarly, clinicians working with young people with emotional disorders need to be aware of the risk of them developing problems with fatigue. Clinicians may be hesitant to diagnose anxiety or depression as they may worry about alienating children and their families, but it is important that these are recognised, discussed and treated because treatments for anxiety and depression43 are very different from those for CFS/ME.7 It is also helpful for families to be aware of this association and that effective treatments are available for anxiety and depression.
We do not have any evidence at the moment that either depression or anxiety is a risk factor for the development of CFS/ME in children. Clearly a large longitudinal population-based study using current diagnostic criteria for CFS/ME is needed in order to clarify the interaction between these illnesses and guide treatment development and clinical practice.
The authors thank Dr Jonathan Evans for his helpful comments.
Competing interests EC is medical advisor for the Association for Young People with ME.
Provenance and peer review Commissioned; externally peer reviewed.