Ministry of Defence Synopsis of Causation Chronic Fatigue Syndrome Author: Dr Adrian Roberts, Medical Author, Medical Text, Edinburgh Validator: Dr Selwyn Richards, Poole Hospital NHS Trust, Poole, Dorset September 2008 Disclaimer This synopsis has been completed by medical practitioners. It is based on a literature search at the standard of a textbook of medicine and generalist review articles. It is not intended to be a meta- analysis of the literature on the condition specified. Every effort has been taken to ensure that the information contained in the synopsis is accurate and consistent with current knowledge and practice and to do this the synopsis has been subject to an external validation process by consultants in a relevant specialty nominated by the Royal Society of Medicine. The Ministry of Defence accepts full responsibility for the contents of this synopsis, and for any claims for loss, damage or injury arising from the use of this synopsis by the Ministry of Defence. 2 1. Definition 1.1 Chronic fatigue syndrome (CFS) is a significant illness that causes severe disabling physical and mental fatigue exacerbated by minimal exertion, in the absence of any conventional physical or psychological disorder to explain the problem. The term “chronic fatigue syndrome” was conceived relatively recently. However, the symptom complex that it describes has been recognised for over a century, during which time it has been classified under a variety of titles including neurasthenia, Royal Free disease, myalgic encephalomyelitis (ME), and post-viral fatigue syndrome. 1.2 CFS is defined by symptoms and disability and has no confirmatory physical signs or characteristic laboratory abnormalities. A number of case definitions have been proposed. The most widely used definition, developed by Fukuda et al in 1994, outlines both inclusion and exclusion criteria for the diagnosis of CFS, as follows:1 1.2.1 Inclusion criteria: A case of the chronic fatigue syndrome is defined by the presence of clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e. not lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities; and 1.2.2 The concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue: • Substantial impairment in short-term memory or concentration • Sore throat • Tender lymph nodes • Muscle pain • Multi-joint pain without joint swelling or redness • Headaches of a new type, pattern, or severity • Unrefreshing sleep • Post-exertional malaise lasting more than 24 hours 1.2.3 Exclusion criteria: The following conditions exclude a patient from the diagnosis of CFS: • Any active medical condition that may explain the presence of chronic fatigue, such as untreated hypothyroidism, sleep apnoea, narcolepsy, and the side effects of medication • Any previously diagnosed medical condition whose resolution has not been documented beyond reasonable clinical doubt and whose continued activity may explain the chronic fatiguing illness e.g. previously treated malignancies • Any past or current diagnosis of a major depressive disorder with psychotic or melancholic features; bipolar affective disorders; schizophrenia; delusional disorders; dementias; anorexia nervosa; or bulimia nervosa • Alcohol or other substance abuse within 2 years prior to the onset of the chronic fatigue and any time afterward 3 • Severe obesity as defined by a body mass index equal to or greater than 45 1.3 In applying the case definition based on the criteria developed by Fukuda et al, ambiguities may arise that contribute to inconsistencies in case identification. A number of standardised and validated instruments involving structured interviews and questionnaires are advocated to improve the assessment of fatigue, disability, and symptoms associated with CFS. It is suggested that the adoption of such methods will improve the precision of case identification and render it more uniform across different sites. These issues are particular germane to researchers but are also of relevance in the clinical setting.2 1.4 “Idiopathic chronic fatigue” is a term used to describe clinically evaluated, unexplained chronic fatigue that fails to meet criteria for the chronic fatigue syndrome. 4 2. Clinical Features 2.1 Studies conducted by the Centers for Disease Control and Prevention in the USA have suggested that the prevalence of CFS may lie in the region of 200 people per 100,000 population. There is evidence that CFS affects all racial and ethnic groups and both sexes, although most surveys support a female preponderance. Past reports of an increased prevalence of CFS amongst white patients have emanated from clinic populations, and it is likely that these results merely reflect a bias attributable to health care access and utilisation. Average age of onset is around 30 years. Adolescents can have CFS with many of the same characteristics as demonstrated in adults. CFS-like illness has been reported in children under 12, although the symptom pattern varies somewhat from that seen in adults and adolescents.3 2.2 The Fukuda criteria for the diagnosis of CFS have been listed at section 1.2. CFS is a diagnosis of exclusion. Thus all other physical and psychiatric bases for the patient’s fatigue must be excluded before a diagnosis of CFS is made. 2.3 The history is useful in eliciting information in a number of areas:4 • Symptoms relevant to the Fukuda criteria, including details of fatigue and its relation to exertion, physical symptoms, sleep disturbance, and cognitive problems such as poor concentration and memory • Disability and distress illustrating how the patient’s life has been changed by the illness • The patient’s understanding of the illness • Coping strategies, especially with regard to rest and activity • Employment situation • The attitude of family members 2.4 The presence of abnormal signs on physical examination is not generally considered to be compatible with a diagnosis of CFS. However, muscle wasting and postural hypotension may become evident in patients with CFS, having arisen as a consequence of inactivity. A mental state examination is also vital to exclude alternative diagnoses and to identify comorbid mental health conditions. 2.5 When the patient first presents, an appropriate range of screening investigations should be carried out to exclude alternative diagnoses. Any pointers to alternative diagnoses that have been elicited from the history and examination may also merit specific investigation in their own right. However, there is no diagnostic test or pattern of tests that will serve to make a diagnosis of CFS. 2.6 Patients may perceive a lack of understanding from others, including health professionals. They may be referred to a variety of specialist clinics or choose to consult alternative practitioners. The struggles of sufferers and professionals to understand the illness may lead to unsatisfactory patient-professional relationships and resentful patients.5 2.7 There is a significant overlap between CFS and other conditions that are characterised by unexplained health symptoms. It has been reported that a significant proportion of 6 Gulf War veterans who present with unexplained fatigue meet the criteria for CFS. 5 CFS also shares many of the clinical features of fibromyalgia (notably muscle pain), and so differentiation is sometimes difficult. The majority of patients with fibromyalgia do fulfil the diagnostic Fukuda criteria for CFS but are traditionally characterised as having a chronic pain rather than a chronic fatigue syndrome. 6 3. Aetiology 3.1 The underlying cause of CFS remains unknown. The most useful approach is to consider CFS as a descriptive term for a type of clinical presentation, i.e. a heterogeneous disease whereby a number of mechanisms may manifest with similar symptoms. 3.2 Aetiological theories abound, but none is established. The following mechanisms are among the theories that have been put forward as causes of CFS: 3.2.1 Disturbance of the hypothalamic-pituitary-adrenal (HPA) axis: the overall balance of evidence points to reduced cortisol output in at least some patients, although recent studies have suggested an absence of HPA axis changes during the early stages of the development of CFS. The later-occurring HPA axis changes can be reversed by modifying behavioural features of the condition such as inactivity, deconditioning and sleep disturbance. Thus, it appears likely that the HPA axis disturbance observed in CFS is of multifactorial origin with some factors occurring as a consequence of the illness. The HPA axis may play a role in exacerbating or perpetuating symptoms later in the course of the disease.7 3.2.2 Other neuroendocrinological factors: studies have assessed the effects of growth hormone, dehydroepiandrostenedione and its sulphate, melatonin, leptin, and neuroendocrine-monoamine interactions. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulphate function and abnormal serotonin function in CFS, but it remains unclear as to whether these changes are of functional importance.8 3.2.3 Immune dysfunction: a variety of abnormalities have been reported including abnormalities in T cells and cytokine levels, although no consistent