Chronic fatigue syndrome: identifying zebras amongst the horses
© Harvey and Wessely; licensee BioMed Central Ltd. 2009
Received: 1 September 2009
Accepted: 12 October 2009
Published: 12 October 2009
There are currently no investigative tools or physical signs that can confirm or refute the presence of chronic fatigue syndrome (CFS). As a result, clinicians must decide how long to keep looking for alternative explanations for fatigue before settling on a diagnosis of CFS. Too little investigation risks serious or easily treatable causes of fatigue being overlooked, whilst too many increases the risk of iatrogenic harm and reduces the opportunity for early focused treatment. A paper by Jones et al published this month in BMC Medicine may help clinicians in deciding how to undertake such investigations. Their results suggest that if clinicians look for common psychiatric and medical conditions in those complaining of prolonged fatigue, the rate of detection will be higher than previously estimated. The most common co-morbid condition identified was depression, suggesting a simple mental state examination remains the most productive single investigation in any new person presenting with unexplained fatigue. Currently, most diagnostic criteria advice CFS should not be diagnosed when an active medical or psychiatric condition which may explain the fatigue is identified. We discuss a number of recent prospective studies that have provided valuable insights into the aetiology of chronic fatigue and describe a model for understanding chronic fatigue which may be equally relevant regardless of whether or not an apparent medical cause for fatigue can be identified.
See the associated research paper by Jones et al: http://www.biomedcentral.com/1741-7015/7/57
Medical students are often told that the sound of approaching hooves is more likely to herald the arrival of horses than zebras. The metaphor reinforces the idea that in medicine common things happen commonly and that clinicians should avoid spending too much time chasing rare or unlikely diagnoses. Fatigue is a very common clinical problem with many possible causes [1, 2]. Some causes of fatigue are common 'horses' such as anaemia, viral infections, sleep deprivation, diabetes and depression. However, potential 'zebras' such as malignancy or auto-immune disorders may also present with fatigue. Even with extensive investigations, the underlying aetiology of an individual's fatigue in many cases remains unknown. Over recent decades there has been increasing recognition of a group of individuals with severe, persistent, and unexplained fatigue . Such persistent fatigue has, at times, been seen as an illness of modern life, although there is good evidence to show that chronic fatigue has been a common problem since at least the 19th century, but under different diagnostic labels, such as neurasthenia [4, 5]. Some, but by no means all, of these individuals fulfil the current criteria for chronic fatigue syndrome (CFS), which requires that persisting or relapsing fatigue be present for at least 6 months, is not relieved by rest, is not explained by medical or psychiatric conditions and is accompanied by a range of cognitive and somatic symptoms . Here, we discuss a paper by Jones et al. published this month in BMC Medicine , as well as recent prospective studies that provide valuable insights into the aetiology and contribute to a model for understanding chronic fatigue.
At present, and despite much effort, there are no investigative tools or physical signs that can confirm the presence of CFS and it remains a diagnosis of exclusion . As a result, clinicians must decide how long to keep looking for alternative explanations for fatigue before settling on a diagnosis of CFS. There are numerous cautionary tales of individuals who have suffered from delayed or missed diagnoses of serious illnesses due to under investigating of fatigue . Yet if the search for unlikely 'zebra' causes of fatigue goes on too long, the risk of iatrogenic harm increases and the opportunity for early focused treatment of CFS may be lost .
Studies based in specialized clinics have suggested that yields from detailed investigations of those with prolonged fatigue are low, with only 5% of laboratory tests revealing an underlying cause . However, fatigued patients seen in specialized clinics differ from those seen in other settings , with some reports suggesting higher yields from investigations may be possible in primary care . The recently published VAMPIRE study based in Dutch primary care found that 8% of patients presenting with fatigue had a blood test detectable somatic illness diagnosed over a 1-year follow-up period, with the vast majority of the disorders identified from a very limited set of simple blood tests (haemoglobin, erythrocyte sedimentation rate, glucose and thyroid-stimulating hormone) . The UK-based National Institute of Health and Clinical Excellence guidelines on the diagnosis and management of CFS recommend a slightly more conservative approach, with a more extensive list of blood and urine investigations suggested (Appendix) . Such lists of physical investigations should not detract from the need to consider psychological causes of fatigue. Depression is very common amongst those with fatigue [4, 15], with recent studies using the British birth cohorts showing over 70% of adults reporting CFS have evidence of psychiatric disorder prior to their fatigue symptoms beginning .
A clinician assessing a patient in the community with apparent CFS may well ask 'If I look, how likely am I to find a contributing medical or psychiatric cause for the fatigue, and what difference will this make?' A paper by Jones et al.  may help to answer these questions. Using random telephone surveys, 904 people who met the criteria for CFS were identified. On telephone history alone they were able to identify a potential cause of the fatigue in 441 (48%). When the remaining cases were seen for a physical examination, psychiatric interview and laboratory screening, potential medical or psychiatric causes of fatigue were identified in a further 49%. Not surprisingly, the most common co-morbid conditions identified were depression, followed by bipolar affective disorder, thyroid disease, substance misuse and diabetes. Obesity, already known to be associated with a number of these conditions [17–19], increased the chances of a medical or psychiatric cause being identified. These results are very similar to a Dutch study published earlier this year, which found concomitant diseases which could cause fatigue in 55.5% of those reporting chronic fatigue lasting more than 6 months . Based on these findings, clinicians should feel encouraged that, if they look for common psychiatric and medical conditions in those complaining of prolonged fatigue, the rate of detection will be higher than previously thought. Thus, current recommendations advising a range of simple investigations (Appendix) for those with persistent fatigue seem well placed. Jones et al. did find some 'zebras' but, as expected, these were relatively rare. A simple mental state examination appears to remain the most productive single investigation in any new person presenting with unexplained fatigue .
Investigations recommended by the UK National Institute of Clinical Excellence to exclude medical causes of chronic fatigue ()
Tests that should usually be done:
urinalysis for protein, blood and glucose
full blood count
urea and electrolytes
erythrocyte sedimentation rate or plasma viscosity
random blood glucose
screening blood tests for gluten sensitivity
assessment of serum ferritin levels (children and young people only).
Additional serology tests that should only be done if the history suggests the possibility of a recent infection:
chronic bacterial infections, such as borreliosis
chronic viral infections, such as HIV or hepatitis B or C
acute viral infections, such as infectious mononucleosis (use heterophile antibody tests)
latent infections, such as toxoplasmosis, Epstein-Barr virus or cytomegalovirus.
chronic fatigue syndrome.
SH and SW are supported by the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, Kings College London and The South London and Maudsley NHS Foundation Trust.
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