Prof Peter D White: Neurology and Psychiatry SpRs Teaching Weekend

Prof PD White: Neurology and Psychiatry SpRs Teaching Weekend

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14 November 2009


Neurology and Psychiatry SpRs Teaching Weekend

12 to 14 December 2008 St Anne’s College – Oxford




09:50 Chronic fatigue syndrome: neurological, psychological or both?

Peter White, Professor of Psychological Medicine, Barts and the London Medical School

The extract I am appending is a summary of Professor Peter Denton White’s presentation (Page 46 of PDF) in which he talks about the taxonomy of CFS “being a mess”.

During his Royal Society of Medicine “CFS” Conference presentation, in April 2008, White had said, ominously:

“…So ICD-10 is not helpful and I would not suggest, as clinicians, you use ICD-10 criteria. They really need sorting out; and they will be in due course, God willing.”

See unofficial transcript of part of White’s RSM presentation, here, in which he presents his thoughts on current ICD taxonomy:

Prof Peter White discouraging RSM Conference from using ICD-10:

In an April 2009 paper, co-authored by White, the authors propose a change to current ICD-10 codings:

Psychological Medicine Preprint “Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study of primary care”

In the section “Implications for Further Research” the authors state that because the paper finds that:

“These data also suggest that fatigue syndromes are heterogeneous (Vollmer-Conna et al. 2006), and that CFS/ME and PVFS should be considered as separate conditions, with CFS/ME having more in common with IBS than PVFS does (Aggarwal et al. 2006). This requires revision of the ICD-10 taxonomy, which classifies PVFS with ME (WHO, 1992)”

 Presentation given at Neurology and Psychiatry SpRs Teaching Weekend



Chronic fatigue syndrome: neurological, psychological or both?

Peter White, Professor of Psychological Medicine, Barts and the London Medical School

Epidemiology of fatigue and CFS

Fatigue is a common symptom in both the community and primary care. When asked, between 10 and 20 per cent of people in the community will report feeling abnormally tired at any one time.

At the same time, fatigue is continuously distributed within the community, with no point of rarity.

Therefore any cut-off is arbitrary and the prevalence will vary by how the question is asked, the symptom volunteered, and its context. Between 1.5 % and 6.5 % of European patients will consult their general practitioner with a primary complaint of fatigue every year, the incidence varying by age and population. Fatigue is more commonly reported and presented to general practitioners by women and the middle-aged, and is most closely associated with mood disorders and reported stress. It does not seem to vary by ethnicity in the UK, but there is an intriguing paradox in that it is reported more commonly by those in high income countries, yet is presented to medical care more often in low income countries.

Prolonged or chronic fatigue is significantly less common than the symptom of fatigue and it is only in the last 10 years that consensus has emerged about the existence of a chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME). CFS is now accepted as a valid diagnosis by medical authorities in the UK, in the United States of America, as well as internationally. About one third of patients presenting to their doctor with six months of fatigue will meet criteria for a chronic fatigue syndrome. The other two thirds have fatigue secondary to another condition, most commonly mood and primary sleep disorders. Its primary symptom is fatigue, both physical and mental, which particularly follows exertion. Other symptoms agreed in consensual guidelines include poor concentration and memory, sleep disturbance, headache, sore throat, tender lymph glands, muscle and joint pain.

There are several criterion based definitions of CFS. These definitions were derived by consensus and have not been supported by empirical studies, and continue to be refined. Their utility stems from providing reliable criteria for research studies, rather than clinical use. The prevalence of CFS is between 2.5 % and 0.4 % depending on the definition used and whether comorbid mood disorders are excluded (that is mood disorders that are not thought to be the primary diagnoses). It is most common in women, the middle-aged, and ethnic minorities (unlike fatigue) – at least in English speaking countries.

The diagnosis and classification of CFS

The clinical taxonomy for CFS is a mess. The ICD-10 classification defines CFS within both the neurology chapter and mental health chapters. Myalgic encephalomyelitis, the alternative name for CFS, is classified as a neurological disease (G93.3) (a.k.a. post-viral CFS), whereas neurasthenia (a.k.a. CFS not otherwise specified) is classified within mental health (F48).

[Ed: Note that White does not mention, here, that Chronic fatigue syndrome is listed in ICD-10: Volume 3, The Alphabetical Index* at G93.3, the same coding as for Benign myalgic encephalomyelitis, and for Postviral fatigue syndrome (ICD-10: Volume 1: The Tabular List).]

*ICD-10: Volume 3, The Alphabetical Index:

[Back to PDW]

(Incidentally, this mess is not specific to CFS, since there are several conditions within the neurology chapter of ICD-10 that are also classified in the mental and behavioural disorders chapter. For instance, Alzheimer’s disease is classified within neurology, whereas dementia due to Alzheimer’s disease is classified under mental health. My personal view is that it is high time that all mental health disorders and neurological diseases affecting the brain were classified within the same chapter, simply called diseases/disorders of the brain and nervous system.)

[Ed: The WHO Department of Mental Health and Substance Abuse, which is overseeing the revision of Chapter V (Mental and Behavioural Disorders), is also managing the technical part of the revision of Chapter VI (Diseases of the Nervous System). According to Dr Geoffrey Reed, Senior Project Officer, WHO Department of Mental Health and Substance Abuse, Proposal forms for ICD Chapter V and Chapter VI are in preparation and expected to be released shortly.]

[Back to PDW]

There is also a current debate between “lumpers” and “splitters” about the nosology of “functional” somatic syndromes (symptom defined conditions), such as CFS, IBS and “fibromyalgia”. Some argue that the close associations between the syndromes (those with CFS are also more likely to have fibromyalgia and/or IBS) argues in favour of their being different manifestations of one over-arching functional somatic syndrome (the “lumpers”). Others argue that these syndromes are best understood by exploring their heterogeneity (the “splitters”). There is evidence to support both arguments, but two large and recent epidemiological studies suggest that chronic unexplained fatigue, for one, is both associated with and separate from other “functional” somatic syndromes. In particular, predisposing risk factors are shared whereas triggering factors are different.

CFS is not an easy diagnosis to make, since misdiagnosis is common in patients diagnosed as having CFS. A recent audit of my CFS clinic revealed that 4 out of 10 new patients (n = 250) assessed did not have CFS, and that was after a third of referrals had already been rejected as not being CFS.

The most common misdiagnoses were mood disorders, especially depressive disorders, and primary sleep disorders, particularly sleep apnoea. Other misdiagnoses included coeliac disease and autoimmune conditions. Alternative neurological diagnoses were made in 2%.

Aetiology and pathophysiology

The aetiology of CFS is unknown, but there is evidence that different risk markers are associated with predisposition, triggering, and maintenance of the illness. Predisposing risk markers include female sex, middle age, mood disorders (especially depressive disorders), other symptom defined syndromes, such as irritable bowel syndrome, and possibly either sedentary behaviour or excessive activity. As might be expected CFS patients are more likely to have attended their GP, than healthy matched controls, even up to 15 years before onset, but recent work shows that those with IBS (and no CFS) have the same tendency.

Triggering risk markers are less well established, but there is sufficient evidence to support certain infections as aetiological factors not only for fatigue but also CFS, with the best replicated evidence supporting a role for Epstein-Barr virus infection, which triggers CFS in 10% of those infected.

Maintaining or perpetuating risk markers are most important in determining treatment programmes, since reversing maintaining factors should lead to improvement. Reasonably well established factors include mood disorders, such as dysthymia, illness beliefs such as believing the whole condition is physical, pervasive inactivity, avoidant coping, membership of a patient support group, and being in receipt of or dispute about financial benefits.

Few pathophysiological findings in CFS have been replicated in independent studies. Those that have been include down-regulated hypothalamic pituitary-adrenal axis, physical deconditioning, and discrepant reports between perception of symptoms and disability and their objective tests.

The latter finding is now supported by functional brain scanning studies suggesting altered brain activity with specific tasks. The discrepancy between subjective states and objective tests has been found before in other symptom defined syndromes, such as “fibromyalgia”, and may be related to enhanced interoception (the perception of visceral phenomena), a concept first described by Charles Sherrington in 1904. One hypothesis currently being tested is that the common predisposition to “functional” somatic syndromes is caused by enhanced interoception.

Recent work suggests that these factors may be reversed by rehabilitation.


Without treatment the prognosis of CFS is poor with a systematic review of outcomes finding the median full recovery rate was 5 % (range 0-31%) and the median proportion of patients who improved of 39.5% (range 8-63%). Being younger, having less fatigue baseline, a sense of control over symptoms and not attributing illness to a physical cause were all associated with a better outcome. The prognosis is considerably better after treatment.


The NICE guidelines, published in 2007, were based on an updated systematic review. The essence of specialist care is rehabilitation, provided on an individual basis with an appropriately qualified and trained therapist. The two approaches with the greatest evidence of efficacy are cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Approximately 60% of patients report significant improvement with these approaches and about 25%report full recovery, which lasts. No pharmacological treatments are recommended (antidepressants are ineffective), but symptomatic pharmacotherapy for specific symptoms (such as pain) or comorbid conditions such as depressive illness) can be helpful complementary treatments.

These rehabilitation approaches have not received universal approval from patient charities, with concerns that patients may be harmed by exercise therapies or that CBT implying that the condition is psychological.

Is CFS neurological or psychological?

This is a nonsensical question when one considers the neuroscience of consciousness and recent advances in functional brain physiology. The philosopher, John Searle, stated the answer to this Cartesian dualism that still bedevils western medicine. “Conscious states are caused by neurophysiological mechanisms, and are realised in neurophysiological systems.” Therefore it is not possible to have a psychological process or event without a neurological mediating process. It is neither of the mind or body; it is both.

Fatigue secondary to neurological diseases

Fatigue is commonly associated with chronic medical disorders, but it should be differentiated from fatiguability. Fatiguability is the onset of a physical sensation of fatigue and weakness after exertion and is commonly reported with neurological diseases such as multiple sclerosis and myopathies.

Apart from measures of disease activity, other associations of secondary fatigue in general that have been repeatedly found include sleep disturbance, mood disorders, inactivity and physical deconditioning. Studies of fatigue associated with multiple sclerosis are instructive and exemplary. As in all studies of secondary fatigue, measures of the severity or pathophysiology of the disease itself are associated with fatigue. Some cytokines are associated, but others are not.

Associations vary depending on the fatigue measure, confirming the multidimensional nature of fatigue, but all measures are associated with depression. Objectively confirmed sleep disturbance is also associated with fatigue. Fatigue associated with MS therefore requires biopsychosocial management.

There have been a number of studies of various treatments aimed at reversing the associations of secondary fatigue in general, in the hope they would help fatigue directly, with variable results. As with CFS, the most consistent evidence of efficacy has been with graded exercise programmes and CBT.

Attarian HP, Brown KM, Duntley SP, et al. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch. Neurol. 61 (2004), 525-8.

Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ 2007 doi: 10.1136/bmj.39302.509005. AE

Chambers D, Bagnall A-M, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med 2006;99:506-20.

Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr. Rev. 24 (2003), 236-52.

Flachenecker P, Bihler I, Weber F, et al., Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult. Scler. 10 (2004), 165-9.

Fulcher KY, White PD. Strength and physiological response to exercise in patients with the chronic fatigue syndrome. J. Neurol. Neurosurg. Psychiatry 69 (2000), 302-7.

Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. Q. J. Med. 90 (1997), 223-33.

Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult. Scler. 6 (2000), 131-6.

Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J. Psychosom. Res. 55 2003), 79-90.

National Institute for Health and Clinical Excellence. Clinical guideline CG53. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management. London, NICE, 2007.

Reeves WC et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.BMC Health Serv Res 3 (2003), 25.

Romani A, Bergamaschi R, Candeloro E, et al., Fatigue inmultiple sclerosis: multidimensional assessment and response to symptomatic treatment. Mult. Scler. 10 (2004), 462-8.

M. C. Tartaglia, S. Narayanan, S. J. Francis, et al., The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch. Neurol. 61 (2004), 201-7.

Wessely SC, Hotopf M, Sharpe M. Chronic Fatigue and its Syndromes (Oxford: Oxford University Press, 1998).

Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many? Lancet 354 (1999), 936-9.

Wessely S, White PD. In debate: there is only one functional somatic syndrome. Br. J. Psychiatry 185 (2004), 95-6.

White PD, Thomas JM, Kangro HO, et al., Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 358 (2001), 1946-54.

White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007;7:6.

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For detailed information on the proposed structure of ICD-11, the Content Model and operation of iCAT, the collaborative authoring platform through which the WHO will be revising ICD-10, please scrutinise key documents on the ICD-11 Revision Google site:

For information around the DSM and ICD revision processes see DSM-V and ICD-11 Directory page:

Suzy Chapman