The Unify Coalition - CFS - mapping the interior

There have been several postings on the co-cure archives recently referring to a paper in the journal Psychological Medicine. This is not an electronically available journal. However, I enclose the entire article so people who wish to can read it in full, as opposed to the few quotes that have been flying around.
I trust this will be helpful.

Kind regards,

Simon Wessely

Professor Simon Wessely,
Professor of Epidemiological and Liaison Psychiatry,
Academic Department of Psychological Medicine,
Guy's, King's & St Thomas's School of Medicine and Institute of Psychiatry,
103 Denmark Hill,
London,
SE5 8AF

Chronic fatigue syndrome – mapping the interior

Dr Matthew Hotopf, MRCPsych MSc

Clinical Senior Lecturer in Psychological Medicine

Professor Simon Wessely, MRCPsych, FRCP, MD

Professor of Epidemiological and Liaison Psychiatry

Correspondence: Dr Matthew Hotopf, Clinical Senior Lecturer in Psychological Medicine, Department of Psychological Medicine, Guy’s King’s and St Thomas’ School of Medicine, and The Institute of Psychiatry, 103 Denmark Hill, London SE5 8AZ

Chronic fatigue syndrome – mapping the interior

Over a century ago Beard referred to fatigue as the "Central Africa of medicine – an unexplored territory which few men enter" (Beard, 1869). The last decade has seen major advances in our understanding of chronic fatigue syndrome (CFS). Much is now known of the epidemiology, clinical features, and prognosis of the condition (Wessely et al. 1998), and a number of recent papers have reported randomised trials of successful treatments involving cognitive therapy and graded exercise (Deale et al. 1997; Sharpe et al. 1996; Fulcher and White, 1997; Wearden et al. 1996). Despite these advances, which have defined some of the broad landmarks of the illness, and improved the care of patients, many areas remain uncharted. Several papers published in this issue of Psychological Medicine take us into such unexplored territory.

Lucile et al’s contribution does not directly address CFS, but will be of interest to most researchers in the field. CFS is frequently attributed to viral illness, and although trivial viral infections are not associated with later chronic fatigue (Wessely et al. 1995), the picture is different with severe infections, such as glandular fever, viral meningitis, and hepatitis A (White et al. 1995; Hotopf et al. 1996; Berelowitz et al. 1995) with cohort studies demonstrating clear associations. Surprisingly little is known of the acute psychological effects of viral illness – the topic of Lucile’s paper. Using a battery of neuropsychological tests, the authors found that subjects experiencing `flu-like symptoms, performed less well than controls on specific memory tasks - an effect which was unrelated to pyrexia. These deficits – the authors argue – may be due to the role of cytokines released during infection. Although cytokines were not measured in this study, recent work on a cute influenza suggests that acute symptoms correlate best with levels of circulating interleukin (IL)-6 (Hayden et al. 1998). Cytokine receptors exist in a variety of brain structures, and may modulate the hypothalamic-pituitary-adrenal axis (HPA) (McEwen et al. 1997), which has in turn been implicated in the pathogenesis of CFS, leading some researchers to argue for a central role of cytokines in CFS (Ur et al. 1992; Hickie and Lloyd, 1995). Such speculation is, of course, a long way from determining a causal pathway between infection and CFS, but suggests that integrative studies assessing the role of immune, neuroendocrine and behavioural factors following viral infection (and other stressors associated with fatigue) might be a useful approach to understanding the condition (Bennett et al. 1998).

Among the cardinal features of CFS is the fact that exertion - be it mental or physical - worsens fatigue. Sufferers are frequently avoidant of exertion, and such avoidance is associated with a poorer outcome (Sharpe et al. 1992; Joyce et al. 1997). It is worth asking why CFS patients avoid, and a number of dynamic studies which observe changes in symptoms or psychomotor function in the context of exertion begin to explain better why this may happen. CFS patients do not show any evidence of peripheral muscular problems (Wessely et al 1998), but they do report more symptoms, and show more marked changes in cognitive function following exercise than healthy controls (LaManca et al. 1998; Blackwood et al. 1998). The study by Smith et al demonstrates a similar picture with CFS patients developing fatigue more rapidly than healthy controls when asked to perform tasks which involved prolonged attention. These findings were not specific to CFS – they occur in sleep deprivation, and sleep disorder is common in CFS.

What does this mean in terms of treatment? Randomised controlled trials show that treatments which aim to overcome fear of exertion have useful benefits in CFS - graded exercise treatment and cognitive behaviour therapy both do this. Deale et al's study of CBT demonstrated that the fear that exertion would lead to lasting damage was the most important attribution to address in CBT - more important than addressing the often contentious issue of aetiology. It is important to remember that the belief that exertion will cause a worsening is founded on real experiences of sufferers, thus behavioural change requires a leap of faith on the part of the patient.

The genetics of fatigue and CFS has been largely ignored, unless one counts previous work showing a high familial loading for neurocirculatory asthenia (Cohen et al. 1951). Given the difficulty of defining the phenotype, it is probably more sensible to start with the genetics of the principal symptom, fatigue, and three studies in this issue add substantially to our knowledge of this neglected issue. Farmer et al explored the issue in a twin study of children deriving a model where up to 76% of the variance of fatigue could be explained by genetic factors. Hickie et al’s studies assessed the heritability of fatigue in mid to late life, and again found a strong heritable component, although they do not report estimates of heritability.

The interpretation of additive models which aim to distribute observed variance into mutually exclusive genetic and environmental categories is problematic (Rothman and Greenland, 1998). The relative contribution of heritable and environmental risk factors to the variance of a disorder in populations is not fixed. Most conditions are likely to involve gene-environment interactions, and heritability depends critically on the prevalence of environmental risk factors. Paradoxically, the more prevalent such risk factors are, the more genetic the condition will appear to be. This point was made intuitively by the epidemiologist Geoffrey Rose, who remarked that in a population where everybody smoked, lung cancer would appear to be a genetic disorder. Allison and Faith (1997) demonstrated the point formally in a model where the increasing prevalence of environmental risk factors was associated with an increase in the heritability of the condition under study (in this case obesity). Thus we believe that the fashion for heritability fractions must be tempered with caution - the fraction is a limited parameter which applies only to the specific population under study.

The strength of the Australian paper (Hickie et al. 1998b) is to go further and explore shared and unique risk factors for fatigue, depression, psychological distress, and anxiety. This approach has proved fruitful in improving understanding of the overlap between anxiety and depression (Kendler et al. 1992). The association between fatigue and common psychiatric disorders has always been controversial. There is no question that the association exists, with patients with CFS experiencing approximately twice as much psychiatric disorder as controls with medical illness. However, there are a number of important differences between CFS and depression. Exploring the neurobiology of these conditions has thrown up interesting leads – such as the relative underactivity of the HPA axis in fatigue as opposed to the opposite overactivity of the axis in depression (Demitrack et al. 1991; Cleare et al. 1995). Hickie’s paper demonstrates that depression, anxiety, psychological distress and fatigue are probably determined by different underlying genetic factors, with one uniquely contributing to fatigue. Similarly they identified a single environmental factor which appears to be unique to fatigue. From these findings they argued that psychiatric classification should include prolonged fatigue states.

A number of caveats have to be applied to these studies – the first of their kind to address the genetics of chronic fatigue. The complex models shown in Hickie et al’s papers are derived by a process of induction. They have managed to partially replicate the same model in two samples, however the results require further replication before the authors’ suggestion that the classification of psychiatric disorders is changed. Farmer et al’s study used parental reporting of fatigue among the twins, however parents and their children often disagree about the presence of symptoms (Taylor et al. 1996). The results may also be due to parents of identical twins seeing them as more similar than do parents of dizygotic twins. Finally, the Australian study relied on twins aged over 50 years, whereas most patients seen and treated for CFS are considerably younger. Their finding of unique heritable and environmental components of fatigue in this sample may be due to confounding by physical illness. Physical illness – commoner in older samples – is strongly associated with fatigue, and is likely to have genetic and environmental determinants entirely independent of depression and anxiety. Thus considerable caution must be taken before generalising this study, and it is premature to use this as evidence to justify a change in psychiatric nosology.

Studies into the immunology of CFS give a confused and contradictory picture. The final genetic study (Hickie et al. 1998a) attempted to separate out the possible contributing factors to psychological distress, fatigue and immune responsiveness. There is a wealth of evidence that stress affects immune functioning (McEwen et al. 1997). Using a small sample of twins, Hickie et al proposed a model by which the same genes coding for psychological distress and fatigue are also implicated in immune responsiveness but that most of the variability in immune responsiveness could be attributed to environmental factors which were unrelated to psychological distress and fatigue. The finding that stress and immune responsiveness are related via a common genetic mechanism has the potential to greatly simplify psychoneuroimmunology and such integrative approaches are welcome in a field which requires links to be made between symptoms and objective markers of immune activity.

Where should CFS research go from here? There is a clear need to follow up the lead given by the genetic studies. The model which suggests separate genetic factors predict fatigue as opposed to depression and anxiety may be important to psychiatric taxonomy, and has implications for the minority of patients with CFS without psychiatric disorder. Further, it may provide clues as to biological markers of susceptibility to CFS, and lead eventually to assessing the role of specific candidate genes for the condition.

There is an increasing need for integrative research into CFS. If anything is clear, it is that CFS cannot be understood via a single mechanism. Given that most research still takes place in patients who have been ill with CFS for many months or years, it is usually impossible to determine whether the biological and psychological changes which have been reported in sufferers are primary or secondary. The relative role of immune changes, viral infections, HPA axis underactivity, behavioural change, and attributional style may be best explored using prospective cohort studies of conditions which are known to be associated with later fatigue states. Such conditions might include stressful life events, viral infection or post-operative states.

References

Allison, D.B. and Faith, M.S. (1997) A proposed heuristic for communicating heritability estimates to the general public, with obesity as an example. Behavior Genetics 27, 441-445.

Beard, G. (1869) Neurasthenia, or nervous exhaustion. Bost. Med. Surg. J. 3, 217-221.

Bennett, B.K., Hickie, I.B., Vollmer-Conna, U.S., Quigley, B., Brennan, C.M., Wakefield, D., Douglas, M.P., Hansen, G.R., Tahmindjis, A.J. and Lloyd, A.R. (1998) The relationship between fatigue, psychological and immunological variables in acute infectious illness. Australian and New Zealand Journal of Psychiatry 32, 180-186.

Berelowitz, G.J., Burgess, A.P., Thanabalasingham, T., Murray-Lyon, I.M. and Wright, D.J.M. (1995) Post-hepatitis syndrome revisited. Journal of Viral Hepatitis 2, 133-138.

Blackwood, S.K., MacHale, S.M., Power, M.J., Goodwin, G.M. and Lawrie, S.M. (1998) Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. J. Neurol. Neurosurg. Psychiatry 65, 541-546.

Cleare, A., Bearn, J., McGregor, A., Alain, S., Wessely, S. and O'Keane, V. (1995) Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J. Affect. Disord.

Cohen, M.E., Badal, D.W., Kilpatrick, A., Reed, W. and White, P.D. (1951) The high familial prevalence of neurocirculatory asthenia (anxiety neurosis, effort syndrome). American Journal of Medical Genetics 3, 126-158.

Deale, A., Chalder, T., Marks, I. and Wessely, S. (1997) A randomised controlled trial of cognitive behaviour versus relaxation therapy for chronic fatigue syndrome. Am. J. Psychiatry 154, 408-414.

Demitrack, M., Dale, J., Straus, S., Laue, L., Listwak, S., Kruesi, M., Chrousos, G. and Gold, P. (1991) Evidence for impaired activation of the hypothalamic-pituitary adrenal axis in patients with chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism 73, 1224-1234.

Fabsitz, R.R., Sholinsky, P. and Carmelli, D. (1994) Genetic influences on adult weight gain and maximum body mass index in male twins. Am. J. Epidemiol 140, 711-720.

Farmer, A., Scourfield, J., Martin, N., Cardno, A. and McGuffin, P. (1999) Is disabling fatigue in childhood influenced by genes? Psychological Medicine (In Press)

Fulcher, K.Y. and White, P.D. (1997) A randomised controlled trial of graded exercise therapy in patients with the chronic fatigue syndrome. Br. Med. J. 314, 1647-1652.

Hayden, F.G., Fritz, R.S., Lobo, M.C., Alvord, W.G., Strober, W. and Straus, S.E. (1998) Local and systemic cytokine responses during experimental human influenza A virus infection. Journal of Clinical Investigation 101, 643-649.

Hickie, I. and Lloyd, A. (1995) Are cytokines associated with neuropsychiatric syndromes in humans? Int. J. Immunopharmac. 17, 677-683.

Hickie, I., Bennett, B., Lloyd, A., Heath, A. and Martin, N. (1998a) Complex genetic and environmental relationships between psychological distress, fatigue and immune functioning: a twin study. Psychological Medicine (In Press)

Hickie, I., Kirk, K. and Martin, N. (1998b) Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychological Medicine (In Press)

Hotopf, M.H., Noah, N. and Wessely, S. (1996) Chronic fatigue and psychiatric morbidity following viral meningitis: a controlled study. J. Neurol. Neurosurg. Psychiatry 60, 504-509.

Joyce, J., Hotopf, M. and Wessely, S. (1997) The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. Quart. J. Med. 90, 223-233.

Kendler, K.S., Neale, M.C., Kessler, R.C., Heath, A.C. and Eaves, L.J. (1992) Major depression and generalized anxiety disorder. Same genes, (partly) different environments? Arch. Gen. Psychiatry 49, 716-722.

LaManca, J.J., Sisto, S.A., DeLuca, J., Johnson, S.K., Lange, G., Parega, J., Cook, S. and Natelson, B.H. (1998) Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. Am. J. Med. 105(3A), 59s-65s

Lucile, C., Didier, L., Robert, D. and Glyn, G. (1998) Attentional and mnemonic deficits associated with infectious disease in humans. Psychological Medicine (In Press)

McEwen, B.S., Biron, C.A., Brunson, K.W., Bulloch, K., Chambers, W.H., Dhabhar, F.S., Goldfarb, R.H., Kitson, R.P., Miller, A.H., Spencer, R.L. and Weiss, J.M. (1997) The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Research Reviews 23, 79-133.

Rothman, K.J. and Greenland, S. (1998) Modern Epidemiology, 2nd edn. Philadelphia: Lippincott-Raven.

Sharpe, M., Hawton, K., Seagroatt, V. and Pasvol, G. (1992) Follow up of patients presenting with fatigue to an infectious diseases clinic. Br. Med. J. 305, 147-152.

Sharpe, M., Hawton, K., Simkin, S., Surawy, C., Hackmann, A., Klimes, I., Peto, T., Warrell, D. and Seagroatt, V. (1996) Cognitive therapy for chronic fatigue syndrome: a randomized controlled trial. Br. Med. J. 312, 22-26.

Smith, A.P., Borysiekwicz, L., Pollock, J., Thomas, M., Perry, K. and Llewelyn, M. (1999) Acute fatigue in chronic fatigue syndrome patients. Psychological Medicine (In Press)

Taylor, D.C., Szatmari, P., Boyle, M.H. and Offord, D.R. (1996) Somatization and the vocabulary of everyday bodily experiences and concerns: a community study of adolescents. J. Am. Acad. Child. Adol. Psychiatry. 35, 491-499.

Ur, E., White, P.D. and Grossman, A. (1992) Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. Eur. Arch. Clin. Neurosci. 241, 317-322.

Wearden, A., Morriss, R., Mullis, R., Strickland, P., Pearson, D., Appleby, L. and Campbell, I. (1996) A double-blind, placebo controlled treatment trial of fluoxetine and a graded exercise programme for chronic fatigue syndrome.

Wessely, S., Chalder, T., Hirsch, S., Palikowska, T., Wallace, P. and Wright, D.J.M. (1995) Post-infectious fatigue: prospective cohort study in primary care. Lancet 345, 1333-1338.

Wessely, S., Hotopf, M. and Sharpe, M. (1998) Chronic fatigue and its syndromes, 1st edn. Oxford: Oxford University Press.

White, P., Thomas, J., Amess, J., Grover, S., Kangro, H. and Clare, A. (1995) The existence of a fatigue syndrome following after glandular fever. Psychological Medicine 25, 907-916.

Design & development by:

Contact us at (910) 272-0903 or via email at: webmaster@unifycoalition.org
Most recent revision Tuesday, October 30, 2001