Why do we not know what causes CFS and why is the field so polarized ?

| Chronic fatigue syndrome (CFS) is a debilitating illness that affects many people. It has been marred by controversy, from initial scepticism in the medical community about the existence of the condition itself to continuing disagreements — mainly between some patient advocacy groups on one side, and researchers and physicians on the other — about the name for the illness, its aetiology, its pathophysiology and the effectiveness of the few currently available treatments. The role of the CNS in the disease is central in many of these discussions. Nature Reviews Neuroscience asked four scientists involved in CFS research about their views on the condition, its causes and the future of research aimed at improving our understanding of this chronic illness. PERSPECTIVES NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1 Nature Reviews Neuroscience | AOP, published online 27 july 2011; doi:10.1038/nrn3087 © 2011 Macmillan Publishers Limited. All rights reserved understand and get better from whatever it is that they suffer from. This paints a different picture to what you might conclude from a brief perusal of the internet, where sometimes the loudest voices seem to be more concerned with attacking anyone who disagrees with them, especially if they are unlucky enough to be working in psychiatry or psychology. Likewise, there is probably a fairly broad consensus among clinicians and academics, with only a very small but vocal minority giving an impression of polarization within the field. Unfortunately, as we know from the measles, mumps and rubella (MMR) vaccination–autism saga, polarization and antipathy always make for better media coverage than consensus and collaboration. Why do studies use different classifications of CFS and how crucial are these differences for research into CFS? S.H. There are currently five case definitions of CFS/ME; however, the most prominent and widely used of these are the Canadian case definition1 and the 1994 US Centers for Disease Control and Prevention (CDC) case definition2. The selection of these two definitions over the others has never been substantiated and it has been criticized for lack of specificity. Although all definitions attempt to capture critical aspects of the illness and to differentiate the symptom complex from similar symptom clusters that are associated with other diseases, none have produced evidence to demonstrate either their accuracy or precision in defining cases of CFS/ME. The root of the difficulty is that CFS/ME is a syndrome and, as with many medical syndromes, there are multiple causes. To call CFS/ME a single disease greatly underestimates the complexity of the problem. Thus, to look for ‘the’ cause of CFS/ ME is a self-defeating exercise. What is now needed is the application of; first, systems approaches to establish subphenotypes of the syndrome through standardized clinical, laboratory and physiological measurements without constraining the data input with preconceived clustering; second, ’omics’ and other platform technologies to identify pathways that associate with particular subphenotypes; and third, pathway analyses to identify key pathopysiological processes and ‘nodes’ of intersection at which focused therapeutic intervention might be effective. A.L.K. Most studies have used the 1994 case definition that was created with the leadership of the CDC2. Two other case definitions — the Canadian1 and Oxford3 case definitions — are also used. I suspect that none of these case definitions is likely to describe a very homogeneous group of patients. However, they are the best definitions that researchers have been able to provide, and having these case definitions surely has advanced CFS research. In my view, it also is important to standardize how each element of the case definition is defined. The CDC has recommended ways of doing this. D.M. There are at least three published case definitions (the 1988 CDC definition4, the 1994 CDC definition2 and the 2003 Canadian Expert Consensus Panel definition1) and most investigators base their participant inclusion and exclusion criteria on one or more of these. However, sometimes the criteria are modified to be more restrictive, to concentrate on severe disease, or less restrictive, to include the wide variety of people with this syndrome. Different classifications reflect the lack of a clear aetiology and the complex nature of the syndrome. Meaningful comparisons across studies are not possible unless the enrolment characteristics of both patients and controls are described. It would be helpful if authors would clearly specify and quantify, as far as possible, the specific criteria that were used to decide which subjects to include or exclude in their studies. The criteria that were used to identify control populations should also be clearly specified. S.W. Case definitions remain vital for research into CFS. At the moment the definition is still symptom-based and indeed there are a number of definitions. In the UK we sometimes use the Oxford criteria3 but overall the most accepted and used