Chronic Fatigue Syndrome: Understanding a Complex Illness

PERSPECTIVES

Sceptics rightly ask whether there is evi- VIEWPOINT dence of objective biological abnormalities underlying CFS. In my judgment, the Chronic fatigue syndrome: literature demonstrates many such abnormalities, both when patients with CFS are understanding a complex illness compared to healthy controls and when they are compared to patients with other fatiguing illnesses, such as multiple sclero- Stephen T. Holgate, Anthony L. Komaroff, Dennis Mangan and Simon Wessely sis or major depression. Many of the docu- Abstract | Chronic fatigue syndrome (CFS) is a debilitating illness that affects many mented abnormalities involve the central and autonomic nervous systems. In my people. It has been marred by controversy, from initial scepticism in the medical experience, most sceptics are unaware community about the existence of the condition itself to continuing disagreements of the extensive literature citing such — mainly between some patient advocacy groups on one side, and researchers abnormalities and become less sceptical and physicians on the other — about the name for the illness, its aetiology, its upon reading it. pathophysiology and the effectiveness of the few currently available treatments. Dennis Mangan. Despite many years of The role of the CNS in the disease is central in many of these discussions. Nature research, no specific factor has been con- Reviews Neuroscience asked four scientists involved in CFS research about their sistently associated with CFS, an illness views on the condition, its causes and the future of research aimed at improving that is sometimes referred to as ME. The our understanding of this chronic illness. diagnosis remains one of exclusion — ruling out all other causes — rather than having a test ‘for’ ME/CFS. A clear defini- Why do we not know what causes professionals who think that the syndrome tion of the disease remains elusive. The CFS and why is the field so polarized? has only psychological and psychosocial current definitions consist of a list of symp- causes. This division is a main reason for toms that are often, but not always, pre- Stephen Holgate. For years the medical patients receiving poor healthcare and for sent and that occur with varying degrees profession did not acknowledge chronic the erosion of patient–medical practitioner of severity. The current definitions also fatigue syndrome (CFS) as a ‘real’ condi- trust. include a requirement that the associated tion. The situation became confused when fatigue has persisted for 6 months (BOX 1). the term myalgic encephalopathy (ME) Anthony L. Komaroff. We do not know was introduced and linked to CFS, with the cause of CFS for the same reason that Simon Wessely. There are many similar many preferring ME because it implied we do not know the cause of many neuro- disorders of which we do not know the (rightly or wrongly) a concept of mecha- logic diseases: we have not yet been clever cause, and given that CFS almost certainly nisms. In 2002, a Lancet commentary enough to figure it out. If the word ‘polar- does not have one cause, it makes identify- noted, “The fact that both names for the ized’ means that opinions will remain ing them even more difficult. But this does illness were used symbolizes respect for unchanged regardless of the evidence, not mean that we cannot help sufferers. different viewpoints while acknowledg- I would like to think that this is not the Why is the field so polarized? I am not sure ing the continuing lack of consensus on a case. And I am not sure that the CFS field that it is. True, there are some CFS activ- universally acceptable name.” This confu- is more polarized than other fields. The ists who have extreme views, verging on sion has been further compounded by reception that the prion hypothesis (which the intolerant, but frankly I think that they major disagreements over the prevalence states that a prion is a protein that can are in the minority. Our CFS service at and pathophysiology of the illness, let replicate without the use of nucleic acid) King’s College and the Maudsley Hospital alone the extraordinary range of available received for more than a decade comes to in South London, UK — one of the first treatments, only a few of which have any mind. So, too, does the current debate over ever NHS services dedicated just to CFS evidence base. As a result, medical prac- the possible aetiologic role of Epstein–Barr — has seen over 3,000 sufferers since its titioners still view the diagnosis of CFS virus in multiple sclerosis. inception, and I have interviewed over with great uncertainty and sometimes with CFS is controversial because the case 1,000 of them. What we see is not antago- outright denial. It is this view that creates definitions (that is, how the illness being nism, abuse or intimidation from these a particularly polarized debate with — and studied is defined) of CFS consist exclu- patients. Perplexity yes and confusion sometimes an angry response from — sively of symptoms — and obviously any- sometimes — because CFS is a confusing patients. The division is especially great one can say they have the constellation of and sometimes baffling condition. But the between patient groups and healthcare symptoms that meets the case definition. patients primarily have a burning desire to

understand and get better from whatever it definitions — the Canadian1 and Oxford3 disease, or less restrictive, to include the is that they suffer from. This paints a dif- case definitions — are also used. I suspect wide variety of people with this syndrome. ferent picture to what you might conclude that none of these case definitions is likely Different classifications reflect the from a brief perusal of the internet, where to describe a very homogeneous group of lack of a clear aetiology and the complex sometimes the loudest voices seem to be patients. However, they are the best defini- nature of the syndrome. Meaningful com- more concerned with attacking anyone tions that researchers have been able to parisons across studies are not possible who disagrees with them, especially if provide, and having these case definitions unless the enrolment characteristics of they are unlucky enough to be working surely has advanced CFS research. In my both patients and controls are described. It in psychiatry or psychology. Likewise, view, it also is important to standardize would be helpful if authors would clearly there is probably a fairly broad consensus how each element of the case definition is specify and quantify, as far as possible, the among clinicians and academics, with defined. The CDC has recommended ways specific criteria that were used to decide only a very small but vocal minority giv- of doing this. which subjects to include or exclude in ing an impression of polarization within their studies. The criteria that were used to the field. Unfortunately, as we know from D.M. There are at least three published identify control populations should also be the measles, mumps and rubella (MMR) case definitions (the 1988 CDC defini- clearly specified. vaccination–autism saga, polarization and tion4, the 1994 CDC definition2 and the antipathy always make for better media 2003 Canadian Expert Consensus Panel S.W. Case definitions remain vital for coverage than consensus and collaboration. definition1) and most investigators base research into CFS. At the moment the def- their participant inclusion and exclusion inition is still symptom-based and indeed Why do studies use different criteria on one or more of these. However, there are a number of definitions. In the classifications of CFS and how crucial sometimes the criteria are modified to be UK we sometimes use the Oxford criteria3 are these differences for research into CFS? more restrictive, to concentrate on severe but overall the most accepted and used

S.H. There are currently five case definitions of CFS/ME; however, the most prominent The contributors* and widely used of these are the Canadian case definition1 and the 1994 US Centers for Stephen T. Holgate is a UK Medical Research Council clinical professor of immmunopharmacology Disease Control and Prevention (CDC) case at the School of Medicine, University of Southampton, UK. He received his medical degree from the University of London, UK, M.D. by thesis and D.Sc. from the University of Southampton. From definition2. The selection of these two defini- 1978 to 1980 he spent a postdoctoral fellowship at Harvard Medical School, Cambridge, tions over the others has never been substan- Massachusetts, USA, researching inflammatory mechanisms. His current research is directed tiated and it has been criticized for lack of towards the pathophysiology of asthma and allied disorders, with a special interest in specificity. Although all definitions attempt understanding how environmental exposures such as allergens, virus infections and air pollutants to capture critical aspects of the illness and interact with the airways in the induction and exacerbation of asthma. to differentiate the symptom complex from Anthony L. Komaroff is the Simcox–Clifford–Higby Professor of Medicine at Harvard Medical similar symptom clusters that are associated School. He received his M.D. from the University of Washington School of Medicine, Seattle, with other diseases, none have produced evi- Washington, USA. Except for 2 years during which he trained at the US National Institutes of dence to demonstrate either their Health (NIH) in Bethesda, Maryland, USA, he has spent his entire career at Harvard Medical School accuracy or precision in defining cases and its affiliated hospitals. He served for 15 years as Director of the Division of General Medicine in of CFS/ME. The root of the difficulty is the Department of Medicine at Brigham and Women’s Hospital, Boston, Massachusetts, USA. Early that CFS/ME is a syndrome and, as with in his career he studied common infectious illnesses that are treated in outpatient settings, such as many medical syndromes, there are multi- respiratory and urinary infections. For 25 years, the study of chronic fatigue syndrome has been his ple causes. To call CFS/ME a single disease primary research interest. greatly underestimates the complexity of the Dennis Mangan is Chair of the Trans-NIH ME/CFS Research Working Group at the NIH. He has a problem. Thus, to look for ‘the’ cause of CFS/ Ph.D. in microbiology and immunology from the West Virginia University, Morgantown, USA, and ME is a self-defeating exercise. What is now training in cellular immunology at the University of Michigan, Ann Arbor, USA, the University of needed is the application of; first, systems Rochester, New York, USA, and the National Institute of Dental and Craniofacial Research, NIH. He approaches to establish subphenotypes of has over 16 years experience as a program official at the NIH, where he coordinates research the syndrome through standardized clinical, support for ME/CFS and serves as a senior advisor on issues related to the biological basis for sex laboratory and physiological measurements differences in diseases and conditions. without constraining the data input with Simon Wessely is a professor and the Chair of the Department of Psychological Medicine and also preconceived clustering; second, ’omics’ Vice Dean for Academic Psychiatry at the Institute of Psychiatry, King’s College London, UK. He and other platform technologies to identify completed basic medical sciences at Cambridge University, UK, followed by clinical training at pathways that associate with particular Oxford University, UK. He then obtained membership of the Royal College of Physicians in subphenotypes; and third, pathway analyses Newcastle, UK, and started to train in psychiatry at the Maudsley Hospital and the National to identify key pathopysiological processes Hospital for Neurology in London, UK. His Master’s and doctorate degrees are in epidemiology, a topic that has been an underlying theme of his research for many years. and ‘nodes’ of intersection at which focused He has authored or co-authored over 600 papers, mainly on unexplained symptoms and therapeutic intervention might be effective. syndromes, the boundaries of medicine and psychiatry, clinical epidemiology, and more recently military health. He is the Director of the King’s Centre for Military Health Research at King’s A.L.K. Most studies have used the 1994 College London, and the Civilian Consultant Advisor in Psychiatry to the British Army. case definition that was created with the * The contributors are listed in alphabetical order. leadership of the CDC2. Two other case

definition, including by our unit, is the Box 1 | 1994 Centers for Disease Control and Prevention case definition for CFS 1994 CDC case definition2, which has been cited 1,700 times, 150 of which were To be diagnosed with chronic fatigue syndrome, a patient must satisfy two criteria2: last year. There have been attempts to • Have self-reported persistent or relapsing fatigue for at least 6 consecutive months or longer; derive a case definition that is somehow other medical conditions of which manifestation includes fatigue must be excluded by clinical ‘neurological’ (with the implicit, and diagnosis. sometimes explicit, assumption that other • Concurrently have four or more of the following symptoms: post-exertional malaise, impaired case definitions identify something that memory or concentration, unrefreshing sleep, muscle pain, multi-joint pain without redness or is ‘psychiatric’ — whatever that means, swelling, tender cervical or axillary lymph nodes, sore throat, headache. although it is rarely something good), but The symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue. this has not been possible. Adding more symptoms, such as sensitivity to noise or light, to the current case definition makes the association with recognized psychiat- encouraged those who believed in a single unproven but plausible. However, it may ric disorders stronger, not weaker as some causative organism, but subsequent stud- not explain all cases that meet case defini- mistakenly believe. Unless and until a ies have dispelled the initial claims, much tions of CFS. validated biomarker for CFS is discovered, to the disappointment of many patients symptom-based case definitions will con- and, indeed, researchers who initially D.M. There is no solid evidence to date that tinue to be used, and although the CDC thought an important aetiological insight any viral or bacterial infection is associated definition could be improved, it is unlikely had been gained. However, one is left with with ME/CFS. There are many scientific to be superseded in the near future. a strong sense that post-viral events are articles claiming to have demonstrated such a common trigger of CFS, but how they an association, but none have withstood How strong is the evidence that viral lead to chronic persistent disease remains subsequent scrutiny by scientists that were infections and/or immune unresolved. unaffiliated with the original research. dysregulation play a part in the aetiology However, many ME/CFS patients have of CFS? A.L.K. I am a clinician and epidemiolo- reported that the onset of their symptoms gist. The majority of the patients with CFS followed an episode of flu-like illness. This S.H. The current understanding of CFS/ that I have evaluated state categorically observation has led to the theory that any ME is that the syndrome has an external that their severe fatiguing illness began of a number of acute infections can trigger environmental or microbiological trig- with an infectious-like syndrome, charac- an as yet unidentified pathological process ger, such as chemical exposure or a virus, terized by respiratory and/or gastrointes- in some people that becomes ME/CFS. but that psychological and social factors tinal symptoms, myalgias (muscle pains), Although the contribution of the immune are important in perpetuating the illness. fever and adenopathy (enlargement of system cannot be discounted and abnor- Certainly, interventions such as cognitive lymph glands). In addition, many clinical malities in immune function may be associ- behavioural therapy and graded exercise and epidemiologic studies have described ated with ME/CFS, there is no definitive have been shown to be helpful in some post-infectious fatigue syndromes that evidence that immune cell dysregulation patients5, but the issue that concerns occur in association with a variety of viral plays a causative part in the development of most patients is the lack of effort by the and bacterial agents. Most persuasive was this syndrome. research community (scientists and clini- a prospective study organized by the CDC cians) in trying to understand the trigger- and conducted in Australia, which docu- S.W. The evidence that certain infections ing factors and how these then translate mented chronic post-infectious fatigue have the ability to trigger CFS is over- into chronic disease and disability. The syndromes in about 10% of subjects fol- whelming. For example, there is a greater sudden occurrence of CFS/ME in children lowing infection with any one of three risk of developing CFS after Epstein–Barr and previously fit and able athletes, often different agents. There are also many stud- virus than other common infections. We following a viral (or viral-like) illness, ies that show a state of chronic immune do not know why this is so, but elegant point to important and as yet unidentified activation in patients with CFS, as well as longitudinal studies have provided firm triggers. As with other chronic diseases selective dysfunction (such as impaired evidence for this link. The same applies to (for example, asthma, inflammatory natural killer cell function). Q fever. Immune dysfunction is likewise bowel disease and multiple sclerosis) the I think that the literature suggests that known to be associated with CFS — we initiating events may be similar to those the following hypothesis is reasonable: and others, for example, have shown that exacerbate the disease once estab- CFS can be triggered by a variety of infec- immune activation in patients with CFS. lished. There is accumulating evidence tious agents, particularly agents that the However, we do not know if this indicates for a wide variety of abnormalities in immune system cannot eradicate and that that immune activation may have an aetio- patients with CFS/ME, including altered can infect the CNS. A low-grade immunological role in the disease or, alternatively, innate and adaptive immunity, disordered logical war then ensues, in both the CNS if it is confounded by low cortisol levels or pain perception, endocrine abnormali- and periphery, and many of the symptoms sleep dysfunction, both of which are com- ties, sleep disorders and cardiovascular of the illness are caused by the effect of monly found in CFS patients and both of dysfunction. This variety does not point cytokines in the CNS. The cytokines may which are associated with immune activa- to an individual cause or group of causes. be made in the CNS or they may penetrate tion. Interventions targeted at infective The initial xenotropic murine leukemia a blood–brain barrier that is made porous agents and/or immune activation have so virus-related virus (XMRV) findings6 by CNS inflammation. This hypothesis is far been ineffective.

Does CFS have a psychiatric and/or after the onset of CFS and can compound CFS sufferers experience doesn’t explain psychological component? Why is the suffering and require treatment. There why they got ill in the first place but can there such resistance from patient groups is much less evidence that patients with play an important part in treatment, as against this idea? CFS have higher rates of psychiatric illness confirmed in the large and elegant PACE in the years before the onset of CFS — in trial5. S.H. Psychiatric manifestations clearly other words, that pre-existing psychopa- Why is there such resistance from play a part in CFS, as in many chronic thology leads to CFS. And all of the stud- some quarters? Some sadly continue to disabling disorders, but other, unidentified ies that have found psychiatric illness in answer my first question above in the pathophysiological factors may be more some patients with CFS simultaneously affirmative. It remains the case that con- directly involved in the CNS manifesta- find many patients with CFS who have no ditions that are perceived or classified as tions. A key issue that is strongly contested current or lifetime evidence of psycho- psychiatric in origin are associated with is whether psychiatric symptoms are pri- pathology but have the same spectrum of stigma and are still being labelled as being mary, secondary or occur in parallel with symptoms. Finally, there are a number ‘all in the mind’, and those who suffer underlying physiological, immunological of objective abnormalities in patients from them are not given the same respect or inflammatory causes. Many patients with CFS that are not found in patients with as those with ‘physical’ illnesses. Unless hold the view that the medical profession major depression. and until this changes, the controversy attributes the entire syndrome to psychi- will persist. atric or psychological disorders in the D.M. This remains to be determined. absence of other mechanisms. This view Many, if not all, chronic diseases can have Is CFS ultimately a disease of the CNS has been reinforced by the only proven an effect on the patient’s mental status. (neurological and/or psychiatric)? effective interventions being those based Depression, brain fog and impaired cogni- on symptom relief rather than on a spe- tion are frequently reported by some ME/ S.H. The variety of systemic symptoms cific set of underlying aetiological causes. CFS patients. Research shows recipro- makes it difficult to believe that the primary Some patients with CFS/ME also consider cal effects of the immune and endocrine dysfunction in patients with CFS lies purely that graded exercise, which clinical trials systems on brain and neuronal activity, in the CNS. However, well documented have shown to be moderately beneficial5, and thus offers possible explanations for disorders of the autonomic nervous sys- initially worsens their symptoms. The many symptoms that are associated with tem, sleep disorders, defective attention, frustration expressed by patients and their ME/CFS. However, labelling this complex abnormalities in cognition, information support groups reflects a perceived failure disease as only a psychiatric illness fails to processing and recall, stress and hypothala- by the medical community to appreciate account for a possible role, for example, of mus–pituitary axis abnormalities, altered that CFS/ME is a ‘real’ disease and not infection, inflammation, immune dysfunc- sensory and pain perception, and reduced ‘all in the mind’ (a term patients associ- tion and endocrine disorders in causing motor speed in patients with CFS point to ate with ‘imagined’ — that is, not real). the symptoms of the illness. major CNS involvement. Even the most fre- Technological developments in neurosci- quently reported symptom of fatigue alone ence ‘such as functional brain imaging’ S.W. I have learned from bitter experience or post-exertional fatigue could have both are providing new ways of studying how that it is best to answer this question with central and peripheral neurological com- the CNS is influenced by systemic disor- another. By psychiatric and psychologi- ponents; so little is known about the patho- ders and vice versa. With such powerful cal do you mean hysterical, non-existent physiology of different types of fatigue. The and innovative tools available to explore or imaginary? In which case the answer occurrence of psychiatric symptoms may disease mechanisms, it would be a missed is unequivocally no. At other times I vary be intrinsic to the underlying disease pro- opportunity and a great disservice to CFS/ my question: do you consider illnesses cess, similar to the situation in infectious ME patients if these tools could not be such as schizophrenia, major depression, mononucleosis, viral encephalitis and auto- used to enhance understanding of this dis- Alzheimer’s disease or autism to be psychi- immune disease. In addition, psychiatric ease because of the prejudice of relatively atric or psychological? If you do, then the manifestations may occur in response to few individuals. answer might be yes. Now, having agreed chronic symptoms and functional disability our terminology, what do we know? associated with the disease, as is the case A.L.K. Some patients resist the suggestion First, we know that prospective stud- in many chronic degenerative and inflam- that they have a psychiatric illness because ies have established that the risk of CFS matory disorders. It is clear that systemic, psychiatric illness remains a stigma for is increased in people with a history of neurological and psychiatric manifestations many people (including some health pro- depression. Second, cross-sectional stud- are all part of the syndrome complex, are fessionals). Indeed, some patients with pri- ies that compared CFS with other medical interdependent and vary in intensity both mary depression may imagine, amplify or conditions have shown that the proportion between patients and in a single patient even fabricate CFS symptoms in order to of CFS patients with co-morbid psychi- over time. seek a diagnosis that is more acceptable atric disorders is too high to be simply to them than depression. explained as a reaction to having the ill- A.L.K. The literature strongly suggests Does CFS have a psychiatric compo- ness but is compatible with the idea that that the CNS and autonomic nervous nent? Many studies have found higher this co-morbidity might reflect a shared system are involved in many patients rates of psychiatric illness — particularly underlying CNS dysfunction. Third, we who meet the case definitions for CFS. mood and anxiety disorders — in patients know that, as with other chronic disa- However, there is no neurologic test that with CFS than in the population at large. bling conditions, addressing the pattern has the sensitivity and specificity neces- The psychiatric illness typically develops of beliefs, emotions and behaviours that sary to constitute a diagnostic test for CFS.

Many published studies have compared What is the best way for the field to A.L.K. Neuroscience already has advanced patients with CFS to patients with other make progress? How will the recent our understanding of CFS. The best way fatiguing illnesses and to healthy control negative XMRV findings affect research for the field to make progress is to pursue subjects. The studies have employed MRI, directions in this field? What could be the the many leads that already exist in the lit- functional MRI, positron emission tomog- role of neuroscience in advancing the field? erature. The evidence that CFS may reflect raphy (PET), magnetic resonance spectros- human infection with mouse retroviruses copy of cerebrospinal fluid, measurements S.H. The first point that needs empha- (XMRV and the polytropic murine leuke- of sympathetic and parasympathetic sising is that the CFS/ME syndrome is mia viruses (MLVs))6 has been seriously function, cognitive testing, electroenceph- a cause of chronic illness, disability and challenged. However, this does not alter alographic measurements, and neuroen- loss of work. The great challenge that the evidence of neurologic dysfunction in docrine measurements. As with virtually faces the field is how to engage scientists CFS, and it does not have a bearing on evi- every question in medicine, the literature to undertake research into the condition dence linking CFS with other neurotropic is not unanimous in its judgment. But that will translate into new diagnostic tests viruses — particularly human herpesvirus 6 the preponderance of the published evi- and treatments that go beyond controlling and enteroviruses. There are many leads for dence indicates that there is neurological symptoms. This presupposes that there are neuroscientists to pursue in uncovering the dysfunction in CFS. It is not possible to underlying organic biological causes that pathology and the aetiology of this terribly summarize this large literature here in a are amenable to detection and interven- debilitating illness that afflicts nearly 1% few words, and I refer interested readers to tion. Small studies have been suggestive of of adults. review articles on this topic. this, but many of these are characterized by poor case–control recruitment strate- D.M. Research into the pathogenesis of ME/ D.M. The symptoms described by ME/ gies, inadequate phenotyping and limita- CFS is essential to obtain a better under- CFS patients, such as light-headedness, tions in methodology, including sample standing of this illness and its determinants, migraines, coldness, orthostatic intoler- collection and storage; this has contributed and to identify preventive and/or therapeutic ance, vasovagal syncope, muscle weakness to the problem of a low-quality evidence targets. The complex symptomatology of and fatigue, all point to a connection with base of CFS/ME. Over a number of years ME/CFS can be challenging to study, not in the CNS. However, ME/CFS is too the UK Medical Research Council (MRC) small part because the syndrome is hetero- complex to be considered only a disease has received few applications for CFS/ME geneous in its manifestations and perhaps in of the CNS. funding and these are mostly restricted to causation as well. A common case definition epidemiological studies and clinical tri- of ME/CFS is essential if research studies are S.W. CFS is an illness, but defining it as als of symptom treatment. This suggests to compare data and outcomes across multi- a disease can only happen once a clear a lack of research capacity in the field. ple studies. pathology is established. Having said that, Importantly, the MRC now has a dedi- Research case definitions are needed if and when that does happen, I would be cated budget for research into autonomic to fully characterize the neural motor, surprised if the pathology does not involve dysfunction, cognitive symptoms, fatigue, sensory, cognitive, endocrine and immune some dysfunction within the CNS. We immune dysregulation, pain and sleep dis- manifestations of the illness, to estab- already know that the pattern of fatigue orders in patients with CFS/ME. The pro- lish clear criteria for diagnosis, and to and fatigability are central and not periph- posal for such an initiative came from the define subcategories within the broader eral in origin, because all are agreed that interdisciplinary MRC CFS/ME Research diagnostic category. Animal models of mental fatigue and fatigability (such as Advisory Group that includes experts disease would be very helpful to advance difficulties in concentration, attention or from a wide range of disciplines as well as an understanding of the basis of this short-term memory) are cardinal to the input from the major UK‑based CFS/ME condition. condition and, as was shown over 20 years patient charities. The remit of this group The XMRV findings6 have brought ago, are not core features of fatigue that is is to review current research into CFS/ME, much publicity and interest to the field of related to, for example, primary myopa- identify new opportunities and encourage ME/CFS. This has resulted in increased thies or neuropathies. We also know about research towards understanding the basis interest among researchers to propose the problems with effortful cognition and of the disease. The aim of the initiative is pilot projects in their own fields to try to the experienced sense of the effort that to improve understanding of pathophysi- understand this challenging medical prob- characterize the condition. In addition, ological mechanisms in CFS/ME, which lem. The negative XMRV findings under- subtle but distinct changes in the hypo- will lead to new diagnostic tests and treat- score the need for further research. thalamus–pituitary–adrenal axis are the ments. Fundamental to the approach is Neuroscientists have been, and will most replicated biological abnormality in the need for new research perspectives, continue to be, key leaders in this arena. CFS patients so far. Lastly, however, the and these will be generated by attracting Strong connections exist between neu- term ‘neurological and/or psychiatric’ experts that are not currently working on roscience and all domains of ME/CFS emphasises the inadequacies of our cur- CFS/ME into the field. To ensure this, the research, including infection and inflam- rent systems of classification to capture MRC has stipulated that all grant applica- mation, environmental stress, immune these complex disorders. After all, why are tions must include at least one researcher dysfunction, sleep, endocrinology, fatigue schizophrenia or autism still classified as from outside of the CFS/ME field. The and pain. New technologies in molecular psychiatric — the answer is nothing to do MRC also welcomes the involvement of biology, genomics and bioimaging are with the nature or aetiology of the condi- research-based medical charities in this providing exciting, non-invasive ways to tion but simply because psychiatrists treat initiative to help to promote a more uni- investigate brain and neural functions them, not neurologists. fied approach to this difficult syndrome. in vivo.

To further interdisciplinary research on replication. There is nothing wrong in this: Dennis Mangan is at the Office of Research ME/CFS, the Trans-US National Institutes although science can occasionally proceed on Women’s Health, Office of the Director, US National Institutes of Health, Bethesda, Maryland of Health (Trans-NIH) ME/CFS Research by a giant leap forward — everyone thinks 20892, USA. Working Group identifies cross-cutting of Helicobacter pylori for example, and the Simon Wessely is at the Department of Psychological areas of research and confronts challenges XMRV–CFS link, if it had been true, would Medicine, Institute of Psychiatry, King’s College that embrace multiple scientific areas, have been similar — in reality it more often London, UK. including the neurosciences. The Working moves in small incremental steps, which e‑mails: [email protected]; Group uses conferences, funding initiatives, is what I suspect will happen with CFS. [email protected]; a website and educational outreach activi- CFS is a difficult area whose boundaries [email protected]; [email protected] ties to advance research on ME/CFS and are indistinct, and that overlaps with many doi:10.1038/nrn3087 attract investigators into this complex field. other symptom-defined conditions, such as Published online 27 July 2011

A related goal of the Working Group is to fibromyalgia or irritable bowel syndrome. 1. Carruthers, B. M. et al. Myalgic encephalomyelitis/ leverage the resources that are available Nearly everyone accepts that it is a heter- chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. for ME/CFS research, such as equipment, ogenous illness; even if at the moment we J. Chronic Fatigue Syndrome 11, 7–36 (2003). methodology, supplies and collaborative cannot distinguish clear divisions or sub- 2. Fukuda, K. et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. expert networks. By working as a team, the groups. It is, however, my opinion that new Ann. Intern. Med. 121, 953–959 (1994). Working Group considers many ways to insights into the nature of CFS are most 3. Sharpe, M. et al. A report — chronic fatigue support ME/CFS projects that may not oth- likely to emerge from the neurosciences, syndrome: guidelines for research. J. R. Soc. Med. 84, 118–121 (1991). erwise be identified. The Working Group by which I mean basic and clinical neuro- 4. Holmes GP. et al. Chronic fatigue syndrome: a working encourages investigators to work together sciences and psychology. Understanding case definition. Ann. Intern. Med. 108, 387–389 (1988). to identify an early diagnosis, treatment the nature of the sense of the mental and 5. White, P. D. et al. Comparison of adaptive pacing and prevention for ME/CFS. physical effort that these patients experi- therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue ence and the consequences of experiencing syndrome (PACE): a randomised trial. Lancet 377, S.W. So long as decent clinical and basic this effort will lie at the heart of it. 823–836 (2011). 6. Lombardi, V. C. et al. Detection of an infectious scientists continue to engage with the But, unfortunately, the XMRV story may retrovirus, XMRV, in blood cells of patients with chronic field it will make progress, although sadly also have had unintended consequences fatigue syndrome. Science 326, 585–589 (2009). that no longer includes myself. I am no beyond generating a rush of papers and Acknowledgements longer active in research in this field, as citations. The ongoing antagonism that Members of the Trans-NIH ME/CFS Research Working Group, the Office of Research on Women’s Health and the Institute some of the unpleasantness (and worse) has been directed towards so many of the Offices of Communications contributed to the responses by that is mentioned above has taken its toll. scientists who failed to replicate the original D.M. 6 I still see CFS patients every week, which finding and who thus came up with what Competing interests statement remains both satisfying and rewarding. the extremists see as the ‘wrong answer’, S.T.H. declares competing financial interests: see web version for details. The remaining authors declare no competing But I now devote most of my time to has alienated yet another group of scientists financial interests. researching military health and trying to from getting involved in this area. This can improve medical education. Nevertheless, only be of harm to science and to patients. FURTHER INFORMATION Centers for Disease Control and Prevention CFS homepage: having been ‘with’ the subject for most of Stephen T. Holgate is at the University of Southampton, http://www.cdc.gov/cfs/general/case_definition/index.html my professional life, I can take a broader Infection, Inflammation and Immunity Division, School UK Medical Research Council CFS/ME funding homepage: of Medicine, Southampton General Hospital, Tremona http://www.mrc.ac.uk/Fundingopportunities/Calls/ perspective. MechanismsofCFSME/MRC007715 Road, Southampton, SO16 6YD, UK. The current furore over XMRV is noth- Trans-NIH ME/CFS Research Working Group: http://orwh. Anthony L. Komaroff is at the Harvard Medical School od.nih.gov/CSF%202011/CFS_home.htm ing new. It now looks as if it will join the Simon Wessely’s homepage: http://www.national.slam.nhs. list of other dramatic discoveries in CFS and the Brigham and Women’s Hospital, 10 Shattuck uk/simonwessely Street, Second Floor, Boston, Massachusetts 02115, ALL LINKS ARE ACTIVE IN THE ONLINE PDF that did not stand the test of time and USA.