Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME-CFS): good practice statement

6. Research and development

This section provides a brief overview only of some aspects of ME-CFS research and development (R&D), including where to obtain further information on research.^[43] A more detailed systematic review of the literature is out with the scope of this guidance. It also provides specific discussion on diagnostic criteria and the need for further progress and development in this important area.

A simple initial search of one database alone – MEDLINE® (1950 to week 2 July 2010) indicates that 3667 research articles or letters have been published using the term: 'myalgic encephalitis mapped to chronic fatigue syndrome', 266 of which have been published in 2009-10 (ovid). This is a substantial underestimate and provides only a rough pointer to the significant volume of the bioscientific and health services research publications on ME-CFS, because of differences and disagreements on terminology/definitions used. This preliminary search is also lacking in any assessment of the nature and quality of these publications, which will vary considerably. Nevertheless, this indicates that there is already a substantial literature on the aetiology, epidemiology and management of ME-CFS.

Ongoing research is required into ME-CFS to improve our understanding of the causes of the illness (aetiology), its prevalence and also to guide optimal management approaches. Please note again that the studies cited below, constitute a limited sample only of the recent literature on ME-CFS and are not part of a formal systematic review.

Aetiology

As outlined in Section 2, the onset of ME-CFS is often linked with the recent presence of an infection. A large number of virological, immunological, neuroendocrine, autonomic nervous system, cardiological and neurological abnormalities have been reported in patients with ME-CFS, including genetic biomarker studies, but there has been a lack of consistency in laboratory findings. This may be contributed to by combining patients into a single heterogeneous group rather than by attempting subgroup analysis – see also below.

Examples of recent research include: reporting of autonomic dysfunction, differential gene expression in ME-CFS, a novel biological abnormality in recovery of muscular pH following standardised exercise, lower/abnormal diurnal blood pressure regulation in patients with ME-CFS,48 and raised F(2) isoprostanes associated with oxidative stress.

Reporting of an association between human retrovirus XMRV (xenotropic murine leukaemia virus-related virus) and ME-CFS in the USA has not been substantiated by further studies in the UK and the Netherlands – the results of other studies are awaited. Discussions continue to take place on possible explanatory models for ME-CFS including bio-psychosocial and biological models – in which inflammatory, oxidative and nitrosative stress (IO&NS), and immune pathways are postulated. It has also been suggested that new drugs should be developed to target these pathways.

In summary, there is accumulating evidence of a number of nervous system, immune, neuroendocrine, autonomic and other abnormalities in patients with ME-CFS. However, as yet, no definitive laboratory test (or tests) have been found for ME-CFS, which must remain a crucial research priority for the diagnosis, classification and sub-typing of this disease.

Epidemiology

As previously indicated, ME-CFS can affect both sexes, at any age, from any ethnic group. Epidemiological evidence is lacking in Scotland but a population prevalence of at least 0.2-0.4% is widely accepted, and over 20,000 people in Scotland may be affected. There is therefore a particular need to study:

The prevalence and impact of all categories of the illness, particularly severe disease.

Factors associated with, and prognostic features of all categories, particularly severe disease.

Reflected in the use of a composite term in this guidance (myalgic encephalitis-chronic fatigue syndrome), ME-CFS is recognised by many as being heterogeneous and there is a growing view that incorporating subtypes might be particularly helpful in a better understanding of the pathophysiology of the illness. Published studies with ME-CFS have been found to differ with respect to characteristics such as the case definition utilised, method of case ascertainment, functional disability, differing biomarkers, physiological parameters studied and psychiatric co-morbidity. Various potential risk factors for the development of ME-CFS have been studied, but no definitive predictors have been characterised, as yet.

Diagnostic Criteria

Good epidemiological studies pivot on robust case definitions and diagnostic criteria. Regrettably, available diagnostic criteria for ME-CFS continue to prove controversial. As previously indicated, a number of diagnostic criteria have been proposed for ME-CFS, including the Oxford (1991),^[44] the US Centres for Disease Control and Prevention (CDC – Fukuda – 1994) the Canadian Consensus Document (2003) and NICE Guideline (2007) definitions, but no one set has been universally agreed. Characteristics of the main available criteria are discussed in the NICE Guideline and in the Scottish Public Health Network's Health Care Needs Assessment of Services for people living with ME-CFS, which also provides a summary comparison of the different diagnostic criteria.

Most research to date has been based on the US Centers for Disease

Control and Prevention (CDC – Fukuda definition – 1994),^[45] while the more recent Canadian Consensus Document definition (2003 – see Appendix 2)^[46] is favoured by a number of patient groups, including UK based ME-CFS charities, as they believe it better reflects patients' experience of the illness.

The Scottish Parliament Cross Party Group on M.E. is also strongly supportive of the Canadian Consensus Document definition. It has been adopted for general use in Australia and New Zealand. The Gibson Inquiry (2006) recently reviewed diagnostic criteria and concluded that the Canadian Consensus Scottish Good Practice Statement on ME-CFS^[47] Document definition was a useful contribution to defining the clinical condition of ME-CFS.^[48]

Reflecting the lack of accord, the Scottish Public Health Care Network's Health Care Needs Assessment of Services for people living with ME-CFS, has recommended the 'pragmatic use of the Canadian Consensus Document for the clinical, symptomatic definition of ME.

The Scottish Neurosciences Council has expressed concerns about some aspects of the Canadian Consensus Document definition – particularly the need for the safe diagnosis of neurological abnormalities and potential misdiagnosis in individuals who present with ataxia, muscle weakness and fasciculations. However, this present guidance makes clear in Section 2 that neurological examination must be done routinely in the differential diagnosis of ME-CFS, to exclude specific neurological abnormalities such as: obvious muscle wasting, ptosis, upper motor neurone signs, ataxia, fasciculations, absent reflexes. If any of these abnormalities are present, neurological specialist referral is recommended for further investigation:

When the Canadian Consensus Document definition is used to assist the diagnosis and management of ME-CFS, clinicians should carefully adhere to this specific neurological referral recommendation.

During the preparation of this guidance, it became clear that diagnostic criteria for ME-CFS is a key and polarising issue, which threatens to impede much needed service improvements for patients. There is a strong case for there to be a further professional and scientific re-appraisal of the diagnostic criteria for ME-CFS, including subgroup analysis, taking into account patient experience of the illness. In order to achieve this, it is imperative that patient groups and health professionals seek to move forward and work more closely together.

Management

In Sections 3-6, advice on the management of ME-CFS was offered and a summary of the current treatment evidence base provided. Robustly designed studies of sufficient power are required to provide significant results on whether or not a treatment is both safe and effective. However, the paucity of such studies also underlines the dilemma for clinicians, caring for people with ME-CFS, when considering potential treatments for individual patients. A number of treatments have been reportedly found helpful in individual cases, but for which robust scientific evidence is lacking – either because the relevant studies have not been done or because those that have been done have been poorly designed, subject to bias, or insufficiently powered. Additionally, it is unlikely that many of these potential treatments will, in the future, be subject to robust trial appraisal. Therefore, in the context of limited scientific evidence, it is crucial to take people's experiences into account and to exercise best professional judgement – in order to tailor interventions to the needs and circumstances of the individual patient. Further progress in investigating treatments for ME-CFS should be appropriately informed by the perspectives of patients and their carers.

In terms of recent research, the FINE Trial (Fatigue Interventions by Nurses Evaluation) a pragmatic rehabilitation programme delivered at home by trained general nurses reported small improvements in fatigue, sleep and depression but not physical functioning. Subsequent criticisms of the study included entry selection criteria (the Oxford criteria was the primary method of inclusion) and the use of the Chalder et al fatigue score.

Further publications are expected from this particular study.

In a recent review of non-antidepressant drug trials performed between 1988 and 2009, the authors concluded that pharmacotherapy should not be considered first line therapy in chronic fatigue syndrome, but pointed out that future research should take specific subgroups into account and should target immunological aspects of the illness. Since that review, a study of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome, has been published and it did not demonstrate any benefit compared to placebo.

In a recent feasibility study, home orthostatic training (HOT) in chronic fatigue syndrome was found to be well tolerated and generally complied with. This study builds on previous work, including Postural Orthostatic Tachycardia Syndrome (POTS) and the authors concluded an adequately powered study, including strategies to enhance compliance, is warranted. The PACE Trial (Pacing, graded Activity and Cognitive behaviour therapy: a randomised Evaluation) has been set up in order to provide a systematic evaluation of these therapies. The trial is expected to report later in 2010.^[49]

The effective relief of pain in ME-CFS is of paramount importance. This is primarily discussed in Section 4 of this guidance. Encouraging recent high grade evidence has emerged for the use of duloxetine and pregabalin for neuropathic pain or when fibromyalgia is present as a co-morbidity. Essentially the classification of chronic pain falls into three broad categories: (1) pain owing to tissue disease or damage (nociceptive pain), (2) pain caused by somatosensory system disease or damage (neuropathic pain), and (3) pain without a known somatic background. Recent helpful guidance on the management of chronic neuropathic pain confirms that it is both under recognised and underrated and that primary care doctors are uniquely placed to diagnose it and to establish an effective treatment plan.

There has been considerable recent interest in the role of vitamin D in the aetiology and treatment of a number of chronic diseases including ME-CFS. Patients with ME-CFS may be at increased risk of osteoporosis due to their relative lack of physical activity and excessive time spent indoors. In a recent retrospective study, 25-hydroxy vitamin D levels were found to be significantly lower in ME-CFS patients than in the general population. A recent editorial pointed out that there was no downside risk to increasing the intake of vitamin D intake by increasing the consumption of foods that naturally contain or are fortified with vitamin D. A prospective randomised controlled study of vitamin D on the vascular health of ME-CFS patients is underway and hopes to report in 2011.

In this particular study, patients have been recruited that fulfil both the CDC (Fukuda) and Canadian Consensus Document diagnostic criteria. This should help to inform whether vitamin D supplements should be routinely offered to patients with ME-CFS. In the interim, where vitamin D supplements are deemed to be clinically indicated the Scottish Good Practice Statement on ME-CFS has recommended, a dose of 1500-2000 IU/day for adults and teenagers.

In relation to the expressed needs of patients with ME-CFS and their carers, a recent systematic review – involving 32 qualitative and quantitative studies and over 2500 people living with ME-CFS with mainly moderate or severe disease – has reported the following major support needs: (1) The need to make sense of symptoms and gain diagnosis, (2) for respect and empathy from service providers, (3) for positive attitudes and support from family and friends, (4) for information on ME-CFS, (5) to adjust views and priorities, (6) to develop strategies to manage impairments and activity, (7) to develop strategies to maintain/regain social participation. The authors conclude that there was consistent evidence that substantial support is needed to rebuild the lives of patients with ME-CFS.

In relation to the roles of GPs and primary care nurses, in treating patients with ME-CFS, recent UK research has found clear concerns among these health professionals. Until GPs feel comfortable making the diagnosis of ME-CFS, facilitating initial management, and have appropriate services to refer patients to, there will continue to be delays in confirming the diagnosis and securing the optimal management of ME-CFS. This finding is echoed in another recent study from Belgium. Additional research on the role of practice nurses in the management of ME-CFS has indicated that their current role is limited and that there is partial understanding of the evidence base for treatment. Practice nurses largely welcomed the potential role for treating people with ME-CFS but identified barriers and training needs, which must be addressed to enable them to feel confident of managing patients with this illness.

The findings of the systematic review of the expressed needs of people with ME-CFS and their carers, also the research on the roles of GPs and primary care nurses, are particularly telling. Taken together, they reinforce the requirement for this Scottish Good Practice Statement, the associated Scottish Public Health Network's Health Care Needs Assessment of Services for people living with ME-CFS and ongoing education for primary care workers on the care of patients living with ME-CFS.

Research and development – looking to the future

As indicated previously, it is vitally important that Scotland develops effective mechanisms for bringing together researchers, practising clinicians and people with ME-CFS to drive forward the optimal care, research and development agenda. This will in turn lead to improved clinical practice in the NHS in Scotland. As we progress this pressing agenda, it is important to recognise the marked increase in the size and quality of the evidence base on our understanding of, and interventions for ME-CFS. It will be important that this trend continues, with a focus on peer-reviewed, high quality scientific publications. While it is not within the scope of this guidance to provide a research agenda, it is clear that a number of areas beckon for further work:

• Aetiology – continued contributions to our understanding of the causes and underlying mechanisms involved and diagnostic investigations, including as yet elusive but definitive diagnostic test(s)
• Epidemiology – greater understanding of prevalence and severity, including Subtypes
• Management – robust studies of new treatment modalities and effective models of service delivery/care management, with specific emphasis for children, young people and for those who are more severely affected.

The RCPCH Guideline^[50] contains a specific section on research priorities for children and young people.³¹ There is also a recommendation for a more focused research strategy in the Scottish Public Health Network's Health Care Needs Assessment of Services for people living with ME-CFS.

Further information on research, its sponsorship and participation in research studies

Government sponsored research

The Chief Scientist Office (CSO), of the Scottish Government Health Directorates, which has responsibility for encouraging and supporting research into health and health care needs in Scotland, is collaborating with the Medical Research Council (MRC) on the implementation of its research strategy into ME-CFS. CSO has contributed funding to the PACE trial.

ME-CFS is a strategic priority area for the MRC and they are continuing to promote research in this area and encourage applications for funding. Research proposals in all areas compete for the funding available. While research excellence continues to be the primary consideration in funding decisions, and the MRC does not as a rule earmark funds (nor commission research) for particular topics, when appropriate, high quality research in the areas MRC is promoting, may be given priority in competition for funds. In 2008, a new Expert Group was set up by the MRC to consider how best to encourage new high-quality research into ME-CFS and to bring researchers from associated areas into the field. In addition, the MRC held a ME-CFS workshop in November 2009^[51] – see their website (Medical Research Council) for any updates.

Charity supported and other research

In Scotland, the charity, ME Research UK (MERUK) is supporting biomedical research, both by direct financial support and through holding international conferences. (ME Research). ME Research UK also holds a large research publications database.

Other charities supporting research are:

• The CFS Research Foundation^[52]
• Action for M.E. website
• The MEA Ramsay Research Fund:^[53] Invest in ME Research

Information about ME-CFS research

In addition to MEDLINE, OVID and other academic reference databases, other sources of information on research are available from other databases, and ME-CFS charities including ME Action and ME Research UK: meresearch.org.uk.

It is important that research on ME-CFS is conducted to the highest standards and subject to robust scientific peer review, as exemplified in the reviews undertaken by the Centre for Reviews and Dissemination, University of York, and by the Cochrane Collaboration Reviews.

Supporting participation in research studies

Research studies, however novel and well designed, will only be successful if enough patients are recruited into them. We must all play our part in pulling together patients, clinicians and researchers, to aid recruitment into studies. It is imperative that in Scotland we have effective structures which bring together researchers, practising clinicians and people with ME-CFS to facilitate future research into the illness.