http://www.mrc.ac.uk/index/public-interest/public-topical_issues/public-cfs_me/public-cfs_draft_research_strategy.htm 

 

MEDICAL RESEARCH COUNCIL

 

 

MRC CFS/ME RESEARCH ADVISORY GROUP

 

 

CFS/ME RESEARCH STRATEGY

 

 

DRAFT DOCUMENT FOR PUBLIC CONSULTATION

 

 

17 December 2002

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table of Contents

 

SUMMARY 3

 

INTRODUCTION 5

 

BACKGROUND 6

 

Method of Working 7

 

Terminology 7

 

TAKING FORWARD RESEARCH INTO CFS/ME 8

 

Research and Refinement of Case Definition 11

 

Developing the Epidemiological Framework 12

 

Descriptive Epidemiology

Aetiology

Outcome Studies

 

Developing Hypotheses about Pathophysiology 14

 

Infections

Neurology

Muscle Fatigue and Weakness

Immunology

Neuroendocrinology

Central Nervous System Function

Cognitive Performance

Psychological factors

 

INTERVENTIONS 22

 

Clinical trials of interventions for CFS/ME

 

Musculoskeletally-Based Interventions

Psychologically-Based Interventions

Other Interventions

 

HEALTH SERVICES RESEARCH 27

 

Health Care Needs Assessment

Descriptive Health Services Research

Health Technology Assessment

Service Delivery and Organisation

 

RESEARCH CAPACITY AND THE INTERFACE WITH SERVICES 29

 

Strengthening Research Capacity

Nurturing the Research – Service Interface

 

THE VALUE OF LAY PARTICIPATION 29

 

Research agenda

Within specific research studies

 

CONCLUSIONS AND RECOMMENDATIONS 33

 

SPECIFIC REFERENCES and OTHER SOURCES OF INFORMATION 33

 

Annex 1 Membership of MRC CFS/ME Research Advisory Group 35

 

Annex 2 PHRU Report on Consultation Exercise 37

 

1. SUMMARY

 

2. This research strategy for CFS/ME has been developed by a Medical

Research Council CFS/ME Research Advisory Group. The Research

Advisory Group was convened in response to the request of the Department

of Health in England for the MRC to develop a broad strategy for advancing

biomedical and health services research on CFS/ME, following the publication

of the Report of the CMO’s Independent Working Group in January 2002.

 

3. The MRC CFS/ME Research Advisory Group fully endorses the conclusions

of the Report of the CMO’s Independent Working Group, namely that

CFS/ME is a real, serious and debilitating condition, and that research into all

aspects of CFS/ME is needed.

 

4. The MRC CFS/ME Research Advisory Group has used the term “CFS/ME”.

The Research Advisory Group acknowledges that the descriptive term

“CFS/ME” does not refer to a specific diagnosis. In the same manner, the

singular term “condition” is used, but this does not indicate that the MRC

CFS/ME Research Advisory Group holds any particular position on whether

CFS/ME is one condition with heterogeneity of cause, pathogenesis and

severity, or is a number of similar conditions with different individual

characteristics.

 

5. The MRC CFS/ME Research Advisory Group met formally (insert number)

times between September 2002 and (insert date), and held numerous other

discussions. A consultation exercise was undertaken over July and August

2002 using a set of structured questions, which was independently analysed.

The lay members of the MRC CFS/ME Research Advisory Group met with

ME charities, and CFS/ ME patients and their carers, to better understand

their perspectives. Further details on the process to be drafted in due course.

 

6. The MRC CFS/ME Research Advisory Group has not provided a detailed

plan for the science, nor set out an agenda of the many research projects that

might merit support. A strategy is proposed which reflects the current state of

knowledge in CFS/ME, and which aims to provide a rational framework for

advancing the understanding of the illness and to reduce suffering.

 

7. In considering ways to advance research on CFS/ME, the Group has focused

on a number of strategic themes: case definition, an epidemiological

framework, pathophysiology, interventions, health service research, research

capacity and the value of lay participation.

 

8. The MRC CFS/ME Research Advisory Group recommends that research

studies should aim to be as inclusive as possible in terms of the recruitment

of participants, and due consideration should be given to sample size to allow

for possible subgroup effects. There should be clearly stated inclusion and

exclusion criteria, with detailed justification if certain types of patients are not

included.

 

9. The MRC CFS/ME Research Advisory Group considers there should be an

agreed standardised case definition and a classification of severity and any

other relevant characteristics that define subgroups. Improved definition of the

phenotypes of potential subgroups that may come under the CFS/ME

spectrum, and overlaps with other conditions, will underpin research on

causes, mechanisms, and management. A definition of a clinically important

improvement in disease status, with a classification of the degree of

improvement, is essential for natural history and intervention studies.

 

10. In the short term, the MRC CFS/ME Research Advisory Group considers that

the research community should be encouraged to develop high quality

research proposals for funding that address key issues for CFS/ME research

that are amenable for study at the present time: case-definition,

understanding symptomology, and new approaches to management.

 

11. In view of the probable multiplicity of causal factors and the widely disparate

findings so far reported, the MRC CFS/ME Research Advisory Group

considers that studies investigating potential causal pathways and

mechanisms, whilst having merit, would not have the same immediate impact

on increasing understanding of CFS/ME, nor reducing the suffering of

patients.

 

12. The MRC CFS/ME Research Advisory Group considers it is appropriate to

explore potential interventions for CFS/ME in the absence of knowledge of

causation or pathogenesis. Randomised controlled trials of adequate size,

using standardised case definitions, eligibility criteria, and baseline and

outcome assessments, could be used to evaluate one or more of the

interventions which have been shown in one or more trials to have a benefit.

Standardisation will allow results to be more widely generalised and

compared between studies.

 

13. Given the present difficulties in identifying priorities for health services

research in CFS/ME, it is not clear whether it is appropriate to make HSR a

priority at this time.

 

14. It is essential that the researcher–funder-lay partnership is nurtured, to ensure

that the best evidence is easily available to all, and to facilitate the growth of

consumer involvement in the design, conduct and dissemination of research -

as a means to enhancing its quality, relevance, and credibility. The MRC

CFS/ME Research Advisory Group considers that there is a key role for

patient organisations to help attract participants to research, especially the

severely ill, and to help in the dissemination of research results.

 

15. INTRODUCTION

 

16. The Medical Research Council (MRC) CFS/ME Research Advisory Group

fully endorses the conclusions of the Report of the Chief Medical Officer’s

(CMO) Independent Working Group (2002) that CFS/ME is a real, serious and

debilitating condition.

 

17. The MRC CFS/ME Research Advisory Group agrees with the CMO’s

Independent Working Group that research into all aspects of CFS/ME is

needed, and welcomes the opportunity to help advance research into this

illness.

 

18. In considering ways to advance research on CFS/ME, the Group has focused

on a number of strategic themes, which are reflected in the headings used in

the remainder of this document. They correspond with the topics outlined in

the research recommendations of the report of the CMO’s Independent

Working Group.

 

! Research and refinement of case definition

 

! Development of an epidemiological framework

 

! Developing and testing hypotheses about pathophysiology

 

! Design and evaluation of interventions

 

! Health service research

 

! Research capacity and the interface with services

 

! The value of lay participation

 

19. The MRC CFS/ME Research Advisory Group has not presumed to provide a

detailed plan for the science, nor set out a prescriptive portfolio of the many

research projects that might merit support. A strategy is proposed which

reflects the current state of knowledge in CFS/ME, and which aims to provide

a rational framework for advancing the understanding of the illness and its

management.

 

20. The Group considers that this strategy should be available to all interested

parties, to help take forward research in CFS/ME.

 

 

21. BACKGROUND

 

22. In 1998, the Chief Medical Officer (CMO) in England requested that an

Independent Working Group be set up, whose terms of reference were:

 

! “to review management and practice in the field of CFS/ME with the

aim of providing best practice guidance for professionals, patients, and

carers to improve the quality of care and treatment for people with

CFS/ME, in particular to:

 

! develop good clinical practice guidance on the healthcare

management of CFS/ME for NHS professionals, using best available

evidence;

 

! make recommendations for further research into the care and

treatment of people with CFS/ME;

 

! identify areas which might require further work and make

recommendations to CMO."

 

23. The Report of the CMO’s Independent Working Group on CFS/ME was

published in January 2002, recommending research on all aspects of CFS /

ME. The Department of Health asked the MRC to develop a broad strategy

for advancing biomedical and health services research on CFS/ME.

 

24. The MRC agreed to convene a CFS/ME Research Advisory Group

(membership at Annex1), made up of individuals who were not active in the

CFS/ME field, but had the relevant scientific expertise, to discuss the CMO’s

Independent Working Group report and make research recommendations to

the MRC of possible ways forward.

 

25. The Terms of Reference for the MRC CFS/ME Research Advisory Group

were:

 

! To consider the Report of the CMO’s Independent Working Group on

CFS/ME, including its recommendations for research,

 

! To consider other recent reviews of current knowledge and understanding

of CFS/ME,

 

! To take account of patient and lay perspectives,

 

! To recommend to MRC a research strategy to advance understanding of

the aetiology, epidemiology and biology of CFS/ME and,

 

! In the light of current knowledge suggest what areas of further research

are needed with regard to possible prevention, management (including

diagnosis) and treatment.

 

26. The MRC CFS/ME Research Advisory Group agreed not to revisit the areas

considered by the CMO’s Independent Working Group, but to recommend

how research that would improve understanding and treatment of CFS/ME

might be undertaken. It was agreed that it was beyond the remit of the

Research Advisory Group to decide how the recommendations for a research

strategy should be implemented, as this would be the responsibility of funders

and sponsors.

 

27. Whilst acknowledging the seriousness of the illness, not only to the affected

individual but also to their carers, families and society, the MRC CFS/ME

Research Advisory Group did not consider the issue of service provision as

this area was not within its role.

 

28. Method of Working to be finalised

 

29. The MRC CFS/ME Research Advisory Group met formally (insert number)

times between September 2002 and (insert date), and held numerous other

discussions. A public consultation exercise was undertaken over July and

August 2002 using a set of structured questions. The NHS Public Health

Resource Unit, Oxford (PHRU) undertook an independent qualitative analysis

of the 187 responses received, and prepared a report for consideration by the

Group (Annex 2).

 

30. The lay members of the MRC CFS/ME Research Advisory Group met with

ME charities, and CFS/ ME patients and their carers, to better understand

their perspectives. Their understanding of the illness was enhanced by

numerous letters from individuals who gave a personal perspective.

 

31. All members of the Research Advisory Group contributed preliminary drafts in

areas relevant to their expertise, which were brought together into a single

document, which was discussed by the Research Advisory Group at its

second meeting and revised subsequently.

 

32. A preliminary draft research strategy was made available for external, open

consultation to key stakeholders, national and international researchers, and

also considered by the MRC Research Boards between December 2002 and

February 2003. t

 

33. – to be completed and finalised in due course

 

34. Terminology

 

35. Chronic fatigue syndrome (CFS) and myalgic encephalomyelitis or

encephalopathy (ME) are two terms that have been used most often as the

illness description given to patients with a combination of non-specific

symptoms, but always with unexplained disabling fatigue. The CMO’s

Independent Working Group report discussed at length the issues

surrounding nomenclature, and the MRC CFS/ME Research Advisory Group

did not revisit this topic.

 

36. In order to develop a research strategy in this area without delay, the MRC

CFS/ME Research Advisory Group agreed with CMO’s Independent Working

Group and used the term “CFS/ME”. The Research Advisory Group

acknowledges that the descriptive term “CFS/ME” does not refer to a specific

diagnosis, and that a number of diagnostic criteria are being used to define

patients. There are separate entries in the World Health Organisation’s

International Classification of Diseases (ICD-10) for “chronic fatigue

syndrome” and “myalgic encephalomyelitis”, but it is not clear whether such a

distinction has empirical validity. In the same manner, this report may use the

singular term “condition”, but this should not indicate that the MRC CFS/ME

Research Advisory Group holds any particular position on whether CFS/ME is

one condition with heterogeneity of cause, pathogenesis and severity, or is a

number of similar conditions with different individual characteristics.

 

37. To avoid potential confusion, in this report “CFS” will be used when

discussing research findings where the specific diagnostic criteria for chronic

fatigue syndrome were used in those studies, and “CFS/ME” will be used as

the descriptive term for the illness.

 

38. It is acknowledged that, as our understanding of the area increases, such an

umbrella term as CFS/ME may no longer be appropriate. However, at the

present time it is considered that an inclusive approach is beneficial in the

development of a research strategy.

 

39. TAKING FORWARD RESEARCH INTO CFS/ME

 

40. There are a number of challenges to advancing the understanding of

CFS/ME, which arise from the heterogeneous nature of the condition, the

individual symptoms that may be associated with it and their variation in

severity, co-morbidity with other conditions, and the variability of response to

potential interventions.

 

41. The MRC CFS/ME Research Advisory Group recognises the urgent need for

research into CFS/ME, and that there are certain groups of patients who have

not been adequately included in research. The report of the CMO’s

Independent Working Group highlighted the severely ill, children, ethnic

minorities and the recovered patient. In the consultation exercise undertaken

at the start of the process of developing a research strategy for CFS/ME, the

inclusion of these patient groups was emphasised as being essential. The

MRC CFS/ME Research Advisory Group reaffirms the need for these groups

to be fully involved in the research effort to understand CFS/ME.

 

42. CFS/ME patients may vary in the intensity and nature of their symptoms, both

between patients and over time for individuals, and it will be important to

ensure that adequate consideration is given to how these potential

confounding factors are addressed. An important question is the extent to

which CFS/ME overlaps with other disorders.

 

43. In addition to these symptomatic issues, CFS/ME affects the whole age

range, which brings additional complexities to undertaking research. The

understanding of the aetiology and outcome for children with CFS/ME is, at

present, an area that is under-researched. It is likely that interventions

developed for an adult may need significant modification before they could be

evaluated in children. There are particular ethical dimensions to children

participating in research which must be considered in great depth by

researchers, and the rights of the child must remain paramount. Whilst

acknowledging the importance of research with children, the MRC CFS/ME

Research Advisory Group endorses the principle that for ethical reasons

research involving children should only be undertaken when it is not

appropriate to undertake such studies in adults.

 

44. The report of the CMO’s Independent Working Group highlighted the

importance of understanding the particular problems experienced by the most

severely ill patients. This patient group was also identified by many

respondents of the MRC consultation exercise as being a priority area for

research. There are many potentially informative comparisons to be made

between severely affected patients, who tend to have a poor prognosis, and

those individuals who recover, to a greater or lesser extent, both in terms of

understanding aetiology and of the reported differential outcomes to a number

of potential management or treatment strategies. Such comparisons may help

to identify subgroups, either in terms of aetiological mechanisms or predictors

of response to interventions. The pathways to chronicity and severity are not

at present understood, and this is a key area for research. There should be a

concerted effort to engage severely affected patients in research. At present

there is a danger that these individuals, who sometimes experience difficulties

in accessing care, might not be included in studies either based in, or

recruited from, that care setting.

 

45. The MRC CFS/ME Research Advisory Group recommends that research

studies should aim to be as inclusive as possible in terms of the recruitment of

participants, and due consideration should be given to sample size to allow

for possible subgroup effects. There should be clearly stated inclusion and

exclusion criteria, with detailed justification if certain types of patient are not

included.

 

46. The range and severity of symptoms for people with CFS/ME mean that

researchers must bear such variability in mind when designing studies. It is

important that the possibility of selection bias is considered at the earliest

stages of any study, as symptomatic patients referred to speciality clinics may

not reflect accurately the majority of patients in the general medical setting.

 

47. An integrated approach to determining causal pathways is needed. It could

combine structural, functional, behavioural and possibly genetic approaches.

As is the case for many chronic diseases, there is limited utility in considering

particular symptoms in isolation. It is likely that a more holistic approach may

be more fruitful in understanding CFS/ME, and potential therapeutic

interventions. There is undoubted benefit to employing a multidisciplinary

approach to research on CFS/ME, where experience and expertise from

appropriate disciplines can be brought together.

 

48. The current understanding of CFS/ME would imply that there are a number of

potential triggering factors for the illness. The report of the CMO’s

Independent Working Group cited infections, immunisations, life events,

physical injuries and environmental toxins as potential triggers, although the

strength of evidence is extremely variable, as discussed by the recent report

of a Working Group convened under the auspices of the Royal Australasian

College of Physicians (2002). Predisposing factors included gender, familial,

personality, other disorders and previous mood disorder. Given that the

causes of CFS/ME are probably diverse and multi-factorial, identification of

specific causal pathways may be of limited value in understanding and

treating the illness. It is entirely possible that an original precipitating factor

may no longer be detectable in a person with CFS/ME, or was present at a

subclinical level, and thus reported abnormalities may not reflect a true causal

association.

 

49. Many reported findings in the area of pathophysiology are not published in the

peer-reviewed literature, or are not well described. Such preliminary findings

need to be confirmed by independent replication in other centres. Currently,

the low volume of research and the lack of methodological rigour and

independent replication mean that many of these claims find little support

from the wider scientific community, but may have strong currency among

some patients and practitioners.

 

50. Findings need be subjected to rigorous and objective scientific analysis and

published in high quality, peer reviewed journals, not least so that the

methods can be replicated and the findings and hypotheses tested

independently by other approaches. Where independent replication and

different approaches fail to demonstrate a significant association, the case for

further work is likely to be weak. Well substantiated, refined hypotheses can

then be tested through a variety of other designs.

 

51. The MRC CFS/ME Research Advisory Group is aware of the difficulty in

publishing negative results, especially in peer-reviewed journals. The Group

considered it important, especially in an area as complex as CFS/ME, that the

results of such research should be disseminated to avoid unnecessary

repetition of studies and the inefficient use of resources. There may be a need

for funders and sponsors of research to investigate additional alternative

mechanisms of dissemination, preferably involving an independent peerreview

mechanism to provide scientific credibility to the results. The MRC has a

reputation for rigorous peer-review, and may need to take the lead in such an

endeavour, in partnership with other funders and sponsors if necessary.

 

52. The MRC CFS/ME Research Advisory Group has been mindful throughout

the development of the research strategy for CFS/ME of the importance of

following existing guidance and approval systems in research. The MRC,

amongst others, has published a number of relevant guidance documents, to

which researchers should refer (e.g. MRC Ethics Series Human Tissue and

Biological Samples for Use in Research, Good Clinical Practice in Clinical

Trials). It is the responsibility of all researchers to ensure that any research

they wish to undertake has obtained the relevant ethical approvals.

 

53. The MRC CFS/ME Research Advisory Group acknowledges the importance

of understanding the international research effort for CFS/ME, in order to

optimise the likely success of any research strategy. There are substantial

programmes of research currently underway in other countries, such as the

United States of America, Australia, and a number of European countries.

The Research Advisory Group was grateful for the information provided by

the US Center for Disease Control about its current research programmes. It

will be important that researchers and funders take an international

perspective when considering the funding of specific research proposals.

 

54. Research and Refinement of Case Definition

 

55. Improved definition of the phenotypes of potential subgroups that may come

under the CFS/ME spectrum, and overlaps with other conditions, will underpin

research on causes and mechanisms. Accuracy and consistency of case

definition and diagnosis is a crucial issue both for services and for research.

Improvements will help researchers compare different studies with each other

and across time. Further research is needed to develop and evaluate the

tools for case definition. The lack of validated biological markers for CFS/ME

has further hampered diagnosis.

 

56. Case definition is fundamental for the assessment, frequency, causes,

outcomes and management of any disease or illness. The development and

validation of instruments for use in research and in services is currently a key

area for research. Consistency between studies and over time can

significantly affect the interpretation of research findings.

 

57. There is clearly an overlap between the need for case definitions that have

utility in the clinical and service context with those specifically designed for

research. For this reason a continuing cross-reference between research

targeting fundamental questions and that aimed at developing and evaluating

tools for services is essential.

 

58. There is some international consensus on the broad criteria used to identify

people with CFS, as demonstrated by the current consensus-based

definitions from the US Centers for Disease Control (CDC), currently known

as the Fukuda criteria (Fukuda et al. 1994). However, questions remain

about the interpretation of conditions that fall within these broad criteria. Some

consider that this inclusive approach compromises research on specific

groups of individuals whose symptoms are considered to be predominantly

neurological, as indicated in the Consultation exercise.

 

59. The MRC CFS/ME Research Advisory Group is aware of the ongoing

effort of the CDC, through an International CFS Study Group, to refine the

current research case definition of CFS. There have been three meetings

of international experts from a wide range of disciplines and perspectives,

coordinated by the CDC, in an effort to identify ambiguities in the current

CFS case definition and to recommend improvements. We understand that

this International CFS Study Group is currently preparing a report for peer-

reviewed publication in an academic journal, and we would anticipate that

this consensus-derived research case definition will help in the development

of well-designed studies. Any new or revised case definition must be subjected

to rigorous and objective scientific analysis and testing to demonstrate its

usefulness.

 

60. The MRC CFS/ME Research Advisory Group has noted that there is support

among some sections of the community for the use of the description of M.E.

from Ramsay (Ramsay, 1998) to identify and study a discrete population of

patients. Whilst acknowledging the potential importance of the identification

of subgroups, the Group does not consider that the current descriptive nature

of these criteria has sufficient methodological rigour to be used in an

epidemiologically robust manner for research. The MRC CFS/ME Research

Advisory Group believes that researchers who wish to pursue this approach

will need to operationalise the Ramsay criteria and then demonstrate their

validity through peer-reviewed publication.

 

61. The MRC CFS/ME Research Advisory Group considers that case definition is

a key area for research, but believes that it is possible that some studies can

be undertaken without delay in reaching consensus. The use of broad, but

clearly and explicitly defined, inclusion and exclusion criteria should allow

subsequent re-appraisal of experimental results in the light of developments

in case definition. It would not be possible to identify potential subgroups

unless inclusion criteria are broad enough to encompass the necessary

heterogeneity.

 

62. Developing the Epidemiological Framework

 

63. Epidemiology has a central role in addressing questions about prevalence,

incidence and their relation to time, place and person within populations. It is

key in formal testing of causal hypotheses, specifically in working out the

contributions of environment and genetic influences. Such a framework is

also necessary for research on case definition, co-morbidity, natural history

and outcome.

 

64. Population-based studies that identify affected individuals using active

ascertainment and agreed diagnostic criteria have several advantages,

including the provision of adequate numbers of affected individuals, identified

using a common methodology, to test important hypotheses about causes

and to provide unbiased estimates of outcome. The fact that CFS/ME affects

the whole age-range, including children, means that such population-based

studies will need to have considered the adequacy of case ascertainment

across the whole age spectrum.

 

65. Considerable advances are being made internationally towards identifying

candidate genes for a wide variety of disorders. New, large epidemiological

studies that include genetic data could allow such advances in CFS/ME to be

taken forward fairly rapidly, in the context of a general population sample, to

address questions about genes and environment. While there is excitement

about these advances, examples from other areas of biomedicine make it

clear that to identify genetic susceptibility loci and determine how they interact

is a complex task requiring a substantial, multidisciplinary research effort. As

with all other genetic studies, precise case definition and phenotypic

categorisation of each case is vital, and it may be premature at this stage to

undertake large scale genetic studies of CFS/ME until there are clearly

agreed and validated diagnostic tools.

 

66. Large epidemiological studies can contribute well-characterised cohorts for

prospective investigation of longer term outcomes. Such a cohort, of affected

people ascertained over a relatively short period of time, is likely to be

qualitatively different from health service registers developed for needs

assessment and health service planning. However, some overlap may exist

where researchers work particularly closely with health services.

 

67. There is a lack of basic epidemiological evidence to help develop effective

prevention strategies and management options for CFS/ME. This may stem

from difficulties about definition and diagnosis of CFS/ME, as well as from the

historical failure to recognise CFS/ME as an illness. Once these constraints

are removed a programme of epidemiological research will become an

important priority. Three types of study are needed: descriptive epidemiology,

studies of aetiology, and epidemiological studies of characteristics associated

with outcome.

 

68. Descriptive Epidemiology

 

69. Basic descriptive epidemiology of population patterns is required to describe

both the incidence and prevalence of CFS/ME, and its duration, nature, and

severity, in terms of patient characteristics. Studies should pay particular

attention to the duration and nature of the symptoms experienced, especially

in terms of whether CFS/ME is a single syndrome or whether there are

several distinct sub-groups; the severity of symptoms, especially in terms of

the extent and types of disability (physical and cognitive) and pain

experienced and the age, sex and ethnicity of patients.

 

70. The UK is uniquely placed to undertake studies of prevalence and incidence

through primary care. Primary care research networks, such as the MRC

General Practice Framework, could provide a study population. If studies

were undertaken in practices which are linked into computerised practice

management systems, incidence could be studied as well as prevalence.

Fundamental to such a study would be an agreed research case definition.

 

71. A linked natural history study might be undertaken based on primary care and

using those practices in computer-based networks, relying largely on routine

health records. A standardised follow-up of cases identified either from

prevalence or incidence studies would be a much larger undertaking but not

impossible within primary care networks. An important caveat to be borne in

mind is the quality and reliability of computerised health records.

 

72. Aetiology

 

73. Aetiological studies could be used to identify characteristics of people, their

physical, work, and social environments, and health histories associated with

the development of CFS/ME by duration, nature and severity of CFS/ME.

 

These studies would need to follow on from basic research into possible

mechanisms of the development of chronic fatigue so that hypotheses about

aetiological factors can be clearly formulated (e.g. to environmental factors),

and will need to pay particular attention to physical and psychological

challenges. Such studies could be conducted as prospective cohort studies

comparing populations exposed and unexposed to putative aetiological

agents. However, it is possible that incidence would be too low to make such

studies feasible and it may be necessary to consider case-control studies that

retrospectively examine exposure.

 

74. It would be particularly helpful if such studies were designed so that they

could answer important outstanding issues around whether neurological and

psychological symptoms found in CFS/ME patients are causally related, are

consequences of the illness, or a combination of the two.

 

75. Outcome Studies

 

76. The current evidence indicates that CFS/ME patients exhibit wide variation in

the time to recovery, with some seriously affected patients never fully

recovering. There is, however, little evidence about which patients recover, or

what factors pre-dispose to recovery. Once outcomes have been clearly

defined, longitudinal studies of cohorts of CFS/ME patients are needed to try

to identify these factors. Very few studies have looked at patterns of

recovery, which the MRC CFS/ME Research Advisory Group considers to be

a potentially fruitful area of research.

 

77. Possibilities for research into potential treatments and management strategies

are considered in more detail below.

 

78. Developing Hypotheses about Pathophysiology

 

79. A wide range and variety of factors have been suggested to play a role in the

pathophysiology of CFS/ME, but the evidence is generally either weak or

contradictory. Greater methodological rigour and independent replication are

crucial in much of this work.

 

80. Many of the observations are interesting and in principle worth investigating.

Moreover, potentially modifiable risk factors are possible targets for

interventions. A useful start might be made to test such hypotheses in robust

but relatively simple research designs, so that the less likely ideas can be put

to one side and further effort and investment can focus on the areas that

preliminary evidence identifies as more likely to be productive.

 

81. In all studies, choices of sampling strategy, case-definition, measures and

controls are crucial and a multidisciplinary collaborative approach is likely to

be beneficial. Some studies will be amenable to case-control or other

epidemiologically- and genetically-sensitive designs, and others to

investigation in experimental models.

 

82. The MRC CFS/ME Research Advisory Group has not undertaken a detailed

review of the current level of scientific knowledge on the aetiology or

pathogenesis of CFS/ME, as this was not its function. The Group notes that

the recent report of a Working Group convened under the auspices of the

Royal Australasian College of Physicians (2002) has assessed the strength of

evidence for a number of factors in the pathophysiology of CFS, including

infections, immunological factors, central nervous system disturbances and a

number of other factors postulated to be involved. In most cases, the

evidence base was not large, with information coming from only a few studies,

and often conflicting. As a consequence of the lack of consistent evidence,

the MRC CFS/ME Research Advisory Group has considered a number of

broad thematic areas with regard to research on CFS/ME.

 

83. It should be emphasised that the research areas discussed below are not the

only ones where there is potential for advancing our understanding of the

pathogenesis of CFS/ME, but reflect the areas that currently show the most

promise. As scientific knowledge increases, other avenues of research may

become increasingly attractive.

 

84. Infections

 

85. Fatigue, cognitive disability and musculo-skeletal pain are commonly found

during the acute phase of many infectious diseases, and generally disappear

spontaneously with the emergence of a normal immune response. However,

following certain infections, a proportion of patients develop prolonged fatigue.

For example, up to 10% of patients with diagnosed infectious mononucleosis

(infection with the Epstein-Barr virus, EBV) or Q fever (Coxiella burnetti

infection) can develop chronic post-infectious fatigue. However the causes of

these chronic responses to infections in a minority of patients are not known.

 

86. It is clear that no single infectious cause of CFS/ME has been identified.

Although EBV can lead to CFS/ME, in the great majority of cases no

infectious cause can be found by routine microbiological investigation. There

is reasonably strong evidence that retroviruses and enteroviruses are not

causally related to CFS/ME.

 

87. Infection with the hepatitis C virus (HCV) may lead to fatigue, and treatment of

HCV-infected patients with interferon-alpha leads to symptoms

indistinguishable from CFS/ME, including fatigue, cognitive dysfunction and

pain. Pathophysiological investigation of well-defined conditions such as this

may represent a reproducible model for CFS/ME.

 

88. Many studies that report a causal association between an infection and

subsequent CFS/ME have reported the detection of antibodies against the

viral or non-viral agent in patients with CFS/ME, and draw the conclusion that

such raised levels of antibodies reflect chronic active infection. However

healthy individuals may also demonstrate raised antibody levels, many years

after the original infection. The Working Group of the Royal College of

Australasian Physicians noted that raised titres of antibodies against common

viruses are often found, but are not of pathophysiological or diagnostic

significance.

 

89. Recent advances in virology and bacteriology enable the detection and

quantification of organisms directly through amplification of their genomes, by

the polymerase chain reaction (PCR). PCR technology will provide a more

robust methodology than antibody detection for the association of known

organisms with CFS/ME within cohort studies.

 

90. The discovery and gene sequencing of new viruses and application of PCR

will allow the investigation of patients with CFS/ME for novel viruses, for

example through the use of degenerative primers or differential display PCR.

 

91. The application of the novel technologies to bacteriology has allowed the

identification of non-culturable organisms, for example through the 16S rRNA

PCR assay. Assays such as these would allow the exploration of a CFS/ME

patient cohort for novel bacterial infection.

 

92. Advances in genomics brought about through the human genome programme

will also allow the investigation of DNA from patients and controls for the

expression of novel mRNAs associated with CFS/ME.

 

93. Application of these new technologies for the investigation of new or known

organisms with CFS/ME would be most epidemiologically relevant within a

cohort study, where defined patients and controls could be studied.

 

94. Neurology

 

95. As the report of the Working Group of the Royal College of Australasian

Physicians indicated, there is conflicting evidence for neurological

abnormalities in CFS/ME, but good evidence that muscle strength, endurance

and recovery are normal. The early reports of inflammation of the brain, spinal

cord or muscles have not been confirmed. It should be borne in mind that it is

likely that abnormalities may be detected in the neuromuscular system of

patients who are severely ill with CFS/ME and possibly immobile, in

comparison to healthy controls. However, abnormalities have been

demonstrated in individuals who have restricted mobility for other clinical

reasons.

 

96. Clinical experience would indicate that most patients with CFS/ME have

neurological signs that lie within the normal range. The initial reports of

inflammation of the brain, spinal cord or muscles have not been confirmed.

Imaging studies using computerised tomography or magnetic resonance

scans can demonstrate detailed brain structure but do not provide information

about brain function. There are reports in the literature of white matter

changes but these are variable and non-specific. Furthermore such imaging

techniques are prone to misinterpretation if there are subtle differences in

brain structure.

 

97. Functional imaging of various types (magnetic resonance (MR), single photon

emission computerised tomography (SPECT) and positron emission

tomography (PET)) are relatively new techniques to have been developed.

Studies from other conditions have demonstrated the many difficulties in

interpreting abnormalities – particularly in determining whether or not such

suspected abnormalities are primary or secondary phenomena. It would

seem possible that functional imaging might be used in the study of CFS/ME,

but such studies are heavily reliant upon clearly defined, homogeneous

groups of participants who are investigated in a consistent manner, with

appropriate controls (and not just healthy volunteers).

 

98. At present, it is not clear that performing invasive, and hence potentially

dangerous, tests such as obtaining cerebrospinal fluid at lumbar puncture or

performing muscle biopsy would be appropriate, unless clinically justified.

Therefore any studies that proposed such tests would need to be very

carefully considered, as there may be serious ethical dilemmas, especially in

the case of children.

 

99. Muscle Fatigue and Weakness

 

100. Muscle weakness can be defined as the inability to generate the required or

expected force output, whilst muscle fatigue can be defined as the inability to

maintain the required or expected force output. Problems with the generation

or maintenance of force output can occur at any point in the ‘chain of

contraction command’ ranging from the brain to the muscle architecture itself.

In terms of muscle weakness problems may occur with electro-mechanical

activation (e.g. impaired neuromuscular transmission; impaired excitation

contraction coupling), fuel supply (e.g. reduced short term energy stores;

impaired energy exchange) and/or the contractile machinery (e.g. smaller

muscle cells, fewer muscle cells).

 

101. Muscle fatigue can be considered in terms of its central or peripheral origin. If

the fatigue is centrally mediated, the mechanisms, if not due to problems with

motivation, are likely to be due to a failure to sustain the number and/or

stimulation frequency of recruited motor units. If peripherally mediated,

mechanisms of fatigue can include impaired neuromuscular transmission

and/or propagation of the muscle action potential and/or impaired

excitation/contraction coupling.

 

102. Many well-validated scientific techniques now exist to determine at which

point in the command chain problems may arise. These techniques in turn

enable the elucidation of the mechanisms responsible for the weakness or

fatigue, including for example: muscle biopsy, strength testing (voluntary and

electrical), electromyography, ultrasonography and magnetic resonance

imaging. Many of these techniques have already been employed in the

assessment of muscle weakness and fatigue associated with CFS/ME. The

general opinion arising from these studies is that there is no physiological

basis to the weakness and/or fatigue. These are general assertions however,

and at no point has the literature been systematically reviewed to determine

the scientific rigor or generalisability of the research findings.

 

103. A key step with regard to undertaking further research in this area might be to

undertake a full systematic review of the literature relating to the assessment

of musculo-skeletal weakness and fatigue associated with CFS/ME. Such a

review could establish current gaps in the research evidence and could inform

recommendations for any further physiological assessments.

 

104. Immunology

 

105. There does not seem to be a consensus on the nature and extent of

immunological disturbances in CFS/ME, even though there are numerous

reports of immunological alterations. There appears to be conflicting evidence

for a variety of potential immunological factors in the pathophysiology of

CFS/ME (such as reduced lymphoctye proliferation and activation status,

levels of specific immunoglobulins, or autoimmune conditions). The Report of

the Royal Australasian College of Physicians Working Group suggested that

the heterogeneity of findings might be explained in terms of variations in

methodology and also inadequate consideration of potential confounding

variables.

 

106. Bidirectional interactions between the immune system, inflammatory or

infected tissue(s) and the central nervous system (CNS) are now well

established, particularly in experimental animal models. Thus systemic or

local disease or injury in peripheral tissues activates neural and humoral

afferent signals to the CNS. The brain regulates and co-ordinates many

aspects of the acute phase response including induction of fever, slow wave

sleep, lethargy, loss of appetite and body weight, and modulation of

endocrine, immune and cardiovascular systems. Furthermore the brain,

previously considered as an “immune privileged organ”, can exhibit

inflammatory responses which contribute to local and systemic disease.

Cytokines are primary mediators and modulators of these responses, and

proinflammatory cytokines act in the brain to induce a syndrome known as

“sickness behaviour syndrome” which includes reduced motivation and

responsiveness, lethargy and loss of appetite (Konsman et al., 2002). All of

these responses are profoundly influenced by environmental stress, by

endocrine status (particularly the activity of the hypothalamic-pituitary-adrenal

axis) and by genetic background and gender in experimental animals.

 

107. Obvious parallels can be drawn between the findings of research on

neuroimmune interactions, the CNS response to injury, cytokine neurobiology

and CFS/ME. The growing field of psycho-neuro-endocrine-immunology,

which seeks to understand the interactions between environmental stresses

(including psychological and immune factors) and the immune, endocrine and

nervous systems may by of direct relevance to our understanding of some

aspects of CFS/ME. Limited data provide some support for the roles of

cytokines in CFS/ME, but this is a notoriously difficult area to study because

cytokines generally act locally within tissues rather than in circulation (and

therefore their concentrations and actions are difficult to access), and exhibit

complex and diverse actions.

 

108. Animal studies in the area of neuroimmunology, particularly in “sickness

behaviour syndrome”, have potential implications for CFS/ME. It will be

important to develop and study chronic, rather than acute, models of

“sickness behaviour syndrome”, to assess outcomes and influences relevant

to CFS/ME (such as objective measures of lethargy, fatigue, and impact of

exercise) and to elucidate potential mechanisms and interventions.

 

109. Clinical neuroimmunological studies are much more difficult to undertake, and

measurements of inflammatory mediators (e.g. cytokines) in the blood

circulation are likely to be of limited value (see above). However,

comparisons of cytokine responses to immune/inflammatory challenges or

levels within some tissues can be assessed, and may be compared in

patients with varying severity of CFS/ME or after recovery, with healthy controls.

110. Understanding inflammation in the brain has generally been restricted to post

mortem studies or analysis of brain tissue or cerebrospinal fluid – techniques

which are not readily amenable in CFS/ME patients. However recent

developments in PET imaging allow assessment of activated microglia.

Analysis of known polymorphisms in the genes of inflammatory mediators,

which have been linked to other chronic inflammatory diseases, may be of

some value within large epidemiological studies of CFS/ME.

 

111. Neuroendocrinology

 

112. Several lines of evidence would indicate that there are neuroendocrinological

abnormalities found in some CFS/ME patients, although it is unclear whether

these are causal or secondary in nature. The reported disturbances in the

hypothalamic-pituitary-adrenal (HPA) axis could be due to a number of

factors, including disturbance of central neurotransmitters such as serotonin

or, more likely, a malfunctioning of the complex relationship between cortisol

and these transmitters. The reported abnormalities are dissimilar to those

found in patients with major depression, which would indicate that there are

different underlying processes for the two conditions. The high degree of comorbidity

of CFS/ME and depression would, however, mean that studies in

this area are fraught with potential confounds.

 

113. The interpretation of basal cortisol levels is problematic, and experiences from

studies of other conditions have demonstrated many potential pitfalls.

However, investigations into disordered functioning of the HPA axis can be

undertaken through the use of specific challenge studies, using for example

corticotrophin releasing hormone, adrenocorticotrophic hormone or serotonin

agonists. However studies to date have provided equivocal data, possibly due

to the heterogeneous nature of the patient groups being studied, although

methodological problems may also have contributed to the uncertainty.

 

114. One area where neuroendocrinological studies may prove informative is in the

study of circadian rhythms and sleep architecture, both of which are affected

by disordered neuroendocrine function. There is currently conflicting evidence

of disturbed circadian rhythms in people with CFS/ME, but sleep disruption is

a commonly reported symptom of the illness.

 

115. There have been a small number of studies investigating the potential

therapeutic benefit of neuroendocrinological manipulations. However, whilst

some studies have shown some promise, the serious side-effects associated

with long term use of corticosteroids would indicate that more basic research

would be needed to justify their use as a therapeutic agent.

 

116. Central Nervous System Function

 

117. Key symptoms of CFS/ME include fatigue, cognitive dysfunction and sleep

disturbance, which are associated with disordered functioning of the CNS. It is

uncertain whether this disordered functioning is solely a consequence of a

primary abnormality in the brain or is mediated by changes in circulating CNS

modulators such as hormones and cytokines, or neural afferent signals.

 

118. Limited laboratory studies of people with CFS suggest abnormalities in the

function of the hypothalamic-pituitary-adrenal axis and brain monoamine

pathways, particularly serotonin. Changes in sleep architecture are also

frequent. The abnormalities reported differ clearly from those observed in

patients with depressive disorders, though the two conditions commonly coexist.

 

119. It is also uncertain whether the various neurobiological changes that have

been reported in CFS/ME are involved in the pathophysiology of the disorder

or are a consequence of the illness and persistent inactivity. To resolve this

important issue, longitudinal studies of people throughout the course of their

illness may be required. Such work could be usefully integrated with

psychological treatment studies. In this way it should be possible to see if

abnormalities are trait or state markers and whether their presence has

prognostic significance. Another, potentially quicker, approach would be to

carry out cross-sectional studies of people who have made good clinical

recoveries from CFS/ME to find evidence of enduring biological “vulnerability”

factors.

 

120. It could also be informative to carry out neurobiological studies of

prospectively selected groups of participants who are known to be at high risk

of CFS/ME-like symptoms (e.g. those infected with Epstein-Barr virus and

patients receiving treatment with interferon for hepatitis). Such an approach

may reveal which biological abnormalities appear to be associated with the

development of fatigue symptoms and might therefore be involved in their

pathophysiology.

 

121. It will also be important to investigate the brain pathways that underlie the

symptoms of CFS/ME. The use of SPECT imaging to study regional cerebral

blood flow in CFS has yielded inconsistent results. However specific ligands

for PET and SPECT are becoming increasingly available and may allow the

delineation of regional neurotransmitter and neurochemical abnormalities.

Functional magnetic resonance imaging (fMRI) studies may help elucidate the

brain pathways that underpin the cognitive impairments in CFS/ME, in a

similar way to that employed in the study of cognitive deficits in mood

disorders. These imaging changes might provide clues for the development of

novel treatments for the cognitive dysfunction in CFS/ME, as well as a way of

monitoring changes in cortical functioning through rehabilitation and clinical

improvement.

 

122. Chronic pain is a widely reported symptom of CFS/ME, but there would

appear to be little research into this aspect of the illness. There are a number

of potential avenues for research, which could build on the knowledge gained

in other chronic conditions such as multiple sclerosis. The use of functional

imaging techniques may be especially useful in elucidating the centrally

mediated aspects of pain perception.

 

123. It will also be important to obtain more understanding of the central processes

that mediate fatigue in healthy animals and humans. A better knowledge of

the neurobiology might yield clues to the pathophysiology of clinical fatigue

states and provide new targets for treatment.

 

124. Cognitive Performance

 

125. People with CFS/ME not only report difficulties with disabling fatigue but also

with cognition. Any studies in cognition must consider a number of key factors

in assessing the levels of impairment that are present in the disorder. These

factors include the heterogeneity of presentations and levels of severity, the

presence of psychiatric factors such as co-morbid mood disorder, as well as

possible relationships between brain dysfunction and cognition.

 

126. The majority of studies have shown little change in overall intellectual

functioning. There is good evidence of attention and concentration problems

in CFS/ME. However, despite reproducible demonstration of some reduction

in performance, the specific nature of such deficits has not been identified. In

particular the attention dysfunction may be a global non-specific impairment

or a specific one relating to selective attention.

 

127. The research in this area has tended to involve small samples of patients and

a small number of tasks, with few studies involving more than 40 participants

per group. Any study attempting to identify subtle deficits will need to include

an adequate number of participants. The variability of results in this area may

be due to the small numbers in most previous studies.

 

128. The understanding of memory impairment in CFS/ME is, at present, limited.

The effects of suggestibility on the subjective and objective experience of

impairment have only recently begun to be investigated.

 

129. There seems to be a positive relationship between objective measures of

cognitive impairment and symptoms of depression in CFS patients. However

depression in CFS patients only accounts for a small amount of the variance

in the subjective complaints of poor cognitive performance, even when there

are no differences between CFS patients and healthy controls.

 

130. The level of model testing in the area of cognitive impairment in CFS/ME is

poor. The variability in the results of studies in this area mirrors that of studies

of other symptom areas. It seems highly likely that a number of different

variables will affect both objective and subjective cognitive performance.

These variables need to be identified and tested with confirmatory, as

opposed to exploratory, analyses in studies with sufficiently large sample

sizes to prevent statistical errors (both Type I and Type II). It will also be

necessary to find objective tests of memory that have some ecological

validity.

 

131. Knowledge of the relevant cognitive factors could contribute to the diagnosis

of CFS/ME, a description of the changes that are seen over time as the

disorder develops (in the same way that they are used in Alzheimer’s

disease), and to the description of the impact of CFS/ME on functioning.

 

132. Cognitive factors could also be used as outcome measures for trials of

interventions. There is a need for agreement about how such measurements

should be made. CFS/ME patients report problems with everyday cognitive

tasks, but are tested on laboratory tasks of specific list learning or dual

tasking. These tasks do not take into account the lengthy practice that

provides the pattern or strategy for performance in everyday tasks. The

mismatch of what people thought they should be able to do and their actual

subjective assessment of their current performance also needs to be

measured.

 

133. It is clear that the cognitive dysfunctions in CFS/ME cannot be entirely

explained by mood variations. It should be noted that, even when cognitive

capacity is intact, cognitive performance may be affected by factors such as

arousal, mood, and strategy use.

 

134. Psychological factors

 

135. The presentation, symptoms and effects on functioning of all illnesses, both

physical and psychiatric, are affected by a variety of factors including

personality factors, coping mechanisms and social support. For example even

when it is possible to measure the scope of a disability with a physical cause,

(e.g. arthritis) the effects on quality of life can differ between individuals

depending on non-illness specific factors. The same will be true of CFS/ME,

irrespective of any causal mechanism.

 

136. Several studies have suggested that personality factors may differ between

those with CFS and other disorders but the available evidence is equivocal. A

prospectively designed study could allow the differentiation of the interplay

between biological and psychological factors which may influence not only the

maintenance of the disorder, but also possible types of intervention that might

be developed. Definitions of CFS/ME that include co-morbid psychiatric

problems may produce confusing evidence of the role of personality factors.

Future studies to test hypothesised models of the relationship between

biological and psychological factors must consider this potentially confounding

variable carefully.

 

137. A key problem when considering CFS/ME is that it is not clear when

psychological factors might play a part. Given that the co-morbidity of

CFS/ME with depression may be as high as 50%, it is often concluded that it

is integral to the disorder rather than a response to it. However there a few

studies that have addressed this issue directly. The studies have often

recruited participants from secondary care, who are therefore generally at the

more severe end of the spectrum of severity. It is, at present, not clear

whether a broader population of CFS/ME patients would allow a clearer

understanding of the influence of psychological factors.

 

138. INTERVENTIONS

 

139. The Chief Medical Officer’s Independent Working Group, in considering

therapeutic interventions, drew on a specifically commissioned systematic

review of management strategies undertaken by the NHS Centre for Reviews

and Dissemination (Whiting et al., 2001). The systematic review identified

350 studies that were considered relevant, but only 43 of these met the

inclusion criteria. Within these 43 studies, 14 different diagnostic criteria were

used to characterise participants, with 31 different interventions being tested

using 39 different outcome measures with 203 outcomes evaluated. Two

specific strategies were identified which potentially may be beneficial for

CFS/ME, graded exercise therapy (GET) and cognitive behavioural therapy

(CBT) techniques. These strategies have been tested individually, together

and in treatments that incorporate numerous different treatment approaches

including adjunctive pharmacotherapy (Whiting et al., 2001; Mulrow et al.,

2001).

 

140. The MRC CFS/ME Research Advisory Group has not considered in detail the

information included in the systematic review, but chosen instead to consider

how the evidence-base for potentially effective management options can be

strengthened.

 

141. The MRC CFS/ME Research Advisory Group considers that there are a

number of important steps to advance the evaluation of potential

management strategies or treatments for CFS/ME. There should be

agreement on a case definition and a classification of severity and any other

relevant characteristics which define subgroups (such as specific symptoms

or co-morbidities). This step is fundamental to any epidemiological study,

including clinical trials.

 

142. A definition of a clinically important improvement in disease status, with a

classification of the degree of improvement, is essential for natural history and

intervention studies. Thus the validation of a range of outcome measures,

and associated changes, is a key step. A review of the many measures used

to date and some pilot work to develop a package of a small number of

existing outcome measures (which have already been tested for validity and

reliability) to be widely adopted would be an important step forward.

 

143. A careful review of studies which have shown positive differences between

treatments and those which have not (testing the same treatments) could be

useful to understand the reasons for the differences (e.g. outcome measures,

details of interventions or chance), as most differences are small.

 

144. Clinical trials of interventions

 

145. All new potential interventions, including complex packages of care, should

ideally first be evaluated in small studies using markers of disease activity to

decide whether to proceed to larger trials. The difficulties in defining objective

outcome measures means that such studies may have positive results even

with ineffective interventions. Alternatively, interventions with only a modest

benefit might be rejected.

 

146. The Medical Research Council has previously considered the challenging

area of the development and evaluation of complex packages of care, and

produced a guidance document for investigators, A Framework for

Development and Evaluation of RCTs for Complex Interventions in Health

(2001). The MRC CFS/ME Research Advisory Group would strongly

recommend that researchers consider the guidance contained within that

document, which provides detailed discussion of many salient points.

 

147. Fundamental to all considerations about intervention studies is the need for

outcome measures which are:-

 

! as objective as possible (this does not mean that patients’ perceptions of

improvement are not important but relates to the difficulties in truly

blinding interventions);

 

! sensitive to clinically relevant changes (spontaneous or intervention–

related);

 

! consistent;

 

! represent different aspects of the syndrome;

 

! if appropriate, have a clinically relevant grading system;

 

! can be documented and consistently applied; and

 

! limited in number (one or a small number of primary outcomes).

 

148. The MRC CFS/ME Research Advisory Group considers that every attempt

should be made to reduce potential bias in clinical trials (e.g. by use of

randomisation and blinding). The attraction of cross-over designs needs to be

weighed against the problem of blinding, which is even more difficult within

individual patients. Factorial designs may be valuable to assess more than

one intervention but the possibilities of interactions must be kept in mind.

 

149. For each trial the balance between broad eligibility criteria with consequent

generalisability and selection of subgroups most likely to respond to a specific

intervention must be considered. The need to assess a promising

intervention in all types of patients must be balanced against the

demonstration of ‘proof of concept’ in a well-defined group. The latter may be

the first stage before extending to a broader group. People who cannot

attend clinics should not be excluded, and efforts should be made to allow the

most severely ill to participate.

 

150. It is appropriate to explore potential interventions in the absence of knowledge

of causation or pathogenesis. The need to adequately define and document

complex interventions so that they can be replicated accurately is crucial.

The duration of the intervention should be adequate to achieve benefit and

the follow-up after the intervention should be long enough to determine if the

effect is sustained.

 

151. All trials should be large enough to have reasonable power to detect a

clinically useful effect in the primary outcome. The need to have more than

one trial to reliably assess risks and benefits is even greater in these

circumstances, with added benefits of being able to combine the results later.

 

152. The importance of following up all the participants, even if they withdraw from

treatment and of undertaking an intention to treat analysis on as complete a

population as possible cannot be emphasised too strongly. The problems of

interpretation associated with other techniques such as excluding

withdrawals, “on treatment” analyses and “last observation carried forward”

which may over-estimate treatment effects are well-known.

 

153. The problems with most of the trials to date, as described in the review from

Whiting et al. (2001) is that very few fulfil all of these criteria. The MRC

CFS/ME Research Advisory Group believe that researchers should consider

from the outset the comprehensive reporting required of any intervention

study, to allow others to understand the design, conduct, analysis and

interpretation of that study. The use of the CONSORT recommendations

(Moher et al., 2001) should allow others in the field to assess the validity of

the results, and will facilitate systematic reviews and meta-analyses.

 

154. Musculo-skeletal-Based Interventions

 

155. There is considerable confusion and disagreement surrounding the optimum

approach to the rehabilitation of people with CFS/ME. It has been suggested

that the greater the fatigability and disability and the longer the illness duration

for an individual, the stronger the associations with a psychological

component to the process (Royal Colleges of Physicians, Psychiatrists and

General Practitioners, 1996). It is not clear whether the psychological

component is a result of the CFS/ME, or vice versa, or indeed whether there

is a mixture of the two. There are parallels to be drawn between patients with

CFS/ME and patients with chronic low back pain of non-specific origin. These

patients are severely disabled, frequently depressed and are wary of

participating in a rehabilitation programme in case it exacerbates their back

pain.

 

156. Despite the assertion from the CMO’s Independent Working Group that

patients with CFS/ME are no less fit than sedentary people, they themselves

recognise that prolonged inactivity leads to muscle wasting. This inactivity

results in a decline into a “vicious spiral of immobility”. It is very difficult to

break into this downward cycle and the key to any effective rehabilitation

programme should be to support the patient through this process.

 

157. The CMO’s Independent Working Group agreed that rehabilitation is

important but it should be graded, tailored to the individuals’ own needs and

must recognise that the whole process invariably needs to start from a low

baseline. Despite the recommendation that this is the best way forwards,

patients remain sceptical, as many believe the graded exercise approach

makes them worse. Any research into rehabilitation must take into account

these concerns and establish why some people experience a deterioration

whilst others find the process beneficial.

 

158. The MRC CFS/ME Research Advisory Group believe that it likely that an

integrated package of care will be the most beneficial in the management of

CFS/ME, as has been shown for other chronic illnesses and conditions.

Graded exercise and cognitive behavioural therapy could be considered in

isolation but the existing literature from research on both ME/CFS and chronic

low back pain would suggest this would not provide optimal benefits.

 

159. The multi-disciplinary, holistic ”back school” approach is an example of a

complex package of care that has proved extremely effective for those

patients with chronic intractable back pain for whom no other approach has

been effective (Nielson & Weir, 2001). This approach incorporates for

example: graded exercise, cognitive behavioural theory, pain management

and relaxation therapy. There is obvious merit in drawing upon other well

researched areas when developing and evaluating packages of care for

CFS/ME.

 

160. It will be important to understand why some people with CFS/ME experience

a deterioration when participating in an exercise approach to treatment. The

wealth of experience from the back pain literature should be drawn upon

when addressing how “graded” should graded exercise be and how the

optimum progression points in treatment should be determined.

 

161. The report of the CMO’s Independent Working Group highlighted the support

by some patients for “pacing” as a management strategy, which was also

evident from the responses received as part of the consultation process

during the development of this research strategy. At present there is no

empirical evidence of efficacy for “pacing”, which should come from

randomised controlled trials.

 

162. Psychologically-Based Interventions for CFS/ME

 

163. Evidence on the effectiveness of treatments needs to take into account the

specific outcomes that are being measured which may change at differing

rates. Various outcomes have been suggested for the evaluation of

psychological interventions, not all of which are psychologically assessed.

For example, primary outcome measurement of anxiety and depression may

be early results of psychological treatments that may be expected to be

observable as soon as therapy has ended. In contrast to these proximal

results, quality of life and use of resources may be later changes which

cannot be measured for some time after therapy has discontinued or will only

become apparent following specific levels of changes in other factors such as

subjective assessments of fatigue or cognitive changes.

 

164. CBT encompasses a variety of different therapeutic techniques. The general

principle of CBT techniques begin with the engagement of the person in a

shared goal and after a number of sessions the identification of a model of the

development and maintenance of the problem which will include

psychological, biological and social variables. The next part of therapy is to

help the person identify any possible barriers to the attainment of a goal. The

technique is essentially the same when CBT is used in health psychology to

improve outcomes for people with physical illness as it is in the treatment of

specific psychiatric disorders.

 

165. The recent systematic review (Whiting et al.) concluded that CBT and GET

therapies were effective. Treatments that lasted a longer time (more than 20

weeks) seemed to have been more successful than those providing brief

therapy. There is some concern about drop out from treatment and this needs

to be investigated in more detail in new trials.

 

166. Many of the intervention studies using CBT and GET for CFS have been

focussed on the effects of therapy on people who have attended outpatient

clinics. This is likely to be a subset of the people who have a diagnosis of

CFS and will miss both the more severe cases as well as the least severe and

least chronic. Further research should concentrate on the effects of these

interventions across the spectrum of the disorder. Larger scale trials would

also allow the intervention to be assessed in a targeted way, to allow

consideration of possible factors that may affect the outcome of therapy e.g.

significant cognitive difficulties in attention and concentration. It may also be

useful to consider specific biological outcomes such as functional brain

imaging in parallel.

 

167. Other Interventions

 

168. There are many pharmacological, behavioural or complementary therapy

interventions that have been proposed for CFS/ME, but for which the

evidence of efficacy is lacking (Whiting et al., 2001; Mulrow et al., 2001), and

in some cases there is no underpinning theoretical scientific rationale. The

MRC CFS/ME Research Advisory Group considers that, in the absence of

knowledge of causation or pathogenesis it can still be appropriate to explore

potential interventions. However, any such study must apply the same

methodological rigour as more conventional therapies.

 

169. HEALTH SERVICES RESEARCH

 

170. Health Services Research (HSR) is used both to help guide evaluative

research into the cost-effectiveness of management strategies and to

evaluate the cost-effectiveness of ways of organising and delivering effective

care. The former research combines descriptive HSR and Health Care

Needs Assessment, and the latter Health Technology Assessment and

Service Delivery Organisation research.

 

171. One difficulty in identifying priorities for HSR in CFS/ME at the current time is

that basic information on the epidemiology of CFS/ME and clinically effective

treatments is lacking. For example it is not known which groups, or subgroups,

of patients might benefit from any particular treatment and hence

health care needs assessments would be premature. The rigorous evaluation

of service delivery models cannot be undertaken until it is clear what services

should be delivered. However, once fundamental research into the definition,

diagnosis, epidemiology, outcomes, and effective management strategies for

CFS/ME begin to clarify the evidence, then HSR will become increasingly

important.

 

172. Health Care Needs Assessment

 

173. Descriptive population-based studies are needed to quantify the incidence

and prevalence of CFS/ME in terms of characteristics which identify groups of

patients that could benefit from different types of management. For example,

age (particularly distinguishing children and adults), gender, and duration,

severity and nature of symptoms might all affect management options. This

research could be combined with epidemiological research into factors

associated with the incidence of CFS/ME. In either case the key

methodological issue is the need for population-based studies.

 

174. Descriptive Health Services Research

 

175. Descriptive health services research should allow greater understanding of

the services that are in place at present to deliver care. As with other chronic

illnesses, there are important issues concerning how these services are

distributed and accessed. Furthermore, it will be important to understand

whether access to these services is equal or does it reflect frequently

observed patterns of socio-economic inequality. Variations in patterns of care

and service provision can often be helpful in identifying areas of need for

evaluative research since they suggest uncertainty around best practice.

 

176. Health Technology Assessment

 

177. Health Technology Assessment considers the effectiveness, appropriateness

and cost of health “technologies”, which can be any method used by those

working in the health services to promote health, prevent and treat disease

and improve rehabilitation and long term care. As well as studies of clinical

effectiveness, it is important that the success of management options for

CFS/ME are evaluated in practical, real-world settings and that a broad range

of consequences are understood. These consequences include acceptability,

costs, effects on carers and families, and training, education and workload for

health service professionals. As well as being pragmatic it is important that

such evaluative research should investigate any variation in costeffectiveness

between sub-groups of patients for which different management

strategies might have different effects. The MRC CFS/ME Research Advisory

Group considers that such studies should utilise pragmatic randomised

controlled trial methodology if possible.

 

178. Service Delivery and Organisation

 

179. Current evidence suggests that CFS/ME patients receive care from a wide

variety of different services based in different settings, and from health care

professionals with different training. The issue of service provision was not

considered by the MRC CFS/ME Research Advisory Group. Service delivery

and organisation research is concerned with understanding which service

model is most cost-effective from the perspective of patients, their families

and carers, the Health Services, and others. Key questions surround the

training and education that doctors and nurses should receive in the care of

CFS/ME, and how services staffed by appropriately trained professionals

should be organised, and accessed. It would be particularly important to

understand whether management of CFS/ME should be part of general

services, or should be provided in specialist centres by appropriately trained

specialists, and if the latter how should these specialist centres themselves be

organised, administered, and located.

 

180. Appropriately designed trials of these ‘complex interventions’ should include

research from the patient perspective around issues of acceptability and accessibility.

181. RESEARCH CAPACITY AND THE INTERFACE WITH SERVICES

 

182. Researchers, funders and service providers need to consider how best to

achieve strategic, integrated research alliances both to sustain excellence

and to develop new areas of enquiry, and to ensure the availability of

sufficient and appropriately skilled manpower at the research-service

interface.

 

183. Strengthening Research Capacity

 

184. There may be a need for specific measures to promote multidisciplinary

collaboration around shared strategic goals, including allied health

professionals. Such collaboration offers established centres of excellence the

kind of new scientific opportunities that are essential if they are to sustain their

competitiveness internationally. In relation to emerging or currently

fragmented national effort, such collaboration can provide access to crucial

partners and expertise. The MRC CFS/ME Research Advisory Group is

conscious of the need to attract high quality researchers, from both basic

scientific and clinical disciplines, to undertake research in CFS/ME.

 

185. Large-scale prospective epidemiological and genetic studies would require

high quality, trained and motivated clinical and basic science researchers to

be based in a number of UK centres that combine service and research.

 

186. Nurturing the Research – Service Interface

 

187. The links between research and services need to be strong in order to recruit

and gain access to participants. Consequently, much research needs to work

through service providers. In this respect, the National Health Service

provides the UK with significant opportunities. As discussed above, the most

severely affected often experience difficulties in accessing services, and

particular efforts should be made to include this patient group.

 

188. THE VALUE OF LAY PARTICIPATION

 

189. The participation of affected individuals and their carers, researchers with

experience of patient support, and advocacy groups has enriched the process

of developing a research strategy for CFS/ME. However, the above

stakeholders have indicated that there are also broader issues, which,

although outside the terms of reference of this research strategy, are

important and to which research could make a significant contribution.

 

190. Further partnerships are likely to be of benefit by providing researchers and

funders with access to user perspectives, and lay organisations with access

to scientific expertise. Specifically, aspects of patient and carer experience

can help scientists better frame their research questions and to work towards

outcomes that are more relevant to the intended beneficiaries.

 

191. In principle, there are important two-way benefits in the active involvement of

consumers in the research process. In the case of the development of a

CFS/ME research strategy, there has already been a high level of

involvement and a range of diverse views expressed, particularly at the

strategic level. This diversity does present some difficulties as it will not be

possible to achieve the approval of all concerned.

 

192. Consumers can participate in research at the strategic level by being involved

in setting the research agenda, and also during the research process within a

particular study.

 

193. Research agenda

 

194. Consumers have been closely involved in the development of this research

strategy, both by major inputs at the start of the process, and also during the

deliberations of the group. Representatives of the MRC Consumer Liaison

Group are members of the MRC CFS/ME Research Advisory Group and have

met with consumers groups to access their views. In addition, a survey of

priorities for research was undertaken and independently analysed by the

NHS Public Health Resource Unit (Annex 2). Consumers have also involved

in the consultation about a preliminary draft of this document (Annex 3). –

delete from consultation document.

 

195. Within specific research studies

 

196. Consumers have the potential to be involved at every stage of the research

process, and there have been studies exploring the extent and perceived

effects of such involvement. By being involved at the earliest stages,

consumers of research can play important roles in the design of a study and

can ensure that multiple perspectives are taken into account. Consumers can

then often liaise with broader groups with which they are associated to ensure

that the perspectives can include a wider constituency. This liaison can also

be beneficial in publicising the studies so that a wider group can be aware of

the issues around participating in, for example, a clinical trial. By being

involved in a research project, consumers can also have an important role in

interpreting the study findings and ensuring that these are widely

disseminated (and implemented) throughout the relevant constituencies. This

involvement could feed back into considering what further research might be

needed.

 

197. The MRC CFS/ME Research Advisory Group believes that patient

organisations and support groups can play an important role in involving

participants in research. The severely ill, who sometimes experience

difficulties in accessing care, have not been adequately represented in

research studies. Patient organisations who represent and are in contact with

severely ill people with CFS/ME should work in partnership with researchers

to identify potential participants, including alerting their constituents to current

projects.

 

198. CONCLUSIONS AND RECOMMENDATIONS

 

199. The MRC CFS/ME Research Advisory Group fully endorses the conclusions

of the Report of the CMO’s Independent Working Group, namely that CFS/ME

is a real, serious and debilitating condition, and that research into all aspects of

CFS/ME is needed.

 

200. In considering ways to advance research on CFS/ME, the Group has focused

on a number of strategic themes: case definition, an epidemiological

framework, pathophysiology, interventions, health service research, research

capacity and the value of lay participation.

 

201. The MRC CFS/ME Research Advisory Group has not provided a detailed plan

for the science, nor set out an agenda of the many research projects that

might merit support. A strategy is proposed which reflects the current state of

knowledge in CFS/ME, and which aims to provide a rational framework for

advancing the understanding of the illness and to reduce suffering.

 

202. The MRC CFS/ME Research Advisory Group considers there should be an

agreed standardised case definition and a classification of severity and any

other relevant characteristics that define subgroups. A definition of a clinically

important improvement in disease status, with a classification of the degree of

improvement, is essential for natural history and intervention studies. Thus

the validation of a range of outcome measures, and associated changes, is a

key step.

 

203. Much of the basic research on the causes and aetiology of CFS/ME will be

long term in nature. New and important findings will emerge, from the current

UK and international research effort, and these too should inform longer term

research and funding strategies.

 

204. It is essential that the researcher–funder-lay partnership is nurtured, to ensure

that the best evidence is easily available to all, and to facilitate the growth of

consumer involvement in the design, conduct and dissemination of research -

as a means to enhancing its quality, relevance, and credibility.

 

205. In the short term, the MRC CFS/ME Research Advisory Group consider that

the research community should be encouraged to develop high quality

research proposals for funding that address key issues for CFS/ME research

that are amenable for study at the present time:

 

! case-definition;

 

! understanding symptomology; and

 

! new approaches to management.

 

206. In view of the probable multiplicity of causal factors and the widely disparate

findings so far reported, the MRC CFS/ME Research Advisory Group

considers that studies investigating potential causal pathways and

mechanisms, whilst having merit, would not have the same immediate impact

on increasing understanding of CFS/ME, nor reducing the suffering of

patients.

 

207. The MRC CFS/ME Research Advisory Group recommends that research

studies should aim to be as inclusive as possible in terms of the recruitment of

participants, and due consideration should be given to sample size to allow

for possible subgroup effects. There should be clearly stated inclusion and

exclusion criteria, with detailed justification if certain types of patients are not

included, with every effort being made to include the severely ill.

 

208. Randomised controlled trials of adequate size, using standardised case

definitions, eligibility criteria, and baseline and outcome assessments, could

be used to evaluate one or more of the interventions which have been shown

in one or more trials to have a benefit. Smaller trials could be undertaken to

study new potential approaches to management or treatment.

 

Standardisation of entry criteria, case definitions and outcome measures will

allow results to be more widely generalised and compared between studies.

 

209. Given the present difficulties in identifying priorities for HSR in CFS/ME

outlined above, it is not clear whether it is appropriate to make HSR a priority

at this time. However, once fundamental research into the definition,

diagnosis, epidemiology, outcomes, and effective management strategies for

CFS/ME begin to clarify the evidence, then HSR will become increasingly

important.

 

210. The MRC CFS/ME Research Advisory Group considers that there is a key

role for patient organisations to help attract participants to research,

especially the severely ill, and to help in the dissemination of research results.

 

211. Findings need to be subjected to rigorous and objective scientific analysis and

published in high quality, peer reviewed journals. The Group considered it

important that research results should be disseminated to avoid unnecessary

repetition of studies and the inefficient use of resources. There may be a need

for funders and sponsors of research to investigate additional alternative

mechanisms of dissemination, preferably involving an independent peer review

mechanism to provide scientific credibility to the results.

 

212. SPECIFIC REFERENCES and OTHER SOURCES OF INFORMATION

 

213. A Framework for Development and Evaluation of RCTs for Complex

Interventions in Health Medical Research Council (2001) (www.mrc.ac.uk/pdfmrc_

cpr.pdf).

 

214. A Report of the CFS/ME Working Group – Report to the Chief Medical Officer

of an Independent Working Group Department of Health

(www.doh.gov.uk/cmo/cfsmereport.html).

 

215. Chronic fatigue syndrome: Clinical practice guidelines – 2002. Working Group

convened under the auspices of the Royal Australasian College of

Physicians. Medical Journal of Australia 176 S17-S55.

(www.mja.com.au/public/guides/cfs/cfs2.html)

 

216. Fukuda K., Straus S., Hickie I., Sharpe M.C. Dobbins J.G., Komaroff A.L., and

the International Chronic Fatigue Syndrome Study Group. Chronic fatigue

syndrome: a comprehensive approach to its definition and study. Ann. Inter.

Med. 121 953-959 (1994).

 

217. International Classification of Diseases, Tenth Revision (ICD-10) World

Health Organisation.

 

218. Konsman J.P., Parnet P., Dantzer R. Cytokine-induced sickness behaviour:

mechanisms and implications. Trends Neurosci 25(3):154-9 (2002)

 

219. Moher D., Schultz K.F. and Altman D. The CONSORT statement: revised

recommendations for improving the quality of reports of parallel-group

randomised trials. Lancet 357(9263):1191-4 (2001) (http://www.consortstatement.

org/).

 

220. Mulrow C.D., Ramirez G., Cornell J.E., Allsup K. Defining and managing

chronic fatigue syndrome. Evidence Report/Technology Assessment No. 42

(Prepared by the San Antonio Evidence-based Practice Center at the

University of Texas Health Sciences Center at San Antonio). AHRQ

Publication No. 02-E001. Rockville (MD): Agency for Healthcare Research

and Quality; October 2001 (www.ahrq.gov/clinic/cfs-sum.htm).

 

221. Nielson WR & Weir R. Biopsychosocial approaches to the treatment of

chronic pain. Clin J Pain 17(4 Suppl):S114-27 (2001)

 

222. Ramsay M. Myalgic encephalomyelitis and post fatigue states – the saga of

Royal Free disease. London: Gower Medical Publishing, for the ME

Association (1998).

 

223. Royal Colleges of Physicians, Psychiatrists and General Practitioners.

Chronic Fatigue Syndrome. Report of a Joint Working Group London (1996).

 

224. The U.S. Department of Health and Human Services Chronic Fatigue

Syndrome Coordinating Committee State of Science Report - "Chronic

Fatigue Syndrome - State of the Science Conference / October 23-24, 2000"

(http://www4.od.nih.gov/cfs/finalmeeting.pdf)

 

225. Whiting P. Bagnall AM. Sowden AJ. Cornell JE. Mulrow CD. Ramirez G.

Interventions for the treatment and management of chronic fatigue syndrome:

a systematic review. JAMA. 286(11):1360-8, 2001.

 

  

Annex 1

Membership of MRC CFS/ME Research Advisory Group

 

 

 

 

Affiliation

Area of expertise

Chair

Professor

Nancy Rothwell

University of Manchester

Neuroinflammation

Members

Jacqueline Apperley

MRC Consumer

Liaison Group

Lay member

 

Professor

Philip Cowen

University of

Oxford

Psychopharmacology

 

Professor Janet Darbyshire  

MRC Clinical

Trials Unit

Clinical Trials

 

Professor

Diana Elbourne

London School of

Hygiene and

Tropical

Medicine and

Institute of

Education

Epidemiology

 

Sue Haselhurst

MRC Consumer

Liaison Group

Lay member

 

Professor Alan

McGregor

Guys, Kings and

St Thomas's

Medical School

Immunology/

endocrinology

 

Professor Jon

Nicholl

University of

Sheffield

Health Services

Research

 

Professor

Jackie Oldham

University of

Manchester

Muscle physiology

 

Dr Chris Verity

Addenbrooke's

hospital

Paediatric neurology

 

Professor

Jonathan

Weber

Imperial College

School of

Medicine

Infections

 

Professor Til

Wykes

Institute of

Psychiatry

Psychological

Medicine

 

 

Annex 2

 

Public Health Resource Unit

 

Summary Report on Medical Research Council CFS/ME Consultation Questionnaire

November 2002

 

In brief…

 

To be honest, there is no single area of research that could currently claim to

provide a "strong research evidence base" for understanding CFS/ME. There are

fragments of information and partial data sets, separated by large tracts of

ignorance. The gaps are usually filled by enthusiastically held hypotheses that have

yet to be evaluated or falsified. There is a wealth of unanalysed and unpublished

data held by clinicians and patients which could be seen as a research base that

could and should be tapped in, at the least, a hypothesis-generating way (charity

representative)

 

I regard all of these [areas for research] as of equal importance. In my view they

should all be approached in a co-ordinated manner and with equal vigour. If we

concentrate on only one or two, we are in danger of perpetuating problems of the

past. (person with).

 

We need to understand the patient's story and the infinitely changing pattern that

CFS/ME may adopt in any individual. As a consequence, the research teams will

need to combine the extremes of narrative medicine with good quality genetic

engineers (researcher/clinician).

 

Kate Saffin

Annette Hackett

Adele Wright

 

 

Table of contents

 

Introduction & method 38

 

Response rates 38

 

Results 38

 

Understandings of CFS/ME 38

 

Communication issues 39

 

Gaps in research 39

 

1. Defining the condition and the research agenda 39

2. Specific gaps in knowledge 40

3. The organisation & process of research 40

 

Important areas for research 40

 

Obstacles 40

 

Moving forward 41

 

In the short term (3yrs) 41

 

In the longer term (5yrs) 41

 

Conclusion 43

 

Appendix: Important areas for research 44

 

Finding the cause. 44

 

What it does to the body (and the person). 45

 

Treatment & management 45

 

Cure 45

 

Introduction & method

 

As part of the consultation process to inform the MRC CFS/ME research strategy

advisory group the Public Health Resource Unit (www. phru.org.uk).were asked to

analyse the consultation qustionnaire. This report is a summary of the analysis.

People with CFS/ME (both current and recovered), carers, charity representatives,

researchers, clinicians and specialists were offered the opportunity to give their views

via a postal and web based questionnaire.

 

Response rates

 

In total 187 responses were received. The majority (131, 70%) were received

electronically. The respondents are a self selected group rather than statistically

representative of any perspective or group. In addition the high rate of electronic

responses means that the majority have access to both a computer and the Internet.

It is likely that people with CFS/ME who are disadvantaged because they are

severely affected, isolated or undiagnosed may be underepresented in the

responses.

 

Half the respondents were people with CFS/ME (35%) or recovered (5%) from

CFS/ME or a carer (10%). A quarter were researchers (22%). Most researchers also

described themselves as clinicians. There is some overlap between categories of

perspective with a number of respondents classifying themselves as belonging to

more than one group.

 

Results

 

The broad themes that emerged were:

 

! Understandings of CFS/ME

 

! Issues in communication

 

! Gaps in the research

 

! Barriers & obstacles to improving research

 

! The important areas for research

 

! Moving forward, making a research strategy work

 

Understandings of CFS/ME

 

! There is a wide range of understandings and meanings for each of the terms. For

some, one exists but not the other; for others, one is a sub-set of the other. Some

feel there are precise criteria, for others no criterion currently in existence means

anything useful, perhaps even damaging understanding. Some feel it is a single

entity, others that there is a range of sub-groups. Overall, there is no agreement

where the boundaries between groups fall.

 

! There are many shades of opinion and they provide the first evidence of the

considerable tensions and frustrations that are currently shaping not only the

research, but the management and treatment of people with CFS/ME.

 

All of which loses sight of the fact that for people with CFS/ME “none of the

definitions match up to how it feels to have the illness (person with)

 

Communication issues

 

In this area there is a clear division between those with personal experience of the

illness and the researcher/clinicians.

 

People with experience of CFS/ME:

 

! have encountered endless disbelief, unhelpful interventions and unsupportive

health professionals.

 

! have little faith in the system and see little point in research.

 

 

! in particular they criticise what they see as a dominance by psychiatry of research

in the area.

 

The researcher/clinicians who responded are probably among the most committed

clinicians and researchers to be found and they recognise:

 

! that the lack of trust that has developed is a major problem

 

! that the lack of consensus about diagnosis and treatment hinders progress

However, some also feel:

 

! frustrated and under attack from patient organisations

 

! a reluctance to engage in an area where there are “with such powerful views from

some support groups with aggressive stance towards clinicians

(researcher/clinician)

 

Gaps in research

 

There are three broad areas.

 

1. Defining the condition and the research agenda

 

! There appears to be no agreed starting point – in defining or agreeing

understandings.

 

! In particular there is a need to find a cause, to understand better the condition.

 

! Many see the potential physical causes as neglected in favour of psychiatric

research.

 

2. Specific gaps in knowledge

 

! Aetiology, epidemiology and prevalence.

 

! Physical cause including infection, especially viral.

 

! Presentation and management in primary care

 

! Physical effects and impact (with particular mention of adolescents and children)

 

3. The organisation & process of research

 

! There has been little structure or planning in research in the field

 

! There have been no long term studies

 

! Where research is happening there is little or no co-ordination between

researchers or teams.

 

! There has been little patient involvement, especially those who are severely

affected and very isolated.

 

Very little sufferer input - this is the first time in ten years that I have been

approached regarding research (person with).

 

Important areas for research

 

The identified areas spanned an enormous range from the potential biological,

biochemical, or genetic causes, to exploring the experience of people with CFS/ME

to better understanding the complex factors influencing the course of the condition.

A detailed summary of the suggestions grouped by: finding the cause, what it does to

the body and the person, treatment & management and finding a cure can be found

at the Appendix.

 

Obstacles

 

! Funding & resources - One of the commonest topics with a total of 364

references from 135 people, thus 72% of respondents mention it at least once.

Resources include funding, time and expertise.

 

! The low status of research in this area. Respondents perceive a lack of political

will to support work in this area, ‘limited interest from serious academic

researchers’. They feel it is difficult to get work on physical causes accepted and

published.

 

! Some feel that young researchers are discouraged, other areas such as cancer

and heart disease are ‘more appealing’ politically.

 

! As a condition it is complex and affects people in a wide range of ways that span

existing service boundaries. No one service ‘claims’ it.

 

! There seems to be general agreement that not enough is known about who has

CFS/ME, where they are, what their experiences/symptoms/needs are. There is

no baseline.

 

! Recruitment & exclusions. There is concern that criteria for inclusion in studies

are not uniform so comparison is difficult. The current diagnostic criteria of

symptoms for more than six months means that a potentially valuable group are

never included in studies (if the cause is an infection or virus it is unlikely that

there will be any trace of it by six months later). Finally those who are severely

affected and housebound may be excluded because they do not attend outpatient

departments.

 

! The dominance of psychiatric research. This was primarily a concern of those

with CFS/ME but not exclusively. Some go as far as to say that they consider that

psychology and psychiatry have no place in the research strategy at all:

 

…we refuse to accept the validity of any research funded by or carried out by

psychiatrists who have no place researching this disease other than to mitigate the

distress it causes (whilst in fact they do the opposite). Any attempt to produce

strategies based on information provided by psychiatrists will be met by heavy

resistance from the "severely affected" patient community. (person with 081302)

 

Whilst this is understandable given their experiences, it is in conflict with the view that

this condition needs and deserves a comprehensive research programme.

 

! The boundaries - between clinicians, between clinician and researcher, between

researchers and between patients and health professionals.

 

! The lack of suitable tools eg measures of fatigue, with criticism about the validity

of existing ones. People with CFS/ME point out that their level of energy/fatigue

change markedly over a day or days and that current snapshot measures are

inadequate.

 

Moving forward

 

In the short term (3yrs)

 

! Implement the CMO report recommendations and create a programme of good

quality, comprehensive research.

 

! Improved management and symptom control

 

! Agree definitions

 

In the longer term (5yrs)

 

Most people with CFS/ME would like to see a cure within five years. However, there

is also a sense of realism that the search will continue.

 

The key issues raised were:

 

! Resources - getting funding and directing it in the right way.

 

! Commitment to the strategy and process from everyone involved. The notion of

commitment is expressed as listening, belief in, trust, and for one researcher –

dissolving artificial boundaries”.

 

! More co-operation and collaboration - involving everyone with an interest: from

people with experience of the condition (including those who are severely ill),

through the clinicians, and other providers of care and treatment (including

complementary therapists) to researchers and the academic scientists whose

focus is cell biology or genetics.

 

Get the politics out of this illness. An open-minded approach firstly, especially

amongst the medical and scientific community A commitment to funding. Talking to

patients and their caregivers at all times. Involving the charities active in this field

(researcher/ person recovered/clinician)

 

! The process needs to be led and many call on the MRC to provide strong

leadership, including the facilitation of better collaboration. One researcher raised

the issue of job insecurity, that few researchers have a contract beyond their

current project and need constantly to be seeking funding.

 

! Most would like to see a managing body of some sort co-ordinating and

disseminating findings. However, there are some tensions in who should provide

this co-ordination Some suggested this might be a specialised centre or an

academic department with others saying that it should be led by organisations

representing people with CFS/ME. This body (however organised) would create

national and international networks, co-ordinate research and disseminate

findings. One respondent suggested a centre for research that would include

facilities for the severely ill to be included as in-patients so that they could take

part in studies/trials.

 

! The calls for a good baseline survey and review are repeated throughout this

section.

 

! ‘Keep an open mind’ is said by a number of respondents – although said mostly

by people with CFS/ME of clinicians it is an essential activity by everyone

involved if the strategy is to progress.

 

! Getting the priorities right. For many this means a shift to biological, biomedical

research

 

! An open debate and opportunities to negotiate meanings & definitions as well as

challenge the contradictions that currently exist.

 

! Finally, whilst not strictly speaking the remit of this strategy development process,

many raised the importance of education, not just in terms of improving

diagnosis, treatment and management but in raising awareness and recruiting

future researchers.

 

Conclusion

 

Overall, many with CFS/ME feel unheard and many researchers feel under attack.

Many see the development of a strategy as an opportunity to improve communication

and make a real difference to the lives of those with CFS/ME

 

A number commented that the consultation exercise was a positive one and that it

was the first time anyone had asked them for their views.

 

I don't know anything about research strategies, but I know that one is vitally

important because so little is known about the illness (person with)

 

PHRU

November 2002

 

Appendix: Important areas for research

 

One respondent with CFS/ME made a succinct list that provides a framework from

the point of view of the person with CFS/ME rather than the clinician.

 

1) Finding the cause of the illness.

2) What it does to the body.

3) Medication and treatment.

4) A cure please

 

Finding the cause.

 

The identified areas spanned an enormous range from the biological, biochemical,

genetic, to exploring the experience of people with CFS/ME to better understand the

complex factors influencing the course of the condition.

 

Approach Examples

 

Cell biology Cell biology, cell metabolism, chemical abnormalities

Genetics Genetic association studies with carefully defined phenotype,

Incidence in closed communities and families, genetic predisposition,

molecular pathogenesis of CFS/ME in immune

cells,

 

Environmental

 

factors/influences

 

Impact of everyday additives, toxins and chemicals,

organophosphates, stress, mercury used in dental treatment,

vaccines, food or chemical sensitivities, toxins from metals,

diet, mineral deficiencies, Virology/infection Is there a viral

cause? Infections e.g. herpes/cocksackie, a family of infective

agents yet to be identified (as H Pylori), serology, Cytokine

regulation and fatigue following viral infection,

 

Epidemiology Looking at common factors, why some people develop it

following infections, the complexity of the conditions, long-term

studies to follow up populations with CFS/ME, demographic

patterns, identifying sub-groups, large scale surveys, defining

the boundaries of CFS, prevalence studies,

 

Diagnosis Criteria, triggers, include those with early symptoms, use of

imaging, reliable tests,

 

Other Similarities to Gulf War syndrome or other medically

unexplained syndromes – chronic pain, irritable bowel syndrome.

 

Narrative patient histories (esp. re the changing nature of the condition

day to day), illness career, illness beliefs, how do sufferers talk

about their condition? How is it constructed by sufferers and by

‘experts’ and to what effect?

 

Definition Unpack the wide and insensitive construct CDC-1994 CFS,

defining outcome measures, aetiology,

 

What it does to the body (and the person).

 

The following are presented broadly by body system as that was the predominant

framework used by respondents. However, throughout the responses there was also

an emphasis on the need to look across systems and traditional boundaries.

 

Area Examples

 

Central Nervous system Brain function & abnormalities, sleep disorders, myelin sheath

degradation, endocrine, Cortisol levels, musculo-skeletal What happens in muscles of

person with CFS/ME, recovery from fatigue/exercise, study over time, Gastro-intestinal

Liver function, immune Fatigue Why some relapse after minimal exertion, Circulatory

Blood volume, Red blood cell shape, mitochondria, red blood cell damage, orthostatic

intolerance, elevation of nitric oxide, Other Hyperventilation, magnetic fields and low

frequency radio, why do women often improve during pregnancy?, child/adult

differences, impact of other/underlying conditions, Social impact On claiming benefits,

workplace pressures, the cost of social & healthcare, Psychological/emotional Assessment

of psychiatric co-morbidity in primary care (most so far has been in specialist centres),

links between cognitive & behaviour and physiological mechanisms, Interfaces Between

neurology and biological psychiatry, between mentalphysical symptoms, neuro-endocrine

changes

 

Treatment & management

 

Approach Examples

 

Management Identifying the techniques/interventions that have helped, include

severe sufferers who cannot access trials and research easily, symptom control,

communication between doctor & patient, attitudes of health professionals,

Learning from others Replication of fruitful studies in other countries,

 

Treatment interventions

 

Trials comparing graded exercise to PACING, alternative & complementary therapies,

multi-centre trial of GET, intervention studies on fatigue with healthy populations,

rehabilitation, Measurement and Monitoring Pain scales,

 

Cure

 

There are, understandably, many requests for a cure but the suggestions as to how

to achieve it are covered by the previous sections. There is also recognition

throughout the responses that this is a complex condition and it is unlikely that there

is a single cause with a single cure.