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National Collaborating Centre for Primary Care (UK). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children [Internet]. London: Royal College of General Practitioners (UK); 2007 Aug. (NICE Clinical Guidelines, No. 53.)

Appendix 1Systematic Evidence Review to support the development of the NICE clinical guideline for CFS/ME in adults and children

Anne-Marie Bagnall, Susanne Hempel, Duncan Chambers, Vickie Orton, and Carol Forbes.

Centre for Reviews and Dissemination, University of York, October 2005

Background

CFS/ME is a relatively common illness that places substantial burden on patients, carers and families, and society. It comprises a range of symptoms including fatigue, which can be triggered by minimal activity, malaise, headaches, sleep disturbances, difficulties with concentration and muscle pain. Symptoms may fluctuate in intensity and severity. It raises especially complex issues in severely affected children and adults.

The evidence suggests a population prevalence of at least 0.2–0.4%, which means that a general practice of 10,000 patients is likely to have at least 20–40 patients with CFS/ME, half of whom will need input from specialist services.1 However, there is a lack of epidemiological data for the UK, which means that population estimates are based on extrapolations from other countries.

CFS/ME, like other chronic illnesses with no certain disease process, poses real problems for healthcare professionals. CFS/ME can cause profound, prolonged illness and disability, which has a substantial impact on patients and their families. Uncertainties about diagnosis and management, and lack of clinical guidance for health professionals exacerbate this impact.

In 2002, the Independent Working Group convened by the Chief Medical Officer reported their findings and the Medical Research Council made research on CFS/ME a priority.1 Guidelines on the diagnosis and treatment of CFS/ME have been published in Canada,2 USA3 and Australia4, and in the UK, the Royal College of Paediatrics and Child Health published guidelines on the management of CFS/ME in children and young people in December 2004.

Previous research into CFS/ME has focussed on possible causes, diagnostic criteria and natural history of the illness, with research into the treatment or management of the condition increasing only in recent years. A number of studies are now available, which have assessed the effectiveness of interventions used in the treatment or management of CFS/ME. A systematic review has been conducted that focussed on defining and managing chronic fatigue syndrome.5 A further systematic review that assessed the effectiveness of all available interventions to treat or manage adults and children with CFS/ME was carried out at the Centre for Reviews and Dissemination.6 There is also a systematic review on the effectiveness of cognitive behavioural therapy. 7

Systematic and scoping reviews of the literature were being carried out to inform the NICE Guidelines on diagnosis and management of CFS/ME. Where appropriate, previous reviews were updated.

Corrections made August 2007

16TableRevised the exclusion details of the London criteria for ME
81Para 2Revised the validity score for the study by Goudsmit
442Table B
112Reference 13Revised the list of authors

Review Questions

The review was undertaken to provide evidence to support the NICE Guideline on the diagnosis and the management/ treatment/ rehabilitation of CFS/ME as well as the support and information needs of people diagnosed with CFS/ME, their carers and health professionals.

The following questions were addressed:

Question 1: What are the existing case definitions for chronic fatigue syndrome in adults and children and what evidence exists to substantiate or validate these case definitions?

Question 2: Are there any substantiated or validated evaluations to support the diagnosis of chronic fatigue syndrome in adults and children? (Subquestion: In people presenting with early suspected CFS/ME (before 6 months) what are the risk factors/ prognostic flags that might be linked with progression to CFS/ME?)

Question 3: Does the evidence show that any particular intervention or combination of interventions is effective in treatment, management or rehabilitation of adults and children with a diagnosis of CFS/ME? (Subquestion: In people presenting with early suspected CFS/ME what interventions might be effective in preventing progression to CFS/ME?)

Question 4: What are the information needs of healthcare professionals, patients and carers?

Question 5: What are the support needs of healthcare professionals, patients and carers?

Review methods

Literature search

One search was carried out to cover all five review questions. The search was broad and not restricted by intervention, diagnostic test or outcome. The search aimed to pick up all studies of CFS/ME and related synonyms.

Individual search strategies were developed for each electronic database searched. The following databases were searched: MEDLINE (1966 to May 2005), EMBASE (1980 to May 2005), PSYCINFO (1872 to April 2005), CENTRAL (May 2005), Social Science Citation Index (1945 – 2005), Science Citation Index (1945 – 2005), Index to Scientific and Technical Proceedings (1982–2005), PASCAL (May 2005), Inside Conferences (May 2005), AMED (1985 – January 2005), HEED (June 2005).

The full search strategies are listed in Appendix 1.

Via the Guideline Development Group (GDG) consultation process, attempts were made to contact experts in the field to identify unpublished literature and ongoing studies. The bibliographies of included studies were also scanned for any additional references.

Study selection

Two reviewers independently assessed all titles and abstracts identified from the searches of electronic databases for potential relevance to the five review questions. All papers that looked potentially relevant were retrieved in full. Two reviewers independently assessed all retrieved studies for possible inclusion, using the inclusion criteria listed for each question below. The use of two reviewers is a method which is commonly employed in systematic reviews, to minimise the risk of introducing bias to the results of the review. If the two reviewers cannot agree, a third reviewer is consulted to resolve the differences.

Inclusion criteria

Question 1

Intervention – papers that report and/or validate case definitions developed specifically for CFS/ME.

Population – adults and/or children aged 5 years or more.

Study design – reports of case definitions and substantiation studies of at least 30 patients that examine if individual or clusters of manifestations occur more frequently in persons with CFS than in other populations.

Question 2

Intervention – any clinical evaluation or diagnostic test aimed at diagnosing CFS/ME (Subquestion: aimed at identifying prognostic flags for CFS/ME).

Population – adults and/or children aged 5 years or more.

Study design – levels I–IV in table 7.2 NICE Guideline Development Technical Manual. (Subquestion: only studies using multivariate analysis or logistic regression were included).

Question 3

Intervention – any intervention or combination of interventions used in the treatment, management or rehabilitation of people with CFS/ME (Subquestion: early interventions used to prevent progression of CFS/ME).

Population – adults or children aged 5 years or more with a diagnosis of CFS/ME based on any criteria (Subquestion: adults and/or children aged 5 years or more with early or suspected CFS/ME not meeting diagnostic criteria).

Outcomes – all outcomes reported in included studies were considered. Specific outcomes are listed in Appendix C

Study design – randomised or controlled clinical trials.

Question 4

Intervention – any form of information (verbal or written) that may be of assistance to patients, carers or healthcare professionals. This may come from the NHS, other healthcare professionals, professional organisations, support groups or other appropriate sources.

Population – adults and/or children aged 5 years or more with CFS/ME; carers or healthcare professionals involved in the care of persons with CFS/ME.

Study design – any study that assessed the information needs or the effectiveness of different types of information for patients, carers or healthcare professionals was eligible for inclusion. Literature reviews, discussion papers and studies with less than 10 participants were excluded.

Question 5

Intervention – any form of support which may be of assistance to patients, carers or healthcare professionals. This may come from the NHS, other healthcare professionals, professional organisations, support groups or other appropriate sources.

Population – adults and/or children aged 5 years or more with CFS/ME; carers or healthcare professionals involved in the care of persons with CFS/ME.

Study design – any study that assessed the support needs or the effectiveness of different types of support for patients, carers or healthcare professionals was eligible for inclusion. Literature reviews, discussion papers and studies with less than 10 participants were excluded.

Data extraction, validity assessment and data synthesis

For all review questions, data were extracted by one reviewer and checked by a second reviewer onto a proforma. Data extraction forms varied for studies of differing designs. Discrepancies were resolved by referral to the original studies. If necessary, arbitration was by a third reviewer. Duplicate publications were actively screened for and where found the latest or most complete report was used.

Question 1 (update of Mulrow et al systematic review5): The following categories of data were extracted from reports of case definitions: Study author; year of publication; country study was carried out in; minimum duration; functional impairment; cognitive or neuropsychiatric symptoms; other symptoms; new onset; medical exclusions; psychiatric exclusions

The following categories of data were extracted from studies which aim to substantiate or validate existing case definitions: Study author; year of publication; country study was carried out in; case definition used; number of study participants; age; gender distribution; duration of illness; setting; study objective; study design; methods of analysis; findings/ conclusions. The information was tabulated. Studies were graded according to 7.2 NICE Guideline Development Technical Manual and a brief narrative summary of the evidence in the tables was presented.

Question 2 (scoping review): The following categories of data were extracted: Study author; year of publication; country study was carried out in; number of study participants; inclusion/ exclusion criteria (if any); information relating to pre-specified subgroups (age/severity) if reported; setting; study design; level of evidence; diagnostic tests or evaluations used; reference standard test(s) (if any); timing of diagnostic test/ evaluation(s); brief summary of main findings.

Subquestion 2: The following categories of data were extracted: Study author; year of publication; country study was carried out in; number of study participants; inclusion/ exclusion criteria (if any); age, duration of illness, baseline functioning, information relating to pre-specified subgroups (age/ severity) if reported; setting; study design; method, analysed variables, level of evidence; brief summary of main findings.

The information was tabulated. Studies were graded according to 7.2 NICE Guideline Development Technical Manual.

Question 3 (update of Bagnall et al. systematic review6): The following categories of data were extracted: Study author; year of publication; country study was carried out in; number of study participants; participant details paying particular attention to the following - inclusion/ exclusion criteria (if any), information relating to subgroups (age/ severity) if reported, baseline functioning and diagnostic criteria used; setting; study design; level of evidence; intervention details (according to whether the intervention is pharmacological or non-pharmacological e.g. drug dose, frequency, duration, content, persons delivering the intervention, setting of intervention (eg. Group or Individual CBT), co-interventions; comparators (if any, details as for interventions); outcomes measured; results.

Two reviewers independently assessed the validity of studies using an existing validity assessment tool. Discrepancies were resolved by discussion or, when agreement could not be reached, by consultation with a third reviewer.

The information was tabulated and summarised in a narrative, grouped by intervention. Interventions were broadly grouped into the following categories:

  • pharmacological
  • immunological;
  • behavioural (including graded exercise, graded activity, pacing, CBT, psychotherapy, counselling, family therapy, rehabilitation);
  • complementary;
  • other (e.g. multicomponent interventions tailored to symptoms of the individual; buddy programmes, dietary);
  • supplements

Information from stronger study designs was emphasised. In addition, where information was presented regarding subgroups (children or severely affected) this was summarised separately.

The homogeneity/ heterogeneity in terms of participants, interventions and outcomes in included studies was assessed in a qualitative manner based on the judgment of the reviewers.

Question 4 (scoping review): The following categories of data were extracted: Study author; year of publication; country study was carried out in; number of study participants; inclusion/ exclusion criteria (if any); age; gender distribution; duration of illness; baseline functioning; subgroups; aim; setting; study design; level of evidence; type of information (e.g. provided by healthcare professional/ other; paper/ electronic); assessment method; agency providing service; brief summary of main findings/ conclusions. The information was tabulated. Studies were graded according to 7.2 NICE Guideline Development Technical Manual.

Question 5 (scoping review): The following categories of data were extracted: Study author; year of publication; country study was carried out in; number of study participants; inclusion/ exclusion criteria (if any); age; gender distribution; duration of illness; baseline functioning; subgroups; aim; setting; study design; level of evidence; type of support (e.g. wheelchair/ equipment provision, environmental adaptation and alterations, emotional support, return to work/ school, welfare, driving); assessment method; agency providing service; brief summary of main findings/ conclusions.

The information was tabulated. Studies were graded according to 7.2 NICE Guideline Development Technical Manual.

Evidence to answer Question 1, part 1: What are the existing case definitions for chronic fatigue syndrome in adults and children?

As of 8th July 2005, one new publication2 was included in the case definition table, in addition to the six definitions included in the Mulrow et al (San Antonio)5 and Bagnall et al6 systematic reviews.

Question 1. Criteria for case definitions of CFS and/or ME.

Question 1

Criteria for case definitions of CFS and/or ME.

Evidence to answer Question 1, part 2: What evidence exists to substantiate or validate the existing case definitions for CFS/ME in adults and/or children?

Research literature evidence

Thirty-six new studies14–49 were included in the section on validation of case definitions, in addition to the thirty-eight studies8, 50–86 included in the review of Mulrow et al.5. Evidence from the previous review is briefly reproduced here and is incorporated into this summary paragraph.

The CDC 1994 case definition was most often investigated (41 studies), followed by CDC 1988 (16 studies), Oxford (6 studies), Australian (3 studies) and the Dowsett and Canadian criteria (1 study each). Studies compared CFS patients to healthy controls (40 studies), depressed patients (8 studies), multiple sclerosis patients (7 studies) and fibromyalgia patients (4 studies). Twenty-four studies examined multiple features of CFS/ME but the majority (51 studies) looked at isolated symptoms and were therefore limited in their validity.

The review of Mulrow et al.5 concluded that the evidence to substantiate the existing case definitions of CFS was severely limited: studies that compared findings in patients with CFS with findings in healthy individuals or patients with other conditions do not provide an adequate basis for validation of any particular case definitions. The reason for this is that most have selected patients based on the case definition that often includes symptoms or findings that are then compared. This would make most studies level 2- or lower. Few studies involved large unselected populations or used comprehensive assessment methods to evaluate whether a distinct group of findings characterised and differentiated CFS from other conditions. One large community study suggested that characteristics that might distinguish CFS are: post-exertional fatigue not alleviated by rest plus a cluster of symptoms including chronic fatigue, sore throat, lymph node pain, post-exertional malaise, memory or concentration problems, and unrefreshing sleep. No studies were able to establish the superiority of one existing case definition over another.

The new studies that looked to be most useful came to the following conclusions: symptoms suggesting infection are less frequently reported and less severe in patients meeting CDC 1994 criteria than in those meeting than CDC 1988 criteria (1 study); patients meeting CDC 1988 criteria had more symptoms and symptoms that were worse in severity than patients meeting 1994 criteria (2 studies); patients meeting CDC 1994 criteria were a more heterogeneous group than patients meeting CDC 1988 criteria (1 study); individuals with high symptom frequency were more severely affected (CDC 1994, 1 study). One community based study that compared CFS 1994 to Dowsett (ME) criteria found that both sets of patients had worse symptoms than patients with chronic fatigue explained by psychiatric reasons, but on different features. The ME and CFS groups did not seem to differ significantly from one another. Another community based study compared patients meeting CDC 1994 CFS criteria to those meeting the Canadian criteria and found that the Canadian group differed from a group with chronic fatigue explained by psychiatric reasons on more variables than the CDC 1994 group. One study that investigated the CDC 1988, CDC 1994 and Australian criteria concluded that criteria-based approaches to diagnosis did not yield homogeneous groups of patients. One study that undertook factor analysis concluded that three factors (musculoskeletal, infection, and cognition/mood/sleep) were essentially defined by CFS symptoms.

Baraniuk (1998)81

51 patients with CFS, 27 with allergic rhinitis, 17 with rheumatologic diseases and 34 healthy controls were examined to determine frequencies of nasal, sinus and chest symptoms and for neurologic, gastrointestinal, rheumatologic and other systems. CFS patients scored significantly higher for fatigue than other groups.

Bazelmans (1997)87

The authors measured fatigue, functional impairment, depression and hyperventilation in patients with CFS, non-CFS patients with known hyperventilation (HV) and healthy controls. Mean CIS fatigue scores (maximum 7) were 5.9 (SD 1.1) for patients with CFS (n = 39), 5.2 (SD 2.2) for HV patients (n = 17) and 2.0 (SD 1.1) for healthy controls (n = 32). The difference between the CFS patients and controls was significant (p < 0.05). In a further comparison of 27 CFS patients with 32 healthy controls, functional impairment (SIP score) and depression (BDI score) were significantly worse in the CFS patients.

Binder (2001)14

Armed Forces Qualification Test (AFQT) cognitive data obtained around date of induction were acquired for 94 veterans of the Gulf war, 32 with CFS and 62 healthy controls. Controls performed better than those with CFS on 3 out of 8 variables of the AFQT.

Blakely (1991)88

The authors administered a battery of psychometric tests to patients with CFS, chronic pain patients and matched healthy controls. There were significant differences (p < 0.01) between the groups on almost all symptom scales. Discriminant analysis classified 65.4% of cases correctly. Overall 88% of healthy controls, 55% of CFS patients and 44% of chronic pain patients were correctly classified; 26% of CFS patients were misclassified as chronic pain and 27% of chronic pain patients were misclassified as CFS.

Blenkiron (1999)82

40 CFS patients referred to tertiary care were compared with 31 healthy controls for perfectionistic personality traits, mood and fatigue. A positive association between CFS and perfectionism was not confirmed. CFS had significantly worse outcomes for fatigue and depression than healthy controls.

Brimacombe (2002) 15

Symptoms reported by patients (n = 200) fulfilling either the 1988 or 1994 case definitions for CFS were evaluated using a variety of statistical methods. The analysis indicated that there was considerable overlap between the two case definitions. Factor analysis identified three factors accounting for significant variation (muscular-skeletal, viral and sleep/memory). The first two factors and self-reported decrease in activity gave 91% accuracy in assigning patients to case definitions. Symptoms suggesting viral infection were less frequently reported and less severe in patients meeting the 1994 case definition for CFS than in those meeting the 1988 definition. The authors concluded that infection as a cause of CFS may be more likely in patients who fulfil the more demanding 1988 case definition.

Buchwald (1994)85

Ninety patients, 30 each with CFS, FM and MCS, were recruited from a University based referral clinic and private practice and a questionnaire on symptoms was given. Post-exertional fatigue was significantly more common among patients with CFS and FM than among those with MCS but prevalence of minor symptoms did not differ. The authors concluded that the three patient groups were remarkably similar.

Buchwald (1996)89

The Medical Outcomes Study Short-Form General Health Survey (SF-36) was used to assess functional status in patients with CFS, non-CFS chronic fatigue (CF), acute infectious mononucleosis (AIM) and major depression (MD), and in healthy controls. The CFS group had the lowest scores for the physical functioning, role functioning, social functioning, general health and body pain subscales of the SF-36. CFS patients had significantly lower scores than patients with non-CFS CF on the physical functioning, role functioning and body pain subscales. The authors concluded that patients with CFS and CF have marked functional impairment and that the SF-36 can distinguish patients with CFS and CF from those with MD and AIM and from healthy controls. However, the scale did not discriminate between CF and CFS.

Busichio (2004) 16

Patients with CFS according to the 1994 CDC case definition (n = 141) were compared with a healthy control group (n = 76) on tests of memory, attention/concentration, speed of information processing, motor speed and executive functioning. On the 18 measures administered, the CFS group scored one standard deviation (SD) below the healthy group mean on nine measures and two SD below the healthy group mean on four measures. CFS patients were significantly more likely than healthy controls to fail (score 1.6 SD below the healthy group mean) at least one test in the domains of attention/concentration (p = 0.004), speed of information processing (p = 0.002) and motor speed (p = 0.000). The number of tests failed across all domains was significantly higher in the CFS group than in the control group (p < 0.01).

Cantor (2003)47

The authors retrospectively compared files for 91 patients with CFS syndromes (CFS, fibromyalgia or multiple chemical sensitivity) and 91 controls from the same private psychiatric practice. The CFS and control groups differed significantly in sleeping patterns (p < 0.01). Too much sleep was reported by 21/88 patients (24%) in the CFS group compared with 6/88 (7%) controls. Seventy-six per cent of the CFS group reported problems with memory or concentration compared with 27% of the controls (p < 0.0005). People with CFS syndromes were more likely to be hopeful (47%) compared to controls (20%), p<0.001. There was no significant difference between the groups with regard to suicidal ideation.

Ciccone (2003)17

163 women referred to a tertiary clinic were assigned to one of four groups: CFS only, CFS/FM, CFS/MCS and CFS/FM/MCS. Participants were assessed for physical and psychiatric symptoms. The authors found that patients with additional illness were also more likely to have depression.

Darbishire (2003)46

Patients presenting to general practitioners with unexplained fatigue lasting 6 months or more as a primary complaint were included in this study. Of 141 patients, 44 met the 1994 CDC criteria for CFS and 97 were classified as having chronic fatigue (CF). Compared with CF patients, patients with CFS had significantly higher scores for fatigue (27.9 (SD 4.4) vs. 23.6 (SD 4.9), p < 0.001), functional impairment (24.9 (SD 5.9) vs. 17.7 (SD 7.3), p < 0.001) and depression (9.8 (SD 3.8) vs. 7.5 (SD 3.1), p < 0.001). Twenty-one (47.7%) patients with CFS and 17 (17.5%) patients with CF were classified as cases of depression (p < 0.001).

De Becker (2001)18

2073 consecutive patients with major complaints of prolonged fatigue were assessed in terms of symptom prevalence and severity and differences between the 1994 and 1988 CFS definitions. The authors found that CFS patients meeting the 1988 definition had an increased symptom prevalence and severity of many symptoms, whereas patients meeting the 1994 CFS definition were less severely affected. They suggest that the addition of some symptoms and removal of others from the checklists would strengthen their ability to select CFS patients.

DeLuca (2004)19

CFS patients with and without concurrent psychiatric illness were compared to patients with rheumatoid arthritis and healthy controls on tests of visual and auditory processing speed and visual and auditory working memory. The group of CFS patients without concurrent psychiatric disease showed significantly worse performance on tests of information processing speed, compared to people with RA and healthy controls. No significant differences were seen between the group of patients with CFS and psychiatric diagnoses, and any other group.

DeLuca (2004)20

29 people with CFS and 22 people with CFS plus a psychiatric disorder were compared to 30 healthy people and to 19 people with rheumatoid arthritis for measures of memory: initial learning, recall and recognition (assessed after 30 and 90 minute delays). Both CFS groups required significantly more trials to learn the word list than did healthy controls.

Evengard (2003)21

A cross-sectional questionnaire survey was performed on patients presenting with fatigue at a hospital infectious diseases clinic. The objective was to look for differences between chronic fatigue and chronic fatigue syndrome patients. Patients with CFS reported significantly more self-reported somatic symptoms, functional impairment and absence from work.

Fischler (1997)90

Patients with CFS and matched healthy controls were compared for sleep characteristics by polysomnography. Sleep initiation and sleep maintenance disturbances were observed in the CFS group. The percentage of stage 4 sleep was significantly lower in the CFS group compared with the healthy controls. A discriminant analysis correctly classified 80.4% of the healthy controls and 87% of the CFS patients. Sleep onset latency and number of stage shifts/hour contributed significantly to the discriminant function.

Fossey (2004)22

To assess the nature and prevalence of sleep disturbance in CFS, patients with CFS were compared with patients with narcolepsy and with healthy controls. Results indicated that the CFS group had a very high incidence (58%) of previously undiagnosed primary sleep disorders. Narcolepsy and CFS patients were similar on psychological adjustment.

Friedberg (2000)91

In a cross-sectional self-report study, patients with long- and short-duration CFS (median 16 and 3 years) with their ‘significant others’ as healthy controls. Principal components analysis of symptom data for the long-duration group gave a three-factor solution: cognitive problems, flu-like symptoms and neurologic symptoms. Compared with the short-duration CFS group, the long-duration group had significantly higher symptom severity scores, largely because of increased cognitive difficulties. A number of viral and immune-related illnesses were reported at significantly higher frequencies in patients with CFS compared with healthy controls.

Hickie (1990)84

Prevalence of psychiatric disorder was determined in 48 CFS patients and 48 patients with depression. Premorbid prevalence of major depression and total psychiatric disorder was no higher than general community estimates. Pattern of psychiatric symptoms in CFS patients was comparable with that observed in other medical disorders but significantly different than the depressed patient. The authors concluded that psychological disturbance is likely to be a consequence of, rather than a risk factor to, symptoms of CFS.

Jason (2003)23

A subset of people identified in a large telephone survey took part in a study to examine differences between people diagnosed using CFS and ME criteria; these were compared to people having chronic fatigue for psychiatric reasons. Significant differences occurred with neurologic, neuropsychiatric, fatigue/weakness and rheumatological symptoms. The authors suggest that it may not be appropriate to combine results of studies using different definitions to select study populations.

Jason (1999)74

This study aimed to address important issues involving the factor structure of symptoms of chronic fatigue within a community sample of individuals. Of 18675 individuals surveyed, 780 reported chronic fatigue; of these 408 were classified as CFS-like.

Principal component analysis resulted in a four-factor solution explaining 38% of total variance: lack of energy, physical exertion, cognitive functioning and fatigue and rest. Compared to ICF-like, CFS-like had significantly more of the following symptoms: sore throat, painful glands, muscle aches or pain, feel worse for >24 hours after exercising, new headaches, joint pain, not rested after a night of sleep, concentration/memory interfere with work/study; and more difficulty with lack of energy, physical exertion, cognitive functioning, greater fatigue following rest or sleep.

Compared to CF-explained, CFS-like had significantly more of the following symptoms: sore throat, painful glands, muscle aches or pain, not rested after a night of sleep

Jason (2000)50

This is another study from the random community sample of 18675 US adults, in which CFS-like people are compared to healthy controls and people with CF explained by psychiatric reasons, in order to examine the CDC 1994 case definition. The authors recommend the use of standardised scales to assess functioning capacity. CFS and CF-explained by psychiatric reasons patients can be distinguished by symptom patterns but only when assessment questions are more specific.

Jason (1999)76

166 individuals were classified by independent physician review panel into four groups: chronic fatigue syndrome (CFS), idiopathic chronic fatigue (ICF), chronic fatigue explained by medical condition (CFM), or chronic fatigue explained by psychiatric condition (CFP).

CFS group had more severe post-exertional fatigue than ICF; CFM had more severe post-exertional fatigue than ICF and CFP.

Cluster analysis resulted in three clusters: 1) relatively low post-exertional fatigue (n=1); 2) most severe post-exertional fatigue and most improvement in fatigue following rest (n=47); and 3) high post-exertional fatigue and fatigue not alleviated by rest (n=117).

Jason (2000)80

This study aimed to determine illness comorbidity rates for people with CFS, fibromyalgia (FM) and multiple chemical sensitivities (MCS). From a random sample of 18675 individuals, a control group and a CFS-like group received medical and psychiatric examinations. Of the 32 people diagnosed with CFS, 40.6% met criteria for MCS and 15.6% met criteria for FM. People with MCS or more than one diagnosis reported more fatigue than those with no diagnosis. People with more than one diagnosis also reported greater mental fatigue and were less likely to be working than those with no diagnosis. People with CFS, MCS, FM or more than one diagnosis reported greater disability than those with no diagnosis. The authors conclude that the findings illustrate differences among the illness groups in the range of functional impairment experienced.

Jason (2003)24

CFS-like cases in the community were identified from a random telephone sample. Those diagnosed with CFS were subclassified based on frequency of symptoms. Important differences emerged: individuals with high symptom frequency had worse physical functioning, physical role functioning, bodily pain and emotional role functioning, impairment of work activities and perceived stress than those with low symptom frequency.

Jason (2004)25

This study examined differences between the CDC 1994 criteria and proposed Canadian criteria. Twenty-three people who met the Canadian criteria (and also the CDC 1994 criteria) were compared with 12 who met CDC 1994 criteria only, and 33 people with chronic fatigue explained by psychiatric reasons. The Canadian criteria group, in contrast to the CDC 1994 group, had more variables that significantly differentiated them from the psychiatric comparison group. The authors suggest that both case definitions select people who are different from psychiatric controls with chronic fatigue. The Canadian criteria select cases with less psychiatric comorbidity, more physical functional impairment and more fatigue/weakness, neuropsychiatric and neurological symptoms.

Jason (2001) 26

Groups of patients meeting the 1988 and 1994 case definitions for CFS were compared with one another and with patients with fatigue explained by psychiatric illness. The groups did not differ significantly in socio-demographic characteristics or rate of sudden illness onset. The 1988 group reported significantly higher rates of sore throat and lymph node pain than the other groups. Participants in the 1988 group also had lower general health scores compared with the 1994 group and significantly more bodily pain and lower physical health composite scores compared with the psychiatric group. Only the 1994 group reported significantly less impairment in daily functioning compared with the psychiatric group. The authors concluded that the 1988 case definition appears to identify a distinct group of patients with more symptoms and more functional impairment than the more heterogeneous group meeting the 1994 case definition.

Johnson (1996)51

This study aimed to determine whether the depressive symptom pattern is similar in CFS, MS and depressed patients. They found that Beck Depression Inventory (BDI) scores were higher for the depressed group than the CFS or MS groups on mood and self-reproach symptoms, but higher than the CFS group on somatic and vegetative items. CFS and MS groups scored significantly lower on self-reproach than depressed patients, but higher on somatic symptoms.

Komaroff (1996)52

This study aimed to measure functional status and well-being of people with CFS, compared to a general population group and six disease comparison groups, including depression and MS. Patients with CFS had marked functional impairment compared with the general population and disease control groups.

Komaroff (1996)53

The objective of this study was to determine whether people who met major criteria for the CDC 1988 case definition also met the minor criteria more frequently than healthy controls, people with MS or people with depression. People with CFS did experience all of the minor criteria more frequently than healthy controls. They experienced all of the minor criteria apart from depression, sleep and concentration problems more frequently than people with depression, and all the minor criteria apart from weakness, joint pain and memory problems more frequently than people with MS.

Krupp (1993)54

This study compared sleep, fatigue and depression characteristics in people with CFS, MS and healthy controls. CFS patients scored significantly higher for all three characteristics than MS patients and healthy controls.

Looper (2004) 27

Patients with CFS/ME (n = 42) were matched for age and sex with a control group of patients with multiple sclerosis. Mean score on the SCL 90-R depression subscale was 12.5 (SD 6.4) for the CFS group and 11.7 (SD 6.4) for the patients with MS; t(73) = 0.57, not significant.

McCue (2002)43

Cognitive tests designed to assess aspects of attention, working memory and long-term memory were administered by two methods (computerized and automated telephone systems) to 30 patients with CFS and 30 healthy controls matched for age and education. The CFS group had significantly slower reaction times on all four cognitive measures in both the computerized and telephone tests. Long-term verbal memory was significantly worse in the CFS group compared with controls. Scores for mood (alertness, contentedness and calmness) were significantly lower in the CFS group than the control group in both tests.

Metzger (2002)28

In this study, 40 CFS patients and 40 healthy controls were examined on measures of cognition, fatigue impact and depression. CFS patients scored significantly worse than healthy controls on cognitive, physical and social impact scales of the fatigue impact scale, and for depression. No significant differences were seen between the group for cognitive performance measured by the Stroop test.

Morriss (1999)55

This study sought to compare depressive, functional and fatigue symptoms among patients with CFS, patients with depression and patients with both CFS and depression. CFS patients experienced more fatigue symptoms but less depressive symptoms than patients with depression, and the groups did not differ significantly on functional impairment.

Moss-Morris (2003)29

This study compared illness perceptions and disability in 74 patients with rheumatoid arthritis and 49 with CFS. Both groups reported equivalent levels of physical disability.

Moss-Morris (2001)30

53 CFS patients were compared with 20 depressed patients and 38 healthy controls on perceptions of health, illness attributions, self-esteem, cognitive distortions, symptoms of distress and coping. The depressed group had significantly more: low self-esteem, cognitive distortions across all situations, attribution of illness to psychological factors. The CFS group had significantly more: low ratings of current health status, strong illness identity, external illness attributions, and cognitive distortions specific to somatic experiences.

Nijs (2003)31

The aim of this study was to compare activity and participation restrictions in 90 patients with fibromyalgia and 47 patients with CFS. No differences in total scores were observed between the two groups for 25 out of 26 items on the CFS-APQ.

Nisenbaum (2004)32

The population of Wichita was surveyed and the occurrence of 21 symptoms in 1391 chronically fatigued patients were measured. Factor analyses were used to identify symptom dimensions of fatigue and cluster analysis to assign people to subgroups. The authors found that although factor scores were higher among people with CFS, CFS and non-CFS distributions overlapped substantially.

Roy-Byrne (2002)33

In this study, 100 female twin pairs, with only one twin reporting prolonged fatigue, were examined : fatigued twins had significantly higher incidence of depression and anxiety than the non-fatigued co-twins.

Sandman (1993)57

This study measured performance on tests of memory in 39 patients meeting CDC 1988 criteria for CFS (CFIDS), 23 patients with depression and 129 healthy controls. CFS/CFIDS patients performed significantly worse on tests of memory than depressed patients or healthy controls.

Schweitzer (1995)59

The aim of this study was to compare quality of life between people with CFS and healthy controls. Results from both the Sickness Impact Profile (SIP) and interviews found that CFS patients had significantly impaired quality of life, particularly with regard to social functioning.

Servaes (2002)34

Fatigue was investigated in 57 severely fatigued disease-free breast cancer patients and 57 CFS patients. CFS patients had worse scores with regard to level of fatigue, functional impairment, physical activity, pain and self-efficacy, compared to breast cancer patients.

Skapinakis (2003)44

This large survey of primary care patients sought to establish whether narrow definitions of unexplained fatigue syndromes that require additional minor somatic symptoms are more strongly associated with psychiatric morbidity than wider ones. 5438 patients from 14 countries were assessed using case definitions for ‘unexplained fatigue’, the ICD-10 definition for neurasthenia and the CDC-1994 definition for CFS.

The authors found that definitions that require more somatic criteria selected more patients with psychiatric disorders.

Smith (2003)42

A cohort study comparing levels of anxiety, depression, somatization, functional disability and illness attribution between three groups of adolescents aged 11–18yrs. 97 adolescents with chronic fatigue (CFS-CDC 1994 n=46, idiopathic chronic fatigue (CF) n=51) were compared with 179 migraine sufferers and 32 age and gender matched healthy controls. Outcome measures were assessed at different time points over a 8yr period with only 115 assessments fully completed; participants were predominantly white females; there were also baseline differences between the three groups some but not all of which were accounted for in the final analysis. Therefore the study was of poor validity and a lower level of evidence. The authors concluded that in general adolescents with CFS meeting CDC-1994 criteria had higher anxiety, depression, somatization, functional disability and illness attribution scores than those suffering with migraine or healthy controls.

Smith (1996)60

In this study, sleep and mental functioning were compared between people meeting Oxford criteria for CFS recruited from a fatigue clinic and healthy controls recruited from a newspaper advert. People with CFS had significantly worse scores on sleep and mental functioning than healthy controls.

Smith (1993)83

Disturbances of memory, concentration, motor function and mood were assessed in 57 CFS patients and 19 healthy controls. The CFS patients had significantly worse outcomes for depression, anxiety, physical symptoms and cognitive failures than controls. They were also slower on psychomotor tasks, showed increased visual sensitivity and impaired attention.

Smith (1999)62

In this study, 67 patients who met Oxford criteria for CFS were compared with 126 matched healthy controls. Acute fatigue and other symptoms were assessed. CFS patients scored significantly worse on fatigue and many other symptom measures than healthy controls.

Sullivan (2002)35

Latent class analysis was applied to 646 patients who met criteria for CFS and/or fibromyalgia. Thirty-two symptoms commonly reported for either disease were entered into the analysis. The results supported an awareness of similarities rather than differences between CFS and fibromyalgia.

Swanink (1995)61

This study compared 88 people who met Oxford criteria for CFS with 77 healthy controls. CFS patients scored significantly worse than healthy controls on measures of fatigue, functional impairment, concentration and depression.

Taillefer (2003)36

45 CFS and 40 MS patients were compared for a variety of psychiatric symptoms including depression. There was no difference between the two groups in terms of number of depressive symptoms. CFS patients had a higher level of illness worry than MS patients.

Taillefer (2002)37

45 CFS and 40 MS patients were compared on measures of functional ability, fatigue severity, depressive symptoms, somatic symptom attribution and illness worry. The results confirmed lower levels of functional status and greater fatigue among CFS patients than MS patients.

Taylor (2003)38

This Chicago study screened a random sample of 18675 adults for chronic fatigue; 227 people with chronic fatigue and 74 healthy people were then given a semi-structured psychiatric interview. Stepwise logistic regression results supported prior findings for increased rates of psychiatric disorder among people with chronic fatigue.

Taylor (2001)64

This large community based study sought to evaluate the diagnostic validity of somatic symptoms associated with CFS, fibromyalgia, somatic depression, somatic anxiety and irritable bowel syndrome. Results of confirmatory factor analysis supported diagnostic disticntions between the five syndromes. Evidence for the existence of discrete diagnoses of fibromyalgia and CFS was particularly strong.

Tiersky (2003)48

Functional well-being, mood and neuropsychological status were assessed in patients with CFS with no history of psychiatric illness, CFS patients with current psychiatric illness that began before or after the onset of CFS, and with healthy controls. All three CFS groups had significantly worse scores for fatigue and physical and mental well-being compared with healthy controls. Physical functional capacity was not worse in CFS patients with a concurrent psychiatric illness compared with those without. Individuals with a psychiatric illness that predated the onset of CFS had the highest levels of emotional distress.

Tiersky (1998)65

This study compared neuropsychological symptoms, including concentration, in 30 people with CFS (CDC 1988 criteria), 33 people with mild traumatic brain injury (MTBI) and 20 healthy controls. People with CFS scored significantly worse on measures on concentration than healthy controls.

Tritt (2004)39

A cross sectional study of a random sample of patients at a German psychosomatic inpatient clinic was carried out to determine indicators of long term disability for people with CFS. 429 patients with CFS were compared with 410 without. CFS patients had significantly worse memory and concentration than people without CFS.

Tuck (2000) 92

Women (n = 42) with CFS were recruited through CFS support groups and compared with a control group matched for age and race. The CFS group reported a mean of 14.2 (SD 2.36) out of 17 CFS symptoms compared with 3.65 (SD 3.85) for the control group. The difference was statistically significant (t = 14.99, p < 0.0001). The CFS group also had significantly higher scores for depression (measured as part of the Derogatis Stress Profile) and disturbance of mood (measured as part of the Profile of Mood States (POMS)).

van der Werf (2002)49

Fatigue (on a 5-point scale) and activity (assessed with an actometer) were measured at different times of day in 132 women with CFS and 70 healthy female controls. Compared with controls, the CFS patients had significantly higher mean waking-up, morning, afternoon and evening fatigue scores (all p < 0.001). Morning and afternoon activity levels were lower in CFS patients than in controls, but night and evening physical activity did not differ between groups.

van Middendorp (2001)45

In this study, 36 adolescent girls with CFS (diagnosed using CDC 1994 criteria) were compared with ‘norm’ data for measures of depression and participation in daily and recreational activities. The group with CFS were found to have statistically significantly worse outcomes than the ‘norm’ group for depression and participation in daily and recreational activities.

Vercoulen (1996)66

This study compared dimensions of fatigue and other symptoms in patients with MS, patients with CFS (Oxford criteria) and healthy controls. Patients with CFS scored significantly worse than healthy controls for all measure apart from sore throat. CFS and MS groups were not compared to each other.

Vercoulen (1998)78

A hypothetical model of factors perpetuating fatigue was tested using structural equation modelling on 50 patients with CFS and 51 patients with MS. The authors concluded that cognitive and behavioural factors are involved in the persistence of fatigue and that treatments should be directed at these factors.

Vercoulen (1998)67

In this study the degree of neuropsychological impairment was compared between people with CFS (Oxford criteria) and healthy controls. People with CFS scored significantly worse than healthy controls on measures of memory and concentration.

Vercoulen (1994)79

In this study which aimed to identify homogeneous subgroups in CFS, 298 CFS patients completed a postal questionnaire. Statistical analyses identified nine relatively independent dimensions of CFS: psychological well-being, functional impairment in daily life, sleep disturbances, avoidance of physical activity, neuropsychological impairment, and causal attributions related to the complaints, social functioning, self-efficacy expectations and subjective experience of the personal situation. The authors recommend that CFS assessment and research be directed along these dimensions.

Vollmer-Conna (1997)86

Cognitive performance and mood were assessed in patients with CFS, depression, acute infection and healthy controls (N=21 in each group). All groups showed increased errors and slower reaction times, and higher workload ratings than healthy controls. Patients with CFS and depression had more severe deficits than patients with acute infection. All patient groups reported more severe mood disturbance and fatigue than healthy controls but patients with CFS and with acute infection reported less severe mood disturbance than patients with depression.

Wearden (1997)69

This study compared cognitive performance and complaints of cognitive impairment in people with CFS (subdivided into groups with and without comorbid depression) and healthy controls. Patients with CFS scored significantly worse than healthy controls on measures of cognitive impairment and subjective cognitive problems.

Wessely (1996)93

This prospective cohort study compared symptoms between people with CFS (Oxford/CDC 1994 definitions) and healthy controls. People with CFS scored significantly worse than healthy controls on all symptom measures. It was also found that 75% to 78% of people with CFS also had a psychiatric disorder.

White (2004)41

A cohort of US primary care patients (n = 150) was followed up 2 and 6 months after onset of infectious mononucleosis. Fifty of these patients were also examined 4 years after onset. Principal components analysis of symptoms identified two fatigue factors at 2 and 6 months and one fatigue factor at 4 years. Latent class analysis at 2 and 6 months divided participants into groups based on number (few vs. many) and type (mood vs. fatigue) of symptoms. The authors concluded that these data support the existence of two discrete chronic fatigue syndromes after infectious mononucleosis, one of them still being present 4 years after onset.

Wilson (2001) 40

Patients (n = 744) with a clinical diagnosis of chronic fatigue were recruited from eight specialist clinics. Patients completed a 119-item self-report questionnaire covering symptoms, illness course and functional impairment. Latent profile analysis divided the patients into two subclasses, with substantial variation in prevalence between centres. Class one (68% overall) was characterized by younger age, lower female:male ratio, shorter illness duration, lower psychiatric morbidity and less functional disability. Class two (32%) had features consistent with a somatoform illness. The authors concluded that criteria-based approaches to the diagnosis of CFS and related conditions do not identify a homogeneous group of patients.

Evidence to answer Question 2: Are there any substantiated or validated evaluations to support the diagnosis of CFS/ME in adults and children?

Research literature evidence

Twenty-seven studies2, 4, 92, 94–118 met inclusion criteria for question 2. All but six were of a low level of evidence (level 3 or 4), being case-control studies or consensus guidelines. Studies at this level of evidence are vulnerable to bias from various sources. The case-control studies often differentiated healthy controls from CFS patients; however it would be more useful to differentiate patients with related illnesses, such as depression and fibromyalgia. Some studies (e.g. the Naschitz publications) used very sophisticated methods to differentiate participants, but it is unclear how sample dependent the results are, they ideally need confirmation in larger samples containing patients with related illnesses (rather than healthy controls).

Three of the six studies that were graded as level 2 reported that the tests evaluated showed no difference between CFS patients and controls. The other three all reported that the tests were able to distinguish CFS patients from controls. All three of these latter studies were of the head-up tilt test, and were published by the same group of authors. Three other level 3 studies published by the same authors also indicated that the head up tilt test was able to discriminate CFS patients from healthy controls. However, we did not find any evaluations of the head up tilt test that did not find in its favour, or any evaluations by other authors, which may suggest the possibility of publication bias (negative studies may exist but may not have been published).

Other diagnostic tests found to discriminate between CFS and non-CFS individuals in level III evaluations were: a panel of five laboratory tests (fibrinogen, prothrombin fragment 1+2, thrombin-anti-thrombin complexes, soluble fibrin monomer (SFM) and platelet activation (CD62P, ADP)); a test for auditory brainstem responses; and electrodermal analysis.

It is perhaps not surprising that no definitive diagnostic test has been described for CFS/ME, given that CFS/ME is a syndrome, as such defined by symptoms rather than cause. It is probably unlikely that a diagnostic marker would be found before a cause or causes of the syndrome are identified.

Bates (1995)115

The ability of several laboratory tests to distinguish between 579 patients with CFS (CDC 1988, Oxford or Australian case definitions) and 149 healthy control blood donors was evaluated in a partially blinded case-control study. Tests included haematology, blood chemistry, and immunology. The authors concluded that although the laboratory tests supported the diagnosis of CFS, individually the tests lacked the sensitivity to be diagnostic tests.

Berg (1999)116

A panel of five laboratory tests were used to try to distinguish CFS and/or FM patients (n=54) from control patients (n=23) in a blinded case-control study. Patients were defined as positive for CFS if they tested positive in at least two of the five tests (fibrinogen, prothrombin fragment 1+2, thrombin-anti-thrombin complexes, soluble fibrin monomer (SFM) and platelet activation (CD62P and ADP)). The false positive rate was 4% and the false negative rate 7.4%. The authors concluded that the panel of tests allows testing for both the diagnosis and monitoring of CFS patients.

Carruthers (2003) 2

A consensus conference organised by an Expert Subcommittee of Health Canada prepared diagnostic protocols based on the participants’ collective clinical experience. The diagnostic protocols are based on clusters of characteristic symptoms and are intended to facilitate a comprehensive and integrated approach to diagnosis of CFS/ME.

Committee for Science and Education, Medical Association of South Africa (1995)114

These clinical guidelines were arrived at using Delphi-type commentary from individual doctors and doctor and patient groups. This is a low level of evidence. With regard to diagnosis of CFS, the guidelines recommend using serial weight measurements, serial morning and afternoon temperature measurements, HIV blood tests and a series of other blood tests, chest radiographs and urine tests to exclude other illnesses. They conclude that these investigations should only be carried out when CFS is reasonably suspected and the CDC criteria are met. The authors referred to ‘major disputes’ about the content of this guideline.

Folks (1993)113

A blinded case-control study evaluated the use of a human T-cell leukaemia virus polymerase chain reaction analysis (HTLV PCR analysis) to distinguish between CFS cases (n=26)and healthy controls (n=28). The authors concluded that the test did not distinguish between the two groups of patients.

Gow (2001)118

Assays for activation of the 2,5A synthetase/ribonuclease latent (RNase L) and RNA-regulated protein kinase (PKR) antiviral pathways have been offered commercially as diagnostic tests for CFS. This study found that expression of genes for RNase L and PKR was significantly different in patients with gastroenteritis compared with patients with CFS and healthy controls. The CFS and control groups did not differ from one another. The authors concluded that assays for activation of these antiviral pathways are unlikely to form the basis of a diagnostic test for CFS.

Gunn (1993)112

A diagnostic case-control study was carried out to determine whether three retroviral laboratory tests can distinguish between 68 patients with CFS and 68 age, sex and race matched healthy controls. The laboratory tests included were the polymerase chain reaction, the modified polymerase chain reaction and the culture for foamy cell cytopathic effect. The reference standard was the CDC-1988 criteria. Study participants were recruited from three different US centres and laboratory tests were performed at one of two sites. None of the three tests could differentiate between the CFS patients and the healthy controls. Very few methodological details were reported and findings did not take into account centre and site differences.

Jason (1997) 111

A screening instrument for CFS was tested on a sample of patients with CFS, other illnesses (MS or SLE) and healthy controls. The screening instrument had high test-retest and inter-interviewer reliability. All 15 people in the CFS group were identified as having CFS whereas none of the members of the other groups met the screening criteria. Members of the MS and SLE groups indicated that they had an exclusionary medical condition; if they had not known this the screening instrument would have identified 11 in the SLE group and four in the MS group as having CFS (100% sensitivity, 67% specificity, 75% agreement and a kappa value of 0.5). The authors concluded that screening with this instrument should be followed by medical assessment to exclude other illnesses with similar symptoms. Further validation of the screening instrument is required.

Levine (2001) 110

A consensus meeting was held in March 2000 to consider the clinical usefulness of research tools and techniques currently under evaluation for CFS. The authors considered a test for low molecular weight (LMW) RNase L to be promising for the diagnosis of CFS. An unpublished study showed that 80% of patients meeting the 1988 CDC case definition and 60% meeting the 1994 definition were positive for LMW RNase. The meeting considered that other tests of immune activation may also play a role in supporting the diagnosis of CFS. Epstein-Barr virus serology was not recommended.

Miller (1991)109

The ability of serological tests for coxsackie B virus to detect cases of postviral fatigue was evaluated in an unblinded case-control study. Findings in 254 patients referred by GPs with postviral fatigue syndrome were compared with those in age and sex-matched healthy controls. None of the tests was distinguishing and few showed any significant abnormal values. A strong seasonal variation in positive antibody tests was reported in cases and controls. The authors concluded that the tests do not help diagnose postviral fatigue syndrome.

Naschitz (2000)104

Thirty-two patients with CFS and 32 healthy controls were evaluated using the capnography head-up tilt test (CHUTT). Blood pressure, heart rate, respiration rate and end-tidal pressure of CO2 did not differ between groups during the supine phase of the CHUTT but values reached during the tilt phase were significantly different for all parameters. One or more pre-defined endpoints of the CHUTT was reached in 25/32 (78%) patients with CFS but in none of the controls. The authors concluded that the CHUTT may provide objective data to support a clinical diagnosis of CFS.

Naschitz (2003)105

This case-control study used the head-up tilt test with haemodynamic instability score (HIS) to differentiate 40 CFS patients from other patient groups and healthy controls. A cut-off of >−0.98 showed a sensitivity of 90.3% and a specificity of 84.5%, potentially providing an objective criterion for the assessment of CFS.

Naschitz (2002)119

Patients with CFS, non-CFS fatigue, syncope of unknown cause and healthy controls underwent a head-up tilt test (HUTT). Abnormal reactions during the HUTT occurred in 79% of patients with CFS, 25% of those with syncope, 25% of those with non-CFS fatigue and 14% of healthy controls. The mean hemodynamic instability score (HIS), a measure of blood pressure and heart rate lability, was 2.02 (SD 4.07) in CFS patients, −2.89 (SD 3.64) in those with non-CFS fatigue, −3.2 (SD 3.0) in patients with syncope and −2.48 (SD 4.07) in healthy controls. The odds ratio for CFS patients to have a HIS greater than −0.98 was 8.8 (95% CI: 1.6, 45.7) compared with non-CFS fatigue cases, 14.6 (95% CI: 2.9, 73.3) compared with recurrent syncope cases and 34.8 (95% CI: 5.0, 241.7) compared with healthy controls. The authors concluded that a HIS greater than −0.98 is an objective criterion to support a clinical diagnosis of CFS.

Naschitz (2002)107

This study analysed numerous cardiovascular reactivity variables obtained during a head-up tilt test to predict CFS. A discriminant ‘FRAS’ score based on fractal analysis and recurrence quantification analysis of heart rate and pulse transit time was derived. A cut-off of FRAS=0.22 achieved a sensitivity of 70% and a specificity of 88% when differentiating CFS patients from a control population consisting of healthy controls and patients with Familial Mediterranean Fever, psoriatic arthritis, syncope or generalised anxiety disorder. The mean FRAS value of the CFS patient group differed stat. sign. from all control groups except patients with generalised anxiety disorder.

Naschitz (2001)106

The paper described a hemodynamic instability score (HIS) measured during the head-up tilt test that can distinguish between CFS patients and healthy controls. A cut-off of −0.98 achieved a sensitivity of 97% and a specificity of 97% differentiating 25 CFS patients and 37 healthy controls.

Neri (1996) 108

Auditory brainstem responses (ABR) and stapedial contraction as measured by a prolonged decay test using impedance audiometry were applied to 21 patients with suspected CFS. The results were compared with clinical diagnosis. ABR findings following high frequency stimulation agreed with the clinical diagnosis in 13 cases (61.9%), with seven (33.3%) false negatives and one (4.8%) false positive. The prolonged decay test results agreed with the clinical diagnosis in 15 cases (71.4%), with five (23.8%) false negatives and one (4.8%) false positive. A combination of the two tests resulted in agreement with the clinical diagnosis in 9/11 patients (81.8%), with two false negatives (18.2%). The authors concluded that a combination of the ABR and prolonged decay tests could be useful for the diagnosis of CFS.

Ojo-Amaize (1994)103

This case-control study looked at natural killer cell activity measured in lytic units (LU) in blood samples of 20 CFIDS patients compared with 50 healthy controls. The blind analysis of the samples showed that the controls displayed a range of 20 to 250 LU with 18% above 100 LU. None of the CFIDS patients showed more than 100 LU. The low level of natural killer cell activity was correlated with the assessed severity of CFIDS.

Pazderka-Robinson (2004) 100

Skin conductance and temperature were measured in patients with CFS, patients with depression and healthy controls during a cross-modal orienting task involving responses to tone and light stimuli. Pre-stimulus tonic skin conductance was significantly lower in the CFS group than in the controls, while the control and depression groups did not differ significantly. Pre-stimulus skin temperature was significantly higher in the CFS group than in the other two groups. A discriminant function incorporating three variables correctly classified 51.4% of participants (54.2% according to table) into the three groups. Fourteen out of 22 CFS patients included in the analysis (63.6%) were correctly classified; 4/33 (12.1%) control participants were incorrectly classified as CFS cases. The authors concluded that electrodermal analysis may be useful in the differential diagnosis of CFS and depression.

Pope (1991) 101

A structured clinical interview module for diagnosis of CFS (using the 1988 CDC criteria) was developed using the format of the Structured Clinical Interview for DSM-III-R. The module had not been evaluated for CFS at the time of publication.

Prins (2003)102

A cohort study of 516 patients attending an outpatient clinic compared diagnoses made by clinicians using a standard protocol (anamnesis, medical examination and laboratory tests) with a computerised questionnaire. In 84% of cases there was agreement between the questionnaire and the clinician’s diagnosis. The authors concluded that the diagnosis of CFS should never solely be based on a computerised questionnaire but that the questionnaire may be complementary to the standard protocol in diagnosing CFS.

Rosner (2000)99

The study was carried out to seek precise parameters for detecting haemodynamic instability on postural challenge (tilt test) in CFS patients compared to FM patients and healthy controls. Blood pressure and heart rate changes were converted into a linear discriminant score (DS) for each participant. DS values differed significantly between CFS patients and healthy controls (p<0.0001) and between CFS and FM patients (p<0.0001) but not between FM patients and healthy controls (p=0.55). Values of DS greater than −0.98 were generally observed in CFS patients (sensitivity 97%) and values of −0.98 or less were usually seen in controls (specificity 96.6%). The authors suggest that DS can reinforce a diagnosis of CFS by providing objective criteria for assessment.

Royal Australasian College of Physicians (2002)4

A Working Group convened under the auspices of the Royal Australasian College of Physicians produced evidence-based guidelines on chronic fatigue syndrome covering definition, evaluation, management, CFS in children and adolescents, and social and legal issues. A diagnosis of CFS is made on clinical grounds based on the presence of characteristic symptoms and the elimination of alternative medical and psychiatric disorders. Initial history taking and physical examination should be directed towards eliminating alternative diagnoses. A diagnosis of CFS should not be made without a psychological evaluation. The following laboratory investigations are recommended for evaluation of chronic fatigue lasting 6 months or more: full blood count and film; erythrocyte sedimentation rate; urea, electrolyte and creatinine levels; serum calcium and phosphate; liver function tests; thyroid stimulating hormone level; and urinalysis for protein, blood and sugar.

Schillings et all (2004)117

A diagnostic case-control study of maximal voluntary contraction (MVC) of the biceps muscle in 14 female patients with CFS (defined by the CDC 1988 criteria) and 14 healthy age-matched female controls was carried out in the Netherlands. The study was unblinded (investigators knew which females had CFS and which did not) and the reference standard used was a checklist of symptoms that included muscle weakness. Therefore the study was of poor validity and a low level of evidence. The results of the study led the authors to conclude that CFS patients showed reduced central activation during MVC.

Scott (1998) 97

Low dose (1 microgram) ACTH was administered to 20 patients with CFS and 20 controls matched for age, sex and weight. Baseline cortisol values did not differ between groups. Maximum increase in cortisol from baseline was significantly lower in the CFS patients than in the controls. Two of the controls (10%) and nine of the CFS patients (45%) failed to reach an arbitrary cut-off point of a maximum cortisol increase of 250 nmol/litre. The relatively low response in the control group compared with that seen in other studies suggested that the test may not be as reliable as previously suggested.

Sendrowski (1997)98

This study tried to demonstrate sympathetic hypersensitivity as a diagnostic sign for CFS. However, the change in pupil size 1h after instillation of phenylephrine was not statistically different between the 29 CFS patients and 33 controls. The samples showed substantial overlap in reactions and the authors concluded that the use of 1% phenylephrine has no diagnostic value in differentiating CFS patients and healthy controls.

Tiev (2005) 95

The RNase L isoform ratio (37/83 kDa) in peripheral blood mononuclear cells was assayed in duplicate once a month for 3 months in nine patients with CFS. The accuracy of the ratio was also tested and correlated with Multidimensional Fatigue Inventory (MFI) scores in a case-control study involving 28 patients with CFS and 24 healthy controls. A value of 0.4 for the 37/83 kDa ratio discriminated best between CFS cases and controls. The authors concluded that the ratio has a high variability and poor reproducibility in patients with CFS and that the ratio varies while MFI scores remain stable.

Tiev (2003) 96

In a prospective case-control study, the RNase L isoform ratio was measured in peripheral blood mononuclear cells from 11 patients with CFS and 14 healthy volunteers. A threshold 37 kDa: 83 kDa ratio of 0.4 allowed diagnosis of CFS with high sensitivity (91%; 95% CI: 57%, 99%) and specificity (71%; 95% CI: 41%, 90%). Positive and negative predictive values were 71% (95% CI: 41%, 90%) and 91% (95% CI: 57%, 99%), respectively. It was concluded that a high RNase L ratio could distinguish CFS patients from healthy volunteers in the absence of acute infection or chronic inflammation.

Yamamoto (2003)94

This study showed that the difference between baseline and after head-up tilt test (HUTT) in the fractal component of heart rate variability amplitude (DeltaAFR) differentiated between 24 female CFS patients and 22 healthy women. A cut-off of DeltaAFR of −2.7 msec achieved a sensitivity of 90% and a specificity of 72%. The authors concluded that a decrease in aperiodic fractal component of heart rate variability in response to HUTT can be used to differentiate between CFS patients and healthy controls.

Evidence to answer Subquestion 2: In people presenting with early suspected CFS/ME (before 6 months) what are the risk factors / prognostic flags that might be linked with progression to CFS/ME?

Research literature evidence

Seven studies120–126 met inclusion criteria for the sub-question about risk factors for progression to CFS/ME. Most of the studies seemed to be cross-sectional studies involving retrospective surveys of people with and without CFS/ME and as such are vulnerable to recall bias and other forms of bias. None seemed to indicate definite prognostic flags for CFS/ME that would be useful to a clinician, however, the following factors were found to be significantly associated with development of CFS/ME in individual studies: sick certification after viral illness, presence of fatigue at time of viral illness, lower physical functioning, higher pain and fatigue scores at baseline, older age (adults and children), exhaustion, being female, low educational level, visits to the GP, longstanding limiting medical condition aged 10 years, higher social class in childhood, fatigue and psychological distress prior to presentation, presence of infectious mononucleosis, positive Monospot tests at time of onset, time in bed at onset, exercise power, mood disorder. A study of ME/CFS in children identified presence of an anxiety disorder as a risk factor for developing the illness. A birth cohort study reported that higher levels of exercise in childhood were associated with a reduced risk of developing CFS/ME.

Chalder (2003) 120

Mothers (n = 10 438) of children aged 5–15 were asked whether their child had ME or CFS and completed the 12 item General Health Questionnaire. A sample (n = 4240) of children aged 11–15 identified from the first sample were interviewed. Prevalence of CFS as defined by the 1994 CDC criteria was 8/4240 (0.19%). Risk factors for CFS were older age (odds ratio (OR) 1.9; 95% CI: 1.0, 3.7) and presence of an anxiety disorder (OR 8.8; 95% CI: 1.8, 43.5). Female sex was not a significant risk factor.

Cope (1996) 121

Sixty-four patients with chronic fatigue (3 months’ duration and a score of 9 or more on a fatigue questionnaire) and 64 matching controls were identified from a cohort of primary care patients recruited 6 months previously with a clinically diagnosed viral illness. Cases of chronic severe fatigue were significantly more likely than controls to have a past psychiatric history and a current psychiatric diagnosis. Twenty-three of the cases fulfilled criteria for CFS (UK 1991 case definition). In a logistic regression analysis, CFS 6 months after viral illness was predicted by sick certification (OR 8.5, 95% CI: 4.2, 17.2; p = 0.002), a psychological attribution style (OR 2.1, 95% CI: 1.6, 2.7; p = 0.007) and presence of fatigue (OR 6.4, 95% CI: 2.5, 16.4; p = 0.05), all measured at the time of viral illness. Psychological morbidity and past psychiatric history did not predict development of CFS.

Huibers (2004)122

Employees (n = 151) who were on sick leave because of fatigue were followed for 12 months. Of these, 66 were CFS-like cases (met research criteria for CFS without a formal diagnosis) at baseline. Logistic regression analysis indicated that lower baseline scores on physical functioning predicted CFS-like caseness at 12 months in the whole group and in those who were not CFS-like cases at baseline. In the CFS-like employees at baseline, CFS-like caseness at 12 months was predicted by higher fatigue and pain scores at baseline. Recovery from fatigue was predicted by psychological attribution of fatigue, pain score, self-rated health, professional efficacy and cognitive difficulties. Return to work was predicted by male sex, age, cognitive difficulties and CFS status at baseline.

Huibers (2004)123

Employees (n = 1143) with unexplained fatigue were followed prospectively for 44 months. At follow-up, 94 participants (8%) met research criteria for CFS without a formal diagnosis (CFS-like caseness), 457 (40%) were non-CFS fatigue cases and 592 (52%) were no longer fatigue cases. Baseline factors that predicted CFS-like caseness compared with non-CFS fatigue at follow-up were older age, exhaustion, female sex, low educational level and visits to the general practitioner (GP). Factors that predicted CFS-like caseness compared with no fatigue were fatigue, exhaustion, low educational level, visits to the GP and occupational physician, and poor self-rated health. The authors concluded that unexplained fatigue is in some cases a precursor to the development of CFS.

Viner (2004) 124

Data obtained from a national birth cohort (babies born in England, Scotland and Wales, 5–11 April 1970) followed up at 5, 10, 16 and 29–30 years were analysed. At the last follow-up, 93 of 11 261 participants (0.8%) reported ever having CFS/ME and 48 (0.4%) reported having the condition currently. Higher risk of ME was associated with having a longstanding limiting medical condition at 10 years, female sex and higher social class in childhood. Higher levels of exercise in childhood were associated with a reduced risk of developing CFS/ME.

Wessely (1995) 126

Questionnaires to assess fatigue and psychiatric morbidity were sent to patients aged 18–45 in participating general practices. Prevalence of chronic fatigue and CFS was subsequently assessed in patients who attended the surgery with a symptomatic infection (exposed cohort) or for other reasons (non-exposed cohort). Most (84%) were followed up at 6 months. There were no significant differences between the exposed and non-exposed cohorts in the proportion with fatigue, chronic fatigue (by fatigue questionnaire) or CFS (by Oxford, Australian or CDC criteria) at 6 months. The strongest predictors of chronic fatigue at 6 months were fatigue prior to presentation (odds ratio (OR) 3.0, 95% CI: 1.9, 4.7) and psychological distress (GHQ score) before presentation (OR 1.8, 95% CI: 1.2, 2.9) and at the time of presentation (OR 1.8, 95% CI: 1.1, 2.8). The authors concluded that this study provides no evidence that common infections in primary care are related to the development of chronic fatigue or CFS.

White (2001) 125

Primary care patients with infectious mononucleosis or an upper respiratory tract infection were followed until 6 months after onset. Significant predictors of CFS by both the Oxford and 1994 CDC criteria at 6 months were belonging to a general rather than a student primary care sample, presence of infectious mononucleosis, positive Monospot test at onset, time in bed at onset, exercise power, GP attendances in the year before onset, GP record of PPD, PMD, and mood disorder at 2 months.

Evidence to answer Question 3: How effective and safe are interventions for the treatment and/or management of CFS/ME in adults and children?

Research literature evidence

Sixty-nine trials are included in this section. Detailed data extraction and validity assessment tables are presented in an appendix. Additionally, four ongoing trials that have not yet been published were identified.127–130

Fifteen papers that were ordered as potentially meeting inclusion criteria for question 3 had not arrived at the time of writing this report.131–145 One paper in the Russian language was identified as potentially meeting inclusion criteria but has not been translated.146 The paper is about a yeast extract supplement but it is unclear whether patients all had CFS.

No RCTs, controlled trials, or good quality cohort studies, case-control studies before-and-after studies or interrupted time series were found for the following treatments which the Guideline Development Group (GDG) had identified a prior as being of interest: Expert Patient Programme; amitriptyline; gabapentin; baclofen; vitamin B12 injections.

EVIDENCE RELATING TO ADULTS WITH CFS/ME

Main results of behavioural treatment trials

CBT with the aim to increase activity and reduce rest time in a systematic manner, independent of symptoms given in weekly or biweekly sessions was evaluated in adults in four RCTs.147–151 A controlled trial of “modified CBT” used a different form of treatment without graded activity, which is normally considered an integral part of CBT for CFS/ME. The intervention used in this study aimed to promote shared coping through relaxation training and guided imagery, cognitive therapy techniques and behavioural prescription involving activity limitations.152 Other types of modified CBT, with occupational therapy/rehabilitation aspects, were examined in another RCT153 and two controlled trials.154, 155 All studies included people diagnosed with CFS according to one of the recognised case definitions, except one which included people with post viral fatigue syndrome.156 CBT was compared to routine medical care in two RCTs,150, 153 and two controlled trials,154, 155 to relaxation in one RCT,147, 148 to natural course (control) in another RCT,151 and to guided support in one controlled trial of “modified CBT”.152 A further RCT compared CBT plus placebo injections to CBT plus leukocyte extract, a control clinic plus leukocyte extract and to a control clinic plus placebo injections.149

Table 1. Results of behavioural treatment trials in adults.

Table 1

Results of behavioural treatment trials in adults.

The RCT which investigated the effects of both leukocyte extract and CBT showed a significantly greater effect on general health in the group receiving both leukocyte extract and CBT compared to the other groups. No differences were found between groups (including CBT alone) for the other outcomes investigated.149 The controlled trial of modified CBT found no difference between intervention and control groups for fatigue, depression or symptom scores.152 This study scored very poorly on the validity assessment, scoring only 1 out of a possible 20.

The remaining three RCTs reported a beneficial effect of CBT when compared to controls.147, 150, 151 All three RCTs found a significant short term improvement in physical functioning, fatigue, and global improvement, but neither of the two studies that assessed depression found any differences between groups.147, 150 One of these RCTs also followed patients for five years after the intervention. At the five year follow-up assessment global improvement was greater in the intervention group, as was the proportion of participants who completely recovered,148 however, no differences were reported between the groups in terms of physical functioning, fatigue, general health, symptoms, relapses or the proportion of participants that no longer met the UK criteria for CFS.

The three studies of modified CBT with rehabilitation153–155 found significant differences between groups for symptoms (one RCT, one controlled trial), emotional distress (one controlled trial) and global health/quality of life (3 controlled trials).

In one RCT two participants dropped out of the CBT group as they felt a deterioration in their symptoms was due to the intervention.150 A second RCT showed very high drop out rates of between 20 and 40% in all three treatment groups.151 Drop out rates were highest in the CBT group and lowest in the control group, reasons for drop-outs were not stated and no adverse effects from treatment were reported.

The effects of graded exercise therapy (GET) were investigated in five fairly large RCTs of patients with CFS, all of which found significant improvements in the intervention compared to the control groups. Improvements in measures of fatigue and physical function were found in all five RCTs.157–161 Two also showed improvement in general health157, 159 and one in physiological measurements and symptoms.158 When exercise was combined with fluoxetine there was no additional effect.158 One RCT assessed different interventions to encourage graded exercise and found benefits of GET compared to standardised medical care for all outcomes investigated. However, there were no differences between the different intervention groups for any of the outcomes investigated. 159, 162

In one of the RCTs evaluating GET, one participant dropped out from each group due to worsening of symptoms.157 In another RCT of exercise (and exercise plus fluoxetine), 11 participants dropped out due to side effects but it is unclear which intervention group they were in.158

Main results of immunological/antiviral treatment trials

Three RCTs of participants diagnosed with CFS investigated the effects of immunoglobulin in adults; two found some positive effect, and the third found no effect of treatment. One RCT found greater improvements in the intervention group on symptom scores and functional capacity but not in depression, immune outcomes or quality of life.164 A second smaller RCT found improved immune measurements (physiological outcome) but not functional or symptom measures.165 A third RCT, which was the largest in the immunoglobulin category, found no improvement in any of the outcomes investigated (functional status, mood, immune outcomes and quality of life).166

Table 2. Results of immunological treatment trials.

Table 2

Results of immunological treatment trials.

Other immunomodulators were investigated in four RCTs, all of which included participants with CFS. Two of these evaluated interferon, one of which suggested some positive effect. In one very small RCT treatment led to increased physical activity and recovery which remained after 8 months follow-up, however it is not reported whether this was statistically significant.167 In the other RCT, alpha-interferon led to an improvement in immune measurements (one outcome) but not in quality of life measurements.168 The effects of Ampligen were investigated in one relatively large (n=92) RCT, which found an improvement in functional ability, activity, exercise, cognitive function and work measures but not in depression scores.169 In the same RCT, elective use of other medications by participants was reported to have increased significantly in the placebo group compared to the intervention group. One RCT assessed the combined effect of leukocyte extract and cognitive behavioural therapy using a factorial design.149 A significant improvement in general health was reported for the group which received both interventions, compared to the other groups. No beneficial effects were reported for physical and functional capacity, mood or immune outcomes for any of the groups in this study.

The effect of acyclovir, an antiviral, was investigated in one small RCT in those who fulfilled criteria for CFS and additionally had prior infection with Epstein Barr virus confirmed.170 A significant negative effect was reported for anxiety, depression and confusion with the control group showing a greater improvement in symptoms than the treatment group, but not for the other outcomes investigated (rest, anger, vigour, fatigue, oral temperature and personal well-being). A very small trial of gancyclovir (n=11) found no beneficial effects, and the trial had to be stopped early due to bleeding during invasive investigations.171 A small trial of inosine pranobex (n=16) found significant improvements in immune function in the treatment group, but no differences between groups for other outcomes (symptoms, cognitive function, global severity, activity).

One RCT of patients with CFS evaluated the antihistamine terfenadine.172 This study found no differences between the groups for any of the outcomes investigated (functional status and symptoms).

The effects of vaccination with staphylococcus toxoid were investigated in one small controlled trial of patients with CFS173 and one fairly large RCT.174 In the controlled trial, no differences were reported in depression, pain or psychological outcomes between the intervention and control group. However, a greater improvement in the clinical global impression in the treatment group was found. In the RCT, the treatment group had a significantly better outcome than the control group for global impression and one item on the fibromyalgia impact questionnaire.

Some severe adverse effects were noted in participants in the immunological intervention groups. Three people had to withdraw from acyclovir treatment due to reversible renal failure170 and two people from immunoglobulin treatment due to severe constitutional symptom reactions.166 One recipient of immunoglobulin therapy also withdrew due to mild but transient liver failure164 and phlebitis has also been noted with immunoglobulin infusions.164 Transient elevation of serum uric acid was noted in the trial of inosine pranobex.175 In the RCT of staphylococcus toxoid, 13 patients in the treatment group and seven in the placebo group experienced side effects. It should be noted that immunoglobulins and leukocyte extract are blood products. There are known risks associated with the use of blood products such as the possible transfer of infectious diseases.

Main results of pharmacological treatment trials

Very few of the RCTs evaluating pharmacological interventions showed a beneficial effect. No benefit was found in patients with CFS from treatment with anticholinergic agents,177–179 antidepressants (either in treating symptoms of depression or any of the other outcome measures reported)158, 180, 181 or growth hormone.182 However some studies reported a positive effect on individual outcomes.

Table 3. Results of pharmacological treatment trials.

Table 3

Results of pharmacological treatment trials.

Oral NADH led to a greater improvement in symptoms (the only outcome investigated) in the intervention group compared to the control group in one small RCT,183 but no significant difference in symptoms in another low quality RCT.184 A trial of melatonin versus phototherapy found significant improvements in sleep, vitality and mental health, but worsening of bodily pain in the melatonin group.185

The effects of steroid treatment were investigated in six RCTs of participants with CFS.186–191 Three of these RCTs evaluated hydrocortisone and all reported some beneficial effect.186–188 One found an improvement in general health but not in activity, depression, mood or symptom measures.186 The second smaller RCT found improvements in clinical global impression, fatigue, symptoms and disability, although the improvement in disability was not significant.187 The third found improvement in fatigue and hormone levels.188 Two RCTs assessed fludrocortisone, and did not find any association between treatment and the outcomes investigated.189, 190 One RCT of fludrocortisone and hydrocortisone combined found no significant benefit of treatment191 and a seventh RCT of topical nasal corticosteroids also found no effect of treatment.192

One RCT and one controlled trial investigated the effect of monoamine oxidase inhibitors in participants with CFS.193, 194 The RCT evaluated moclobemide, and found no benefit of treatment.193 The small controlled trial of selegiline was associated with greater improvement in tension, anxiety and vigour in the intervention group compared to the control group, but not with functional capacity, fatigue, illness severity or symptom measures.194

A trial of dexamphetamine found significant improvements in fatigue in the treated group.195 Reduced food consumption was a side effect in this group.

One very small RCT (n=10) evaluated the effects of the antihypertensive drug clonidine and found no significant effect on cognitive function.71

Adverse events serious enough to cause people to withdraw from the study occurred with galanthamine hydrobromide,177, 178 phenelzine180, fludrocortisone190 and fluoxetine.181

Main results of alternative medicine treatment trials

Two RCTs assessed the effectiveness of homeopathy.196, 197 One study reported ‘greater improvement’ with treatment, however no measurements were presented and so it is difficult to interpret the findings.196 The authors of the study state that participants were suffering from ME, however the Oxford criteria for CFS were used to make the diagnosis. This study also scored poorly on the validity assessment (6 out of 20). The other, high quality RCT reported significant improvements in fatigue and on some physical dimensions of the functional limitations profile in the treatment group.197 No adverse effects were reported in either group.

Table 4. Results of alternative therapy (homeopathy) treatment trial.

Table 4

Results of alternative therapy (homeopathy) treatment trial.

Massage therapy improved measures of fatigue, pain and sleep, depression and cortisol levels in one small RCT in those diagnosed with chronic fatigue immune deficiency syndrome (CFIDS).198 Osteopathy also reportedly improved measures of fatigue, back pain and sleep, anxiety and cognitive function and general health in a controlled trial of patients diagnosed with ME. However the quality of this study was poor (score = 0 out of 20).199

Main results of supplement treatment trials

Two studies investigated the effect of essential fatty acid supplements. One RCT in patients with CFS found some non-significant improvement as perceived by the participants, as well as non-significant improvements in depression, but not in general symptoms.200 A slightly larger controlled trial investigated the effect of essential fatty acid supplements in those diagnosed with post viral fatigue syndrome (PVFS).156 Improvement (as perceived by the participants) was reported in the intervention group, along with an improvement in symptoms and a greater shift towards normal levels of cell fatty acid concentration.

Table 5. Results of supplement treatment trials.

Table 5

Results of supplement treatment trials.

Magnesium supplements led to improvements in measures of energy and pain, emotional reactions, general health and laboratory measures but not in sleep, physical mobility or social isolation in one small RCT of patients with CFS.201 One very small RCT assessed the effects of liver extract in patients with CFS but found no difference in outcomes between the intervention and control groups.202

General supplements had no effect in two RCTs and one controlled trial of patients with CFS.203–205 These studies also scored poorly on the validity assessment (6–10 out of 20).

RCTs of pollen extract206 and medicinal mushrooms207 reported no significant effects of treatment. A controlled trial of acclydine and amino acids208 reported significantly more improvement in IGF-1 levels in the intervention than control group, but no significant difference in global improvement or symptoms. A RCT of acetyl-L-carnitine and propionyl-L-carnitine found significant improvements in fatigue and cognitive function associated with treatment.209

Reasons for dropping out of the studies were not well described in the supplement trials, however in the magnesium trial, two participants left the intervention group after experiencing a generalised rash.201

Main results of other treatment trials

One controlled trial of combination treatment (including CBT) in patients with CFS was also included.210 A greater number of participants returned to work in the intervention group (the only outcome measured), however 49 of the 71 original participants were not followed up. This study also scored very poorly on the validity assessment, receiving a score of two out of a possible 20 and so these results should be interpreted with caution.

Table 6. Other treatment trials.

Table 6

Other treatment trials.

A controlled trial of ‘broad-based management’ (mainly information and advice) in people diagnosed with post-infectious fatigue syndrome found significant improvements in the intervention group in measurements of fatigue, somatic symptoms and self-efficacy.211 Again, a low score on validity assessment (two points out of 20) indicates that these results should be treated with caution.

A very small controlled trial of a buddy/mentor programme found significant improvements in the treatment group compared to control for fatigue severity but not for any of the other six outcomes investigated.212

A trial of ‘group therapy’, which was not well described, found no significant effects of treatment.213

An unpublished trial of a low sugar, low yeast diet, compared to healthy eating, also found no significant effect of treatment.214

A RCT of multiple symptom-based treatments (including supplements) found significant improvements in favour of the treatment group in symptoms scores, overall response and fibromyalgia-specific symptoms.215 This trial scored 19 points out of a possible 20 in the validity assessment.

Severely affected

One RCT assessed participants who had been ill for three years or more, separately from participants who had been ill for less than three years. The study reported no differences in response to fludrocortisone between the two groups.190 A controlled trial of broad-based management also found no differences in response between those who had been ill for shorter and longer periods of time.211 In the same study, participants were also grouped according to degree of initial functional impairment, emotional distress, and fatigue. No differences in response were seen in those with a greater degree of initial functional impairment and emotional distress, however those who reported more initial fatigue showed greater improvements in self-efficacy scores (p=0.04).211

One study of rehabilitation treatment for inpatients found some benefits of treatment.155 Patients with high fatigue and disability scores were included in an RCT of a general supplement, but no significant treatment effects were seen.204

The inclusion criteria for the trial of pollen extract state that only relatively serious cases were included.206

Very limited numbers of studies considered subgroups of patients. For example, no studies were found that compared the effects of treatment in bed and wheelchair bound patients with those who were less restricted by their illness, or that assessed whether treatment had different effects in those where the diagnosis had been made using criteria for CFS compared with those where the diagnosis had been made using criteria for ME. It was unclear in many trials how severely affected the participants were.

EVIDENCE RELATING TO CHILDREN

One RCT of immunoglobulin G included only children.216 A significant improvement in functional score (based on attempts and attendance at school or work and physical or social activities) was reported in the intervention group compared to the control group. Significantly more children in the intervention group had an improvement in score of 25% or more. A second RCT of immunoglobulin included both adults and children according to standard definitions, although no participants under the age of 16 were included.166 Significant improvements were seen in symptom scores and in functional capacity in the intervention group compared to the control group. The findings from both of these studies have also been presented in the main immunological section. The use of blood products such as immunoglobulin is associated with known risks and so the use of this treatment should be carefully considered.

Table 7. Treatment trials in children.

Table 7

Treatment trials in children.

One controlled trial of rehabilitation/ CBT in children reported significant improvements in the treatment group for measures of global wellness.217 One RCT of CBT in children reported significant improvements in symptoms and attendance at school.218 In both, the intervention was compared to routine care.

No evaluations of other interventions investigated in children were identified.

Validity of included studies

Most RCTs scored well on the objectivity and validity of outcomes, blinding of investigators and participants, baseline comparability of groups, completeness of follow-up and appropriate statistical analysis. RCTs generally scored poorly on the concealment of treatment allocation and many failed to use an intention to treat analysis. Controlled trials scored less well on the objectivity and validity of outcomes and on all other validity criteria. Two of the eight controlled trials in which groups were not comparable at baseline did adjust for baseline differences or confounding factors. Only one of the controlled trials used a sample size calculation.

No one intervention type scored more highly on the validity criteria than any other.

Summary of results

The results of each trial, ranked according to validity score, are presented in Table 8. Trials were classified as having a positive, negative or no effect, under the classifications of overall effect and any effect. Studies were judged to show some effect of treatment if any of the outcomes measured showed a statistically significant difference between the intervention and control groups. Studies were classified as having an overall effect (positive or negative) if they showed a statistically significant effect for more than one clinical (i.e. not a physiological/ laboratory) outcome or, if only one clinical outcome was measured, it was found to show a statistically significant effect. The effect was considered to be positive if the intervention group showed a greater improvement than the control group and negative if the control group showed the greater improvement. Where no statistically significant differences occurred, this was classified as showing no effect. Where studies presented their findings as within group differences rather than as differences between the intervention and control group, these results are presented but should be treated with caution. The findings from each study should be considered alongside the methodological quality.

Table 8. Summary of study results.

Table 8

Summary of study results.

Of the 69 included trials 34 (49%) showed some beneficial effect of the intervention and 20 of these (29%) showed an overall beneficial effect, one study reported a negative effect of the intervention. Overall, of those studies that found some beneficial effect of the intervention, three studies (two of immunological interventions and one of supplements) found a benefit for physiological outcome measurements only. Some studies investigated a large number of outcomes - the range across studies was from 1 to 15 - making it possible that any statistically significant differences could have arisen by chance. The results of those studies evaluating multiple outcomes should therefore be treated with caution.

Behavioural

In the behavioural category, cognitive behavioural therapy showed positive results. Four147, 150, 218, 219 of the five RCTs evaluating CBT found a positive overall effect of the intervention and these studies also scored highly on validity assessment. One RCT which also included immunologic therapy149 and one RCT163 and two controlled trials of modified CBT,152, 217 did not find overall beneficial effects of CBT. These studies also scored lower on the validity assessment, especially one of the controlled trials which scored 1 out of a possible 20. Two studies (one RCT, one controlled trial) of rehabilitation, including CBT, showed a positive overall effect153, 155 but scored less than 50% on validity assessment. An overall beneficial effect was also found in two controlled trials of two different multi-treatment approaches, one of which included CBT210 and one of which was based on providing information and advice.211 However, the methodological quality of both these studies was very poor. A controlled trial of a buddy/mentor programme found a beneficial effect for one of the seven outcomes investigated; this study scored poorly on the validity assessment and only included 12 participants.212

Graded exercise therapy (GET) also showed promising results: four of five RCTs found an overall beneficial effect of the intervention compared to the control groups. Two of these RCTs scored highly in the validity assessment, (scoring 17 out of a possible 20).157, 159

Immunological

In the immunological category two small RCTs evaluated interferon, one of these found no beneficial effect167 and the other showed some positive effects although this was in relation to physiological outcomes only.168 The methodological quality of both these studies was fairly poor; scoring 6 and 11 respectively, out of a possible 20 on the validity assessment. Four RCTs assessed the effects of immunoglobulin in patients with CFS, of these one showed an overall beneficial effect,216 one showed some positive effects164, and two found no effect.165, 166 All four of these RCTs scored reasonably well on the validity assessment, achieving scores of between 13 and 16 out of 20. Immunoglobulin is a blood product and so there is a risk of the possible transfer of, for example, infectious diseases..

One immunological RCT of Ampligen found an overall beneficial effect,169 and a positive effect was found in one small controlled trial of staphylococcus toxoid173 and one larger RCT.174 A small RCT of the antihistamine oral terfenadine reported no beneficial effects.176 These three studies score between 9 and 12 on the validity assessment.

A small RCT of acyclovir, reported a greater improvement in anxiety, depression and confusion in the control group compared to the treatment group, however, no differences in treatment effect were found for the other six outcomes investigated.170 This study scored 15 out of 20 on the validity assessment. Small RCTs of gancyclovir171 and inosine pranobex220 showed no effect of treatment.

Pharmacological

In the pharmacological category two RCTs of fludrocortisone reported no effect of treatment, these studies were of reasonable quality.189, 190 Also in the pharmacological category, trials of anti-depressants179–181, 193 reported no effects of treatment either on symptoms of depression or on any of the other outcome measures reported. Some beneficial effects of hydrocortisone were found in two RCTs.187, 188 One of these studies scored highly on the validity assessment with a score of 18 out of 20, the other was of poor quality with a validity score of 2.

One poor quality RCT showed an overall beneficial effect of oral NADH183 and another of lower quality showed no effect.184 One controlled trial of selegiline reported some positive effects of treatment but found no overall effect.194

Alternative / complementary

Homeopathic therapies were evaluated in two RCTs, one of poor quality196 and one of good quality.197 Some positive effects of homeopathy were seen in the better quality trial. One controlled trial of osteopathy found some non-significant improvements in the intervention group, but the values were estimated from graphs and so the results may not be entirely accurate.199 This study scored very poorly on the validity assessment, scoring 0. A poor quality study of massage therapy also found some positive effects.198

Supplements

In the supplements category one good quality RCT of essential fatty acids reported no beneficial effects of the intervention200 and one found an overall beneficial effect.156 Magnesium supplements were found to have an overall beneficial effect in the one good quality RCT where these were evaluated.201 Three fairly poor quality RCTs evaluated general supplements, none found a positive effect.203–205 Poor quality RCTs of liver extract,202 pollen extract206 and medicinal mushrooms207 reported no beneficial effects.

Poor quality RCTs of melatonin185 and of acetyl-L-carnitine209 reported overall beneficial effects, and a poor quality trial of acclydine and amino acids reported beneficial effects in physiological measures.208

Other

Two controlled trials210, 211 and one high quality RCT of combined treatments showed overall beneficial effects of treatment.215 A controlled trial of a buddy/ mentor programme showed some positive effects.212

It must be noted for most of the interventions the results are based on one or two studies, which may limit the generalisability of the findings. Another factor which may limit the applicability of the findings is the inclusion criteria specified in some trials. For example, in some studies participants were only eligible if they could physically get to the clinic, which implies a certain level of fitness. Those people who were unable to walk or to get out of bed were automatically excluded and so it is not possible to assess whether the interventions investigated would be effective, ineffective or even hazardous for a more severely disabled group of people. However, in many of the trials very limited information was given about participants who were ineligible or indeed about the baseline functioning on many of those who were included. Therefore, it is difficult to extrapolate how the findings might transfer to other people with CFS and/or ME.

Evidence to answer question 4: What are the information needs of healthcare professionals, patients and carers?

Research literature evidence (adults)

Twelve research reports considered the information needs of adult patients with CFS/ME, their carers and healthcare professionals. In addition two guideline documents also contained relevant statements.

All the identified studies used surveys to gather data. The majority were surveys of members of support groups (7 studies) 221–227, in particular Action for ME. A further four studies were in general groups of patients.228–231 One survey of black and ethnic minority adults did not report where respondents were recruited.231 All of the studies were in general agreement that healthcare professionals often lack information regarding CFS/ME. This was also the conclusion of one survey of doctors232 and the two guideline documents.1, 233 The types of information required covered all aspects of CFS in general, including diagnosis, treatment, management and support. Survey respondents also expressed the need for further information in general for patients and carers. Various types (verbal, written, electronic) and sources of information (healthcare professional, support group, internet, leaflets/books, telephone advice lines) were discussed and opinions varied as to which was required. There were, however, no studies with a strong research design evaluating the effectiveness of different types and sources of information.

Empirical studies (adults)

Action for M.E. (2001)221

All the organisation's members (7529) received a survey on their experiences of the health and social services systems. 31% responded. The majority of respondents (65%) received no advice from their GP on managing their illness; 19% received advice within 6 months and 17% after more than 6 months. 41% felt that this lack of information contributed to their illness becoming more severe or chronic.

Action for M.E. (2003)222

Of 1100 randomly selected members who received a questionnaire on 'Your views' or 'Your experiences', 58% responded. A high percentage (85%) considered that the organisation's magazine provided them with useful information. Over 70% of respondents wanted more information on medicines, complementary therapies, symptoms and their management, welfare benefits and practical issues. A high percentage wanted more information on pacing (84%). About two-thirds of respondents felt that the charity should provide more information on graded exercise and cognitive behavioural therapy, although 23% disagreed. Some 90% believed that health professionals should be provided with more information about the illness.

Akid (2002) 228

Information from an article about the Stockport M.E. Outreach Nurse Service was supplemented by information supplied by the service. In a 2004 questionnaire survey of users of the service (76 respondents), 99% had received written information from the nurse; 72% regarded this information as very useful and 28% as quite useful. Prior to contact with the service, 33% reported that they had received significant advice from a medical professional about their illness, while 67% had received no advice. Thirteen respondents rated information from medical professionals as very helpful, 8 as quite helpful and 7 as not helpful. To improve the service, respondents suggested training for consultants, GPs, nurses, social services etc., GPs should be more aware of the service, a video on CFS/ME management techniques/audio tape or CD information, a website and email contact.

Åsbring (2003)232

Semi-structured interviews were carried out with 26 doctors involved in treating patients with CFS (13 doctors) or fibromyalgia. The doctors expressed a need for more information about how to manage patients with CFS and fibromyalgia and pointed out gaps in medical training.

Ax (1997)223

This analysis of interviews with 18 CFS, ME and Post viral fatigue syndrome sufferers highlighted the missing informational support from physicians.

Clarke (2000)224

The author interviewed 60 members of CFS/ME support groups by telephone. Seventy-eight per cent of male respondents and 70% of women regarded a local support group as a reliable source of information, compared with 44% of men and 22% of women who regarded a physician in this way.

Cooper (2000)225

A postal survey of 347 members of ME support groups was carried out to investigate the issues and concerns of CFS/ME sufferers and their carers. Although the authors highlighted a number of limitations, the survey found that advice lines and written resources were the most helpful sources of information. Press articles and web sites were found to be the least helpful.

Deale (2001)229

Sixty-eight patients referred to a specialist fatigue clinic completed a questionnaire survey on medical care since the onset of their illness. The majority of respondents felt that the doctors consulted did not know about CFS (79%) and had not given enough advice about managing CFS (81%). The authors concluded that there is a need for better education and training of doctors in the diagnosis and management of CFS and allied conditions.

Jason (1994)230

984 people with diagnosed CFS/ME responded to a survey on their use of and need for social and health care services. Regular self-help groups providing accurate and up-to-date information were rated as desirable by respondents. Respondents also supported the idea of telephone services providing information about benefits, community resources and peer counselling opportunities. The participants supported providing community members and legislators, as well as the medical community, with information about CFS/ME.

Osborne (2000)231

A series of qualitative interviews with Black and ethnic minority people with ME/CFS (number unknown) was carried out by the SAMEC Trust Research Centre. Although subject to a number of limitations, the study reported a general lack of understanding and knowledge about ME/CFS amongst medical professionals, government agencies and people in general. Respondents highlighted problems in getting advice from medical professionals due to their lack of knowledge. In addition respondents reported that family members did not have access to information about the illness in their own language and often information from support agencies was Eurocentric, based on white middle class experiences.

Schoofs (2004)226

Surveys (n=46) and interviews (n=16) of fibromyalgia and CFS patients in US support groups identified that healthcare providers lack knowledge and require further information and training about FMS/CFS and more information on FMS and CFS is needed in medical and nursing textbooks. The authors identified several study limitations.

Stark (1999)227

Observations of 62 members of a CFS support group in Germany raised concerns about the provision of medical services. This study had a number of limitations, but one of the main findings was that respondents thought there was a lack of physicians who were familiar with CFS. Physicians were criticised for having a substantial deficit of information about CFS.

Guideline statements (adults)

CFS/ME Working Group (2002)1

A report by the UK CFS/ME Working Group in 2002 makes a number of recommendations concerning the information and education needs of healthcare professionals, patients and others. It recommends that healthcare professionals need sufficient knowledge of CFS/ME to enable them to give appropriate and clear advice. The education and training of healthcare professionals should include CFS/ME at a postgraduate level. Also in general, awareness and understanding of the disease needs to be increased among the general public through a variety of sources.

The National Task Force on CFS/ME (1998)233

A UK report by the National Task Force on CFS/ME makes a number of recommendations concerning the information needs of NHS services. Published in 1998 the report recommends that NHS service commissioners and providers should develop and distribute accurate and appropriate information regarding CFS/ME for healthcare professionals, patients and their carers. In addition the report recommends that the NHS Executive should develop a central body of information on CFS/ME.

Research literature evidence (children and adolescents)

There is limited evidence regarding the particular needs of children and adolescents. Only two studies were identified. Both were surveys, one of young people with CFS/ME who were members of AYME (Association of Youth with ME)234 and one of educational professionals.235 In addition one guideline document referred to the information needs of children and adolescents with CFS/ME.236. The publications agreed overall that patients, carers and health professional need more information but what kind and type of information is needed is less clear. However, one set of guidelines236 stated that paediatricians should assist children and adolescents with CFS/ME in finding out more about their condition, as well as being aware of government guidance on education of children with special educational needs. The survey of educational professionals also highlighted the importance of providing information for teachers of students with CFS/ME.235 Studies evaluating the effectiveness of different types of information with strong research designs, however, were not found.

Empirical studies (children and adolescents)

Everett (2002)235

A small (n=12) focus group of UK teachers was studied to ascertain their beliefs and attitudes towards CFS and adolescent students with CFS. The respondents identified a need for teachers and schools to be provided with sound scientific and practical information about CFS. In addition respondents wanted further information from health professionals and others as to how best to support students with CFS.

Tucker (2000)234

This report was based on an analysis of data from questionnaires completed by 474 members of AYME (Association of Youth with ME) and interviews with 27 young people with CFS/ME and 11 parents. The authors concluded that members placed a high value on information services provided by AYME (magazine, annual conference, AYME office and website). Nine percent of questionnaire respondents used the website regularly and 18% did so occasionally. Several survey respondents were unaware of a telephone service on educational advice.

Guideline statements (children and adolescents)

Royal College of Paediatrics and Child Health (2004)236

Evidence-based guidelines by the Royal College of Paediatrics and Child Health published in 2004 make a number of recommendations about the information needs of patients and paediatricians. Paediatricians should assist patients in finding out more about their condition and also discuss information provided by patient support groups to patients. Paediatricians also need to be aware of guidance from the Department for Education and Skills on education for children and young people with medical needs or equivalent statutory guidance.

Evidence to answer question 5: What are the support needs of healthcare professionals, patients and carers?

Research literature evidence (adults)

Fourteen studies provided evidence regarding the support needs of patients with CFS/ME, carers and healthcare professionals. In addition two guideline documents also refer to support needs.

All identified studies were surveys or interviews assessing support needs. Eight studies surveyed the opinions of CFS/ME support group members221–227, 237 in particular Action for ME. A further three surveys used respondents within the community or clinics. 228–230 One study focussed on Black and ethnic minority adults with CFS/ME.231 Only one study examined the support needs of doctors.232 Overall the studies agreed that patients, carers and health professionals need more support. The one survey of health professionals highlighted a need for support from medical colleagues and other relevant professionals such as social workers. Guidelines also support the need for collaborative working.233 Types of support for patients and carers varied and included support from health and social services. In particular help with claiming benefits, and obtaining housing and medical services were reported. Guidelines also recommend that support services should extend to patients family and carers.1 One report included also an evaluation of the effectiveness of a support service using a suitable research design (a sparsely documented before-and-after study of a nurse support service) it did however not assess directly whether the support needs were met.228

Empirical studies (adults)

Action for M.E. (2001)221

All the organisation's members (7529) received a survey on their experiences of the health and social services systems. 31% responded. The majority of respondents (65%) reported receiving no advice from their GP on managing their illness; 41% felt that this contributed to their illness becoming worse. 53% reported that their condition was not regularly monitored by an NHS practitioner. Of the 110 currently bedridden, 50 reported that they are monitored. The majority of respondents (64%) received state benefits; 44% had applied for Disability Living Allowance and of these 44% had to go to appeal and 25% were refused the benefit. The report concluded that statutory agencies are failing to support people with M.E. and that those who are most severely affected receive the least support and care.

Action for M.E. (2003)222

Of 1100 randomly selected members who received a questionnaire on 'Your views' or 'Your experiences', 58% responded. The majority of respondents wanted the organisation to provide more support services such as help-lines, supported its role in campaigning and wanted it to provide more information to health professionals. Just over half of respondents rated their relationship with their GP as supportive. Half of the respondents had seen an NHS specialist about their M.E. in the past 3 years; of these, two-thirds felt that the specialist had a professional approach and that they were listened to.

Akid (2002) 228

Information from an article about the Stockport M.E. Outreach Nurse Service was supplemented by information supplied by the service. In surveys of service users, 98% of respondents in 2002 and 97% in 2004 rated the service as excellent or good. In 2004, 65% of patients said that overall their illness was better than 1 year before, 73% were able to do more, 87% were coping better and 85% were better able to control their symptoms. 24% of respondents had started new paid work, training or voluntary work. The majority of carers reported that they understood the illness better and were more able to give appropriate support. To improve the service, respondents suggested more nurses, more visits and time with patients, a nationwide service, long term funding by the NHS, GPs to refer patients earlier and liaise better, a residential centre for severely affected patients, patient progress calls after initial visits, improved access to counselling, telephone/admin support, dietician links and early interventions. A 1 year follow up of 43 patients showed improvements in fatigue (Chalder fatigue scale), anxiety and depression (HAD) and general health (Nottingham Health Profile).

Åsbring (2003)232

Semi-structured interviews were carried out with 26 doctors involved in treating patients with CFS (13 doctors) or fibromyalgia. The doctors identified a need for more support and supervision from colleagues and other staff. Respondents expressed doubts as to whether doctors are the most suitable professional group to support patients with CFS and related conditions. Other professionals, for example medical social workers and nurses, were thought to have a role in providing support to these patients.

Ax (1997)223

This analysis of interviews with 18 CFS, ME and Post viral fatigue syndrome sufferers highlighted the missing support and dissatisfaction with physicians.

Clarke (2000)224

The author interviewed 60 members of CFS/ME support groups by telephone. Respondents stated that obtaining a diagnosis for their symptoms was difficult and 62% sought a diagnosis from more than three doctors. Seventy-five per cent of participants stated that they had to deal with a 'bad' doctor, whose attitude they considered made their situation worse. Seventy-eight per cent of male respondents and 70% of women regarded a local support group as a reliable source of information, compared with 44% of men and 22% of women who regarded a physician in this way.

Cooper (2000)225

A postal survey of 347 members of ME support groups was carried out to investigate the issues and concerns of CFS/ME sufferers and their carers. Although the authors highlighted a number of limitations, the survey identified difficulties in obtaining benefits and disparities in medical services provided for CFS/ME sufferers. GPs were found to be more helpful than other services, with outpatient clinics second. However, 24% of respondents found their GPs unhelpful.

Deale (2001)229

Sixty-eight patients referred to a specialist fatigue clinic completed a questionnaire survey on medical care since the onset of their illness. The majority of respondents (67% of women and 52% of men) were dissatisfied with their care. Half of respondents rated their doctors' attitudes as sceptical or openly disbelieving, while 41% considered their doctors to be supportive. Most respondents also felt that their diagnosis was not adequately explained (60%) and that doctors were reluctant to arrange tests or referrals (57%).

Hammond (2002)238

This study used data from official statistics and interviews with people with CFS and benefits advisers to assess access to Disability Living Allowance (DLA). Official statistics showed that first awards of DLA to people with CFS were made less often at the initial stage and more often after appeal compared with the general population of claimants. Interview data indicated that people with CFS perceived difficulty in submitting the evidence required to support a claim. Claimants and advisers believed that decisions about claims were often made on the basis of inadequate evidence. The author concluded that access to disability benefits may be more difficult for people with CFS compared with those with disability caused by other conditions.

Heiman (1995)237

A survey questionnaire was distributed to members of CFS support groups in Wisconsin, USA, to assess unmet needs for support services and support for employment. Respondents (119) reported high levels of unmet needs in both areas. The areas rated as highest priority were medical treatment, physician's respect for CFS as a real illness and financial assistance. Factors regarded as most important for supporting employment were reducing stress factors at work, professional assistance in negotiating with employers for accommodation to their needs, assistance with career change, control of environmental conditions and support for working from home. CFS support groups were rated as meeting needs well.

Jason (1994)230

984 people with diagnosed CFS/ME responded to a survey on their use of and need for social and health care services. Respondents identified a number of barriers to accessing services, including low income/lack of affordability and lack of knowledge about available services. No single arrangement for supported housing was preferred by a majority of respondents. Self-help groups able to provide emotional support were perceived as desirable, as was support from volunteers with tasks such as cooking, cleaning and shopping.

Osborne (2000)231

A series of qualitative interviews with Black and ethnic minority people with ME/CFS (number unknown) was carried out by the SAMEC Trust Research Centre. Although subject to a number of limitations, the study reported a lack of support. Respondents reported that support from the medical profession, family and friends was virtually non-existent and no practical support was given from social services. Government agencies were also reported as being reluctant to give benefits (i.e. disability living allowances) due to a lack of knowledge about ME/CFS. Employers were highlighted as being reluctant to allow employees to go on sick leave due to a lack of understanding about the illness.

Schoofs (2004)226

Surveys (n=46) and interviews (n=16) of fibromyalgia and CFS patients in US support groups, identified increased social support, healthcare services, and help with benefits as being of importance. In particular respondents identified a need for healthcare professionals to take FMS and CFS seriously. Respondents felt that nurses were more compassionate than other professionals, but did not have any influence over doctors. In addition support groups were found to be helpful for some but not all respondents and social support from a family member correlated positively with an improved quality of life. The authors identified several study limitations.

Stark (1999)227

Observations of 62 members of a CFS support group in Germany raised concerns about the provision of medical services. Given a number of study limitations one of the major problems identified by respondents was a lack of physicians who were familiar with CFS. Physicians were also criticised for displaying a fundamental scepticism about CFS, providing insufficient time for medical evaluations and failing to display a caring attitude.

Guideline statements (adults)

CFS/ME Working Group (2002)1

A report by the UK CFS/ME Working Group in 2002 recommends that support of patients with CFS/ME should usually extend to the patient's carers and family.

The National Task Force on CFS/ME (1998)233

A UK report by the National Task Force on CFS/ME makes a number of recommendations concerning the support needs of NHS services. Published in 1998 the report recommends that NHS service commissioners and providers should actively encourage training programmes for GPs and the development of local and national networks of interested healthcare professionals and patient representatives. The report also recommends that healthcare professionals and patient/voluntary organisations work together to help and support patients.

Research literature evidence (children and adolescents)

Three research reports provided evidence about the support needs of children and adolescents with CFS/ME, their carers and healthcare professionals. In addition one set of guidelines from the Royal College of Paediatrics and Child Health referred to support needs.

All of the studies were surveys or interviews. One focussed on educational professionals,235 one on children and adolescents belonging to AYME (Association of Youth with ME)234 and another on parents, teachers and doctors of school pupils with CFS/ME.239 The existing publications generally expressed the need for more support for children and adolescents with CFS/ME, their carers, teachers and health professionals. Two of the surveys suggested the possible need for home tuition, but this feeling was not shared by all parties concerned.234, 239 Guidelines from The Royal College of Paediatrics and Child Health 2004236 recommended closer liaisons between paediatricians and schools.

Empirical studies (children and adolescents)

Arzomand (1998)239

A postal survey was carried out in two London schools to explore the Special Educational Needs (SEN) of pupils diagnosed with CFS. Fifty-six questionnaires (out of a total of 104) were included from parents, doctors and educational staff. There were a number of study limitations. Although respondents were generally agreed about SEN arrangements, differences existed on home tuition and physical education (PE). Parents were more against PE (71%) than doctors (14%) and educational staff (11%). Fifty-seven percent of parents felt home tuition was necessary, while only 7% of doctors and 26% of teachers agreed. The majority of respondents felt that the educational needs of children should be met by a combination of SENCO, personal and class tutors.

Everett (2002)235

A small (n=12) focus group of UK teachers was studied to ascertain their beliefs and attitudes towards CFS and adolescent students with CFS. The respondents reported their concern about giving students the right sort of support. The authors detected a feeling of helplessness which pervaded the discussion of the management of pupils with CFS. Some teachers felt that home tuition for adolescents with CFS was the only answer to scarce resources.

Tucker (2000)234

This report was based on an analysis of data from questionnaires completed by 474 members of AYME and interviews with 27 young people with CFS/ME and 11 parents. The majority of respondents received home tuition when too ill to attend school, but this was often limited to 2 or 3 hours per week. The quality of home tuition was rated as variable. Within school, lack of understanding by teachers and the physical layout of school buildings were seen as creating difficulties. Parents viewed LEAs as not very supportive of children with CFS/ME. Medical, educational and psychological support provided by AYME were rated highly, although no quantitative data are provided. The pen pal service, which allows young people with CFS/ME to contact others for friendship and support, was used regularly by 26% of questionnaire respondents and occasionally by 32%.

Guideline statements (children and adolescents)

Royal College of Paediatrics and Child Health (2004)236

Evidence-based guidelines by the Royal College of Paediatrics and Child Health published in 2004 make a number of recommendations about the support of children and young people with CFS/ME. The report recommends that paediatricians need to liaise closely with schools to ensure that education forms part of the management plan. They should liaise where appropriate with the school, family and other educational professionals to initiate early referral to the Educational Welfare Service or ensure an individualised educational plan is implemented and monitored.

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Martin RWY, Ogston SA, Evans JR. Effects of vitamin and mineral supplementation on symptoms associated with chronic fatigue syndrome with Coxsackie B antibodies. Journal of Nutritional Medicine. 1994;4:11–23.
204.
Brouwers FM, Van Der Werf S, Bleijenberg G, Van Der Zee L, Van Der Meer JW. The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial. QJM. 2002;95:677–83. [PubMed: 12324640]
205.
Stewart W, Rowse C. Supplements help ME says Kiwi study. J Altern Complement Med. 1987;5:19–20.
206.
Ockerman PA. Antioxidant treatment of chronic fatigue syndrome. Clinical Practice of Alternative Medicine. 2000;1:88–91.
207.
Walker M. Clinically proven treatment for Chronic fatigue syndrome. RM-10(TM): the newest breakthrough in immune system enhancement - part 3. Townsend Letter for Doctors and Patients. 2002;230:80–5.
208.
De Becker P, Nijs J, Van HE, McGregor N, De MK. A double-blind, placebo-controlled study of acclydine in combination with amino acids in patients with chronic fatigue syndrome. AHMF Proceedings, “Myalgic Encephalopathy/Chronic Fatigue Syndrome ‘The Medical Practitioners’ Challenge in 2001” 2001
209.
Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004;66:276–82. [PubMed: 15039515]
210.
Marlin RG, Anchel H, Gibson JC, Goldberg WM, Swinton M. An evaluation of multidisciplinary intervention for chronic fatigue syndrome with long-term follow-up, and a comparison with untreated controls. Am J Med. 1998;105:110S–14S. [PubMed: 9790492]
211.
Goudsmit E. Learning to cope with post-infectious fatigue syndrome, a follow-up study. Brunel: 1996.
212.
Schlaes J, Jason L. A buddy/ mentor program for PWCs. CFIDS Chronicle. 1996:21–5.
213.
Soderberg S, Evengard B. Short-term group therapy for patients with chronic fatigue syndrome. Psychother Psychosom. 2001;70:108–11. [PubMed: 11244392]
214.
Hobday RA, Thomas SAOD, Murphy M, Pinching AJ. Chronic fatigue syndrome - impact of a low sugar, low yeast diet on fatigue and quality of life - a randomised intervention trial. In press.
215.
Teitelbaum JE, Bird B, Greenfield RM, Weiss A, Muenz L, Gould L. Effective treatment of chronic fatigue syndrome and fibromyalgia- a randomized, double-blind, placebo-controlled, intent-to-treat study. J Chronic Fatigue Syndr. 2001;8:3–28.
216.
Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res. 1997;31:133–47. [PubMed: 9201655]
217.
Viner R, Gregorowski A, Wine C, Bladen M, Fisher D, Miller M, et al. Outpatient rehabilitative treatment of chronic fatigue syndrome (CFS/ME). Arch Dis Child. 2004;89:615–9. [PMC free article: PMC1719984] [PubMed: 15210489]
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Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ. 2005;330:14. [PMC free article: PMC539840] [PubMed: 15585538]
219.
Hoad A. Coming to terms with ME. Health Visit. 1994;67:302–3. [PubMed: 7960845]
220.
Dimitrov M, Grafman J. Neuropsychological assessment of chronic fatigue syndrome. J Chronic Fatigue Syndr. 1997;3:31–42.
221.
Action for M.E, Severely neglected: M.E. in the UK - membership survey. London: Action for M.E.; 2001.
222.
Action for M.E, Member survey: your view and your experiences [unpublished] London: Action for M.E.; 2003.
223.
Ax S, Gregg VH, Jones D. Chronic fatigue syndrome: Sufferers’ evaluation of medical support. J R Soc Med. 1997;90:250–54. [PMC free article: PMC1296257] [PubMed: 9204018]
224.
Clarke JN. The search for legitimacy and the “expertization” of the lay person: the case of chronic fatigue syndrome. Soc Work Health Care. 2000;30:73–93. [PubMed: 10880009]
225.
Cooper L. Report on survey of members of local ME groups [unpublished] 2000.
226.
Schoofs N, Bambini D, Ronning P, Bielak E, Woehl J. Death of a lifestyle: the effects of social support and healthcare support on the quality of life of persons with fibromyalgia and/or chronic fatigue syndrome. Orthop Nurs. 2004;23:364–74. [PubMed: 15682879]
227.
Stark FM, Sobetzko HM. Approaches to coping with chronic fatigue syndrome (CFS). Zentralbl Hyg Umweltmed. 1999;202:179–90. [PubMed: 10507127]
228.
Akid M. Myalgic encephalomyelitis. Gold standard care. Nurs Times. 2002;98:10–1. [PubMed: 12219451]
229.
Deale A, Wessely S. Patients’ perceptions of medical care in chronic fatigue syndrome. Soc Sci Med. 2001;52:1859–64. [PubMed: 11352411]
230.
Jason L, Slavich S, Taylor R, Ferrari J, Stenzel C. Toward an understanding of service and housing needs of people with CFIDS. The CFIDS Chronicle. 1994:10–11.
231.
Osborne V, Khan S. Experiences of black and ethnic minorities with ME and CFS [unpublished] London: The SAMEC Trust; 2000.
232.
Asbring P, Narvanen AL. Ideal versus reality: physicians perspectives on patients with chronic fatigue syndrome (CFS) and fibromyalgia. Soc Sci Med. 2003;57:711–20. [PubMed: 12821018]
233.
National Task Force on CFS/ME. NHS services for people with chronic fatigue syndrome. Bristol: Westcare; 1998.
234.
Tucker S, Tatum C. Speaking Up: An Examination of the Experiences of Children and Young People with ME. Milton Keynes: Association of youth with ME; 2000.
235.
Everett T, Fulton C. An exploration of secondary school teachers’ beliefs and attitudes about adolescent children with chronic fatigue syndrome. Support for Learning. 2002;17:27–33.
236.
Royal College of Paediatrics and Child Health. Evidence based guideline for the management of CFS/ME (chronic fatigue syndrome/myalgic encephalopathy) in children and young people. London: Royal College of Paediatrics and Child Health; 2004.
237.
Heiman TH. Chronic fatigue syndrome and vocational rehabilitation: unserved and unmet needs. Clinical management of chronic fatigue syndrome: Clinical Conference, American Association of Chronic Fatigue Syndrome. Klimas NG, Levine PH, Patarca R, editors. New York: Haworth Medical Press; 1995. pp. 105–18.
238.
Hammond C. A poorly understood condition: disability living allowance and people with CFS/ME. Social Policy & Administration. 2002;36:254–74.
239.
Arzomand ML. Chronic fatigue syndrome among school children and their special educational needs. J Chronic Fatigue Syndr. 1998;4:59–69.
240.
Shor S. Pathogenesis of chronic fatigue syndrome, a multisystem hypothesis. J Chronic Fatigue Syndr. 2003;11:51–68.

Appendix 1. Literature search strategies

The following databases were searched, no limits were imposed. The results were then imported to individual Endnote libraries for appraising.

DatabaseDate searchedNumber of hits
AMED24/08/051281
Cochrane Library CENTRAL09/05/054666
Embase25/04/052513
HEED01/06/050
Inside Conferences11/05/05203
Medline25/04/056318
Medline (economic searches)01/06/0561
NHSEED01/06/050
PASCAL11/05/051065
PsycINFO26/04/051195
SSCI26/04/051279

AMED (1985 – April 2005), Ovid

Searched 26/04/05

  1. Fatigue Syndrome, Chronic/
  2. chronic fatigue syndrome.ti,ab.
  3. myalgic encephalomyelitis.ti,ab.
  4. akureyri disease$.ti,ab.
  5. chronic epstein barr virus.ti,ab.
  6. cfids.ti,ab.
  7. (chronic fatigue and immune dysfunction syndrome$).ti,ab.
  8. chronic mononucleosis.ti,ab.
  9. effort syndrome$.ti,ab.
  10. iceland$ disease$.ti,ab.
  11. low natural killer cell syndrome$.ti,ab.
  12. neuromyasthenia.ti,ab.
  13. post viral fatigue syndrome$.ti,ab.
  14. postviral fatigue syndrome$.ti,ab.
  15. post viral syndrome$.ti,ab.
  16. postviral syndrome$.ti,ab.
  17. post infectious fatigue.ti,ab.
  18. postinfectious fatigue.ti,ab.
  19. raggedy ann$ syndrome$.ti,ab.
  20. royal free disease$.ti,ab.
  21. royal free epidemic$.ti,ab.
  22. royal free hospital disease$.ti,ab.
  23. tapanui disease$.ti,ab.
  24. yuppie flu.ti,ab.
  25. yuppy flu.ti,ab.
  26. chronic infectious mononucleosis like syndrome$.ti,ab.
  27. ME.ti.
  28. CFS.ti,ab.
  29. myalgic encephalopathy.ti,ab.
  30. or/1–29

1281 records were retrieved.

Cochrane Library, CENTRAL, ( 2005 Issue2 )

http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME

Searched 09/05/05

  • 1 MeSH descriptor Fatigue Syndrome, Chronic explode all trees in MeSH products
  • #2 “myalgic encephalomyelitis” in Record Title or “myalgic encephalomyelitis” in Abstract
  • #3 chronic fatigue syndrome in Record Title or chronic fatigue syndrome in Abstract
  • #4 biography in Publication Type
  • #5 duplicate-publication in Publication Type
  • #6 historical-article in Publication Type
  • #7 interview in Publication Type
  • #8 retraction-of-publication in Publication Type
  • #9 cases in Publication Type
  • #10 (#1 OR #2 OR #3)
  • #11 (#4 OR #5 OR #6 OR #7 OR #8 OR #9)
  • #12 (#10 AND NOT #11)
  • #13 “akureyri disease*” in Record Title or “akureyri disease*” in Abstract
  • #14 “chronic epstein barr virus” in Record Title or “chronic epstein barr virus” in Abstract
  • #15 “cfids” in Record Title or “cfids” in Abstract
  • #16 (chronic fatigue and immune dysfunction syndrome*) in Record Title or (chronic fatigue and immune dysfunction syndrome*) in Abstract
  • #17 (chronic mononucleosis) in Record Title or (chronic mononucleosis) in Abstract
  • #18 “effort syndrome*” in Record Title or “effort syndrome*” in Abstract
  • #19 (iceland* next disease*) in Record Title or (iceland* next disease*) in Abstract
  • #20 (low next natural next killer next cell next syndrome*) in Record Title or (low next natural next killer next cell next syndrome*) in Abstract
  • #21 neuromyasthenia in Record Title or neuromyasthenia in Abstract
  • #22 (post next viral next fatigue next syndrome) in Record Title or (post next viral next fatigue next syndrome) in Abstract
  • #23 (postviral next fatigue next syndrome*) in Record Title or (postviral next fatigue next syndrome*) in Abstract
  • #24 (post next viral next syndrome*) in Record Title or (post next viral next syndrome*) in Abstract
  • #25 (postviral next syndrome*) in Record Title or (postviral next syndrome*) in Abstract
  • #26 (post next infectious next fatigue) in Record Title or (post next infectious next fatigue) in Abstract,
  • #27 (postinfectious next fatigue) in Record Title or (postinfectious next fatigue) in Abstract
  • #28 (raggedy next ann* next syndrome*) in Record Title or (raggedy next ann* next syndrome*) in Abstract
  • #29 (royal next free next disease*) in Record Title or (royal next free next disease*) in Abstract
  • #30 (royal next free next epidemic*) in Record Title or (royal next free next epidemic*) in Abstract
  • #31 (royal next free next hospital next disease*) in Record Title or (royal next free next hospital next disease*) in Abstract
  • #32 (tapanui next disease*) in Record Title or (tapanui next disease*) in Abstract
  • #33 “yuppie flu” in Record Title or “yuppie flu” in Abstract
  • #34 “yuppy flu” in Record Title or “yuppy flu” in Abstract
  • #35 (chronic next infectious next mononucleosis next like next syndrome*) in Record Title or (chronic next infectious next mononucleosis next like next syndrome*) in Abstract
  • #36 (ME) in Record Title
  • #37 (CFS) in Record Title or (CFS) in Abstract
  • #38 (myalgic next encephalopathy) in Record Title or (myalgic next encephalopathy) in Abstract
  • #39 (#13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24)
  • #40 (#25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38)
  • #41 (#39 OR #40)
  • #42 (#41 AND NOT #11)
  • #43 (#42 OR #12)
  • 4,666 records were retrieved

Embase (1980 – 2005 Week 17), Ovid

Searched 25/04/05

  1. Fatigue Syndrome, Chronic/
  2. chronic fatigue syndrome.ti,ab.
  3. myalgic encephalomyelitis.ti,ab.
  4. akureyri disease$.ti,ab.
  5. chronic epstein barr virus.ti,ab.
  6. cfids.ti,ab.
  7. (chronic fatigue and immune dysfunction syndrome$).ti,ab.
  8. chronic mononucleosis.ti,ab.
  9. effort syndrome$.ti,ab.
  10. iceland$ disease$.ti,ab.
  11. low natural killer cell syndrome$.ti,ab.
  12. neuromyasthenia.ti,ab.
  13. post viral fatigue syndrome$.ti,ab.
  14. postviral fatigue syndrome$.ti,ab.
  15. post viral syndrome$.ti,ab.
  16. postviral syndrome$.ti,ab.
  17. post infectious fatigue.ti,ab.
  18. postinfectious fatigue.ti,ab.
  19. raggedy ann$ syndrome$.ti,ab.
  20. royal free disease$.ti,ab.
  21. royal free epidemic$.ti,ab.
  22. royal free hospital disease$.ti,ab.
  23. tapanui disease$.ti,ab.
  24. yuppie flu.ti,ab.
  25. yuppy flu.ti,ab.
  26. chronic infectious mononucleosis like syndrome$.ti,ab.
  27. ME.ti.
  28. CFS.ti,ab.
  29. myalgic encephalopathy.ti,ab.
  30. or/1–29

5213 records were retrieved

HEED (June 2005)

Searched 01/06/05

  • TI=chronic fatigue syndrome
  • AB=chronic fatigue syndrome
  • TI=myalgic encephalomyelitis
  • AB=myalgic encephalomyelitis
  • TI=akureyri disease*
  • AB=akureyri disease*
  • TI=chronic epstein barr virus
  • AB=chronic epstein barr virus
  • TI=CFIDS
  • AB=CFIDS
  • CS=1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or10
  • TI=(chronic fatigue and immune dysfunction syndrome*)
  • AB=(chronic fatigue and immune dysfunction syndrome*)
  • TI=chronic mononucleosis
  • AB=chronic mononucleosis
  • TI=effort syndrome*
  • AB=effort syndrome*
  • TI=iceland* disease*
  • AB=iceland* disease*
  • TI=low natural killer cell syndrome*
  • AB=low natural killer cell syndrome*
  • CS=12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21
  • CS=11 or 22
  • TI=neuromyasthenia
  • AB=neuromyasthenia
  • TI=post viral fatigue syndrome*
  • AB=post viral fatigue syndrome*
  • TI=postviral fatigue syndrome*
  • AB=postviral fatigue syndrome*
  • TI=post viral syndrome*
  • AB=post viral syndrome*
  • TI=postviral syndrome*
  • AB=postviral syndrome*
  • TI=post infectious fatigue
  • AB=post infectious fatigue
  • TI=postinfectious fatigue
  • AB=postinfectious fatigue
  • TI=raggedy ann* syndrome*
  • AB=raggedy ann* syndrome*
  • TI=royal free disease*
  • AB=royal free disease*
  • CS=24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45
  • CS=46 or 23
  • TI=royal free epidemic*
  • AB=royal free epidemic*
  • TI=royal free hospital disease*
  • AB=royal free hospital disease*
  • TI=tapanui disease*
  • AB=tapanui disease*
  • TI=yuppie flu
  • AB=yuppie flu
  • TI=yuppy flu
  • AB=yuppy flu
  • TI=chronic infectious mononucleosis like syndrome*
  • AB=chronic infectious mononucleosis like syndrome*
  • TI=CFS
  • TI=myalgic encephalopathy
  • AB=myalgic encephalopathy
  • CS=48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58
  • CS=59 or 47
  • 0 records were retrieved

Inside Conferences, Dialog

Searched 11/05/05

  1. (CHRONIC(W)FATIGUE(W)SYNDROME)/TI,AB
  2. (MYALGIC(W)ENCEPHALOMYELITIS)/TI,AB
  3. (AKUREYRI(W)DISEASE?)/TI,AB
  4. (CHRONIC(W)EPSTEIN(W)BARR(W)VIRUS)/TI,AB
  5. CFIDS/TI,AB
  6. (CHRONIC(W)FATIGUE(3W)IMMUNE(W)DYSFUNCTION(W)SYNDROME?)/TI,AB
  7. (CHRONIC(W)MONONUCLEOSIS)/TI,AB
  8. (EFFORT(W)SYNDROME?)/TI,AB
  9. (ICELAND?(W)DISEASE?)/TI,AB
  10. (LOW(W)NATURAL(W)KILLER(W)CELL(W)SYNDROME?)/TI,AB
  11. NEUROMYASTHENIA/TI,AB
  12. (POST(W)VIRAL(W)FATIGUE(W)SYNDROME?)/TI,AB
  13. (POSTVIRAL(W)FATIGUE(W)SYNDROME?)/TI,AB
  14. (POST(W)VIRAL(W)SYNDROME?)/TI,AB
  15. (POSTVIRAL(W)SYNDROME?)/TI,AB
  16. (POST(W)INFECTIOUS(W)FATIGUE)/TI,AB
  17. (POSTINFECTIOUS(W)FATIGUE)/TI,AB
  18. (RAGGEDY(W)ANN? (W)SYNDROME?)/TI,AB
  19. (ROYAL(W)FREE(W)DISEASE?)/TI,AB
  20. (ROYAL(W)FREE(W)EPIDEMIC?)/TI,AB
  21. (ROYAL(W)FREE(W)HOSPITAL(W)DISEASE?)/TI,AB
  22. (TAPANUI(W)DISEASE?)/TI,AB
  23. (YUPPIE(W)FLU)/TI,AB
  24. YUPPY(W)FLU)/TI,AB
  25. (CHRONIC(W)INFECTIOUS(W)MONONUCLEOSIS(W)LIKE(W)SYNDROME?)/TI,AB
  26. (MYALGIC(W)ENCEPHALOPATHY)/TI,AB
  27. S1:S26
  28. RD S27

203 records were retrieved

Medline (1966 – April Week 2 2005), Ovid

Searched 25/04/05

  1. Fatigue Syndrome, Chronic/
  2. chronic fatigue syndrome.ti,ab.
  3. myalgic encephalomyelitis.ti,ab.
  4. or/1–3
  5. biography.pt.
  6. duplicate-publication.pt.
  7. historical-article.pt.
  8. interview.pt.
  9. retraction-of-publication.pt.
  10. cases.pt.
  11. or/5–10
  12. 4 not 11
  13. akureyri disease$.ti,ab.
  14. chronic epstein barr virus.ti,ab.
  15. cfids.ti,ab.
  16. (chronic fatigue and immune dysfunction syndrome$).ti,ab.
  17. chronic mononucleosis.ti,ab.
  18. effort syndrome$.ti,ab.
  19. iceland$ disease$.ti,ab.
  20. low natural killer cell syndrome$.ti,ab.
  21. neuromyasthenia.ti,ab.
  22. post viral fatigue syndrome$.ti,ab.
  23. postviral fatigue syndrome$.ti,ab.
  24. post viral syndrome$.ti,ab.
  25. postviral syndrome$.ti,ab.
  26. post infectious fatigue.ti,ab.
  27. postinfectious fatigue.ti,ab.
  28. raggedy ann$ syndrome$.ti,ab.
  29. royal free disease$.ti,ab.
  30. royal free epidemic$.ti,ab.
  31. royal free hospital disease$.ti,ab.
  32. tapanui disease$.ti,ab.
  33. yuppie flu.ti,ab.
  34. yuppy flu.ti,ab.
  35. chronic infectious mononucleosis like syndrome$.ti,ab.
  36. ME.ti.
  37. CFS.ti,ab.
  38. myalgic encephalopathy.ti,ab.
  39. or/13–38
  40. 4 or 39
  41. 40 not 11

6318 records were retrieved.

Medline (1966 – Week 3 May 2005), Ovid

Searched 01/06/05

Economic searches
  1. Fatigue Syndrome, Chronic/
  2. chronic fatigue syndrome.ti,ab.
  3. myalgic encephalomyelitis.ti,ab.
  4. or/1–3
  5. biography.pt.
  6. duplicate-publication.pt.
  7. historical-article.pt.
  8. interview.pt.
  9. retraction-of-publication.pt.
  10. cases.pt.
  11. or/5–10
  12. 4 not 11
  13. akureyri disease$.ti,ab.
  14. chronic epstein barr virus.ti,ab.
  15. cfids.ti,ab.
  16. (chronic fatigue and immune dysfunction syndrome$).ti,ab.
  17. chronic mononucleosis.ti,ab.
  18. effort syndrome$.ti,ab.
  19. iceland$ disease$.ti,ab.
  20. low natural killer cell syndrome$.ti,ab.
  21. neuromyasthenia.ti,ab.
  22. post viral fatigue syndrome$.ti,ab.
  23. postviral fatigue syndrome$.ti,ab.
  24. post viral syndrome$.ti,ab.
  25. postviral syndrome$.ti,ab.
  26. post infectious fatigue.ti,ab.
  27. postinfectious fatigue.ti,ab.
  28. raggedy ann$ syndrome$.ti,ab.
  29. royal free disease$.ti,ab.
  30. royal free epidemic$.ti,ab.
  31. royal free hospital disease$.ti,ab.
  32. tapanui disease$.ti,ab.
  33. yuppie flu.ti,ab.
  34. yuppy flu.ti,ab.
  35. chronic infectious mononucleosis like syndrome$.ti,ab.
  36. CFS.ti,ab.
  37. myalgic encephalopathy.ti,ab.
  38. economics/
  39. exp “COSTS AND COST ANALYSIS”/
  40. economics,dental/
  41. “VALUE OF LIFE”/
  42. exp ECONOMICS, HOSPITAL/
  43. economics, medical/
  44. economics, nursing/
  45. economics, pharmaceutical/
  46. or/38–45
  47. (econom$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).tw.
  48. (expenditure$ not energy).tw.
  49. (value adj1 money).tw.
  50. budget$.tw.
  51. or/47–50
  52. 46 or 51
  53. letter.pt.
  54. editorial.pt.
  55. historical article.pt.
  56. or/53–55
  57. 52 not 56
  58. animal/
  59. Humans/
  60. 58 not (58 and 59)
  61. 57 not 60
  62. (metabolic adj cost).ti,ab,sh.
  63. ((energy or oxygen) adj cost).ti,ab,sh.
  64. 61 not (62 or 63)
  65. or/12–37
  66. 64 and 65

61 records were retrieved.

NHSEED (1995 – 2005), Cairs B

Searched 01/06/05

  • s chronic w fatigue w syndrome
  • s myalgic w encephalomyelitis
  • s akureyri w disease*
  • s chronic w epstein w barr w virus
  • s CFIDS
  • s (chronic w fatigue) and (immune w dysfunction w syndrome*)
  • s chronic w mononucleosis
  • s effort w syndrome*
  • s iceland* w disease*
  • s low w natural w killer w cell w syndrome*
  • s neuromyasthenia
  • s post w viral w fatigue w syndrome*
  • s postviral w fatigue w syndrome*
  • s post w viral w syndrome*
  • s postviral w syndrome*
  • s post w infectious w fatigue
  • s postinfectious w fatigue
  • s raggedy w ann* w syndrome*
  • s royal w free w disease*
  • s royal w free w epidemic*
  • s royal w free w hospital w disease*
  • s tapanui w disease*
  • s yuppie w flu
  • s yuppy w flu
  • s chronic w infectious w mononucleosis w like w syndrome*
  • s CFS
  • s myalgic w encephalopathy
  • s 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 29 or 21 or 22 or 23 or 24 or 25 or 26 or 27
  • 0 records were retrieved.

PASCAL, Dialog

Searched 11/05/05

  1. (CHRONIC(W)FATIGUE(W)SYNDROME)/TI,AB
  2. (MYALGIC(W)ENCEPHALOMYELITIS)/TI,AB
  3. (AKUREYRI(W)DISEASE?)/TI,AB
  4. (CHRONIC(W)EPSTEIN(W)BARR(W)VIRUS)/TI,AB
  5. CFIDS/TI,AB
  6. (CHRONIC(W)FATIGUE(3W)IMMUNE(W)DYSFUNCTION(W)SYNDROME?)/TI,AB
  7. (CHRONIC(W)MONONUCLEOSIS)/TI,AB
  8. (EFFORT(W)SYNDROME?)/TI,AB
  9. (ICELAND?(W)DISEASE?)/TI,AB
  10. (LOW(W)NATURAL(W)KILLER(W)CELL(W)SYNDROME?)/TI,AB
  11. NEUROMYASTHENIA/TI,AB
  12. (POST(W)VIRAL(W)FATIGUE(W)SYNDROME?)/TI,AB
  13. (POSTVIRAL(W)FATIGUE(W)SYNDROME?)/TI,AB
  14. (POST(W)VIRAL(W)SYNDROME?)/TI,AB
  15. (POSTVIRAL(W)SYNDROME?)/TI,AB
  16. (POST(W)INFECTIOUS(W)FATIGUE)/TI,AB
  17. (POSTINFECTIOUS(W)FATIGUE)/TI,AB
  18. (RAGGEDY(W)ANN? (W)SYNDROME?)/TI,AB
  19. (ROYAL(W)FREE(W)DISEASE?)/TI,AB
  20. (ROYAL(W)FREE(W)EPIDEMIC?)/TI,AB
  21. (ROYAL(W)FREE(W)HOSPITAL(W)DISEASE?)/TI,AB
  22. (TAPANUI(W)DISEASE?)/TI,AB
  23. (YUPPIE(W)FLU)/TI,AB
  24. YUPPY(W)FLU)/TI,AB
  25. (CHRONIC(W)INFECTIOUS(W)MONONUCLEOSIS(W)LIKE(W)SYNDROME?)/TI,AB
  26. (MYALGIC(W)ENCEPHALOPATHY)/TI,AB
  27. S1:S26
  28. RD S27

1065 records were retrieved.

PsycINFO (1872 – 2005/04 Week 2), WebSPIRS

Searched 26/04/05

  • #33 #30 or #31 or #32
  • #32 #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29
  • #31 #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
  • #30 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
  • #29 ((myalgic encephalopathy)in AB) or ((myalgic encephalopathy)in TI)
  • #28 ((CFS)in AB) or ((CFS)in TI)
  • #27 ((chronic infectious mononucleosis like syndrome*)in AB) or ((chronic infectious mononucleosis like syndrome*)in TI)
  • #26 ((yuppy flu)in AB) or ((yuppy flu)in TI)
  • #25 ((yuppie flu)in AB) or ((yuppie flu)in TI)
  • #24 ((tapanui disease*)in AB) or ((tapanui disease*)in TI)
  • #23 ((royal free hospital disease*)in AB) or ((royal free hospital disease*)in TI)
  • #22 ((royal free epidemic*)in AB) or ((royal free epidemic*)in TI)
  • #21 ((royal free disease*) in AB) or ((royal free disease*)in TI)
  • #20 ((raggedy ann* syndrome*) in AB) or ((raggedy ann* syndrome*) in TI)
  • #19 ((postinfectious fatigue)in AB) or ((postinfectious fatigue)in TI)
  • #18 ((post infectious fatigue)in AB) or ((post infectious fatigue)in TI)
  • #17 ((post viral syndrome*)in AB) or ((post viral syndrome*)in TI)
  • #16 ((postviral syndrome*)in AB) or ((postviral syndrome*)in TI)
  • #15 ((postviral fatigue syndrome*)in AB) or ((postviral fatigue syndrome*)in TI)
  • #14 ((post viral fatigue syndrome*)in AB) or ((post viral fatigue syndrome*)in TI)
  • #13 ((neuromyasthenia)in AB) or ((neuromyasthenia)in TI)
  • #12 ((low natural killer cell syndrome*)in AB) or ((low natural killer cell syndrome*)in TI)
  • #11 ((iceland* disease*) in AB) or ((iceland* disease*) in TI)
  • #10 ((effort syndrome*) in AB) or ((effort syndrome*) in TI)
  • #9 ((chronic mononucleosis) in AB) or ((chronic mononucleosis) in TI)
  • #8 ((chronic fatigue and immune dysfunction syndrome*) in AB) or ((chronic fatigue and immune dysfunction syndrome*) in TI)
  • #7 ((cfids)in AB) or ((cfids)in TI)
  • #6 ((chronic epstein barr virus) in AB) or ((chronic epstein barr virus)in TI)
  • #5 ((akureyri disease*) in AB) or ((akureyri disease*) in TI)
  • #4 ((myalgic encephalomyelitis) in AB) or ((myalgic encephalomyelitis) in TI)
  • #3 ((myalgic encephalomyelitis) in AB) or ((myalgic encephalomyelitis) in TI)
  • #2 CHRONIC-FATIGUE-SYNDROME
  • #1 ( (chronic fatigue syndrome) in AB )or( (chronic fatigue syndrome) in TI )
  • 1195 records retrieved.

Science Citation Index (1945 – 2005), ISI Web of Knowledge

Searched 26/06/05

  • TI=chronic fatigue syndrome or TS= chronic fatigue syndrome
  • TI= myalgic encephalomyelitis or TS= myalgic encephalomyelitis
  • (TI=akureyri disease* or TS=akureyri disease*)
  • (TI=chronic epstein barr virus or TS=chronic epstein barr virus)
  • (TI=cfids or TS=cfids)
  • (TI=(chronic fatigue and immune dysfunction syndrome*) or TS=(chronic fatigue and immune dysfunction syndrome*))
  • (TI=chronic mononucleosis or TS=chronic mononucleosis)
  • (TI=effort syndrome* or TS=effort syndrome*)
  • (TI=iceland* disease* or TS=iceland* disease*)
  • (TI=low natural killer cell syndrome* or TS=low natural killer cell syndrome*)
  • (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10)
    • (TI=neuromyasthenia or TS=neuromyasthenia)
    • (TI=post viral fatigue syndrome* or TS=post viral fatigue syndrome*)
    • (TI=postviral fatigue syndrome* or TS= postviral fatigue syndrome*)
    • (TI= post viral syndrome* or TS=post viral syndrome*)
    • (TI=postviral syndrome* or TS=postviral syndrome*)
    • (TI=post infectious fatigue or TS=post infectious fatigue)
    • (#23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33)
    • (TI=postinfectious fatigue or TS= postinfectious fatigue)
    • (TI=raggedy ann* syndrome* or TS= raggedy ann* syndrome*)
    • (TI=royal free disease* or TS=royal free disease*)
    • (TI=royal free epidemic* or TS=royal free epidemic*)
    • (#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
    • (TI=royal free hospital disease* or TS=royal free hospital disease*)
    • (TI=tapanui disease* or TS=tapanui disease*)
    • (TI= yuppie flu or TS= yuppie flu)
    • (TI=yuppy flu or TS=yuppy flu)
    • (TI=(chronic infectious mononucleosis like syndrome*) or TS=(chronic infectious mononucleosis like syndrome*))
    • (TI=CFS or TS=CFS)
    • (TI=myalgic encephalopathy or TS=myalgic encephalopathy)
    • (#23 or #24 or #25 or #26 or #27 or #28 or #29 or #30)
    • (#11 or #22 or #31)

1279 records retrieved. This search was run without using ME as a search term as this skewed the results by including titles with “me” in not just ME. In most cases a paper about ME would include one of the other terms for ME as well so it is not anticipated that any major papers were missed.

Social Science Citation Index (1945–2005), ISI Web of Knowledge

Searched 03/05/05

  • #31 (#11 or #22 or #30)
  • #30 (#23 or #24 or #25 or #26 or #27 or #28 or #29)
  • #29 (TI=myalgic encephalopathy or TS=myalgic encephalopathy)
  • #28 (TI=CFS or TS=CFS)
  • #27 (TI=(chronic infectious mononucleosis like syndrome*) or TS=(chronic infectious mononucleosis like syndrome*))
  • #26 (TI=yuppy flu or TS=yuppy flu)
  • #25 (TI=yuppie flu or TS=yuppie flu)
  • #24 (TI=tapanui disease* or TS=tapanui disease*)
  • #23 (TI=royal free hospital disease* or TS=royal free hospital disease*)
  • #22 (#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
  • #21 (TI=royal free epidemic* or TS=royal free epidemic*)
  • #20 (TI=royal free disease* or TS=royal free disease*)
  • #19 (TI=raggedy ann* syndrome* or TS=raggedy ann* syndrome*)
  • #18 (TI=postinfectious fatigue or TS=postinfectious fatigue)
  • #17 (TI=postviral syndrome* or TS=postviral syndrome*)
  • #16 (TI=post infectious fatigue or TS=post infectious fatigue)
  • #15 (TI=post viral syndrome* or TS=post viral syndrome*)
  • #14 (TI=postviral fatigue syndrome* or TS=postviral fatigue syndrome*)
  • #13 (TI=post viral fatigue syndrome* or TS=post viral fatigue syndrome*)
  • #12 (TI=neuromyasthenia or TS=neuromyasthenia)
  • #11 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10)
  • #10 (TI=low natural killer cell syndrome* or TS=low natural killer cell syndrome*)
  • #9 (TI=iceland* disease* or TS=iceland* disease*)
  • #8 (TI=effort syndrome* or TS=effort syndrome*)
  • #7 (TI=chronic mononucleosis or TS=chronic mononucleosis)
  • #6 (TI=(chronic fatigue and immune dysfunction syndrome*) or TS=(chronic fatigue and
  • #5 (TI=cfids or TS=cfids)
  • #4 (TI=chronic epstein barr virus or TS=chronic epstein barr virus)
  • #3 (TI=akureyri disease* or TS=akureyri disease*)
  • #2 TI=myalgic encephalomyelitis or TS=myalgic encephalomyelitis
  • #1 TI=chronic fatigue syndrome or TS=chronic fatigue syndrome
  • 691 records retrieved. This search was run without using ME as a search term as this skewed the results by including titles with “me” in not just ME. In most cases a paper about ME would include one of the other terms for ME as well so it is not anticipated that any major papers were missed.

Appendix 2. Data extraction Tables for Question 1

Validation of case definition

Appendix 3. Data Extraction Tables for Question 2

Question 2

Appendix 4. Data extraction tables for subquestion 2

Subquestion 2

Appendix 6. Validity Assessment for Question 3

a. RCTs

b. Controlled trials

Appendix 7. Data extraction tables for Question 4

Information needs

Appendix 8. Data extraction tables for Question 5

Support needs

Copyright © 2007, Royal College of General Practitioners.
Cover of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy)
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children [Internet].
NICE Clinical Guidelines, No. 53.
National Collaborating Centre for Primary Care (UK).

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