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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.)

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Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children [Internet].

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5Making a diagnosis of CFS/ME

5.1. Introduction

CFS/ME is a condition for which causation is uncertain and diagnostic criteria variable. Although a diagnosis of CFS/ME is straightforward in many cases, in others, reaching a diagnosis can be a particular problem, for a number of reasons.

  • The onset may be relatively sudden or gradual, following a physical illness or stressful event, or apparently ‘out of the blue’.
  • The range of presenting symptoms is wide, and fatigue and pain may not always be the prominent disabling features at initial presentation.
  • Patients may have been investigated extensively, but fruitlessly, for varied physical symptoms and may feel frustrated by the lack of help received from the medical profession by the time the diagnosis is made.
  • Symptoms tend to vary in intensity and type over a period of weeks or months (and evolve into what is more clearly CFS/ME with time), leading to uncertainty for both the patient and clinician about the course and nature of the underlying problem.
  • CFS/ME cannot be diagnosed by any test currently available.

However, clinicians can use pattern recognition to facilitate the diagnosis process. The diagnosis depends on recognition of a characteristic set of symptoms (see recommendations), appropriately classified according to type/range and by the affecting factors.

It is important to explore the nature of the fatigue (as with other symptoms), because the patient will then be able to clarify how different this experience is from everyday fatigue or fatigue associated with some other conditions.

A positive provisional diagnosis is most likely to be achieved by setting aside sufficient time to characterise the history upon which a diagnosis depends, and to recognise characteristic features, such as delayed symptoms (fatigue and malaise) after over-activity.

Consequently, diagnosis rests on the alertness of the clinician to the possibility of CFS/ME and a systematic approach to history-taking, examination and observation, assisted by the use of various investigations to rule out the possibility of other conditions.

Investigations have a particularly important role in ruling out the presence of alternative diseases. The patient is likely to be justifiably worried, and the clinician should investigate any symptoms that may indicate the presence of other serious conditions. ‘Red flags’ in the history and examination indicate the need for urgent specialised investigation.

Observation, over a limited period of time, in those patients with suggestive clinical features and negative investigations forms part of the process of diagnosis. This is needed to determine whether the condition meets diagnostic criteria for CFS/ME, or whether it is some self-limiting condition. Of course, should new symptoms develop, particularly ‘red flags’, the working diagnosis must be reviewed and further investigations instituted.

5.1.1. Key clinical question 2

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

5.1.2. Evidence statements

5.1.2.1There is insufficient evidence to show that potential diagnostic tests for CFS/ME are useful diagnostically for adults and children. Specific diagnostic tests reviewed are:

the head-up tilt test (Evidence level II and III)

five laboratory blood tests (fibrinogen, prothrombin fragment 1 + 2, thrombin–anti-thrombin complexes, soluble fibrin monomer (SFM) and platelet activation (CD62P, ADP)) (Evidence level III)

auditory brainstem responses (Evidence level III)

electrodermal conductivity (Evidence level III).

5.1.2.2Evaluations of potential diagnostic tests for CFS/ME in children are of very limited validity (Evidence level III and IV).

5.1.3. Key clinical 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?

5.1.4. Evidence statements

5.1.4.1Clear risk factors for CFS/ME have not been identified (Evidence level 2−).
5.1.4.2Clear risk factors for development of CFS/ME in children and young people have not been identified (Evidence level 2−).

5.1.5. Clinical evidence summary

5.1.5.1. Summary of evidence presented in Appendix 1

The studies reviewed for question 2 assessed the utility of potential diagnostic tests. Of the 27 studies that met the inclusion criteria, only six were not of a low quality (level 3 or 4, where there was a higher risk of bias from various sources).

In the mainly case–control studies, the head-up tilt test, 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 were able to discriminate between people with CFS/ME and mainly healthy controls.

One case–control study involving 112 participants concluded that electrodermal analysis may be useful in the differential diagnosis of CFS/ME and depression.

When the evidence was reviewed for subquestion 2, there appeared to be an association between certain characteristics and CFS/ME; however, there were no definite prognostic flags for CFS/ME that would be useful to a clinician.

5.1.5.2. Additional clinical evidence

No new evidence was found in the update searches.

However, a recent paper in the BMJ26 concluded that ‘prolonged fatigue states after infections are common and disabling’ and that chronic fatigue syndrome (termed post-infective fatigue syndrome in the paper) was predicted ‘largely by the severity of the acute illness, rather than by demographic, psychological, or microbiological factors’.

5.1.6. Health economics evidence summary

The investigations needed to rule out other significant disease before making a positive diagnosis of CFS/ME have a number of components which are of importance from an economic perspective.

Firstly, any aid towards either exclusion or diagnosis has a benefit in terms of clinical information to the clinician and to the individual. The value of this information is described in the systematic review, supplemented by the body of experience that exists within the wider healthcare community.

The second component, above and beyond the value of information gained through investigation before a definitive diagnosis has been made, is a possible negative effect on the patient of repetitive or extensive investigatory procedures. Therefore, if investigations can be undertaken simultaneously, this might improve the satisfaction of the individual for the same cost. The disbenefit of continued investigation must be weighed against the value of the clinical information the investigation is likely to elicit.

The third component is the cost attributable to these investigations. In the systematic evidence review, all investigations included some healthcare provider input, whether a consultation or the performance of a procedure. Any approach that produces the same outcome for less healthcare provider time will improve the cost effectiveness of the overall process.

After a positive diagnosis of CFS/ME has been made, the likelihood of the result of any investigation changing management should be considered, together with the potential improvement in quality of life, and these should be contrasted with the cost of the investigation and the disutility of the investigation to the individual.

5.1.7. Clinical scenario questionnaire to GDG and wider group

So that consistent principles were applied when rating the evidence statements, the GDG and the wider group assumed the following.

  1. The person with CFS/ME and healthcare professionals involved in their care will make decisions in partnership. These are directed by the patient’s personal preferences and build on the existing experience and skills of the professional.
  2. All treatments are offered allowing the person with CFS/ME to refuse without compromising the further therapeutic relationship.
  3. There is a good rapport in which the patient and their families/carers feel believed and validated.
  4. Treatment is provided by the NHS in the context of availability of adequate numbers of competent, appropriately trained healthcare professionals.
  5. Minimal waiting times for good-quality services are adhered to.
GDG Round 1GDG Round 2Wider GroupDiscussion
1(g)The following investigations or examinations are appropriate in establishing a diagnosis of CFS/ME in an adult....
1. The head up tilt testDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
2. Neurological examinationAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
3. Auditory brainstem responsesDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
4. Electrodermal conductivityDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
5. Urinalysis for protein, blood, glucoseAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
6. ECG if there are cardiological symptomsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
7. Endoscopy if there are gastro-intestinal (gut) symptomsUncertainUncertainDisagreeGDG was uncertain at round 2, progressed to wider survey
Allergy test if there are gastro-intestinal (gut) symptomsCoeliac antibodies if there are gastro-intestinal (gut) symptomsThe GDG found this question unclear and clarified for the second round
8.UncertainAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
9.Blood tests
a. Full Blood CountOmitted from questionnaire and discussed in round 1 - Agreed
b. Combined laboratory tests including fibrinogen, prothrombin fragment 1+2, thrombin-anti-thrombin complexes, soluble fibrin monomer (SFM) and platelet activation (CD62P, ADP)Disagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
c. Creatine KinaseAgreed...Omitted from questionnaire and discussed in round 1
d. Circulating red blood cell volumeUncertainDisagreeThe GDG thought this referred to Full Blood Count which they regarded as uncontroversial.

The GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
e. Erythrocyte sedimentation rateAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
f. C-reactive proteinAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
g. ElectrophoresisUncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
h. FerritinUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
i. B12UncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
j. FolateUncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
k. CholesterolDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
l. Liver Function TestsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
Lactate DehydrogenaseUncertainIn discussion this was clarified and the GDG decided that this was inappropriate as a diagnostic test.
m. Thyroid Function TestsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
n. CalciumAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2s
General virus serology, including heterophile antibody tests for Infectious MononucleosisIn the absence of any indicative history, general virus serology, including heterophile antibody tests for Infectious Mononucleosis are appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
Serology for chronic virus infections: HIV (Human Immunodeficiency Virus), hepatitis B & CIn the absence of any indicative history, serology for chronic virus infections: HIV, hepatitis B & C are appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
Serology for chronic bacterial infections e.g. borelliosisIn the absence of any indicative history, serology testing for chronic bacterial infections (e.g. borelliosis) is appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
Serology for latent infections: toxoplasma, EBV (Epstein Barr virus), CMV (cytomegalovirus)In the absence of any indicative history, serology testing for latent infections: toxoplasma, EBV (Epstein Barr virus), CMV (cytomegalovirus) is appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
1(h)The following investigations or examinations are appropriate in establishing a diagnosis of CFS/ME in a child....
1. The head up tilt testDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
2. Neurological examinationAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
3. Auditory brainstem responsesDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
4. Electrodermal conductivityDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
5. Urinalysis for protein, blood, glucoseAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
6. ECG if there are cardiological symptomsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
7. Endoscopy if there are gastro- intestinal (gut) symptomsDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
Allergy test if there are gastro-intestinal (gut) symptomsCoeliac antibodies if there are gastro-intestinal (gut) symptomsThe GDG found this question unclear and clarified for the second round
DisagreeUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
9.Blood tests
a. Full Blood CountOmitted from questionnaire and discussed in round 1 - Agreed
b. Combined laboratory tests including fibrinogen, prothrombin fragment 1+2, thrombin-anti-thrombin complexes, soluble fibrin monomer (SFM) and platelet activation (CD62P, ADP)Disagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
c. Creatine KinaseOmitted from questionnaire and discussed in round 1 – Agreed at meeting
d. Circulating red blood cell volumeUncertainDisagreeUncertain
e. Erythrocyte sedimentation rateAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
f. C-reactive proteinAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
g. ElectrophoresisDisagreed...The GDG reached a consensus in the first round and the statement did not progress to Round 2
h. FerritinUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
i. B12Disagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
j. FolateDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
k. CholesterolDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
l. Liver Function TestsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
Lactate dehydrogenaseDisagreeThe GDG reached a consensus in the first round and the statement did not progress to Round 2
m. Thyroid Function TestsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
n. CalciumAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
Serology for chronic virus infections: HIV, hepatitis B & CIn the absence of any indicative history, general virus serology, including heterophile antibody tests for Infectious Mononucleosis are appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
p. Serology for chronic virus infections: HIV, hepatitis B & CDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
q. Serology for chronic bacterial infections e.g. borelliosisDisagree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
Serology for latent infections: toxoplasma, EBV (Epstein Barr virus), CMV (cytomegalovirus)In the absence of any indicative history, serology testing for latent infections: toxoplasma, EBV (Epstein Barr virus), CMV (cytomegalovirus) is appropriateThis question was clarified to indicate in the absence of an indicative history.
UncertainDisagreeAgreeGDG was uncertain at round 2, progressed to wider survey

5.1.8. Recommendations

Note: numbers in square brackets are as in the NICE guidelines.

History, examinations and investigations [1.2.2]

A full history (including exacerbating and alleviating factors, sleep disturbance and intercurrent stressors) should be taken, and a physical examination and assessment of psychological wellbeing should be carried out. [1.2.2.1]

A child or young person who has symptoms suggestive of CFS/ME should be referred to a paediatrician for assessment to exclude other diagnoses within 6 weeks of presentation. [1.2.2.2]

The following tests should usually be done:

  • urinalysis for protein, blood and glucose
  • full blood count
  • urea and electrolytes
  • liver function
  • thyroid function
  • erythrocyte sedimentation rate or plasma viscosity
  • C-reactive protein
  • random blood glucose
  • serum creatinine
  • screening blood tests for gluten sensitivity
  • serum calcium
  • creatine kinase
  • assessment of serum ferritin levels (children and young people only).

Clinical judgement should be used when deciding on additional investigations to exclude other diagnoses. [1.2.2.3]

Tests for serum ferritin in adults should not be carried out unless a full blood count and other haematological indices suggest iron deficiency. [1.2.2.4]

Tests for vitamin B12 deficiency and folate levels should not be carried out unless a full blood count and mean cell volume show a macrocytosis. [1.2.2.5]

The following tests should not be done routinely to aid diagnosis:

  • the head-up tilt test
  • auditory brainstem responses
  • electrodermal conductivity. [1.2.2.6]

Serological testing should not be carried out unless the history is indicative of an infection. Depending on the history, tests for the following infections may be appropriate:

  • chronic bacterial infections, such as borreliosis
  • chronic viral infections, such as HIV or hepatitis B or C
  • acute viral infections, such as infectious mononucleosis (use heterophile antibody tests)
  • latent infections, such as toxoplasmosis, Epstein–Barr virus or cytomegalovirus. [1.2.2.7]

5.1.9. Deriving recommendations

The GDG decided that certain investigations (over and above routine screening tests such as those for anaemia, thyroid disease and coeliac disease) should be carried out to rule out other diseases and conditions, but it was not possible, or appropriate, to recommend a definitive, comprehensive list. The GDG discussed which investigations would help to rule out conditions with similar symptoms to those of CFS/ME.

The GDG decided that investigations should be carried out only where the history, signs or symptoms suggested an alternative diagnosis, and therefore many of the questions in the first round of the questionnaire were qualified to include this. Exceptions were tests for anaemia and thyroid function, and immunological tests for coeliac disease, which the GDG decided should be undertaken in the absence of clinical indications.

Recommendation [1.2.2.7] above states that viral serology should not be carried out in the absence of a recent history suggesting viral infection. On reviewing the results from the wider survey, the GDG decided that it was difficult to establish a link between CFS/ME and serology indicating past viral infection, and that serological evidence of past infection would not alter the patient’s management. Therefore the GDG could not recommend these tests routinely. The GDG also found that the evidence base was too weak to make a recommendation on EBV screening tests.

In the first round of the questionnaire many members of the GDG assumed that the clinical scenario regarding measurement of circulating red blood cell volume formed part of a full blood count, with which they agreed. After clarification, the GDG was uncertain whether a circulating red blood cell volume was in itself helpful in making a diagnosis. This went forward to the second round of the questionnaire where the GDG reached a consensus that it was not appropriate.

The GDG had mixed views about the value of measuring serum vitamin B12 levels, particularly as many laboratories will not carry out this investigation unless it is indicated by full blood count (FBC) and mean cell volume (MCV) results. As the GDG had a divergence of views, it was agreed that it should be included in the questionnaire for the wider group. The wider survey rated it as ‘uncertain’ but patients and carers ‘agreed’ that this test was appropriate. The GDG decided that this test should only be carried out if the results of the FBC and MCV suggest the presence of macrocytosis.

The view of the GDG was mixed regarding the testing of ferritin levels as part of diagnosis. One member reported that there was an RCT of women presenting with tiredness with normal haemoglobin but low ferritin. [Note: this was not in the evidence review as the subjects of the study did not have CFS/ME.] The GDG’s decision was that this was not a positive diagnostic tool. However, as for tests for vitamin B12 levels, the GDG decided that ferritin levels should be tested if the results of the FBC and MCV suggested a microcytosis that may be due to iron deficiency.

In the wider survey, there was a trend to disagreement on the appropriateness of endoscopy as an investigation to aid diagnosis; a high proportion of respondents answered ‘don’t know’. The decision of the GDG was that a recommendation for routine endoscopy should not be made as this is a invasive investigation. Neither should a negative recommendation be made as endoscopy may be appropriate for certain individuals with particular symptoms and signs that would necessitate the exclusion of upper gastrointestinal pathology. In this context, endoscopy is an investigation not for CFS/ME, but for alternative or coexistent pathology.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

5.2. Arriving at a diagnosis

5.2.1. Evidence statements

Key clinical question 1

Part 1 What are the existing case definitions for CFS/ME in adults and children?

Part 2 What evidence exists to substantiate or validate the existing case definitions for CFS/ME in adults and/or children?

Adults
5.2.1.1Evidence to substantiate existing case definitions of CFS or ME is limited. No studies have established the superiority of one case definition over another (Evidence level 2−).
5.2.1.2Community-based studies have indicated that patients meeting CDC 1994 criteria form a more heterogeneous group than patients meeting CDC 1988 criteria (Evidence level 2−).
5.2.1.3There is currently limited evidence that patients meeting Dowsett ME or the Canadian criteria are more likely to have more symptoms than those meeting CDC 1994 criteria (Evidence level 2−).
Children
5.2.1.4Evidence to substantiate existing case definitions of CFS or ME in children and young people is very limited (Evidence level 2−).
5.2.1.5One study has shown that adolescents who meet CDC 1994 criteria for CFS had more higher anxiety, depression, somatisation, school absence and illness attribution scores than those suffering with migraine or healthy controls.(Evidence level 2−).

5.2.2. Clinical evidence summary

5.2.2.1. Summary of evidence presented in Appendix 1 Question 1 part 1 – diagnostic criteria

The current definitions of CFS/ME are characterised by descriptions of symptoms rather than by underlying causes. The systematic review conducted by the CRD at the University of York formed the primary evidence base for adult-onset CSF/ME in this guideline. Some of the criteria reviewed (presented in chronological order) are below; for the full list, see Appendix 1 Question 1: ‘Criteria for case definitions of CFS and/ or ME’ for a table of all criteria reviewed.

The Oxford Criteria of CFS/ME§, developed in 1991 by a panel of clinicians and scientists, defined CFS/ME as a ‘syndrome in which fatigue has been present for at least six months, during which time it has been present more than 50 per cent of the time.’ Other symptoms may also be present, such as myalgia, and mood and sleep disturbance.27

In 1994, new criteria were drawn up by the US Centers for Disease Control (CDC), the 1994 CDC/Fukuda CFS Criteria.28 The CDC definition included the requirement of the presence of new-onset fatigue lasting at least 6 months and the presence of at least four of eight other physical symptoms.

‘A case of the chronic fatigue syndrome is defined by the presence of the following:

  1. clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities; and
  2. the concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue: self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities; sore throat; tender cervical or axillary lymph nodes; muscle pain; multijoint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.’28

The 2003 Canadian definition11 is more stringent and was developed by an international clinical CFS team. Fatigue in CFS/ME was characterized as ‘…post-exertional fatigue (with) a pathologically slow recovery period (it takes more than 24 hours to recover)’. The 2003 Canadian definition also states that cardinal symptoms are no longer optional and that patients must have neurological, immune and/or neuroendocrine manifestations.11

The Royal College of Paediatrics and Child Health in their ‘Evidence based Guideline for the Management of CFS/ME’ defined CFS/ME in children as ‘…generalized fatigue (fatigue causing disruption of daily life) persisting after routine tests and investigations have failed to identify an obvious underlying ‘cause.’’1.

5.2.2.2. CFS/ME diagnostic criteria: adapted from comparative analysis by the New Zealand Guidelines Group 200329

Diagnostic criteria in other guidelines
Australian 2002UK 2002 (CMO Report)US 2002Canadian 2003
1. Fatigue
  • unexplained
  • persistent
  • > 6 months
  • new/definite onset
  • not resulting from exertion
  • not alleviated by rest
  • result in reduction in previous activity levels
AND

2. Other symptoms
  • concurrent with fatigue
  • persistent
  • >6 months
  • new/definite onset
Four or more of the following:
  • impaired short-term memory/concentration
  • sore throat
  • tender cervical/ancillary lymph nodes
  • muscle pain
  • multijoint pain without arthritis
  • headaches (of new type/pattern/severity)
  • post-exertional malaise lasting > 24 hours
Idiopathic chronic fatigue:
Diagnose if formal criteria for CFS are not met and other conditions are excluded.
In routine clinical practice, a diagnosis of CFS may be appropriate even though the requirement of 4 out of 8 additional symptoms above is not formally met.
Such patients can have comparable levels of disability, and may also benefit from the assessment and intervention strategies described in these guidelines.
1. Worsening of symptoms following physical or mental exertion beyond the person’s tolerance with a delayed impact and a prolonged recovery period.
This is the prime feature of the condition.

PLUS some of other common symptoms:

2. Tiredness or fatigue (physical and cognitive)
  • excessive
  • persistent (> 6 weeks)
3. Cognitive impairment
  • reduced attention span
  • impairment of short-term memory
  • word-finding difficulty
  • inability to plan/organise thoughts
  • spatial disorientation
  • loss of ability to concentrate
4. Post-exertional malaise
  • may be flu-like symptoms
5. Pain
  • persistent
  • poor response to standard analgesia
May include
  • muscular pain
  • joint pain
  • neuropathic pain (with or without paraesthesiae)
  • head pain and/or headache
6. Sleep disturbance
May include:
  • early morning wakening
  • insomnia
  • hypersomnia
  • unrefreshing sleep
  • disturbed sleep/wake cycle
7. Other symptoms
  • Temperature disturbance
  • Dizziness, vertigo, postural hypotension
  • Increased sensitivity to sensory stimuli
  • Serious neurological symptoms – double vision, blackouts, atypical convulsions, loss of speech, and loss of swallowing necessitating nasogastric feeding in a minority of severely affected patients.
  • Recurrent sore throat +/− lymphadenopathy
  • Digestive disturbances – nausea, loss of appetite, indigestion, bloating, abdominal cramps, alternating diarrhoea and constipation. Symptoms are similar to irritable bowel syndrome (a differential diagnosis)
  • Intolerances – alcohol, foods, medication, or other substances
1. Unexplained fatigue

AND

Any of the following:
  • impaired memory loss
  • sore throat,
  • tender neck (cervical) or armpit (axillary) lymph nodes,
  • muscle pain (myalgia),
  • headache,
  • unrefreshing sleep,
  • post-exertional malaise lasting more than 24 hours, and
  • multijoint pain (arthralgia) without swelling or redness
Symptom checklist:
  • Prolonged (>24 hrs) generalised fatigue
  • Non-refreshing sleep
  • Sore throat
  • Painful cervical or axillary lymph nodes
  • Unexplained generalised muscle weakness
  • Generalised headaches
  • Migratory painful joints without swelling or redness
  • Areas of lost or depressed vision
  • Visual intolerance of light
  • Forgetfulness
  • Excessive irritability
  • Confusion
  • Difficulty thinking
  • Inability to concentrate
  • Depression
Idiopathic chronic fatigue:
Diagnose if alternative causes for fatigue have been ruled out, but criteria for CFS are not met. Treat as CFS.
1. Fatigue (physical and mental)
  • unexplained
  • persistent
  • new/definite onset
or
  • recurrent
  • results in substantial reduction in previous activity levels
AND

2. Post-exertional malaise/fatigue
  • inappropriate loss of physical and mental stamina
  • rapid muscular and cognitive fatigability
  • post exertional malaise
and/or
  • pain and a tendency for other associated symptoms to worsen
  • recovery period of > 24 hours
AND

3. Sleep dysfunction
  • unrefreshing sleep and/or
  • sleep quantity or rhythm disturbances

    a small number of people may not suffer sleep dysfunction but CFS/ME is the only diagnosis that fits

AND

4. Pain
  • a significant degree of myalgia.
  • may be experienced in muscles and/or joints
  • may be migratory in nature
  • may be significant headaches of new type, pattern or severity
    -

    a small number of people may not suffer pain but CFS/ME is the only diagnosis that fits

AND

5. Two or more of the following neurological/cognitive manifestations:
  • confusion
  • impairment of concentration and short-term memory consolidation
  • disorientation
  • difficulty with information processing, categorising and word retrieval
  • perceptual and sensory disturbances e.g. spatial instability, disorientation and inability to focus vision
Ataxia, muscle weakness and fasciculations are common.
Overload phenomena may occur leading to ‘crash’ periods and/or anxiety – cognitive, emotional, and/or sensory e.g. photophobia, noise hypersensitivity.

AND

6. At least 1 symptom from 2 of the following categories:

A. Autonomic dysfunction
  • Orthostatic intolerance – neurally mediated hypotension, postural orthostatic tachycardia syndrome, delayed postural hypotension
  • Light-headedness, extreme pallor
  • Nausea and irritable bowel syndrome
  • Urinary frequency and bladder dysfunction
  • Palpitations with or without cardiac arrhythmias
  • Exertional dyspnoea.
B. Neuroendocrine manifestations
  • Heat/cold intolerance
  • Marked weight change – anorexia or abnormal appetite
  • Loss of adaptability and worsening of symptoms with stress.
C. Immune manifestations
  • Tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms
  • General malaise
  • New sensitivities to food, medications and/or chemicals.
AND

7. Chronic duration
Symptoms persisting for at least 6 months.
Preliminary diagnosis may be possible earlier. Three months is appropriate for children. It usually has a distinct onset (although it may be gradual).

AND

8. Exclusion of active disease processes that explain most of the symptoms.

Idiopathic chronic fatigue: If the patient has unexplained prolonged fatigue (6 months or more), but has insufficient symptoms to meet the criteria for ME/CFS, it should be classified as idiopathic chronic fatigue.
AGREE appraisals of included guidelines

For information, reviewers in the NCC-PC applied the AGREE Appraisal tool to the guidelines included in the New Zealand Guidelines Group (NZGG) comparative review. Results were as follows.

Overall assessment NCC-PC (number of reviewers in agreement)Comments from NCC-PCComments on rigour from NZGG
Australian 2002Recommend (with provisos or alterations) (2/2)
  • Seems to be a very well produced, methodologically sound guideline.
  • The formation of the GDG group includes all relevant professionals, as well as a patient presence.
  • Key recommendations are easily found, and are specific.
  • Guideline has been piloted previously on target users.
  • Search strategies not detailed, but statement that NHMRC guidelines for guidelines followed (implies systematology)
  • No discussion of outcomes
  • Not enough attention to harms and risks
  • Outdated evidence base
Canadian 2003Would not recommend (3/3)
  • This guideline reads like a description of the results, but without the description of the methodology. There is not enough detail of the process the group went through when assessing the evidence and formulating their recommendations.
  • No key clinical questions were described, and the patient population was not specifically taken into account.
  • Poor methodology in my opinion.
  • However, as there is such a lack of evidence, the discussion around the non-systematically evidence reviews is interesting and the recommendations are very detailed.
  • But, methodologically poor guidelines overall.
  • Little documentation and accountability.
  • Follows evidence-based and consensus protocols
  • No search strategies detailed, but research base is comprehensive and current
  • Excellent consideration of risks/harms as well as benefits
CMO 2002Recommend (with provisos or alterations) (2/2)
  • These guidelines are explicit and unambiguous in their recommendations.
  • Methodologically, some key aspects are left out (incl. cost analysis for implementation, procedure for updating), but more importantly the authors fail to specifically describe the clinical questions used.
  • GDG includes the majority of relevant professionals, however does not include some of the specified target users (physiotherapists, occupational therapists, etc).
  • Good sources of information: research, consumer submissions, clinical experience)
  • No systematic searching
  • Limited scope of literature reviewed (overlooks much non-UK literature).
  • Limited appraisal of evidence.
  • No levels of evidence or grading of recommendations.
  • No links between evidence and body of report – more information in annexes than report.
  • Glossing over of some potential harms – e.g. of medications.
  • Makes some recommendations which may be harmful (e.g. GET).
  • Couldn’t be effectively peer- reviewed due to poor referencing.
US New Jersey 2002Would not recommend (2/2)
  • This document is more of a theoretical text book/manual than a clinical guideline.
  • Recommendations are hidden in the narrative, and key messages are not identifiable.
  • There is no description of the guideline methodology.
  • No patient perspective is taken into account.
  • No systematic literature search, but comprehensive, up-to-date literature base supporting guideline, with no obvious gaps.

Domain and overall scores were as follows.

AustraliaCanadaCMOUS New Jersey
NCC-PCNZNCC-PCNZNCC-PCNZNCC-PCNZ
Scope and purpose61%63%26%83%61%92%28%86%
Stakeholder involvement79%70%14%70%54%77%17%71%
Rigour of development45%58%13%73%45%63%12%78%
Clarity and presentation67%57%33%80%75%77%21%73%
Applicability17%33%9%51%33%60%0%44%
Editorial independence33%47%6%48%42%50%8%67%
Overall52%57%16%70%52%70%15%72%
Common features as noted by the New Zealand Guidelines Group29
1. Fatigue (physical and mental)
  • unexplained
  • persistent
    AND some of
2. Post-exertional malaise/fatigue: inappropriate loss of physical and mental stamina with long recovery period
3. Sleep disturbance
May include
  • early morning wakening
  • insomnia
  • hypersomnia
  • unrefreshing sleep
  • disturbed sleep/wake cycle
4. Pain
May include
  • muscles and/or joint pain
  • significant headaches of new type, pattern or severity
  • painful lymph nodes
  • sore throat
5. Cognitive impairment
  • confusion
  • difficulty thinking
  • inability to concentrate
  • impairment of short-term memory
  • word-finding difficulty
  • inability to plan/organise thoughts
  • spatial disorientation
Idiopathic chronic fatigue: diagnose if alternative causes for fatigue have been ruled out, but criteria for CFS are not met. Treat as CFS.

5.2.2.3. Summary of evidence presented in Appendix 1 Question 1 part 2 – case definitions

The evidence base for existing case definitions of CFS/ME is not robust. Although 36 studies were reviewed by the CRD, study designs were primarily case–control, with small sample sizes and different comparative groups ranging from healthy individuals to severely ill people5. Diagnostic criteria for CFS/ME varied among studies. Outcomes of fatigue, impaired sleep, cognition, concentration, quality of life and social functioning generally appeared to be significant among CFS/ME patients. However, measurement of these outcomes was essentially subjective and therefore potentially biased. Tests of cognitive function and assessment of functional ability were more robust, and these generally appeared to be impaired in CFS/ME patients. Higher depression scores were noted among CFS/ME patients in some studies but it was unclear whether depression occurred before or after CFS/ME symptoms began. In an earlier review by Mulrow, Ramirez, Cornell and Allsup30 the authors concluded that there were no studies that provided the basis of a definitive case definition. It would appear that this is still the case.

Fatigue is a cardinal feature of patients with a diagnosis of CFS/ME. The expected consequences of fatigue follow, including effects on cognitive ability and concentration, and general functional capabilities. However support for specific physical and psychological features of the syndrome was weak and inconsistent in the studies reviewed for this guideline.

5.2.2.4. Update searches

One case–control study31 (n = 227) was identified that implemented the recommendations of the International CFS Study Group28 for the diagnosis of CFS. The international recommendations were compared to the ‘usual algorithm’ based on patients’ subjective responses to direct questions about fatigue, reduction in daily activities and presence of at least 4 case defining symptoms. Only 13% of patients who met 1994 surveillance criteria for CFS met those same criteria in this study, indicating fluctuation in illness levels over time. Forty per cent of patients fulfilled the CFS criteria of the International CFS Study Group using a clinically empirical definition, based on functional impairment, fatigue and accompanying symptoms. Thus, the clinically empirical case definition may be less affected by illness fluctuations and more truly reflect the underlying chronic illness process.

5.2.3. Health economics evidence summary

The literature review identified no published cost-effectiveness studies of a suitable structure and quality. Therefore, the GDG were presented with an outline of the key cost-effectiveness considerations in the diagnosis, investigation and referral of individuals with suspected CFS/ME.

When an individual first enters primary care, most likely with an uncertain diagnosis, the healthcare professional has available a range of exclusory procedures and approaches, each either suggesting an alternative diagnosis to CFS/ME or adding evidence to corroborate a CFS/ME diagnosis. The choice of the point at which diagnosis is made (i.e. when we define the evidence as ‘weighty enough’) has economic considerations, in that we have to accept a number of either false negatives, false positives, or most likely, both. This idea is illustrated in the use of receiver operating characteristic (ROC) curves. Such curves were not identified in the diagnosis of CFS/ME.

While such curves were not identified, the trade-off between false negatives and false positives illustrated by this approach is crucial when discussing diagnosis. Assuming all other factors are held constant, if a false negative becomes relatively more problematic (however that is defined) than a false positive, it would be logical to diagnose when the evidence supporting a diagnosis is smaller. However, if the opposite is true, we should be more willing to delay the diagnosis.

The costs attached to false diagnoses

False positivesFalse negatives
IndividualStructuralIndividualStructural
Stress associated with a diagnosisCost of initial CFS/ME treatment/managementCondition has deteriorated over timeCost of treating/managing incorrect condition
Delayed treatment/management of true conditionIncreased cost of treating true condition if this has become more severeIncreased cost of treating CFS/ME if this has become more severe

While there is evidence on these elements of the decision-making process, evidence of the magnitude of each of these relative to the others is largely inconclusive and the likelihood of being able to contrast the negative aspects of a false negative with the negative aspects of a false positive is small.

5.2.4. Clinical scenario questionnaire to GDG and wider group

So that consistent principles were applied in rating the evidence statements, the GDG and the wider group assumed the following.

  1. The person with CFS/ME and healthcare professionals involved in their care will make decisions in partnership. These are directed by the patient’s personal preferences and build on the existing experience and skills of the professional.
  2. All treatments are offered allowing the person with CFS/ME to refuse without compromising the further therapeutic relationship.
  3. There is a good rapport in which the patient and their families/carers feel believed and validated.
  4. Treatment is provided by the NHS in the context of availability of adequate numbers of competent, appropriately trained healthcare professionals.
  5. Minimal waiting times for good-quality services are adhered to.

The symptoms listed in the clinical scenarios were derived from the common features in the Australian, Canadian, US and UK guidance. 1;6;11;28

GDG Round 1GDG Round2Wider GroupDiscussion
1(a)Fatigue indicative of CFS/ME in an adult.....
1. is persistent and/or recurrentAgreeThe GDG reached a consensus in the first round and the statement did not progress to Round 2
2. is unexplained by mental or physical conditionsAgreeThe GDG reached a consensus in the first round and the statement did not progress to Round 2
3. results in substantial reduction in previous activity levelsAgreeThe GDG reached a consensus in the first round and the statement did not progress to Round 2
4. characterised by post-exertion malaise and/or fatigue (often delayed with slow recovery)AgreeThe GDG reached a consensus in the first round and the statement did not progress to Round 2
1(b)Other symptoms indicative of CFS/ME in an adult can, but not necessarily always, include....
1. Difficulty with sleeping (e.g. early morning waking, insomnia, hypersomnia, unrefreshing sleep, disturbed sleep/wake cycle)Agree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
2. Muscles and/or joint painAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
3. Significant headaches of new type, pattern or severityAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
4. Painful lymph nodesAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
5. Sore throatAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
6. Cognitive impairment for example confusion, difficulty thinking, inability to concentrate, impairment of short-term memory, word-finding difficulty, inability to plan/organise thoughts, spatial disorientation, difficulty with information processingAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
7. Physical or mental exertion making symptoms worseAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
8. Recurrent flu-like symptomsAgreeAgreeAgreeRandom selection for wider survey
9.9 Neuroendocrine symptoms e.g. orthostatic intolerance, nausea and palpitations9. Orthostatic intolerance (problems standing upright), nausea and palpitationsOrthostatic intolerance (problems standing upright), nausea and palpitationsGDG did not consider the symptoms as neuroendocrine and reworded and re-rated
AgreeAgreeAgree
10Autonomic symptoms e.g. loss of thermostatic stability and marked weight changeSignificant weight change(s)The GDG decided that the grouping of the symptoms was confusing. The symptoms were separated and re-rated.
UncertainUncertainGDG decided that weight loss was a concern of other conditions but not a symptom of CFS/ME and that weight gain was not a significant symptom but the consequence of inactivity.
11Loss of thermostatic stability (difficulty controlling temperature)
Not includedAgree
1(c)After ruling out other possible likely causes of the symptoms, a diagnosis of CFS/ME should be made in an Adult
1. After symptoms have persisted for at least 6 weeksUncertainDisagreeUncertainRandom selection for wider survey
2. After symptoms have persisted for at least 4 monthsAgreeAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
3. After symptoms have persisted for at least 6 monthsAgreeAgreeAgreeRandom selection for wider survey
1(d)Fatigue indicative of CFS/ME in a child is....
1. persistent and/or recurrentAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
2. unexplained by mental or physical conditionsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
3. results in substantial reduction in previous activity levelsAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
4. characterised by post-exertion malaise and/or fatigue (often delayed with slow recovery)Agree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
1 (e)Other symptoms indicative of CFS/ME in a child can, but not necessarily always, include.....
1. Difficulty with sleeping (e.g. early morning wakening, insomnia, hypersomnia, unrefreshing sleep, disturbed sleep/wake cycle)Agree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
2. Muscles and/or joint painAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
3. Significant headaches of new type, pattern or severityAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
4. Painful lymph nodesAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
5. Sore throatAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
6. Cognitive impairment for example confusion, difficulty thinking, inability to concentrate, impairment of short-term memory, word-finding difficulty, inability to plan/organise thoughts, spatial disorientation, difficulty with information processingAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
7. Physical or mental exertion making symptoms worseAgree...The GDG reached a consensus in the first round and the statement did not progress to Round 2
8. Recurrent flu-like symptomsAgreeUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
9. Neuroendocrine symptoms e.g. orthostatic intolerance and palpitations8. Orthostatic intolerance (problems standing upright), nausea and palpitationsOrthostatic intolerance (problems standing upright), nausea and palpitationsThe GDG decided that the grouping of the symptoms was confusing. The symptoms were separated and re-rated.
UncertainUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
10. Autonomic symptoms e.g. loss of thermostatic stability and marked weight change9. Significant weight change(s)Significant weight change(s)The GDG decided that the grouping of the symptoms was confusing. The symptoms were separated and re-rated.
UncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
10. Loss of thermostatic stability (difficulty controlling temperature)Discussed and not included in wider survey
Uncertain.......
1(f)After ruling out other possible likely causes of the symptoms, a diagnosis of CFS/ME should be made in a child....
1. After symptoms have persisted for 6 weeksUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
2. After symptoms have persisted for 4 monthsAgreeAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
3. After symptoms have persisted for 6 monthsAgreeAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.

5.2.5. Recommendations

Note: numbers in square brackets are as in the NICE guidelines.

Presentation [1.2]

Presenting symptoms suspicious of CFS/ME [1.2.1]

CFS/ME is recognised on clinical grounds alone. Primary healthcare professionals should be familiar with and be able to identify the characteristic features of CFS/ME. [1.2.1.1]

Healthcare professionals should consider the possibility of CFS/ME if a person has:

  • fatigue with all of the following features:

    new or had a specific onset (that is, it is not lifelong)

    persistent and/or recurrent

    unexplained by other conditions

    has resulted in a substantial reduction in activity level

    characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days)

    and

  • one or more of the following symptoms:

    difficulty with sleeping, such as insomnia, hypersomnia, unrefreshing sleep, a disturbed sleep–wake cycle

    muscle and/or joint pain that is multi-site and without evidence of inflammation

    headaches

    painful lymph nodes without pathological enlargement

    sore throat

    cognitive dysfunction, such as difficulty thinking, inability to concentrate, impairment of short-term memory, and difficulties with word-finding, planning/organising thoughts and information processing

    physical or mental exertion makes symptoms worse

    general malaise or ‘flu-like’ symptoms

    dizziness and/or nausea

    palpitations in the absence of identified cardiac pathology. [1.2.1.2]

Healthcare professionals should be aware that the symptoms of CFS/ME fluctuate in severity and may change in nature over time. [1.2.1.3]

Signs and symptoms that can be caused by other serious conditions (‘red flags’) should not be attributed to CFS/ME without consideration of alternative diagnoses or comorbidities. In particular, the following features should be investigated**:

  • localising/focal neurological signs
  • signs and symptoms of inflammatory arthritis or connective tissue disease
  • signs and symptoms of cardiorespiratory disease
  • significant weight loss
  • sleep apnoea
  • clinically significant lymphadenopathy. [1.2.1.4]
Re-assessment before diagnosis [1.2.4]

If symptoms do not resolve as expected in a person initially suspected of having a self-limiting condition, primary healthcare professionals should listen carefully to the person’s and their family and/or carers’ concerns and be prepared to reassess their initial opinion. [1.2.4.1]

If considering the possibility of CFS/ME or another serious alternative condition, primary healthcare professionals should consider discussion with a specialist if there is uncertainty about the interpretation of signs and symptoms and whether a referral is needed. This may also enable the primary healthcare professional to communicate their concerns and a sense of urgency to secondary healthcare professionals if symptoms are unusual. [1.2.4.2]

Diagnosis [1.3]

Making a diagnosis [1.3.1]

A diagnosis should be made after other possible diagnoses have been excluded and the symptoms have persisted for:

  • 4 months in an adult
  • 3 months in a child or young person; the diagnosis should be made or confirmed by a paediatrician. [1.3.1.1]

When a diagnosis of CFS/ME is made, healthcare professionals should provide honest, realistic information about CFS/ME and encourage cautious optimism.

  • Most people with CFS/ME will improve over time and some people will recover and be able to resume work and normal activities.
  • However, others will continue to experience symptoms or relapse and some people with severe CFS/ME may remain housebound.
  • The prognosis in children and young people is more optimistic. [1.3.1.2]

The diagnosis of CFS/ME should be reconsidered if none of the following key features are present:

  • post-exertional fatigue or malaise
  • cognitive difficulties
  • sleep disturbance
  • chronic pain. [1.3.1.3]

5.2.6. Deriving recommendations

Diagnostic criteria

The GDG reviewed the existing diagnostic criteria, but did not consider them particularly helpful in clinical practice when making a definitive diagnosis or managing the condition.

The Gibson Inquiry2 recently reviewed diagnostic criteria and concluded that the Canadian criteria11 were a useful contribution to defining the clinical condition of CFS/ME. They are more detailed than the Oxford criteria27, for example. However, since the cause or causes of CFS/ME are unknown, we cannot be sure that the proposed criteria do accurately identify people who have CFS/ME. It is possible that diagnostic criteria that delineate a particular set of symptoms wrongly exclude patients with early disease or with minor disability, when such patients might benefit from early intervention and avoid progression to severe or prolonged disability. As the Gibson Inquiry made clear, research is required into the biological basis of CFS/ME, but until that research has been completed the clinician and the patient need practical guidance.

The GDG recognised that if broader criteria were used, some people might be falsely diagnosed with CFS/ME when in fact they have other conditions that would respond to appropriate treatment. Therefore, the GDG viewed the diagnosis of CFS/ME as a process rather than a discrete, isolated event (see next section – The diagnostic process).

The case definition or diagnostic criteria were proposed by Carruthers et al.11 and are followed in the Canadian guidelines.

Table 1Clinical working case definition of CFS/ME from the Canadian guidelines11

A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine and immune manifestations; and adhere to item 7.
Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level.
Post-exertional malaise and/or fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post-exertional malaise and/or fatigue and/or pain and a tendency for associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period – usually 24 hours or longer.
Sleep dysfunction: There is unrefreshed sleep or sleep quantity or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.
Pain: There is a significant degree of myalgia. Pain can be experienced in the muscles and/or joints, and is often widespread and migratory in nature. Often there are significant headaches of new type, pattern or severity.
Neurological/cognitive manifestations: Two or more of the following difficulties should be present: confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances – e.g. spatial instability and disorientation and inability to focus vision. Ataxia, muscle weakness and fasciculations are common. There may be overload phenomena: cognitive, sensory – e.g. photophobia and hypersensitivity to noise – and/or emotional overload, which may lead to ‘crash’ periods and/or anxiety.
At least one symptom from two of the following categories:
Autonomic manifestations: orthostatic intolerance – neurally mediated hypotension (NMH), postural orthostatic tachycardia syndromes (POTS), delayed postural hypotension; light-headedness; extreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrhythmias; exertional dyspnoea.
Neuroendocrine manifestations: loss of thermostatic stability – subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities; intolerance of extremes of heat and cold; marked weight change – anorexia or abnormal appetite; loss of adaptability and worsening of symptoms with stress.
Immune manifestations: tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food, medications and/or chemicals.
The illness persists for at least 6 months. It usually has a distinct onset, although it may be gradual. Preliminary diagnosis may be possible earlier: 3 months is appropriate for children.
To be included, the symptoms must have begun or have been significantly altered after the onset of this illness. It is unlikely that a patient will suffer from all symptoms in criteria 5 and 6. The disturbances tend to form symptom clusters that may fluctuate and change over time. Children often have numerous prominent symptoms but their order of severity tends to vary from day to day. There is a small number of patients who have no pain or sleep dysfunction, but no other diagnosis fits except ME/CFS. A diagnosis of ME/CFS can be entertained when this group has an infectious illness type onset. Some patients have been unhealthy for other reasons prior to the onset of ME/CFS and lack detectable triggers at onset and/or have more gradual or insidious onset.
Exclusions: Exclude active disease processes that explain most of the major symptoms of fatigue, sleep disturbance, pain, and cognitive dysfunction. It is essential to exclude certain diseases, which would be tragic to miss: Addison’s disease, Cushing’s syndrome, hypothyroidism, hyperthyroidism, iron deficiency, other treatable forms of anaemia, iron overload syndrome, diabetes mellitus, and cancer. It is also essential to exclude treatable sleep disorders such as upper airway resistance syndrome and obstructive or central sleep apnoea; rheumatological disorders such as rheumatoid arthritis, lupus, polymyositis and polymyalgia rheumatica; immune disorders such as AIDS; neurological disorders such as multiple sclerosis (MS), Parkinsonism, myasthenia gravis and B12 deficiency; infectious diseases such as tuberculosis, chronic hepatitis, Lyme disease, etc.; primary psychiatric disorders and substance abuse. Exclusion of other diagnoses, which cannot be reasonably excluded by the patient’s history and physical examination, is achieved by laboratory testing and imaging. If a potentially confounding medical condition is under control, then the diagnosis of ME/CFS can be entertained if patients meet the criteria otherwise.
Co-morbid entities: fibromyalgia syndrome (FMS), myofascial pain syndrome (MPS), temporomandibular joint syndrome (TMJ), irritable bowel syndrome (IBS), interstitial cystitis, irritable bladder syndrome, Raynaud’s phenomenon, prolapsed mitral valve, depression, migraine, allergies, multiple chemical sensitivities (MCS), Hashimoto’s thyroiditis, Sicca syndrome etc. Such co-morbid entities may occur in the setting of ME/CFS. Others such as irritable bowel syndrome may precede the development of ME/CFS by many years, but then become associated with it. The same holds true for migraines and depression. Their association is thus looser than between the symptoms within the syndrome. ME/CFS and FMS often closely connect and should be considered to be ‘overlap syndromes’.
Idiopathic chronic fatigue: if the patient has unexplained prolonged fatigue (6 months or more) but has insufficient symptoms to meet the criteria for ME/CFS, this should be classified as idiopathic chronic fatigue.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

The diagnostic process

The GDG considered whether making a confirmed diagnosis of CFS/ME was necessary, as once this is done healthcare professionals may not continue to consider other possibilities and risk overlooking another potentially serious condition. However, the GDG decided that a diagnosis was crucial to the patient and their families in understanding their symptoms and receiving appropriate treatment. It must however, be considered a working diagnosis and regularly reviewed.

In the first stage of the process, CFS/ME is suspected. This requires the clinician to have knowledge of the presenting features of CFS/ME.

The second stage involves systematic assessment to determine the likelihood of CFS/ME and to rule out other conditions. The assessment includes clinical examination, appropriate investigations and, depending on the duration of symptoms, a period of observation, subject to the findings of the investigations.

In the third stage, the diagnosis is reached, other conditions having being ruled out. At this stage, standard diagnostic criteria may be used if found helpful by the clinician and patient in assessing the extent of symptoms. However, the criteria should not be used to restrict interventions to only a limited group of patients.

In the fourth stage, the patient is reviewed at regular intervals and the diagnosis reconsidered if new symptoms or signs arise or if the patient’s condition deteriorates or fails to improve.

The timing of diagnosis was discussed by the GDG. There was no evidence on when a diagnosis should be made, although some of the diagnostic criteria (see Appendix 1 Q.1) required that symptoms persisted for 6 months. There was concern about leaving a diagnosis this late and this perhaps resulting in a delay in access to services and support. On the other hand, there was also concern about making a diagnosis including the word ‘chronic’ at an early stage in the illness. There was general consensus that, depending on individual circumstances, a diagnosis in a child should generally be made at about 3 months following the onset of symptoms. This is in accordance with the Royal College of Paediatrics & Child Health (RCPCH) guideline.1 The GDG considered that 4 months was an appropriate timeframe for adults.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

Signs and symptoms

There was strong agreement that persistent, debilitating, post-exertional fatigue characterised CFS/ME. Such fatigue may be accompanied by a wide spectrum of other symptoms. Healthcare professionals should be therefore be aware of other symptoms that frequently present with fatigue, in order to raise awareness of the possibility of CFS/ME, and promote appropriate, early intervention.

The GDG discussed ‘red flag’ symptoms – those that might indicate another serious illness. These included the following.

Weight loss: while weight gain might be an indication of CFS/ME, unexplained weight loss is not generally characteristic of CFS/ME and could signify a more acute disease such as cancer. It was noted that people with CFS/ME may have explained weight loss due to difficulty eating. This would need to be managed but was not a symptom defining CFS/ME.

Spatial disorientation is not generally characteristic of CFS/ME, and is usually indicative of brain damage. Concentration and memory difficulties (‘brain fog’) are, however, typical.

Sleep apnoea: if a patient has sleeping problems, the healthcare professional should ask specifically about symptoms that suggest a diagnosis of sleep apnoea as suspected sleep apnoea requires prompt referral and investigation.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

History and examination

The GDG decided that, as for investigations, the examination, based on the history, should be targeted to ‘rule out’ other conditions. The GDG’s view was that the individual doing the examination should have competencies in the recognition of CFS/ME.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

5.3. Referral to specialist CFS/ME care

5.3.1. Evidence statements

No evidence was found regarding referral to specialist CFS/ME care.

5.3.2. Clinical evidence summary

There is currently no robust evidence concerning timescales for referring to a specialist or to specialist CFS/ME centres people in whom a diagnosis of CFS/ME is suspected or has already been made.

As is reflected in the recommendations, the GDG decided that referral to specialists or specialist CFS/ME centres is dependent on the following factors: local service provisions; and the severity of the individual’s condition. Any decisions on the types of investigations or therapies to be accessed should be made between the lead healthcare professional and patient.

5.3.3. Health economics evidence summary

No evidence on referral was identified.

5.3.4. Clinical scenario questionnaire to GDG and wider group

So that consistent principles were applied in rating the evidence statements, the GDG and the wider group assumed the following.

  1. The person with CFS/ME and healthcare professionals involved in their care will make decisions in partnership. These are directed by the patient’s personal preferences and build on the existing experience and skills of the professional.
  2. All treatments are offered allowing the person with CFS/ME to refuse without compromising the further therapeutic relationship.
  3. There is a good rapport in which the patient and their families/carers feel believed and validated.
  4. Treatment is provided by the NHS in the context of availability of adequate numbers of competent, appropriately trained healthcare professionals.
  5. Minimal waiting times for good-quality services are adhered to.
GDG Round 1GDG Round 2Wider GroupDiscussion
1(i)For an adult with mild CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurDisagreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careDisagreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
3. only after symptoms have persisted for about 3–4 months following treatment in primary careUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
4. only after symptoms have persisted for at least 6 months following treatment in primary careUncertainAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
5. never or only very exceptionallyAgreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
1(j)For an adult with moderate CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurDisagreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careDisagreeUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
3. only after symptoms have persisted for about 3–4 months following treatment in primary careUncertainAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
4. only after symptoms have persisted for at least 6 months following treatment in primary careAgreeAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
5. never or only very exceptionallyAgreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
1(k)For an adult with severe CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurUncertainUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
3. only after symptoms have persisted for about 3–4 months following treatment in primary careUncertainAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
4. only after symptoms have persisted for at least 6 months following treatment in primary careAgreeAgree
5. never or only very exceptionallyAgreeDisagreeThe interpretation of this statement was discussed at the GDG meeting and subsequently re-rated. The GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
1(l)For a child with mild CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurDisagreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careDisagreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
3. only after symptoms have persisted for about 3–4 months following treatment in primary careUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
4. only after symptoms have persisted for at least 6 months following treatment in primary careUncertainUncertainDisagreeGDG was uncertain at round 2, progressed to wider survey
5. never or only very exceptionallyAgreeDisagreeThe interpretation of this statement was discussed at the GDG meeting and subsequently re-rated. The GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
1(m)For a child with moderate CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurUncertainDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careUncertainUncertainUncertainGDG was uncertain at round 2, progressed to wider survey
3. only after symptoms have persisted for about 3–4 months following treatment in primary careUncertainAgreeUncertainGDG was uncertain at round 2, progressed to wider survey
4. only after symptoms have persisted for at least 6 months following treatment in primary careAgreeAgreeDisagreeGDG was uncertain at round 2, progressed to wider survey
5. never or only very exceptionallyAgreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
1(n)For a child with severe CFS/ME symptoms a referral for specialised care is appropriate….
1. as soon as symptoms occurUncertainUncertainAgreeGDG was uncertain at round 2, progressed to wider survey
2. only after symptoms have persisted for about 4–6 weeks following treatment in primary careUncertainAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
3. only after symptoms have persisted for about 3–4 months following treatment in primary careAgreeAgreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.
4. only after symptoms have persisted for at least 6 months following treatment in primary careAgreeAgreeDisagreeGDG was uncertain at round 2, progressed to wider survey
5. never or only very exceptionallyAgreeDisagreeThe GDG reached a consensus in the round 2 and the statement did not progress to wider survey.

5.3.5. Recommendations

Note: numbers in square brackets are as in the NICE guidelines.

Referral to specialist CFS/ME care [1.5]

Any decision to refer a person to specialist CFS/ME care should be based on their needs, the type, duration, complexity and severity of their symptoms, and the presence of comorbidities. The decision should be made jointly by the person with CFS/ME and the healthcare professional. [1.5.1.1]

Referral to specialist CFS/ME care should be offered:

  • within 6 months of presentation to people with mild CFS/ME
  • within 3–4 months of presentation to people with moderate CFS/ME symptoms
  • immediately to people with severe CFS/ME symptoms. [1.5.1.2]

5.3.6. Deriving recommendations

The GDG found no research evidence on the criteria for or the timing of referral to specialist CFS/ME care. The GDG recognised that the need to intervene early in the course of the illness must be balanced against the effects of a referral for possibly self-limiting symptoms, which raises anxiety and unnecessarily labels the patient. As there was no certainty on the most appropriate time to refer the GDG decided to include these questions in the wider survey. These results were also uncertain.

Referral for specialist advice

The GDG, with advice from the children’s expert co-optee, advisors, decided that children should be cared for by a general paediatrician and thus an early referral to general paediatric services was required. This recommendation is in line with the National Service Framework for Children32 (see http://www.dh.gov.uk). The paediatrician can exclude other illnesses and manage symptoms. Adults may be cared for by their general practitioner in the first instance unless there is a need for specialist advice on the most appropriate management of symptoms.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

Transitional care

Transitional care is recognised as a key component of adolescent healthcare as young people move from paediatric to adult services. Most young people make this transition successfully but some adolescents find it more difficult for a number of reasons and this may include young people with chronic illnesses/disabilities.33

It is clearly important that there are positive outcomes in the transfer of care yet, whilst there is evidence from young people and parents that transition processes need to be improved, many healthcare professionals are not sure what changes should be implemented in practice.33

The literature review by Janet E McDonagh of the evidence base for transition from paediatric to adult services ‘Growing Up Ready for Emerging Adulthood’33 provides examples of transitional models and details the key components of transition. Other useful resources can be found on the Department of Health’s website, such as the ‘Good Practice Guide Transition: getting it right for young people’, ‘National Service Framework database of emerging practice’, ‘Transition - Getting it Right’ DVD and additional resources to support service development for transition for young people with long-term health conditions. Please see http://www.dh.gov.uk/PolicyAndGuidance/HealthAndSocialCareTopics/ChildrenServices/Transitions/fs/en

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

Referral to a multidisciplinary team specialising in CFS/ME

The GDG decided that a referral should be made following a diagnosis. However, this may be a provisional rather than a definitive diagnosis. The view of the GDG was that 3–6 weeks following the onset of symptoms was generally too short a time but that 6 months was too long. The GDG decided that 3–4 months following the onset of symptoms, once exclusion tests were completed and following a provisional diagnosis, was generally the appropriate time to refer patients to a multidisciplinary team specialising in CFS/ME. However, the timing needed to be based on individual circumstances, as people with severe symptoms needed to be referred immediately.

After consultation on the draft guideline was complete, the GDG continued discussions on the recommendations, based on the comments from the stakeholders. For details of changes and responses to stakeholder comments, please see the comments table which can be found on the NICE website at www.nice.org.uk

5.4. A conceptual framework for patients, carers and healthcare professionals when making a diagnosis of CFS/ME

Different people hold different beliefs about the underlying causes of CFS/ME based on the available evidence and their personal experience of living with or caring for this condition. It is unclear whether CFS/ME is one condition or part of a spectrum of similar conditions that have overlapping features. The current debate about the causes and definition of CFS/ME has generated a need for further well-designed research, focusing on key areas; for example, how do the symptoms of CFS/ME originate and develop? What are the best ways of subgrouping patients to aid in diagnosis and management? What are the predisposing, precipitating and perpetuating factors in CFS/ME?

As the Gibson Inquiry report made clear, the available evidence is very limited: ‘although there are many theories as to its cause or causes, none have been proven beyond reasonable doubt’, and ‘research has been undertaken which offered tantalizing glimpses of abnormalities in sufferers but thus far no specific causal factor has been established’.2

The range of views held by different people about the causes of CFS/ME were reflected in the views held by members of the GDG. Consideration of the causes of CFS/ME was outside the scope of the guideline, and the aim of the GDG was to reach consensus on practical clinical management in order to improve the care of people with CFS/ME. In working towards this aim, the GDG adopted the following approach, which may also be helpful to healthcare professionals caring for people with CFS/ME.

  • Recognition of the limitations of available evidence about the underlying cause(s) of CFS/ME.
  • Avoidance of dogmatic belief in a particular view.
  • Encouragement of further appropriate research to identify causative factors and hence further effective treatments and therapeutic approaches.
  • Adoption of a patient-centred approach that fosters a mutual respect between patients/carers and healthcare professionals as people. Respect is given to others’ views in a patient-centred approach where shared decision-making about treatment plans can occur, and personal views or beliefs are not allowed to impede any individual’s access to care and support.

Footnotes

Defined as clinical features indicating an increased risk of other conditions that require urgent investigation.

§

Note: the criteria are presented in chronological order, not in order of perceived utility.

**

Follow ‘Referral guidelines for suspected cancer’ (NICE clinical guideline 27) or other NICE guidelines as the symptoms indicate. See www​.nice.org.uk for details.

Copyright © 2007, Royal College of General Practitioners.
Bookshelf ID: NBK53567

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