1.1. Standardization of Clinical Procedures and Services for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe: The Origins
1.2. The Population Burden of the Disease and the Need for Better Recognition
2.1. Development of Recommendations
2.2. Considerations on ME/CFS Diagnosis for Clinical Purposes
|The required symptoms, listed below, must be persistently or recurrently present for at least 6 months in adults (3 months in children and adolescents). If other conditions have the same symptoms, those conditions must be assessed and treated optimally first before a diagnosis of ME/CFS can be made. Exclusionary conditions should be ruled out by a combination of clinical history, physical examination, and complementary tests.|
Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is:
The concurrent occurrence of three or more of the following symptoms:
* Modified for use in clinical diagnosis of ME/CFS, to include PEM as compulsory symptom (EUROMENE recommendation). Source: Fukuda et al. 1994 .
|A diagnosis is based on persistent symptoms as below:|
3. Approach to the Diagnosis and Characterisation of Patients
3.1. Steps to Recognising ME/CFS Cases in Clinical Practice
• Symptoms may start following infectious or other insults or insidiously. These are persistent, but they may fluctuate from day to day or during the day. Some people experience temporary partial remission of symptoms, which is followed by recurrence and may occur after physical or mental exertion beyond their tolerance level.
Although specific symptoms vary in presentation and severity, the symptoms tend to follow a typical pattern of inter-relatedness. This means that patients may have difficulties in distinguishing whether their symptoms arise from lack of energy, pain, or sleep deprivation, for example.
Fatigue and intolerance to efforts are key symptoms which are not always easy to interpret
3.2. Clinical Examination
- General physical examination may be entirely normal. However, some patients present with general aspect of tiredness or of being unwell. Nutritional status is usually satisfactory, though overweight or obesity may result from long-term inactivity or as a neuro-endocrine manifestation of the disease. On the other hand, signs of weight loss or low body mass index (BMI) may be present, more commonly in severely affected patients, although they may also raise suspicion of other severe morbidity; signs of neglect or poor care with basic needs, if noticed, should raise concerns about the wellbeing of the patient. Paleness and cold extremities may be noted.
- Orientation and cognition; patients are oriented, but they may show signs of slow thinking, poor attention and short memory and be lost for words; long consultations may elicit increasing cognitive and physical difficulties as the patient tires; on the other hand, some patients may show signs of anxiety and “wired-tiredness”, where they are restless in spite of being very tired physically and mentally. Emotional responses may be triggered as patients go through their histories and common difficulties experienced with their symptoms and lack of validation of their diagnosis and degree of disability, which are often not obvious to the untrained observer. In general, patients are highly motivated and willing to do whatever may be needed to improve their symptoms. However, secondary anxiety and depressed mood may be observed, and lack of motivation or despondency should raise the possibility of associated low mood.
- Skin: Paleness and cold extremities may be noted, often aggravated by upright position, which may be associated with low peripheral perfusion or autonomic dysfunction. Redness of lower extremities when sitting or standing may also be noted as a consequence of venous congestion.
- Head and neck: Enlarged lymph nodes may be noted especially on the neck and might be tender; non-exudative pharyngitis might be observed, and crimson crescents in the oral pharyngeal region have often been described .
- Chest and cardio-vascular: Examination of the lungs and heart is usually unremarkable, except for possible changes in heart rate and blood pressure. Mild regular tachycardia may be present at rest. Postural tachycardia (standing heart rate of >30/min above normal in patients older than 20 years and > 40/min above normal in younger patients, compared to lying down or >120 standing heart rate at any age) may happen immediately or within 10 min or more after standing up from the recumbent or sitting position; it may result from dysautonomia or relative hypovolemia and result in the diagnosis of postural tachycardia syndrome (POTS). Some patients develop hypotension upon standing, sometimes after a brief period of raised blood pressure. These signs are more common in the young and in some over-medicated patients and may be associated with postural hyperaemia or cold extremities.
- Abdomen: General standard examination is conducted to rule out other explaining diseases; mild diffuse abdominal tenderness is not uncommon.
- Musculoskeletal: Joints appearance is usually normal (no oedema or redness); tenderness of joints and soft tissues may also be present. Some patients have hypermobile joints or fulfil the clinical criteria of hypermobile Ehlers–Danlos syndrome (hEDS) [35,36], which should be recognized as a comorbidity.
- In the more severely affected, signs of frailty may be evident; patients may be virtually bed-bound, sit in a wheelchair, have a pale and puffy face, have cold extremities, and not be able to remain or feel very uncomfortable in the upright position for longer than a few seconds or minutes. There is a general sense of weakness and lack of stamina, and short periods of break during clinical assessment may be required as the patient becomes visibly tired and shows signs of increasing cognitive difficulty. Symmetrical reduction in limb muscle strength may be observed on formal neurological examination, and the hand grip manometer will usually show reduced power, with decreasing values on repeated measurements.
3.3. Differential Diagnosis
3.4. Detailed Clinical Characterization, Laboratory, and Other Tests
|Domain or Specific Clinical Situations||Clinical, Laboratory, and Imaging Assessments or Measurement Instruments|
|Severity assessment||UKMEB-PQsymp; DPQ, RAND-36, Pain and fatigue analogue scales|
|Disability screening||RAND-36 summary scales (physical and mental component summaries)|
|Muscle power and general health||Hand grip measurements, dynamometer|
|Routine tests not done recently and justified clinically||Tests as appropriate|
|If clinical history suggests autoimmune or immunodeficiency||ANA, ENA, TPO, AMA, APA, immunoglobulins, and others according to clinical findings|
|Serious neurocognitive symptoms that increase risks for patients||Neurocognitive tests—e.g., Creteil battery of tests; NIH CDE Toolbox (National Institute of Neurological Disorders and Stroke (NINDS), 2018) |
|Neuroimaging as needed for further neurological investigations||MRI scan, CT|
|Obstructive sleep apnoea suspected||Sleep studies, polysomnography|
|Signs of small fibre neuropathy, peripheral neuropathy, marked muscle symptoms, objective peripheral findings||Nerve conduction studies, electromyography (EMG), skin (for intradermal nerve fibre density) or muscle (rarely necessary) biopsy|
|POTS, orthostatic intolerance||Tilt table test or repeated recumbent and standing heart rate and blood pressure (standing test)|
|Objective assessment of PEM or disability||2-day CPT (use with caution as can cause or aggravate PEM)|
|Other more recent tests which may be useful||Metabolomics, e.g., those revealed through organic acid testing and amino acid urine and serum, cytokine panels, and autoantibodies to receptors such as adrenergic receptors.|
|* A selection or the full range of tests may be conducted routinely or in support of disability assessment. AMA: anti-mitochondrial antibody. ANA: anti-nuclear antibodies. APA: anti-phospholipid antibodies. CPT: cardio-pulmonary testing. DPQ: DePaul Symptom Questionnaire. ENA: extractable nuclear antigens. PEM: post-exertional malaise. POTS: postural orthostatic tachycardia syndrome. TPO: thyroid peroxidase. UKMEB PQsym.: UK ME/CF Participant Questionnaire.|
3.5. Steps to Recognising ME/CFS in Children
3.6. Diagnostic Categories
Prolonged fatigue: persistent profound fatigue or lack of energy, usually (but not necessarily) accompanied by other symptoms; should be present for at least one month
Chronic fatigue (CF): persistent fatigue or lack of energy, that leads to reduced activity levels lasting over 3–6 months*. This may be explained by a condition other than ME/CFS (e.g., cancer-related fatigue) or unexplained (“idiopathic chronic fatigue”). It does not require other symptoms that are typically found in ME/CFS
Post-infectious fatigue or post-viral illness (PIF or PVI): new onset symptom complex including persistent profound fatigue with exercise intolerance following an infectious trigger and which is not otherwise explained by a diagnosed condition or lifestyle. It is usually accompanied by at least 2 further symptoms** from: post-exertional malaise, unrefreshing or poor sleep quality, cognitive or autonomic symptoms for at least 3 months (i.e., this is a subset, where the viral aetiology is clear, of patients with chronic fatigue).
|Examples of stratification categories:|
|* CCC 2003 , IOM 2015 , and Rowe et al., 2017 , criteria require 6 months of symptoms; experienced clinicians should be able to diagnose adults with 3 months of symptoms. For children, CCC criteria requires 3 months , and Rowe et al., 2017 , require 3 months in post-infectious cases. ** The 2 additional symptoms criterium is not required when the fatigue symptoms can be clearly linked to the triggering infection and are not explained by other pathologies.|
3.7. Recommendations for Health Care provision
3.8. Criteria for Referral for Specialist Services
|Diagnosis confirmation |
Severe cases or significant disability, especially if local support is limited
Short duration of symptoms (less than 1 or 2 years)
Rapid deterioration of symptoms
Complex diseases, where diagnosis and treatment are challenging
Inability to provide adequate care in the community or when management and treatment are only available at specialist services
3.9. The Continuing Role of Primary Care and the General Practitioner
4. The ME/CFS Specialist Consultation
4.1. Preparing for the Consultation and the Waiting Room
4.2. Diagnosis Confirmation and Continued Search for Alternative Diagnoses and Co-Morbidities
4.3. Management and Treatment
4.4. Professional-Patient Partnership, Self-Management, and Support
4.5. Managing Patients’ Expectations
4.6. Non-Pharmacological Treatment for Symptoms Relief and Available Support Therapies
|A professional view on symptom management and relief|
|“Periods of rest and “pacing” are important components of all management strategies for ME/CFS patients. Physicians should advise people with ME/CFS on the role of adequate rest, how to introduce breaks into their daily routine, and their frequency and length which may be appropriate for each patient. Excessive rest may be counterproductive, except in the initial stages of disease, in the very severe cases, or in cases of acute exacerbation; so it is important to introduce ‘low level’ physical and cognitive activities within the patient’s capacity, according to the severity of symptoms.|
Sleep management is tailored to the individual, the role and effect of disordered sleep is explained, common changes in sleep dysfunction that may exacerbate fatigue symptoms are identified; common manifestations include insomnia, hypersomnia, sleep reversal, altered sleep-awake cycle and non-refreshing sleep. The professional provides general advice on good sleep hygiene and encourages gradual changes in sleep pattern, though of course there is no implication that poor sleep hygiene is the cause of non-refreshing sleep. Relaxation techniques appropriate for ME/CFS should be offered for the management of pain, sleep problems and comorbid stress or anxiety. Examples include guided visualisation and breathing techniques, which can be incorporated into daily routines and rest periods”, while mindfulness ma be of value as a sympathetic nervous system modulator. Although exclusion diets are not generally recommended for managing ME/CFS, many people find them helpful for some symptoms, including bowel symptoms. The patient may attempt an exclusion diet or dietary manipulation under professional guidance and supervision, e.g., from a dietitian. For those with nausea, advice includes eating small portions and snacking on dry starchy food and sipping fluids. The use of anti-emetic drugs should be considered if the nausea is severe.” Dr. L. Lorusso (personal communication)
4.7. Symptoms Relief and Management Using Available Pharmacological Drugs
|* Refer to local guidelines on the use of medications that are not specifically licensed for use in ME/CFS.|
4.8. Following the Consultation and Clinical Monitoring
4.9. Needs of Patients with Different Severities
5. Concluding Remarks and Recommendations for Developing and Organising ME/CFS Services
|Specific societal sectors|
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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