**2. Methods**

#### *2.1. Development of Recommendations*

The EUROMENE network activities were organised in Working Groups (WG), including the Clinical Group, tasked to explore existing methods used for the diagnosis of cases in Europe and to develop recommendations for the diagnosis and treatment of people with ME/CFS in the continent. The recommendations for standardising the diagnostic criteria for ME/CFS to be used by European researchers are covered in a related EUROMENE document [26], which will allow comparability and better estimates.

We have not systematically reviewed the evidence in relation to diagnostic criteria and interventions, as this has been done by others. Thus, the following recommendations are pragmatic and were based on the working group member's collective and consensual assessment of key documents on clinical definitions of ME/CFS [2,4–6,27,28] and existing studies and guidelines for clinical assessments and care used in Europe and internationally [1]. The WG members met on various occasions (WG meetings) to agree on key documents and to consider them, based on the members' experiences and expertise and relevance for clinical practice in Europe. We recognise that there is still limited evidencebased research on ME/CFS; as we witness progresses in this field, we recognise the need for frequent reviews of these recommendations, in line with emerging evidence.

#### *2.2. Considerations on ME/CFS Diagnosis for Clinical Purposes*

Many diagnostic criteria have been proposed for use in clinical practice, of which those by the Institute of Medicine (currently, National Academy of Medicine), known as the IOM criteria, have received international recognition. Their relative simplicity makes them ideal for use in primary care. An editorial in the Lancet in 2015 [29] suggested that the adoption of the new name Systemic Exertion Intolerance Disease (SEID) could lead to changed attitudes and greater acceptance of the condition. However, despite the fact that the term ME/CFS implies a particular underlying pathology which has ye<sup>t</sup> to be demonstrated, this remains the most widely used diagnostic term, and it is arguable also that SEID understates the severity of the condition, since exertion intolerance is by no means its only clinical feature. The term ME, an abbreviation for myalgic encephalomyelitis, in particular, is unsatisfactory as it suggests that the pathological process underlying the disease is an inflammatory process affecting the brain. There is a lack of convincing evidence for this, and the truth is undoubtedly both more arcane and more complex. The term CFS, short for chronic fatigue syndrome, is equally unsatisfactory, as it implies that fatigue is the main symptom of the illness, whereas in fact its clinical features are far more wide-ranging. The composite term ME/CFS thus carries the disadvantages and shortcomings of both contributary terms. We use it and recommend its use, on purely pragmatic grounds despite these problems, since most clinicians and researchers working in the field use the term and understand its shortcomings. It is part of the lingua franca and enables those working in the field to communicate effectively with each other and, it is to be hoped, to make progress which will enable us ultimately to establish the underlying pathology with greater precision, leading in turn to the development of more appropriate and accurate terminology.

A case of ME/CFS in an adult patient requires the presence of symptoms for at least 6 months and are typically present for at least half of the time (Box 1).

**Box 1.** Institute of Medicine (IOM) criteria for the diagnosis of ME/CFS.

Required symptoms



For full details, see Institute of Medicine (IOM), 2015 [6].

The Canadian Consensus Criteria (CCC) are particularly suitable for diagnosis confirmation and case sub-grouping in secondary care, as well as in research (Box 2). The CDC-1994/Fukuda et al. criteria [27] may also be used as a screening tool for diagnosis in clinical practice, but we recommend that only cases with post-exertional malaise (PEM) (which is optional in that definition), are included for diagnosis (Box 3). Note that although the CDC-1994 criteria have been developed for research purposes, they have often been used for diagnosis purposes in clinical practice and are still a preferred case definition by some in Europe.

For children, the IOM [6] and Rowe et al., 2017, criteria [4] (Box 4) may be used. The latter is based on 6 cardinal paediatric symptoms and a disease duration of 6 months; a diagnosis of "postinfectious fatigue syndrome" (PFS) is made when the symptoms are present for 3 months following an acute infection. The Canadian Consensus criteria [2] may also be used in children, as proposed by Jason et al. [5,30]. However, using 3 months of symptoms is sufficient for diagnosis in children and adolescents.

Diagnosis in both adults and children can be suspected earlier, and the primary care physician should be proactive in starting diagnostic investigations. Initial managemen<sup>t</sup> and referral may be considered when diagnosis is suspected or with 3 months of symptoms, as appropriate.

**Box 2.** Canadian Consensus Criteria for the diagnosis of ME/CFS.

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.


In addition, at least one symptom from two from the following categories of symptoms are required:


For full details, see Carruthers et al., 2003 [2]. The structure of the CCC definition in adults and some aspects of the CDC-1994 [26] criteria were used to create a paediatric cases definition of ME/CFS [5,30].

#### **Box 3.** Modified\* CDC-1994 Criteria for the diagnosis of ME/CFS.

## Primary symptoms

•

Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is:


## Additional symptoms

The concurrent occurrence of three or more of the following symptoms:

Substantial impairment in short-term memory or concentration;


These symptoms must have persisted or reoccurred during 6 or more consecutive months of illness and must not have started before the fatigue.

\* Modified for use in clinical diagnosis of ME/CFS, to include PEM as compulsory symptom (EUROMENE recommendation). Source: Fukuda et al. 1994 [27].

**Box 4.** Paediatric diagnosis of ME/CFS.

A diagnosis is based on persistent symptoms as below:

Compulsory symptoms:


A diagnosis is made if all the criteria below apply:


For full details, see Rowe et al., 2017 [4]. For research we recommend using the DePaul Symptom Questionnaire Pediatric (DSQ-Ped) [5].

#### **3. Approach to the Diagnosis and Characterisation of Patients**

*3.1. Steps to Recognising ME/CFS Cases in Clinical Practice* Clinical History

History reveals the main symptoms, including extreme fatigue, fatigability, and cognitive difficulties that are worsened by physical or mental effort. Physical fatigue is often expressed as "lack of energy or stamina", profound tiredness, or general weakness (Box 5).

Mental fatigue is expressed as cognitive problems, such as slowness of response, attention, and concentration problems; they are often referred by patients as "brain-fog" and result in reduced ability to perform "mental tasks".

There is significant intolerance to efforts, both physical and mental, with post-exertional aggravation of symptoms or PEM. PEM typically has delayed onset, often noticed hours later or the following day, and lasts for variable and often extended periods of timee.g., from a day in milder cases to many days or weeks in moderately and severely affected individuals.

Sleep is characteristically "non-restorative" or "unrefreshing", and difficulty in initiating or maintaining sleep is common.

Orthostatic intolerance may be manifested with light-headedness and worsening of symptoms (such as fatigue, malaise, dizziness, nausea, palpitations) when assuming or persisting in the upright position for some time, usually a few minutes, but it may happen very soon after raising from the recumbent position or within up to 10 min or more, depending on severity of the dysautonomia. The most severely affected may be unable to stand for more than a few seconds.

Pain can be generalised and referred to joints, muscles, and adjacent soft tissues, with frequent headaches commonly reported. Pain may be migratory and variable in nature and is not associated with signs of inflammatory arthritis or myositis, with typical absence of joint swelling or redness.

There is considerable symptom overlap between ME/CFS and fibromyalgia [30], and a concomitant diagnosis of fibromyalgia [31,32] is often made. The latter requires pain to be generalised (present in at least 4 of 5 body regions) and is widespread and accompanied by other symptoms, such as fatigue, poor sleep, and cognitive difficulties [33].

Importantly, the symptoms of ME/CFS lead to substantial reductions in previous levels of activity and function. Some individuals will still manage full-time work or education, at least for some time. However, very often patients are unable to take up or continue full-time work or education, or any at all, with a significant minority (often quoted as corresponding to 25% of all patients) virtually home- or bedbound. Educational, social, and economic consequences take their toll, with a resulting compromise in emotional wellbeing.

#### *3.2. Clinical Examination*


**Box 5.** Symptoms and complaints to consider when taking a clinical history.

*Key symptoms*


*Additional symptoms*


*Symptoms' characteristics*

• 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


>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.


#### *3.3. Differential Diagnosis*

Since fatigue is a common complaint in daily life and in association with a range of medical problems, it is important to note that most people with ongoing fatigue do not have ME/CFS but rather have symptoms that are caused by other conditions, emotional well-being, or life-style-factors. The presence of PEM, however, raises the level of suspicion, as this is quite typical, though not specific of ME/CFS.

The list of co-morbid conditions and differential diagnoses is not exhaustive. Examples are listed in Boxes 6 and 7. Some conditions are often present concomitantly to ME/CFS (co-morbidities). Other conditions may potentially exclude a diagnosis if they fully or mainly explain the symptoms. However, such conditions may also be co-morbid when their presence does not explain most of the symptoms and signs observed. In general, when one of these conditions is present and is not well-controlled, the patient should be offered optimum treatment and stabilization, before a diagnosis of ME/CFS is considered. Severe conditions should be explored early and excluded or treated promptly. Action is prompted by clinical suspicion and red flags, such as unintentional weight loss, prolonged fever ≥ 38 ◦C, persistently elevated inflammatory markers, significant abnormalities in physical examination, or suicidal ideation. Box 8 includes suggested diagnostic sub-categories, which may change as the clinical picture and further clinical and related information arise. It should be noted also that some comorbid conditions occur largely in the presence of ME/CFS and so their presence or otherwise should be noted when considering whether the possible comorbid condition fully explains the patient's symptoms.

**Box 6.** Co-morbid conditions which do not exclude ME/CFS diagnosis.


**Box 7.** List of diseases where fatigue may be a prominent feature, which may preclude a diagnosis of ME/CFS if the disease largely explains the symptoms. They may, however, be co-morbidities with ME/CFS if they do not fully explain symptoms characteristic of ME/CFS (including fatigue, cognitive complains, sleep dysfunction, PEM).



#### *3.4. Detailed Clinical Characterization, Laboratory, and Other Tests*

Further patient characterization may involve the use of standard questionnaires— which may be self-completed or applied by an interviewer, and physical measures, which are used to assess function and disease severity. They are useful for patient's baseline evaluation, and, when repeated subsequently, they provide indicators of disease course and evaluation of response to treatment. Core assessments shown in Box 8 include examples of tests that may be used routinely for that aim. When research studies are linked to clinical practice, these and other questionnaires and instruments may also be used [26]. Further laboratory tests and imaging studies may be needed to identify potential co-morbidities, and/or to exclude other diagnoses. These should be guided by clinical assessment and the need to exclude conditions that may explain the symptoms.

Examples of useful screening tests for initial investigations in primary care include full blood count, ferritin, liver enzymes, renal function, thyroid function, high-sensitivity C reactive protein (CRP) or erythrocyte sedimentation rate, electrolytes including sodium, potassium, calcium, inorganic phosphate, creatine phosphokinase (CK), and fasting glucose or glycated haemoglobin.

Serology screening for EBV, hepatitis B and C, HIV, Lyme, and other tick-borne diseases may be useful according to clinical and epidemiological features [40].

Other tests may be required according to availability of resources or as clinically guided. These are usually reserved for specialist centres or are done through referral to other specialties. These are usually aimed at differential diagnosis but could also be used for better characterization of pathology or for the assessment of function and disability (Box 6). Examples include anti-CCP, transglutaminase antibodies, morning cortisol, vitamin B12, NT-pro BNP, and vitamin D3 or 25(OH)D. In some cases, an extended auto-immune screening, allergy testing, serum tryptase levels, and/or lymphocyte differentiation may be required. Imaging and other specialised tests may be appropriate in some cases but are usually reserved for specialist centres, e.g., brain or spine MRI, cardiopulmonary exercise testing (CPET), cognitive testing panel, echocardiography, and tilt table or standing test.

Tests results will often be unremarkable, though subtle abnormalities may be observed [40]. Routine inflammatory markers are usually not elevated in ME/CFS. Low CK suggests severe disease or very low physical activity levels [41]. Elevated LDH and GPT/GOT are found in a subset of patients. Elevated NT-pro BNP might be found and is associated with lower cardiac volume [42]; this should be investigated further. A subset of patients has diminished IgG/A/M levels and/or IgG subclass deficiency [43]. Marked abnormalities should raise the suspicion of an alternative diagnosis.

#### *3.5. Steps to Recognising ME/CFS in Children*

None of the criteria used in adults have been validated for the diagnosis of paediatric ME/CFS. Diagnosis of ME/CFS in children is especially challenging for two main reasons: First, younger children may not report symptoms accurately and might assume fatigue as normal, when not remembering the experience of full health. Second, there are differences in how children perceive and report symptoms of ill health, and proxy reporting by parents may not always accurately reflect children's experience. To account for the latter, paediatric ME/CFS should be diagnosed if CCC are fulfilled for as little as 3 months and no other underlying disease has been identified (Box 2). Owing to differences in manifestations and their ascertainment in children, compared to adults, a paediatric case definition that uses the structure of the CCC 2003 adults' definition and some aspects of the CDC-1994 criteria was published in 2006 [30] and modified in 2018 [5]. Most recently, a group of experienced paediatricians suggested a "Clinical Diagnostic Worksheet" [4] (Box 4). This guidance refers to "impaired function" or a "substantial reduction in the child's ability to take part in personal, educational, and/or social activities" associated with fatigue and PEM as cardinal symptoms. Other symptoms including headaches, myalgia, joint pain, sore throat, painful lymph nodes, and abdominal pain are scored as "pain" [4].

Symptoms usually start acutely, often following symptoms of infection, e.g., flu-like symptoms, or gastroenteritis, but may have an insidious or episodic onset. In children, about half of the cases of ME/postinfectious fatigue syndrome manifest after typical Epstein–Barr-virus (EBV)-associated infectious mononucleosis [44–46]. Symptoms are usually fluctuating in type and severity (especially in the early stages of the disease), with patients typically reporting "good" and "bad" days. A more careful analysis of the pattern of symptoms may reveal correlation with physical or mental efforts.

Primary care professionals may suspect a diagnosis in children and adolescents presenting with persistent or recurrent moderate to severely impaired function, fatigue, and post-exertional symptoms, especially if associated with autonomic symptoms, sleep disturbance, neurocognitive problems, and pain (e.g., headaches and abdominal pain), following history, clinical examination, and routine tests that exclude other diagnoses that may explain the symptoms. We recommend paediatricians use the full criteria from Rowe et al.

(2017) [4] as part of diagnostic approach and the CCC 2003 criteria [2] if symptoms are present for 3 months.


Questionnaire. ENA: extractable nuclear antigens. PEM: post-exertional malaise. POTS: postural orthostatic tachycardia syndrome. TPO: thyroid peroxidase. UKMEB PQsym.: UK ME/CF Participant Questionnaire.

## *3.6. Diagnostic Categories*

A proposed diagnostic characterization of patients, which builds on previous disease criteria definitions, is shown in Box 9, which also suggests stratification variables that may be used for sub-grouping of cases.

Chronic fatigue-spectrum disorder (CFSd) is an encompassing term and may be used to refer to persistent profound fatigue for over 3–6 months associated with other symptoms, including the following sub-categories: (a) cases meeting diagnostic criteria for ME/CFS; (b) cases that do not fully meet diagnostic criteria (Non-ME chronic fatigue-Sd) but cannot

be explained otherwise; (c) cases totally or partially explained by other diseases known to cause chronic fatigue (disease-associated CFS; or ME/CFS of combined aetiology).

**Box 9.** Diagnostic categories and sub-grouping.
