Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME-CFS): good practice statement

3. Clinical assessment and diagnosis

3.1 Initial presentation

This may be sudden or gradual. It may follow an infection, typically but not always viral for example: flulike illness, glandular fever, viral hepatitis, enteroviruses (including Coxsackie A & B), labyrinthitis, herpes viruses (including herpes zoster and cytomegalovirus) and parvovirus B19. In the region of one in ten to one in eight people may be affected by ME-CFS after contracting the Epstein-Barr Virus (EBV). Other infections, such as Coxiella burnetti/Q fever and Mycoplasma pneumoniae can also precipitate ME-CFS. Patients commonly describe themselves as never having fully recovered from the infection.

The role of trauma, surgery and stressful major life events as trigger factors is possible, but less well established. Toxin and pesticide exposures have also been suggested by some as trigger factors. In a minority of cases, the onset can be more insidious with no identifiable precipitating factor and here the diagnosis can be harder to make, particularly in the early stages.

As with any long term illness, early and accurate diagnosis brings significant benefits. For most adults, six weeks from the onset of abnormal fatigue is a time to be considering ME-CFS as a differential working diagnosis. The aim should be to make a diagnosis 3-4 months into the illness. Further guidance on children and young people, including early diagnosis, is presented in Section 5.

Making a diagnosis is an essential first step in active management of the illness. It diminishes uncertainty, reduces fear and provides an explanatory model that justifies appropriate change in a person's lifestyle and expectations. Like many neurological diseases, the diagnosis is based on clinical evaluation and there are no confirmatory diagnostic tests. The diagnosis should be a positive one based on pattern recognition of a range of recognised symptoms, and other conditions excluded as appropriate.

3.2 Diagnostic criteria

A number of diagnostic criteria have been proposed for ME-CFS, including the Oxford (1991),^[2] the US Centres for Disease Control and Prevention (CDC – Fukuda – 1994)^[3] the Canadian Consensus Document (2003)^[4] and NICE Guideline (2007)^[5] definitions, but no one set has been universally agreed. This important issue is discussed in greater detail in Section 6. (The Canadian Consensus Document definition is provided in Appendix 2, including a list of differential diagnoses, exclusions and possible co-morbidities).

NICE 2021 Update

1. Debilitating fatigue worsened by activity but not caused by excessive cognitive, physical, emotional or social exertion and is not significantly relieved by rest.

2. Post exertional malaise after activity in which the worsening of the symptoms:

a. Is often delayed in onset by hours or days

b. Is disproportionate to the activity

c. Has a prolonged recovery time that may last hours, days, weeks or longer?

3. Unrefreshing sleep or sleep disturbance (or both), which may include:

a. Feeling exhausted, feeling flu-like and stiff on waking

b. Broken or shallow sleep, altered sleep pattern or hypersomnia

4. Cognitive difficulties (sometimes described as 'brain fog'), which may include problems finding words or numbers, difficulty in speaking, slowed responsiveness, short-term memory problems, and difficulty concentrating or multitasking.

3.3 Symptoms and history

ME-CFS usually presents with a combination of persistent or recurrent fatigue, myalgic and/or joint pain (in the absence of joint swelling or redness), that can be widespread and migratory. Pain, rather than fatigue may often be the patient's worst symptom. Symptoms are provoked by physical or mental exertion and can be very disabling. Post-exertional malaise lasting for more than 24 hours is commonplace. There is a substantial reduction in activity levels. The illness may have an acute or more insidious onset, and persists for at least six months. The symptoms of ME-CFS usually fluctuate in their severity and nature over time and diurnal variation is common.

It is helpful to create a list of all current symptoms as "polysymptomatology" can be a significant diagnostic clue. The following symptoms may be present:

• Fatigue – a significant degree of new onset, unexplained persistent or recurrent physical and mental fatigue or malaise that substantially reduces activity level.
• Post exertional malaise and/or fatigue – loss of previous physical and mental stamina and rapid fatigability, malaise and/or pain and a worsening of other symptoms that the patient may have. The recovery period is prolonged – 24 hours or longer is common.
• Sleep disturbance – hypersomnia, insomnia, reversed or chaotic diurnal sleep rhythms and unrefreshing sleep.
• Pain-significant myalgia is common. Arthralgia without swelling, redness or joint deformity, may be present. Muscle and/or joint pain can be experienced which is often widespread and migratory in nature.
• Headaches – are often present, usually migraine or tension type but a variety of patterns and severity may occur. New onset headache should be assessed according to standard clinical practice.
• Cognitive symptoms almost always present – particularly sluggish or 'fogging' of thinking, poor attention/concentration and forgetfulness. Perceptual and sensory disturbances may be experienced – eg inability to focus vision. Hypersensitivity to light (photophobia) or noise (hyperacusis), are common problems.
• Neurological symptoms – muscle twitches, spasms and weakness – are common occurrences.
• Postural light headedness, dizziness, pallor, palpitations – are common features. Postural light headedness/dizziness may lead to an unsteady gait. An increase in heart rate may suggest Postural Orthostatic Tachycardia Syndrome (PoTS) – see Examination, below.
• Paraesthesia – peri-oral and peripheral paraesthesia.
• Flulike symptoms – recurrent symptoms of sore throat; tender, painful and/or swollen lymph nodes. Feeling of fever, shivering and/or temperature fluctuation, sweating episodes, cold intolerance, cold extremities, intolerance of extremes of heat and cold.
• Nausea
• Irritable bowel symptoms
• Altered appetite anorexia or abnormal appetite, loss of adaptability and worsening of symptoms with stress. Marked weight change may also be a feature and can be exacerbated by stress.
• Urinary symptoms – frequency and urgency

Symptoms of ME-CFS usually fluctuate in their severity and nature with time. It is important to ask about recent travel, tick/insect bites, unusual infections, drug and alcohol use (alcohol intolerance may be present in ME-CFS). Current medication should be reviewed, where applicable.

3.4 Examination

A full physical examination must be performed.

• Height and weight (severe obesity can cause fatigue; very small stature can raise the possibility of rare mitochondrial diseases)
• Supine erect blood pressure and pulse rate (to exclude significant postural hypotension which can resemble some of the symptoms of ME-CFS or be a sign of Addison's disease. An increase in heart rate over 30 bpm may indicate Postural Orthostatic Tachycardia Syndrome (POTS),^[6] a recognised comorbid finding in ME-CFS – consider cardiology referral for further assessment).
• General medical examination including looking for signs of anaemia, tanning in unusual sites (for Addison's), enlarged or tender lymph nodes and organomegaly
• Skin and joints for evidence of systemic inflammatory diseases – note any peri-articular tenderness typical of fibromyalgia.
• Neurological examination to exclude specific neurological abnormalities such as: obvious muscle wasting, ptosis, upper motor neurone signs, ataxia, fasciculations, absent reflexes. If any of these abnormalities are present, neurological specialist referral is indicated.

Note: Muscle twitches and spasms commonly occur and some give way weakness is also common in ME-CFS because of pain and fatigue, but normal power is usually possible even if only for a few seconds with encouragement. In terms of differential diagnosis, fatigue is a very common presentation in general practice. In addition to assessment for physical causes, mental state examination should be carried out to identify patients with major depressive disorder or panic disorder with agoraphobia. Questions should be tailored enquiring about the ability to enjoy anything (including those activities the patient is physically capable of) and 'situationally specific' somatic symptoms of panic (i.e. chest pain, palpitations, dizziness, weakness after a typical time gap on leaving the house). This can be the sole cause of persistent fatigue or present as important and reversible co-morbid disorders.

Some patients presenting with complaints of persistent fatigue and/or pain will have somatisation disorder; previous frequency and history of medical contact should be reviewed.

Features suggestive of other disorders or requiring further investigation

Fatigue is a symptom of many diseases and therefore a definitive list is not possible. The following should be regarded as 'red flags' for alternative diagnostic explanations, as part of the process of differential diagnosis:

• Substantive unexplained weight loss
• Objective neurological signs
• Symptoms or signs of inflammatory arthritis or connective tissue disease
• Symptoms or signs of cardio-respiratory disease
• Symptoms of sleep apnoea
• Clinically significant lymphadenopathy

3.5 Investigations

Relevant investigations should be performed to aid in the differential diagnosis of ME-CFS and to exclude other illnesses.

All patients

• Full blood count (FBC)
• Urea, electrolytes and creatinine (U&Es)
• Liver function tests, including albumin (LFTs)
• Thyroid function tests (TFTs)
• Glucose (random)
• Erythrocyte Sedimentation Rate (ESR)
• C-reactive protein (CRP)
• Calcium
• Creatine kinase
• Ferritin
• Urinalysis

When indicated by history or examination

• Antimitochondrial antibodies (AMA) (if minor alterations in LFTs)
• Antinuclear antibody test (ANA)
• Cytomegalovirus (CMV)
• Coeliac serology (if diarrhoea/altered bowel habit, weight loss or history of autoimmune disorders and in patients with a family history of coeliac disease)
• Epstein-Barr Virus (EBV)
• Extractable Nuclear Antigens (ENA)
• Human Immunodeficiency Virus (HIV)
• Hepatitis B and C
• Lyme serology
• Serology for chronic bacterial infections
• Toxoplasma
• Electrocardiogram (ECG) (if any cardiological symptoms)

Tests or investigations that are not currently indicated in clinical practice Laboratory tests not indicated:

• Vitamin B12 & folate (where normal FBC)
• Candida albicans
• Fibrinogen
• Lactate dehydrogenase
• Mitochondrial testing
• Platelet activation
• Protein electrophoresis
• Prothrombin fragment 1&2
• Soluble fibre monomer
• Thrombin-antithrombin complexes
• Xenotropic murine leukaemia virus-related virus (XMRV) serology

Other investigations not indicated:

• Magnetic Resonance Imaging (MRI) brain scan (in the absence of objective neurological signs)
• Tilt table testing (in the absence of unexplained syncope or other clinical indications)
• Auditory brainstem responses
• Electroencephalography (EEG)
• Electrodermal activity
• Positron Emission Tomography (PET) imaging
• Single Photon Emission Computed Tomography (SPECT) imaging