History and exam
Key diagnostic factors
common
post-exertional malaise/fatigue (PEM; exertional exhaustion)
PEM is the characteristic finding in ME/CFS.[6] Minor levels of physical and/or mental exertion are poorly tolerated. Low levels of physical or cognitive activity or emotional stressors lead to exacerbations of fatigue, pain, and cognitive dysfunction. Such exacerbations may have immediate onset or be delayed by several hours, and they may persist for 24 hours or more.
PEM is a required symptom for diagnosis according to the 2021 UK National Institute for Health and Care Excellence (NICE) guideline, the Institute of Medicine definition of systemic exertion intolerance disease, and the Canadian working group definition of chronic fatigue syndrome ME/CFS.[5][6][8]
persistent disabling fatigue
Not alleviated by sleep, rest, or activity restriction. The pattern of fatigue may be persistent or relapsing and remitting, and may be present for over 6 months in adults. The NICE guideline suggests reducing this timeframe to 3 months.[8]
Fatigue may show mild remissions but without a return to the usual, previous state of health and activity. Fatigue must be moderate to severe and persist for more than 50% of the time.[6]
cognitive dysfunction
Disruption of working memory is common.[6] However, long-term memory disruption is uncommon.
Attention or concentration difficulties, word-finding difficulties, and slowness of information processing may also be apparent.[6]
Exertion-induced cognitive dysfunction affecting working memory may occur.
Memory impairment is not permanent or progressive as found in mild cognitive impairment or Alzheimer’s disease.
sore throat
Episodic discomfort that may be associated with flu-like complaints and tender lymph nodes (without palpable lymphadenopathy).[6]
headache
New-onset headaches or significant change in headache locus or severity.
Comorbid migraine and tension headaches are common, but are often not treated.
sleep alteration
Sleep is characteristically ‘non-restorative’ or ‘unrefreshing.’[10]
Sleep disruption may be characterised by hyposomnia, hypersomnia, or fragmented sleep.
Sleep disruption compounded by behavioural changes to sleep cycle (e.g., increased resting and sleeping during normal waking hours).
Poor sleep hygiene with reversal of sleep and wake cycles may occur.
orthostatic intolerance
Dizziness, lightheadedness, spatial disorientation, or malaise after standing up from a recumbent or resting position.[6][107]
May limit activities such as standing in a queue or shopping. Postural changes in vital signs may not be found despite standing for 1 or 2 minutes. Although symptoms of orthostatic intolerance are often associated with significant postural orthostatic tachycardia and hypotension, many patients have incapacitating symptoms without these autonomic disruptions
pain and hyperalgesia
Chronic pain and hyperalgesia affecting muscles, joints, subcutaneous tissues, mucosal surfaces, and any other location innervated by somatic and sympathetic sensory neurons are common presenting symptoms in ME/CFS.[3]
There are typically no signs of joint inflammation.
uncommon
tender lymph nodes
There may be tender axillary, cervical, and/or subauricular nodes.[6]
Discrete, palpable lymph nodes suggest an alternative diagnosis (e.g., infection or neoplasm).
Other diagnostic factors
common
age of onset (adolescence and 30-50 years)
flu-like symptoms (malaise, myalgia, feverishness)
Frequent waxing and waning of flu-like symptoms, including malaise, myalgia, and feverishness.[10]
anxiety, affective disorder
Around 40% of ME/CFS patients have clinical depression and/or anxiety, which is similar to many other chronic medical illnesses.[160] Anxiety, depressed affect, and maladaptive coping skills may predate or co-occur with ME/CFS.
Other stigmata of depression, such as anhedonia, psychomotor agitation or retardation, feelings of worthlessness, excessive or inappropriate guilt, and recurrent thoughts of death and suicide, are not typical of ME/CFS but instead indicate comorbid depressive disorder.
sensations of altered temperature or feverishness
Symptoms such as intolerance of ambient hot or cold temperatures, feverishness, sweating, chills, or the need to wear extra clothing compared with others may occur.[10]
uncommon
irritant sensitivities
Some patients with ME/CFS become more sensitive to astringent chemicals and odours, such as house cleaning fluids, bleach, cigarette smoke, and gasoline.[10] Airway symptoms may be akin to multiple chemical sensitivity disorder. Nasal congestion and rhinorrhoea may be due to non-allergic rhinopathy with hyperactive cholinergic reflexes, which may be responsive to anticholinergic nasal sprays such as ipratropium or tiotropium bromide. Rates of positive allergy skin tests and ranges of IgE levels appear to be similar for patients with ME/CFS and those without ME/CFS.[161]
Risk factors
strong
female sex
Approximately 2-3 times more common among women than among men.[18][25] Little research has investigated sex differences in ME/CFS. The differing prevalence of ME/CFS in men compared with women suggests a potential role of endocrine disturbances; however, current research is limited by small sample sizes and the use of less specific inclusion criteria.[129]
Epstein-Barr infection in adolescents
Epstein-Barr virus infection (infectious mononucleosis) evolves into ME/CFS in 13% of adolescents after 6 months.[36] The rate drops to around 4% at 24 months indicating a high rate of remission in adolescents.
coronavirus disease 2019 (COVID-19)
People with post-COVID-19 syndrome (i.e., long COVID) have chronic disabling fatigue and other symptoms that overlap with ME/CFS.[49] Longitudinal studies will determine the rate of improvement of post-COVID-19 syndrome (i.e., long-COVID), prevalence of chronic ME/CFS in post-COVID-19 patients, and differences in their pathogenesis.[51]
weak
positive family history of ME/CFS
genetic factors
There is some evidence of a genetic component to ME/CFS, although multiple genome-wide association studies have not yielded consistently significant associations to date.[130]
specific infectious diseases in adults
To date, there is no consistent evidence to support any individual viral or other infectious agent in the majority of ME/CFS cases, and antiviral medications have not been successful in treating the broad spectrum of ME/CFS.[31][52][53][54] Long COVID is likely to be the exception to this finding.
However, infectious diseases in adults are reported prior to the onset of ME/CFS including Q fever, parvovirus, West Nile virus, SARS, influenza, and other infections.[32][39][40][41]
autoimmunity
dysfunction of gut microbiome
major depressive disorder
While there is a relationship between fatigue and depression when measured by the Center for Epidemiologic Studies Depression Scale (CES-D), fatigue is neither sensitive nor specific for the diagnosis of depression.[132]
Depression before age 36 was associated with subsequent development of ME/CFS (odds ratio 2.65).[133] However, the relationship of depression with ME/CFS must be tempered by the criteria used to diagnose ME/CFS (for example, major depressive disorder within the past 5 years is an exclusionary condition for the Canadian ME/CFS criteria) and by the high rate of mental health conditions in the general population.[4] Fatigue is a common manifestation of major depressive disorder in the greater general population and this combination is not synonymous with ME/CFS.[132]
ancestry
Community surveys found that English-speaking white Americans had a lower risk of ME/CFS than Latino, African-American, or Native American people.[22][26][27] In England the prevalence of ME/CFS among people of Pakistani ancestry has been found to be 3.5%, while its prevalence is 0.8% in white people.[28]
joint hypermobility/laxity
Joint hypermobility is associated with fatigue in children, ME/CFS (21%), anxiety, postural orthostatic tachycardia syndrome, irritable bowel syndrome, other functional somatic syndromes, and brainstem alterations on magnetic resonance imaging.[134][135][136] Impaired range of motion in the spine and limbs has been reported in adolescents with ME/CFS.[137]
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