Approach

Introduction

It is important to acknowledge that a large proportion of patients worldwide have only very limited access to appropriate health care for ME/CFS for several reasons, including disability, inaccessibility, lack of appropriate clinical services, and limited knowledge of the disease by healthcare professionals. Diagnosis is frequently delayed, or missed altogether.[10] While waiting for a diagnosis, people with ME/CFS often encounter difficulties in obtaining necessary help and support from healthcare and social services.[10]​ 

Diagnosis is based on the characteristic, self-reported patient history of substantial disabling fatigue (reduced productivity) with post-exertional malaise (PEM), alongside appropriate exclusion of alternative diagnoses. Symptoms include significant and prolonged physical, cognitive, and nociceptive impairments. Orthostatic intolerance may be an additional feature.[10]​ Substantial fatigue and PEM have formed the basis of several diagnostic criteria for ME/CFS.[3][4][5][6][93]

PEM refers to the fatigue and cognitive dysfunction that may develop immediately following exertion of any sort or, more characteristically, after a delay of up to 24 hours. PEM does not respond to rest and may last several days or longer. Although many of the symptoms commonly reported in ME/CFS may occur in several other diseases, the presence of PEM should always prompt consideration of the diagnosis.[10]​

Fatigue in ME/CFS may be profound and must be of new or definite onset (i.e., not lifelong). It is not due to ongoing excessive exertion. It is moderate to severe in intensity and leads to a substantial reduction or impairment in the ability to engage in occupational, social, or personal activities compared with pre-illness levels.

Diagnostic criteria stipulate that diagnosis in adults should not be made until after 6 months of symptoms (3 months for children) and negative medical evaluation.[3][4][5][6]​​​ However, the 2021 UK National Institute for Health and Care Excellence (NICE) guidance discusses the 6-month interval for diagnosis, and the negative impact of a 6-month delay in starting management. NICE therefore recommends that observation in adults be reduced to 3 months before initiating therapy.[8] NICE also recommends that the diagnosis may be suspected if an adult has experienced relevant symptoms for a minimum of 6 weeks (4 weeks in children and young people).[8]

Likewise, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) advises that although full diagnostic confirmation may take 3-6 months, it is important to contemplate the diagnosis at an earlier stage, in order to facilitate disease management and diagnosis and treatment of alternative conditions as soon as possible.[10] EUROMENE recommends that primary care clinicians carry out regular reviews when the diagnosis is suspected in primary care, to explore the possibility of alternative diagnoses, at the same time as carrying out preliminary management strategies for symptoms of ME/CFS.[10]​

Significant functional impairments are predominantly based on self-reported symptoms. The DePaul symptom questionnaire is a validated screening tool and can be used as part of diagnosis.[138] DePaul symptom questionnaire Opens in new window​ Symptoms can then be tracked using a rating scale, such as the Bell Disability Score.[139] Bell Disability Score Opens in new window

Physicians are encouraged to conduct a thorough treatment history, identify all physicians and healthcare professionals (e.g., chiropractor, acupuncturist) currently involved in the patient's care, and obtain a list of prescribed medications, over-the-counter medications, vitamins, supplements, and homeopathic remedies. It is important to check for medications that may lead to fatigue, as well as autonomic and other symptoms.[10]​ ​

Medical exclusions

Early assessment for exclusionary conditions is essential. Primary care professionals play a key role in the initial diagnosis, including consideration of alternative conditions leading to similar symptoms.[10] Many symptoms of ME/CFS are common and nonspecific, and so clinicians must exclude other medical and psychiatric conditions in the differential diagnosis of chronic fatiguing and interoceptive, nociceptive, and cognitive illnesses. 

Up to 30.5% of the population have chronic fatigue that may be part of another disease or idiopathic in nature.[140] One study involving a UK-based tertiary referral clinic found that 19% of people initially referred for ME/CFS evaluation had other chronic medical diseases, 8% had primary sleep disorders, 6% had psychological or psychiatric illnesses, and 2% had cardiovascular disease.[141]​ History should address other conditions that are implicated by each patient’s individualized differential diagnosis. Periodic reevaluation is of value to identify other medical conditions with similar symptoms to ME/CFS.

​The following conditions may potentially exclude a diagnosis if they fully or mainly explain the symptoms:[10]​​​​

  • Organ failure (e.g., emphysema, cirrhosis, cardiac failure, chronic renal failure)

  • Chronic infections (e.g., HIV/AIDS, hepatitis B or C); fatigue has also been reported following recovery from Ebola virus infection[142]

  • Rheumatic and chronic inflammatory diseases (e.g., systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, inflammatory bowel disease, chronic pancreatitis)

  • Major neurologic diseases (e.g., multiple sclerosis, neuromuscular diseases, epilepsy, or other diseases requiring ongoing medication that could cause fatigue, stroke, or head injury with residual neurologic deficits)

    • Optic neuritis and other neuropathies are suggestive of an alternative diagnosis to ME/CFS, and warrant referral to an appropriate specialist (e.g., neurologist)

  • Diseases requiring systemic treatment (e.g., organ or bone marrow transplantation; systemic chemotherapy; radiation of brain, thorax, abdomen, or pelvis)

  • Major endocrine diseases (e.g., hypopituitarism, adrenal insufficiency)

  • Primary sleep disorders (e.g., narcolepsy)

Sleep apnea may be a coexisting but independent finding that should be treated to see whether the fatigue and unrefreshing sleep improve. Conditions found at exam that exclude ME/CFS include adverse effects of medications, chronic sleep deprivation or poor sleep hygiene, untreated hypothyroidism, untreated or unstable diabetes mellitus, and body mass index greater than 40.

Psychiatric exclusions for ME/CFS include lifetime diagnoses of bipolar affective disorders, schizophrenia, delusional disorders, dementia, organic brain disorders, and alcohol or substance use disorder within 2 years before onset of the fatiguing illness.[3]​ Major depressive disorder with psychotic or melancholic features, anorexia nervosa, or bulimia that have resolved for more than 5 years before the onset of the current chronically fatiguing illness should not be considered exclusionary.

Differences in diagnostic criteria

A complicating factor in ME/CFS is the presence of 9 sets of subjective clinical criteria. Criteria that are commonly used in both research and clinical practice include the NICE guidelines for ME/CFS; the Institute of Medicine (IOM, now the National Academy of Medicine) criteria for ME/CFS/Systemic Exertion Intolerance Disease (SEID); the International Consensus Criteria (ICC) criteria for ME; the Canadian Consensus Criteria (CCC) criteria for ME; and the Fukuda or Centers for Disease Control and Prevention (CDC) criteria for CFS.[3][4]​​[6][8][93]​

See Criteria.

​ME/CFS criteria have evolved based on the consensus of experts, rather than the evidence-based surveys of patients. The 1994 CDC criteria for CFS ("Fukuda") and 2003 CCC criteria for ME are the most widely used criteria for ME/CFS.[3][4]​ A new approach was advocated by the IOM in 2015, leading to the definition of SEID.[6] However, this diagnostic term has not become widely adopted in clinical practice. Each iteration has aimed to narrow the diagnosis by requiring disabling fatigue, PEM, plus a series of other complaints, and by introducing exclusionary conditions. However, each set of criteria define slightly different clinical sets of patients.

One historical footnote of relevance in the UK are the Oxford criteria, which were published in 1991.[143]​ Under these criteria fatigue, but not PEM or other symptoms, is required for diagnosis, and these criteria do not explicitly exclude atypical and major depressive disorder and other comorbidities.[6]​​[143][144]​​​ Clinical trials using the Oxford criteria have been fraught with problems. The NICE guidance and the National Institutes of Health (NIH) Pathways to Prevention working group strongly recommend that the Oxford criteria be retired because they may impair progress and cause harm.[145]​  

​The 1994 CDC "Fukuda" case definition is widely used in ME/CFS research, and it is also frequently used for clinical evaluation of patients, particularly in the US.[3] A limitation of the CDC criteria is that PEM is not a requirement for diagnosis. Another limitation is symptom scoring, as the original criteria allowed symptoms to be “present” without grading for severity. A stricter interpretation requires moderate or severe complaints for diagnosis. 

PEM is the essential symptom according to the 2003 CCC and the 2015 IOM criteria.[4][5][6][93]​ As a result, patients identified using these criteria have more severe symptoms and impairment than those selected using the CDC criteria.[6][146][147]​ In 2010 the CCC were updated to specify moderate to severe symptom severity with symptoms present at least half of the time.[4][5]​ The 2011 ICC criteria attempted to include symptom clusters, but these were not organized by pathophysiologic mechanisms, decreasing the value of this version.[93] Patients who fulfill the ICC have more severe functional impairment, physical, mental, and cognitive problems than those who meet the CDC "Fukuda" definition.[3][93]

The IOM revised the clinical diagnostic criteria for ME/CFS in 2015 following a comprehensive analysis of the literature and expert consultation. SEID was proposed as an alternative term for ME/CFS to emphasize the primary symptoms of the disease: sustained fatigue, PEM, and unrefreshing sleep.[6] National Academy of Medicine (Institute of Medicine): proposed diagnostic criteria for ME/CFS Opens in new window Pain was not included as it was not specific to SEID. In contrast to previous diagnostic criteria that include nominal (present versus absent) scoring systems, the IOM criteria set more stringent standards for the severity (moderate, substantial, or severe) and frequency (present at least half the time) of symptoms.

The 2021 UK NICE guideline addresses the continuing debate surrounding the best approach for the diagnosis and management of ME/CFS.[8] The guideline suggests that a diagnosis of ME/CFS should be suspected if the patient has all four key symptoms (e.g., post-exertional malaise, debilitating fatigue, cognitive difficulties, unrefreshing sleep or sleep disturbance) for a minimum of 6 weeks in adults and 4 weeks in children and young people.[8]​ The NICE guidelines provide a pragmatic approach to diagnosis and treatment, and have been adopted in several countries around the world as the standard practice and care for diagnosis and management of ME/CFS.

Other additional resources for diagnosis and management of adults and children with ME/CFS are also available.[11][148]​​[149]

[Figure caption and citation for the preceding image starts]: Overview of clinical criteriaCreated by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@4a5141e8

History

Prior to the onset of significantly impairing chronic fatigue, patients typically report normal levels of physical fitness, activity, and energy. Some patients report historical patterns of overactivity and underactivity prior to disease onset. Fatigue may be of sudden onset, or it may follow a gradual or relapsing-remitting pattern before becoming chronic. In some cases, documented viral infections or stressful events may predate the onset of chronic fatigue. For other patients, although clinical symptoms and presentation may mimic viral infections or other known medical conditions, a review of the clinical history may not reveal any biologic cause for the fatigue.

Key symptoms of ME/CFS include:

  • PEM. This is the most characteristic feature of ME/CFS according to the US IOM criteria.[6][7]​ PEM has been described as a group of symptoms following mental or physical exertion, lasting 24 hours or more. PEM may develop immediately following exertion of any sort or, more characteristically, after a delay of up to 24 hours. Symptoms of PEM include fatigue, headaches, muscle aches, cognitive defects, and insomnia. It can occur after even simple tasks (e.g., walking or holding a conversation) and requires people with ME/CFS to make significant lifestyle changes to conserve their physical resources and mental concentration to stay competent in normal occupational, educational, and social settings.[9] PEM does not respond to rest. Delayed onset of dysfunction is typical in ME/CFS.

  • Persistent disabling fatigue. Fatigue refers to the cognitive and physical state of weariness with an inability to plan and execute usual tasks. It is a complex and multidimensional construct that has been defined as a feeling that interferes with usual functioning, a sense of diminished energy, and an increased need to rest, as well as physical or mental weariness resulting from exertion.[150] Greater cognitive and physical effort is required to complete even routine daily tasks. The fatigue experienced by people with ME/CFS is not related to other medical or psychiatric conditions, and is not idiopathic in nature. The terminology regarding "fatigue" in ME/CFS is multisystemic and distinct from other more generalized forms. Consideration of “fatigue” as mental or physical tiredness is too simplistic to encompass the scope of impairment in ME/CFS and belies the inadequacy of the vocabulary of fatigue. 

  • 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]​ The definition of SEID by the IOM does not include pain due to lack of evidence from the published literature.[6]​ However, pain may be more common than reported in the literature. Joint laxity, which can be the cause of diffuse joint pain, exists in around 21% of patients with ME/CFS.[135]​ Swelling and inflammation is absent. 

  • Headache. Comorbid migraine and tension headaches may occur. New-onset headaches must be distinguished from perimenstrual migraine or post-concussion/post-mild traumatic brain injury headaches. Migraines may occur several days per week to per month and isolate the patient from family and work. The light and sound sensitivity can be moderate during interictal periods between migraines but lead to sound avoidance, extensive use of sunglasses, and closed drapes during the daytime. Sensory sensitivities become more overwhelming during migraines and lead to avoidance behaviors. Chronic daily headaches suggest an alternative diagnosis, and warrant referral to an appropriate specialist (e.g., neurologist).

  • Sleep alteration. Sleep alterations are almost universal in ME/CFS, but are difficult to distinguish from the poor sleep hygiene of the general population. Insomnia may be accompanied by rumination about tasks not completed. Sleep interruption is common, and should be distinguished from overactive bladder and other other medical interruptions during sleep. Prolonged sleep until noon indicates circadian dysregulation. Frequent napping during the day or falling asleep after returning from work or social events are common. Even after a normal or long night’s sleep, patients often report feeling unrefreshed. Sleep apnea may be an independent but coexisting finding and may occur with the usual risk factors, such as obesity; in this situation the addition of continuous positive airway pressure therapy or oral appliances to aid breathing are unlikely to reverse the overall ME/CFS symptom profile.

  • Cognitive dysfunction. Cognitive impairment in ME/CFS includes problems with thinking or executive function exacerbated by exertion, effort, or stress or time pressure. Working memory, the very-short-term resource needed to perform tasks effectively, accounts for the loss of train-of-thought. Working memory is impaired more than long-term episodic memory.[6] Memory impairment is not permanent or progressive as in mild cognitive impairment or Alzheimer disease. It may manifest as "brain fog," "confusion," and/or inability to focus or concentrate on usual activities, find the right word, or do arithmetic.[4][93]​ Patients may struggle with tasks such as watching a film, reading a book or magazine, driving, and participating in a conversation.

  • Orthostatic intolerance. Orthostatic intolerance is a feature of the SEID criteria.[6]​ Symptoms include dizziness, lightheadedness, unsteadiness, impaired balance, nausea, vertigo, or fear of falling that last for more than 30 seconds after standing up.[121] It may limit activities such as standing in line or shopping. Symptoms abate once supine.[107] Although symptoms of orthostatic intolerance are often associated with significant postural orthostatic tachycardia and hypotension, many patients have incapacitating symptoms without these autonomic disruptions. Dehydration is an important factor to consider in these patients. Vestibular dysfunction may also contribute but is not fully evaluated in ME/CFS.

Patients may also describe waxing and waning of recurrent flu-like symptoms (e.g., malaise, myalgia, feverishness), nausea, intolerance of ambient hot or cold temperatures, dizziness, and increased sensitivity to astringent chemicals and odors (e.g., house cleaning fluids, bleach, cigarette smoke, gasoline).[10] Sore throat and tender nonpalpable lymph nodes may also be present.[6]​ Gastrointestinal symptoms akin to irritable bowel syndrome and food intolerances are commonly reported in ME/CFS.[10]

Physical exam

There are no typical objective findings from physical exam of a patient with ME/CFS, and the general physical exam may be entirely normal.[10][151] However, signs of visual dysfunction in ME/CFS are under investigation.[152] Patients may present with a variety of signs and symptoms not specific to ME/CFS, such as resting and orthostatic tachycardia, orthostatic hypotension, lightheadedness or imbalance when standing up but without changes in vital signs, tender nonenlarged lymph nodes (without palpable lymphadenopathy), abdominal tenderness below the xiphisternum and inferolateral to the umbilicus (gastritis and IBS, Chia sign), joint hypermobility/laxity, and muscle and joint hyperalgesia ("tender points").

Tenderness to palpation ("systematic hyperalgesia") may suggest fibromyalgia according to the 1990 American College of Rheumatology criteria; however, note that in subsequent criteria for fibromyalgia the definition has been modified to encompass widespread pain, fatigue, waking unrefreshed, cognitive dysfunction, and somatic complaints, removing the necessity of measuring and quantifying tender points as part of the diagnosis of fibromyalgia.[153][154][155]

The presence of allodynia may support a diagnosis of chronic widespread pain.

Autonomic intolerance such as orthostatic hypotension (with a decrease in systolic blood pressure of greater than 20 mmHg) and postural orthostatic tachycardia may be present. These are unlikely to be detected by lying and standing vital signs. Postural orthostatic tachycardia syndrome (POTS) is diagnosed by an incremental increase in heart rate of ≥30 beats per minute (≥40 beats per minute in adolescents) between 5 minutes of recumbent rest, and 5 minutes of standing.[156] If lying and standing vital signs are normal, but the clinical suspicion of POTS is high, a tilt-table test may be helpful.[121] Idiopathic sinus tachycardia may lead to elevated resting and supine heart rate as well as sinus tachycardia upon standing.

Evidence of frailty may be noted in people with severe symptoms of ME/CFS, and some people may be virtually bed-bound or require use of a wheelchair.[10] (Note that frailty of old age would typically be considered an exclusion for the diagnosis ME/CFS.)

Neurologic exam is usually normal. Neurologic signs such as nystagmus, delayed accommodation, frontal release signs, ataxia, swaying on standing during Romberg testing, muscle weakness, asymmetric reflexes, and fasciculations should be documented for progression by serial physical exams with appropriate referral for consideration of other neurologic diseases.

Signs that are not typical of ME/CFS, such as palpable and firm lymphadenopathy, high fever, tremors, muscle wasting, or asymmetric neurologic signs require further investigation to exclude other medical conditions.

Investigations

The standard battery of laboratory testing is typically normal in patients with ME/CFS. Extensive laboratory or imaging studies are not indicated. The NIH has recommended the following panel of tests for patients presenting with persistent, debilitating fatigue lasting at least 6 months:[157]

  • CBC with WBC differential

  • HIV test

  • Erythrocyte sedimentation rate

  • CRP

  • BUN, creatinine, and electrolytes

  • Blood glucose

  • Calcium, phosphorus

  • Thyroid-stimulating hormone

  • Alkaline phosphatase, aspartate and alanine aminotransferases

  • Total protein, albumin, and globulin

The 2021 UK NICE guideline suggests the same panel of tests, but recommends testing when symptoms have been present for 3 months.[8] Other laboratory tests include antibody tests for antinuclear antibody (ANA) and rheumatoid factor. The panel should be ordered to establish a baseline when first establishing care with a patient. ANA has been frequently stated to be positive in ME/CFS.[158][159]​ Therefore, it is prudent to determine whether there is a high titer (suggestive of systemic lupus erythematosus) or low titer. Rheumatoid factor is not typically elevated in ME/CFS. C-reactive protein may be at the upper range of normal.[76]

Antibody testing for gluten sensitivities/celiac disease may be warranted if gastrointestinal symptoms are present. A serum ferritin test may be valuable in patients with borderline anemia that may exacerbate the effects of decreased circulating volume and dysautonomia leading to orthostatic imbalance.

More extensive or repeat laboratory testing is not recommended due to lack of sensitivity or specificity of laboratory studies in diagnosing ME/CFS, and due to the risk of false-positive results and unnecessary evaluations. The panel should be used to exclude, identify, or treat other clinical conditions contributing to fatigue (e.g., hypothyroidism) and other diseases in the differential diagnosis. Extensive serologic testing for hepatitis B or C, Epstein Barr, cytomegalovirus and other herpes viruses, and Borrelia burgdorferi and other Lyme disease; related organisms have not been effective at identifying cohorts with treatable infections. Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsids may assist in identifying long COVID. Anti-spike protein may indicate vaccination or infection.

Drug-seeking behaviors and evidence of substance use problems can be identified if required by blood or urine drug testing if history taking is inconclusive. A history of chronic recurrent purulent sinusitis and bronchitis may warrant testing for hypogammaglobulinemia. Hemoglobin A1c is useful to assess comorbid type 2 diabetes mellitus with fatigue, neuropathy, or autonomic dysfunction that may appear similar to ME/CFS.

Physicians are cautioned against using extensive and costly evaluative and diagnostic procedures given the absence of known biologic underpinnings of ME/CFS and the lack of verified biomarkers.[10]

Co-occuring conditions

Co-occurring conditions and medications may complicate and prolong assessment and management strategies.

The CCC and ICC recognize numerous comorbidities that are often diagnosed with ME/CFS. These include:[4][5][93]​​​​ 

  • Neurologic disorders:

    • Migraine headaches

    • Peripheral neuropathy

  • Rheumatologic disorders:

    • Fibromyalgia

    • Ehlers-Danlos syndrome

    • Temporomandibular joint dysfunction

    • Sjogren syndrome

  • Autonomic dysfunction:

    • Orthostatic intolerances (i.e., POTS)

  • Immunologic disorders:

    • Mast cell activation syndrome

    • Multiple chemical sensitivities

    • Chronic infections and immunodeficiencies

  • Gastrointestinal disorders:

    • Irritable bowel syndrome

  • Genitourinary disorders:

    • Interstitial cystitis

  • Endocrine disorders:

    • Hypothyroidism

  • Psychiatric disorders:

    • Secondary anxiety

    • Secondary depression

  • Cardiovascular disorders:

    • Raynaud phenomenon

    • Prolapsed mitral valve.

Use of this content is subject to our disclaimer