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From Ramsay to SEID – defining ME

 JUMP  | 1969 WHO Classification | 1986 Ramsay Definition | CDC 1988 Definition (Holmes) | Oxford 1991 Definition | CDC 1994 Definition (Fukuda) | 1994 London Definition | 2003 Canadian Consensus Criteria (CCC) | CDC 2005 Empiric Definition | 2010 Revised Canadian Consensus Definition (CCC) | 2011 International Consensus Criteria (ICC) | NIH/IOM 2015 Definition (SEID)


Since the first documented outbreak of a chronic fatigue-like illness over 200 years ago1, there has there been little evidence of progress in the treatment, diagnosis and social acknowledgement of a disease which affects as many as 2.5 million in the US alone2.

Much of the debate about the illness, commonly referred to as CFS, ME or conflated to ME/CFS, is still mired in uncertainties about the nature of symptoms, causes and biological processes, and the presumed effectiveness and safety of so called biopsychosocial interventions such as cognitive behavioral therapy (CBT) and graded exercise therapy (GET).

Over the years, although a number of formal definitions of the illness, called criteria, have guided clinical diagnosis and treatment of ME and CFS, determined government policy on research funding, even influenced public perceptions about its nature and severity, consensus between researchers, governments and even patients on which criteria is best suited is far from settled.

The criteria for the illness actually define two distinct, partially overlapping, entities: Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS).

Fundamental to the historical narrative of the illness, says Frank Twisk, is the reality that although ME and CFS are considered to be the same, the criteria define two distinct, partially overlapping, clinical entities3.

In the video below, Leonard Jason presents his extensive research into the merits and weaknessses of ME/CFS definitions at the 2014 NIH P2P Workshop.



Fundamental differences between ME and CFS

Twisk goes on to define ME and CFS separately:

Myalgic Encephalomyelitis (ME) is a neurological disease4,5 that has been described in the medical literature since 1934 under various names6, including epidemic neuromyasthenia and atypical poliomyelitis, often relating to outbreaks7,8,9.

Characteristic symptoms of ME, classified as a disease of the nervous system by the WHO since 196910, are muscle weakness, neurological dysfunction, especially of cognitive, autonomic and neurosensory functions; variable involvement of the cardiac and other systems; a prolonged relapsing course; but above all general or local muscular fatigue after minimal exertion with prolonged recovery times (post-exertional malaise)2.

Chronic Fatigue Syndrome (CFS) was introduced as a clinical entity much later, in 1988,11 and redefined in 199412. The diagnosis CFS is primarily based upon a vague notion of chronic fatigue13,14.

According to commonly used criteria for CFS2 chronic fatigue must be accompanied by at least four out of eight symptoms, e.g., tender lymph nodes and muscle and joint pain.

However, five of the eight minor symptoms, i.e., headaches, lymph node pain, sore throat, joint pain, and muscle pain, do not differentiate people with melancholic depression group from healthy controls15.

The CFS criteria by definition select a heterogeneous population of people with chronic fatigue16,17,18,19.

Myalgic Encephalomyelitis (ME) is a neurological disease defined by the WHO, while the diagnosis Chronic Fatigue Syndrome (CFS) is primarily based upon a vague notion of chronic fatigue.


Why it matters

If the illness can be differentiated by symptom severity and functional impairment, in a sense so can the different criteria.  For example, the Canadian Consensus Criteria (CCC) identifies a subset of ME/CFS patients with more functional impairments and physical, mental, and cognitive problems than the Fukuda Definition ((Jason LA, Brown A, Clyne E, Bartgis L, Evans M, Brown M. Contrasting Case Definitions for Chronic Fatigue Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. Evaluation & the health professions. 2012;35(3):280-304. doi:10.1177/0163278711424281. [Full Text])).


In the video below, Prof Leonard Jason explains why good definitional criteria are important for ME/CFS, and exposes the weakness of those definitions in use up to 2010.




1969 WHO Classification

Benign Myalgic Encephalomyelitis was classified in 196910 as a neurological disease by the World Health Organisation in its International Classification of Disease (currently listed under Other disorders of brain:Postviral fatigue syndrome:WHO ICD 10 G93.3).

1986 Ramsay Definition

Following the Royal Free Hospital outbreak in the UK, Wallis (1955) and Acheson (1959) made the earliest attempts to formally describe the disease, their descriptions focusing on the hallmark muscular and neurological symptoms, including ease of fatigability and potentially relapsing and remitting course. Acheson coined the term ‘Myalgic Encephalomyelitis’ (1956) reflecting the muscular, brain and CNS involvement thought characteristic of the disease.

Dr Melvin Ramsay in 1986 added to these descriptions drawing on his extensive first-hand experience of the Royal Free Hospital outbreak20.

Dr Melvin Ramsay
Dr Melvin Ramsay

Then in 1986 Ramsay published a definition21 of this disease using the term myalgic encephalomyelitis and the term benign was dropped due to the seriousness of the disability created by the illness22.

Ramsay’s criteria differentiated the disease into two main groups: symptoms at onset and symptoms in chronic state. He further differentiated the chronic state into three main groups: muscle phenomena, circulatory impairment, and cerebral dysfunction. Interestingly, fatigue was not a cardinal feature of Ramsay’s chronic state ME.

1990 Revised Ramsay Definition. In 1990, Ramsay collaborated with Dr Elizabeth Dowsett, to publish revisions to his definition, which emphasized an initial viral trigger, and also introduced the concept of prolonged recovery time23.

Note, Ramsay’s Definition did not use validated criteria published in a peer review journal.

For details of the criteria of 1986 and 1990 Ramsay Definitions, toggle the panels below.

1986 Ramsay Definition criteria

1986 Ramsay Definition criteria

Symptoms at onset

They are similar to those described in the various recorded outbreaks. Thus it may be sudden and without apparent cause, as in cases where the first intimation of illness is an alarming attack of acute vertigo, but usually there is a history of infection of the upper respiratory tract or, occasionally, the gastrointestinal tract with nausea and/or vomiting.

Instead of an uneventful recovery the patient is dogged by:

  • Persistent and profound fatigue accompanied by a medley of symptoms such as
  • Headache
  • Giddiness
  • Muscle pain, cramps, or twitchings
  • Muscle tenderness and weakness
  • Paraesthesiae [numbness or tingling in the extremeties]
  • Frequency of micturition [urination]
  • Blurred vision and/or diplopia [double vision]
  • Hyperacusis [sensitivity to noise sometimes alternating with deafness or normal hearing]
  • Tinnitus [constant sound in the ears], and a
  • General sense of “feeling awful.”


Some patients report the occurrence of fainting attacks relieved by a small meal or just eating a biscuit; these attacks were the result of hypoglycaemia …

All cases run a low-grade pyrexia (fever), seldom exceeding 100°F (c. 38°C) and usually subsiding within a week.

A very thorough examination of the central nervous system should be made and this should be accompanied by a careful estimation of muscle power, especially in the limbs and neck. A search for enlarged lymph nodes should never be omitted. If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME cases can make more.

Symptoms in chronic state

Once the syndrome is fully established the patient presents a multiplicity of symptoms which can most conveniently be described in three groups.

Muscle phenomena

  • Fatiguability: Muscle fatigability, whereby, even after a minor degree of physical effort, three, four or five days, or longer, elapse before full muscle power is restored and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME, but it is most important to stress the fact that cases of ME or mild or even moderate severity may have normal muscle power in a remission. In such cases, tests for muscle power should be repeated after exercise.
  • Pain: In severe cases of ME, muscle spasms and twitchings are a prominent feature and give rise to swollen bands of tissue which are acutely tender. In less severe cases, muscle tenderness may not be so readily elicited but careful palpation of the trapezii and gastrocnemii (the muscle groups most commonly involved) with the tip of the forefinger should enable the examiner to detect minute foci or exquisite tenderness….
  • Clumsiness: In the aftermath of the disease patients frequently fumble with relatively simple manoevres such as turning a key in a lock or taking the cork of a bottle.


Circulatory impairment. Most cases of ME complain of:

  • Cold extremities and
  • Hypersensitivity to climactic change…
  • Ashen-grey facial pallor, some twenty or thirty minutes before the Patient complains of feeling ill


Cerebral dysfunction

  • The cardinal features:
    • Impairment of memory
    • Impairment of powers of concentration and
    • Emotional lability
  • [Other] common deviations from normal cerebral function:
    • Failure to recall recent or past events,
    • Difficulty in completing a line of thought…
    • Becoming tongue-tied in the middle of a sentence, and a
    • Strong inclination to use wrong words, saying “door” when they mean “table” or “hot” when they mean “cold”…
    • Complete inability to comprehend a paragraph even after re-reading it
    • Bouts of uncontrollable weeping . . .
    • Alterations of sleep rhythm or vivid dreams, or both…
  • [Accompanying] features [that] can only be attributed to involvement of the Autonomic nervous system:
    • Frequency of micturition (urination)
    • Hyperacusis (hypersensitivity to noise)
    • Episodic sweating
    • Orthostatic tachycardia…


Variability and fluctuation of both symptoms and physical findings in the course of a day is a constant feature in the clinical picture of myalgic encephalomyelitis.

An alarming tendency to become chronic. [Added in the 2nd edition, 1988]

1990 Ramsay Definition criteria

1990 Ramsay Definition criteria

A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.

The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are:

  • Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time.
  • Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal.
  • Variable involvement of cardiac and other bodily systems.
  • An extended relapsing course with a tendency to chronicity.
  • Marked variability of symptoms both within and between episodes.



CDC 1988 Definition (Holmes)

The first US chronic fatigue syndrome definition, the CDC 1988 Definition, perhaps better known as the Holmes Definition, introduced the term chronic fatigue syndrome in an attempt to better describe the symptom complex previously known as chronic Epstein-Barr virus syndrome.24

Guided by the US Centers for Disease Control and Prevention (CDC), the Holmes working group documented concern regarding the invalidity of Epstein-Barr virus serologic tests and the lack of a causal relationship between Epstein-Barr virus infection and some patients who had been diagnosed with the chronic Epstein-Barr virus syndrome.

Anthony L. Komaroff, M.D., a member of the Holmes Definition team.
Anthony L. Komaroff, M.D., a member of the Holmes Definition team.

The 1988 definition was proposed for research purposes, as a basis for future epidemiologic and clinical studies, with the understanding that it did not necessarily define a single disease but a syndrome – a complex of potentially related symptoms that may have several causes.

According to this case definition, individuals needed to report 6 or more months of persistent or relapsing, debilitating fatigue that does not resolve with bedrest.

Also, participants were required to report at least 8 of 11 minor symptoms (fever or chills, sore throat, lymph node pain, muscle weakness, muscle pain, postexertional malaise, headaches of a new or different type, migratory arthralgia, neuropsychiatric complaints, sleep disturbance, and a sudden onset of symptoms).

Participants were also required to report at least a 50% impairment of daily functioning, as compared to premorbid levels.

The new definition shifted the focus of the disease away from Ramsay’s earlier work and in so doing omitted or under-emphasized many of its cardinal symptoms instead giving undue prominence to chronic fatigue.

Another major concern was that the requirement of eight or more minor symptoms could inadvertently select for individuals with psychiatric problems25.

For details of the CDC 1988 Definition (Holmes) criteria, toggle the panel below.

CDC 1988 definition (Holmes)

Case Definition for The Chronic Fatigue Syndrome

A case of the chronic fatigue syndrome must fulfill major criteria 1 and 2, and the following minor criteria: 6 or more of the 11 symptom criteria and 2 or more of the 3 physical criteria; or 8 or more of the 11 symptom criteria.


  1. New onset of persistent or relapsing, debilitating fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with bedrest, and that is severe enough to reduce or impair average daily activity below 50% of the patient’s premorbid activity level for a period of at least 6 months.
  2. Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings.
    These conditions include malignancy; autoimmune disease; localized infection (such as occult abscess); chronic or subacute bacterial disease (such as endocarditis, Lyme disease, or tuberculosis), fungal disease (such as histoplasmosis, blastomycosis, or coccidioidomycosis), and parasitic disease (such as toxoplasmosis, amebiasis, giardiasis, or helminthic infestation); disease related to human immunodeficiency virus (HIV) infection; chronic psychiatric disease, either newly diagnosed or by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); chronic inflammatory disease (such as sarcoidosis, Wegener granulomatosis, or chronic hepatitis); neuromuscular disease (such as multiple sclerosis or myasthenia gravis); endocrine disease (such as hypothyroidism, Addison disease, Cushing syndrome, or diabetes mellitus); drug dependency or abuse (such as alcohol, controlled prescription drugs, or illicit drugs); side effects of a chronic medication or other toxic agent (such as a chemical solvent, pesticide, or heavy metal); or other known or defined chronic pulmonary, cardiac, gastrointestinal, hepatic, renal, or hematologic disease.

Specific laboratory tests or clinical measurements are not required to satisfy the definition of the chronic fatigue syndrome, but the recommended evaluation includes serial weight measurements (weight change of more than 10% in the absence of dieting suggests other diagnoses); serial morning and afternoon temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine, blood urea nitrogen; calcium, phosphorus; total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase; creatine phosphokinase or aldolase; urinalysis; posteroanterior and lateral chest roentgenograms; detailed personal and family psychiatric history; erythrocyte sedimentation rate; antinuclear antibody; thyroid-stimulating hormone level; HIV antibody measurement; and intermediate-strength purified protein derivative (PPD) skin test with controls.

If any of the results from these tests are abnormal, the physician should search for other conditions that may cause such a result. If no such conditions are detected by a reasonable evaluation, this criterion is satisfied.


Symptom Criteria

To fulfill a symptom criterion, a symptom must have begun at or after the time of onset of increased fatigability, and must have persisted or recurred over a period of at least 6 months (individual symptoms may or may not have occurred simultaneously). Symptoms include:

  1. Mild fever – oral temperature between 37.5 degrees C and 38.6 degreesC, if measured by the patient – or chills. (Note: oral temperatures of greater than 38.6 degrees C are less compatible with chronic fatigue syndrome and should prompt studies for other causes of illness.)
  2. Sore throat.
  3. Painful lymph nodes in the anterior or posterior cervical or axillary distribution.
  4. Unexplained generalized muscle weakness.
  5. Muscle discomfort or myalgia.
  6. Prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient’s premorbid state.
  7. Generalized headaches (of a type, severity, or pattern that is different from headaches the patient may have had in the premorbid state).
  8. Migratory arthralgia without joint swelling or redness.
  9. Neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression).
  10. Sleep disturbance (hypersomnia or insomnia).
  11. Description of the main symptom complex as initially developing over a few hours to a few days (this is not a true symptom, but may be considered as equivalent to the above symptoms in meeting the requirements of the case definition).

Physical Criteria

Physical criteria must be documented by a physician on at least two occasions, at least 1 month apart.

  1. Low-grade fever – oral temperature between 37.6° C and 38.6° C, or rectal temperature between 37.8° C and 38.8° C. (See note under Symptom Criterion 1.)
  2. Nonexudative pharyngitis.
  3. Palpable or tender anterior or posterior cervical or axillary lymph nodes. (Note: lymph nodes greater than 2 cm in diameter suggest other causes. Further evaluation is warranted.)


Oxford 1991 Definition

In 1991, a small group of British psychosocial psychiatrists (Sharpe et al)26 created guidelines to facilitate their research into fatiguing conditions.

The guidelines became known as the Oxford 1991 Definition and included CFS of unknown etiology and a subtype of CFS called post-infectious fatigue syndrome (PIFS), which “either follows an infection or is associated with a current infection.”

However, in reality, this definition shifted the focus of the illness away from the biological entity described in Ramsay’s Definition (1986) and the London Definition (1994) towards a biopsychosocial model.

The presence of mental fatigue is required to fulfill the criteria and symptoms are accepted that may suggest a psychiatric disorder27.

These guidelines were not intended to investigate ME or any other neuro-immune disease26,28 and in essence identified people with idiopathic chronic fatigue29,30.

Shortly after publication of the Oxford criteria Anthony David wrote: “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic fatigue in the absence of neurological signs (but) with psychiatric symptoms as common associated features”31.

Less specific criteria, based on the presence or absence of fatigue as the only mandatory symptom, increased the likelihood of patients with primary psychiatric disorders being included in trial cohorts labeled with CFS32,33,34.

For details of the Oxford 1991 Definition criteria, toggle the panel below.

Oxford Definition 1991 criteria



There are no clinical signs characteristic of the condition, but patients should be fully examined, and the presence or absence of signs reported.

Two broad syndromes can be defined:

  1. Chronic fatigue syndrome (CFS)
    1. A syndrome characterized by fatigue as the principal symptom.
    2. A syndrome of definite onset that is not lifelong.
    3. The fatigue is severe, disabling, and affects physical and mental functioning.
    4. The symptom of fatigue should have been present for a minimum of 6 months during which it was present for more than 50% of the time.
    5. Other symptoms may be present, particularly myalgia, mood and sleep disturbance.
    6. Certain patients should be excluded from the definition. They include:
    7. Patients with established medical conditions known to produce chronic fatigue (eg severe anaemia). Such patients should be excluded whether the medical condition is diagnosed at presentation or only subsequently. All patients should have a history and physical examination performed by a competent physician.
    8. Patients with a current diagnosis of schizophrenia, manic depressive illness, substance abuse, eating disorder or proven organic brain disease. Other psychiatric disorders (including depressive illness, anxiety disorders, and hyper- ventilation syndrome) are not necessarily reasons for exclusion.
  2. Post-infectious fatigue syndrome (PIFS)
    This is a subtype of CFS which either follows an infection or is associated with a current infection (although whether such associated infection is of aetiological significance is a topic for research). To meet research criteria for PIFS patients must:
  1. fulfil criteria for CFS as defined above, and
  2. should also fulfil the following additional criteria:
    1. There is definite evidence of infection at onset or presentation (a patient’s self-report is unlikely to be sufficiently reliable).
    2. The syndrome is present for a minimum of 6 months after onset of infection.
    3. The infection has been corroborated by laboratory evidence.


CDC 1994 Definition (Fukuda)

The CDC 1994 Definition for CFS (1994), also known as the Fukuda Definition, was a US Centers for Disease Control and Prevention (CDC) initiative, primarily developed for research studies of CFS in adults. It is currently favored for use research and clinical diagnosis.

The Fukuda Definition requires a person to experience 6 or more months of chronic fatigue of a new or definite onset, that is not substantially alleviated by rest, not the result of ongoing exertion, and results in substantial reductions in occupational, social, and personal activities.

Because the Fukuda criteria only require four symptoms out of a possible eight, critical CFS symptoms such as postexertional malaise, and memory and concentration problems are not required of all patients.

The Fukuda definition is regarded as less specific than the Holmes criteria which selected a group of patients with higher symptomatology and functional impairment35.

Furthermore, these differences do not appear to be influenced by psychiatric variables, as they occurred in the absence of differences in rates of psychiatric comorbidity between the two groups35.

Another criticism is that Fukuda lacks clinical application, that it is characterized by vaguely worded criteria that are lacking operational definitions and guidelines to assist health care professionals in their interpretation and application of the diagnostic tool36.

Several investigations have contrasted the Holmes and Fukuda Definitions.  In a study of 2,376 primary care patients, 1.2% of the sample were diagnosed with CFS by using the 1988 case definition (Holmes), compared to 2.6% using the 1994 case definition (Fukuda)37.

Another study of 71 primary care patients with CFS found that participants meeting only the 1994 definition experienced a greater duration of illness than those meeting the 1988 definition38. In contrast, those in the 1988 group reported greater frequency of sore throats, joint pain, tender lymph nodes, headaches, and fever. Finally, the 1988 group was more likely to report a sudden illness onset and a greater reduction in premorbid activity levels than the 1994 group.

See Also:


For a full list of the CDC 1994 Definition (Fukuda) criteria, toggle the panel below.

Fukuda Case Definition for CFS

CDC 1994 Definition (Fukuda) criteria

Guidelines for the Evaluation and Study of CFS:

A thorough medical history, physical examination, mental status examination, and laboratory tests must be conducted to identify underlying or contributing conditions that require treatment. Diagnosis or classification cannot be made without such an evaluation. Clinically evaluated, unexplained chronic fatigue cases can be classified as chronic fatigue syndrome if the patient meets both the following criteria:

  1. The individual has severe chronic fatigue for 6 or more consecutive months that is not due to ongoing exertion or other medical conditions associated with fatigue (these other conditions need to be ruled out by a doctor after diagnostic tests have been conducted)
  2. The fatigue significantly interferes with daily activities and work
  3. The individual concurrently has four or more of the following symptoms:
    • post-exertion malaise lasting more than 24 hours
    • unrefreshing sleep
    • significant impairment of short-term memory or concentration
    • muscle pain
    • pain in the joints without swelling or redness
    • headaches of a new type, pattern, or severity
    • tender lymph nodes in the neck or armpit
    • a sore throat that is frequent or recurring

These symptoms persisted or recurred during 6 or more consecutive months of illness and they cannot have first appeared before the fatigue.

Conditions that Exclude a Diagnosis of CFS

  1. Any active medical condition that may explain the presence of chronic fatigue, such as untreated hypothyroidism, sleep apnea and narcolepsy, and iatrogenic conditions such as side effects of medication.
  2. Some diagnosable illnesses may relapse or may not have completely resolved during treatment. If the persistence of such a condition could explain the presence of chronic fatigue, and if it cannot be clearly established that the original condition has completely resolved with treatment, then such patients should not be classified as having CFS. Examples of illnesses that can present such a picture include some types of malignancies and chronic cases of hepatitis B or C virus infection.
  3. Any past or current diagnosis of:
    • major depressive disorder with psychotic or melancholic features
    • bipolar affective disorders
    • schizophrenia of any subtype
    • delusional disorders of any subtype
    • dementias of any subtype
    • anorexia nervosa
    • or bulemia nervosa
  4. Alcohol or other substance abuse, occurring within 2 years of the onset of chronic fatigue and any time afterwards.
  5. Severe obesity as defined by a body mass index [body mass index = weight in kilograms ÷ (height in meters)2] equal to or greater than 45. [Note: body mass index values vary considerably among different age groups and populations. No “normal” or “average” range of values can be suggested in a fashion that is meaningful. The range of 45 or greater was selected because it clearly falls within the range of severe obesity.]

Any unexplained abnormality detected on examination or other testing that strongly suggests an exclusionary condition must be resolved before attempting further classification.

Conditions that do not Exclude a Diagnosis of CFS

  1. Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or melancholic depression, neurasthenia, and multiple chemical sensitivity disorder.
  2. Any condition under specific treatment sufficient to alleviate all symptoms related to that condition and for which the adequacy of treatment has been documented. Such conditions include hypothyroidism for which the adequacy of replacement hormone has been verified by normal thyroid-stimulating hormone levels, or asthma in which the adequacy of treatment has been determined by pulmonary function and other testing.
  3. Any condition, such as Lyme disease or syphillis, that was treated with definitive therapy before development of chronic symptoms.
  4. Any isolated and unexplained physical examination finding, or laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary condition. Such conditions include an elevated antinuclear antibody titer that is inadequate, without additional laboratory or clinical evidence, to strongly support a diagnosis of a discrete connective tissue disorder.

A Note on the Use of Laboratory Tests in the Diagnosis of CFS

A minimum battery of laboratory screening tests should be performed. Routinely performing other screening tests for all patients has no known value. However, further tests may be indicated on an individual basis to confirm or exclude another diagnosis, such as multiple sclerosis. In these cases, additional tests should be done according to accepted clinical standards.

The use of tests to diagnose CFS (as opposed to excluding other diagnostic possibilities) should be done only in the setting of protocol-based research. The fact that such tests are investigational and do not aid in diagnosis or management should be explained to the patient.

In clinical practice, no tests can be recommended for the specific purpose of diagnosing chronic fatigue syndrome. [Emphasis added.] Tests should be directed toward confirming or excluding other possible clinical conditions. Examples of specific tests that do not confirm or exclude the diagnosis of chronic fatigue syndrome include serologic tests for Epstein-Barr virus, enteroviruses, retroviruses, human herpesvirus 6, and Candida albicans; tests of immunologic function, including cell population and function studies; and imaging studies, including magnetic resonance imaging scans and radionuclide scans (such as single-photon emission computed tomography and positron emission tomography).


1994 London Definition

The 1994 London Definition, based on Dr Melvin Ramsay’s clinical description of ME, was developed on behalf of M.E. Action, now Action for M.E. (AfME), for research purposes. Although these criteria were an improvement over the Oxford criteria, their legitimacy has been compromised – they have never been published or submitted for peer review, nor have they been consistently defined or validated.

The London Definition places an emphasis on exercise-induced muscle fatigue plus delayed recovery of muscle power after exertion ends, evidence of central nervous involvement and impaired circulation (also known as the diagnostic triad).

Two versions of the London Definition appeared around 1993/94. Version 1 was devised for AFME. A truncated and inaccurate revision39, Version 2, published in the 1994 National Task Force Report40 did not include the exclusion diagnoses and the physical examination findings.

Another subverted form of the London Definition, based on version 1, was used as secondary criteria in the PACE trial, after the application of the fatigue-based Oxford to exclude those with neurological symptoms, contrary to the original purpose of the original version41.

So it should be noted that the only documented application of the London Definition, in the PACE trial, was to filter out serious illness and focus more on fatigue (as a psychological component).

For a full list of each of the London Definition criteria, toggle the panels below.

London Definition criteria (Version 1)

adopted by M.E. Action (now Action For M.E..)

Major Criteria

These five major criteria must all be present for a diagnosis of M.E./PVFS to be made. The presence of minor criteria listed below lends further support to the diagnosis but if they occur in the absence of the major criteria then the volunteer research subject should not be used for the purpose of research into M.E./PVFS and an alternative diagnosis should be keenly sought.

    1. An identifiable viral illness immediately preceding the development of M.E./PVFS. This usually presents with upper respiratory symptoms and is usually attributed to ‘flu or glandular fever. Other prodromal (and/or concurrent) illnesses which have been reported are: gastro-intestinal infections, meningitis, myocarditis, thyroiditis, labyrinthitis, Bornholm’s disease, hand, foot & mouth disease.
    2. Exercise-induced fatigue precipitated by trivially small exertion – physical or mental – relative to the patient’s previous exercise tolerance. Pain and coarse fasciculations in exercised muscles is common. These symptoms may sometimes be immediate or delayed for a few hours and may persist for several days.
    3. Thus a previously accomplished athlete may liken the after-effects of climbing a single flight of stairs to those of running a marathon or a previously able-bodied housewife may find a normal day’s housework beyond her physical capacity.
    4. Impairment of short-term memory and loss of powers of concentration, usually coupled with other neurological and psychological disturbances such as emotional lability, nominal dysphasia, disturbed sleep patterns, vertigo or tinnitus.
    5. Fluctuation of symptoms, usually precipitated by either physical or mental exercise (see b) above.

These major symptoms should have been present for at least 6 months and should be ongoing.

Minor Criteria
These can be subdivided into the following two categories:

  1. Autonomic: Bouts of inappropriate night or day-time sweating; Raynaud’s phenomenon; postural hypotension; disturbances of bowel motility manifesting as recurrent diarrhoea or occasionally constipation (these symptoms are frequently indistinguishable from those of irritable bowel syndrome); photophobia; blurred vision due to disturbed accommodation; hyperacusis; frequency of micturition; nocturia.
  2. Immunological: Symptoms suggesting persistent viral infection, e.g. episodes of low-grade fever (i.e. not exceeding an oral temperature of 38.6C) combined with feeling feverish (i.e. a down-regulated ‘thermostat’); sore throat which may be persistent or recurrent (i.e. present for at least one week per month); arthralgia of a fixed or migratory nature.

This list is by no means exhaustive: headaches, nausea and bloating, for instance. are common symptoms in many patients but are not sufficiently discriminative because of their widespread occurrence in many other disorders.

The curious intolerance to alcohol and hypersensitivity to drugs are highly specific in this context. It should also be emphasised that the symptoms of ME tend to vary capriciously from hour to hour and day to day. Nevertheless it is absolutely characteristic that they tend to be exacerbated by physical or mental exertion and this association should always be sought whilst taking the history. We recommend the use of M.E. Action’s questionnaire for Research subjects Volunteers.

London Definition criteria (Version 2)

adopted by M.E. Action (now Action For M.E..)

[Important Note: The exclusion diagnoses and the physical examination findings omitted in publication have been added by Shoutout About ME.]

Three criteria must be present for a diagnosis of ME/PVFS to be made:

  1. Exercise-induced fatigue precipitated by trivially small exertion -physical or mental – relative to the patient’s previous exercise tolerance.
  2. Impairment of short-term memory and loss of powers of concentration, usually coupled with other neurological and psychological disturbances such as emotional lability (= being upset by things that would not normally cause distress), nominal dysphasia (= difficulty finding the right word), disturbed sleep patterns, dysequilibrium (= imbalance or unsteadiness rather than vertigo/spinning round) or tinnitus (= noises in the ear).
  3. Fluctuation of symptoms, usually precipitated by either physical or mental exercise (see above).

These symptoms should have been present for at least 6 months and should be ongoing.

Although ME/PVFS typically follows an infection, usually a viral illness (which may be subclinical) in a previously fit and active person, it has also been observed to be triggered by other factors such as immunisations, life traumas and exposure to chemicals. Furthermore, in a minority of patients, ME/PVFS has a gradual onset with no apparent triggering factor. For these reasons proof of a preceding viral illness is not a prerequisite for diagnosis.

Many symptoms are experienced by people suffering from M.E./PVFS and in the right symptomatic context they contribute to the validity of the diagnosis. Nevertheless, not all people suffering from M.E./PVFS experience all these symptoms and their absence does not exclude the condition.

These can be subdivided into the following two categories:

  • Autonomic:
    • bouts of inappropriate night or day-time sweating;
    • Raynaud’s phenomenon (= cold extremities);
    • postural hypotension (= lowered blood pressure on standing);
    • disturbance of bowel motility manifesting as recurrent diarrhoea or occasionally constipation (these symptoms are frequently indistinguishable from those of irritable bowel syndrome);
    • photophobia (= sensitivity to bright light); vision due to disturbed accommodation;
    • hyperacusis (= sensitivity to loud noise);
    • frequency of micturition (= passing urine more often than normal); nocturia (= passing urine at night).
  • Immunological (Symptoms suggesting persistent viral infection):
    • episodes of low-grade fever (not exceeding an oral temperature of 38.6C) combined with feeling feverish, (i.e. a down-regulated ‘thermostat’);
    • sore throat which may be persistent or recurrent (i.e. present for at least one week per month);
    • arthralgia (fixed or migratory).


This list is by no means exhaustive; headaches, nausea and bloating, for instance, are common symptoms in many patients but are not sufficiently discriminative because of their widespread occurrence in many other disorders. The curious intolerance to alcohol and hypersensitivity to drugs are highly specific in this context. It should also be emphasised that the symptoms of M.E. tend to vary capriciously from hour to hour and day to day. Nevertheless it is absolutely characteristic that they tend to be exacerbated by physical or mental exertion and this association should always be sought whilst taking the history.

Sometimes evident in people suffering from M.E. / PVFS

Characteristic physical signs are seen in M.E./PVFS and in the right symptomatic context they contribute to the validity of the diagnosis. Nevertheless their absence does not exclude the condition, and they are as follows:

  • Pharyngitis which is either persistent or recurrent (present for at least one week every month) with or without tonsillar enlargement. This is nearly always non-exudative and when present may be accompanied by the low-grade fever mentioned under immunological symptoms.
  • Tender and possible enlargement of lymph nodes, particularly of the cervical groups; these also may accompany the fever and they may decrease in size during the afebrile periods.
  • Muscle tenderness with a particular predilection for the neck and shoulder girdle and the major muscles of locomotion. Points of exquisite tenderness are occasionally found by palpating the affected muscles with the tip of a finger.
  • A positive Romberg test.


Although M.E./PVFS typically follows an infection, usually a viral illness (which may be subclinical) in a previously fit and active person, it has also been observed to be triggered by other factors such as immunisations, traumas and exposure to chemicals. Furthermore, in a minority of patients, M.E./PVFS has a gradual onset with: no apparent triggering factor. For these reasons proof of a preceding viral illness is not a prerequisite for diagnosis or inclusion in a study group.

When diagnosing M.E. for research purposes, particular attention must be paid to two factors:

  • many of the symptoms and signs evident in people suffering from M.E./PVFS could be due to a large number of other important diseases/conditions.
  • M.E. may run in parallel with other diseases having similar symptoms and signs.


Because it is vital that the M.E. study groups we use in research are as ‘pure’ as possible, the existence of a parallel disease would be grounds for disqualification. The most common alternative diagnoses/parallel. diseases to be borne in mind before referring a research subject volunteer to an M.E. study group can be considered under the following headings:

  • Chronic infections:  toxoplasmosis, Lyme disease, HIV infection, chronic active hepatitis, schistosomiasis, brucellosis, occult sepsis, tuberculosis, giardia.
  • Endocrine disorders:  hypothyroidism, thyrotoxicosis, Addison’s disease, Cushing’s syndrome, diabetes mellitus, hyperparathyroidism.
  • Neuromuscular disorders: myasthenia gravis, multiple sclerosis, mitochondrial myopathy, Parkinson’s disease.
  • Cardiovascular disorders: cardiac ischaemia.
    Metabolic disorders: sleep apnoea syndrome, chronic renal failure.
  • Malignant disease: occult tumours such as undiagnosed lymphomas, retroperitoneal sarcomas; renal and liver tumours; frontal lobe tumours.
  • Auto-immune disease: rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, Sjogrens syndrome.
  • Haematological disorders: leukaemias and anaemias of varying origin
  • Miscellaneous: heavy metal poisoning, chronic intoxications due to prolonged exposure to chemicals such as petrol, benzene, organo-phosphorous compounds and methylene chloride; drug side effects such as those due to beta-blockers, and long-term benzodiazepine usage; chronic alcoholism; coeliac disease.
  • Psychiatric: primary depressive illness, anxiety neurosis.


Of particular importance is to eliminate chronic fatigue primarily associated with psychological factors. If there are signs of persistent anhedonia, apathy, low self-esteem, feelings of worthlessness and guilt, the possibility: of primary depressive illness should be actively considered and, if there is any doubt whatsoever, the subject eliminated from the research study.

If the subject has had any other diseases or conditions in the last three months they should be excluded from, research into M.E.

If the subject has taken any treatments – orthodox, complementary or nutritional – in the last three months they may have to be excluded from certain research projects.

London Definition criteria (Modified Version 1 - used in the Pace Trial)


Criteria 1 to 4 must be present for a diagnosis of ME to be made.

  1. Exercise-induced fatigue precipitated by trivially small exertion (physical or mental) relative to the patient’s/participant’s previous exercise tolerance.
  2. Impairment of short-term memory and loss of powers of concentration,usually coupled with other [neurological and psychological] disturbances such as:
    [NB These should be asked for as symptoms, not tests, and do not have to be total or persistent for the whole period. These symptoms (in a-e) should be recorded but are not necessary, in order to make the diagnosis.]
  1. emotional lability [feeling easily upset by things that would not normally upset the participant, but the upset is brief and has usually gone within a few hours, and certainly by the next day]
  2. nominal dysphasia [difficulty finding the right word]
  3. disturbed sleep patterns [of any sort]
  4. disequilibrium [a feeling of imbalance]
  5. tinnitus [ringing in the ears]
  • Fluctuation of symptoms
    [The usual precipitation by physical or mental exercise, should be recorded, but is not necessary to meet the criteria.]
    – usually precipitated by either physical or mental exercise.
  • These symptoms should have been present for at least 6 months and should be
  • There is no primary depressive illness present and no anxiety/neurosis.[N.B. This means that if any depressive or anxiety disorder are present, the London criteria are not met.]


2003 Canadian Consensus Criteria (CCC)

The Canadian Consensus Criteria (CCC)42 were written in 2003 by ME/CFS professionals for use in clinical practice.

The CCC diverged from Fukuda by de-emphasizing fatigue as the sole major (compulsory) criteria, and elevating the importance of other cardinal symptoms, including post-exertional malaise, pain, sleep disturbances, and cognitive dysfunction.

Jason et al. found that CCC captured many of the cardiopulmonary and neurological abnormalities which were not currently assessed by the Fukuda criteria15.

Furthermore, Jason also found that CCC also selected cases with “less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms” and individuals selected by these criteria were significantly different from psychiatric controls with CFS.

2010 Revised Canadian Consensus Definition (CCC). In 2010 the Revised Canadian Consensus Definition43 specified explicit rules for determining whether critical symptoms meet ME/CFS criteria and a questionnaire was developed to assess core symptoms.

It was intended that these developments would lead to increased reliability of the Canadian case definition as well as more frequent use of these criteria by investigators.

For a full list of the 2003 Canadian Consensus Criteria for ME/CFS, toggle the panel below.

2003 Canadian Consensus Criteria for ME/CFS (CCC)

A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and adhere to item 7.

  1. Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level.
  2. Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period – usually 24 hours or longer.
  3. Sleep Dysfunction:* There is unrefreshed sleep or sleep quantity or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.
  4. Pain:* There is a significant degree of myalgia. Pain can be experienced in the muscles, and/or joints, and is often widespread and migratory in nature. Often there are significant headaches of new type, pattern or severity.
  5. Neurological/Cognitive Manifestations: Two or more of the following difficulties should be present: confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances – e.g. spatial instability and disorientation and inability to focus vision. Ataxia, muscle weakness and fasciculations are common. There may be overload phenomena: cognitive, sensory – e.g. photophobia and hypersensitivity to noise – and/or emotional overload, which may lead to “crash” periods and/or anxiety.
  6. At Least One Symptom from Two of the Following Categories:
    1. Autonomic Manifestations: orthostatic intolerance – neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension; light-headedness; extreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrhythmias; exertional dyspnea.
    2. Neuroendocrine Manifestations: loss of thermostatic stability – subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities; intolerance of extremes of heat and cold; marked weight change – anorexia or abnormal appetite; loss of adaptability and worsening of symptoms with stress.
    3. Immune Manifestations: tender lymph nodes, recurrent sore throat, recurrent flulike symptoms, general malaise, new sensitivities to food, medications and/or chemicals.
  7. The illness persists for at least six months: It usually has a distinct onset, **although it may be gradual. Preliminary diagnosis may be possible earlier. Three months is appropriate for children.

To be included, the symptoms must have begun or have been significantly altered after the onset of this illness. It is unlikely that a patient will suffer from all symptoms in criteria 5 & 6. The disturbances tend to form symptom clusters that may fluctuate and change over time. Children often have numerous prominent symptoms but their order of severity tends to vary from day to day. *There is a small number of patients who have no pain or sleep dysfunction, but no other diagnosis fits except ME/CFS. A diagnosis of ME/CFS can be entertained when this group has an infectious illness type onset. **Some patients have been unhealthy for other reasons prior to the onset of ME/CFS and lack detectable triggers at onset or have more gradual or insidious onset.

Exclusions: Exclude active disease processes that explain most of the major symptoms of fatigue, sleep disturbance, pain, and cognitive dysfunction. It is essential to exclude certain diseases, which would be tragic to miss: Addison’s disease, Cushing’s Syndrome, hypothyroidism, hyperthyroidism, iron deficiency, other treatable forms of anemia, iron overload syndrome, diabetes mellitus, and cancer. It is also essential to exclude treatable sleep disorders such as upper airway resistance syndrome and obstructive or central sleep apnea; rheumatological disorders such as rheumatoid arthritis, lupus, polymyositis and polymyalgia rheumatica; immune disorders such as AIDS; neurological disorders such as multiple sclerosis (MS), Parkinsonism, myasthenia gravis and B12 deficiency; infectious diseases such as tuberculosis, chronic hepatitis, Lyme disease, etc.; primary psychiatric disorders and substance abuse.

Exclusion of other diagnoses, which cannot be reasonably excluded by the patient’s history and physical examination, is achieved by laboratory testing and imaging. If a potentially confounding medical condition is under control, then the diagnosis of ME/CFS can be entertained if patients meet the criteria otherwise.

Co-morbid Entities: Fibromyalgia Syndrome (FMS), Myofascial Pain Syndrome (MPS), Temporomandibular Joint Syndrome (TMJ), Irritable Bowel Syndrome (IBS), Interstitial Cystitis, Irritable Bladder Syndrome, Raynaud’s Phenomenon, Prolapsed Mitral Valve, Depression, Migraine, Allergies, Multiple Chemical Sensitivities (MCS), Hashimoto’s thyroiditis, Sicca Syndrome, etc. Such co-morbid entities may occur in the setting of ME/CFS. Others such as IBS may precede the development of ME/CFS by many years, but then become associated with it. The same holds true for migraines and depression. Their association is thus looser than between the symptoms within the syndrome. ME/CFS and FMS often closely connect and should be considered to be “overlap syndromes”.

Idiopathic Chronic Fatigue: If the patient has unexplained prolonged fatigue (6 months or more) but has insufficient symptoms to meet the criteria for ME/CFS, classify it as idiopathic chronic fatigue.

2010 Revised Canadian Consensus Criteria for ME/CFS (CCC)

2010 Revised Canadian Consensus Criteria for ME/CFS (CCC)

  1. Over the past 6 months, persistent or recurring chronic fatigue that is not lifelong and results in substantial reductions in previous levels of occupational, educational, social and personal activities. The concurrent occurrence of the following classic ME/CFS symptoms (See II through VI), which must have persisted or recurred during the past six months of illness (symptoms may predate the reported onset of fatigue).
  2. Post-exertional malaise and/ or post-exertional fatigue. With activity (it need not be strenuous and may include walking up a flight of stairs, using a computer, or reading a book), there must be a loss of physical or mental stamina, rapid/sudden muscle or cognitive fatigability, post- exertional malaise and/or fatigue and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. The recovery is slow, often taking 2-24 hours or longer.
  3. Unrefreshing sleep or disturbance of sleep quantity or rhythm disturbance. May include unrefreshing sleep, prolonged sleep (including frequent naps), disturbed sleep (e.g., inability to fall asleep or early awakening) and/or day/night reversal.
  4. Pain (or discomfort) that is often widespread and migratory in nature. At least one symptom from any of the following:Myofascial and/or joint pain. Myofascial pain can include deep pain, abdomen/stomach pain, or achy and sore muscles. Pain, stiffness, or tenderness may occur in any joint but must be present in more than one joint and lacking edema or other signs of inflammation.Abdominal and/or head pain. May experience stomach pain or chest pain. Headaches often described as localized behind the eyes or in the back of the head. May include headaches localized elsewhere, including migraines. Headaches would need to be more frequent than they were before, which would indicate new pattern, of a new type as compared to headaches previously experienced (i.e., location of pain has changed, nature of pain has changed), or different in severity type as compared to headaches previously experienced by the patient.
  5. Two or more neurological/cognitive manifestations:
    • Impaired memory (self-reported or observable disturbance in ability to recall information or events on a short-term basis)
    • Difficulty focusing vision and attention (disturbed concentration may impair ability to remain on task, to screen out extraneous/excessive stimuli)
    • Loss of depth perception
    • Difficulty finding the right word
    • Frequently forget what wanted to say
    • Absent mindedness
    • Slowness of thought
    • Difficulty recalling information
    • Need to focus on one thing at a time
    • Trouble expressing thought
    • Difficulty comprehending information
    • Frequently lose train of thought
    • Sensitivity to bright lights or noise
    • Muscle weakness/muscle twitches
  6. At least one symptom from two of the following three categories:
    1. Autonomic manifestations: Neurally mediated hypotension, postural orthostatic tachycardia, delayed postural hypotension, palpitations with or without cardiac arrhythmias, dizziness or fainting, feeling unsteady on the feet–disturbed balance, shortness of breath, nausea, bladder dysfunction, or irritable bowel syndrome.
    2. Neuroendocrine manifestations Recurrent feelings of feverishness and cold extremities, subnormal body temperature and marked diurnal fluctuations, sweating episodes, intolerance of extremes of heat and cold, marked weight change-loss of appetite or abnormal appetite.
    3. Immune manifestations: Recurrent flu-like symptoms, non-exudative sore or scratchy throat, repeated fevers and sweats, lymph nodes tender to palpitation–generally minimal swelling noted, new sensitivities to food, odors, or chemicals.
  7. Exclusionary versus Non-Exclusionary conditions:
    1. Exclusionary conditions:
      1. Any active medical condition that may explain the presence of chronic fatigue, such as:
        1. Untreated hypothyroidism
        2. Sleep apnea
        3. Narcolepsy
        4. Malignancies
        5. Leukemia
        6. Unresolved hepatitis
        7. Multiple Sclerosis
        8. Juvenile rheumatoid arthritis
        9. Lupus erythematosus
        10. HIV/AIDS
        11. Severe obesity (BMI greater than 40; but if weight gain follows onset of ME/CFS, the patient could meet the Clinical Criteria)
        12. Celiac disease
        13. Lyme disease
      2. Some active psychiatric conditions that may explain the presence of chronic fatigue, such as:
        1. Schizophrenia or psychotic disorders
        2. Bipolar disorder
        3. Active alcohol or substance abuse-except as below:
          1. Alcohol or substance abuse that has been successfully treated and resolved should not be considered exclusionary.
        4. Active anorexia nervosa or bulimia nervosa-except as below:
          1. Eating disorders that have been treated and resolved should not be considered exclusionary.
        5. Depressive disorders with melancholic or psychotic features
    2. Not necessarily exclusionary
      1. May have presence of concomitant disorders that do not adequately explain fatigue and are, therefore, not necessarily exclusionary.
        1. Psychiatric diagnoses such as:
          1. Anxiety disorders
          2. Somatoform disorders
          3. Depressive disorders
        2. Other conditions defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, such as:
          1. Multiple food and/or chemical sensitivity
          2. Fibromyalgia
        3. Any condition under specific treatment sufficient to alleviate all symptoms related to that condition and for which the adequacy of treatment has been documented.
        4. Any condition that was treated with definitive therapy before development of chronic symptomatic sequelae.
        5. Any isolated and unexplained physical examination, laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary condition.


CDC 2005 Empiric Definition

The CDC set out to address criticisms that Fukuda lacked standardized reproducible criteria with the publication of the CDC 2005 Empiric Definition44, also known as the Reeves Definition.

The Reeves Definition assesses disability using the Medical Outcomes Survey Short-Form-36 (Ware, Snow, & Kosinski, 2000), assesses symptoms using the Symptom Inventory (Wagner et al., 2005), and assesses fatigue using the Multidimensional Fatigue Inventory (Smets, Garssen, Bonke, & DeHaes, 1995).

An evaluation of the Reeves Definition compared 27 patients with a prior diagnosis of CFS with 37 patients diagnosed with a Major Depressive Disorder. The researchers reported that 38 percent of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC definition45.

Leonard Jason criticized the diagnostic utility of the definition because it lacked sensitivity and specificity46.

Reeves led to a tenfold prevalence estimate as compared with Fukuda47, probably due to misclassification and inclusion of patients with major depressive disorder48.

The purpose of rigour had not been achieved, and the Reeves Definition was never broadly implemented.

For a full list of the Empiric Definition, toggle the panel below.

2005 Empiric Definition


A case of chronic fatigue syndrome in defined by the following questionnaire scores – the “empirical” or empiric criteria:

SF-36. The Medical Outcomes Short Form-36. (Ware et al., “SF-36 Health Survey: Manual and Interpretation Guide,” Quality Metric Incorporated, 2000.)

Functional Impairment:

≤ 70 on the physical function or ≤ 50 on the role physical or ≤ 75 on the social function or ≤ 66 on the role emotional subscales.

From Jason, 2010, “Sensitivity and Specificity of the CDC Empirical Chronic Fatigue Syndrome Case Definition.”

“The disability criterion for the Reeves et al. empirical CFS case definition [2][Reeves, 2005] would be met by scoring below the 25th percentile on any one of the following four SF-36 sub-scales [3][Ware, 2000]: Physical Functioning (less than or equal to 70), Role Physical (less than or equal to 50), Social Functioning (less than or equal to 75), or Role Emotional (less than or equal to 66.7). Because a person could meet the disability criterion for the empirical CFS case definition by only showing impairment in one or more of these four areas, a person could meet the disability CFS criterion by only having an impairment in role emotional areas (e.g., problems with work or other daily activities as a result of emotional problems). Ware et al. [3][Ware, 2000] found that the mean for Role Emotional for a clinical depression group was 38.9, indicating that almost all those with clinical depression would meet the CFS disability criterion, as they would be within the lower 25th percentile on this sub-scale.” (Page 9)

MFI. The Multidimensionl Fatigue Inventory. (Smets, et al., “The Multidimensional Fatigue Inventory (MFI): Psychometric Properties of an Instrument to Assess Fatigue,” Journal of Psychosomatic Research, Vol. 39, 1995, pp. 315-325.)

Severe Fatigue:

≥ 13 on the general fatigue or ≥ 10 on the reduced activity subscales.

From Jason, 2010, “Sensitivity and Specificity of the CDC Empirical Chronic Fatigue Syndrome Case Definition.”

“To meet the fatigue criterion, the Reeves et al. empirical case definition [2][Reeves, 2005] requires a score on the MFI [4][Smets, 1995] of greater than or equal to 13 on the General Fatigue subscale, or greater than or equal to 10 on the Reduced Activity sub-scale. In one study of three groups with CFS [6][Tiersky et al., “Functional Status, Neuropsychological Functioning, and Mood in Chronic Fatigue Syndrome,” Journal of Nervous and Mental Disease, Vol. 191, 2003, pp. 324-331.], the mean MFI General Fatigue scores ranged from 18.3 to 18.8 and these scores are clearly higher than the Reeves et al. cutoff of 13. In addition, Reduced Activity items refer to issues that a person with depression might easily endorse. If a person indicated that the following two items were entirely true: “I get little done,” and “I think I do very little in a day”; they would meet criterion for fatigue on this sub-scale.” (Page 9)

Symptom Inventory. The CDC Symptom Inventory. (Wagner et al., “Psychometric Properties of the CDC Symptom Inventory for Assessment of Chronic Fatigue Syndrome,” Population Health Metrics, Vol. 3, 2005.)

Symptom Complex:

≥ 4 of 8 symptoms and scoring ≥ 25.

From Jason, 2010, “Sensitivity and Specificity of the CDC Empirical Chronic Fatigue Syndrome Case Definition.”

The SI [5][Wagner, 2005] assesses information about the presence, frequency, and intensity of fatigue related symptoms during the past one month. The frequency and severity scores were multiplied for each of the eight critical Fukuda et al. [1][Fukuda, 1994] symptoms and were then summed. To meet the Reeves et al. [2][Reeves, 2005] symptom criterion, a person needed to have four or more symptoms and a total score greater or equal to 25 on the SI. This overall level of symptoms seems relatively low for patients with classic CFS symptoms (the criterion would be met if an individual rated only 2 core symptoms as occurring all the time, and if one was of moderate and the other of severe severity). In addition, the 8 case definition symptoms for the empirical case definition were based on a time period comprising the last month compared to what is specified in the Fukuda et al. criteria, which states that: “There needs to be the concurrent occurrence of 4 or more of the following symptoms, and all must be persistent or recurrent during 6 or more months of the illness and not predate the fatigue.” (Page 9-10)


2011 International Consensus Criteria (ICC-ME)

Consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3), the International Consensus Criteria (ICC-ME) were developed in 2011 by an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate.

The ICC-ME defines myalgic encephalomyelitis (ME) as an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features.

The ICC-ME arose out of the Canadian Consensus Criteria (CCC), with some significant changes:

For a full list of the ICC-ME criteria, toggle the panel below.

Myalgic encephalomyelitis: International Consensus Criteria

Myalgic encephalomyelitis is an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features. Although signs and symptoms are dynamically interactive and causally connected, the criteria are grouped by regions of pathophysiology to provide general focus.

A patient will meet the criteria for postexertional neuroimmune exhaustion (A), at least one symptom from three neurological impairment categories (B), at least one symptom from three immune/gastro-intestinal/genitourinary impairment categories (C), and at least one symptom from energy metabolism/transport impairments (D).

  1. Postexertional neuroimmune exhaustion (PENE pen’-e): Compulsory
    This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are as follows:

    1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
    2. Postexertional symptom exacerbation:e.g.acute flu-like symptoms, pain and worsening of other symptoms.
    3. Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
    4. Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.
    5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.

    Operational notes: For a diagnosis of ME, symptom severity must result in a significant reduction of a patient’s premorbid activity level.Mild(an approximate 50% reduction in pre-illness activity level),moderate(mostly housebound),severe(mostly bedridden) or very severe(totally bedridden and need help with basic functions). There may be marked fluctuation of symptom severity and hierarchy from day to day or hour to hour. Consider activity, context and interactive effects.Recovery time: e.g. Regardless of a patient’s recovery time from reading for ½ hour, it will take much longer to recover from grocery shopping for ½ hour and even longer if repeated the next day – if able. Those who rest before an activity or have adjusted their activity level to their limited energy may have shorter recovery periods than those who do not pace their activities adequately.Impact: e.g. An outstanding athlete could have a 50% reduction in his/her pre-illness activity level and is still more active than a sedentary person.

  2. Neurological impairments
    At least one symptom from three of the following four symptom categories

    1. Neurocognitive impairments
      1. Difficulty processing information: slowed thought, impaired concentration e.g. confusion, disorientation, cognitive overload, difficulty with making decisions, slowed speech, acquired or exertional dyslexia
      2. Short-term memory loss:e.g. difficulty remembering what one wanted to say, what one was saying, retrieving words, recalling information, poor working memory
    2. Pain
      1. Headaches:e.g. chronic, generalized headaches often involve aching of the eyes, behind the eyes or back of the head that may be associated with cervical muscle tension; migraine; tension headaches
      2. Significant pain can be experienced in muscles, muscle-tendon junctions, joints, abdomen or chest. It is noninflammatory in nature and often migrates. e.g. generalized hyperalgesia, widespread pain (may meet fibromyalgia criteria), myofascial or radiating pain
    3. Sleep disturbance
      1. Disturbed sleep patterns:e.g. insomnia, prolonged sleep including naps, sleeping most of the day and being awake most of the night, frequent awakenings, awaking much earlier than before illness onset, vivid dreams/nightmares
      2. Unrefreshed sleep:e.g. awaken feeling exhausted regardless of duration of sleep, day-time sleepiness
    4. Neurosensory, perceptual and motor disturbances
      1. Neurosensory and perceptual:e.g. inability to focus vision, sensitivity to light, noise, vibration, odour, taste and touch; impaired depth perception
      2. Motor:e.g. muscle weakness, twitching, poor coordination, feeling unsteady on feet, ataxia

    Notes: Neurocognitive impairments, reported or observed, become more pronounced with fatigue. Overload phenomena may be evident when two tasks are performed simultaneously. Abnormal accommodation responses of the pupils are common. Sleep disturbances are typically expressed by prolonged sleep, sometimes extreme, in the acute phase and often evolve into marked sleep reversal in the chronic stage. Motor disturbances may not be evident in mild or moderate cases but abnormal tandem gait and positive Romberg test may be observed in severe cases.

  3. Immune, gastro-intestinal and genitourinary Impairments
    At least one symptom from three of the following five symptom categories

    1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion.e.g. sore throat, sinusitis, cervical and/or axillary lymph nodes may enlarge or be tender on palpitation
    2. Susceptibility to viral infections with prolonged recovery periods
    3. Gastro-intestinal tract:e.g. nausea, abdominal pain, bloating, irritable bowel syndrome
    4. Genitourinary: e.g. urinary urgency or frequency, nocturia
    5. Sensitivities to food, medications, odours or chemicals

    Notes: Sore throat, tender lymph nodes, and flu-like symptoms obviously are not specific to ME but their activation in reaction to exertion is abnormal. The throat may feel sore, dry and scratchy. Faucial injection and crimson crescents may be seen in the tonsillar fossae, which are an indication of immune activation.

  4. Energy production/transportation impairments: At least one symptom
    1. Cardiovascular: e.g. inability to tolerate an upright position – orthostatic intolerance, neurally mediated hypotension, postural orthostatic tachycardia syndrome, palpitations with or without cardiac arrhythmias, light-headedness/dizziness
    2. Respiratory: e.g. air hunger, laboured breathing, fatigue of chest wall muscles
    3. Loss of thermostatic stability: e.g. subnormal body temperature, marked diurnal fluctuations; sweating episodes, recurrent feelings of feverishness with or without low grade fever, cold extremities
    4. Intolerance of extremes of temperature

    Notes: Orthostatic intolerance may be delayed by several minutes. Patients who have orthostatic intolerance may exhibit mottling of extremities, extreme pallor or Raynaud’s Phenomenon. In the chronic phase, moons of finger nails may recede.

Paediatric considerations

Symptoms may progress more slowly in children than in teenagers or adults. In addition to postexertional neuroimmune exhaustion, the most prominent symptoms tend to be neurological: headaches, cognitive impairments, and sleep disturbances.

  1. Headaches: Severe or chronic headaches are often debilitating. Migraine may be accompanied by a rapid drop in temperature, shaking, vomiting, diarrhoea and severe weakness.
  2. Neurocognitive impairments: Difficulty focusing eyes and reading are common. Children may become dyslexic, which may only be evident when fatigued. Slow processing of information makes it difficult to follow auditory instructions or take notes. All cognitive impairments worsen with physical or mental exertion. Young people will not be able to maintain a full school programme.
  3. Pain may seem erratic and migrate quickly. Joint hypermobility is common.

Notes: Fluctuation and severity hierarchy of numerous prominent symptoms tend to vary more rapidly and dramatically than in adults.

——— Myalgic encephalomyelitis
——— Atypical myalgic encephalomyelitis: meets criteria for postexertional neuroimmune exhaustion but has a limit of two less than required of the remaining criterial symptoms. Pain or sleep disturbance may be absent in rare cases.

Exclusions: As in all diagnoses, exclusion of alternate explanatory diagnoses is achieved by the patient’s history, physical examination, and laboratory/biomarker testing as indicated. It is possible to have more than one disease but it is important that each one is identified and treated.

Primary psychiatric disorders, somatoform disorder and substance abuse are excluded. Paediatric:‘primary’ school phobia.

Comorbid entities: Fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve, migraines, allergies, multiple chemical sensitivities, Hashimoto’s thyroiditis, Sicca syndrome, reactive depression. Migraine and irritable bowel syndrome may precede ME but then become associated with it. Fibromyalgia overlaps.


NIH/IOM 2015 Definition (SEID)

The recently proposed NIH/IOM 2015 Definition2 (SEID) diagnostic criteria developed by the US Institute of Medicine (IOM) at the request of the Department of Health and Human Services (HHS) redefines CFS for clinical application.

The IOM recommended that the name of the disease be changed from ME/CFS to Systemic Exertion Intolerance Disease (SEID).

Also on Shoutout About ME:


The IOM concluded that the term myalgic encephalomyelitis was inappropriate because there was a lack of evidence for encephalomyelitis (brain inflammation) in ME/CFS patients, and myalgia (muscle pain) was not a core symptom of the disease (this point is heavily disputed by researchers and patient groups).

SEID was not intended to replace usage of ME.

Dr. Lucinda Bateman, member of the IOM Committee on redefining ME/CFS (Ravell Call, Deseret News)
Dr. Lucinda Bateman, IOM Committee (Ravell Call, Deseret News)

According to the IOM, “This name captures a central characteristic of the disease: the fact that exertion of any sort—physical, cognitive, or emotional—can adversely affect patients in many organ systems and in many aspects of their lives. The committee believes systemic exertion intolerance disease appropriately captures the complexity and severity of the illness.”

The new criteria were not evaluated with data sets of patients and controls49. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria49.

SEID may also categorize many individuals with major depressive disorder, as well as other medical illnesses50.

As a result of omitting these exclusions, SEID increased the prevalence rate for the illness of 0.42 percent as defined by Fukuda, by 2.8 times50.

For a full list of the NIH/IOM 2015 Definition (SEID) criteria for ME/CFS, toggle the panel below.

NIH/IOM 2015 Definition (SEID) criteria for ME/CFS

Diagnosis requires that the patient have the following three symptoms:

  1. A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
  2. Post-exertional malaise,* and
  3. Unrefreshing sleep*

At least one of the two following manifestations is also required:

  1. Cognitive impairment* or
  2. Orthostatic intolerance

* Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.


PHOTO: The Mask Collaboration: Out-takes and BTS by Adam Purcell


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Written by Russell Logan

Russell Logan worked as a magazine publisher and editor until forced into early retirement through ill health with ME. He has battled with moderate to severe ME for 25 years. He now lives in Noosaville, Australia.

87 posts


Leave a Reply
  1. Hi Russell,

    I have just come across your blog and Facebook page – Wow! I can certainly appreciate how your background has helped create such an impressive platform.

    The content of this particular blog alone must have taken some time to put together. I also thought Dr Jaon’s presentation at the NIH P2P conference was exemplary and have tweeted and quoted from it many times to help explain the overlapping criteria and their potential effects on patient populations.

    I would like to add that Ramsay never published a definition – despite apparently being encouraged to do so. The closest he came was to the description he provided in the book you cite above.

    Also, the London criteria were developed and published originally by Dowsett, MacIntyre, Goudsmit and Shepherd. And Dr Shepherd is medical advisor to the ME Association. I am not sure where you obtained the link to Action for ME but I believe it to be erroneous.

    Some further background to the London criteria can be found here: which was produced at the time of the PACE trial.

    Finally, I think that Goudsmit and Shepherd published an updated version of the London Criteria last year (2014), but I am having trouble locating it this morning (having just again woken up and feeling rather groggy).

    I will certainly now refer to your platforms in future for the news updates a blogs on my Twitter feed. You are doing a tremendous job. Thank you.


    • Hi Russell, Thank you for your kind words. I will need a clear head day to fully follow through on your comments. However just quickly, the me assoc reference you provided for version 2 was provided in my article.

      It does appear that I have omitted the link for version 1, and I will endeavor to fix this ASAP. I suspect this will address your comments on the issue of authorship and agency involvement. From memory there was significant content missing in the Task Force content (version 2) and also a bitter dispute between authors concerning the authorship of this work, hence the two versions.

      I did note that Ramsay’s Criteria were not published in a peer reviewed publication: “Note, Ramsay’s Definition did not use validated criteria published in a peer review journal.”

      Yes, the article did my head in a bit and I suspect there are quite a few errors sprinkled throughout. Thanks for taking the time to help out.

  2. Great work on this. I know it’s not easy to dig up and parse all of this information to present it in a readable manner but you have done so quite well.

    The only important definition of the disease that is missing is Dr. Hyde’s Nightingale definition. Dr. Hyde is one of the only clinicians to have examined patients of several of the historical outbreaks including LA, Iceland, and several of Dr. Richardson’s patients in the UK. His definition of the disease is probably one of the most accurate, second only to Ramsay’s description.

    For the sake of completeness, you could also include the UK NICE guidelines and the Australian national guidelines.

    • Hi Frank. It was off the back of your published work, so thank you. It was only after reading your papers that things clarified for me. So please continue publishing.

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