The 1988 Holmes Definition for CFS -The earliest CFS definition
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.
- 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.
- 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.
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:
- 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.)
- Sore throat.
- Painful lymph nodes in the anterior or posterior cervical or axillary distribution.
- Unexplained generalized muscle weakness.
- Muscle discomfort or myalgia.
- Prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient’s premorbid state.
- Generalized headaches (of a type, severity, or pattern that is different from headaches the patient may have had in the premorbid state).
- Migratory arthralgia without joint swelling or redness.
- Neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression).
- Sleep disturbance (hypersomnia or insomnia).
- 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 must be documented by a physician on at least two occasions, at least 1 month apart.
- 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.)
- Nonexudative pharyngitis.
- 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.)
CDC 1994 criteria (Fukuda definition)
Currently the most widely used and recognised diagnostic criteria for CFS
Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is:
- of new or definite onset (has not been lifelong);
- is not the result of ongoing exertion;
- is not substantially alleviated by rest; and
- results in substantial reduction in previous levels of occupational, educational, social, or personal activities.
The concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue:
- self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities;
- sore throat;
- tender cervical or axillary lymph nodes;
- muscle pain;
- multi-joint pain without joint swelling or redness;
- headaches of a new type, pattern, or severity;
- unrefreshing sleep;
- post-exertional malaise lasting more than 24 hours.
All other known causes of chronic fatigue must have been ruled out, specifically clinical depression, side effects of medication, eating disorders and substance abuse.
The clinical evaluation should include:
- A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements;
- A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done;
- A thorough physical examination;
- A minimum battery of laboratory screening tests, including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis.
Other diagnostic tests have no recognized value unless indicated on an individual basis to confirm or exclude a differential diagnosis, such as multiple sclerosis.
Canadian 2003 criteria
Clinical Working Case Definition of ME/CFS
A comprehensive criteria favoured by many patients and organisations due to it clearly defining ME/CFS as opposed to other more general definitions of CF or CFS
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.
- Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level.
- 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.
- Sleep Dysfunction:* There is unrefreshed sleep or sleep quantity or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.
- 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.
- 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 overload1 phenomena: cognitive, sensory–e.g., photophobia and hypersensitivity to noise–and/or emotional overload, which may lead to “crash”2 periods and/or anxiety.
- At Least One Symptom from Two of the Following Categories:
a. Autonomic Manifestations: orthostatic intolerance–neurally mediated hypotenstion (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.
b. 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.
c. Immune Manifestations: tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food, medications and/or chemicals.
- 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 and 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 and/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, it should be classified as idiopathic chronic fatigue.
The Oxford Criteria
A very broadly defined criteria for diagnosing chronic fatigue illness of any cause, favoured by UK researchers particularly of the Wessley school.
As used in the PACE trial
Must respond yes to all but item 6
- ls your fatigue (or a synonym). the principal (main, primary) symptom (e.g. tiredness. lack of energy, weariness, exhaustion)?
- For the Research Nurse to judge: Can the fatigue be distinguished from low mood, sleepiness and lack of motivation?
- ls your fatigue out of proportion to what you would expect as normal for this level of exertion?
- is your fatigue a clear change from how you were previously’?
- Did your fatigue start with a deﬁnite onset (which may be gradual)?
- Have you had this fatigue all your life, as far as you can remember ? (must answer no)
- Have you had your fatigue for the last 6 months. during which it was present for more than half of the time’?
- Does your illness affect both your physical ability and mental functioning (thinking, concentrating, talking, reading or remembering)?
London Criteria for M.E. (unpublished)
Version as used by UK researchers in the PACE trial
Criteria 1 to 4 must be met for a diagnosis of ME to be made
- Exercise-induced fatigue precipitated by trivially small exertion (physical or mental) relative to the patients / participant’s previous exercise intolerance
- 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 am not necessary to make the diagnosis]
a) emotional liability [feeling easily upset by things that would not upset the participant, but the upset is brief and has usually gone within a few hours. and certainly by the next day]
b) nominal dysphasia [difficulty finding the right word]
c) disturbed sleep pattens [of any sort]
d) disequilibrium [A feeling of imbalance]
- Fluctuations of symptoms
[NB The usual precipitation by ‘physical or mental exercise ” should be recorded, but is not necessary to meet criteria.]
usually precipitated by either physical or mental exercise
- These symptoms should have been present for at least 6 months and should be ongoing.
- There is no primary depressive illness present and no anxiety disorder/neurosis
[N.B. This means if any depressive or anxiety disorder is present. the London criteria are not met]
PACE Trial medical exclusions
- Established medical conditions known to produce chronic fatigue
- Manic depressive (bipolar) illness
- Substance misuse
- Eating disorder
- Proven organic brain disease
Other psychiatric disorders (including depressive illness‘ anxiety disorders‘ and hyperventilation syndrome) are not reasons for exclusion.
Myalgic Encephalomyelitis: International Consensus Criteria
Published July 2011
The most recent criteria, supported my a large group of international researchers, a refinement to the Canadian criteria.
A. Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e)
This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are:
- 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.
- Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms
- Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.
- Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
- Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.
B. Neurological Impairments
At least One Symptom from three of the following four symptom categories
- Neurocognitive Impairments
a. Difficulty processing information: slowed thought, impaired concentration e.g. confusion, disorientation, cognitive overload, difficulty with making decisions, slowed speech, acquired or exertional dyslexia
b. Short-term memory loss: e.g. difficulty remembering what one wanted to say, what one was saying, retrieving words, recalling information, poor working memory
a. 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
b. Significant pain can be experienced in muscles, muscle-tendon junctions, joints, abdomen or chest. It is non-inflammatory in nature and often migrates. e.g. generalized hyperalgesia, widespread pain (may meet fibromyalgia criteria), myofascial or radiating pain
- Sleep Disturbance
a. 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
b. Unrefreshed sleep: e.g. awaken feeling exhausted regardless of duration of sleep, day-time sleepiness
- Neurosensory, Perceptual and Motor Disturbances
a. Neurosensory and perceptual: e.g. inability to focus vision, sensitivity to light, noise, vibration, odour, taste and touch; impaired depth perception
b. Motor: e.g. muscle weakness, twitching, poor coordination, feeling unsteady on feet, ataxia
C. Immune, Gastro-intestinal & Genitourinary Impairments
At least One Symptom from three of the following five symptom categories
- 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
- Susceptibility to viral infections with prolonged recovery periods
- Gastro-intestinal tract: e.g. nausea, abdominal pain, bloating, irritable bowel syndrome
- Genitourinary:e.g.urinaryurgencyorfrequency,noctur ia
- Sensitivitiestofood,medications,odours or chemicals
D. Energy Production/Transportation Impairments:
At least One Symptom
- 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
- Respiratory: e.g. air hunger, laboured breathing, fatigue of chest wall muscles
- 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
- Intolerance of extremes of temperature