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Understanding Historical Case Definitions and Criteria

It is not uncommon to have more than one case definition that is used to diagnose or study an illness. From a clinical perspective, case definitions are used to make the appropriate diagnosis and guide therapy and management. From a research perspective, case definitions are used to identify the appropriate study population. Multiple case definitions may be required for different applications and can co-exist if there is a good understanding of how they are being used.

Table 1 summarizes the key features of the three definitions most often used in the United States prior to the publication of the IOM report in 2015. All previously used case definitions for chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME)/CFS have been based on expert opinion, all are symptom-based, and most were developed for research. There is no consensus on whether CFS and ME are synonyms, different spectrums of the same illness, or distinct conditions. There are many similarities between these definitions, and most agree that there is significant overlap in the patients meeting these criteria. The major differences are whether post-exertional malaise (PEM) is required and in the number of required symptoms.

Table 1: Summary of Key Features of the Case Definitions for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

1994 International Research1 2003 Canadian Consensus2 2011 ME International Consensus3
Overview of Inclusions Fatigue + 4 out of 8 case-defining symptoms:
  • PEM 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
Fatigue, post-exertional malaise ±fatigue, sleep dysfunction, and pain; have 2 or more neurological/cognitive manifestations and 1or more from 2 categories of autonomic, neuroendocrine and immune manifestations Post-exertional neuroimmune exhaustion, ≥1 symptom from 3 neurological impairment categories, ≥ 1 symptom from the immune/gastrointestinal/genitourinary impairment categories , ≥ 1 symptom from energy metabolism/transport impairments
Duration ≥ 6  months (clinical evaluation starts at one month – prolonged fatigue) ≥ 6  months (preliminary diagnosis can be earlier) Not included
Fatigue ≥ 6 months new onset severe persistent or relapsing fatigue
  • unexplained after clinical evaluation
  • not explained by ongoing exertion
  • not substantially  relieved by rest
  • results in substantial reduction in occupational, educational, social, or personal activities
Significant new onset persistent or recurrent physical or mental fatigue
  • unexplained after clinical evaluation
  • substantially reduces activity level
Not included
Post-exertional malaise Not required but one of the 8 case defining symptoms Required Required, renamed post-exertional neuroimmune exhaustion (PENE)
Minimum # of symptoms 5 8 8
Exclusions Active medical condition that explains chronic fatigue – untreated hypothyroidism, sleep apnea, narcolepsy, medication side effects

Previous diagnosis not unequivocally resolved – chronic hepatitis, malignancy

Past or current major depressive disorder with psychotic or melancholic features, bipolar disorder, schizophrenia, delusional disorders, dementias, anorexia nervosa, bulimia nervosa

Alcohol or substance abuse within 2 years of illness onset or anytime after

Severe obesity (BMI > 45)

Active disease processes that explain symptoms, specifies:

Addison’s disease, Cushing syndrome, hypo- or hyperthyroidism, iron deficiency, anemia, iron overload, diabetes mellitus, cancer, sleep apnea, rheumatoid arthritis, lupus, polymyositis, polymyalgia rheumatic, AIDS, multiple sclerosis, tuberculosis, chronic hepatitis, Lyme disease, primary psychiatric disorders, substance abuse

Alternative explanatory diagnoses (untreated), primary psychiatric disorders, somatoform disorder, substance abuse
Accepted co-morbidities Fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or melancholic depression, neurasthenia, multiple chemical sensitivity disorder, treated Lyme disease or syphilis before chronic sequelae, isolated unexplained lab or physical abnormality insufficient to suggest exclusionary diagnosis Fibromyalgia, myofascial pain, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, irritable bladder syndrome, Raynaud’s phenomenon, mitral valve prolapse, migraines, allergies, multiple chemical sensitivities, Hashimoto’s thyroiditis, sicca syndrome, depression Fibromyalgia, myofascial pain, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, Raynaud’s phenomenon, mitral valve prolapse, migraines, allergies, multiple chemical sensitivities, Hashimoto’s thyroiditis, sicca syndrome, reactive depression

1 Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study.  Ann Intern Med 121:953-959, 1994.
2 Carruthers BM, Jain AK, DeMeirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndrome 11:7-115, 2003.
3 Carruthers BM, van de Sande MI, DeMeirleir KL, et al. Myalgic encephalomyelitis: International consensus criteria. J Intern Med 270:327-338, 2011.