CFS is a condition defined by the presence of chronic fatigue that results in significantly decreased function, that is of definite onset (not lifelong), not readily explained by an identifiable underlying medical or mental health condition, and usually accompanied by some or all of the following symptoms: impairment of memory or concentration, headaches, muscle or joint pain, unrefreshing sleep, sore throats, tender lymph nodes and post exertional flare of symptoms. See discussion of Case Definitions at the end of the handout.

CFS may occur in a "genetically predisposed" individual, who is often "run down" by ordinary or unusual "life stressors," and may start with a "flu syndrome" that seems to leave chronic symptoms and fatigue rather than resolving in a normal fashion. Epidemiologic studies suggest that a large number of people who meet criteria for CFS may not have distinct flu-like onset of symptoms, and that symptoms meeting CFS most common in lower socioeconomic groups and minorities.

The exact cause of CFS is unknown. No single infection has been proven a primary cause of CFS, although many viral and atypical pathogens have been studied as possible primary or secondary co-factors. Research suggests that patients with CFS have mildly suppressed Natural Killer cell activity and cell mediated immunity (probably abnormal CD4 activation of CD8 viral killing), with a shift toward upregulated B-cell mediated immunity. In the later stages of illness patients have more B-cell derived illness such as "allergy" symptoms, upregulated antibody systems (antithyroid and antinuclear antibodies), and pro-inflammatory cytokine release. Flow cytometry studies of lymph node biopsy show chronically activated T-cells (compared to peripheral blood) consistent with this chronically up-regulated state. It is not clear if recurrent or latent virus(s) are currently present and driving the system, if it is chronically "immune" driven, or if there are other involved processes extrinsic to the immune pathways.

Many patients have significant autonomic nervous system dysfunction, manifest by orthostatic intolerance or postural orthostatic tachycardia (POTS), sweating or temperature intolerance, Sicca syndrome (dry eyes and mouth), irritable bowel and gastric reflux, bladder spasm, etc. Neurocognitive and neuropsychological symptoms are often prominent, and flare as the symptom complex flares. Abnormal sleep patterns with alpha intrusion, abnormal Stage III, IV and REM phases are often present. In addition, Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction has been documented as low CRH, cortisol, and perhaps a contribution to the marked orthostatic intolerance or Neurally Mediated Hypotension (NMH) documented on Tilt Table testing. Numerous forms of brain imaging have demonstrated regional flow abnormalities (SPECT), areas of hypometabolism (PET), and areas of nonspecific demyelination or infarct (MRI). In addition these areas of research, genetic studies underway in twins and affected families show a familial predisposition to developing CFS.

Since the cause of CFS is still unknown, the best general treatments at this point for the illness complex and associated symptoms are to:

---If primary or secondary viral or bacterial infection or known immune dysfunction (allergies and asthma) can be identified, treating the condition might reduce CFS symptoms.

---If orthostatic intolerance is prominent, it may respond partially to standard interventions such as oral fluids (2 liters of water daily), sodium (2–4 gms per day) and electrolyte supplementation, fludrocortisone (Florinef) 0.1-0.2 mg daily, a trial of midodrine (ProAmatine) 2.5-10 mg 3 to 4 times a day while up and active (i.e. not while sleeping or resting).

—Replacing identifiable hormone deficiencies can be useful in modulating symptoms, but should be monitored carefully due to the known potential side effects associated with each hormone.

---Stimulants and Provigil are occasionally helpful, but should be used cautiously because of impact on sleep, anxiety, and the tendency to over exert instead of pace appropriately.

---Anti-depressant, anti-anxiety and anti-convulsant medications can be helpful for some aspects of the syndrome independent of affect on mood.

The 1988 (CDC or Holmes) CFS Case Definition (or "Working Case Definition of CFS") requires that patients meet the Major Criteria of new onset fatigue and fatigability that does not resolve with rest, that causes at least a 50% reduction in activity, for at least 6 months, and the exclusion of all other illnesses that can cause fatigue, including existing psychiatric illness, and Minor Criteria of > 6 month duration, including at least 6 of 8 symptoms (fever, sore throat, painful lymph nodes, general weakness, prolonged fatigue after exercise, headaches, arthralgia, sleep disturbance, neuropsychological complaints, and sudden onset of symptoms complex) and 2 signs (low grade fever, non-exudative pharyngitis, and palpable or tender lymph nodes).

The 1994 "Revised Case Definition of CFS" (Annals of Internal Medicine, December 1994, Fukuda) is reached after a process of excluding other illnesses and is defined as: clinically evaluated, unexplained persistent or relapsing chronic fatigue of > 6 month duration, not otherwise explained by another known medical or psychiatric condition (, of new or definite onset, not the result of ongoing exertion, not substantially alleviated by rest, and that results in substantial reduction in previous levels of function; plus concurrent presence of (at least 4): impairment in short term memory or concentration, muscle pain, joint pain, headaches of a new pattern or severity, unrefreshing sleep, sore throat, tender cervical or axillary lymph nodes, and post exertional malaise. Specific exclusions include: an ongoing medical illness that can obviously cause such fatigue, psychiatric illness psychotic features, dementia, anorexia or bulimia, alcohol or other substance abuse, and obesity defined as a Body Mass Index (BMI) > 45.

No Case Definition was intended to exclude patients from the diagnosis, but rather to help identify and treat underlying problems, and to define a better, more homogeneous, "CFS" group for research purposes. The larger populations of patients with chronic fatigue, exertion intolerance, ill defined pain, insomnia, cognitive dysfunction and other symptoms probably have a number of underlying problems that include atypical presentation of known diseases, combined processes, psychological factors, and disease processes we still poorly understand.

Several other Case Definitions are evolving, including the "Canadian Case Definition" formulated by a panel of experts from Canada and the US, that is generally accepted as a better clinical tool than the 1988 and 1994 versions. (This is published as "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols" in the Journal of CFS; Vol.11, No 1, 2003.) The CDC is working on a new case definition based on further study of CFS patients identified in their epidemiological study in Wichita, Kansas.

Mounting research in the last 10 years has clearly shown that in spite of their weaknesses, all of the CFS Case Definitions successfully separate a group of afflicted and often disabled patients who do not simply have a mood disorder, poor motivation or any other readily identifiable problem. These patients deserve support and medical attention both clinically and on a research basis until more data is forthcoming. Most likely, the CFS Case Definitions encompass a group made of up more than one cause and combination of causes. More work is needed to develop objective markers that will delineate subgroups of CFS and related conditions such as fibromyalgia syndrome, multiple chemical sensitivity syndrome, and others.

There is discussion about what else to call this complex and often disabling condition, which is arguably not well served by the term Chronic Fatigue Syndrome. In Europe and Canada, the term Myalgic Encephalomyelitis (ME) was used long before the CDC coined the term "CFS" in the mid 1980's. Patient advocates in the U.S. often prefer the term "CFIDS" (Chronic Fatigue Immune Dysfunction Syndrome), a synonym for CFS. Much debate within the CFS community has focused on when and what to better name the condition. At this point, most researchers and clinicians hope that emerging information regarding pathophysiology will help resolve the conflicts.

Updated 10/04