1. Have severe chronic fatigue of six months or longer duration with other known medical conditions excluded by clinical diagnosis, and
2. Concurrently have four or more of the following symptoms: substantial impairment in short-term memory or concentration, sore throat, tender lymph nodes, muscle pain, multi-joint pain without swelling or redness, headaches of a new type, pattern or severity, unrefreshing sleep, and post-exertional malaise lasting more than 24 hours.

What is CFS?

Chronic fatigue syndrome, or CFS, is a debilitating and complex disorder characterized by profound fatigue that is not improved by bed rest and that may be worsened by physical or mental activity. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of illness. In addition to these key defining characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia and post-exertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years. The cause or causes of CFS have not been identified and no specific diagnostic tests are available. Moreover, since many illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known and often treatable conditions before a diagnosis of CFS is made.

A. Definition of CFS 

A great deal of debate has surrounded the issue of how best to define CFS. In an effort to resolve these issues, an international panel of CFS research experts convened in 1994 to draft a definition of CFS that would be useful both to researchers studying the illness and to clinicians diagnosing it. In essence, in order to receive a diagnosis of chronic fatigue syndrome, a patient must satisfy two criteria: 

1) Have severe chronic fatigue of six months or longer duration with other known medical conditions excluded by clinical diagnosis

2)Concurrently have four or more of the following symptoms:

• Substantial impairment in short-term memory or concentration
  
• Sore throat
  
• Tender lymph nodes
  
• Muscle pain
  
• Multi-joint pain without swelling or redness
  
• Headaches of a new type, pattern or severity
  Unrefreshing sleep
  
• Post-exertional malaise lasting more than 24 hours
  
  

The symptoms must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue. 

B. Similar Medical Conditions 

A number of illnesses have been described that have a similar spectrum of symptoms to CFS. These include fibromyalgia syndrome, myalgic encephalomyelitis, neurasthenia, multiple chemical sensitivities, and chronic mononucleosis. Although these illnesses may present with a primary symptom other than fatigue, chronic fatigue is commonly associated with all of them. 

C. Other Conditions That May Cause Similar Symptoms 

In addition, there are a large number of clinically defined, frequently treatable illnesses that can result in fatigue. Diagnosis of any of these conditions would exclude a definition of CFS unless the condition has been treated sufficiently and no longer explains the fatigue and other symptoms. These include hypothyroidism, sleep apnea and narcolepsy, major depressive disorders, chronic mononucleosis, bipolar affective disorders, schizophrenia, eating disorders, cancer, autoimmune disease, hormonal disorders*, subacute infections, obesity, alcohol or substance abuse, and reactions to prescribed medications. 

D. Other Commonly Observed Symptoms in CFS 

In addition to the eight primary defining symptoms of CFS, a number of other symptoms have been reported by some CFS patients. The frequencies of occurrence of these symptoms vary from 20% to 50% among CFS patients. They include abdominal pain, alcohol intolerance, bloating, chest pain, chronic cough, diarrhea, dizziness, dry eyes or mouth, earaches, irregular heartbeat, jaw pain, morning stiffness, nausea, night sweats, psychological problems (depression, irritability, anxiety, panic attacks), shortness of breath, skin sensations, tingling sensations, and weight loss. 

* Not all hormonal aberrations necessarily exclude a diagnosis of CFS.

Demographics

A. How Common Is CFS? 

One of the earliest attempts to estimate the prevalence of CFS was conducted by the Centers for Disease Control and Prevention (CDC) from 1989 to 1993. Physicians in four U.S. cities were asked to refer possible CFS patients for clinical evaluation by medical personnel participating in the study. The study estimated that between 4.0 and 8.7 per 100,000 persons 18 years of age or older have CFS and are under medical care. However, these projections were underestimates and could not be generalized to the U.S. population since the study did not randomly select its sites. A more recent study of the Seattle area has estimated that CFS affects between 75 and 265 people per 100,000 population. This estimate is similar to the prevalence observed in another CDC study conducted in San Francisco, which put the occurrence of CFS-like disease (not clinically diagnosed) at approximately 200 per 100,000 persons. In general, it is estimated that perhaps as many as half a million persons in the United States have a CFS-like condition.

B. Who Gets CFS? 

This question is complex and does not have a definitive answer. The CDC four-city surveillance study of CFS identified a population of patients that was 98% Caucasian and 85% female, with an average age at onset of 30 years. More than 80% had advanced education and one-third were from upper income families. However, these data included only patients who were under a physician's care. There is now evidence that CFS affects all racial and ethnic groups and both sexes. The Seattle study found that 59% of the CFS patients were women. Eighty-three percent were Caucasian, an underrepresentation, since over 90% of the patients in the study were white. CDC's San Francisco study found that CFS-like disease was most prevalent among women, among persons with household annual incomes of under $40,000, and among blacks, and was least common among Asians and whites. Adolescents can have CFS, but few studies of adolescents have been published. A recently published CDC study documented that adolescents 12 to 18 years of age had CFS significantly less frequently than adults and did not identify CFS in children under 12 years of age. CFS-like illness has been reported in children under 12 by some investigators, although the symptom pattern varies somewhat from that seen in adults and adolescents. The illness in adolescents has many of the same characteristics as it has in adults. However, it is particularly important that the unique problems of chronically ill adolescents (e.g., family social and health interactions, education, social interactions with peers) be considered as a part of their care. Appropriate dissemination of CFS information to patients, their families, and school authorities is also important. CDC and the National Institutes of Health (NIH) are currently pursuing studies of CFS in children and adolescents. 

C. Is CFS Contagious? 

There is no evidence to support the view that CFS is a contagious disease. Contagious diseases typically occur in well-defined clusters, otherwise known as outbreaks or epidemics. While some earlier studies, such as investigations of fatiguing illness in Incline Village, Nev., and Punta Gorda, Fla., have been cited as evidence for CFS acting as a contagious illness, they did not rigorously document the occurrence of person-to-person transmission. In addition, none of these studies included patients with clinically evaluated fatigue that fit the CFS case definition; therefore, these clusters of cases cannot be construed as outbreaks of CFS. CDC worked with state health departments to investigate a number of reported outbreaks of fatiguing illness and has yet to confirm a cluster of CFS cases. Implicit in any contagious illness is an infectious cause for the disease.

Carefully designed case-control studies involving rigorously classified CFS patients and controls have found no association between CFS and a large number of human disease agents. Finally, none of the behavioral characteristics typically associated with contagious disease, such as intravenous drug use, exposure to animals, occupational or travel history, or sexual behavior, have been associated with CFS in case-control studies. It therefore seems unlikely that CFS is a transmissible disease. Nevertheless, the lack of evidence for clustering of CFS, the absence of associations between specific behavioral characteristics and CFS, and the failure to detect evidence of infection more commonly in CFS patients than in controls do not rule out the possibility that infectious agents are involved in or reflect the development of this illness. For example, important questions remain to be answered concerning possible reactivation of latent viruses (such as human herpes viruses) and a possible role for infectious agents in some cases of CFS. 

D. Clinical Course of CFS 

It is vital to understand the clinical course of CFS. This knowledge is required to facilitate communication between physicians and patients, to evaluate possible new treatments, and to address insurance and disability issues. The clinical course of CFS varies considerably among persons who have the disorder; the actual percentage of patients who recover is unknown, and even the definition of what should be considered recovery is subject to debate. Some patients recover to the point that they can resume work and other activities, but continue to experience various or periodic CFS symptoms. Some patients recover completely with time, and some grow progressively worse. CFS often follows a cyclical course, alternating between periods of illness and relative well being. CDC continues to monitor the patients enrolled in the four-city surveillance study; recovery is defined by the patient and may not reflect complete symptom-free recovery. Approximately 50% of patients reported "recovery," and most recovered within the first 5 years after onset of illness. No characteristics were identified that made one patient more likely to recover than another. At illness onset, the most commonly reported CFS symptoms were sore throat, fever, muscle pain, and muscle weakness. As the illness progressed, muscle pain and forgetfulness increased and the reporting of depression decreased.

Possible Causes of CFS

A. Infectious Agents 

Due in part to its similarity to chronic mononucleosis, CFS was initially thought to be caused by a virus infection, most probably Epstein-Barr virus (EBV). It now seems clear that CFS cannot be caused exclusively by EBV or by any single recognized infectious disease agent. No firm association between infection with any known human pathogen and CFS has been established. CDC's four-city surveillance study found no association between CFS and infection by a wide variety of human pathogens, including EBV, human retroviruses, human herpes virus 6, enteroviruses, rubella, Candida albicans, and more recently bornaviruses and Mycoplasma. Taken together, these studies suggest that among identified human pathogens, there appears to be no causal relationship for CFS. However, the possibility remains that CFS may have multiple causes leading to a common endpoint, in which case some viruses or other infectious agents might have a contributory role for a subset of CFS cases. 

B. Immunology 

It has been proposed that CFS may be caused by an immunologic dysfunction, for example inappropriate production of cytokines such as interleukin-1, or altered capacity of certain immune functions. One thing is certain at this juncture: there are no immune disorders in CFS patients on the scale traditionally associated with disease. Some investigators have observed anti-self antibodies and immune complexes in many CFS patients, both of which are hallmarks of autoimmune disease. However, no associated tissue damage typical of autoimmune disease has been described in patients with CFS. The opportunistic infections or increased risk for cancer observed in persons with immunodeficiency diseases or in immunosuppressed individuals is also not observed in CFS. Several investigators have reported lower numbers of natural killer cells or decreased natural killer cell activity among CFS patients compared with healthy controls, but others have found no differences between patients and controls. 

T-cell activation markers have also been reported to have differential expression in groups of CFS patients compared with controls, but again, not all investigators have consistently observed these differences. One intriguing hypothesis is that various triggering events, such as stress or a viral infection, may lead to the chronic expression of cytokines and then to CFS. Administration of some cytokines in therapeutic doses is known to cause fatigue, but no characteristic pattern of chronic cytokine secretion has ever been identified in CFS patients. In addition, some investigators have noted clinical improvement in patients with continued high levels of circulating cytokines; if a causal relationship exists between cytokines and CFS, it is likely to be complex. Finally, several studies have shown that CFS patients are more likely to have a history of allergies than are healthy controls. Allergy could be one predisposing factor for CFS, but it cannot be the only one, since not all CFS patients have it. 

C. Hypothalamic-Pituitary Adrenal (HPA) Axis 

Multiple laboratory studies have suggested that the central nervous system may have an important role in CFS. Physical or emotional stress, which is commonly reported as a pre-onset condition in CFS patients, activates the hypothalamic-pituitary-adrenal axis, or HPA axis, leading to increased release of cortisol and other hormones. Cortisol and corticotrophin-releasing hormone (CRH), which are also produced during the activation of the HPA axis, influence the immune system and many other body systems. They may also affect several aspects of behavior. Recent studies revealed that CFS patients often produce lower levels of cortisol than do healthy controls. Similar hormonal abnormalities have been observed by others in CFS patients and in persons with related disorders like fibromyalgia. Cortisol suppresses inflammation and cellular immune activation, and reduced levels might relax constraints on inflammatory processes and immune cell activation. As with the immunologic data, the altered cortisol levels noted in CFS cases fall within the accepted range of normal, and only the average between cases and controls allows the distinction to be made. Therefore, cortisol levels cannot be used as a diagnostic marker for an individual with CFS. A placebo-controlled trial, in which 70 CFS patients were randomized to receive either just enough hydrocortisone each day to restore their cortisol levels to normal or placebo pills for 12 weeks, concluded that low levels of cortisol itself are not directly responsible for symptoms of CFS, and that hormonal replacement is not an effective treatment. However, additional research into other aspects of neuroendocrine correlates of CFS is necessary to fully define this important, and largely unexplored, field. 

D. Neurally Mediated Hypotension 

Rowe and coworkers conducted studies to determine whether disturbances in the autonomic regulation of blood pressure and pulse (neurally mediated hypotension, or NMH) were common in CFS patients. The investigators were alerted to this possibility when they noticed an overlap between their patients with CFS and those who had NMH. NMH can be induced by using tilt table testing, which involves laying the patient horizontally on a table and then tilting the table upright to 70 degrees for 45 minutes while monitoring blood pressure and heart rate. Persons with NMH will develop lowered blood pressure under these conditions, as well as other characteristic symptoms, such as lightheadedness, visual dimming, or a slow response to verbal stimuli. Many CFS patients experience lightheadedness or worsened fatigue when they stand for prolonged periods or when in warm places, such as in a hot shower. These conditions are also known to trigger NMH. One study observed that 96% of adults with a clinical diagnosis of CFS developed hypotension during tilt table testing, compared with 29% of healthy controls. Tilt table testing also provoked characteristic CFS symptoms in the patients. A study (not placebo-controlled) was conducted to determine whether medications effective for the treatment of NMH would benefit CFS patients. A subset of CFS patients reported a striking improvement in symptoms, but not all patients improved. A placebo-controlled trial of NMH medications for CFS patients is now in progress. 

F. Nutritional Deficiency 

There is no published scientific evidence that CFS is caused by a nutritional deficiency. Many patients do report intolerances for certain substances that may be found in foods or over-the-counter medications, such as alcohol or the artificial sweetener aspartame. While evidence is currently lacking for nutritional defects in CFS patients, it should also be added that a balanced diet can be conducive to better health in general and would be expected to have beneficial effects in any chronic illness. 

Diagnosis of CFS

B. Appropriate Tests for Routine Diagnosis of CFS 

While the number and type of tests performed may vary from physician to physician, the following tests constitute a typical standard battery to exclude other causes of fatiguing illness: alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), blood urea nitrogen (BUN), calcium, complete blood count, creatinine, electrolytes, erythrocyte sedimentation rate (ESR), globulin, glucose, phosphorus, thyroid stimulating hormone (TSH), total protein, transferrin saturation, and urinalysis. Further testing may be required to confirm a diagnosis for illness other than CFS. For example, if a patient has low levels of serum albumin together with an above-normal result for the blood urea nitrogen test, kidney disease would be suspected. The physician may choose to repeat the relevant tests and possibly add new ones aimed specifically at diagnosing kidney disease. If autoimmune disease is suspected on the basis of initial testing and physical examination, the physician may request additional tests, such as for antinuclear antibodies. 

C. Psychological/Neuropsychological Testing 

In some individuals it may be beneficial to assess the impact of fatiguing illness on certain cognitive or reasoning skills, e.g., concentration, memory, and organization. This may be particularly relevant in children and adolescents, where academic attendance, performance, and specific educational needs should be addressed. Personality assessment may assist in determining coping abilities and whether there is a co-existing affective disorder requiring treatment. 

D. Theoretical and Experimental Tests 

A number of tests, some of which are offered commercially, have no demonstrated value for the diagnosis of CFS. These tests should not be performed unless required for diagnosis of a suspected exclusionary condition (e.g., MRI to rule out suspected multiple sclerosis) or unless they are part of a scientific study. In the latter case, written informed consent of the patient is required. No diagnostic tests for infectious agents, such as Epstein-Barr virus, enteroviruses, retroviruses, human herpes virus 6, Candida albicans, and Mycoplasma incognita, are diagnostic for CFS and as such should not be used (except to identify an illness that would exclude a CFS diagnosis, such as mononucleosis). In addition, no immunologic tests, including cell profiling tests such as measurements of natural killer cell (NK) number or function, cytokine tests (e.g., interleukin-1, interleukin-6, or interferon), or cell marker tests (e.g., CD25 or CD16), have ever been shown to have value for diagnosing CFS. Other tests that must be regarded as experimental for making the diagnosis of CFS include the tilt table test for NMH, and imaging techniques such as MRI, PET-scan, or SPECT-scan. Reports of a pathway marker for CFS as well as a urine marker for CFS are undergoing further study; however, neither is considered useful for diagnosis at this time. 

Careful Consideration of Information about CFS

• (i) there is no evidence that CFS patients lose their fingerprints;
  
• (ii) there is no scientific evidence of any nutritional deficiency in CFS patients; and
• (iii) suicides of CFS patients have been reported, but the rate of occurrence has not been well-studied and it is not known whether the rate is higher or lower than what would be expected in the general population. It is not practical to address all of the information that circulates or emerges regarding CFS. Simply be advised to be wary of information that points to sure cures or that alludes to pathological damage as a consequence of CFS. Specific questions should be discussed with the patient's physician, local or state health department, CDC, or one of the national patient support organizations.

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