Chronic Fatigue Syndrome (CFS), also known as chronic fatigue and immune dysfunction syndrome (CFIDS) and myalgic encephalomyelitis (ME), is a serious health concern. CFS is a debilitating condition characterized by severe and persisting fatigue, not attributable to ongoing exertion or lack of rest, and worsened by physical or mental activity. There is widespread disruption of central and peripheral nervous system and physiological function, which waxes and wanes over time. Little is known about the etiology and pathophysiology of this condition; in ignorance, people with CFS have been accused of malingering or faking. Historically, case descriptions of CFS date to the late 18th century. The lack of understanding of this syndrome by the medical community has provided tremendous hardship and obstacles for persons with CFS seeking treatment. Recent estimates indicate that about 1.3 million people in the United States have CFS, but 85-90 percent of these persons go undiagnosed and untreated. These individuals are either unaware that they are suffering from CFS or they are fearful of the stigma attached to such a diagnosis. At this time, treatment plans are symptom focused and relatively ineffective in ameliorating the symptomatology. However, there are significant clues that have led to scientific investigation and have provided hope for more rapid progress in establishing the underlying pathological mechanisms.
Chronic Fatigue Syndrome Definition, Symptoms, and Differential Diagnosis
The term “chronic fatigue syndrome” was proposed by the U.S. Centers for Disease Control and Prevention in 1988 and revised in 1994. To exclude other mental and physical causes of their symptoms, persons with CFS must undergo an extensive battery of tests before the CFS diagnosis is considered. The International CFS Working Groups 1994 CFS case definition criteria include 6 months or more of clinically evaluated, unexplained, persistent or relapsing fatigue and four of eight concurrent symptoms that do not predate the fatigue. The fatigue must (1) be of new or definite onset, (2) not be the result of ongoing exertion, (3) not be substantially alleviated by rest, and (4) result in substantial reduction in previous levels of occupational, educational, social, or personal activities. Concurrent symptoms include four or more of the following symptoms: (1) impaired short-term memory or concentration, (2) sore throat, (3) tender lymph nodes, (4) muscle pain, (5) multijoint pain without arthritis, (6) headaches of a new type, pattern, or severity, (7) unrefreshing sleep; and (8) postexertional malaise lasting more than 24 hr.
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Fatigue is a prominent symptom in a number of other clinical disorders including fibromyalgia, irritable bowel syndrome, major depression, anxiety, and somatoform disorders. In persons with these disorders there are also several symptoms that overlap with CFS symptomatology including sleep disturbance, neurocognitive impairment, mood changes, and musculoskeletal pain. For example, CFS and fibromyalgia are so similar that an emphasis on musculoskeletal pain symptoms is the main characteristic that distinguishes them. In addition, up to 75 percent of CFS patients report either current or past major depression, whereas lifetime prevalence of depressive disorders in the general population is only 13-25 percent. Such comorbidity is not surprising, as diagnostic criteria for both CFS and major depression includes fatigue, sleep disturbance, and cognitive impairment. Even more challenging is the distinction between CFS and somatoform disorders, as the latter describe persons with unexplainable physical symptoms that are believed to result from underlying psychological processes. Other co-morbid conditions include irritable bowel syndrome, multiple chemical sensitivities, temporomandibular disorder, interstitial cystitis, postconcussion syndrome, tension headache, chronic low back pain, chronic pelvic pain (women), and chronic nonbacterial prostatitis (men). Therefore, when making a CFS diagnosis, a careful assessment to exclude alternative diagnoses is essential.
Chronic Fatigue Syndrome Prevalence and Demographics
CFS primarily affects individuals between 20 and 50 years of age. Accurate prevalence studies are difficult to conduct in absence of a sensitive laboratory marker. Although fatigue is a relatively frequently reported symptom, affecting up to 74 percent of all people visiting general practitioners, CFS prevalence following the exclusion of comorbid conditions is considerably lower, with 200-1000 cases occurring per 100,000 adults, or 0.2-1 percent. A recent epidemiologic study estimates the CFS prevalence at approximately 422 per 100,000 adults in the United States. Thus, as many as 1.3 million people nationwide may suffer from the condition. To put CFS prevalence into perspective, systemic lupus affects 50 per 100,000, multiple sclerosis affects 104 per 100,000, and rheumatoid arthritis affects 1,022 per 100,000 adults. In addition, CFS has been identified in children and adolescents, albeit with diminished prevalence; an Australian study reported 5 cases per 100,000 children up to age 9 years and 48 pediatric cases per 100,000 for ages 10 to 19 years.
Of those diagnosed with CFS, about 70 percent are women. This sex specificity may be because women seek medical care more frequently than men do. However, studies indicate that fatigue symptoms appear to be more prevalent in people from more socially disadvantaged groups, who have poorer access to medical care. There is now evidence that CFS affects all racial and ethnic groups. Another study has indicated that a high rate of CFS occurs in nurses, suggesting that specific environmental influences may pose additional risk.
Chronic Fatigue Syndrome Etiological Clues
Although twin studies suggest a genetic vulnerability to the disorder, there is growing evidence that CFS is heterogeneous, and it is likely that it will have no single cause. There is no evidence that CFS is caused by a neuromuscular pathology. Several other possible etiologies have been proposed, including central nervous system (CNS), neuroendocrine and autonomic nervous system functional dysregulation, infections, and immunological factors.
CNS, Neuroendocrine, and Autonomic Nervous System
Among psychological factors, no link has been found between psychological events (e.g., childhood abuse) and CFS. However, CFS patients were more likely to have experienced critical life events prior to disease onset. Although several other lines of investigation suggest altered CNS function in CFS, including high rates of major depression, the pattern of psychological changes observed in CFS patients is different from that seen in people with depression; hence, different pathophysiologic processes are indicated. No conclusive evidence of a link to CFS from other premorbid psychiatric disorders has been documented.
CFS patients frequently suffer from sleep disturbances; research on increased sensitivity to serotonin and on changes in brain structure and function has yielded no definitive findings. Impairments in neuroendocrine function, namely in hypothalamic-pituitary-adrenal axis (HPA) activation, have also been reported in CFS patients. Physical, emotional, and mental challenges induce fatigue and other CFS symptoms that may last about 2-4 days. Such stressful challenges induce HPA axis activation and result in Cortisol and corticotrophin-releasing hormone (CRH) secretion. These substances influence immune function by suppressing inflammation and cellular immunoactivation and also affect other systemic function. Some studies have shown a reduction in Cortisol levels and HPA axis/CRH functionality in CFS patients. Therefore, depressed HPA axis function may affect CFS patients by its influence on systemic function.
There is accumulating data that most CFS patients have difficulty sustaining an upright posture. Significant hypotension, racing heart rate, and light-headedness are common observations during postural challenges. These confluent signs are consistent with autonomic dysregulation of circulation, manifesting as orthostatic intolerance in which postural tachycardia syndrome and/or hypotensive syncope, dizziness, and a transient loss of consciousness and postural tone may be observed. Moreover, there is evidence that many CFS patients have diminished red blood cell volume. Because the red blood cell transports oxygen and blood sugar to the cells, the impairment of this function could account for persistent fatigue and circulatory dysfunction in CFS.
In addition to fatigue, CFS is associated with chronic or recurrent flulike symptoms, including sore throat, lymph node pain and tenderness, headache, and muscle and joint pain, suggesting an infectious etiology. A majority of patients self-report an infectious onset to their illness. Epstein-Barr virus, triggering infectious mononucleosis, has been shown to precede CFS onset. However, Epstein-Barr viral reactivation is not more prevalent in CFS. There is a strong support against a role in CFS of retroviruses, viruses such as human immunodeficiency virus, spumavirus, and leukemia virus that use the DNA machinery of the cell to reproduce. However, evidence is conflicting for a role of enteroviruses, such as human herpesvirus-6 and borna disease virus, which are small viruses that multiply in the gut lining and are transmitted from person to person by the fecal-oral route. Among the nonviral infections, Lyme disease and Q fever have been implicated. The consensus is that CFS is not contagious and cannot be caused exclusively by any single recognized infectious agent.
CFS patients demonstrate altered immunological profiles including increased numbers of neutrophils and activated lymphocytes but depressed amounts of some kinds of antibody and decreased numbers and function of other immune cells, suggesting that chronic and perhaps multiple infectious and/or allergic sources are exerting an etiological role. Still, some cells are working too hard, making chemical messengers called cytokines that cause inflammation, which are associated with that “flulike” feeling. The fine tuning of the immune system does not seem to turn off this inflammatory process. Among proinflammatory conditions associated with CFS, serum elevations of immune cytokines (e.g., IL-6) have been reported. Proinflammatory mediators produced, for example, in response to infectious or allergic sources have been shown to induce fatigue, sleep-wake cycle disruption, mental confusion, and diminished red blood cell production. In addition, studies of CFS patients have reported reduced numbers of natural killer (NK) cells along with a reduction in their function. The NK cell is an immune cell that provides first-line defense against infection and also releases perforin, a chemical messenger that turns off proinflammatory activity. The lack of perforin may to lead to prolonged persistence of inflammatory conditions. In sum, there are a number of findings that suggest an immune-mediated CFS etiology exists that has system-wide biobehavioral impact.
Chronic Fatigue Syndrome Treatment
The several clinical treatment approaches available are symptom focused. No specific diagnostic test for CFS has been identified. Laboratory blood tests are conducted primarily to rule out underlying medical conditions. Initially, control of key symptoms such as pain, sleep disturbance, and depressed mood with standard pharmacologic treatments is explored. Once these methods prove helpful for the patient, treatment may be coordinated with nonpharmacologic forms of care.
Drug treatment clinical trials based on immune/allergy approaches have demonstrated only marginal improvements in some studies. Antidepressants have also been assessed, but limited improvements in fatigue have been observed. Although serotonin reuptake inhibitor agents are popular for treating depression and mood instability, there has been little evidence of their usefulness in alleviating CFS symptoms. Corticosteroid trials demonstrated some reduction in fatigue, but the observed effect was due to a significant depression of adrenal function; long-term use of corticosteroids is associated with serious morbidity and cannot be recommended.
Due to some reports of nutritional deficiencies in CFS patients, studies were undertaken to provide nutrient supplements, such as folic acid, vitamins B12 and C, magnesium, zinc, and omega 3 fatty acids. Results from these studies are inconclusive. Trials evaluating graded exercise therapy reported overall but limited improvements in fatigue, functional work capacity, and fitness of CFS patients. Cognitive-behavioral therapy also has produced positive outcomes for a majority of CFS patients, for whom decreased frequency of primary care visits, improvements in fatigue severity, physical functioning, and increased self-confidence were observed. In addition to skill-training methods for coping with stressful challenges, the cognitive component of this therapy is aimed at identifying beliefs and behaviors that may impair recovery. In contrast with earlier treatment beliefs, which advocated prolonged rest and social withdrawal, current evidence suggests that behavioral approaches may be an essential component of managing CFS. Alternative treatments, including herbal supplements, physical rehabilitation, acupuncture, homeopathy, chiropractic, guided imagery, self-hypnosis, massage therapy, energy healing, religious healing, oxygen therapy, and dietary restrictions, have been proposed, but scientific evidence for these approaches is lacking.
The historical record indicates that CFS is an old clinical problem derailed by ignorance and biases. Scientific examination of this syndrome is in its infancy. From what is known about CFS, it can be characterized as an illness that has widespread and complex physiological and psychological impact. Together, the difficulty in diagnosing CFS, the broad range of prevailing symptomatology, and the evidence of multisystem (i.e., CNS, immune, neuroendocrine, and circulatory) abnormalities suggest that multifactorial interactive biobehavioral processes are likely underlying its etiology. Hence a formidable scientific challenge exists that perhaps requires a more multidisciplinary biobehavioral approach to ascertain an understanding of the pathophysiologic basis of CFS.
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