Despite several decades of research, the etiology of CFS remains unclear. In any potential etiological domain, studies reporting positive findings are nearly always counterbalanced by studies that are negative. Nonetheless, tentative conclusions can be drawn concerning physiological systems that may be abnormal in at least some patients with CFS. It is important to remember, however, that it remains unknown whether any given abnormality represents a cause or a consequence of CFS.

Early etiological theories of the disorder focused on the immune system and infection with Epstein Barr and other latent viruses. Although cases of CFS may follow such infections, it is clear that specific viral infections are not a primary cause of the disorder. A variety of immune system abnormalities have also been reported, including decreases in natural killer cell activity and increases in proinflamma-tory cytokines, especially in patients with sudden-onset CFS. A recent study indicated that CFS patients have increased delayed type hypersensitivity reactions, suggesting an abnormality in T-cell-mediated immunity.

Patients with CFS also may exhibit decreased activity of the hypothalamic-pituitary-adrenal (HPA) axis, the body's primary stress response system. Several studies report decreased levels of circulating cortisol and decreased adreno-cortical reserve. Concordant with this observation, one study reported that CFS patients demonstrate adrenocor-tical atrophy on CT scan. In addition to decreased functioning, the HPA axis has also been reported to lose its normal circadian rhythm in CFS patients. Clinical improvement has been associated with normalization of this rhythm.

Other physiological abnormalities have been reported in patients with CFS. Many patients with CFS complain of unrefreshing sleep. In keeping with this, fibromyalgia, which has symptoms that overlap with those of CFS, has been characterized by an increase in awake-state (alpha) brain rhythms during deep (stage 4) sleep. It has also been reported that abnormal autonomic nervous system functioning may be common in patients with CFS, based on the fact that at least some CFS patients demonstrate orthosta-tic intolerance when subjected to tilt table testing. Con versely, patients with postural orthostatic intolerance syndrome often manifest symptoms similar to those seen in CFS. Alterations in central nervous system serotonin, argi-nine vasopressin, and growth hormone have also been described.

Finally, psychological and stress-related factors have been associated with CFS. Many patients report an increase in life stress in the year prior to disease development, especially when the illness develops slowly. Recent work with identical twins suggests that patients with CFS are more affected by similar levels of somatic distress than are genetically identical but unaffected persons.

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