The search for what causes chronic fatigue syndrome (CFS) continues. After testing several theories for a decade or so, researchers may know more about what the syndrome is not than what it is.

Dedra Buchwald, M.D., a professor of medicine and director of the CFS clinic at the University of Washington in Seattle, described the impact of research on several theories about medical causes of CFS at the Academy of Psychosomatic Medicine (APM) meeting in November in Palm Springs, Calif.

Infectious agents have been considered a primary cause because fatigue-related symptoms often appear with the onset of a viral or bacterial infection. However, research shows that only a small percentage of patients with infectious diseases such as the Epstein-Barr virus develop CFS, said Buchwald.

The revised criteria for CFS published by the Centers for Disease Control and Prevention in 1994 call for the presence of four or more symptoms that have a definite onset and are present for at least six months. The symptoms are short-term memory loss or a severe inability to concentrate that affects work, school, or other normal activities; sore throat; swollen lymph nodes in the axilla or neck; muscle pain; joint pain without redness or swelling; intense or changing patterns of headaches; unrefreshing sleep; and weariness after exertion that lasts for more than a day.

The fatigue must be severe, not relieved by sleep or rest, and not the result of excessive work or exercise, according to the CDC.

Researchers have also examined a theory that immune system deficiencies cause CFS. In spite of the fact that CFS patients have three times the rate of allergies of healthy control subjects, researchers have not found evidence to support a specific immune complex, according to Buchwald.

"However, some studies suggest that there are differences in the expression of lymphocytes in CFS patients compared with normal controls, but what that means is unclear," said Buchwald.

Because patients often complain of daytime sleepiness, researchers have also looked at narcolepsy. They found, however, that only a fraction of CFS subjects had the condition.

Investigators have also compared CFS patients with depressed patients in several studies because of several overlapping symptoms including lethargy and problems with concentration and sleep.

"Decreased levels of cortisol have been found in CFS patients, which means they have an inadequate response to stress. In contrast, depressed patients have elevated levels of cortisol, which suggests that the underlying physiology is different," Buchwald commented.

According to Michael Sharpe, M.D., a psychiatrist and expert in CFS at the University of Edinburgh in Scotland, low cortisol levels are also found in anxiety disorders including PTSD, but the link between low cortisol and CFS is unclear.

Sharpe, who also spoke about CFS at the APM meeting, mentioned that recent neuroimaging studies show that brain abnormalities in the prefrontal cortex in CFS patients appear to be related to decreased perfusion.

Other studies comparing CFS patients with depressed patients have found contradictory responses to exercise and antidepressants. "Unlike depressed patients who improve after exercise, CFS patients tend to feel worse afterward, with greater fatigue," said Buchwald.

Sharpe believes that CFS patients need a more tailored approach to exercise. "Just telling patients to go out and exercise doesn’t work." He referred to a study conducted in the United Kingdom on an exercise program that used a therapist and gradual increases in the level of activity. The results were positive in CFS patients, said Sharpe.

Studies on antidepressants in CFS patients have produced mixed results. CFS patients did not respond to fluoxetine in one study, but showed some benefit from phenelzine, a monoamine oxidase inhibitor, in another study, according to Sharpe.

Recent studies of cognitive-behavioral therapy (CBT) show promising results in CFS patients. "My study in 1996 found that intensive CBT combined with regular clinical care was superior to seeing only a primary care physician or an infectious disease specialist. There was a significant benefit at 12 months," Sharpe said. Another study in 1997 that compared CBT with relaxation techniques found CBT was superior after six months, noted Sharpe.

However, Sharpe said he would like to see more research on anxiety disorders, in particular panic and agoraphobia. "In some patients of mine, a sudden episode of panic will trigger the symptoms of fatigue, and agoraphobia becomes part of the disability." Compared with research on depression, Sharpe noted, the role of anxiety disorders in CFS has been neglected.

Although the CDC criteria for CFS may be helpful in advancing research, the diagnosis remains controversial among physicians. Many don’t believe the syndrome exists, and some believe it is a psychiatric phenomenon, according to Sharpe.

This belief puts them at odds with some patients who believe the opposite, that they have a medical condition. Sharpe said he resolves this dilemma by giving patients who meet the criteria a diagnosis of CFS with comorbid depression or anxiety.

Another controversy exists over the name chronic fatigue syndrome. Patient advocacy groups in the U.S. and the United Kingdom are using other names, such as chronic fatigue and immune deficiency syndrome (CFIDS) in the U.S. and myalgic encephalomyelitis in the U.K..

The concern these groups have is that people misunderstand the term fatigue, because it doesn’t adequately describe the severity of the condition they experience and the resulting disability, according to CFIDS Association of America.

The Department of Health and Human Services Chronic Fatigue Syndrome Coordinating Committee, made up of patient advocates and representatives of federal agencies conducting research in this field, is addressing the issue of whether to change the name, according to the CFIDS association.

More information about CFS is posted on the CFIDS Association of America’s Web site at www.cfids.org and the CDC’s Web site at www.cdc.gov/ncidod/diseases/cfs. ▪