Causes

Sudden- and Gradual-Onset CFS. One interesting theory is that CFS can be categorized as either sudden- or gradual onset, with each subgroup having different causes. In over half of patients, the onset is sudden, while the remaining patients have a slow onset. Some experts believe that sudden-onset CFS may be triggered by a virus or neurologic abnormality, while gradual-onset CFS might have a psychological or other cause. Supporting this theory was a study that observed that MRI scans of the brains of CFS patients without an accompanying psychiatric problem showed small injuries suggesting either a viral infection or neurologic problem. Still other experts believe that in some cases, gradual-onset CFS may be traced to cognitive disorders that were present during childhood, but went unrecognized until symptoms advanced into adulthood.

Genetic Defects

New evidence suggests genes involved in the body's response to stress may play key roles in CFS. A series of 14 articles published in 2006 linked CFS with genes involved in the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Julie Gerberding, MD, MPH, director of the Centers for Disease Control, called the research, "the first credible evidence of a biological basis for chronic fatigue syndrome." The researchers were able to locate a common variation of DNA sequences that predicted CFS with 76% accuracy. The genes control response to trauma, injury, and other stressful events. Nevertheless, the researchers were unable to find genetic markers of CFS or to determine how the genetic variations influenced symptoms.

In 2005, English researchers found that people with CFS are more likely than people without CFS to have human leukocyte antigen (HLA) class II alleles, variations that produce antibodies to certain immune factors. Another British study of people with CFS found alternations in 16 specific genes involved with immune function, communication between cells, and transfer of energy to cells.

Central Nervous System and Hormone Abnormalities

Another subgroup of CFS involves abnormalities in the central nervous system, particularly abnormal levels of certain chemicals regulated in the brain system known as the hypothalamus-pituitary-adrenal (HPA) axis. This system controls important functions, including sleep, response to stress, and depression. Of particular interest to researchers are the following chemicals and other factors controlled by the HPA axis:

• Changes in Important Neurotransmitters. Other research has reported that some patients with CFS have abnormally high levels of serotonin, a neurotransmitter (chemical messenger in the brain). Such elevated levels in the brain are associated with fatigue. Studies also suggest that deficiencies in dopamine, an important neurotransmitter associated with feelings of reward, may play a role in CFS. Imbalances between norepinephrine and dopamine have been identified in certain CFS patients in several studies. Unfortunately, routine clinical testing for such chemical imbalances is cost-prohibitive. Drugs that improve the chemical balance in the brain are very effective for certain patients, however.
• Stress Hormone Deficiencies. A number of studies on CFS patients have observed low levels of cortisol, a stress hormone produced in the adrenal glands. Cortisol is a precursor of dehydroepiandrosterone (DHEA), a weak male hormone that may also be important in CFS. Deficiencies may be the reason why CFS patients have an impaired and weaker response to psychological or physical stresses, such as infection or exercise. (Administering replacement cortisol improves symptoms in some, but not all, patients, indicating other factors are involved.) According to research published in 2005, chronic high levels of adrenocorticotropin hormone (ACTH) auto-antibodies worsen the problem of cortisol deficiency and lead to physical and psychological symptoms in people with CFS.
• Disturbed Circadian Rhythms. Evidence suggests that in certain patients, CFS is a disorder of the sleep-wake cycle, which is regulated by the so-called circadian clock, a nerve cluster in the hypothalamus-pituitary-adrenal (HPA) axis. In a 2003 study of identical twins, those with CFS complained of disturbed sleep although they didn't differ from their non-CFS twins in their ability to fall or stay asleep or other objective measures of insomnia. The CFS twins did, however, exhibit more REM sleep, which is the active, dreaming phase of sleep, suggesting this may play some role. Some experts suggest that some mentally or physically stressful event, such as a viral infection, may disrupt natural circadian rhythms, and that an inability to reset these rhythms results in a perpetual cycle of sleep disturbances. Medications that improve sleep can be very helpful for certain patients.