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What is Chronic Fatigue Syndrome?

· Definition

According to the American Center for Disease Control, Chronic Fatigue Syndrome (CFS) is defined by "the presence of unexplained persistent fatigue that is not relieved by rest and that results in a substantial reduction in occupational, social and personal activities."

· Symptoms

As criteria for CFS diagnosis, at least four of the following symptoms must have been present for a minimum of six consecutive months with a history of previous well-being:

· Epidemiology

In the USA, early attempts to estimate the prevalence of CFS reported that 4 to 10 adults per 100,000 (0.004 % to 0.01 %) suffer from CFS. It appears now that this was an underestimation of the true figures. Recent studies have more realistically estimated that 200-700 per 100,000 people may suffer from CFS (0.2% to 0.7%). The syndrome potentially affects people of all ages but the onset is most common in the early thirties (Dowsett, 1990; Shepherd, 1999). CFS afflicts women more then men, in a proportion of 2:1 (Ho-Yen, 1991). Social background seems to be irrelevant.

· Etiology

No single cause can explain CSF. It rather appears to develop through exposure to convergent factors (Fig. 1), such as:

· Neurohormonal factors

There is a high incidence of abnormalities in the HPA axis of people suffering from CFS. The HPA axis is a major component of the body's response to stress and refers to the hypothalamus, pituitary, and adrenal glands. The hypothalamus is located in the brain where it physically interacts and stimulates the pituitary gland through the release of the corticotrophin-releasing hormone (CRH).

The pituitary gland itself is considered as the key master of the endocrine system. Hormones that are produced by the pituitary control other glands activities at distant sites throughout the body. As an example, liberation of the adrenocorticotropic hormone (ACTH) in the blood stream by the pituitary commands the adrenal to secrete cortisol. Cortisol is a glucocortical hormone also referred as the *stress hormone*. Its role is to mobilize the glucose reserves so that the body can respond quickly to a challenging situation. Both CRH and cortisol influence the immune system and cortisol. additionally can suppress inflammation.

CFS has been associated with smaller adrenal glands (Scott, 1999) and mild signs of adrenal failure as well as reduced levels of related hormones are seen in almost half of the people suffering from CFS (Demitrack, 1998). The CRH and cortisol levels are generally low, although still in the normal range, in these patients. The negative feedback loop of the HPA axis is prolonged, contributing to maintain the cortisol level in its lower range (Gaab, 2002). Moreover, the CRH response to exercise (Ottenweller, 2001) and the response to cortisol. inducers (Scott, 1998) are deemed to be impaired.

Lower levels of CRH and cortisol, per se, are known to result in extreme fatigue, decreased plasma volume, myalgias, arthralgias, fever, allergic responses, as well as mood and sleep disturbances, all common complaints in CFS.

· Immune imbalance

Several immunological anomalies have been inconsistently reported in CFS. For instance, decreased number and activity of natural killer cells are sometimes seen in CFS (Levine, 1998). In other cases, the RNAse antiviral pathway is impaired opening the door to infections (DeMeirleir, 2000). Other patients have higher titer of infection-fighting CD8+ T cells combined with a low count of suppressor T cells leading to an exhausting immune overactivity (Landay, 1991). But the most striking immunological trait in CIPS remains a shift from cell-mediated (Thl) to humoral immunity (Th2). The shift to humoral immunity is marked by an increased production of Th2 type cytokines. More IL-5 is produced that stimulates antibodies formation. The levels of IL-6 and IL-8 are raised as well, and these cytokines are presumed to be involved in myopathic pain and hyperalgesia respectively, as seen in CFS (Wolfe, 1997).

· Infectious agents

A viral origin has long been suspected for CSF. Indeed some features of CSF are reminiscent of those of viral infection. For instance, a sudden unset of illness and a high level of antibodies to many virus are commonly seen in patients with CSF (Manian, 1994). Arguing against an infectious origin are the facts that most cases of CSF appear sporadically (US Dept. of Health, 1995), CSF does not spread through contacts of any kind and no single pathological agent could be pointed out (Farrar, 1995).

· Oxidative stress

Recent studies are suggestive of oxidative stress involvement in CIPS (Logan, 2001; Richards, 2000; Fulle, 2000). Oxidative stress results from the accumulation of free radical species inside the cell. Free radicals are molecules with an impaired electron. This makes them very unstable molecules that react quickly with neighboring molecules from which they try to steal the missing electron. Once started the process may generate a cascade of oxidation reactions ending in serious damages to the cell.  Free radicals arise spontaneously during normal metabolic activities so the cell has evolved antioxidant defenses to handle them. But the cell defense system may become overwhelmed by excessive oxidative assaults generated by environmental factors or in the course of illness.

Mitochondrial. dysfunction can further exacerbate this oxidative stress phenomenon by releasing additional oxidants.

Signs of oxidative stress involvement in CIPS include a high level of oxidative damage to DNA and lipids, as seen in biopsy samples of patients with CFS (Fulle, 2000). Reduced oxidative metabolism  (McCully, 1996) and mitochondrial abnormalities in CIPS, (Behan, 1991) support a mitochondrial defect as a contributor. Moreover, since mitochondria supply energy to the cell through oxidative phosphorylation, the lowe rlevel of ATP that results from a low mitochondrial activity may explain the low exercise capacity reported in patients with CFS (Lane, 1998).

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