Chronic Fatigue Syndrome
Chronic fatigue syndrome (CFS), fibromyalgia and multiple chemical sensitivities (MCS) constitute three different clinical entities that are, however, associated (Jason et al., 2000; White et al., 2000) and that in the past were grouped under the term neurasthenia (Schäfer, 2002).
It was not until the mid-1980s that CFS was recognized as a separate disease. At the time, and to the detriment of patients, CFS was regarded as a relatively rare pathology with an underlying psychological disorder, especially since CFS and depression present with some symptoms in common (Dickinson, 1997; Jason et al., 1997). Not until the mid-1990s did detailed epidemiological studies identify a disease prevalence that was clearly more significant.
Occurrence of CFS varies between 0.01 and 2.6% of the population depending on geographic location and applied diagnostic criteria (Kawakami et al., 1998; Lawrie and Pelsi; 1995, Steele et al., 1998; Jason et al., 1999). According to the Center for Disease Control, Atlanta (CDC), 2 to 5 million Americans have the disease (Tick and Wallace, 2000). More than 80% of CFS cases are women, and the average age for the appearance of the disease is 30 (Gunn et al., 1993). The incidence of the disease is highest in the winter and spring months (Jason et al., 2001). A reliable laboratory test for diagnosing CFS is currently unavailable. Clinical biological analyses show an activation of the immune system and neuroendocrine disorders.
The diagnosis is exclusively based on patient history and clinical findings. It is based on the exclusion of potential other causes of chronic fatigue and on criteria corresponding to definitions adopted by the CDC in 1988 and 1994 (Gonzalez et al., 1996, Fukuda et al., 1994). CFS is a relatively heterogeneous disease characterized by:
Prolonged fatigue disproportionate to the intensity of effort sustained that is exhibited during at least six months and manifests at least 50% of the time, generally preceded by an infection, trauma or sustained major psychological stress. In athletes competing at the highest level, overtraining or a negative energy balance can trigger CFS (Shephard, 2001).
To meet the definition of CFS proposed by the CDC, chronic fatigue must be accompanied by at least four of the following eight symptoms:
- Reduced neurocognitive functions (memory and concentration disorders)
- Sleep disorders
- Somatic manifestations such as subfebrile temperature or intermittent fever
- cervical or axillary ganglionic adenopathy
- feeling of recurring dry mouth
- multiple myalgias and arthralgias
- postural malaise
- headaches (which were not present before presentation of the disease)
The prognosis for the disease is relatively unfavourable with prolonged morbidity, which can worsen over time, and a relatively low spontaneous cure rate (Hill et al., 1999). The etiology of CFS is probably multi-factorial; the exact causes, however, remain unknown. Personality disorders, dysfunction of the hypothalamic-pituitary-adrenal axis (HPA), hormonal imbalance, nutritional deficiency, immunosuppression or activation of the immune system have been identified as triggering factors. CFS is probably related to a disruption of the interactions between various organs, and more specifically between the neuroendocrine and immune systems, the cause of which may be a disproportionate immune response in subjects with a genetic predisposition. The nervous and immune systems have a very significant interaction (Elenkov et al., 2000). Mental stress influences the immune response via complex interactions involving the HPA axis and the autonomic nervous system. Cells of the immune system also express receptors for hormones and neurotransmitters. Activation of these receptors modulates the immune response. In the event of CFS, the HPA axis is no longer able to respond to physiological stimuli. This is probably why patients with CFS cannot respond emotionally to stress and exhibit sleep disorders (Theorell et al., 1999). Although many subjects with CFS exhibit chronic low level immune activation, which is identified by an increase in the number of active T lymphocytes and elevated circulating levels of cytokines (IL-4, IL-6, IL-10 and TNFa) (Cannon et al., 1999; Hanson et al., 2001; Moss et al., 1999; Visser et al., 2001). The neuropsychiatric effects may not only be the effects of circulating cytokines but also the result of an unchecked production of cytokines by central nervous system glial cells (Vollmer-Conna et al., 1998). On the whole, however, the immune response is poor, with weak NK cell activity and a weak level of lymphocyte response to mitogens and immunoglobulin deficiencies, especially IgG1 and IgG3 (Patarca, 2001). The immune activation is basically type TH2, while TH1 activity (reduced levels of IFNg and IL-12) is reduced (Borish et al., 1998; Visser et al., 1998, 2001). Neuroendocrine mediators (glucocorticoids, norepinephrine, epinephrine, histamine and adenosine) have modulating effects on immune regulation through selective action on the IL-10/IL-12 regulatory circuit. On the one hand, active TH1 cells are suppressed as well as cell-type immunity; on the other hand, TH2 responses and humoral immunity are enhanced by glucocorticoids (Visser et al., 2000). Production of IL-12 (TH1) is suppressed while expression of IL-10 remains unchanged or increased. This driving force for TH2 response by endogenous stress mediators, such as histamine and adenosine, may be increased substantially under certain conditions by increased susceptibility to infectious agents that under normal conditions are eliminated by a TH1 response (Elenkov et al., 2000) and by reactivation of formerly latent viral infections (cytomegalovirus (CMV)), Epstein-Barr Virus (EBV) and Human Herpes Virus 6 (HHV-6)) (Patarca-Montero et al., 2001). Furthermore, conditions that contribute to increasing or reducing these mediators by modulating the IL-12/IL-10 balance may play a role in the induction, expression and development of some auto-immune diseases, allergic reactions and tumour growth. These conditions include:
1. Acute or chronic stress
2. Cessation of chronic stress
3. Very intense physical exercise
4. Major surgery
5. Traumas
6. Extensive burns
7. Severe ischemia and hypoxia
8. Pregnancy and post partum
The cause and effect relationship is difficult to establish for CFS. On the one hand, auto-immune and allergic responses and hypersensitivity may be the cause or the effect of the disruption of TH1/TH2 equilibrium and may lead to a neurovegetative disorder in predisposed subjects. On the other hand, conditions that increase the secretion of neuroendocrine mediators may activate the humoral immune response to the detriment of cellular immunity. This results in a vicious cycle.
In subjects with CFS, T-lymphocyte proliferation is less sensitive to the inhibitory effects of dexamethasone, and cytokine production by monocytes is relatively resistant to the action of beta2-adrenergic receptor agonists (Kavellars et al, 2000). This reduced sensitivity is not due to reduced cortisol and ACTH secretion, but to a reduction in active receptors or reduced intracellular signal transduction. Reduced levels of dehydroepiandrosterone (DHEA) and a reduced response following the administration of ACTH is also present in CFS cases (De Becker et al., 1999; Kuratsune et al., 1998). The reticular activating system (RAS) of the brain stem and/or its cortical projections (Dickinson, 1997) is also affected. Reduction in regional blood flow is emphasized by PET scans in CFS, multiple sclerosis and post-polio syndrome, conditions in which chronic fatigue is also present. Regarding elements that trigger CFS, there seem to be various sub-groups of patients. At least two thirds of subjects with CFS and their relatives have auto antibodies against serotonin, gangliosides and phospholipids (Klein and Berg, 1995). Some authors have mentioned an elevated association between atopy, allergies and CFS (Borish et al., 1998). In fact, subjects with CFS exhibit the same immunological changes as those with allergies (elevated TNFa and INFa and lowered IL-10). Seasonal allergy exacerbations are accompanied by elevated levels of circulating IFNa. Similarly, worsening of CFS symptoms is associated with a rise in IFNa and occurs during periods of seasonal exposure to allergens. The close association between CFS and atopy suggests that CFS occurs in predisposed subjects by abnormal psychological and neurovegetative responses to a chaotic expression of pro-inflammatory and inflammatory cytokines. Hypersensitivity to food would also be common in CFS cases (Logan and Wong, 2001; Manu et al., 1993., 1993). On the other hand, an elevated prevalence of serum markers of celiac disease is observed in subjects with CFS (Skowera et al., 2001). Deficiencies in vitamin B, vitamin C, magnesium, sodium, zinc, L-tryptophane, L-carnitine and coenzyme Q10 and essential fatty acids appear regularly in cases of CFS. It is more likely a phenomenon related to the disease and underlying oxidative stress than the result of an inadequate diet (Werbach, 2000). Dietary hypersensitivity through the production of cytokines may be at the origin of oxidative stress (Logan and Wong, 2001) with the creation of free radicals. Therefore, in CFS cases we observe higher concentrations of malondialdehyde, methemoglobin and 2,3-diphosphoglycerate and a higher erythrocyte volume than in controls (Richards et al., 2000). Methemoglobin would be associated with variations in the manifestation of symptoms such as fatigue, muscle weakness, pain and sleep disorders. Oxidative stress is involved in the pathogenesis of CFS and the presentation of symptoms. Oxidative stress also translates into oxidative damage of the DNA and lipids in muscles with an increase in antioxidant enzyme activity (catalase, glutathion peroxydase and transferase) and an increase in the levels of plasma glutathione (Fulle et al., 2000). Thus oxidative stress in muscles is accompanied by an increase in antioxidative defences.
Conclusion
CFS is a multi-factorial disease with a likely hereditary predisposition for developing an inadequate neurovegetative response to various stimuli, including dietary hypersensitivity and autoimmune and allergic responses. The close association between the neuroendocrine and immune systems involves a disturbance of immune responses, particularly with respect to infectious agents, with the generation of oxidative stress and somatic manifestations related to neurovegetative imbalance. These various phenomena may increase on their own and mutually potentiate thereby engendering a vicious cycle, which explains the relatively low incidence of spontaneous remissions.
Guidelines for measurement of anti-food IgG.
A diagnostic focus in CFS would involve a measurement of food-induced IgG since a significant percentage of cases may be associated with food intolerance. On the other hand, food hypersensitivity can cause or increase autoimmune responses, which are also frequently present in subjects with CFS. Independent of the etiological role of food, an exclusion diet would also be highly beneficial to attenuate disruption of immune system regulation as well as inflammatory response and oxidative stress. An early diagnosis is important to limit the somatic manifestations and increase the chances of a cure or rapid improvement.
