Chronic Fatigue Syndrome: How Far Have We Come?

The symptom complex which qualifies for the modern diagnosis of chronic fatigue syndrome (CFS) has a long heritage. While perhaps described earlier, Charles Beard, an American neurologist, popularized the diagnosis of 'neurasthenia' in the nineteenth century with descriptions of a clinical presentation quite similar to that of CFS.

In the mid-1980s, studies found elevated levels of antibody to Epstein-Barr virus in people with CFS-like symptoms; however, it eventually became clear that healthy people could have elevated Epstein-Barr antibody titers, while some sufferers of this illness had normal titers.

DEFINITION

Nowadays, the generally accepted criteria for CFS are those of the research case definition developed by the (US) Centers for Disease Control and Prevention and published in 1994 [ 1]. This definition bases the diagnosis on the most common presenting characteristics of the illness, namely a combination of both of the following (in the absence of other fatigue-related syndromes):

I. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that:

(i) is of new or definite onset (has not been lifelong)

(ii) is not the result of ongoing exertion

(iii) is not substantially alleviated by rest

(iv) results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

II. The concurrent occurrence of 4 or more of the following symptoms, all of which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue:

(i) self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities

(ii) sore throat

(iii) tender cervical or axillary lymph nodes

(iv) muscle pain

(v) multi-joint pain without joint swelling or redness

(vi) headaches of a new type, pattern, or severity

(vii) unrefreshing sleep

(viii) postexertional malaise lasting more than 24 hours.

The muscle pain which is a frequent complaint of CFS patients often qualifies them for another diagnosis, namely that of fibromyalgia. The most commonly accepted definition of fibromyalgia was formulated by the American College of Rheumatology in 1990. According to this definition, the patient must have a history of widespread pain as well as pain in at least 11 of 18 specific tender point sites upon finger pressure [ 2].

While the diagnosis of fibromyalgia is often made in the absence of the criteria for diagnosing CFS, a recent study of 74 fibromyalgia cases found that 58% of females and 80% of males met the full criteria for the syndrome [ 3]. Moreover, many of the laboratory findings of CFS and fibromyalgia are similar, suggesting that they may represent different expressions of the same spectrum of dysfunctional syndromes [ 4]--although it is certainly possible that the combination of muscle pain and fatigue represents a discrete illness which will eventually be clearly differentiated from CFS presenting without muscle pain [ 5].

Both the diagnosis of CFS and the diagnosis of fibromyalgia are based on clinical symptomatology, not on any understanding of underlying mechanisms which have promoted and initiated the development of the illness. Thus, the awarding of these diagnoses to the patient fails to suggest a unifying approach to treatment. Moreover, they create artificial hurdles over which patients must jump in order to qualify. Left behind are patients with milder or atypical presentations of syndromes with the same etiologies.

Whatever their shortcomings, these diagnoses do provide a simple means of communication, enabling clinicians and researchers to speak to one another with the confidence that they are talking about patients with similar clinical presentations.

ETIOLOGY

Early in the evolution of the diagnosis, there was a major battle over whether CFS is primarily biological or psychological in etiology. More recently, less energy is being spent on this issue as it has become clearer that such a clean dualistic separation is overly simplistic. No single etiologic agent and no consistent cellular or biochemical alteration has been found which differentiates the syndrome from similar illnesses [ 5].

The more we learn about CFS, the more it appears that the development of the illness can result from a number of possible factors [ 6, 7]. In each case, certain factors appear to predispose the patient to the illness, while others seem to precipitate it. Moreover, abnormalities which appear as the illness progresses towards the expression of the clinical syndrome may themselves promote the development of the illness. Some of the major factors which seem to be implicated are:

Infections
Many patients report nonspecific 'flu-like' symptoms at the onset of the illness. While it is known that CFS can be triggered by acute infectious mononucleosis, Lyme disease, Q fever and certain other infectious agents, it remains unclear whether most flu-like symptoms prior to the onset of the syndrome are caused by infectious agents [ 6].

Several lines of evidence point to an infectious etiology for a large portion of patients for whom the host-parasite relationships are modified. Antibody titers against infectious agents are often elevated, and reactivation of persistent or latent infectious agents could cause the common finding of immune activation [ 8]. Patients may have chronic activation of the 2-5A pathway, an antiviral lymphocyte enzyme system, suggesting chronic viral infection [ 9]. Moreover, a case-control study involving more than 700 patients found that patients had a much higher frequency of atypical lymphocytes than healthy controls [ 10].

Mycoplasma species appear to be one of the infectious organisms. Colonizers of human mucosal surfaces, they are known to be associated with human immunodeficiency virus infection. One study has found evidence of mycoplasma infections in more than 50% of a group of patients with CFS as compared to only 14% of healthy controls [ 11]. Another example is HHV-6, a virus whose reactivation has been shown to play a role in the pathogenesis of AIDS and several other diseases. CFS patients have been found to have increased levels of antibody to HHV-6 and HHV-6 DNA, suggesting that viral reactivation may play a role in its pathogenesis [ 12].

Also, research presented in this journal in 1990 found that 28% of 218 patients with a chief complaint of chronic fatigue were infected with Giardia lamblia. This sub-group was in many ways typical of patients now diagnosed as having CFS. While all had minor gastrointestinal symptoms, depression, muscle weakness, myalgia and flu-like feelings were also common [ 13].

Toxic Exposures
Exposure to toxic agents can result in an illness identical to CFS. For example, a group of CFS patients was shown to have significantly higher total organochlorine levels than matched controls [ 14]. Chronic lead poisoning has also been reported to present as CFS [ 15].

This journal has reported evidence that chronic low-dose exposure to organophosphates may eventually produce a symptom complex which not only meets the criteria for the diagnosis of CFS, but is also associated with the same neuroendocrine findings that are commonly found in the syndrome [ 16]. Subsequently, this journal published a letter to the editor which argued that chronic, low-level exposure to carbon monoxide may also produce a CFS-like syndrome [ 17].

Food and Chemical Sensitivities
CFS patients often exhibit some degree of sensitivity to foods and chemicals [ 18]. Not only has chronic fatigue long been reported to be a common presenting complaint among patients found to be food-intolerant, but the next most common complaint in this population has been reported to be aching and soreness in skeletal muscles and joints [ 19].

A recent case report described a man with a 26-year history of severe muscle pain, headache, fatigue, tachycardia and hypertension which began after a stay at a dairy farmhouse with an influenza-like illness. The diagnosis of CFS had been suggested. Eventually, lactose intolerance was found to be the cause of his symptoms [ 20].

Patients with both chronic fatigue and multiple food intolerances are more apt to have a lifetime of functional somatic symptoms and to fulfil the diagnostic criteria for somatization disorder [ 21]. Assuming that this is also true for patients who meet the current diagnostic criteria for CFS, it is unclear whether the earlier history of somatic symptoms was a milder manifestation of the same disorder or evidence of a different etiology of CFS for this group of patients.

CFS patients may also present with a history of multiple chemical sensitivities (MCS). When 30 patients with either CFS, fibromyalgia or MCS were compared, symptoms reported by all three patient groups were remarkably similar. Moreover, 30% of those with MCS met the criteria for CFS [ 22]. These findings fail to suggest whether MCS is one of the causes of CFS or simply another of its manifestations.

Immunologic Dysfunctions
A number of immunologic abnormalities are found in CFS, although it is not known to what extent they are secondary to the illness. Particularly striking is the regular finding that natural killer cell function is depressed [ 23]. While this finding is not specific to the syndrome, natural killer cells are believed to be central in the defence against viral infections.

Several common findings suggest immune activation, so it has been theorized that a state of chronic immune activation could lead to the production of cytokines that disrupt neurotransmitter function to cause the clinical symptomatology. Thus, cytokines may be the link between an infectious agent and the development of the illness [ 6].

Neuroendocrine Dysfunctions
There is substantial evidence of central nervous system pathology, particularly in the limbic system whose structures are the only cortical areas to receive major projections from the hypothalamus. Moreover, there is recent evidence that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system [ 24], thus suggesting that impairment in immune function may be at least partly due to faulty neuroendocrine control mechanisms.

In CFS, the activity of the corticotropin-releasing hormone (CRH) becomes attenuated, causing generally low activity in the whole hypothalamus-pituitary-adrenocortical (HPA) axis [ 25]. In a small and brief randomized crossover trial, CFS patients were found to respond to low-dose ( 5-10mg/day) hydrocortisone, suggesting adrenal depletion [ 26]. Similarly, more than half of a group of CFS patients with evidence of adrenal hypofunction were found to have significant adrenal atrophy on computer tomographic (CT) scanning [ 27].

One hypothesis proposes that a chronic viral encephalitis initiates the sequence of events that results in CFS [ 6]. Since viruses are known to be able to affect the HPA axis [ 28], and hypothalamic dysfunction could explain many of the symptoms of the illness, this theory is intriguing.

Stress
Stress appears to promote the development of the illness. We now believe that the neuroendocrine and immune systems share a common chemical language [ 29]. It is therefore not surprising that stress would promote alterations in the functioning of both systems. Except at low levels, it impairs immune system function as well as the immune defence against viral illness [ 30]. Moreover, chronic stress affects the HPA axis.

In a case-control study which sought to identify physical, behavioural, and psychological factors related to the occurrence of CFS, the greatest difference between 20 cases and matched controls on a self-administered questionnaire was the reported level of stress in the 5 years prior to the onset of the illness [ 31].

Psychopathology
Symptoms of fatigue along with sleep and cognitive disturbances are consistent with the presence of a psychiatric disorder, and patients suffering from CFS commonly feel depressed, yet the accumulating evidence suggests that these symptoms are simply the result of the underlying illness process(es) [ 6]. However, CFS patients may also suffer from certain co-morbid psychiatric illnesses.

Marginal Nutrient Deficiencies
Among patients with CFS and/or fibromyalgia, B vitamin deficiencies appear to be common, including folic acid [ 32], riboflavin [ 33], thiamine [ 34], and vitamin B12 [ 35]. There is also some evidence for deficiencies of zinc [ 34], L-tryptophan [ 36, 37], L-carnitine [ 38], and coenzyme Q10 [ 39], and specific essential fatty acid [ 40] and amino acid [ 41] levels may be abnormal.

This wide variety of possible deficiencies is consistent with the multicausal hypothesis. For example, a result of an inadequate supply of certain of these nutrients may be fatigue (such as with low folic acid levels), muscle pain (such as with low magnesium), immunodepression (such as with low vitamin C), and depression (such as with low L-tryptophan).

Nutrient deficiencies, while possibly promoting the development of the illness, do not appear to be due to dietary inadequacies, as the diets of CFS patients appear to be comparable to those of healthy volunteers [ 34]. Factors other than diet thus appear to be primarily responsible for their development, suggesting that they may occur as the result of other etiologic factors.

TREATMENT

In light of the multiple etiologic contributions to CFS, it is not surprising that a wide variety of treatments has been proposed:

Nutritional and Botanical Medicines
Nutrients which appear to be relevant to the treatment of CFS have been recently reviewed in some detail [ 42]. Not only may repletion of nutrient deficiencies be beneficial, but preliminary findings suggest that pharmacological dosages of certain nutrients may promote remission of both subjective and objective measures of the illness.

In this issue of the Journal, Dunstan et al. continue their valuable series of original research studies on the biochemical and microbiological anomalies in CFS with a study of amino acid excretion profiles. They found six major types of amino acid homeostasis, each with its own specific nutritional requirement for amino acids, suggesting that appropriate amino acid supplementation may theoretically normalize homeostasis and reduce symptomatology. This extends the findings of Eaton and Hunnisett who, in a 1991 issue of the Journal, reported abnormal patterns of both reduced and increased amino acid excretion [ 41].

Many botanical medicines have shown efficacy in double-blind trials in the treatment of fatigue, such as Ginkgo biloba and Panax ginseng [ 43]. Moreover, there is an intriguing case report of the successful treatment of CFS with licorice [ 44]. (Assuming that the improvement was not due to placebo, the efficacy of licorice is most likely due to its ability to improve adrenal function.)

Elsewhere in this issue, Edwards et al. report the results of a small double-blind, placebo-controlled, randomized crossover trial of a mixture of anthocyanidins derived from grape seeds, bilberries and cranberries. While these patients specifically met the diagnostic criteria for primary fibromyalgia, the patients' and investigators' ratings of fatigue levels were similar to their ratings of pain and sleep disturbance, suggesting that they may be similar to CFS patients who present with muscle pain.

Despite a lack of effect of anthocyanidins on the primary outcome variables of pain and fatigue as recorded by the patients, the investigators found significant improvement in fatigue with the active treatment versus placebo. Moreover, there was significant improvement in sleep and general health with the active treatment versus placebo as recorded by the investigators. In clinical terms, these improvements are small; however, they do suggest that the administration of anthocyanidins may add to the efficacy of other treatments.

Environmental Medicine
It has previously been argued in this journal that, given the multi-factorial nature of CFS, and the common findings of both food and chemical sensitivities and nutritional deficiencies, environmentally inclined allergists may be the physicians who are best equipped to treat patients with this challenging illness [ 45]. Such allergists are knowledgeable about a broad range of diagnostic and treatment techniques which may be of benefit [ 45].

Other Treatments
While numerous treatments have been suggested, there are only a few other than some of those already mentioned for which there is some evidence of efficacy from randomized trials. These include low doses of tricyclic antidepressants (for fibromyalgia) [ 46], cognitive behaviour therapy [ 47], the immune modulator Ampligen [ 48], and low doses of hydrocortisone [ 49]. (Physicians reluctant to utilize low-dose hydrocortisone long term should read the book [ 50] or at least the journal article [ 51] by Jefferies.)

CONCLUSIONS

We have made substantial progress in our understanding of the etiology of CFS, and our ability to successfully treat the illness is gradually improving. We have yet to achieve, however, a unified, comprehensive theory which explains the development of the syndrome and provides a fully rational approach to treatment.

This failure is not due to a lack of serious attention by researchers and clinicians. Most likely, it is at least partly due to the inherent inadequacies of a symptom-based working diagnosis which cannot help but incorporate heterogeneous groups under a simplistic label.

Hopefully, there will be continued progress towards a redefinition of this amorphous entity we now call CFS into discrete pathobiologic groupings. That development, plus the continued development of effective treatments, will continue to strengthen our hand in treating patients suffering from this frustrating illness.

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By Melvyn R. Werbach, MD, Member, Editorial Advisory Board, Journal of Nutritional & Environmental Medicine

Adapted by MD

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