Chronic Fatigue Syndrome: Pathogenesis, Manifestations and Treatment

Chronic fatigue syndrome (CFS)


Chronic fatigue syndrome (CFS) is the current name for a disorder characterized by debilitating fatigue and several associated physical, constitutional, and neuropsychological complaints (Table 384-1). This syndrome is not new; in the past, patients diagnosed with conditions such as the vapors, neurasthenia, effort syndrome, chronic brucellosis, epidemic neuromyasthenia, myalgic encephalomyelitis, hypoglycemia, multiple chemical sensitivity syndrome, chronic candidiasis, chronic mononucleosis, chronic Epstein-Barr virus (EBV) infection, and postviral fatigue syndrome may have had what is now called CFS. A subset of ill veterans of military campaigns suffer from CFS. The U.S. Centers for Disease Control and Prevention (CDC) has developed diagnostic criteria for CFS based upon symptoms and the exclusion of other illnesses (Table 384-2).

Table 384-1 Specific Symptoms Reported by Patients with Chronic Fatigue Syndrome
Difficulty concentrating
Sore throat
Tender lymph nodes
Muscle aches
Joint aches
Difficulty sleeping
Psychiatric problems
Abdominal cramps
Weight loss
Rapid pulse
Weight gain
Chest pain
Night sweats

Source: From SE Straus: J Infect Diseases 157:405, 1988; with permission.

Table 384-2 CDC Criteria for Diagnosis of Chronic Fatigue Syndrome
A case of chronic fatigue syndrome is defined by the presence of:
1.        Clinically evaluated, unexplained, persistent or relapsing fatigue that is of new or definite onset; is not the result of ongoing exertion; is not alleviated by rest; and results in substantial reduction of previous levels of occupational, educational, social, or personal activities; and
2.        Four or more of the following symptoms that persist or recur during six or more consecutive months of illness and that do not predate the fatigue:
-          Self-reported impairment in short-term memory or concentration
-          Sore throat
-          Tender cervical or axillary nodes
-          Muscle pain
-          Multijoint pain without redness or swelling
-          Headaches of a new pattern or severity
-          Unrefreshing sleep
-          Postexertional malaise lasting more than 24 h

Note: CDC, U.S. Centers for Disease Control and Prevention.
Source: Adapted from K Fukuda et al: Ann Intern Med 121:953, 1994; with permission.

Patients with CFS are twice as likely to be women as men and are generally 25–45 years old, although cases in childhood and in later life have been described. Cases are recognized in many developed countries. Most arise sporadically, but many clusters have also been reported. Famous outbreaks of CFS occurred in Los Angeles County Hospital in 1934; in Akureyri, Iceland, in 1948; in the Royal Free Hospital, London, in 1955; and in Incline Village, Nevada, in 1985. While these clustered cases suggest a common environmental or infectious cause, none has been identified.
Estimates of the prevalence of CFS have depended on the case definition used and the method of study. Chronic fatigue itself is a common symptom, occurring in as many as 20% of patients attending general medical clinics; CFS is far less common. Community-based studies find that 100–300 individuals per 100,000 population in the United States meet the current CDC case definition.

The diverse names for the syndrome reflect the many and controversial hypotheses about its etiology. Several common themes underlie attempts to understand the disorder: (1) it is often postinfectious; (2) it is associated with mild immunologic disturbances and sedentary behavior during childhood; and (3) it is commonly accompanied by neuropsychological complaints, somatic preoccupation, and/or depression.
Many studies over the past quarter century sought to link CFS to acute and/or persisting infections with EBV, cytomegalovirus, human herpesvirus type 6, retroviruses, enteroviruses, Candida albicans, Mycoplasma spp., or Coxiella burnetii, among other microbial pathogens. Compared to findings in age-matched control subjects, the titers of antibodies to some microorganisms are elevated in CFS patients. Reports that viral antigens and nucleic acids could be specifically identified in patients with CFS, however, have not been confirmed. One study from the United Kingdom failed to detect any association between acute infections and subsequent prolonged fatigue. Another study found that chronic fatigue did not develop after typical upper respiratory infections but did in some individuals after infectious mononucleosis. Thus, while antecedent infections are associated with CFS, a direct microbial causality is unproven and unlikely.
Changes in numerous immune parameters of uncertain functional significance have been reported in CFS. Modest elevations in titers of antinuclear antibodies, reductions in immunoglobulin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell activity, disturbances in cytokine production, and shifts in lymphocyte subsets have been described. None of these immune findings appears in most patients, nor do any correlate with the severity of CFS. Comparison of monozygotic twin pairs discordant for CFS showed no substantive immunologic differences between affected and unaffected individuals. In theory, symptoms of CFS could result from excessive production of a cytokine, such as interleukin 1, that induces asthenia and other flulike symptoms; however, compelling data in support of this hypothesis are lacking. A recently published population-based study from Wichita, Kansas, reported differences in gene expression patterns and in candidate gene polymorphisms between CFS patients and controls; these results are controversial and await confirmation. In some but not the more recent studies, patients with CFS commonly manifested sensitivity to sustained upright posture or tilting, resulting in hypotension and syncope, so as to suggest a form of dysautonomia.
Disturbances in hypothalamic-pituitary-adrenal function have been identified in several controlled studies of CFS, with some evidence for normalization in patients whose fatigue abates. These neuroendocrine abnormalities could contribute to the impaired energy and depressed mood of patients.
Mild to moderate depression is present in half to two-thirds of patients. Much of this depression may be reactive, but its prevalence exceeds that seen in other chronic medical illnesses. Some propose that CFS is fundamentally a psychiatric disorder and that the various neuroendocrine and immune disturbances arise secondarily.

Typically, CFS arises suddenly in a previously active individual. An otherwise unremarkable flulike illness or some other acute stress leaves unbearable exhaustion in its wake. Other symptoms, such as headache, sore throat, tender lymph nodes, muscle and joint aches, and frequent feverishness, lead to the belief that an infection persists, and medical attention is sought. Over weeks to months, despite reassurances that "nothing serious is wrong," the symptoms persist and other features of the syndrome become evident—disturbed sleep, difficulty in concentration, and depression (Table 384-1).
Depending on the dominant symptoms and the beliefs of the patient, additional consultations may be sought from allergists, rheumatologists, infectious disease specialists, psychiatrists, ecologic therapists, homeopaths, or other professionals, frequently with unsatisfactory results. Once the pattern of illness is established, the symptoms may fluctuate somewhat. Many patients report that CFS symptoms, including cognitive problems, are exacerbated by intensive physical or other stressors, yet recent prospective studies have not confirmed this impression.
Most patients remain capable of meeting family, work, or community obligations despite their symptoms; discretionary activities are abandoned first. Some feel unable to engage in any gainful employment. A minority of individuals requires help with the activities of daily living. Econometric analyses conducted by the CDC have confirmed that CFS exacts a significant toll on household and workforce productivity.
Ultimately, isolation, frustration, and pathetic resignation can mark the protracted course of illness. Patients may become angry at physicians for failing to acknowledge or resolve their plight. Fortunately, CFS does not appear to progress. On the contrary, many patients experience gradual improvement, and a minority recover fully.

A thorough history, physical examination, and judicious use of laboratory tests are required to exclude other causes of the patient's symptoms. Prominent abnormalities argue strongly in favor of alternative diagnoses. No laboratory test, however, can diagnose this condition or measure its severity. In most cases, elaborate, expensive workups are not helpful. Early claims that MRI or single photon emission CT can identify abnormalities in the brain of CFS patients have not withstood further study. The dilemma for patient and clinician alike is that CFS has no pathognomonic features and remains a constellation of symptoms and a diagnosis of exclusion. Often the patient presents with features that also meet criteria for other subjective disorders such as fibromyalgia and irritable bowel syndrome. Questions have been raised as to the relative merits of rendering a diagnosis of CFS. Being diagnosed can provide validation of a patient's perceived symptoms but may also perpetuate or exacerbate them. Refusal to label a patient as having CFS, however, can deny the patient the opportunity to undertake treatments that are of proven merit.

Chronic Fatigue Syndrome: Treatment
After other illnesses have been excluded, there are several points to address in the long-term care of a patient with chronic fatigue. The patient should be educated about the illness and what is known of its pathogenesis; potential impact on the physical, psychological, and social dimensions of life; and prognosis. Periodic reassessment is appropriate to identify a possible underlying process that is late in declaring itself and to address intercurrent symptoms that should not be simply dismissed as additional subjective complaints.
Many symptoms of CFS respond to treatment. Nonsteroidal anti-inflammatory drugs alleviate headache, diffuse pain, and feverishness. Allergic rhinitis and sinusitis are common; when present, antihistamines or decongestants may be helpful. Although the patient may be averse to psychiatric diagnoses, depression and anxiety are often prominent and should be treated. Expert psychiatric assessment is sometimes advisable. Nonsedating antidepressants improve mood and disordered sleep and may attenuate the fatigue. Even modest improvements in symptoms can make an important difference in the patient's degree of self-sufficiency and ability to appreciate life's pleasures.
Practical advice should be given regarding life-style. Sleep disturbances are common; consumption of heavy meals, alcohol, and caffeine at night can make sleep even more elusive, compounding fatigue. Total rest leads to further deconditioning and the self-image of being an invalid, whereas overexertion may worsen exhaustion and lead to total avoidance of exercise. A carefully graded exercise regimen should be encouraged and has been proven to relieve symptoms and enhance exercise tolerance.
Controlled therapeutic trials have established that acyclovir, fludrocortisone, galantamine, modafinil, and IV immunoglobulin, among other agents, offer no significant benefit in CFS. Low doses of hydrocortisone provide modest benefit but may lead to adrenal suppression. Countless anecdotes circulate regarding other traditional and nontraditional therapies. It is important to guide patients away from those therapeutic modalities that are toxic, expensive, or unreasonable.
The physician should promote the patient's efforts to recover. Several controlled trials conducted in the United Kingdom, in Australia, and in the Netherlands showed cognitive-behavioral therapy to be helpful in adolescents and adults with CFS. This approach aims to dispel misguided beliefs and fears about CFS that can contribute to inactivity and despair. For CFS, as for many other conditions, a comprehensive approach to physical, psychological, and social aspects of well-being is in order.

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