General

Chronic fatigue syndrome (chronic mononucleosis, chronic Epstein-Barr virus infection, myalgic encephalomyelitis, immune dysfunction syndrome) describes the syndrome of unusual fatigability associated with mild to debilitating somatic symptoms. This syndrome was formally defined by the Centers for Disease Control and Prevention (CDC) in 1988 as chronic fatigue syndrome (CFS) because persistent and unexplained fatigue was considered the principal and invariable physical symptom. It results in severe impairment of daily functioning and is associated with a variety of physical symptoms. The fatigue does not require exertion by the patient, nor does rest relieve it. The current definition was created in 2003 to exclude psychiatric cases. CFS is a complex, diverse illness requiring fatigue, impairment in function, and selected symptoms for diagnosis. A definitive identifiable infectious agent does not cause it, although the differential diagnosis includes many infectious and inflammatory diseases. It is not a single disease with consistent physiologic or pathologic abnormalities but rather the measurable experience of symptoms that occur with various clinical conditions of somatic, psychologic, and mixed causes. The understanding of this condition is largely from studies among adults and adolescents, with limited descriptions of chronic fatiguing illness among young children.

Epidemiology

CFS includes severe functional impairment and is a diagnostic subset of chronic fatigue, which is a common presenting symptom of adolescents and adults. Chronic fatigue encompasses a broader category defined as unexplained fatigue of >6 mo, which in turn is a subset of prolonged fatigue, which is defined as fatigue lasting more >1 mo. Fatigue of >1 mo is estimated to occur in 2,333/100,000 adolescents. Prevalence rates vary significantly, but chronic fatiguing illnesses are encountered in all patient populations.

The incidence of CFS among children <12 yr of age remains uncertain. Among children <18 yr of age in the United Kingdom with debilitating generalized fatigue, 16% were <12 yr of age. The understanding of CFS among young children is amplified by focusing on disabling fatigue rather than diagnosing CFS, which allows identification of children with a variety of fatiguing illnesses in need of diagnosis and therapy.

Adults diagnosed with CFS are of various ethnic and racial origins, with a preponderance of those identified in population-based studies being 45-55 yr of age and of lower socioeconomic status. These epidemiologic observations vary from the earlier reports based on patients seen in specialty clinics. The prevalence in the USA among adults older than 18 yr of age who fulfill a strict case definition is estimated to be 250-400/100,000.

The number of adult CFS-like cases defined as individuals who fulfill a clinical definition of CFS but who have not undergone comprehensive medical and psychiatric evaluation, approaches 1250/100,000. The number of CFS-like cases in adolescents is 338/100,000. Females constitute 75% of adult CFS-like cases, but only 50% of CFS cases.

Most cases of CFS are sporadic and are not associated with secondary cases. There is no evidence supporting transmission of the illness from person to person, in utero to a fetus, or via blood products. Questions continue regarding the possible heritability of the syndrome in children.

Pathogenesis

The cause of CFS is unknown. Some patients correlate the onset with a recent episode of a virus-like illness such as infectious mononucleosis (10-12%) or influenza (2.9%). In many cases, underlying symptoms of depression, such as fatigue, lack of energy and interest, and inability to concentrate, merge with or are intensified by the weakness often perceived during convalescence from a systemic infectious disease, resulting in debilitating fatigue. Persistent fatigue and symptoms consistent with CFS are well recognized following many primary infections, especially infectious mononucleosis and influenza, and occur in up to 10% of cases. Susceptible persons may experience fatigue and exhaustion that is present for months to a few years and may be accompanied by signs of clinical depression. Prolonged illness after infectious mononucleosis is not predicted by control of viremia, an altered host response to Epstein-Barr virus infection, personality style, or psychologic disorders (depression), but by the individual’s perception of severity of the primary infectious illness. Human gammaretrovirus xenotropic murine leukemia-related virus (XMRV) has been identified in prostate cancer specimens and, in a few reports, patients with CFS. Its significance in CFS and as a potential pathogen in human disease remains to be determined.

Approximately half of adult and adolescent patients with gradual onset of CFS fulfill criteria for co-morbid psychiatric disorders, primarily anxiety and depressive disorders. Patients with CFS have higher rates of somatization and higher anxiety scores. Personality does not affect the predisposition, precipitation, and perpetuation of chronic fatigue. There is strong concordance in CFS patients between subjective complaints of mental fatigue and objective measurements of cognitive impairment, which suggests that mental fatigue is an important component of CFS-related cognitive dysfunction.

Orthostatic intolerance syndromes of circulatory dysfunction including neurally mediated hypotension, instantaneous orthostatic hypotension, and postural tachycardia syndrome have been observed in some patients with CFS. These findings are not uncommon in adolescents, thus contributing to the possible association to CFS in this age group. The pathophysiology of these manifestations among patients with CFS is unclear. The origin may be as simple as a problem with functional vascular volume or as complex as control of cerebral blood flow and heart rate variability.

Diverse and conflicting in vitro immunologic alterations (hypo- or hypergammaglobulinemia, immunoglobulin subclass deficiencies, elevated levels of circulating immune complexes, mild increased helper/suppressor lymphocyte ratios, natural killer cell dysfunction, and monocyte dysfunction) have been reported inconsistently in patients with CFS. These findings defy correlation with the majority of patients and fail to provide a unified explanation for CFS. A history of food, inhalant, or drug allergy is reported by 55-80% of patients. No characteristic profile of immune dysfunction has been identified, and the values of the laboratory immunologic changes are usually not outside the normal range. Similarly, imaging studies of the brain have not identified reproducible abnormalities.

Adults with CFS may have a history of childhood stress in the form of sexual, physical, and emotional abuse and emotional and physical neglect; this has been associated with neuroendocrine dysfunction as measured by the salivary cortisol response to awakening. How such trauma affects neuroendocrine function in children and adolescents and contributes to CFS remains to be determined.

Clinical Manifestations

The dominant symptoms of CFS include fatigue that contributes to loss of activity, cognitive problems, nonrestorative sleep, pain, and an increased level of illness following physical or mental activity. Fatigue as a symptom should not be dismissed as a minor ailment, but consideration needs to be given to the consequences of both the fatigue and the accompanying symptoms. Although the primary symptom of fatigue is perceived as subjective, the presence and magnitude of impairment, as well as the number and magnitude of associated symptoms, can be measured. The syndrome is characterized by fatigue of >6 mo duration associated with significant impairment of the work or school schedule, recreation, and interpersonal relationships. Fatigue is generally manifested as lassitude, profound tiredness, intolerance to exertion with easy fatigability, and general malaise. Nonrestorative nighttime sleeping is common, but there are no common sleep abnormalities. Myalgias and arthralgias may accompany fatigue. Onset of new headache, sore throat, and lymph node tenderness are uncommon but continue to be included as symptom criteria for diagnosis. Cognitive problems and an increase in the magnitude of syndromic symptoms following mental or physical activity complete the definition requirements. There is concern that CFS might be mistaken for readily identifiable psychiatric disorders.

Patients diagnosed with CFS in primary-care practices relate an abrupt onset to their symptoms, often as part of an initial virus-like illness characterized by low-grade fever accompanied by sore throat and cough. Individuals identified in population-based studies describe a gradual onset of their illness.

Symptoms among adolescents are similar to those observed in adults. School absenteeism is a major problem, with two thirds missing >2 wk and one third requiring a home tutor. Resolution of symptoms, particularly if the onset follows an infection, as is common among adolescents as well as adults, usually follows within 2 yr of onset of the illness.

Abnormal physical examination findings are conspicuously absent, which provides reassurance to both the patient and the physician. The presence of other physical symptoms (chest palpitations, visual blurring, nausea, dizziness, paresthesias, dry eyes and mouth, diarrhea, cough, night sweats, and rash) should suggest a diagnosis other than CFS. Weight loss, as seen in chronic infections or inflammatory conditions, is uncommon in CFS.

Diagnosis

There are no pathognomonic signs or diagnostic tests for CFS. The diagnosis is a clinically defined condition based on inclusion and exclusion criteria (Fig. 115-1). The diagnostic criteria are applicable to adults and adolescents >11 yr of age because of the current requirement for a self-generated history. Reliance on parental history for diagnosis is fraught with confusion because of the inaccuracy of the historical information. An empiric definition has been tested in adults that enhances diagnostic reliability. The process relies on results of 3 readily available questionnaires: Multidimensional Fatigue Inventory, Medical Outcomes Short Form 36, and CDC Symptom Inventory.

Figure 115-1 The clinical evaluation and classification of unexplained chronic fatigue. The case definition for chronic fatigue syndrome was proposed by the Centers for Disease Control and Prevention in 1988 (Holmes GP, Kaplan JE, Gantz NM, et al: Chronic fatigue syndrome: a working case definition, Ann Intern Med 108:387-389, 1988) and refined and simplified by an international working group in 1994

(Fukuda K, Straus SE, Hickie I, et al: The chronic fatigue syndrome: a comprehensive approach to its definition and study, Ann Intern Med 121:953-959, 1994).

CFS is difficult to diagnose in children, who have trouble describing their symptoms and articulating their concerns. Criteria have been developed to address the development of fatigue in relationship to immunization that are applicable to children >5 yr of age. CFS should be diagnosed in children or adults only after a thorough medical and psychiatric evaluation. Careful attention must be directed to the family dynamics to identify and resolve family problems or psychopathology that may be contributing to a child’s perceptions of his or her symptoms. Applying the label of CFS may delay the diagnosis of a treatable medical illness, avoid the detection of psychologic problems or family dysfunction, and perpetuate inappropriate illness behaviors that may have a profound effect on the child’s psychosocial development.

The diagnosis of CFS can be established only after alternative medical and psychiatric causes of fatigue, many of which are treatable, have been excluded. These include any medical condition that may explain the presence of chronic fatigue, such as untreated hypothyroidism, sleep apnea, narcolepsy, drug abuse, an adverse effect of medication, or severe obesity as defined by a body mass index [body mass index = weight in kg/(height in meters)²] of >45. A previously diagnosed medical condition with uncertain resolution that may explain chronic fatigue should be clarified, such as unresolved cases of hepatitis B or C virus infection. CFS should not be diagnosed in persons with prior diagnoses of a major depressive disorder with psychotic or melancholic features, bipolar affective disorders, schizophrenia of any subtype, delusional disorders of any subtype, dementias of any subtype, anorexia nervosa, bulimia nervosa, or alcohol or other substance abuse within 2 yr before the onset of the chronic fatigue or at any time afterward.

Fibromyalgia is a relatively common rheumatic syndrome characterized by widespread musculoskeletal pain in addition to numerous specific tender point sites (Chapter 162) and symptoms similar to those of CFS. Fibromyalgia and CFS may be diagnosed in the same patient since both are diagnoses by definition and both lack confirmatory laboratory findings.

Although evaluation of each patient should be individualized, initial laboratory evaluation should be limited to screening laboratory tests to provide reassurance of the lack of significant organic dysfunction (see Fig. 115-1). Further tests should be directed primarily toward excluding treatable diseases that may be suggested by the symptoms or physical findings that are present in specific patients. Diagnostic evaluation of chronic fatigue should include psychologic evaluation for anxiety and depression disorders, which should precede exhaustive searches for organic causes.

Treatment

Development of definitive treatment for CFS awaits delineation of the causes of the symptoms. No specific therapeutic agents are recommended. Cognitive behavioral therapy and graded exercise therapy are the only interventions that have been shown to be beneficial.

Cognitive-behavioral therapy is directed at changing condition-related cognitions and behaviors through explanation, challenging and changing cognition of fatigue-related symptoms, developing coping skills, emotional support for patients and their families, relief of symptoms that actually interfere with function, and minimizing unnecessary and misleading diagnostic and therapeutic tests. Particular attention should be made to identification and specialist treatment of sleep disorders and disturbances. Psychologic or psychiatric intervention is a principal component of treatment if a co-morbid psychiatric disorder is present.

Graded exercise therapy is based on a deconditioning model. Patients with limitation of activity should be started on a schedule of graded remobilization determined by individual tolerance and, if warranted, physical therapy leading to a regular regimen of moderate exercise. The key element is stopping the physical activity before becoming tired or inducing symptoms. Complete bed rest and lack of exercise only perpetuate immobility and lead to deconditioning; rapid remobilization, for whatever reason, usually exacerbates symptoms and should be avoided. Return to school should also be initiated gradually but systematically to resume normal attendance and socialization. Home tutoring may be an interim alternative. Patients and their families should clearly understand that there is no evidence that activity causes permanent harm in patients with CFS.

Continued empathy and support by the treating physician are important in maintaining a physician-patient relationship conducive to identification and resolution of both organic and psychologic illness. Periodic medical re-evaluation is warranted for early detection of other identifiable causes of chronic fatigue, especially with interval development of new symptoms. No data suggest relief of symptoms or cure of CFS by dietary or vitamin supplements.

Prognosis

The clinical course of CFS is highly variable with a mean duration among adults of 3-9 yr. Patients should be informed that their symptoms will likely wax and wane. Preoccupation with return to the pre-illness level of activity can actually prolong illness and should not be a short-term goal. Approximately 75% of patients whose illness began with an infection have significant recovery within 2 yr of onset, although exacerbations and relapses may occur. Approximately 60% of adult patients report gradual but marked improvement in symptoms over a period of 2-3 yr without specific therapy, although some patients appear to have no improvement or occasionally deteriorate. Longitudinal studies have shown improvement in patients with illness durations of >10 yr, but the eventual clinical course is unpredictable and complete resolution is not the rule. Patients who deal with stress by somatization and who deny the modulating role of psychosocial factors have a less favorable prognosis.

Children and adolescents with chronic fatiguing illnesses appear to have a more optimistic outcome, typically with an undulating course of gradual but substantial symptomatic improvement, or full recovery, 1-4 yr after diagnosis, and an overall good functional outcome in 80% of cases. Poor prognostic factors include increasing time missed from school, lower socioeconomic status, chronic maternal health problems, and untreated co-morbid individual or family psychiatric disorders. Favorable prognostic factors include patient control of their individual rehabilitation program with continued support from health professionals and family members.

There are no increased risks of cancer, autoimmune disease, multiple sclerosis, opportunistic infections, or other complications. Unidentified depression, however, can lead to self-inflicted injury or death.