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Chapter 115 Chronic Fatigue Syndrome
James F. Jones, Hal B. Jenson
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.
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.
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.
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