You are in: eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease Chronic Fatigue SyndromeArticle Last Updated: Feb 4, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 10
 
Author: Robert W Tolan Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine Robert W Tolan, Jr, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility Coauthor(s): Julian M Stewart, MD, PhD, Director of Center for Pediatric Hypotension, Professor, Departments of Pediatrics and Physiology, Division of Pediatric Cardiology, Westchester Medical Center and New York Medical College; Bryan D Carter, PhD, Professor of Child Psychology in Psychiatry and Behavioral Sciences, Chief Psychologist in Division of Child and Adolescent Psychiatry, Director of Predoctoral Internship in Clinical Child/Pediatric Psychology, Director of Postdoctoral Fellowship Program in Pediatric Psychology, Director of Pediatric Consultation-Liaison Service to Kosair Children's Hospital, University of Louisville School of Medicine Editors: Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center Author and Editor Disclosure Synonyms and related keywords: chronic fatigue immune dysfunction syndrome, CFIDS, chronic fatigue syndrome, CFS, chronic mononucleosis, cognitive difficulties, Da Costa syndrome, headache, joint pain, muscle pain, myalgic encephalitis, neurasthenia, pharyngitis, poor sleep, postexercise malaise, postural orthostatic tachycardia syndrome, POTS, sleep disturbance, tender lymphadenopathy, vapors, Epstein-Barr virus INTRODUCTIONSection 2 of 10
 
Fatigue is one of the most common symptoms in clinical medicine; nevertheless, fatigue may be difficult to define because it is rather loosely partitioned into physical and mental components. Fatigue often proves evanescent or, if chronic, relates to an underlying systemic illness. Fatigue may also be associated with a psychiatric disorder. Less commonly, patients may have chronic persistent fatigue that lasts longer than 6 months without an apparent etiology and that is associated with exercise intolerance, sleep difficulties, and an inability to perform mental or physical activities in a competent fashion. Because a healthy body requires robust, functionally integrated organ systems to ensure optimal operation, intact organ parenchyma, intact organ regulatory systems, and intact delivery of nutrients and oxygen to the tissues by the cardiovascular-circulatory system must be present to avoid malfunction. Any defect in these 3 components causes organ dysfunction. Signals sent via the nervous system indicating such dysfunction may be perceived as pain or fatigue. If dysfunction progresses to critical organ impairment, the organ system may ultimately fail; however, more gradual and persistent decline in function of single or multiple organ systems can produce a chronic fatigue state without complete organ system breakdown. The etiology of organ fatigue remains elusive, and, indeed, the precise definition of fatigue remains controversial. Nevertheless, standardized questionnaires and examinations are currently used to assess fatigue and to separate mental fatigue from physical fatigue on the basis of general physical condition and on the ability to perform cognitive or muscle tasks in an age-appropriate fashion. For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center, Muscle Disorders Center, and Back, Ribs, Neck, and Head Center. Also, see eMedicine's patient education articles Chronic Fatigue Syndrome, Fibromyalgia, and Fatigue. CHRONIC FATIGUE SYNDROME DEFINEDSection 3 of 10
As a distinct clinical entity, chronic fatigue syndrome (CFS) has only recently been defined for adults as a distinct disorder characterized by chronic (often relapsing but always debilitating) fatigue lasting at least 6 months (occasionally lasting much greater lengths of time), which causes impaired overall physical and mental functioning. Centers for Disease Control and Prevention (CDC) criteria have been broadly formulated in order to standardize research in the field, resulting in an operating framework that includes cognitive difficulties, pharyngitis, tender lymphadenopathy, muscle pain, joint pain, headache, sleep disturbance, poor sleep, and postexercise malaise. The most recent CDC diagnostic criteria state:1
The revised CDC case definition (abridged version) states:
Laboratory tests can neither confirm nor definitely exclude CFS, although the CDC recommends a "basic battery" that usually includes a CBC count, liver function tests, thyroid function tests, erythrocyte sedimentation rate, and serum electrolyte level measurement. The authors also usually include an antinuclear antibody and morning cortisol measurements. HISTORIC ASPECTS OF CHRONIC FATIGUE SYNDROMESection 4 of 10
Although only recently codified by CDC case definition, chronic fatigue syndrome (CFS) has had its homologues for many years, including such poorly described disease states as neurasthenia, Da Costa syndrome (reported after the American Civil War), chronic mononucleosis, and vapors. Straus nicely summarizes these homologues in his historic monograph.2 More current terms, such as myalgic encephalitis (a British designation), presume an origin for an illness with no established pathogenesis; however, a common thread embedded within this nomenclature includes an underlying stressor, which is often an inflammatory antecedent. Also, diverse nomenclature provides clues to the etiology. In this sense, the illness is similar to posttraumatic stress disorder and the recently reported Gulf War syndrome; however, no causative relation between infection and the syndrome has been definitely established, despite strenuous efforts by scholars who study the Epstein-Barr virus, herpes viruses 6 and 7, enteroviruses, and many others. CFS may represent a particular response to nonspecific preceding infectious disease. PEDIATRIC CHRONIC FATIGUE SYNDROME - DESCRIPTION AND PREVALENCESection 5 of 10
Chronic fatigue syndrome (CFS) is poorly defined in children and most investigations have been summaries of case presentations and small series, rather than pathophysiologic endeavors. Starting with the early reports of Bell and colleagues concerning a group of cases in Lyndonville, NY, numerous studies emanate from facilities around the United States.3 Those studies are nicely summarized in the report generated from a CDC workshop concerning CFS in adolescents. In brief, the reports indicate that pediatric patients with CFS are typically teenage females with severe school absenteeism. As in adults, a large fraction of pediatric patients with CFS report preceding inflammatory conditions but these patients have a better chance of recovery than corresponding adult patients. However, many studies may have incorporated patients who belong to a superset of patients who have CFS-like symptoms and clinical features but who have greatly improved prognosis (see Differential diagnosis). Also, most studies of CFS in the pediatric age range have followed the CDC criteria. However, whether the adult CDC case definition can be applied to children and adolescents is debatable. To date, the CDC has declined to modify the CFS case definition for the pediatric age group, even when common pediatric findings such as frequent sore throat and swollen glands are included in the criteria; these findings fail to distinguish patients from their otherwise healthy contemporaries. Moreover, the CDC has indicated that CFS is unlikely to occur in patients younger than 10 years. However, establishing the existence of a self-reported illness in younger age groups is difficult and the truth concerning juvenile CFS remains unclear. Given a relative paucity of studies and some reluctance to conduct large epidemiologic exercises, the fact that estimates of prevalence widely vary and have yet to be accurately determined is not surprising. A range in prevalence of 2 to nearly 300 cases per 100,000 children has been proposed in many studies and some reports of incidence of several percent have been published. Surveys have been performed using various polling techniques and were conducted in different parts of the United States, as well as in other countries. Regional differences in CFS incidence and prevalence may be observed. CLINICAL PROFILE AND DIFFERENTIAL DIAGNOSISSection 6 of 10
The clinical profile of an individual with chronic fatigue syndrome (CFS) is of a high-achieving student or athlete who is usually female (80%), Caucasian, and in the middle-class or upper–middle-class socioeconomic level. This may reflect referral bias but appears consistent throughout most studies. As suggested by the term chronic, the clinical course is punctuated by remissions and relapses often triggered by intercurrent infection or stress. The course in adolescents is similar to that in adults. Recently, the 15-year follow-up data from the Lyndonville outbreak were reported and indicated successful resolution in most cases, based on self-assessment measures. However, improvement was often a matter of interpretation on the part of the patients. When questioned further, many had persistence of symptoms but had tailored their lifestyles to the persistent disability. Careful perusal of the CDC criteria indicates that, essentially, any chronic illness that produces extensive disability in a setting of persistent fatigue may be included in the differential diagnosis. Many of these illnesses are mentioned among the diagnostic exclusions in the Introduction section. However, once such a specific illness has been diagnosed, the diagnosis of CFS then is excluded by definition. These illnesses certainly include the following:
Note that other chronic illness must be investigated and, in some cases, reinvestigated several times. CFS is, in large measure, a diagnosis of exclusion. Based on the CDC case definition, no specific physical findings serve to confirm the diagnosis of CFS. CFS is defined by symptoms and not signs. However, adolescents, particularly girls, may have signs and symptoms of postural tachycardia syndrome, including upright and sometimes supine tachycardia, pallor, hypotension, and other vasomotor findings discussed later in this article (see Altered Neurovascular Regulatory Systems in Chronic Fatigue Syndrome). VARIED PATHOGENESES PROPOSED FOR CHRONIC FATIGUE SYNDROMESection 7 of 10
Investigations into the pathophysiology of chronic fatigue syndrome (CFS) have remained inconclusive, although several possibilities have been suggested. For example, CFS patients may be expected to demonstrate striated muscle deficiencies; however, skeletal muscle energetics, structure, histopathology, physiology, and glycolytic activity have been normal, and electromyographic results have been inconclusive in these patients. In vivo, analyses of muscle energetics are also suggestive of disability but are not definitive and often indicate modest alteration disproportionate to symptomatology. Progress has been made in 2 seemingly disparate areas of investigation: altered neurovascular regulation and psychological and somatization disorders. Treatment is based on specific pathophysiology. Thus, disabilities that fall within the purview of neurovascular or psychological disorders can be specifically addressed by treatment modalities developed within these respective fields. ALTERED NEUROVASCULAR REGULATORY SYSTEMS IN CHRONIC FATIGUE SYNDROMESection 8 of 10
Studies of the integrative and regulatory systems have been provocative. Compelling information has been reported concerning abnormalities in the cardiovascular regulatory areas of the brain stem and in other vasoregulatory CNS areas that may be associated with impaired vagal tone, malfunction of central and peripheral nervous systems, an inability to completely activate skeletal muscle, and abbreviated exercise capacity due to inappropriately low heart rate and early fatigue during treadmill testing. Associated neuroendocrine dysfunction, impaired hypothalamic-pituitary-adrenal interactions, and associated neurohumoral findings have been described. Thus, some evidence suggests a deficit in neuroendocrine regulatory mechanisms that may directly or indirectly limit organ and tissue function through decreased blood pressure (BP) and impaired tissue perfusion. The peripheral circulatory beds and CNS are particularly vulnerable to cardiovascular inadequacy. Maladaptive changes in BP and blood flow can produce many of the signs and symptoms associated with CFS, such as light-headedness, impaired cognition, inappropriate sweating, and temperature instability. Orthostatic intolerance in adolescents with chronic fatigue syndrome (CFS) is consistent with the postural orthostatic tachycardia syndrome (POTS). Upright posture is a fundamental stressor requiring rapid and effective circulatory and neurologic compensations in order to maintain BP, cerebral blood flow, and effective neurocognitive capabilities. The physiology of upright posture is unique to hominids and cannot be easily studied in animals. Recent investigations lend credence to the hypothesis that CFS results, at least in part, from low upright BP or central blood flow by strongly implicating neurally mediated hypotension, a form of orthostatic intolerance, in the symptomatology of CFS in adults. In their landmark observations, Rowe and coworkers produced neurally mediated hypotension in 21 of 22 adult patients with CFS using the head-up tilt-table test (HUTTT), a standard orthostatic test that produces enhanced sympathetic tone while decreasing parasympathetic tone in healthy subjects.4 More importantly, treatment of orthostatic intolerance improved symptoms in many patients. These observations have focused on the neurologic aspects of orthostasis and have led some investigators to posit an autonomic defect in CFS. Overt dysautonomia has not been demonstrated. Clues to the nature of orthostatic intolerance in CFS are present in Rowe's earlier work, in which he reported tachycardia often associated with hypotension during orthostasis in adolescents. At least since 1940, orthostatic tachycardia of this sort has been described using many aliases; Streeten referred to orthostatic tachycardia as hyperadrenergic syndrome,5 and Fouad et al described it as idiopathichypovolemia.6 Orthostatic tachycardia is probably the most common reason for referral to autonomic laboratories for chronic orthostatic intolerance. The syndrome has recently undergone a renaissance as POTS (reported in adults by investigators at the Mayo clinic) and as the syndrome of chronic orthostatic intolerance (reported by the Vanderbilt group). Those who reported the first pediatric cases of POTS demonstrated that orthostatic intolerance during HUTTT in adolescents with CFS is predominantly POTS. An operational definition of POTS includes symptoms of orthostatic intolerance, such as fatigue, light-headedness, nausea, vomiting, headache, palpitations, and tremulousness, associated with an increased heart rate exceeding 30 beats per minute or a heart rate of more than 120 beats per minute within 10 minutes of HUTTT. Onset of symptoms often follows an infectious disease and may be related to inflammatory mediators. Some adult and pediatric patients with POTS fulfill CDC criteria for CFS, whereas others do not; however, most patients with non-CFS POTS have symptoms that mimic symptoms of CFS to a lesser extent. Some patients with non-CFS POTS have likely been classified as having CFS. The clinical course of non-CFS POTS is frequently relatively short-lived but may easily exceed 6 months in some patients. Many of the patients with short-lived POTS have little fatigue or exercise intolerance, and some patients remain competitive athletes. Others have a more prolonged course, although without the extent of disability present in many patients with CFS. A review of patients with delayed orthostatic hypotension (delayed POTS) demonstrated a high degree of association with chronic fatigue. POTS is common and mostly affects females (approximately 80%) aged 12-50 years. Symptoms of orthostatic intolerance in POTS read almost as a litany for CFS, including light-headedness, fatigue, headache, sleep disorders, and neurocognitive difficulties. Preliminary data suggest that autonomic findings may be related to circulatory abnormalities at rest and during orthostasis. Thus, CFS may represent a severe form of POTS in adolescents. PSYCHOLOGICAL ASPECTS OF CHRONIC FATIGUE SYNDROMESection 9 of 10
Children and adolescents with chronic fatigue syndrome (CFS), as defined using modified CDC criteria, also demonstrate psychological morbidity. However, this morbidity does not approach the levels observed in control subjects with psychiatric diagnoses. Whether psychological morbidity predates the development of CFS or occurs in reaction to it is controversial, although most authors reject a simple linear psychological model of pathogenesis. Nonetheless, the absence of laboratory markers, failure to implicate a single infectious agent, conflicting immunologic data, and marked discrepancies between symptoms and physical findings continue to lead many health practitioners to conclude that CFS is primarily a psychological disturbance. Psychiatric syndromes that have been proposed include depression, anxiety disorders, and somatization, all of which have been implicated in adults with CFS. Although some studies in adults suggest that psychiatric illness is more likely to precede the onset of CFS than to follow it, a common etiological pathway has been suggested for both conditions. Some studies demonstrate the premorbid incidence of psychological disturbance in patients with CFS to be similar to that in other general medical populations. Other studies have designated CFS as a psychiatric somatoform disorder, along with conditions such as recurrent abdominal pain. Unfortunately, most studies have been limited by their reliance on retrospective data gathered from patient interviews, chart review, or purely anecdotal conjecture. Pediatric patients with CFS are less likely to have severe mood-related symptoms compared with patients who are suffering from clinical depression (eg, major depression, dysthymia). These mood-related symptoms include negative affect, suicidal ideation or previous suicidal behavior, externalizing or acting-out behaviors, problems with angry or aggressive behavior, low self-esteem, and feelings of reduced self-efficacy. Thus, research findings with pediatric patients suggest that children and adolescents with CFS are not depressed in the conventional sense. Nevertheless, these patients are psychologically distressed when compared with healthy people of the same age. Although social and academic activities may be disrupted, children with CFS do not demonstrate the same level of decline in these areas experienced by children with clinical depression. Many children with CFS are high achievers and report dissatisfaction even with above-average performance. Self-esteem and self-concept concerns are less likely to be issues than with depressed youth. Anecdotally, numerous investigators and clinicians have noted that pediatric patients with CFS and their family members are inclined to deny the need for psychological assistance for their personal problems, to minimize the role of stressors in their symptoms, and to reject suggestions that psychological assistance may facilitate their recovery. They generally attribute their symptoms to infectious and immunologic causes, which may be strongly reinforced by the lay literature. To date, only a few studies have attempted to document the natural history and long-term outcome of pediatric CFS, both in terms of health status and psychosocial morbidity. In general, the physical outcome of CFS in these studies (ie, mean time since initial evaluation; range of 1.6-3.8 y) was favorable, with most patients reporting either resolution or improvement in their symptoms; however, a sizable proportion of these patients reported continued symptoms and significant functional limitations. As in many chronic diseases, children with CFS face significant functional limitations (eg, frequent absences from school, disruptions in social activities, adjustments in family dynamics) surrounding the symptoms and treatment of their illness. A recent follow-up study of children and adolescents with CFS revealed that although most subjects reported improvements in the number and severity of symptoms (>90% of the sample reported feeling better than they did at the initial assessment, and many believed that they currently did not meet criteria for a formal diagnosis of CFS), many subjects described individual symptoms that persisted as long as 5 years after the onset of illness. This finding is consistent with findings in previous investigations. A large degree of variability was reported in terms of severity of CFS symptoms and outcome, onset of illness, periods of remission and exacerbation of symptoms, health care use and perceived effectiveness, and subsequent diagnoses. In spite of varying improvements in physical status, many subjects reported that their illness had a long-term adverse impact on academic attendance and performance, occupational functioning, and social relationships. Clearly, a disease this debilitating affects multiple aspects of functioning and development, as well as the life of the family as a whole. Many subjects reported regression via increased dependence in their relationship with their parents because of their physical limitations. The patients spent more time with their parents than the average adolescent or young adult and believed their health status made their parents overprotective and more cautious. At a time when many healthy peers are gaining more freedom and independence from their parents, these families displayed a level of involvement that may have delayed some of these common rites of passage, such as moving out of the home, going away to college, and working full-time. In terms of their school functioning, many subjects in the study reported cutting back on the hours and days that they spent in class, despite previous successes achieved in the academic arena. Curiously, although many subjects believed that their grades had declined, they still believed that they performed at a level either commensurate with or superior to their classmates. Subjects reported a preference for quieter activities with smaller groups of friends and indicated that they received criticism and disbelief from some peers and teachers regarding the validity of their illness and lengthy absences. To elucidate the psychological factors operative in patients with CFS, a number of studies have compared case subjects with controls suffering from serious chronic medical conditions, such as multiple sclerosis in adults, childhood cancer, and cystic fibrosis. However, controls like these may not be ideal because patients with these diseases and their parents live with the knowledge that their illness is life threatening; this knowledge can drastically affect perception and interpretation of symptoms. Studies with more appropriate control subjects (eg, juvenile idiopathic arthritis) revealed that the psychological distress found in pediatric patients with CFS exceeded that found in pediatric patients with juvenile idiopathic arthritis, despite similar patterns of functional disability in both groups. This finding suggests that psychological factors may interact with the characteristics of CFS in a way that plays a more active role in debilitating chronic fatigue in youth than can be explained by the stress of coping with a chronic non–life-threatening illness alone. At present, the effect of psychological factors in CFS in children and adolescents is unclear. Professionals tend to align themselves with either the organic or the psychological group and accordingly interpret symptoms. Because of the medically oriented providers' frustration with diagnosis and management of CFS, ascribing CFS symptoms to psychological causes or to the sometimes vague field of somatoform illness is appealing. Transcendence of the limited perspective of mind-body dualism is needed to understand and effectively treat patients with CFS. Integrating psychological factors into models of pathogenesis Currently, no single model fully explains the pathogenesis of CFS. A simple linear medical model, wherein a single infectious agent causes a specific series of detrimental biologic effects, has not been supported. In more complex models, the final common pathway may be the result of various insults, including viral infection and stress. The consequence of these insults may be immune system activation and dysregulation. The resulting cytokine release and epiphenomena, such as reactivation of latent viruses, contribute to fatigue and associated symptoms. Very unconvincing support also exists for a simple psychological model, which posits that fatigue is the expression of a primary psychopathologic condition. A more dynamic biopsychosocial model proposes that an acute infectious and/or immunologic event, associated with a physiologic state of fatigue, initiates a cycle in which avoidant behaviors that diminish symptom severity may become associated with various attributional and cognitive factors. Thus, symptoms are attributed to an external agent (eg, virus). Behaviorally, the patient retreats from a previously active lifestyle into a state of learned helplessness. Because the cause of CFS is perceived to be external and beyond the individual's control, the patient's self-esteem is preserved. Prolonged disability and inactivity may trigger depression and anxiety or exacerbate premorbid psychological symptoms in some individuals. Re-exposure to activity elicits further symptomatic behavior, whereas avoidant behavior further reduces tolerance for physical activity. Repeated (ie, usual, minor) exacerbations via additional viral illnesses or neurovascular instability perpetuate the cycle of symptoms: attribution, avoidance, fatigue, and withdrawal. The finding that both children and adults with CFS maintain strong convictions that their fatigue is purely physiologic, rejecting psychological explanations, lends some support to this attributional model. A prospective study of patients experiencing a viral illness found that the presence of an attributional style characterized by belief in vulnerability to illness, along with physician indecisiveness in making a diagnosis, predicted which patients developed CFS better than prediction by viral illness factors. Therefore, some psychological factors inherent in patients with CFS may exist and clinicians have yet to understand these factors. These factors result in a differential prolonged response to the initial physical insult and interact with response to treatment approaches such that outcome is more variable despite the potential validity of the physical explanatory model (eg, use of antihypotensive medications for neurally mediated hypotension). Pathogenetic synthesis In summary, psychological factors and, more recently, neurovascular factors are active in CFS. Synergism of these factors at the level of the CNS appears likely. Support for these notions is derived from other areas of orthostatic and autonomic study; for example, fluoxetine has been used as highly effective therapy for persons with refractory vasovagal faint, migraine, and panic disorder. Although the pathogenesis of CFS remains unclear, a synthesis of psychology with physiology is attractive. Treatment Treatment is otherwise largely supportive and responsive to symptomatology. This includes physical therapy and modest aerobic or anaerobic exercise (if possible) to avoid cardiovascular deconditioning. Sleep may be addressed with medication; often, melatonin or night-time amitriptyline is helpful. If present and severe, pain is often addressed in a pain clinic. Headache may be successfully treated with antimigraine therapy, and biofeedback regimens have been helpful at times. If concurrent with orthostatic intolerance, headache may be amenable to measures designed to improve blood flow and BP. Fatigue and neurocognitive defects are harder to address. Some clinicians have used stimulants, including dexamphetamine and methylphenidate, with some success. Treatment has remained entirely controversial. Trials of antiviral agents such as poly I: poly C12U (Ampligen) and immunotherapy have been confined to adults. Treatment for orthostatic intolerance may aid approximately 50% of patients. A rehabilitative program of gentle exercise has proved helpful, as has cognitive therapy. A general problem-oriented approach can be helpful in dealing with certain issues such as sleep. Compelling evidence presented by Rowe and Bell at the American Association of Chronic Fatigue Syndrome meeting in January 2001 demonstrated that most children with CFS improve and that improvement is independent of short-term therapy with various agents. Nevertheless, a substantial minority of children have long-term symptoms and morbidity. REFERENCESSection 10 of 10
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