Leonard R Krilov

 Chronic fatigue syndrome in youth:
 Maybe not so chronic after all 

 By Leonard R. Krilov, MD, and Martin Fisher, MD 

 Chronic fatigue in children and adolescents shares many features with the adult variant of the syndrome. The most important differences for younger patients? A shorter course and better outcome. 

 Chronic fatigue syndrome (CFS) is characterized by severe fatigue accompanied by numerous systemic complaints that may include headache, sore throat, lymphadenopathy, low-grade fever, musculoskeletal complaints, dizziness, inability to concentrate, confusion, sleep disturbance, and depression. Although no single cause or diagnostic test for CFS is accepted by the medical community, the Centers for Disease Control and Prevention (CDC) has generated a working definition for study purposes that describes the extent of fatigue, dysfunction, and associated symptoms in CFS patients (Table 1, available in the print edition, adapted from Fukada K, Straus SE, Hickie I, et al: The chronic fatigue syndrome: A comprehensive approach to its definition and study. 

 International groups have established similar definitions.

After reviewing this article the physician should be able to: 

 The published criteria for CFS do not include age limits, and some experts have questioned whether the term should be applied to children and adolescents.

 Nevertheless, chronic fatigue is a common complaint to pediatricians and a frequent reason for referral to pediatric subspecialists. 

 Several series of pediatric patients with chronic fatigue have been reported in the medical literature, and we have evaluated and treated more than 100 children and adolescents with this complaint.

 Although many children and adolescents described in these series do not meet the full research definition of CFS cited above, they share most of the features described in adult cases. 

 Most children and adolescents date the onset of their symptoms to a specific, often flu-like or mononucleosis-like, illness. At the evaluation for chronic fatigue, the physical examination and laboratory studies are normal. Although we still see patients referred for chronic fatigue in association with "abnormal" or "elevated" titers of Epstein-Barr virus (EBV), the serologic analyses generally do not document anything other than evidence of past EBV infection when reviewed in detail. Whether in children and adolescents or in adults, therefore, CFS is not merely an extension of a mononucleosis syndrome but a specific entity with a cause that remains to be determined. 

 Children and adolescents with CFS have a multitude of complaints in addition to the fatigue and other symptoms described in the official CDC criteria. Table 2 in the print issue (Adapted from Krilov LR, Fisher M Friedman SB, et al: Course and outcome of chronic fatigue in children and adolescents. 

 1998;102:360) lists symptoms reported by patients in our published series. Significant absences from school usually mark the extent of impairment. As with adults, most pediatric cases of CFS occur in young people from an upper-middle-class socioeconomic background, the majority of whom (68%) are female. Most patients range in age from 13 to 15 years, with few younger than 10 years of age. Most reported cases of CFS in children and adolescents appear to significantly improve or resolve over several years of follow-up.

 This is in contrast to the more protracted or unresponsive course usually seen in adults.

The primary exception to the CDC definition of CFS in most pediatric series, including our own, has been inclusion of patients with fatigue of fewer than six months' duration. This may, in part, account for the better outcomes described in some studies, although we noted no difference in outcome between our patients with less than and those with longer than six months of symptoms.

 Based on similarities between chronic fatigue in young people and in adults noted earlier and other physiologic and psychological features of the illness discussed later in this article, we strongly believe that chronic fatigue in children and adolescents is an analogous syndrome to CFS in adults. 

 Many assessments of CFS (or what in retrospect was likely CFS) have focused on finding an infectious or other specific cause for this illness. Infections proposed as the cause of CFS have included chronic mononucleosis or EBV infection, enteroviral disease, chronic candidiasis, infection with a unique retrovirus, human herpesvirus 6, and chronic Lyme disease. Other suggested causes for CFS, or syndromes that appear equivalent to CFS, include total allergy syndrome, chronic fatigue immunodeficiency syndrome (CFIDS), chronic hypoglycemia, neurasthenia, and myalgic encephalomyelitis. No definitive diagnostic test exists for any of these conditions. 

 No infectious agent has been shown to cause CFS; at present, identification of any active infection 

 excludes CFS. It appears, however, that infection may play a role in precipitating CFS: A majority of patients with the syndrome (more than two thirds of our patients) relate the onset of their symptoms to a specific infectious illness. 

 Cardiovascular, immune, and endocrine factors 

 Other physiologic factors that may be involved in the pathogenesis or perpetuation of CFS include alterations in cardiovascular, immunologic, and endocrine function.

 In 1995, Rowe and colleagues described autonomic dysfunction in seven adolescents with chronic fatigue assessed by tilt-table testing.

 Symptoms resolved in four subjects treated with increased salt intake and b-blocking drugs or disopyramide. Subsequent studies by this group

 have provided further evidence for a role of orthostatic intolerance in CFS. Stewart and colleagues proposed a unique pattern of response to orthostatic stress (upright tilt-table testing), involving syncope and tachycardia, that is different from the pattern seen in neurally mediated hypotension. 

 Further studies of the course and treatment of orthostatic intolerance in adolescents with CFS should confirm or refute the importance of this observation. Additional studies will also be necessary to determine whether these orthostatic changes cause CFS or are secondary to factors, such as deconditioning, that result from prolonged fatigue and inactivity. Regardless: Evaluation and therapy of orthostatic changes may be indicated, especially if dizziness is a significant component of the patient's complaints. 

 A role for immunologic dysfunction in CFS has been suggested based on a number of studies that show in vitro abnormalities in lymphocyte function or cytokine production.

 Reproducible abnormalities in different groups of CFS patients have not been demonstrated, however, and unusual or opportunistic infections have not been seen in these individuals. Intravenous immunoglobulin infusion used to treat an immunodeficient state has not demonstrated clear benefit in CFS.

 Compared with their preCFS state, many CFS patients report more frequent and longer-lasting infections, although these tend to be routine viral infections. 

 The preceding observations, although not definitive, raise the possibility of subtle perturbations of immune function in CFS. Similar findings may be seen with depression, however, and it is difficult to determine whether such changes are the causes or effects of illness. Moreover, some reports by patients of increased or more severe infections may reflect an altered perception of symptoms, which may be a major factor in perpetuating CFS.

 Decreased hypothalamic-pituitary- adrenal axis function has also been considered as a factor in CFS. Gross changes have not been seen but, as with immunologic issues noted earlier, only subtle abnormalities have been described,

 and confirmation of those findings is needed. 

 The role of psychological variables in causing and perpetuating CFS has prompted much study and speculation. Research on adults has demonstrated that patients with CFS more often have a history of depression and other psychiatric disorders than do age-matched controls.

 Although no similar studies of children and adolescents have been donethey would be very difficult to performanecdotal evidence indicates that many children and adolescents who develop CFS have experienced short- or long-term stress related to friends, family, or school before the onset of illness. Several studies have shown significant psychological findings, especially depression, in children and adolescents with CFS during their illness, compared to healthy controls and those with other major illnesses (including juvenile rheumatoid arthritis and malignancy).

 Several possible relationships linking depression or stress with the onset and perpetuation of CSF have been considered: 

  Depression and stress may create a psychological vulnerability that is one of the necessary components for the onset of CFS. Several long-established studies have demonstrated the role of psychological factors in the response to illness, including viral illnesses such as mononucleosis and influenza, and it may be that such factors play a similar role in CFS.

  Depression may be one physiological consequence of changes in the brain that take place in people with CFS. Cognitive changes, including decreased concentration and memory, are part of the diagnostic criteria for CFS; it may be that psychological changes could occur in a similar way.

  Depression and other psychological reactions may occur as a natural reaction to feeling fatigued and ill for a long time. Certainly, many children and adolescents with CFS express strong frustration at not being able to participate in their regular activities in and out of school. 

  CFS could be a manifestation of separation anxiety or school phobia in which secondary gain, in the manner of a conversion reaction, plays a major role. In our experience, some children and adolescents with CFS do not appear at all eager to return to normal activities in school or with friends, and secondary gain may help perpetuate their illness. 

  Some have suggested that CFS is simply an alternate manifestation of depression, because CFS and depression are both characterized by fatigue and other physical symptoms. Although this last possibility cannot be disproved, it is our clinical impression that the manifestations of CFS are distinct from those of depression. 

 In general, we believe that each of the possible links between depression or stress and CFS that have been considered may play a role, with the relative contribution of each component varying from person to person. This is in keeping with the general theory that the role of each possible contributing cause (infectious, cardiovascular, immunologic, endocrine, psychological) may vary among persons with CFS and that no single explanation accounts for all manifestations in all patients. 

 Evaluation of the child or adolescent suspected of having CFS includes: 

  A comprehensive history provided by the patient and parent(s). Allow sufficient time for the history because details are often complicated, long-standing, and a source of debate between patient and parent(s). 

  A complete physical examination. Despite the multitude of symptoms, the examination is almost always completely normal. Mild pharyngeal edema and adenopathy are common in CFS. Fever, weight loss, or significant lymphadenopathy, however, should alert you to the possibility of alternate diagnoses. 

  Laboratory testing aimed at ruling out other possibilities in the differential diagnosis. This is often done before referring a patient for evaluation of CFS but may be repeated or completed as part of the initial CFS evaluation. Specialized testing to evaluate possible causes of CFS that are amenable to treatment are discussed during the initial consultation and will be described below. 

 The differential diagnosis of CFS (Table 3 in the print edition, adapted from Krilov LR: Chronic fatigue syndrome. 

 1995;24:290) is lengthy because fatigue and the other general symptoms occur in a number of disorders. Clearly, it is impractical to rule out every potential diagnosis; the work-up is guided, therefore, by the history, physical examination, and screening for inflammation and infection. In general, the longer the duration and the greater the number of symptoms, the less the need for extensive evaluation to support a diagnosis of CFS. Alternative diagnoses should be considered if a single symptom dominates the clinical picture. 

 The general laboratory evaluation of the child or adolescent suspected of having CFS includes screening to evaluate for infection or inflammation (complete blood count, erythrocyte sedimentation rate, liver function tests) as well as specific tests, when indicated, for conditions that could account for fatigue and other symptoms (such as thyroid function tests, antinuclear antibody and rheumatoid factor tests, and toxicology screening). A chest radiograph, sinus films, and HIV testing are performed if indicated, as are other tests based on the history and physical examination (such as a cortisol level, Lyme titer, antistreptolysin assay, and EBV titers). 

 Cardiopulmonary and neurologic testing may be done to consider possible alternate diagnoses and evaluate variables that may be contributing to symptoms of CFS. Cardiac tests, including an electrocardiogram, echocardiogram, and tilt-table testing, have been performed more often recently in patients with CFS, especially those with significant postural symptoms (dizziness).

 Patients who have a history of asthma or allergyas many with CFS domay undergo pulmonary function testing or allergy tests to determine whether asthmatic or allergic symptoms are contributing to fatigue. 

 Neurologic testing, including a computed tomography scan or magnetic resonance imaging of the brain and an electroencephalogram, is indicated for some patients with CFS who have specific neurologic symptoms or findings. Those with significant cognitive changes in concentration or memory may require neuropsychological testing.

 Sleep studies may help uncover problems such as delayed sleep phase syndrome (initial insomnia and difficulty awakening in the morning) or sleep apnea, which can contribute to sleep disturbances and daytime fatigue.

 A psychosocial evaluation is indicated for all children and adolescents with suspected CFS. The evaluation can be carried out at different levels, based on severity and duration of chronic fatigue, degree of psychosocial dysfunction, and presence of psychosocial risk factors. A comprehensive psychosocial history by the evaluating clinician may suffice for some patients; evaluation by a social worker or psychologist may be required for others. Psychiatric consultation may be indicated in the case of severe dysfunction or significant risk factors in the patient or family. 

 No single definitive or curative treatment exists for CFS, either in adults or children and adolescents. However, our experience in evaluating and treating more than 100 children and adolescents with CFS during the past decade has revealed several important components of evaluation and management that can have a significant impact on patients and families. Table 4 summarizes those components. 

Steps in managing CFS in children and adolescents

Evaluate the patient and explain the diagnosis 

 Reassure patient and family that symptoms are real and generally get better over time 

 Counsel family to minimize doctor shopping, unnecessary testing, family strain, and unconventional, unproven, and experimental therapies 

 Provide anticipatory guidance and preventive strategies regarding secondary problems, chronic disease, and secondary gain 

 Help patient and family to develop coping skills: lifestyle modifications, stress reduction, realistic expectations, and schedule 

 Discuss cognitive-behavioral approaches: gradual increase in activity, exercise program, attention to sleep pattern, attention to nutrition 

 Provide psychological support for patient and family 

 Discuss educational issues: return to classes, home tutors, neuropsychiatric testing as indicated 

 Explore relationship issues: friends and family 

 Implement a follow-up plan: monitor physical symptoms and psychological issues, provide ongoing guidance and reassurance (follow-up visits every 46 wk) 

 The initial evaluation aims to confirm the diagnosis of CFS, exclude underlying pathology, and assess psychological status. We ask families to bring all medical records and test results and pertinent school records. Lengthy discussion with the patient and family follows the evaluation. We explain the diagnosis of CFS, describing in depth why the patient does or does not meet diagnostic criteria and, if not, in what ways the patient's symptoms overlap with those of CFS. We review, in detail, laboratory tests done earlier and those ordered during this evaluation; families are often confused about the implications of test findings, especially EBV antibody tests. And we explain the relationship between physical and psychological symptoms and reassure the patient and family that, first, symptoms are real, even if they have psychological aspects, and, second, the patient is neither "crazy" nor "lazy," as others may have suggested. 

 The most important reassurance we give to patients and families is that most children and adolescents with CFS do very well over time.

The literature, as discussed below, demonstrates that children and adolescents with CFS have a much better outcome than adults with CFS.

 We work hard, therefore, to ensure that patients and families view CFS as a time-limited illness, not a chronic disease, and we encourage children and adolescents to participate in as many normal activities and accomplish as many developmental tasks as possible while ill. We also work with families to prevent secondary problems (such as family strife over the condition) and secondary gain (such as missing school when the patient is really well enough to attend). 

 Families of children and adolescents with CFS often see many different physicians, partly because CFS can be a difficult diagnosis to establish and partly because families may search for an identifiable cause and cure. Although we use specialists as needed, we try to keep consultations to a reasonable minimum. We also discuss experimental therapies with patients and families and discourage them from pursuing expensive or dangerous treatments. When approached by families about using unproven therapies, such as vitamins and herbs, we discuss our philosophy frankly, but we also make certain to recognize that a family may need to try certain alternative approachesas long as they are safeto feel that they have not left possibilities unexplored. 

 Symptomatic treatment can help some patients with CFS function better during the course of the illness, even though it is not curative. Patients with depression may benefit from antidepressant medication, and some with sleep difficulties can benefit from sleep-promoting medications, although these drugs should be used sparingly in children and adolescents. Anti-inflammatory medications may relieve joint or muscle aches. Other medications, including antidepressants, have been used to treat pain in some patients with CFS in a manner similar to the way they are used in patients with fibromyalgia. 

 Most recently, medications given to ameliorate the hypotension and dizziness experienced by many patients with CFSincluding the a-agonist midodrine and the stimulant methylphenidate (Ritalin)have been found to help alleviate fatigue in some of these patients. In our experience, methylphenidate has also proved useful in managing the difficulty concentrating that affects most children and adolescents with CFS. 

 One of the goals of treating symptoms is to allow patients to resume as much of their normal life as possible. Despite treatment, however, most patients and families still require guidance on how to modify lifestyle, decrease stress, set realistic schedules, and establish realistic expectations. Studies from the United Kingdom have demonstrated the benefits of both cognitive-behavioral therapy and graded exercise programs.

 These strategies have been used less formally in the United States. Nevertheless, it is important that patients remain as active as possible, including participating in some exercise if they can. Our experience has been that children and adolescents who attempt to be too active may suffer a temporary setback, but such setbacks are not long-term, and we therefore encourage ongoing activities and exercise. 

 Adequate nutrition is important, although there do not appear to be any definitive findings indicating that specific dietary approaches improve the health of patients with CFS. Most patients have a normal appetite and maintain their regular weight, despite multiple other symptoms; we have seen some who have lost weight, however, resulting in increased fatigue. 

 Sleep is also important. Many patients end up with a virtual reversal of the sleep-wake cyclesleeping during the day and remaining awake most of the night. They and their families need guidance on returning to as normal a sleep schedule as possible. At times this requires a complete reorientation of the sleep-wake cycle. 

 Attention to psychological and educational issues is crucial in managing CFS in children and adolescents. CFS disrupts family patterns and makes friendships difficult to maintain. Depression is common, as are psychological issues that predate the development of CFS. Many patients need both individual therapy and family meetings. Adult patients with CFS often benefit from a self-help group, but we are concerned that such groups may prove somewhat problematic for children and adolescents: A self-help group may foster an identity as a patient with CFS, rather than as a person who will be back to normal activities relatively soon. 

 Addressing educational issues may be one of the most complicated aspects of providing care for children and adolescents with CFS.

 Some children require home tutoring; some can participate in a partial school program; some can attend school full-time but not participate in extracurricular activities; and others can maintain a full schedule despite their symptoms. As a rule, we recommend maintaining as full a schedule as possible and making changes as the syndrome gets better or worse. 

 Working with school districts to maximize the educational experience of children and adolescents who have CFS is sometimes difficult, however. Although some school personnel show flexibility and compassion in working with families, others are inflexible and skeptical of the diagnosis. The clinician who treats patients with CFS must be prepared to work with both educators and psychological staff to optimize the patient's activity level while the illness persists. Last, the clinician must establish a follow-up plan. We generally see patients every three or four weeks initially. On those visits, we monitor physical symptoms, ordering additional laboratory testing or consultations if necessary; monitor psychological and educational issues, providing guidance and referrals as needed; and offer continued reassurance, based especially on the information available to us from follow-up studies, as described below. Depending on the patient's course, subsequent visits may be spread over longer intervals. 

 Although it is well documented that most adults with CFS remain ill for many years, a growing number of studies show that most children and adolescents with CFS improve dramatically one to three years after onset of the illness.

  More than half were back to their premorbid state most of the time in the year after their first visit with us 

  More than two thirds were well most of the time within the second year 

  More than three quarters were well most of the time within the third year. 

 Improvements included a significant decrease in fatigue and other symptoms and a return to normal function in school and to normal relationships with friends.

 Other studies have shown the same optimistic outcome.

 We discuss these positive outcome data with patients and families during their initial evaluation, and we reiterate it at subsequent visits. We explain, however, that although the outcome is expected to be good, the course may still be difficult. Improvement comes slowly and unpredictably for most patients, and progress is seldom steady. What we have observed over time is that most patients reach a point at which symptoms begin to improve and they observe a shift in the ratio of "better days" to "worse days." 

 Intermittent illness, changes in schedule, and stressful events may cause a relapse at any time, leading patients and families to believe that the condition will never get better. As time goes by, however, relapses tend to become briefer and less severe, and almost all children and adolescents are able to increase their activities gradually. We continue to see patients through these phases of improvement until they are back to normal and do not require further visits. 

 Although CFS in children and adolescents is analogous to the adult form of the syndrome, outcome and time to recovery appear to be better than in adults. This observation may, by itself, have a major beneficial impact in supporting young CFS patients and their families. 

 	1.	Fukuda K, Straus SE, Hickie I, et al: The chronic fatigue syndrome: A comprehensive approach to its definition and study. 

 	2.	Lloyd AR, Hickie I, Boughton CR, et al: Prevalence of chronic fatigue syndrome in an Australian population. 

 	3.	Sharpe M, Archard L, Banatuala J, et al: A reportChronic fatigue syndrome: Guidelines for research. 

 	4.	Plioplys AV: Chronic fatigue syndrome should not be diagnosed in children. 

 	5.	Bell KM, Cookfair D, Bell DS, et al: Risk factors associated with chronic fatigue syndrome in a cluster of pediatric cases. 

 	6.	Smith MS, Mitchell J, Corey L, et al: Chronic fatigue in adolescents. 

 	7.	Feder HM, Dworkin PH, Orkin C: Outcome of 48 pediatric patients with chronic fatigue: A clinical experience. 

 	8.	Marshall GS, Gesser RM, Yamanishi K, et al: Chronic fatigue in children: Clinical features, Epstein-Barr virus and human herpesvirus 6 serology and long term follow-up. 

 	9.	Carter BD, Edwards JF, Kronenberger WG, et al: Case control study of chronic fatigue in pediatric patients. 

 	10.	Krilov LR, Fisher M, Friedman SB, et al: Course and outcome of chronic fatigue in children and adolescents. 

 	11.	Wilson A, Hickie I, Lloyd A, et al: Longitudinal study of outcome of chronic fatigue syndrome. 

 	12.	Joyce J, Hotopf M, Wessely S: The prognosis of chronic fatigue and chronic fatigue syndrome: A systematic review. 

 	13.	Marshall GS: Report of a workshop on the epidemiology, natural history, and pathogenesis of chronic fatigue syndrome in adolescents. 

 	14.	Rowe PC, Bou-Holaigah I, Kan JS, et al: Is neurally mediated hypotension an unrecognized cause of chronic fatigue? 

 	15.	Bou-Holaigh I, Rowe PC, Kan JS, et al: The relationship between neurally mediated hypotension and the chronic fatigue syndrome. 

 	16.	Stewart J, Gewitz MH, Weldon A, et al: Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue. 

Articles

Chronic fatigue in children and adolescents shares many features with the adult variant of the syndrome. The most important differences for younger patients? A shorter course and better outcome.

Leonard R Krilov

Articles

CME: Chronic fatigue syndrome in youth: Maybe not so chronic after all