NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10.

Cover of Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.

Show details

6Pediatric ME/CFS

Pediatric ME/CFS has been defined as a complex, multisystemic, and debilitating illness that is characterized by severe and medically unexplained fatigue and is usually accompanied by post-exertional malaise (PEM), orthostatic intolerance and other signs of autonomic dysfunction, and cognitive problems, as well as by unrefreshing sleep, headache, and other pain symptoms (Carruthers et al., 2003, 2011; Jason et al., 2006, 2010). Pediatric ME/CFS presents with either an acute (which can be infectious or noninfectious) or a gradual onset. Several studies showed that a gradual-onset pattern is more frequent (Bell et al., 2001; Nijhof et al., 2011), while others found an acute infectious onset to be more common, seen in 88 to 93 percent of young patients with ME/CFS (Kennedy et al., 2010b; Sankey et al., 2006). Patients often follow a prolonged and complex path before receiving a diagnosis of pediatric ME/CFS. Sankey and colleagues (2006) estimate that the median time from the start of symptoms to diagnosis is 8.5 months, while Nijhof and colleagues (2011) report 17 months. The challenges of diagnosis are described in Chapter 2.

The Royal College of Paediatrics and Child Health proposed pediatric criteria for ME/CFS in 2004 (Royal College, 2004). These authors considered whether a shorter time frame for diagnosis—3 months' duration rather than the 6 months for adults—is appropriate for children. In the absence of compelling epidemiological data, the authors concluded that the diagnosis of ME/CFS requires 6 months. They nonetheless suggest that pediatricians be “prepared to make a positive diagnosis of CFS/ME when a child or young person has characteristic symptoms supported by normal results and when the symptoms are causing significant functional impairment. This diagnosis does not depend on a specific time frame and a positive diagnosis of CFS/ME is not a prerequisite for the initiation of an appropriate management plan” (Royal College, 2004). The British National Institute for Health and Clinical Excellence (NICE) guidelines, published in 2007, recommend a duration of symptoms of 3 months for children and young people (NICE, 2007).

The International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) developed a case definition for diagnosis of ME/CFS in children and adolescents using the DePaul Pediatric Health Questionnaire (DPHQ), a self-report measure for assessing ME/CFS symptoms in this population. This tool measures not only the presence of the symptoms but also their severity and frequency (Jason et al., 2006). The IACFS/ME Pediatric Case Definition incorporates elements of the Fukuda definition (see Chapter 3) and follows the structure of the 2003 Canadian Consensus Criteria (CCC). To make a diagnosis of ME/CFS, this definition requires the presence of symptoms more specific than those in the Fukuda definition, and it emphasizes the importance of such symptoms as dizziness, decreased endurance with symptoms, pain, and flu-like symptoms, which have frequently been reported by young ME/CFS patients (Jason et al., 2006). An important difference from the other case definitions is that the duration of symptoms required to make a diagnosis is 3 months rather than 6 months. However, subsequent work has shown that a large proportion of those with acute fatigue following infectious mononucleosis will take up to 6 months to improve (Jason et al., 2014; Katz et al., 2009). Most physicians and researchers still elect to apply the Fukuda definition when diagnosing these patients even though this definition was developed for use in research on the adult ME/CFS population (Knight et al., 2013b; Werker et al., 2013).

The prevalence of pediatric ME/CFS has been estimated in British, Dutch, and U.S. populations with numbers that vary widely, from 0.03 to 1.29 percent (Chalder et al., 2003; Crawley et al., 2011; Farmer et al., 2004; Jordan et al., 2006; Nijhof et al., 2011; Rimes et al., 2007). The differing estimates may be due to the different methodologies used in these studies, the application of different ME/CFS definitions, the use of self-reported data obtained from patients instead of physician diagnoses, and the use of community-based rather than tertiary care samples. Besides differences in methodology, underreporting of ME/CFS may occur if physicians make a diagnosis of postural orthostatic tachycardia syndrome (POTS) without assessing for ME/CFS, considering the large overlap in symptoms between these two entities in both children (Stewart et al., 1999b) and adults (Okamoto et al., 2012). ME/CFS has been reported less frequently in children younger than 10 years old than in older children (Bell et al., 2001; Davies and Crawley, 2008; Farmer et al., 2004). Some have argued that this may reflect a lesser ability of children at these younger ages to describe changes in their activity and the degree of fatigue they experience (Bell, 1995a). Regarding gender, most studies found a greater prevalence in girls, with a female-to-male ratio ranging from 2:1 to 6:1 (Farmer et al., 2004; Knight et al., 2013a; Nijhof et al., 2011).

Although the prognosis in this group often is described as being better than that in adults (Andersen et al., 2004; Cairns and Hotopf, 2005; Kennedy et al., 2010b), a very limited number of long-term follow-up studies reported recovery rates in the ME/CFS pediatric population. Several studies found that 20 to 48 percent of pediatric patients diagnosed using the Fukuda definition showed no improvement or actually had worse fatigue and physical impairment at follow-up times ranging from 2 to 13 years (Bell et al., 2001; Gill et al., 2004; Van Geelen et al., 2010).

There is clear evidence of the impact of ME/CFS on the education and social development of these young people (Kennedy et al., 2010b; Walford et al., 1993). The stigma and social effects of pediatric ME/CFS include the loss of normal childhood activities and, in some extreme instances, inappropriate forcible separation of children from their parents (Holder, 2010). Numerous studies found that school attendance is significantly reduced in a large percentage of patients (Crawley and Sterne, 2009; Smith et al., 1991; Van Geelen et al., 2010; Werker et al., 2013). For instance, Nijhof and colleagues (2011) found that approximately 90 percent of the patients they studied had “considerable” school absence (defined as missing 15 to 50 percent of all school days) during the previous 6 months. Further, a U.K. study showed that ME/CFS was the primary cause of long-term health-related school absence (Dowsett and Colby, 1997). Therefore, the use of such labels as “school refusal” or “school phobia” should be considered only after careful and thorough assessment of these patients. A consistent definition is required to make an accurate diagnosis and to allow physicians to provide adequate treatment for these patients as well as to prevent erroneously labeling them as having a psychiatric condition or as being malingerers (Jason et al., 2006).

When evaluating the available research to develop its findings, conclusions, and recommendations on pediatric ME/CFS, the committee was struck by the paucity of the research conducted to date in this population. For major ME/CFS symptoms such as PEM and sleep disturbances, no more than 10 papers were available on each of these topics. The methodology used to review the literature is described in Chapter 1. Moreover, to the limitations of the research base described in Chapter 4, it is important to add that numerous pediatric studies used a less restrictive ME/CFS definition than that used in other studies and classified children presenting with only “chronic fatigue” lasting for 3 months as ME/CFS cases, further complicating the understanding of this disease. With these caveats, the remainder of this chapter reviews the evidence for pediatric patients with respect to the symptoms of adult ME/CFS discussed in Chapters 4 and 5: PEM, orthostatic intolerance and autonomic dysfunction, neurocognitive manifestations, sleep-related symptoms, infection, immune impairment, neuroendocrine manifestations, and other symptoms (fatigue and pain). The potential for development of symptom constructs in pediatric ME/CFS also is discussed.

POST-EXERTIONAL MALAISE

PEM, as defined in Chapter 4, is the exacerbation of fatigue, cognitive problems, lightheadedness, pain, and a general sense of feeling sick after effort (see the section on PEM in adults in Chapter 4). It is widely considered to be a central feature of ME/CFS. The prevalence of PEM was found to be 71 percent in Australian children at the time of presentation of ME/CFS (Knight et al., 2013a), 80 percent in a cross-sectional study of Dutch adolescents (Nijhof et al., 2011), and 97 percent in a large referral population of British children with ME/CFS (Davies and Crawley, 2008).

Methodological differences account for some of the variability in PEM prevalence rates among studies. These differences may be related to the definition of the illness used, the duration of the illness at the time of the survey, the way the questions about PEM were posed, the types of effort (cognitive/physical activity or orthostatic stress) considered capable of provoking PEM symptoms, the duration of symptom provocation that qualified as PEM (hours versus more than 1 day), whether questions addressed symptom provocation for fatigue alone or for a wider range of posteffort symptoms, the numbers of questions asked to capture the desired information (the higher the number of questions asked, the higher the probability of detecting the phenomenon), the severity of the symptom provocation required to count as having PEM, and differences in the ongoing activity levels of the participants. As an example of the latter, after being evaluated and treated for ME/CFS, individuals might follow recommendations to modulate their activity to avoid triggering worse symptoms. The result would be a lower reported prevalence of PEM than these individuals might have reported if exposed to the same levels of physical, orthostatic, or cognitive stress (or combinations of these physiologic stressors) they experienced prior to the onset of illness.

Assessment of PEM in Pediatric ME/CFS

There is no standardized method of assessing PEM in children. Differences among studies in this regard may reflect in part the variability in the methods used to ask about the patients' symptoms.

Evidence for PEM in Pediatric ME/CFS

The committee examined the literature on the presentation of PEM in children and adolescents with ME/CFS and the differences compared with healthy or diseased controls. Data on PEM prevalence rates among active children or otherwise healthy sedentary controls typically have not been reported. No studies with concurrent controls investigated PEM symptoms in the days following formal exercise tests, and in contrast to the adult literature, no studies using a cardiopulmonary exercise test repeated the test the next day (Katz et al., 2010). Little work has been published on the prevalence of PEM in subsets of children or adolescents diagnosed with ME/CFS (e.g., those with gradual onset versus those with an apparent postinfectious onset).

All three studies involving an exercise stress test identified autonomic or circulatory differences between ME/CFS cases and controls during the exercise challenge (Katz et al., 2010; Takken et al., 2007; Wyller et al., 2008b). Katz and colleagues (2010) compared 21 adolescents who developed ME/CFS after infectious mononucleosis with 21 controls who had recovered from mononucleosis. The ME/CFS individuals exercised less efficiently than recovered controls, with a borderline significant 11 percent difference in predicted peak oxygen consumption (p = 0.05) and a significantly lower peak oxygen pulse (O2 consumption per heartbeat) (p = 0.03). This study, however, did not find a significant difference in peak work capacity between ME/CFS patients and controls. Wyller and colleagues (2008b) compared 15 Norwegian adolescents with ME/CFS and 56 healthy adolescent controls. Those with ME/CFS had increased sympathetic activity at rest, with exaggerated cardiovascular responses to orthostatic stress, but attenuated cardiovascular responses to isometric exercise. Only one study assessed fatigue levels in pediatric ME/CFS patients and found that no child among the 20 who underwent exercise testing “reported excessive fatigue levels in the three days after the exercise test” (Takken et al., 2007, p. 582).

Overall, despite the limited research on the effect of exercise testing in pediatric ME/CFS, there is sufficient evidence that PEM is common in these patients.

ORTHOSTATIC INTOLERANCE AND AUTONOMIC DYSFUNCTION

The overlap in symptoms of pediatric orthostatic intolerance, most notably neurally mediated hypotension (NMH) and POTS, and pediatric ME/CFS was first emphasized in a small case series (Rowe et al., 1995) and a controlled study that included both adolescents and adults (Bou-Holaigah et al., 1995). (The definitions of NMH and POTS are discussed in the section on orthostatic intolerance and autonomic dysfunction in adults with ME/CFS in Chapter 4.) Stewart and colleagues (1999b) described in greater detail the differences among those with ME/CFS, those with POTS, and healthy controls. The prevalence of several symptoms was significantly higher in ME/CFS patients than in healthy controls: fatigue (100 versus 8 percent), lightheadedness (100 versus 15 percent), cognitive dysfunction (100 versus 0 percent), exercise intolerance (96 versus 23 percent), headache (92 versus 23 percent), sleep difficulties (80 versus 15 percent), and tender points (20 versus 0 percent). Those with POTS had an intermediate prevalence of the same symptoms. Of interest, frequent sore throat did not discriminate between ME/CFS patients and healthy children. The prevalence of orthostatic symptoms for adolescents with ME/CFS is above 90 percent (Stewart et al., 1999b; Wyller et al., 2008b).

Assessment of Orthostatic Intolerance and Autonomic Dysfunction in Pediatric ME/CFS

The methods used to assess for orthostatic intolerance are described in the section on orthostatic intolerance and autonomic dysfunction in adults with ME/CFS in Chapter 4.

Evidence for Orthostatic Intolerance and Autonomic Dysfunction in Pediatric ME/CFS

The committee examined the literature on the presentation of orthostatic intolerance and related autonomic abnormalities based on both patient report measures and objective testing in pediatric ME/CFS patients and the differences compared with healthy or diseased controls.

Orthostatic Testing in Pediatric ME/CFS

The committee reviewed five studies that compared rates of orthostatic intolerance between controls and those with ME/CFS. Bou-Holaigah and colleagues (1995) included some adolescents, but the mean age of participants was 34, so this paper is not included here.

Stewart and colleagues (1999a) describe NMH, POTS, or both in 96 percent (25/26) of adolescents with ME/CFS during the head-up tilt test. ME/CFS adolescents had a higher prevalence of circulatory abnormalities and clinical signs of acrocyanosis and cool extremities relative to those with recurrent syncope and healthy controls. Individuals with ME/CFS had a significantly higher mean heart rate and lower systolic blood pressure at rest and throughout the head-up tilt test compared with controls.

A study that assessed the impact of a 7-minute period of active standing in 28 Japanese adolescents with ME/CFS and 20 healthy adolescents showed that 57 percent of those with ME/CFS had orthostatic intolerance, compared with no healthy controls (p < 0.01), despite the brief duration of the orthostatic challenge. Among adolescents with ME/CFS, 18/28 experienced a prolonged reduction in oxy-hemoglobin during the 7 minutes of standing, compared with 4/20 controls (p < 0.01), a finding consistent with impaired cerebral hemodynamics (Tanaka et al., 2002).

Wyller and colleagues (2007a) in Norway examined the response to mild orthostatic stress (15 minutes of head-up tilt to just 20 degrees) in 27 adolescents with ME/CFS and 33 controls. At rest, those with ME/CFS had a higher total peripheral resistance index (TPRI), lower stroke index, and lower end-diastolic volume index than controls. With a 20-degree upright tilt, individuals with ME/CFS had greater increases in heart rate, diastolic blood pressure (both p < 0.001), mean blood pressure, and TPRI, as well as greater decreases in stroke index. Several other studies published by Stewart's and Wyller's groups substantiate the findings from their studies mentioned above. However, the independence of the participants from one study to the next is not always clear.

Galland and colleagues (2008) in New Zealand conducted a case-control study of 26 adolescents with ME/CFS and 26 controls. Participants underwent head-up tilt to 70 degrees for a maximum of 30 minutes, but could request that the test be stopped because of orthostatic symptoms before completion. Orthostatic intolerance was identified in 50 percent of ME/CFS patients versus 20 percent of controls (p = 0.04), with POTS being the most prominent problem in the ME/CFS patients. Adolescents with ME/CFS had a 3.2-fold increased risk of tachycardia during tilt.

Katz and colleagues (2012) conducted a nested case-control study comparing responses to 10 minutes of active standing in 36 adolescents with ME/CFS after infectious mononucleosis and 43 recovered controls. At the 6-month point after recovery from infectious mononucleosis, 25 percent of ME/CFS patients and 21 percent of controls met the study definition for orthostatic intolerance, a null finding that stands out from the rest of the literature.

Regardless of differences in methods of orthostatic testing, all studies with controls that examined adolescents with ME/CFS showed a numerically higher prevalence of circulatory disorders, most notably POTS and NMH, in ME/CFS patients. In most studies, the differences between ME/CFS patients and controls were statistically significant.

Heart Rate Variability

Six studies compared heart rate variability in pediatric ME/CFS patients and controls (Galland et al., 2008; Stewart, 2000; Stewart et al., 1998; Wyller et al., 2007c, 2008a, 2011). These studies showed that the R-R interval and measures of heart rate variability were reduced in those with ME/CFS. All of the studies revealed a sympathetic predominance of heart rate control and enhanced vagal withdrawal during either mild or moderate orthostatic stress or lower-body negative pressure (a method of simulating orthostatic stress). Traditional autonomic tests, such as the response to Valsalva maneuver, were found to be normal in pediatric ME/CFS patients (Stewart, 2000), although there are few studies on the topic.

Other Physiological Abnormalities Associated with Orthostatic Intolerance

Sommerfeldt and colleagues (2011) identified polymorphisms in adrenergic control genes (catechol-O-methyltransferase, beta 2 adrenergic receptor) that were associated with differential changes in sympathovagal balance in ME/CFS. Rowe and colleagues (1999) found an association of ME/CFS and orthostatic intolerance with Ehlers-Danlos syndrome (EDS). The association among EDS, joint hypermobility, chronic fatigue, and orthostatic intolerance has been confirmed by several other studies (De Wandele et al., 2014a,b; Gazit et al., 2003).

Treatment

One large randomized controlled trial compared the therapeutic and physiological responses to blocking of sympathetic tone with clonidine in 120 adolescents with ME/CFS. This study showed that successfully blocking sympathetic output with clonidine, as confirmed by a lower norepinephrine level in the treatment arm, led to worse ME/CFS symptoms, a lower number of steps per day, and lower C-reactive protein (Sulheim et al., 2014). The results were consistent with the hypothesis that systemic inflammation and sympathetic enhancement are mechanisms compensating for other physiological derangements in pediatric ME/CFS.

Open treatment of orthostatic intolerance has been described as being associated with improvement in ME/CFS symptoms in at least a subset of adolescents with ME/CFS (Bou-Holaigah et al., 1995; Rowe et al., 1995). Sulheim and colleagues (2012) report on a cohort study in which participants were seen at baseline and 3 to 17 months later. They confirm a correlation between improved hemodynamic variables on repeat 20-degree head-up tilt and improvement in fatigue, PEM, concentration problems, and overall function. The authors conclude that the concomitant improvement in symptoms, autonomic cardiovascular control, severity of ME/CFS-associated fatigue, and functional impairments is consistent with a possible causal relationship among these variables.

NEUROCOGNITIVE MANIFESTATIONS

Neurocognitive manifestations are among the most commonly reported symptoms in children and adolescents with ME/CFS, cited by 66 to 84 percent of patients in recent studies from Australia, Great Britain, and the Netherlands (Davies and Crawley, 2008; Knight et al., 2013a; Nijhof et al., 2011).

Assessment of Neurocognitive Manifestations in Pediatric ME/CFS

Other than a history that focuses on problems with concentration, short-term memory, and attention span, more formal methods used to assess neurocognitive symptoms in ME/CFS include neuropsychological testing at baseline and under conditions of cognitive or physiological stress. One such measure is the n-back test, which evaluates working memory, attention, concentration, and information processing (see the section on neurocognitive manifestations in adults with ME/CFS in Chapter 4). Questionnaires such as the Wood Mental Fatigue Inventory and elements from symptom surveys that address mental fatigue also are used to evaluate adolescents (Bentall et al., 1993; Wood et al., 1991).

Evidence for Neurocognitive Manifestations in Pediatric ME/CFS

The committee reviewed the literature to evaluate the neurocognitive symptoms experienced by pediatric ME/CFS patients and their differences from healthy and diseased controls. There are some broadly consistent themes. In study and clinic samples of those with pediatric ME/CFS not selected on the basis of greater difficulty with cognitive tasks, results of baseline neuropsychological testing are similar to those for healthy controls. Abnormalities emerge when participants are selected on the basis of increased difficulty with memory and concentration and when more complex challenges are employed, most notably those combining orthostatic and cognitive stresses (Haig-Ferguson et al., 2009; Kawatani et al., 2011; Ocon et al., 2012; Stewart et al., 2012; Tomoda et al., 2007; van de Putte et al., 2008).

Two studies conducted with adequate methodology, describing the same group of patients, assessed the effects of combined orthostatic stress and increasingly challenging neurocognitive tasks (Ocon et al., 2012; Stewart et al., 2012). The studies measured the response to n-back testing while supine and during progressive orthostatic stress (tilt table angles of 0, 15, 30, 45, 60, and 75 degrees). The authors conclude that orthostatic stress results in neurocognitive impairment in CFS/POTS but not in healthy controls. Stewart and colleagues (2012) also found that the expected increase in cerebral blood flow velocity during cognitive neuronal activation did not occur.

These findings are partially supported by Wyller and Helland (2013), who examined relationships among symptoms and autonomic cardiovascular control in 38 children with ME/CFS using the NICE guidelines. Cognitive symptoms were significantly and independently associated with a higher baseline heart rate, an enhanced heart rate response to orthostatic challenge, and older age within the adolescent age range (Wyller and Helland, 2013).

SLEEP-RELATED SYMPTOMS

Unrefreshing sleep and specific sleep disturbances—including insomnia, sleep cycle disturbances, and excessive sleeping—are among the most common symptoms reported in pediatric ME/CFS patients. The prevalence estimates for these sleep problems range from 84 to 96 percent (Davies and Crawley, 2008; Knight et al., 2013a; Nijhof et al., 2011).

Assessment of Sleep-Related Symptoms in Pediatric ME/CFS

Sleep problems usually are assessed by patient self-report during the clinical history. More formal studies are supplemented by sleep quality questionnaires, actigraphy, and polysomnography. (See the section on sleep-related symptoms in adults with ME/CFS in Chapter 4.)

Evidence for Sleep-Related Symptoms in Pediatric ME/CFS

The committee examined the literature on the presence of sleep-related symptoms in children/adolescents diagnosed with ME/CFS compared with other children/adolescents (healthy or otherwise). Taken together, these studies (Bell et al., 1994; Huang et al., 2010; Knook et al., 2000; Ohinata et al., 2008; Stores et al., 1998) suggest that children with ME/CFS have sleep disturbances, but they do not have a high prevalence of more severe sleep disorders such as obstructive sleep apnea or narcolepsy. The studies included in the committee's review used different case definitions and different measures with limited overlap in outcome variables, and there was little replication of results. Their findings therefore need to be interpreted with caution.

Two studies yielded higher-level data. Stores and colleagues (1998) performed home polysomnography in 18 British children with ME/CFS and 18 controls. Sleep efficiency was lower in those with ME/CFS (p < 0.001), in whom there were more awakenings of less than 2 minutes' duration, more awakenings of greater than 2 minutes, less non-rapid eye movement (NREM) stage 2 sleep, and less rapid eye movement (REM) sleep.

Hurum and colleagues (2011) compared ambulatory recordings of heart rate and blood pressure in 44 adolescents with ME/CFS and 52 healthy controls. This study used a relatively broad definition of ME/CFS, requiring at least 3 months of fatigue but no other somatic symptoms. Participants with ME/CFS were studied while staying overnight at an accommodation service, and controls were studied at home. During sleep, the ME/CFS patients had significantly higher heart rate, diastolic blood pressure, and mean arterial pressure. They also had higher heart rate during the waking hours.

INFECTION

The abrupt onset of illness for some adolescents with ME/CFS has stimulated investigation into infectious etiologies of the illness. Estimates of the proportion of pediatric ME/CFS patients with an abrupt infectious onset vary greatly across studies, from 22 to 93 percent. In a population-based study of 184 children from the Netherlands, Nijhof and colleagues (2011) found an overall rate of 32 percent with an acute onset, 22 percent of whom had an illness that began with an apparent infection. This study used the Fukuda definition. In a retrospective review of 59 Australian children attending an ME/CFS specialist clinic, 62 percent reported an infectious onset (Knight et al., 2013a). In a retrospective cohort study, Sankey and colleagues (2006) reported an acute onset in 93 percent of children diagnosed using the Oxford criteria (Sharpe et al., 1991) and evaluated in an English ME/CFS specialty service.

Assessment of Infection in Pediatric ME/CFS

Methods for assessing the association of ME/CFS with infection are described in the section on infection in adults with ME/CFS in Chapter 5.

Evidence for Infection in Pediatric ME/CFS

The committee identified and reviewed the two largest studies of the highest methodological quality on this topic. One prospective cohort study examined the rates of ME/CFS following acute infectious mononucleosis (Katz et al., 2009). To be eligible, participants had to have infectious mononucleosis, defined as a monospot-positive form of the illness. At 6, 12, and 24 months after infection, 13 percent, 7 percent, and 4 percent of adolescents, respectively, met criteria for ME/CFS, defined using the Jason pediatric criteria (Jason et al., 2006). There was a striking preponderance of females meeting ME/CFS criteria at all time points. At 6 months, 11.6 percent of females and 1.3 percent of males met criteria for ME/CFS, but only females continued to meet the criteria at 12 and 24 months (Katz et al., 2009). In a separate nested case-control study, stepwise logistic regression analysis identified (1) autonomic symptoms at baseline and (2) days spent in bed with the initial infection as the only significant risk factors for developing ME/CFS after infectious mononucleosis (Jason et al., 2014).

In a cross-sectional comparison of 120 Norwegian adolescents with established ME/CFS and 68 healthy controls, Sulheim and colleagues (2014)1 examined serology for B. burgdorferi, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19. They also obtained results of polymerase chain reaction (PCR) tests for those organisms as well as for human herpes virus type 6 (HHV-6), enterovirus, and adenovirus. No adolescents with ME/CFS or controls were positive on PCR testing for B. burgdorferi, CMV, enterovirus, or adenovirus. PCR rates were low for the other infectious agents and did not differ between ME/CFS cases and healthy controls. Rates of seropositivity for immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies did not differ between ME/CFS patients and controls for any of the organisms for which testing was conducted (Sulheim et al., 2014).

In investigating a cluster of seven cases of ME/CFS in a rural community of northern New York state, Bell and colleagues (1991) found no evidence that the following organisms were a cause of the illness: Brucella species, Coxiella, CMV, EBV, human immunodeficiency virus, hepatitis B, parvovirus B19, Toxoplasma gondii, B. burgdorferi, and Francisella tularensis. A questionnaire distributed to the local school district identified 21 patients who met the criteria for ME/CFS, including 6 of the 7 index cases. These 21 were compared with 42 healthy controls, matching 2 controls to each case. Ingestion of raw milk, the presence of a second family member with ME/CFS symptoms, and a history of allergies or asthma emerged as risk factors for pediatric ME/CFS.

One study examined antibodies to human T-cell lymphotropic virus (HTLV)-I antigens by Western blot and HTLV-II gag sequences by PCR. The total pediatric sample is reported as 21, but results are given for only 18 pediatric ME/CFS patients. Of these, 11 (61 percent) had evidence of anti-HTLV-I antibodies, versus 3/17 (18 percent) controls (comprising 7 healthy adults and 10 umbilical cord blood samples from newborns). PCR amplification of retroviral DNA was positive for the HTLV-II gag protein in 72 percent of the pediatric cases versus 12 percent of controls (DeFreitas et al., 1991). No age-matched pediatric controls were used in this study, and in the 23 years since publication of these results, they have not been independently confirmed.

A paper from Scotland describes coxsackie B virus antibody seropositivity in 47 children ages 5 to 14 years with a diagnosis of ME/CFS. Using an enzyme-linked immunosorbent assay (ELISA) technique, 18/47 (38 percent) were positive, compared with a published rate in children ages ≤ 14 years of 5.5 percent with a positive coxsackie B virus IgM (Bell et al., 1988). Other studies, notably the Norwegian study of Sulheim and colleagues (2014), did not confirm such a high seroprevalence rate, and it is unclear why the IgM antibodies would remain positive long after the onset of ME/CFS.

A retrospective study of 53 children with ME/CFS in New Jersey found seropositivity for EBV and/or B. burgdorferi in 66 percent of patients. For those with less than 12 months' (n = 30), 12 to 24 months' (n = 17), or more than 24 months' (n = 6) duration of ME/CFS, seropositivity for EBV or B. burgdorferi or both was 63 percent, 82 percent, and 33 percent, respectively (Petrov et al., 2012).

Evidence of active infection has not been detected after the initial onset of ME/CFS. Pathogens for which the serological evidence argues against a causal role in a large proportion of pediatric ME/CFS cases are CMV, HHV-6, coxsackie viruses, and parvovirus B19.2 There has been relatively little study of enteroviruses, however, and there is a relative paucity of data on B. burgdorferi.

IMMUNE IMPAIRMENT

Because ME/CFS often begins after an apparent infection, an important issue regarding the pathophysiology of the illness is whether its symptoms are due to a persistent infection or to the triggering infection acting as a “hit and run” phenomenon, initiating immune system or other physiologic dysfunctions that in turn cause chronic symptoms.

Assessment of Immune Impairment in Pediatric ME/CFS

Methods for assessing immune system dysfunction are described in the section on immune impairment in adults with ME/CFS in Chapter 5.

Evidence for Immune Impairment in Pediatric ME/CFS

Among the five studies identified as relevant to this topic, one used the Jason pediatric definition of ME/CFS (Jason et al., 2006) and the remaining four used the Fukuda definition (CDC, 2012). These study results should be interpreted with caution. Several important methodological factors limit the strength of the results, including the relatively small sample size of four of the studies (Broderick et al., 2012; Itoh et al., 2012; Kavelaars et al., 2000; Kennedy et al., 2010a), which raises questions about the representativeness of the results. No study reporting an abnormality appears to have been replicated.

The studies varied widely in the types of immune dysfunction addressed. Abnormalities were examined in the following areas:

Kavelaars and colleagues (2000) examined T cell proliferative responses to dexamethasone, as well as cytokine production by terbutaline, in 15 adolescents with ME/CFS and 14 controls. The peripheral blood cells of those with ME/CFS had higher proliferative responses of T cells to phytohemagglutinin (p = 0.044) and a lower inhibition of proliferation with dexamethasone (p = 0.001). The inhibitory effect of terbutaline on tumor necrosis factor (TNF)-alpha production was significantly lower in the ME/CFS patients, and terbutaline led to less enhancement of IL-10 production.

Broderick and colleagues (2012) used a 16-cytokine ELISA assay to compare 9 adolescents who met criteria for ME/CFS after infectious mononucleosis with 12 recovered controls at 24 months postinfection. There were significant differences in IL-8 and IL-23 between the two groups. IL-8 was significantly higher in the ME/CFS patients. IL-2 was also higher in the ME/CFS patients but less dramatically different from IL-2 levels in controls than was IL-8. IL-23 was significantly lower in the ME/CFS patients. IL-5 was lower as well, but less dramatically so. Katz and colleagues (2013) conducted a small case-control study in 9 adolescents who developed ME/CFS after infectious mononucleosis and 9 controls who had recovered uneventfully from the same illness. There were no differences between the groups in natural killer (NK) cell numbers or function.

Itoh and colleagues (2012) studied 15 Japanese children with fibromyalgia and 21 with ME/CFS over time. All had presented with fatigue. The authors measured antinuclear antibodies (ANAs), precipitin antibodies, T cells, B cells, and NK cells. Most fibromyalgia patients had low positive ANA titers in the 1:40 to 1:80 range; one had anti-Sa antibodies. ME/CFS participants had higher ANA titers, 11 of which had increased by the time ME/CFS was diagnosed. Among those with ME/CFS, 86 percent were positive for anti-Sa antibodies. The target antigen for anti-Sa antibodies is a lens epithelium-derived growth factor thought to confer resistance to stress-induced cell death (Itoh et al., 2012). These results have not been replicated in large samples. In contrast to data in adults with ME/CFS, lymphocyte subsets and NK cell activity were in the normal range in these ME/CFS patients.

Kennedy and colleagues (2010a) examined 25 children with ME/CFS from Great Britain and 23 healthy controls, focusing on markers of oxidative stress and measures of apoptosis. The ME/CFS participants had a significantly lower proportion of normal neutrophils (28 versus 46 percent) and a correspondingly higher proportion of neutrophils undergoing apoptosis relative to the healthy children (54 versus 36 percent). Similarly, those with ME/CFS had a significantly lower proportion of normal lymphocytes (44 versus 65 percent) and a correspondingly higher proportion of lymphocytes undergoing apoptosis (40 versus 25 percent).

Rowe (1997) conducted a randomized placebo-controlled trial of IVIG in 71 Australian adolescents with ME/CFS. There was a significant improvement in overall function at 6-month follow-up in those who had received IVIG in a dose of 1 gram/kg (max 60 grams) monthly for 3 months. Cell-mediated immunity was abnormal in 52 percent of ME/CFS participants at baseline. Given the scientific strength of the randomized controlled trial design, the larger sample size, and the reported benefit of IVIG for pediatric ME/CFS patients, further investigation of IVIG in the pediatric ME/CFS population is warranted.

NEUROENDOCRINE MANIFESTATIONS

The overlap of ME/CFS symptoms with those of adrenal insufficiency, together with inconsistent reports of lower cortisol values in adults with ME/CFS, has prompted several investigations into neuroendocrine abnormalities in pediatric ME/CFS. Similarly, reports of orthostatic intolerance have led to investigations of catecholamines and other hormones involved in the regulation of circulation in pediatric ME/CFS patients.

Assessment of Neuroendocrine Manifestations in Pediatric ME/CFS

Methods for assessing neuroendocrine abnormalities are described in the section on neuroendocrine manifestations in adults with ME/CFS in Chapter 5.

Evidence for Neuroendocrine Manifestations in Pediatric ME/CFS

The committee reviewed the available literature on neuroendocrine abnormalities in pediatric ME/CFS and the differences from those presented in healthy and diseased controls when available.

Adrenocortical Abnormalities

Several studies consistently found statistically lower mean cortisol levels in those with ME/CFS compared with controls (Nijhof et al., 2014; Segal et al., 2005; Sulheim et al., 2014; Tomoda et al., 2001). A study in the Netherlands compared a group of 108 adolescents with ME/CFS and 38 controls and found that those with ME/CFS had lower cortisol levels after awakening. The shape of the cortisol curves was similar for those with ME/CFS and controls, and it is unclear whether any adolescent with ME/CFS had clinically significantly low cortisol levels as opposed to statistically significant differences from controls. Cortisol levels at baseline did not predict recovery from ME/CFS during follow-up. The initial hypocortisolism was reversed after recovery from ME/CFS (Nijhof et al., 2014). In another cross-sectional study comparing 120 individuals with ME/CFS and 68 controls, performed in conjunction with a randomized trial of clonidine, those with ME/CFS showed lower urine cortisol-to-creatinine ratios (Sulheim et al., 2014). Tomoda and colleagues (2001) also found lower levels of cortisol and a 3-hour delay in the peak shift in cortisol in ME/CFS patients using 24-hour indwelling catheter measurements of cortisol every 4 hours.

Segal and colleagues (2005) used the low-dose synacthen test (LDST) to evaluate for subtle hypocortisolism in 23 children with ME/CFS and 17 controls of similar age and sex. The controls were retrospective, selected from among those with other endocrine disorders in whom an LDST had been performed with normal results. Studying a group suspected of having adrenal insufficiency would have been expected to bias against detection of a lower cortisol level in those with ME/CFS. Despite this limitation, children with ME/CFS had significantly lower mean cortisol levels than controls throughout the test. Their peak cortisol was lower, and the time to reach the peak level was longer. Girls had a more attenuated response to synacthen than boys.

One study examined the interaction between the neuroendocrine and immune systems by measuring cortisol, adrenocorticotropin hormone (ACTH), adrenaline, noradrenaline, and T cell proliferative responses to phytohemagluttinin and dexamethasone; cytokine production in response to terbutaline; and the response to corticotropin-releasing hormone (CRH) in a small sample of ME/CFS patients and controls. ACTH and cortisol responses were similar in response to CRH. Those with ME/CFS had higher proliferative responses of T cells to phytohemagluttinin but lower inhibition of proliferation with dexamethasone. The inhibitory effect of terbutaline on TNF-alpha production was lower in the ME/CFS patients, and there was less enhancement of IL-10 production (Kavelaars et al., 2000).

It is important to note, however, that even in studies reporting lower cortisol levels in adolescents with ME/CFS than in controls, the mean cortisol levels reported for those with ME/CFS remain within the normal range. Very little work has been done to determine whether the cortisol differences are related to sleep cycle abnormalities, as has been suggested in some adult studies, or are a secondary reflection of another aspect of being chronically ill.

Catecholamines

Two studies found elevations in supine epinephrine and norepinephrine in pediatric ME/CFS patients compared with controls (Sulheim et al., 2014; Wyller et al., 2008b). Kavelaars and colleagues (2000) also found higher epinephrine levels but no differences in supine norepinephrine levels in ME/CFS patients compared with controls. No differences were found between patients and controls for dopamine, normetanephrines, and metanephrines at rest (Wyller et al., 2007b).

Temperature Regulation

Tomoda and colleagues (2001) monitored deep body temperature in 41 Japanese children with ME/CFS and 9 controls. They found that the mean and nadir core body temperatures were higher in the ME/CFS patients than in the controls (both p < 0.0001).

Wyller and colleagues (2007b) studied thermoregulatory responses in 15 Norwegian ME/CFS adolescents and 57 controls. At baseline, ME/CFS patients had higher norepinephrine, epinephrine, and tympanic temperature than controls. During cooling of one hand, acral skin blood flow was reduced, vasoconstrictor events occurred at lower temperatures, and tympanic temperatures decreased more. However, catecholamines increased similarly in the two groups.

Other Neuroendocrine Findings

Knook and colleagues (2000) examined salivary melatonin levels in 13 adolescents with ME/CFS and 15 controls. Sleep onset and duration were the same in the two groups, but melatonin levels were higher in the ME/CFS patients, particularly after 10 PM. Wyller and colleagues (2010) examined 67 Norwegian adolescents with ME/CFS and 55 controls. Antidiuretic hormone (ADH) levels were lower in those with ME/CFS. Plasma renin and osmolality were increased; aldosterone, cortisol, and sex hormones did not differ. Segal and colleagues (2005) found that thyroid-stimulating hormone (TSH), free thyroxine, and prolactin were no different between ME/CFS and control groups. Levels of dehydroepiandrosterone (DHEA), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) for ME/CFS patients were similar to age and pubertal stage norms. These findings are relevant in light of the high incidence of orthostatic and circulatory dysfunction in pediatric ME/CFS.

A study suggesting a role for childhood trauma in ME/CFS used the broad empirical definition of ME/CFS, which resulted in a biased sample with overrepresentation of individuals with depression and posttraumatic stress disorder (PTSD) (Heim et al., 2009). The unusually high proportion of subjects with serious psychiatric problems likely explains the study finding of an association between ME/CFS and adverse childhood experiences. No other studies have suggested a higher rate of childhood trauma in those with confirmed ME/CFS as opposed to nonspecific chronic fatigue. In a study of 22 Norwegian adolescents with ME/CFS, no participant reported prior sexual abuse (Gjone and Wyller, 2009).

OTHER SYMPTOMS

Fatigue is universal in pediatric ME/CFS, usually to a degree that is sufficient in combination with other symptoms to lead to marked functional impairment (Davies and Crawley, 2008; Knight et al., 2013a; Nijhof et al., 2011). Kennedy and colleagues (2010b) showed that among 25 children with ME/CFS, recruited from support groups in the United Kingdom, only 1 attended regular classes. Compared with healthy controls, Child Health Questionnaire scores for the ME/CFS group were lowest on global health, physical function, and role/social limitations due to physical problems. Those with ME/CFS had lower physical function and greater general impairment than children with type 1 diabetes and asthma. Of 211 children with ME/CFS referred to a specialist clinic in England, 62 percent attended school 2 days per week or less. The factor most closely associated with school attendance was better physical function, whereas anxiety, gender, and age at assessment were not associated. Increasing fatigue was associated with worse physical function (Crawley and Sterne, 2009).

In pediatric ME/CFS studies, the prevalence of pain symptoms in the aggregate is relatively common at the time of presentation of ME/CFS, as demonstrated by a study of Australian children (Knight et al., 2013a), a cross-sectional study of Dutch adolescents (Nijhof et al., 2011), and a study of a large referral population of British children (Davies and Crawley, 2008). The most prevalent pain symptom is headaches, reported in 75 to 81 percent of patients in these studies. Reports of other specific pain symptoms are much more variable across studies and are less frequent than reports of headaches overall. Myalgia was observed in 52 to 73 percent, abdominal pain in 16 to 100 percent, arthralgia in 12 to 67 percent, sore throat in 25 to 62 percent, and tender glands in 12 to 50 percent of children (Bell, 1995b; Davies and Crawley, 2008; Knight et al., 2013a; Nijhof et al., 2011).

SYMPTOM CONSTRUCTS

Two pediatric studies used factor analysis to examine whether ME/CFS symptoms can be grouped in a way that defines separate phenotypes. Rowe and Rowe (2002) found that the pattern of symptoms in adolescents with ME/CFS was similar to the pattern in Australian adults, although nausea, abdominal pain, fevers, sweats, sore throat, and tender glands were more prevalent among the adolescents. Their sample included 189 adolescents ages 10 to 18 years who had noted a definite onset of ME/CFS over hours to several days, as well as 68 healthy adolescents. Among those with ME/CFS, more than 87 percent had experienced the following within the preceding month: prolonged fatigue following minor activity, headache, the need for excessive sleep, loss of ability to concentrate, disturbed sleep, excessive muscle fatigue, and myalgia following minor activity. In more than 60 percent, these symptoms were rated as moderately severe or severe. Interestingly, 14 of the symptoms had a low response frequency among both ME/CFS cases and controls and were grouped as somatic or involuntary muscle sensations. These factors were not a good fit to the data, accounting for less than 79 percent of the variance and covariance. Reports of symptoms unrelated to ME/CFS had low frequencies. The authors concluded that evidence for somatization disorder among those with ME/CFS was negligible. In contrast, factor analysis applied to the 24 symptoms judged to be salient on the basis of their frequency and severity scores identified five factors labeled muscle pain and fatigue, neurocognitive, abdominal/head/chest pain, neurophysiological, and immunological. This model accounted for 97 percent of the variance and covariance in the observed data. The immunological symptoms had significant direct and indirect effects on the other four key symptom factors and were thus judged to be primary (Rowe and Rowe, 2002).

May and colleagues (2010) performed exploratory factor analysis on 333 children and adolescents evaluated at the Bath specialist ME/CFS service. The median age of the participants was 14.9 years, with a range of 2 to 18 years. Three main phenotypes were identified. Based on the symptom clusters, these were labeled musculoskeletal, migraine, and sore throat. The musculoskeletal factor had the heaviest loading on muscle pain, joint pain, and hypersensitivity to touch, and it appears to be closest to the category for muscle pain and fatigue in the Australian model. The migraine factor had the heaviest loading on headaches, abdominal pain, nausea, hypersensitivity to light/noise/touch, and dizziness, and it appears to be similar to the abdominal, head, and chest pain factor in the Australian model. The sore throat phenotype loaded most heavily on sore throat and tender glands, thereby appearing to be similar to the immunological factor in the Australian model. The British factor analysis did not identify factors that corresponded to the neurocognitive and neurophysiological models in the Australian work. Among the three phenotypes, the musculoskeletal factor had the strongest association with fatigue, while the sore throat phenotype was the least severely affected group. The migraine group had the lowest physical function and had worse school attendance. None of the phenotypes was associated with depression; the migraine phenotype was associated with increased anxiety (May et al., 2010).

The two factor analyses thus achieved some qualitative similarity, although comparisons are limited by the different methods used to group and rate symptoms and by the types of symptoms collected. For example, the ascertainment of lightheadedness and other symptoms of orthostatic intolerance was incomplete. Whether the heterogeneous phenotypes reflect distinctive pathophysiologic factors is unknown.

SUMMARY

The data on orthostatic intolerance (notably POTS and NMH) and autonomic dysfunction in pediatric ME/CFS are strong and consistent across case definitions. While the available studies suggest the presence of only subtle neurocognitive problems at rest, children and adolescents with ME/CFS develop more robust and significant cognitive abnormalities under conditions of orthostatic stress or distraction. The evidence also indicates that PEM and unrefreshing sleep are common in pediatric ME/CFS, although studies are needed to better characterize the optimal method of assessing for these phenomena in children. Despite the evidence that these different pain symptoms are common in the aggregate, the high variability in the prevalence of these symptoms supports the committee's decision to not require pain for a diagnosis of ME/CFS. It is well documented that ME/CFS can follow EBV and non-EBV infectious mononucleosis. There is no evidence that other pathogens are consistently associated with the onset of pediatric ME/CFS. While there is no evidence of classic immunodeficiency or endocrine disorders in pediatric ME/CFS, the literature describes several discrete abnormalities in immune and endocrine system function in affected children and adolescents. These findings need to be interpreted with caution because of several important methodological issues and the lack of replications of these studies.

The committee adopted a 6-month duration of symptoms for the diagnosis of ME/CFS in children based on the literature described earlier in the chapter. Nonetheless, the committee emphasizes that this time criterion should not interfere with initiating appropriate symptom-based management long before 6 months has elapsed in children presenting with prolonged fatigue. Symptomatic treatment can begin at any point after the onset of fatigue as the diagnostic process continues to evaluate and exclude other potential causes for the patient's symptoms. Chapter 7 presents the committee's recommendations on diagnostic criteria for ME/CFS in children and adolescents.

Conclusion: There is sufficient evidence that orthostatic intolerance and autonomic dysfunction are common in pediatric ME/CFS; that neurocognitive abnormalities emerge when pediatric ME/CFS patients are tested under conditions of orthostatic stress or distraction; and that there is a high prevalence of profound fatigue, unrefreshing sleep, and post-exertional exacerbation of symptoms in these patients. There also is sufficient evidence that pediatric ME/CFS can follow acute infectious mononucleosis and EBV.

REFERENCES

  • Andersen MM, Permin H, Albrecht F. Illness and disability in Danish chronic fatigue syndrome patients at diagnosis and 5-year follow-up. Journal of Psychosomatic Research. 2004;56(2):217–229. [PubMed: 15016582]
  • Bell DS. Chronic fatigue syndrome in children and adolescents: A review. Focus & Opinion Pediatrics. 1995a;1(5):412–420.
  • Bell DS. Chronic fatigue syndrome in children. Journal of Chronic Fatigue Syndrome. 1995b;1(1):9–33.
  • Bell DS, Bell KM, Cheney PR. Primary juvenile fibromyalgia syndrome and chronic fatigue syndrome in adolescents. Clinical Infectious Diseases. 1994;18(Suppl. 1):S21–S23. [PubMed: 8148447]
  • Bell DS, Jordan K, Robinson M. Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. Pediatrics. 2001;107(5):994–998. [PubMed: 11331676]
  • Bell EJ, McCartney RA, Riding MH. Coxsackie B viruses and myalgic encephalomyelitis. Journal of the Royal Society of Medicine. 1988;81(6):329–331. [PMC free article: PMC1291624] [PubMed: 2841461]
  • Bell KM, Cookfair D, Bell DS, Reese P, Cooper L. Risk factors associated with chronic fatigue syndrome in a cluster of pediatric cases. Reviews of Infectious Diseases. 1991;13(Suppl. 1):S32–S38. [PubMed: 2020801]
  • Bentall RP, Wood GC, Marrinan T, Deans C, Edwards RHT. A brief mental fatigue questionnaire. British Journal of Clinical Psychology. 1993;32(3):375–377. [PubMed: 7902751]
  • Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. Journal of the American Medical Association. 1995;274(12):961–967. [PubMed: 7674527]
  • Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas N, Smith FA, O'Gorman MR, Vernon SD, Taylor R. Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. Journal of Translational Medicine. 2012;10:191. [PMC free article: PMC3480896] [PubMed: 22973830]
  • Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occupational Medicine (Oxford). 2005;55(1):20–31. [PubMed: 15699087]
  • Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lemer AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI. Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols (Canadian case definition). Journal of Chronic Fatigue Syndrome. 2003;11(1):7–115.
  • Carruthers BM, van de Sande MI, De Meirleir kl, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis: International consensus criteria. Journal of Internal Medicine. 2011;270(4):327–338. [PMC free article: PMC3427890] [PubMed: 21777306]
  • CDC (Centers for Disease Control and Prevention). Chronic fatigue syndrome: 1994 case definition. 2012. [December 16, 2013]. http://www​.cdc.gov/cfs​/case-definition/1994.html .
  • Chalder T, Goodman R, Wessely S, Hotopf M, Meltzer H. Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds: Cross sectional study. British Medical Journal. 2003;327(7416):654–655. [PMC free article: PMC196393] [PubMed: 14500438]
  • Crawley E, Sterne JA. Association between school absence and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy. Archives of Disease in Childhood. 2009;94(10):752–756. [PubMed: 19001477]
  • Crawley EM, Emond AM, Sterne JAC. Unidentified chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a major cause of school absence: Surveillance outcomes from school-based clinics. BMJ Open. 2011;1(2) [PMC free article: PMC3244656] [PubMed: 22155938]
  • Davies S, Crawley E. Chronic fatigue syndrome in children aged 11 years old and younger. Archives of Disease in Childhood. 2008;93(5):419–422. [PubMed: 18192312]
  • De Wandele I, Calders P, Peersman W, Rimbaut S, De Backer T, Malfait F, De Paepe A, Rombaut L. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism. 2014a;44(3):353–361. [PubMed: 24968706]
  • De Wandele I, Rombaut L, Leybaert L, Van de Borne P, De Backer T, Malfait F, De Paepe A, Calders P. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism. 2014b;44(1):93–100. [PubMed: 24507822]
  • DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(7):2922–2926. [PMC free article: PMC51352] [PubMed: 1672770]
  • Dowsett EG, Colby J. Long-term sickness absence due to ME/CFS in UK schools: An epidemiological study with medical and educational implications. Journal of Chronic Fatigue Syndrome. 1997;3(2):29–42.
  • Farmer A, Fowler T, Scourfield J, Thapar A. Prevalence of chronic disabling fatigue in children and adolescents. British Journal of Psychiatry. 2004;184:477–481. [PubMed: 15172940]
  • Galland BC, Jackson PM, Sayers RM, Taylor BJ. A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome. Pediatric Research. 2008;63(2):196–202. [PubMed: 18091356]
  • Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. American Journal of Medicine. 2003;115(1):33–40. [PubMed: 12867232]
  • Gill AC, Dosen A, Ziegler JB. Chronic fatigue syndrome in adolescents: A follow-up study. Archives of Pediatrics & Adolescent Medicine. 2004;158(3):225–229. [PubMed: 14993080]
  • Gjone H, Wyller VB. Chronic fatigue in adolescence—autonomic dysregulation and mental health: An exploratory study. Acta Paediatrica, International Journal of Paediatrics. 2009;98(8):1313–1318. [PubMed: 19432823]
  • Haig-Ferguson A, Tucker P, Eaton N, Hunt L, Crawley E. Memory and attention problems in children with chronic fatigue syndrome or myalgic encephalopathy. Archives of Disease in Childhood. 2009;94(10):757–762. [PubMed: 19001478]
  • Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome association with neuroendocrine dysfunction. Archives of General Psychiatry. 2009;66(1):72–80. [PubMed: 19124690]
  • Holder N. Mountain Xpress. Sep 14, 2010. [April 15, 2014]. Local family feels vindicated by breakthrough research. http://mountainx​.com​/news/community-news​/091510local-family-feels-vindicated-by-breakthrough-research .
  • Huang Y, Katz BZ, Mears C, Kielhofner GW, Taylor R. Postinfectious fatigue in adolescents and physical activity. Archives of Pediatrics and Adolescent Medicine. 2010;164(9):803–809. [PMC free article: PMC3050621] [PubMed: 20819961]
  • Hurum H, Sulheim D, Thaulow E, Wyller VB. Elevated nocturnal blood pressure and heart rate in adolescent chronic fatigue syndrome. Acta Paediatrica, International Journal of Paediatrics. 2011;100(2):289–292. [PubMed: 21059182]
  • Itoh Y, Shigemori T, Igarashi T, Fukunaga Y. Fibromyalgia and chronic fatigue syndrome in children. Pediatrics International. 2012;54(2):266–271. [PubMed: 22115414]
  • Jason LA, Bell DS, Rowe K, Van Hoof ELS, Jordan K, Lapp C, Gurwitt A, Miike T, Torres-Harding S, De Meirleir K. A pediatric case definition for myalgic encephalomyelitis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2006;13(2-3):1–44.
  • Jason LA, Porter N, Shelleby E, Till L, Bell D, Lapp C, Rowe K, De Meirleir KL. Examining criteria to diagnose ME/CFS in pediatric samples. Journal of Behavioral Health and Medicine. 2010;3:186–195.
  • Jason LA, Katz BZ, Shiraishi Y, Mears C, Im Y, Taylor RR. Predictors of post-infectious chronic fatigue syndrome in adolescents. Health Psychology & Behavioural Medicine. 2014;2(1):41–51. [PMC free article: PMC3956649] [PubMed: 24660116]
  • Jordan KM, Jason LA, Mears CJ, Katz BZ, Rademaker A, Huang CF, Richman J, McCready W, Ayers PM, Taylor KK. Prevalence of pediatric chronic fatigue syndrome in a community-based sample. Journal of Chronic Fatigue Syndrome. 2006;13(2-3):75–78.
  • Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic fatigue syndrome following infectious mononucleosis in adolescents. Pediatrics. 2009;124(1):189–193. [PMC free article: PMC2756827] [PubMed: 19564299]
  • Katz BZ, Boas S, Shiraishi Y, Mears CJ, Taylor R. Exercise tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis. Journal of Pediatrics. 2010;157(3):468–472. [PMC free article: PMC2975670] [PubMed: 20447647]
  • Katz BZ, Stewart JM, Shiraishi Y, Mears CJ, Taylor R. Orthostatic tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis. Clinical Pediatrics. 2012;51(9):835–839. [PubMed: 22850676]
  • Katz BZ, Zimmerman D, Gorman MRG, Mears CJ, Shiraishi Y, Taylor R. Normal salivary cortisol and NK cell function in adolescents with chronic fatigue syndrome following infectious mononucleosis. Archives of Pediatric Infectious Diseases. 2013;2(4):211–216.
  • Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ. Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. Journal of Clinical Endocrinology & Metabolism. 2000;85(2):692–696. [PubMed: 10690878]
  • Kawatani J, Mizuno K, Shiraishi S, Takao M, Joudoi T, Fukuda S, Watanabe Y, Tomoda A. Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome—a 6-month follow-up study. Brain & Development. 2011;33(10):832–841. [PubMed: 21530119]
  • Kennedy G, Khan F, Hill A, Underwood C, Belch JJF. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Archives of Pediatrics and Adolescent Medicine. 2010a;164(9):817–823. [PubMed: 20819963]
  • Kennedy G, Underwood C, Freda Belch JJ. Physical and functional impact of chronic fatigue syndrome/myalgic encephalomyelitis in childhood. Pediatrics. 2010b;125(6):e1324–e1330. [PubMed: 20478937]
  • Knight S, Harvey A, Lubitz L, Rowe K, Reveley C, Veit F, Hennel S, Scheinberg A. Paediatric chronic fatigue syndrome: Complex presentations and protracted time to diagnosis. Journal of Paediatrics and Child Health. 2013a;49(11):919–924. [PubMed: 24251657]
  • Knight SJ, Scheinberg A, Harvey AR. Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: A systematic review. Journal of Adolescent Health. 2013b;53(2):154–165. [PubMed: 23643337]
  • Knook L, Kavelaars A, Sinnema G, Kuis W, Heijnen CJ. High nocturnal melatonin in adolescents with chronic fatigue syndrome. Journal of Clinical Endocrinology & Metabolism. 2000;85(10):3690–3692. [PubMed: 11061525]
  • May M, Emond A, Crawley E. Phenotypes of chronic fatigue syndrome in children and young people. Archives of Disease in Childhood. 2010;95(4):245–249. [PubMed: 19843509]
  • NICE (National Institute for Health and Clinical Excellence). Chronic fatigue syndrome/ myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of CFS/ME in adults and children. London, UK: NICE; 2007.
  • Nijhof SL, Maijer K, Bleijenberg G, Uiterwaal C, Kimpen JLL, van de Putte EM. Adolescent chronic fatigue syndrome: Prevalence, incidence, and morbidity. Pediatrics. 2011;127(5):E1169–E1175. [PubMed: 21502228]
  • Nijhof SL, Rutten JM, Uiterwaal CS, Bleijenberg G, Kimpen JL, Putte EM. The role of hypocortisolism in chronic fatigue syndrome. Psychoneuroendocrinology. 2014;42:199–206. [PubMed: 24636516]
  • Ocon AJ, Messer ZR, Medow MS, Stewart JM. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clinical Science. 2012;122(5):227–238. [PMC free article: PMC3368269] [PubMed: 21919887]
  • Ohinata J, Suzuki N, Araki A, Takahashi S, Fujieda K, Tanaka H. Actigraphic assessment of sleep disorders in children with chronic fatigue syndrome. Brain & Development. 2008;30(5):329–333. [PubMed: 18031961]
  • Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, Black BK, Robertson D, Biaggioni I. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clinical Science. 2012;122(4):183–192. [PMC free article: PMC3203411] [PubMed: 21906029]
  • Petrov D, Marchalik D, Sosin M, Bal A. Factors affecting duration of chronic fatigue syndrome in pediatric patients. Indian Journal of Pediatrics. 2012;79(1):52–55. [PubMed: 21617905]
  • Rimes KA, Goodman R, Hotopf M, Wessely S, Meltzer H, Chalder T. Incidence, prognosis, and risk factors for fatigue and chronic fatigue syndrome in adolescents: A prospective community study. Pediatrics. 2007;119(3):e603–e609. [PubMed: 17332180]
  • Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. Journal of Psychiatric Research. 1997;31(1):133–147. [PubMed: 9201655]
  • Rowe KS, Rowe KJ. Symptom patterns of children and adolescents with chronic fatigue syndrome. In. In: Singh NN, Ollendick TH, Singh AN, editors. International perspectives on child and adolescent mental health. Vol. 2. Oxford, UK: Elsevier; 2002. pp. 395–421.
  • Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue. Lancet. 1995;345(8950):623–624. [PubMed: 7898182]
  • Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. Journal of Pediatrics. 1999;135(4):494–499. [PubMed: 10518084]
  • Royal College. Evidence based guideline for the management of CFS/ME in children and young people. 2004. [August 15, 2014]. http://www​.rcpch.ac.uk​/system/files/protected​/page/RCPCH%20CFS.pdf .
  • Sankey A, Hill CM, Brown J, Quinn L, Fletcher A. A follow-up study of chronic fatigue syndrome in children and adolescents: Symptom persistence and school absenteeism. Clinical Child Psychology and Psychiatry. 2006;11(1):126–138. [PubMed: 17087490]
  • Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. Journal of Pediatric Endocrinology and Metabolism. 2005;18(3):295–301. [PubMed: 15813608]
  • Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, McDonald EM, Mowbray JF, Pearson DJ, Peto TE, Preedy VR, Smith AP, Smith DG, Taylor DJ, Tyrrell DA, Wessely S, White PD. A report-chronic fatigue syndrome—guidelines for research. Journal of the Royal Society of Medicine. 1991;84(2):118–121. [PMC free article: PMC1293107] [PubMed: 1999813]
  • Smith MS, Mitchell J, Corey L, Gold D, McCauley EA, Glover D, Tenover FC. Chronic fatigue in adolescents. Pediatrics. 1991;88(2):195–202. [PubMed: 1861915]
  • Sommerfeldt L, Portilla H, Jacobsen L, Gjerstad J, Wyller VB. Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatrica. 2011;100(2):293–298. [PubMed: 21059181]
  • Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatric Research. 2000;48(2):218–226. [PubMed: 10926298]
  • Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome. Clinical Autonomic Research. 1998;8(4):221–230. [PubMed: 9791743]
  • Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999a;103(1):116–121. [PubMed: 9917448]
  • Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue. Journal of Pediatrics. 1999b;135(2, Pt. 1):218–225. [PubMed: 10431117]
  • Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. American Journal of Physiology—Heart & Circulatory Physiology. 2012;302(5):H1185–H1194. [PMC free article: PMC3311460] [PubMed: 22180650]
  • Stores G, Fry A, Crawford C. Sleep abnormalities demonstrated by home polysomnography in teenagers with chronic fatigue syndrome. Journal of Psychosomatic Research. 1998;45(1):85–91. [PubMed: 9720858]
  • Sulheim D, Hurum H, Helland IB, Thaulow E, Wyller VB. Adolescent chronic fatigue syndrome; a follow-up study displays concurrent improvement of circulatory abnormalities and clinical symptoms. BioPsychoSocial Medicine. 2012;6 [PMC free article: PMC3337799] [PubMed: 22436201]
  • Sulheim D, Fagermoen E, Winger A, Andersen AM, Godang K, Muller F, Rowe PC, Saul JP, Skovlund E, Oie MG, Wyller VB. Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: A combined cross-sectional and randomized clinical trial. JAMA Pediatrics. 2014;168(4):351–360. [PubMed: 24493300]
  • Takken T, Henneken T, van de Putte E, Helders P, Engelbert R. Exercise testing in children and adolescents with chronic fatigue syndrome. International Journal of Sports Medicine. 2007;28(7):580–584. [PubMed: 17357961]
  • Tanaka H, Matsushima R, Tamai H, Kajimoto Y. Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance. Journal of Pediatrics. 2002;140(4):412–417. [PubMed: 12006954]
  • Tomoda A, Jhodoi T, Miike T. Chronic fatigue syndrome and abnormal biological rhythms in school children. Journal of Chronic Fatigue Syndrome. 2001;8(2):29–37.
  • Tomoda A, Mizuno K, Murayama N, Joudoi T, Igasaki T, Miyazaki M, Miike T. Event-related potentials in Japanese childhood chronic fatigue syndrome. Journal of Pediatric Neurology. 2007;5(3):199–208.
  • van de Putte EM, Bocker KB, Buitelaar J, Kenemans JL, Engelbert RH, Kuis W, Kimpen JL, Uiterwaal CS. Deficits of interference control in adolescents with chronic fatigue syndrome. Archives of Pediatrics and Adolescent Medicine. 2008;162(12):1196–1197. [PubMed: 19047552]
  • Van Geelen SM, Bakker RJ, Kuis W, Van De Putte EM. Adolescent chronic fatigue syndrome: A follow-up study. Archives of Pediatrics and Adolescent Medicine. 2010;164(9):810–814. [PubMed: 20819962]
  • Walford GA, Nelson WM, McCluskey DR. Fatigue, depression, and social adjustment in chronic fatigue syndrome. Archives of Disease in Childhood. 1993;68(3):384–388. [PMC free article: PMC1793898] [PubMed: 8096688]
  • Werker CL, Nijhof SL, van de Putte EM. Clinical practice: Chronic fatigue syndrome. European Journal of Pediatrics. 2013;172(10):1293–1298. [PubMed: 23756916]
  • Wood GC, Bentall RP, Gopfert M, Edwards RHT. A comparative psychiatric-assessment of patients with chronic fatigue syndrome and muscle disease. Psychological Medicine. 1991;21(3):619–628. [PubMed: 1946850]
  • Wyller VB, Helland IB. Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: An exploratory study. BioPsychoSocial Medicine. 2013;7(5) [PMC free article: PMC3570350] [PubMed: 23388153]
  • Wyller VB, Due R, Saul JP, Amlie JP, Thaulow E. Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls. American Journal of Cardiology. 2007a;99(7):997–1001. [PubMed: 17398200]
  • Wyller VB, Godang K, Mørkrid L, Saul JP, Thaulow E, Walløe L. Abnormal thermoregulatory responses in adolescents with chronic fatigue syndrome: Relation to clinical symptoms. Pediatrics. 2007b;120(1):e129–e137. [PubMed: 17606539]
  • Wyller VB, Saul JP, Amlie JP, Thaulow E. Sympathetic predominance of cardiovascular regulation during mild orthostatic stress in adolescents with chronic fatigue. Clinical Physiology and Functional Imaging. 2007c;27(4):231–238. [PubMed: 17564672]
  • Wyller VB, Barbieri R, Thaulow E, Saul JP. Enhanced vagal withdrawal during mild orthostatic stress in adolescents with chronic fatigue. Annals of Noninvasive Electrocardiology. 2008a;13(1):67–73. [PMC free article: PMC6932180] [PubMed: 18234008]
  • Wyller VB, Saul JP, Walloe L, Thaulow E. Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome. European Journal of Applied Physiology. 2008b;102(6):623–632. [PubMed: 18066580]
  • Wyller VB, Evang JA, Godang K, Solhjell KK, Bollerslev J. Hormonal alterations in adolescent chronic fatigue syndrome. Acta Paediatrica, International Journal of Paediatrics. 2010;99(5):770–773. [PubMed: 20199497]
  • Wyller VB, Barbieri R, Saul JP. Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress. European Journal of Applied Physiology. 2011;111(3):497–507. [PMC free article: PMC3037975] [PubMed: 20890710]

Footnotes

1

This information can be found in the supplemental material of the Sulheim et al. (2014) paper.

2

Ibid.

Copyright 2015 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK284896

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (1.4M)

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...